Patrick H. Nachman J. Charles Jennette Ronald J. Falk
|
General Description of Glomerular Syndromes, 987 |
||
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Isolated Proteinuria, 987 |
||
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Recurrent or Persistent Hematuria, 989 |
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Nephrotic Syndrome, 990 |
||
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Glomerular Diseases that Cause Nephrotic Syndrome, 995 |
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Minimal Change Glomerulopathy, 995 |
||
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Focal Segmental Glomerulosclerosis, 1000 |
||
|
C1q Nephropathy, 1006 |
||
|
Membranous Glomerulopathy, 1007 |
||
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Membranoproliferative Glomerulonephritis (Mesangial Capillary Glomerulonephritis), 1014 |
||
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Glomerulonephritis, 1019 |
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|
Acute Poststreptococcal Glomerulonephritis, 1019 |
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IgA Nephropathy, 1024 |
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Fibrillary Glomerulonephritis and Immunotactoid Glomerulopathy, 1032 |
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Rapidly Progressive Glomerulonephritis and Crescentic Glomerulonephritis, 1034 |
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Immune Complex-Mediated Crescentic Glomerulonephritis, 1035 |
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Anti-Glomerular Basement Membrane Glomerulonephritis, 1038 |
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Pauci-Immune Crescentic Glomerulonephritis, 1042 |
The underlying cause of most glomerular diseases remains an enigma. Infectious agents, autoimmunity, drugs, inherited disorders, and environmental agents have been implicated as causes of certain glomerular diseases. Until the precise etiology and pathogenesis of glomerular disorders is unraveled, we continue in the tradition of Richard Bright—studying the relationship of clinical, pathological, and laboratory signs and symptoms of disease, and basing our diagnostic categorization on these features rather than on etiology.
Glomerular diseases may be categorized into those that primarily involve the kidney (primary glomerular diseases), and those in which kidney involvement is part of a systemic disorder (secondary glomerular diseases). This chapter will focus on primary glomerular diseases. This separation of glomerular disease into primary versus secondary is somewhat problematic, because in some instances, what are considered primary glomerular diseases is similar, if not identical, to secondary glomerular diseases. For example, IgA nephropathy, pauci-immune necrotizing and crescentic glomerulonephritis, anti-GBM glomerulonephritis, membranous glomerulopathy, and type I membranoproliferative glomerulonephritis can occur as primary renal diseases or as components of systemic diseases (i.e., Henoch-Schönlein purpura, pauci-immune small-vessel vasculitis, Goodpasture syndrome, systemic lupus erythematosus, and cryoglobulinemic vasculitis, respectively). This chapter will focus on the diagnosis and management of glomerular diseases that do not appear to be a component of a systemic disease.
When a patient presents with glomerular disease, clinicians must evaluate the clinical signs and symptoms of renal disease, and must also be vigilant for evidence of a systemic disease that could be causing the renal disease. Clinical evaluation includes assessment of proteinuria, hematuria, the presence or absence of renal insufficiency, and the presence or absence of hypertension. Some glomerular diseases cause isolated proteinuria or isolated hematuria with no other signs or symptoms of disease. More severe glomerular disease often results in the nephrotic syndrome or nephritic (glomerulonephritic) syndrome. Glomerular disease may have an indolent course or begin abruptly, leading to acute or rapidly progressive glomerulonephritis. Whereas some glomerular disorders consistently cause a specific syndrome (e.g., minimal change glomerulopathy resulting in the nephrotic syndrome), most disorders are capable of causing features of both nephrosis and nephritis ( Table 30-1 ). This sharing and variability of clinical manifestations among different glomerular diseases confounds determination of an accurate diagnosis based on clinical features alone. Therefore, renal biopsy has an important role in the evaluation of many patients with glomerular disease.
This chapter will focus initially on the clinical syndromes caused by glomerular diseases, including isolated proteinuria, isolated hematuria, the nephrotic syndrome, and nephritic syndrome. Then, specific forms of primary glomerular disease that cause these syndromes will be considered in detail, beginning with glomerular diseases that cause predominantly the nephrotic syndrome, and concluding with glomerular diseases that cause predominantly the nephritic syndrome.
TABLE 30-1 -- Manifestations of Nephrotic and Nephritic Features by Glomerular Disease
|
|
Nephrotic Features |
Nephritic Features |
|
Minimal change glomerulopathy |
++++ |
- |
|
Membranous glomerulopathy |
++++ |
+ |
|
Focal segmental glomerulosclerosis |
+++ |
++ |
|
Fibrillary glomerulonephritis |
+++ |
++ |
|
Mesangioproliferative glomerulopathy[*] |
++ |
++ |
|
Membranoproliferative glomerulonephritis[†] |
++ |
+++ |
|
Proliferative glomerulonephritis[*] |
++ |
+++ |
|
Acute diffuse proliferative glomerulonephritis[‡] |
+ |
++++ |
|
Crescentic glomerulonephritis[¶] |
+ |
++++ |
Modified from Jennette JC, Mandal AK: The nephrotic syndrome. In Mandel SR, Jennette JC (eds): Diagnosis and Management of Renal Disease and Hypertension, 2nd ed. Durham, Carolina Academic Press, 1994, pp 235–272.
|
* |
Mesangioproliferative and proliferative glomerulonephritis (focal or diffuse) are structural manifestations of a number of glomerulonephritides, including IgA nephropathy and lupus nephritis. |
|
† |
Both type I (mesangiocapillary) and type II (dense deposit disease). |
|
‡ |
Often a structural manifestation of acute post-streptococcal glomerulonephritis. |
|
¶ |
Can be immune complex mediated, anti-glomerular basement membrane antibody mediated, or associated with anti-neutrophil cytoplasmic autoantibodies. |
GENERAL DESCRIPTION OF GLOMERULAR SYNDROMES
Isolated Proteinuria
Proteinuria can be caused by systemic overproduction (e.g., multiple myeloma with Bence Jones proteinuria), tubular dysfunction (e.g., Fanconi syndrome), or glomerular dysfunction. It is important to identify patients in whom proteinuria is a manifestation of substantial glomerular disease as opposed to those patients who have benign functional, transient, postural (orthostatic), or intermittent proteinuria.
Plasma proteins larger than 70 kD cross the basement membrane in a manner normally restricted by both size-selective and charge-selective barriers. [1] [2] The functional characteristics of the glomerular capillary filter have been extensively studied by the evaluation of the fractional clearance of molecules of different size and charge.[3] The size-selective barrier is most likely a consequence of functional pores within the glomerular basement membrane that restrict the filtration of plasma proteins of more than 150 kD. There is also a shape restriction of molecules that allows elongated molecules to cross the glomerular capillary wall more readily than molecules of the same molecular weight, and there is a charge-selective nature of the barrier largely a consequence of glycosaminoglycans arranged along the capillary wall. Loss of charge selectivity may be the defect in minimal change glomerulopathy, whereas a loss of size selectivity may be the cause of proteinuria in, for instance, membranous glomerulopathy.[2]
A number of factors have proven to be important in the disruption of the glomerular capillary wall as a consequence of tissue-degrading enzymes, complement components that assemble upon it, and oxygen radicals that target both the glomerular basement membrane and the slit diaphragm. Heparinase and hyaluronidase alterations in the amino glycan content of the glomerular capillary wall may play a role in increased protein excretion. [4] [5] Genetic studies have provided exciting clues to the specific components of the glomerular capillary wall, including mutations in the podocyte or proteins in the slit diaphragm, which result in proteinuria (recently reviewed by Tryggvason and colleagues[6]).
Another major mechanism resulting in proteinuria is impaired reabsorption of plasma proteins by proximal tubular epithelial cells. A number of low-molecular-weight proteins, including b1, b2, and α1 microglobulins, are filtered by the glomerulus and absorbed by tubular epithelial cells. When tubular epithelial cells are damaged, these proteins are excreted. The qualitative nature of proteinuria forms the basis for the observation that excretion of high-molecular-weight proteins (e.g., fractional excretion of IgG) is indicative of glomerular damage, whereas excretion of low-molecular-weight proteins (e.g., fractional excretion of alpha1 microglobulin) is more likely when there is tubular epithelial damage. This separation of high- from low-molecular-weight proteinuria has been suggested to be a predictor of clinical outcome in a number of glomerular diseases.[7] The uptake of filtered proteins, including albumin by tubular cells, may produce a reaction that results in tubular atrophy and interstitial fibrosis. This is a controversial area, however, in that a number of studies suggest that exposure of tubular epithelium to albumin or other proteins may not be a phlogistic event. [8] [9] [10] [11]
The term “isolated proteinuria” is used in several conditions, including mild transient proteinuria of less than one gram that typically accompanies physiologically stressful conditions such as fever in hospitalized patients, exercise, and congestive heart failure.[12] In other patients, transient proteinuria is a consequence of the overflow of proteins of low molecular weight due to over-production of light chains, heavy chains, or other fragments of immunoglobulins. The differential diagnosis of overproduction of proteinuria in-cludes multiple myeloma, Bence Jones proteinuria, b2 microglobinuria, and hemoglobinuria.
The term “orthostatic proteinuria” is defined by the absence of proteinuria while the patient is in a recumbent posture and its appearance during upright posture, especially during ambulation or exercise.[13] The total amount of protein excretion in a 24-hour period is generally less than 1.0 gram, but may be as much as 2 grams. Orthostatic proteinuria is more common in adolescents and is uncommon in individuals over the age of 30. [13] [14] Two to five percent of adolescents have orthostatic proteinuria. Renal biopsy of patients with orthostatic proteinuria reveals that 47% have normal glomeruli by light microscopy, 45% have minimal to moderate glomerular abnormalities of nonspecific nature, and the remainder have evidence of a primary glomerular disease.[15] Why is proteinuria increased during upright posture in individuals with normal glomeruli by light microscopy? Although the answer to this question remains an enigma, there are several likely possibilities. Orthostatic proteinuria may occur as a consequence of alterations in glomerular hemodynam-ics. It is possible that even in histologically “normal” glomeruli, where there are no specific lesions, there are subtle glomerular abnormalities, including abnormal basement membranes, or focal changes of the mesangium.[16] Alternatively, orthostatic proteinuria has been demonstrated with entrapment of the left renal vein by the aorta and superior mesenteric artery. Thirteen of 15 children with orthostatic proteinuria had venous entrapment compared with 9 of 80 with normal protein excretion.[17] In addition, the observation that surgical correction of a kink in an allograft renal vein resulted in the disappearance of orthostatic proteinuria gives credence to venous entrapment as a cause for orthostatic proteinuria.[16]
There are several approaches to the diagnosis of orthostatic proteinuria. These include comparison of protein excretion in two 12-hour urine collections, one recumbent and one during ambulation. Another approach is to compare protein in a split collection of 16 hours during ambulation and 8 hours of overnight collection. Importantly, patients should be recumbent for at least 2 hours before their ambulatory collection is completed to avoid the possibility of contamination of the “recumbent” collection by urine formed during ambulation. The diagnosis of orthostatic proteinuria requires that protein excretion during recumbency is less than 50 mg during those 8 hours. Little convincing data exists on the usefulness of urinary protein-to-creatinine ratio measurements during recumbency versus ambulation as a diagnostic test for orthostatic proteinuria.
Long-term follow-up of orthostatic proteinuria for 20 years suggests a benign long-term course.[14] Orthostatic proteinuria resolves in most patients. It is present in one half of patients after 10 years and only 17% of patients after 20 years.[14] In the absence of a kidney biopsy, an underlying glomerulopathy cannot be completely excluded, and an orthostatic component of proteinuria may be found in early glomerular disease. Thus, it is important to reassess patients after an interval of about 1 year to be certain that the degree or pattern of proteinuria has not changed.
Fixed proteinuria is present whether the patient is upright or recumbent. The proteinuria disappears in some patients whereas others will have a more ominous glomerular lesion that portends an adverse long-term outcome. The prognosis depends on the persistence and severity of the proteinuria. If proteinuria disappears, it is less likely that the patient will develop hypertension or reduced glomerular filtration rate. These patients must be evaluated periodically for as long as proteinuria persists.
RECURRENT OR PERSISTENT HEMATURIA
Hematuria is the presence of an excessive number of red blood cells in the urine and is categorized as either microscopic (visible only with the aid of a microscope) or macroscopic (urine that is tea-colored or cola-colored, pink, or even red). Hematuria can result from injury to the kidney or to another site in the urinary tract.
Healthy individuals may excrete as many as 105 red cells in the urine in a 12-hour period. An acceptable definition of hematuria is more than two red cells per high-power field in centrifuged urine.[18] However, the approach to processing urine varies from laboratory to laboratory, thus the number of red cells per high-power field that is an accurate indicator of hematuria may vary slightly among different laboratories. The urinary dipstick detects one to two red cells per high power field and results in a very sensitive test. A negative dipstick examination virtually excludes hematuria.[19]
Hematuria is present in about 5% to 6% of the general population[20] and 4% of school children. In the majority of children, follow-up urinalyses are normal.[21] In most people, the hematuria emanates from the lower urinary tract, especially in the conditions affecting the urethra, bladder, and prostate. Less than 10% of hematuria is caused by glomerular bleeding.[18] Persistent hematuria, especially in older individuals, should raise the possibility of malignancy. The incidence of malignancy, especially from the bladder, ranges from 5% in individuals with persistent microscopic hematuria to over 20% in individuals with gross hematuria.[22] Other causes of non-glomerular hematuria include neoplasms, trauma, metabolic defects such as hypercalciuria, vascular diseases including renal infarctions and renal vein thrombosis, cystic diseases of the kidney including polycystic kidney disease, medullary cystic disease and medullary sponge kidney, and interstitial kidney disease such as papillary necrosis, hydronephrosis, and drug-induced interstitial nephritis. In children with asymptomatic hematuria, hypercalciuria is the cause in 15% of cases, and 10% to 15% will have IgA nephropathy. Up to 80% of children and 15% to 20% of adults with hematuria will have no identifiable cause.[23]
Transient hematuria has been found in a number of settings. Transient hematuria is present in 13% of postmenopausal women.[24] Episodic hematuria in a cyclical pattern during a menstrual cycle is most likely a consequence of the invasion of the urinary tract by endometrial implants.[25] In 1000 males between the ages of 18 and 33, hematuria was present at least once in 39%, and on two or more occasions in 16%. Patients with isolated, asymptomatic hematuria without proteinuria or renal insufficiency have resolution of their hematuria in 20% of cases; however, even in these cases, some will develop hypertension and proteinuria.[26] In older individuals, transient hematuria should raise a concern of malignancy. [18] [27] [28] In some individuals, transient hematuria may be a consequence of exercise.
Glomerular hematuria, in contrast to hematuria caused by injury elsewhere in the urinary tract, is characterized by misshapen red cells that have been distorted by osmotic and chemical stress to red blood cells as they passed through the nephron. Dysmorphic hematuria, especially cells that have membrane blebs producing the picture of acanthocyturia, is strong evidence for glomerular bleeding.[22] The findings of proteinuria (especially >2 grams per day), hemoglobin, or red cell casts enhance the possibility that hematuria is of glomerular origin. Although the presence of brown or cola-colored urine is most commonly associated with glomerular hematuria, its absence does not exclude glomerular disease. Interestingly, the presence of clots in the urine does not occur with glomerular bleeding.
The differential pathologic diagnosis of glomerular hematuria without proteinuria, renal insufficiency, or red blood cell casts is IgA nephropathy, thin basement membrane nephropathy, hereditary nephritis, or histologically normal glomeruli.[29] In a study by Tiebosch,[30] 80 normotensive adults underwent renal biopsy to evaluate recurrent macroscopic hematuria or persistent microscopic hematuria. Twenty-seven individuals had IgA nephropathy, 42 had normal renal tissue by light microscopy, of which electron microscopy revealed thin basement membrane nephropathy in 18 patients, and normal glomerular basement membrane thickness in 24 patients. Hematuria disappeared in 13 of these latter patients. The remaining 11 patients had mesangioproliferative glomerulonephritis, interstitial nephritis, or focal glomerulosclerosis. Importantly, of the 54 patients who presented with microscopic hematuria, 31% had thin basement membrane nephropathy, illustrating the importance of this disease as a cause for asymptomatic glomerular hematuria.
Table 30-2 provides data from an analysis of native kidney biopsy specimens of patients from the University of North Carolina Nephropathology Laboratory, all of whom had hematuria. Patients with systemic lupus erythematosus were excluded from the study. The patients were selected based on a serum creatinine of less than 1.5 mg/dL or greater than 3 mg/dL. The patients with a serum creatinine of less than 1.5 mg/dL were further divided into those with proteinuria less than 1 gram per day, versus those with proteinuria of 1 gram to 3 grams per day. The data showed that patients with relatively normal serum creatinine, hematuria, and less than 1 gram per day of proteinuria were most likely to have thin basement membrane nephropathy, IgA nephropathy, or no identifiable renal lesion. When hematuria is accompanied by 1 gram to 3 grams per day of proteinuria, but no significant renal insufficiency, IgA nephropathy was the most likely specific cause. Patients with hematuria and a serum creatinine of greater than 3 mg/dL most often have aggressive glomerulonephritis with crescents.
TABLE 30-2 -- Renal Disease in Patients with Hematuria Undergoing Renal Biopsy
|
|
Hematuria Proteinuria <1 Creatinine <1.5 |
Hematuria Proteinuria 1–3 Creatinine <1.5 |
Hematuria Creatinine >3 |
|
No abnormality |
30% |
2% |
0% |
|
Thin basement nephropathy |
26% |
4% |
0% |
|
IgA nephropathy |
28% |
24% |
8% |
|
Glomerulonephritis without crescents[*] |
9% |
26% |
23% |
|
Glomerulonephritis with crescents[*] |
2% |
24% |
44% |
|
Other renal disease[†] |
5% |
20% |
25% |
|
Total |
100% n = 43 |
100% n = 123 |
100% n = 255 |
Derived from Caldas MLR, Jennette JC, Falk RJ, Wilkman AS, NC Glomerular Disease Collaborative Network Lab Invest 62:15A, 1990.
|
An analysis of renal biopsy specimens evaluated at by the University of North Carolina Nephropathology Laboratory. Patients with systemic lupus erythematosus were excluded from the analysis. Units: proteinuria, g/24 h; serum creatinine, mg/dl. |
|
* |
Proliferative or necrotizing glomerulonephritis other than IgA nephropathy or lupus nephritis. |
|
† |
Includes causes for the nephrotic syndrome, such as membranous glomerulopathy and focal segmental glomerulosclerosis. |
Despite these overall tendencies, it is not possible to definitively determine the cause of asymptomatic hematuria without renal biopsy, and even renal biopsy evaluation fails to reveal a cause in a minority of patients. Certain rules generally apply to the clinical prediction of the most likely cause. Gross hematuria is most commonly found in IgA nephropathy or hereditary nephritis. Patients with thin basement membrane nephropathy typically do not have substantial proteinuria.
Potential benefits of renal biopsy in patients with isolated hematuria include reduction of patient and physician uncertainty by confirming a specific diagnosis. Nonetheless, the role of renal biopsy in the evaluation of individuals with asymptomatic hematuria without proteinuria, hypertension, or kidney insufficiency remains unclear. In biopsy series from patients in whom asymptomatic hematuria is accompanied by low-grade proteinuria, specific glomerular diseases including IgA nephropathy and membranoproliferative glomerular disease may be discovered when there is no proteinuria, and IgA nephropathy and thin basement membrane disease or non-diagnostic minor changes remain the most common findings. [31] [32] Confirmation of a glomerular cause eliminates repeated unnecessary urologic studies and determination of a more accurate long-term prognosis can be made (e.g., thin basement membrane nephropathy is less likely to progress than IgA nephropathy). However, isolated glomerular hematuria without proteinuria or renal insufficiency may not warrant a renal biopsy because the findings often will not affect management. In one study of patients with isolated hematuria, the biopsy results altered patient management in only 1 of 36 patients.[33]
Nephrotic Syndrome
The nephrotic syndrome results from greater than 3.5 grams per day of proteinuria and is characterized by edema, hyperlipidemia, hypoproteinemia, and other metabolic disorders (described in detail below). In addition to primary (idiopathic) glomerular diseases, the nephrotic syndrome may be secondary to a large number of identifiable disease states ( Table 30-3 , modified from previous edition). Despite the differences in these causes, the loss of substantial amounts of protein in the urine results in a shared set of abnormalities that comprise the nephrotic syndrome.
TABLE 30-3 -- Classification of the Disease States Associated with the Development of Nephrotic Syndrome
|
Idiopathic Nephrotic Syndrome due to Primary Glomerular Disease |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Nephrotic Syndrome Associated with Specific Etiologic Events or in Which Glomerular Disease Arises as a Complication of Other Diseases: |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
* |
Diseases and other agents in italics are the more commonly encountered causes of nephrotic syndrome. |
|
† |
Single case reports or small series in which cause-and-effect relationship cannot be established. Other factors (e.g., mercurial diuretics in heart failure) may have been true inciting event. |
|
‡ |
See Chapter 31 for detailed discussion of the secondary forms of nephrotic syndrome. |
Edema
Edema is the most common presenting symptom of patients with the nephrotic syndrome. Various theories for the cause of nephrotic edema have been proposed. Hypovolemia as a consequence of reduced plasma oncotic pressure has long been considered the proximal cause of salt and water retention by the kidney. Enhanced tubular sodium reabsorption is thought to be a function of multiple mediator systems responding to the “perceived volume depletion” with activation of the renin-angiotensin aldosterone, sympathetic nervous, and vasopressor systems.[34]
Although there is evidence to support the “underfilling” hypothesis of edema formation,[35] other investigators have suggested that a primary disorder of the kidney results in increased intravascular volume and subsequent suppression of renin angiotensin aldosterone access and elevated natriuretic peptide levels.[36] The literature is unclear whether plasma volume is low or high. These issues are of more than academic interest, in that fluid assessment in a patient with the nephrotic syndrome may require substantial alterations in diuretic use.[35]
It is reasonable to assert that hypoproteinemia results in a fall in the plasma oncotic pressure and the movement of fluid into the interstitial space. Several factors mitigate this phenomenon. Normally, the transcapillary oncotic pressure gradient (plasma oncotic pressure minus the interstitial oncotic pressure) acts synergistically to retain fluid within the vascular space. In normal patients, colloid osmotic pressure in the plasma is approximately 26 mm Hg. The interstitial oncotic pressure may be as high as 10 mm Hg to 15 mm Hg because of the filtration of albumin across the capillary wall. In nephrotic patients, the interstitial oncotic pressure may fall to as low as 2.6 mm Hg in the lower extremity. The fall in the interstitial oncotic pressure functions as a protecting factor in hypoproteinemic patients.[37] There may be a consequent parallel decline in interstitial oncotic pressure matching the fall in the plasma oncotic pressure and minimizing the change in the transcapillary gradient. Thus, there would be a smaller change in the transcapillary gradient and a reduced drive of fluid shifting from the vascular compartment into the interstitium. Other factors limiting the amount of fluid movement into the interstitium include compliance of the interstitium in most tissues and increased lymphatic fluid flow. Marked dietary salt ingestion or the administration of saline to patients who are hypoproteinemic may result in a rapid fall in the transcapillary oncotic pressure gradient and subsequent substantial edema.
What factors are responsible for sodium retention in the nephrotic state? Does the propensity for avid sodium retention derive entirely from hypovolemia due to loss of fluid into the interstitium? Most likely in some patients, hypovolemia plays an important role in the retention of salt and water by the kidney.[38] However, there have been several challenges to the concept that sodium retention and edema formation are the consequence of hypovolemia. These arguments suggest that in adult patients with the nephrotic syndrome, there may be normal or even increased plasma volume.[39] High blood pressure argues against hypovolemia and, in fact, suggests hypervolemia.[40]
The resolution of edema due to normalization of plasma oncotic pressure, for example by administration of albumin, supports the argument that hypoalbuminemia is important in the generation of edema. In some patients, however, the administration of albumin does not result in amelioration of edema, nor does maintenance of a normal serum albumin level in any given patient necessarily prevent the development of edema over the course of time. There are normal levels of serum albumin in some edematous patients. This may be due to contraction of the blood volume, or of homeostatic increase in other proteins that may rise to varying degrees. Thus, the serum albumin may not be indicative of the plasma oncotic pressure. Some of the most convincing data that hypovolemia may not necessarily play a role in the development of edema stems from studies in children with relapse of minimal change glomerulopathy. Vande Walle and colleagues investigated the cause of sodium retention in the nephrotic syndrome in children with early relapse of minimal change glomerulopathy.[41] In this study, children presented with severe hypoproteinemia and the nephrotic syndrome with or without clinical symptoms or laboratory signs of hypovolemia. Sodium retention preceded the reduction in serum protein concentrations in some patients, and natriuresis developed before proteinuria had resolved in others.
The levels of atrial natriuretic factor (ANF) and plasma renin activity (PRA) in patients with acute glomerulonephritis have been compared to patients with the nephrotic syndrome and to normal individuals.[42] The amount of edema was similar in the two groups of patients with glomerular disease, and they had similar urinary sodium excretion. Interestingly, patients with acute glomerulonephritis had five times higher levels of ANF and six times lower PRA when compared to patients with the nephrotic syndrome. In fact, the degree of edema correlated with the ANF levels found with acute glomerulonephritis, but not in those patients with the nephrotic syndrome. There was a strong negative correlation between the level of ANF and the PRA. At the same level of sodium excretion, nephrotic patients had ANF and PRA levels equivalent to normal subjects ingesting a usual amount of sodium in their diet. These results suggest that renal sodium retention in nephrosis is probably a consequence of primary renal sodium retention rather than a consequence of plasma hormone effects on the kidney. It is reasonably certain that sodium retention in nephrotic states is not dependent on changes in activity in the renin-angiotensin-aldosterone system. [43] [44] [45] [46] Whether the inability of angiotensin converting enzyme inhibitors to result in natriuresis is a function of over-activity of this system that cannot be inhibited, or this system is not causing sodium retention has not been elucidated. On the other side of the controversy, capillary filtration capacity at the calf, a noninvasive measure of capillary pressure, demonstrated that patients with the nephrotic syndrome had no evidence of capillary hypertension or evidence to support the overflow hypothesis of edema formation. In fact, there was no difference in capillary pressure between nephrotic subjects and controls.[47]
Recently, a hypothesis has been advanced that sodium and water retention in the nephrotic syndrome is due to over-excretion of vasopressin as a consequence of either volume or osmotic stimuli. This vasopressin-dependent process results in fluid retention.[48] The availability of selective antagonists of vasopressin's action with respect to vascular and tubular effects should make it possible to explore this hypothesis more fully.
There are certain important issues to consider when making decisions about management of edema in the nephrotic syndrome. In some patients, the edema is only of minimal discomfort whereas in others the edema causes substantial morbidity. The goal should be to have a slow resolution of edema. In all instances, the institution of rapid diuresis, resulting in hypovolemia and even hypotension, must be avoided. Dietary restriction of sodium intake has been the mainstay of therapy in the management of nephrotic edema. Patients with nephrosis have sodium avidity and therefore the amount of sodium in the urine may be as low as 10 mmol/day.[49] Consequently, it is virtually impossible to lower the sodium intake to these levels. It is more important to suggest mild sodium restriction. Mild diuretics, including thiazide diuretics, may be sufficient in many patients with mild edema. Potassium sparing diuretics, such as triamterene, amiloride, or spironolactone, are useful in those patients in whom hypokalemia becomes a clinical problem, but their use is limited in those patients with renal insufficiency. Furosemide and other loop diuretics are typically used for moderate to severe nephrotic edema. Although the high protein content of tubular fluid was once thought to inhibit furosemide and other loop diuretics by binding to them, data now suggests that urinary protein binding does not effect the response to furosemide. [50] [51] Metolazone may be effective when used by itself or in combination with loop diuretics (i.e., furosemide) in patients with refractory nephrotic edema. In patients treated with diuretics, episodes of profound volume depletion may occur. The resultant peripheral vasoconstriction, tachycardia, orthostatic hypotension and, at times, oliguria and renal insufficiency are usually amenable to cessation of the diuretic and rehydration. Albumin infusions transiently increase plasma volume and are most useful in patients with profound volume depletion. [52] [53] Unfortunately, because of the rapid excretion of the infused albumin within 48 hours,[54] the utility of this approach is short-lived and may result in transient development of pulmonary edema. In extreme cases of marked edema, and especially pulmonary edema typically in the setting of reduced glomerular filtration rate, filtration using either intermittent or continuous extracorporeal dialysis is useful.
Hyperlipidemia
Hyperlipidemia is one of the sentinel features of the nephrotic syndrome. Patients develop numerous alterations in lipid profiles including hypercholesterolemia and hypertriglyceridemia with elevations in low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and lipoprotein(a) [LP(a)]. Reduced or unchanged high-density lipoprotein (HDL) concentrations result in an increase in the adverse cardiovascular risk ratio of LDL/HDL cholesterol. [55] [56] [57] [58] [59] Hyperlipidemia is thought to be the consequence of both increased synthesis and decreased catabolism of individual lipid fractions. In part, hypercholesterolemia is due to the overproduction by the liver of lipoproteins that contain both cholesterol and lipoprotein B. [55] [57] It has been hypothesized that this overproduction by the liver is a consequence of a fall in the oncotic pressure. Oncotic pressure may play a role in the regulation of the transcription of albumin and apolipoprotein B genes.[60] Data now suggest that hyperlipidemia in nephrotic patients is driven by a complex interplay of relative elevation or diminution of a number of enzymes that are important in cholesterol synthesis. In a number of studies, Vaziri and colleagues have shown that there is a relative elevation of hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis, and a reduction in hepatic cholesterol (Ch) 7α-hydroxylase. The expression of Ch 7α-hydroxylase is rate-limiting in the catabolism of cholesterol. In addition, LDL receptor deficiency limits hepatic cholesterol uptake and is complemented by the upregulation of the liver-specific enzyme acylcoenzyme A:cholesterol acyltransferase-2 (ACAT-2) that lowers liver-free cholesterol concentrations.[61] In the nephrotic syndrome, abnormalities in HDL may be a consequence of urinary loss of the critical enzyme lecithin:cholesterol acyltransferase (LCAT), which decreases HDL-mediated uptake of surplus cholesterol from tissues outside of the liver. Accompanying the loss of LCAT is the down-regulation of hepatic HDL receptor-limiting cholesterol and triglyceride removal by the liver. Hypertriglyceridemia seen in the nephrotic syndrome is most likely a consequence of a number of factors, including the down-regulation of lipoprotein lipase, the down-regulation of the VLDL receptor, and the impairment of hepatic triglyceride lipase (reviewed by Vaziri[61]).
Finally, LP(a) is an independent risk factor for atherosclerotic disease.[62] In patients with the nephrotic syndrome, plasma LP(a) increases significantly as a consequence of an increased rate of synthesis with a normal fractional catabolic rate.[63] LP(a) binds to apolipoprotein(a) [Apo(a)] with a disulfide bond. Apo(a) has a high degree of homology with plasminogen,[64] and Apo(a) interferes with plasminogen-mediated fibrinolysis; thus, an elevation of LP(a) produces a prothrombotic event.
There are many clinical benefits of lipid-lowering therapy. In the landmark study of the Lipid Research Clinics Program coronary primary prevention trial, cholestyramine demonstrated a reduction of serum cholesterol that could reduce the rate of adverse coronary events. [65] [66] Numerous subsequent studies have further elucidated the relationship of coronary artery disease with hypercholesterolemia. [67] [68] [69] [70] [71] [72] Premature coronary atherosclerosis and increased incidence of myocardial infarction have been reported in patients with the nephrotic syndrome.[73] Hyperlipidemia of the nephrotic syndrome is likely a separate risk factor for atherosclerotic cardiovascular disease. [56] [58] In a case-controlled study, individuals with nephrotic syndrome were at a substantially increased risk of coronary artery disease with a relative risk when compared to controls of 5.5 for myocardial infarction and a relative risk of 2.8 for coronary death in general.[73] Most studies, however, have not confirmed a predisposition for accelerated atherosclerosis in nephrotic patients.[74] This may be due to the relatively small number of younger patients studied and the relatively short duration that patients have been examined.
Sensitive measures of endothelial dysfunction suggest that in patients with the nephrotic syndrome, endothelial function is altered. Postischemic flow-mediated dilatation (FMD) of the brachial artery was significantly lower in nephrotic patients and primary hyperlipidemia patients when compared with control patients.[75] Using an HMG-CoA reductase inhibitor, brachial artery endothelial function improved.[76]
In addition to the cardiovascular risk, there is a risk of the hyperlipidemia promoting progression of renal disease. These data largely stem from animal studies suggesting that hyperlipidemia enhances the rate of progressive glomerular injury.[77] The potentially atherogenic apo-B containing lipoproteins may be associated with glomerular and interstitial lesions. How these lipoproteins cause renal disease is not clear, although there is non-receptor-mediated uptake of lipoproteins by mesangial cells that accelerate both sclerotic processes and proliferative ones. Most importantly, increased concentrations of APO-B containing lipoproteins are associated with more rapid progression of renal injury in both diabetic nephropathy and primary glomerular diseases.[78] In some patients, hyperlipidemia may persist well after clinical remission has occurred.
The management of hyperlipidemia in the nephrotic syndrome is difficult. Remission of the nephrotic syndrome leads to optimum resolution of hypercholesterolemia and hypertriglyceridemia. Dietary therapy provides very little benefit.[79] However, Gentile and colleagues evaluated the effect of a soy vegetable diet rich in mono- and polyunsaturated fatty acids.[80] Using this approach, a 25% to 30% reduction in lipid levels was observed that could not be improved by the addition of fish oils to the diet. This approach must be confirmed by larger trials.
Virtually all forms of lipid-lowering drugs have been used to treat patients with the nephrotic syndrome. [79] [81] [82] [83] [84] [85] [86] The most useful agents to lower lipid levels in patients with nephrosis are the HMG-CoA reductase inhibitors and agents that sequester bile acids, including cholestyramine and colestipol. The bile acid sequestrants lower total cholesterol levels by up to 30% when used alone[81] and when used with HMG-CoA reductase inhibitors, they have an additive benefit. The HMG-CoA reductase inhibitors lower total and LDL cholesterol levels by between 10% and 45%, coupled with a reduction in triglyceride levels. [56] [79] [82] The use of these agents in patients with unremitting nephrotic syndrome resulted in a moderate decline in Lp(a) in patients with an elevated Lp(a).[84] Although the fibric acid derivatives including gemfibrozil and clofibrate lower cholesterol by only 10% to 30%, they also lower plasma triglycerides and may raise HDL level. Unfortunately, they are associated with increased risk of myopathy. Nicotinic acid may have a positive effect on hyperlipidemia, but the side effects of headaches and flushing usually limit its usefulness. At present, treatment of HMG-CoA reductase inhibitors appears to be the treatment of choice.
Functional Consequence of Urinary Loss of Plasma Proteins
In addition to the urinary losses of albumin in the nephrotic syndrome, glomerular permeability causes the loss of proteins of similar molecular weight ( Table 30-4 ). Not all proteins are lost in the urine, especially larger proteins such as IgM, fibrinogen, alpha-1 and alpha-2 macroglobulin, and larger lipoproteins that never traverse the glomerular capillary wall and thus are of normal or increased concentration in the plasma.[87]
TABLE 30-4 -- Alterations of Plasma Protein in the Nephrotic Syndrome [114] [115] [1280] [1281] [1282] [1283] [1284] [1285] [1286] [1287] [1288] [1289] [1290] [1291] [1292] [1293]
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Hormone-binding proteins are typically lost in the urine resulting in several endocrine or metabolic abnormalities. The urinary loss of thyroid binding globulins and thyroxine results in a low T4, both free and bound, in about one half of all patients with the nephrotic syndrome and a normal glomerular filtration rate. [88] [89] [90] Additionally, total T3 levels are reduced probably because of decreased binding to thyroid binding globulins.[90] Total reversed T3 levels tend to be normal in the nephrotic syndrome, but the free reverse T3 level is elevated.[90] Despite these abnormalities, most patients remain clinically euthyroid. In some patients, loss of thyroid proteins in the urine has been associated with hypothyroidism in patients with the nephrotic syndrome,[91] with hypothyroidism resolving coincident with remission of the nephrotic syndrome. Moreover, treatment of the nephrotic syndrome with corticosteroid therapy may reduce TSH levels and, in some patients, inhibit the conversion of T4 to T3,[92] As a practical matter, free T4 levels or the level of the TSH are the best markers of the clinical status of the thyroid.
Calcium and vitamin D levels are typically altered in the nephrotic syndrome. Vitamin D binding protein is a relatively small protein of 59 kD that is filtered as readily as albumin.[93] 25-hydroxyvitamin D, the precursor of Calcitriol, is bound to vitamin D binding proteins and is lost in the urine with the nephrotic syndrome. [94] [95] Similarly, there may be low serum concentrations of total 1,25-dihydroxyvitamin D.[96] With the loss of vitamin D binding protein, it is important to measure free 1,25-dihydroxyvitamin D levels to accurately assess the status of this factor in these patients. Further, hypoalbuminemia results in low total serum calcium concentration. Coupled with alterations in vitamin D binding proteins, of issue is which patients with true hypocalcemia are at risk for osteopenia. Bone biopsies in patients with normal serum PTH levels, relatively normal levels of 1,25-hydroxyvitamin D3, and low to normal range normal vitamin D binding proteins usually have no evidence of osteomalacia or hyperparathyroidism on bone biopsy.[97] Because osteomalacia and hyperparathyroidism have been reported to occur with low levels of 25-hydroxyvitamin D in other situations, this report provides comfort that preservation of bone occurs in this group of patients. Thus, in patients with nephrotic syndrome, normal renal function, and abnormalities in circulating vitamin D and calcium, there is little data to suggest that there are alterations in bone mineralization. The concomitant use of corticosteroid therapy or the development of renal insufficiency or other mitigating factors will induce osteoporosis. Therefore, replacement of either calcium or vitamin D in patients with the nephrotic syndrome is not recommended except in prolonged courses of nephrosis or when patients receive corticosteroid therapy. Careful evaluation of bone mineralization with bone densitometry scanning and early administration of vitamin D and other agents may prevent loss of bone mineralization.
Because of the urinary loss of immunoglobulins and defects in the complement cascade, nephrotic patients have an increased susceptibility of infection, particularly peritonitis. Peritonitis caused by either gram-negative or gram-positive organisms remains a serious complication of the nephrotic syndrome. [98] [99] [100] Children of African American descent appear to be at greater risk for peritonitis. [100] [101] The etiology of the susceptibility to bacterial infections, especially by encapsulated organisms, is not entirely clear. Acquired IgG deficiency due to urinary losses is certainly a cause of enhanced infection. The deficiency of both factor B and D urinary protein loss results in impaired opsonization of these microorganisms. Controversy regarding the presence of functional splenic abnormalities is a matter of debate. [102] [103] Treatment protocols include intravenous antibiotics with broad-spectrum coverage of both gram-positive and gram-negative organisms until appropriate culture results are available. Although pneumococcal vaccination is recommended with the nephrotic syndrome,[104] there are reports of patients who develop peritonitis despite vaccination. Whether this results from poor immunoglobulin response to the vaccine or exposure to other serotypes of pneumococcus is uncertain.[98]
Hypoalbuminemia is a cardinal feature of the nephrotic syndrome. Serum albumin levels are depressed not only as a consequence of loss in the urine, but also because of an increased albumin catabolism.[105] Hepatic albumin synthesis is increased from 145 ± 9 mg/kg/day to 213 ± 17 mg/kg/day in nephrotic patients.[106] The transcriptional regulation of human albumin synthesis is not correlated with plasma oncotic pressure or serum albumin concentration, but rather with a urinary albumin excretion.[107] In fact, a fall in plasma oncotic pressure may not be a stimulus to albumin synthesis by the liver at all.[105] Although there is a correlation between the amount of proteinuria and the degree of hypoalbuminemia, there are individuals who have normal, or near normal levels of serum albumin despite severe proteinuria. [108] [109] [110] Prolonged and massive proteinuria may lead to malnutrition.
There are several abnormalities of the coagulation system in the nephrotic syndrome ( Table 30-5 ). The thrombotic abnormalities in the nephrotic syndrome are a consequence of hyperfibrinogemia, increased in vitro platelet hyperaggregability, increased fibrinogen to fibrin transition, decreased levels of antithrombin III, and decreased fibrinolysis. These abnormalities may result in venous and arterial thrombi. Prevalence of coagulation disorders in series of adult nephrotic patients varies substantially, but averages 26% in an accumulated study of eight series.[111] The incidence of thromboembolic problems in children is substantially less, and is approximately 1.8%. Deep venous thrombosis may occur in virtually any venous bed, whereas arterial thromboses occur less frequently in almost any vessel. [112] [113] The cause of hypercoagulability is uncertain, but there are numerous possibilities. [114] [115] [116] [117] Studies on the plasma levels of fibrinopeptide, anti-thrombin III complex, products of thrombin activation in 21 patients with the nephrotic syndrome compared with 16 controls suggest that the low anti-thrombin III level in nephrotic patients may not only be due to urinary loss, but also to intravascular consumption.[118] Steroid administration alters the level of certain clotting factors and may provide yet another stimulus for procoagulant activity.[114]Many patients with the nephrotic syndrome are anemic as a consequence of decreased renal function and decreased erythropoietin levels. The increase in hepatic synthesis of transferrin does not match urinary losses of transferrin. There are urinary losses of erythropoietin as well. [119] [120]
TABLE 30-5 -- Coagulation Factors in the Nephrotic Syndrome [116] [529] [1292] [1294] [1295] [1296] [1297] [1298] [1299] [1300] [1301] [1302] [1303] [1304] [1305] [1306] [1307]
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Increased blood viscosity |
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Hemoconcentration |
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Increased plasma fibrinogen |
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Increased intravascular fibrin formation |
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Increased α-2 macroglobulins |
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Increased tissue type plasminogen activator |
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Increased factors II, V, VII, VIII, X, XIII |
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Decreased factors IX, XI, XII |
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Decreased α-antitrypsin |
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Decreased fibrinolytic activity |
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Decreased plasma plasminogen |
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Decreased antithrombin III |
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Decreased protein S |
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Thrombocytosis |
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Increased platelet aggregability |
GLOMERULAR DISEASES THAT CAUSE NEPHROTIC SYNDROME
Minimal Change Glomerulopathy
Epidemiology
Minimal change glomerulopathy, also known as minimal change disease, was first described in 1913 by Monk who called it “lipoid nephrosis” because of the lipid in the tubular epithelial cells and urine.[121] Minimal change glomerulopathy is most common in children, accounting for 70% to 90% of nephrotic syndrome in children under age 10 and 50% in older children. Minimal change glomerulopathy also causes 10% to 15% of primary nephrotic syndrome in adults ( Fig. 30-1 ).
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FIGURE 30-1 Graph depicting the frequencies of different forms of glomerular disease identified in renal biopsy specimens from patients with proteinuria of greater than 3 g/day evaluated in the University of North Carolina Nephropathology Laboratory. Some diseases that cause proteinuria are underrepresented because they are not always evaluated by renal biopsy. For example, many patients with steroid-responsive proteinuria may be given a presumptive diagnosis of minimal change glomerulopathy and are not subjected to biopsy, and most patients with diabetes and proteinuria are presumed to have diabetic glomerulosclerosis and are not biopsied. |
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The incidence of minimal change glomerulopathy has geographic variations. Minimal change glomerulopathy is more common in Asia than in North America or Europe.[122] This may be a consequence of differences in renal biopsy practices, or of differences in environmental or genetic influences. The disease may also affect elderly patients in whom there is a higher propensity for the clinical syndrome of minimal change glomerulopathy and acute renal failure (discussed later). There appears to be a male preponderance of this process in some series, especially in children in whom male-to-female ratio is 2 to 3:1,[123] however, our own data do not support this ( Table 30-6 ).
TABLE 30-6 -- Diseases that Cause the Nephrotic Syndrome[*]
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Glomerular Lesion |
N |
Male : Female Ratio |
White : Black Ratio |
|
Minimal change glomerulopathy |
522 |
1.1:1.0 |
1.9:1.0 |
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Focal segmental glomerulosclerosis (FSGS) (typical) |
1103 |
1.4 : 1.0 |
1.0 : 1.0 |
|
Collapsing glomerulopathy FSGS |
135 |
1.2:1.0 |
1.0:7.8 |
|
Glomerular tip lesion FSGS |
94 |
1.0:1.0 |
4.7:1.0 |
|
Membranous glomerulopathy |
1120 |
1.4:1.0 |
1.9:1.0 |
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C1q nephropathy |
114 |
1.0:1.0 |
1.0:4.8 |
|
Fibrillary glomerulonephritis |
76 |
1.0:1.2 |
14.3:1.0 |
|
* |
Information in this table is from 9605 native kidney biopsies from the UNC Nephropathology Laboratory. This laboratory evaluates kidney biopsies from a base population of approximately 10 million throughout the southeastern United States and centered in North Carolina. The expected white-to-black ratio in this renal biopsy population is approximately 2 : 1. |
Pathology
Light Microscopy
Minimal change glomerulopathy has no glomerular lesions by light microscopy ( Fig. 30-2 ), or only minimal focal segmental mesangial prominence.[124] This mesangial prominence should have no more than three or four cells embedded in the matrix of a segment, and the matrix should not be expanded to the extent that capillary lumens are compromised. Capillary walls should be thin and capillary lumens patent.
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FIGURE 30-2 Unremarkable light microscopic appearance of minimal change glomerulopathy. Glomerular basement membranes are thin, and there is no glomerular hypercellularity or mesangial matrix expansion. (Jones methenamine silver, ×300.) |
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The most consistent tubular lesion is increased protein and lipid resorption droplets in tubular epithelial cells. These droplets are periodic acid-Schiff positive. Conspicuous re-sorbed lipid in epithelial cells prompted the designation lipoid nephrosis for this disease prior to the recognition of the ultrastructural glomerular lesion. Interstitial edema is rare, even in patients with severe nephrotic syndrome and anasarca. Focal proximal tubular epithelial flattening (simplification), which is histologically identical to that seen with ischemic acute renal failure, occurs in patients who have the syndrome of minimal change glomerulopathy with acute renal failure.[125]
Focal areas of interstitial fibrosis and tubular atrophy in a specimen that otherwise looks like minimal change glomerulopathy, especially in a young person, should raise the possibility of focal segmental glomerulosclerosis that was not sampled in the biopsy specimen. Examination of additional levels of section may reveal a sclerotic glomerulus.
Immunofluorescence Microscopy
Glomeruli usually show no staining with antisera specific for IgG, IgA, IgM, C3, C4, or C1q. The most frequent positive finding is low-level mesangial staining for IgM, sometimes accompanied by low-level staining for C3. If the IgM staining is not accompanied by mesangial electron dense deposits by electron microscopy, it is consistent with a diagnosis of minimal change glomerulopathy. Patients with mesangial IgM by immunofluorescence microscopy (in the absence of dense deposits by electron microscopy) do not have a worse prognosis than those without IgM. [126] [127] The presence of mesangial dense deposits identified by electron microscopy worsens the prognosis and thus justifies altering the diagnosis, for example to IgM mesangial nephropathy.[128] Anything more than trace staining for IgG or IgA casts substantial doubt on a diagnosis of minimal change glomerulopathy. Even when no sclerotic glomerular lesions are seen by light microscopy, well-defined irregular focal segmental staining for C3 and IgM should raise the possibility of focal segmental glomerulosclerosis because sclerotic lesions usually trap C3 and IgM. Glomerular and tubular epithelial cell cytoplasmic droplets and tubular casts may stain positively for immunoglobulins and other plasma proteins when there is substantial proteinuria.
Electron Microscopy
The pathologic sine qua non of minimal change glomerulopathy is effacement of visceral epithelial cell foot processes observed by electron microscopy (Figs. 30-3 and 30-4 [3] [4]). However, this is not a specific feature, because it occurs in the glomeruli of patients with severe proteinuria of any cause. During active nephrosis, the effacement often is very extensive, with only a few scattered intact foot processes. As the patient enters remission, the extent of foot process effacement diminishes. The effacement usually is accompanied by microvillous transformation, which is the development of numerous villous projections from the epithelial surface into the urinary space. The effacement also is accompanied by increased density of the cytoskeleton, including actin filaments, in clumps near the basement membrane surface of the visceral epithelial cells. These intracytoplasmic densities should not be confused with subepithelial immune complex dense deposits. Glomerular and proximal tubular epithelial cells have increased clear and dense cytoplasmic droplets.
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FIGURE 30-3 Diagrams depicting the ultrastructural features of a normal glomerular capillary loop (A) and a capillary loop with features of minimal change glomerulopathy (B). The latter has effacement of epithelial foot processes (arrow) and microvillous projections of epithelial cytoplasm. (Used with permission from J.C. Jennette.) |
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FIGURE 30-4 Electron micrograph of a glomerular capillary wall from a patient with minimal change glomerulopathy showing extensive foot process effacement (arrows) and microvillous transformation (magnification ×5000). |
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All of these ultrastructural glomerular changes occur in other glomerular disease when there is nephrotic-range proteinuria. Therefore, minimal change glomerulopathy is a diagnosis by exclusion that is made only when there is no evidence by light, immunofluorescence, and electron microscopy for any other glomerular disease.
Pathogenesis
Although the pathogenesis of minimal change glomerulopathy remains unclear, this disorder is most likely a consequence of abnormal regulation of T-cell subset [129] [130] [131] [132] [133] and pathologic elaboration of circulating permeability factor. Specifically, corticosteroids and alkylating drugs cause a remission of minimal change glomerulopathy, there is an association of minimal change glomerulopathy with Hodgkin disease, [134] [135] and remissions are associated with depression of cell-mediated immunity during viral infections such as measles. Specific evidence stems from the finding that a glomerular permeability factor is produced by human T cell hybridomas obtained from a patient with minimal change nephrosis. When this factor was injected into rodents, proteinuria occurred with partial fusion of glomerular epithelial cell foot processes.[136] Although there are no observable abnormalities in T or B cell populations in patients with relapsing or quiescent minimal change glomerulopathy, [137] [138] [139] [140] lymphocytes have depressed reactivity when challenged with mitogens. [141] [142] [143] [144] [145] [146] [147] [148] [149] T cells apparently produce a product, most likely a lymphokine, which increases glomerular permeability to protein. When the glomerular permeability factor is removed from the kidney, it functions normally. This is supported by the intriguing observation that transplantation of a kidney from a patient with refractory minimal change glomerulopathy resulted in rapid disappearance of proteinuria.[150]
This factor my have specificity for glomerular epithelial cells that results in loss of the charge selective barrier of the glomerular basement membrane. The loss of charge selectivity has been assessed by dextran studies. [151] [152] In these studies, there is less evidence for a defect in the size selective barrier and more of an alteration of the basement membrane electrostatic charge. The glomerular negative charge is reduced in relapse.[153]
There are other potential pathogenic mechanisms for the pathological changes described as minimal change glomerulopathy. Circulating immune complexes have been found in patients who have been presumed to have minimal change glomerulopathy, [154] [155] the level of which fell during remission. Moreover, there have been studies of the presence of an IgM rheumatoid factor in patients with minimal change glomerulopathy. The significance of these observations is questionable given the lack of immune complex deposition within glomeruli.
Clinical Features and Natural History
The cardinal clinical feature of minimal change glomerulopathy in children is the relatively abrupt onset of proteinuria and development of the nephrotic syndrome with heavy proteinuria, hypoalbuminemia, and hyperlipidemia.[124]The edematous picture is typically what prompts the parents of children to seek medical attention. Hematuria is distinctly unusual, and in children, hypertension is uncommon. In the International Study of Kidney Disease in Children (ISKDC) series, diastolic hypertension was found in 13% of patients.[156] The clinical features of adults with minimal change glomerulopathy tend to be somewhat different. In a group of 89 adults over the age of 60, hypertension, sometimes severe, as well as renal insufficiency, was more common.[157] Because individuals over the age of 60 account for almost one-quarter of adult patients with minimal change glomerulopathy, this presentation must be considered.
Minimal change glomerulopathy has been associated with several other conditions, including viral infections, pharmaceutical agents, malignancy, and allergy ( Table 30-7 ). In some patients, there is a history of a drug reaction before the onset of minimal change glomerulopathy. The use of non-steroidal anti-inflammatory drugs and, in particular, fenoprofen has been associated with, and may cause minimal change glomerulopathy.[158] In this setting, most patients have not only proteinuria, but also pyuria and renal insufficiency as a consequence of the simultaneous development of acute tubulointerstitial nephritis. This same process has also been described with other compounds, including interferon,[159] penicillins, and rifampin. In most of these patients, discontinuation of the offending drug leads to resolution of the proteinuria, but it may take weeks to months for complete amelioration of pyuria and renal insufficiency.
TABLE 30-7 -- Common Disease Associations with Minimal Change Glomerulopathy [159] [169] [194] [195] [196] [877] [1308] [1309] [1310] [1311] [1312] [1313] [1314] [1315]
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Rarely, minimal change glomerulopathy is associated with a lymphoid malignancy, usually Hodgkin disease.[160] Minimal change glomerulopathy may also occur with solid tumors as an apparent paraneoplastic phenomenon.
There is also an association of minimal change glomerulopathy with food allergy. This is an important association in that, in some patients, removal of the allergen has resulted in the resolution of the proteinuria. In 42 patients of non-biopsied idiopathic nephrotic syndrome, 16 of 42 had positive skin tests for food allergy. In 13 of 42 an oligo-antigenic diet was prescribed resulting in a significant reduction in proteinuria.[161] Thus, it is important to ask patients about potential allergens, especially those found with food.
A syndrome of minimal change glomerulopathy accompanied by a reversible acute renal failure has a higher incidence in adults than in children. [157] [162] [163] This syndrome of adult minimal change glomerulopathy with acute renal failure was studied in 21 patients who, on presentation, had a serum creatinine greater than 177 mmol/L, and were compared with 50 adult patients with minimal change glomerulopathy and a serum creatinine of less than 133 mmol/L. Patients who presented with acute renal failure were older (59 years versus 40 years), had a higher systolic blood pressure (158 mm Hg versus 138 mm Hg), and had more proteinuria (13.5 versus 7.9 grams/24 hours). Importantly, renal biopsy demonstrated evidence of atherosclerosis and focal tubular epithelial simplification compatible with ischemic acute renal failure. Of the 18 patients with renal failure for whom follow-up data were available, all had recovery of renal function, but some only after substantial dialytic support.[125]
A review of 79 patients in the literature since 1966 revealed a similar finding in an older population with high urinary protein excretion, a low serum albumin, and the persistence of acute renal failure for up to 77 weeks. The presence of histopathological findings of acute tubular necrosis was found in 60% of these patients.[162] When treating older patients, it is important to recognize that acute renal failure may be present in the setting of minimal change glomerulopathy, and that dialytic therapy may be necessary to tide the patient over while corticosteroid treatment induces a response.
Laboratory Findings
The ubiquitous laboratory feature of minimal change glomerulopathy is severe proteinuria.[124] Microscopic hematuria is seen in less than 15% of patients, with only rare episodes of macroscopic hematuria. The rapidity of the develop-ment of proteinuria in some patients is associated with evidence of volume contraction with increased hematocrit and hemoglobin. The erythrocyte sedimentation rate is increased as a consequence of the hyperfibrinogenemia as well as hypoalbuminemia. The serum albumin concentration is usually depressed, whereas the total cholesterol, LDL, and triglyceride levels are increased. Total serum protein concentration is usually reduced to between 4.5 g/dL and 5.5 g/dL with a serum albumin concentration of generally less than 2 g/dL and, in more severe cases, less than 1 g/dL. Pseudohyponatremia has been observed in the setting of marked hyperlipidemia. Serum calcium may be low largely due to hypoproteinemia.
Several abnormalities that promote thrombosis are frequent in patients with severe nephrosis, including increased plasma viscosity, increased red cell aggregation, low plasminogen, and low anti-thrombin III.[164] Renal function is usually normal, although the serum creatinine may be slightly increased at the time of presentation. A minority of patients (usually older adults) has substantial acute renal failure as discussed earlier.
The loss of albumin into the urine is largely a function of a loss of charge-selective permselectivity. [151] [152] [165] [166] Consequently, the fractional excretion of albumin is proportionately greater than the fractional excretion of IgG. IgG levels, however, may be profoundly decreased—a factor that occurs most notably during episodes of relapse. This low level of immunoglobulin may result in susceptibility to infections. IgM levels may be elevated after a remission.[167] Mean serum IgA levels may be substantially elevated in patients with minimal change glomerulopathy compared to those with other renal disease 168 and are also elevated in association with relapse in children.[169]Among adult patients with minimal change glomerulopathy, over half have elevated levels of serum IgE and two thirds of patients have evidence of some allergic symptoms.[170] Elevation of IgE suggests a relationship between minimal change glomerulopathy and allergy. Complement levels are typically normal in patients with minimal change glomerulopathy.
Treatment
The general approach to treatment of patients with minimal change glomerulopathy has been to institute corticosteroid therapy. For children, the dose of prednisone is 60 mg/m2/day. For adults, the dose of prednisone is 1 mg/kg of body weight, not to exceed 80 mg/day. In children, this form of therapy results in a complete remission with disappearance of proteinuria in over 90% of patients within 4 to 6 weeks of therapy. A response to prednisone therapy has occurred if the patient has had no proteinuria by dipstick analysis for at least three days. It should be noted that the serum albumin and serum lipid levels might not return to normal for prolonged periods of time following resolution of proteinuria.[171]
Treatment is generally continued for 6 weeks after there is complete remission of proteinuria. During those 6 weeks, the dose should be changed to alternate-day prednisone or to a step-wise reduction in the daily dose of prednisone. If the dose is changed to alternate-day when remission has occurred, the dose may be decreased in children from 60 mg/m2/day to 40 mg/m2/day. [133] [172] [173] [174] [175] [176] In adult patients with minimal change glomerulopathy, a response to corticosteroid treatment may take up to 15 weeks.[157] In a study of 89 adult patients given prednisolone, 60% were in remission after 8 weeks, 76% after 16 weeks, and 81% over the course of the study. Of the 58 treated patients who responded, 24% never relapsed, 56% relapsed on a single occasion or infrequently, and only 21% were frequent relapsers. Of these 89 patients, only four remained nephrotic, and two of these presented with acute renal failure. Cyclophosphamide therapy was administered in 36 of the 89 patients, with 66% of these patients being in remission at 5 years.
One of the most controversial issues with respect to treatment pertains to the regimen for tapering the prednisone after the initial response. Sudden withdrawal of corticosteroids, or a rapid taper of prednisone immediately following complete remission, may prompt a relapse. Whether this is a consequence of adrenal insufficiency or depression of the pituitary adrenal access has been a matter of debate. [176] [177] [178] At least in children, likelihood of relapse is decreased with prolonged use of corticosteroids over a 10- to 12-week period. [174] [179] [180] Once remission has been obtained, an alternate-day schedule should begin within at least 4 weeks of the response in order to decrease the steroid-induced side effects.
In children who have not been biopsied prior to treatment, a renal biopsy is usually appropriate when there is failure to respond to a 4- to 6-week course of prednisone, particularly if there have been changes in the clinical course during this period of time, suggestive of another glomerular disease. Many pediatricians advocate a biopsy at the onset of the disease if there are clinical features suggesting a diagnosis other than minimal change glomerulopathy (e.g., hypertension, red blood cell casts in the urine, or hypocomplementemia), or if the nephrotic syndrome begins in the first year of life or after 6 years of age.
After the clinical response to initial treatment, as few as 25% have a long-term remission,[163] 25% to 30% have infrequent relapses (no more than one per year), and the remainder have frequent relapses, steroid-dependence or steroid-resistance ( Table 30-8 ). The treatment of frequently relapsing or steroid-dependent nephrotic patients requires additional forms of therapy. The treatment is aimed at minimizing the complications of corticosteroid therapy. In general, induction of a remission with prednisone therapy followed by the institution of cyclophosphamide results in higher urine flow rates and reduced risk of hemorrhagic cystitis. When cyclophosphamide has been used in doses of 2 mg/kg for 8 to 12 weeks, 75% of patients remain free of proteinuria for at least 2 years. [157] [181] [182] [183] The response to cyclophosphamide may be predicted from the response to corticosteroids. Patients who have had an immediate relapse after the cessation of corticosteroids will have a greater chance of relapsing immediately after the cessation of cyclophosphamide. Those who have had longer remissions after corticosteroid therapy will have a decreased risk of relapse after cyclophosphamide.[184] In those patients who are steroid-dependent, the response to cyclophosphamide has been improved by increasing the duration of therapy to up to 12 weeks.[181] In at least one other study, the 12-week course of cyclophosphamide has not been proven efficacious.[185]
TABLE 30-8 -- Patterns of Response of Minimal Change Glomerulopathy to Corticosteroid Treatment [156] [174] [175] [191]
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Primary responder, no relapse |
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Primary responder with only one relapse in the first 6 months after an initial response |
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Initial steroid response with two or more relapses within 6 months (frequent relapse) |
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Initial steroid-induced remission with relapses during tapering of corticosteroid, or within 2 weeks after their withdrawal (steroid dependent) |
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Steroid-induced remission, but no response to a subsequent relapse |
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No response to treatment (steroid resistant) |
Chlorambucil has many of the same toxicities as cyclophosphamide, and in children, may be associated with a higher incidence of malignancy. [186] [187] However, the use of chlorambucil at a dose of 0.1 mg/kg/day to 0.2 mg/kg/day in an 8-week course may produce more stable remission than cyclophosphamide, [188] [189] and has been reported to be effective even in some cyclophosphamide-resistant children.[190] Both cyclophosphamide and chlorambucil have profound side effects that include life-threatening infection, gonadal dysfunction, hemorrhagic cystitis, bone marrow suppression, and potential mutagenic event. The disadvantage of chlorambucil is the inherent higher risk of leukemia than with cyclophosphamide.[160]
In individuals who do not respond to an alkylating agent, yet have a predictable response to corticosteroid therapy, the challenge becomes how best to decrease the major complications associated with prolonged and repetitive bouts of corticosteroid therapy. In addition to the development of life-threatening infections, prolonged corticosteroid therapy may lead to osteoporosis, diabetes mellitus, and accelerated atherosclerosis. Many patients have profound mental status changes, especially emotional lability with intermittent corticosteroid treatment. Thus, in those patients not responding to alkylating therapy, the question is whether other forms of therapy are indicated. Notably, end-stage renal failure is an extremely unusual event in minimal change glomerulopathy. In light of these considerations, additional forms of therapy must be considered carefully with respect to the cumulative addition of other immunosuppressive drugs.
Steroid-Resistant Minimal Change Glomerulopathy
Approximately 5% of children with minimal change glomerulopathy appear to be steroid-resistant. In those patients who never had a renal biopsy, resistance to corticosteroid therapy is an indication for renal biopsy. Often, the renal biopsy evaluation will demonstrate focal segmental glomerulosclerosis or other forms of glomerular injury other than minimal change glomerulopathy.[191]
If the diagnosis remains minimal change glomerulopathy after renal biopsy evaluation, there may be several reasons for steroid resistance. Some patients, especially those for whom corticosteroid therapy is overly toxic, may skip doses or not fully comply with therapy. In other patients, especially some adults, alternate-day therapy may not provide sufficient amounts of corticosteroid to induce clinical remission. In very edematous patients, oral corticosteroid therapy may not be well absorbed, and a dose of intravenous methylprednisolone may provide a more reliable route of administration. Available data suggest that pulse methylprednisolone may induce remission in some corticosteroid-resistant children. In one study, five of eight corticosteroid-resistant children had a remission with pulse methylprednisolone,[192] although this experience is not universal.[193]
Cyclosporine can be administered at a dose of approximately 5 mg/kg. Up to 90% of patients may have either a partial or complete remission with cyclosporine. [169] [174] [194] [195] [196] Unfortunately, there are only rare patients who experience long-term remission once cyclosporine is discontinued.[175] Two trials examined the use of cyclosporine in steroid-resistant nephrosis. The French Society of Pediatric Nephrologyused cyclosporine with prednisone at a dose of 30 mg/m2/day for the first month, and then alternate-day prednisone for 5 months. Cyclosporine was administered at a dose of 150 to 200 mg/M2/day.[197] In this study, 48% of patients with minimal change glomerulopathy had complete remission, some within the first month of therapy. A minority of the responders became steroid-sensitive when they later relapsed. In a study by Ponticelli,[198] 13 of 45 patients had minimal change glomerulopathy and were treated with cyclosporine. In those patients with minimal change glomerulopathy, partial or complete remission occurred within 2 months of beginning therapy. Unfortunately, the early positive results of this study were associated with relapses in all patients after cyclosporine was stopped.
In a summary of nine studies,[199] only 20% of children had complete remission with cyclosporine, and many, if not most, relapsed with cessation of therapy. Moreover, cyclosporine and cyclophosphamide appear to have a similar degree of efficacy with respect to controlling the nephrotic syndrome, but cyclophosphamide-treated patients have a more stable long-term remission.[200] In this study, the likelihood of a long-term remission in patients treated with cyclophosphamide was 63%, and was only 25% in those treated with cyclosporine.
To counteract the usual relapse of nephrosis when cyclosporine has been used for 6 months, an alternative approach to cyclosporine treatment relies on a long-term course of this drug, using gradually lower doses in order to maintain the patient in remission. In one study,[201] patients in complete remission for more than 1 year on cyclosporine remained in remission if the cyclosporine was gradually tapered and then stopped. Repeat biopsies in patients treated for as long as 20 months showed no overt sign of nephrotoxicity.
Levamisole is an anti-helminthic drug that also has an immunostimulating role. [197] [202] A typical dose is 2.5 mg/kg of body weight given orally on alternate days or three times per week. In one study, 61 children were given a 3- to 4-month course of placebo or levamisole after remission of proteinuria was induced by corticosteroids. In that study, 14 of 31 patients using levamisole were able to discontinue steroid use and remain in remission, compared with only 4 of 30 control subjects.[202] Moreover, when levamisole was administered to patients after a steroid-induced remission, relapse was substantially decreased from 5.2 episodes to less than 0.7 episodes per year during 24 months of treatment.[203] The side effects of this drug, at least in children, include transient cytopenia in two thirds of patients. More profound complications have been reported in treatment with levamisole.[112] Levamisole is not currently available in the United States.
Focal Segmental Glomerulosclerosis
Focal segmental glomerulosclerosis (FSGS) is not a single disease but rather is a diagnostic term for a clinical-pathological syndrome that has multiple etiologies and pathogenic mechanisms. [204] [205] The ubiquitous clinical feature of the syndrome is proteinuria, which may be nephrotic or non-nephrotic, and the ubiquitous pathologic feature is focal segmental glomerular consolidation or scarring, which my have several distinctive patterns ( Fig. 30-5 ). These patterns can be classified as collapsing FSGS, tip lesion FSGS, cellular FSGS, perihilar FSGS and FSGS not otherwise specified (NOS). [204] [205] The collapsing variant of FSGS is a clinically aggressive variant that is much more common in African American than Caucasian populations, and is characterized pathologically by segmental collapse of capillaries accompanied by hypertrophy and hyperplasia of epithelial cells. The glomerular tip lesion variant of FSGS, which typically presents with marked nephrosis but often has a good outcome, is characterized by consolidation and sclerosis in the glomerular segment that is adjacent to the origin of the proximal tubule.[205] The term cellular FSGS has been used in a number of ways in the literature. For example, this term has been used to describe the collapsing variant and the tip lesion variant of FSGS. Thus care must be taken when reading the literature to determine if this term is being used as defined by D'Agati and colleagues or in some other way.[204] As defined by D'Agati, the cellular variant is relatively uncommon.[205] The perihilar variant of FSGS is characterized pathologically by sclerosis at the hilum of the glomerulus that typically contains foci of hyalinosis.[204] As shown in Table 30-9 , FSGS may appear to be a primary renal disease, or it may be associated with, and possibly caused by, a variety of other conditions. When FSGS is secondary to obesity or reduced numbers of nephrons, it often has a perihilar pattern and is accompanied by glomerular enlargement. FSGS that is associated with HIV infection has a collapsing pattern.
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FIGURE 30-5 Light micrographs and diagrams depicting patterns of focal segmental glomerulosclerosis. One pattern (A and D) has a predilection for sclerosis in the perihilar regions of the glomeruli. The glomerular tip lesion variant has segmental consolidation confined to the segment adjacent to the origin of the proximal tubule (B and E). The collapsing glomerulopathy variant has segmental collapse of capillaries with hypertrophy and hyperplasia of overlying epithelial cells (C and F). (Jones methenamine silver, ×100.) |
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TABLE 30-9 -- Focal Segmental Glomerulosclerosis
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Epidemiology
Over the past two decades, there has been an increased incidence of focal segmental glomerulosclerosis (FSGS). Whether this is a true increase in incidence or whether the condition has been better defined and more readily diagnosed by nephropathologists is debatable. Nonetheless, for the past 20 years, the yearly incidence of primary FSGS has risen from less than 10% to approximately 25% of adult nephropathies. [206] [207] [208] [209] [210] A substantial portion of this increase may be attributable to an increase in the collapsing glomerulopathy variant of FSGS [210] [211] and obesity.[212]
Moreover, there appears to be an emerging racial difference in the prevalence of FSGS in that there are progressively more African-American patients with FSGS than there are white patients. [209] [213] [214] The data in these studies are similar to the cases seen in the UNC Nephropathology Laboratory, which demonstrates that the proportional prevalence of typical FSGS and collapsing FSGS in African-American patients is substantially higher than in whites, although the glomerular tip lesion variant of FSGS has a predilection for whites (see Table 30-6 ).[214] Although the ratio of African Americans to whites is equivalent in FSGS, the proportion of African American patients in our biopsy population is approximately 30%. Thus, the relative incidence of FSGS is higher for African American than Caucasian patients.
Pathology
Light Microscopy
Focal segmental glomerulosclerosis is characterized by focal and segmental glomerular sclerosis. [204] [205] The sclerosis may begin as segmental consolidation caused by insudation of plasma proteins causing hyalinosis, by accumulation of foam cells, by swelling of epithelial cells, and by collapse of capillaries resulting in obliteration of capillary lumens. These events are accompanied by increase in collagenous matrix material that ultimately produces a genuinely sclerosis component to the lesion.
Focal segmental glomerulosclerosis is, by definition, a focal process and the limited number of glomeruli in a renal biopsy specimen may not include any of segmentally sclerotic glomeruli that are present in the kidney. In this instance, focal tubulointerstitial injury or glomerular enlargement, which often accompanies focal segmental glomerulosclerosis, can be used as surrogate markers. For example, focal segmental glomerulosclerosis should be considered in renal biopsy specimens of patients with the nephrotic syndrome when there is relatively well-circumscribed focal tubular atrophy and interstitial fibrosis with slight chronic inflammation, even when there are no light microscopic glomerular lesions, no immune deposits, and no ultrastructural changes other than foot process effacement. Diagnostic segmental sclerosis that is adequate for diagnosis may be present only in the tissue examined by immunofluorescence or electron microscopy.
The focal segmental glomerular scarring is not specific. Many injurious processes can cause focal glomerular scarring and must be ruled out before making a diagnosis of focal segmental glomerulosclerosis. For example, hereditary nephritis causes progressive glomerular scarring that can mimic focal segmental glomerulosclerosis. This is revealed by identification of the ultrastructural changes that are characteristic for hereditary nephritis. Focal segmental glomerulonephritis, for example caused by IgA nephropathy, lupus nephritis, anti-neutrophil cytoplasmic antibody-(ANCA) associated glomerulonephritis, can result in focal segmental glomerular scarring that is histologically indistinguishable from that caused by focal segmental glomerulosclerosis. Findings by immunofluorescence and electron microscopy, and by serology, can reveal a glomerulonephritic basis for focal glomerular scarring.
Based on the character and glomerular distribution of lesions, five major structural variants of focal segmental glomerulosclerosis can be recognized that correlate to a degree with the outcome (prognoses) and may be caused by different etiologies and pathogenic mechanisms. [204] [205] The five pathologic variants are collapsing FSGS, tip lesion FSGS, cellular FSGS, perihilar FSGS, and FSGS not otherwise specified (NOS). [204] [205]
The collapsing variant of FSGS has segmental to global collapse of capillaries with obliteration of lumens. The characteristic feature is focal segmental or global collapse of glomerular capillaries with obliteration of capillary lumens. Visceral epithelial cells overlying collapsed segments are usually enlarged and contain conspicuous resorption droplets. Hyperplasia of visceral epithelial cells raises the possibility of crescentic glomerulonephritis. The convention among most renal pathologists is not to refer to the epithelial hyperplasia of collapsing glomerulopathy as crescent formation. The degree of adhesion formation relative to the extent of glomerular sclerosis is much less in collapsing glomerulopathy than in typical focal segmental glomerulosclerosis. This may result in contracted (collapsed) tuft basement membranes and sclerotic matrix separated from Bowman capsule by hypertrophied and hyperplastic epithelial cells. The collapsing glomerulopathy variant of focal segmental glomerulosclerosis is the major pathologic expression of HIV nephropathy, [124] [215] [216] [217] and also occurs with intravenous drug abuse and as an idiopathic process. [210] [211] In renal transplants, this phenotype of FSGS occurs as both recurrent and de novo disease. [218] [219]
Relative to the extent of glomerular sclerosis, tubulointerstitial injury is more severe in collapsing glomerulopathy than in typical focal segmental glomerulosclerosis. Tubular epithelial cells have larger resorption droplets, extensive proteinaceous casts, and marked focal dilation of lumens (microcystic change). There also is more extensive interstitial infiltration by mononuclear leukocytes. Immunofluorescence microscopy findings are similar to those observed in typical focal segmental glomerulosclerosis except for the usual finding of larger resorption droplets in glomerular visceral epithelial cells and tubular epithelial cells. Electron microscopy reveals the same structural changes seen by light microscopy. In a specimen with the collapsing glomerulopathy variant of focal segmental glomerulosclerosis, the most important ultrastructural assessment is for the presence or absence of endothelial tubuloreticular inclusions. Endothelial tubuloreticular inclusions are identified in over 90% of patients with HIV infection and collapsing glomerulopathy, but in less than 10% of patients with idiopathic collapsing glomerulopathy or collapsing glomerulopathy associated with intravenous drug abuse. The only other settings in which endothelial tubuloreticular inclusions are numerous are in patients with systemic lupus erythematosus and in patients treated with alpha-interferon.
The tip lesion variant of FSGS has consolidation of segments contiguous with the proximal tubule. These lesions may be sclerotic or cellular. However, the increased cellularity is predominantly within the tuft unlike the extracapillary hypercellularity of collapsing FSGS. Foam cells often contribute to this endocapillary hypercellularity.
The glomerular tip lesion variant of FSGS was first described by Howie and is characterized by consolidation of the glomerular segment that is adjacent to the origin of the proximal tubule, and thus opposite the hilum ( Figs. 30-5B and 30-5E ). [220] [221] [222] [223] [224] [225] The initial consolidation usually has obliteration of capillary lumens by foam cells, swollen endothelial cells, and increase in collagenous matrix material (sclerosis). Hyalinosis is seen less often than with typical focal segmental glomerulosclerosis. Visceral epithelial cells adjacent to the consolidated segment are enlarged and contain clear vacuoles and hyaline droplets. These altered visceral epithelial cells often are contiguous to, if not attached to, adjacent parietal epithelial cells and tubular epithelial cells at the origin of the proximal tubule, which also have irregular enlargement and vacuolation. The tip lesion may project into the lumen of the proximal tubule. Some lesions are less cellular with a predominance of matrix and collagenous adhesions to Bowman capsule at the origin of the proximal tubule.
The cellular variant of FSGS as defined by D'Agati and colleagues has lesions that resemble the cellular lesion for the tip variant, but they are distributed throughout the glomerular tuft.[204] Perihilar FSGS is characterized by the perihilar predilection of lesions and the presence of hyalinosis. The NOS FSGS category is a nonspecific category that is used when the lesions do not have the distinctive features of any of the other four distinctive variants.
As will be discussed later, different pathologic variants of FSGS have distinctive clinical presentations and outcomes.
Immunofluorescence Microscopy
In all of the histologic variants, non-sclerotic glomeruli and segments usually have no staining for immunoglobulins or complement. As in patients with minimal change glomerulopathy, as well as individuals with no renal dysfunction, a minority of patients with focal segmental glomerulosclerosis will have low-level mesangial staining for IgM in non-sclerotic glomeruli. Low-level mesangial C3 staining is less frequent and low-level IgG and IgA is rare. The presence of substantial staining of non-sclerotic glomeruli for immunoglobulins, especially if immune complex-type electron dense deposits are present, points toward the sclerotic phase of a focal immune complex glomerulonephritis rather than focal segmental glomerulosclerosis.
Sclerotic segments typically have irregular staining for C3, C1q, and IgM ( Fig. 30-6 ). Other plasma constituents are less frequently identified in the sclerotic areas. Epithelial resorption droplets stain for plasma proteins.
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FIGURE 30-6 Immunofluorescence micrograph showing irregular segmental staining for C3 corresponding to a site of segmental sclerosis. (Fluorescein isothiocyanate [FITC] anti-C3, ×3000.) |
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Electron Microscopy
The ultrastructural features of focal segmental glomerulosclerosis are nonspecific. Electron microscopy plays an important role in the diagnosis of focal segmental glomerulosclerosis by helping to identify other causes for glomerular scarring that can be mistaken for focal segmental glomerulosclerosis by light microscopy alone.
Foot process effacement in focal segmental glomerulosclerosis affects sclerotic and non-sclerotic glomeruli, and usually is more focal than in minimal change glomerulopathy. Foot process effacement is less extensive in some forms of secondary FSGS than in idiopathic FSGS. Occasionally, glomerular capillaries have focal denudation of foot processes. Non-sclerotic glomeruli and segments should have no immune complex-type electron dense deposits. One must be careful not to confuse electron dense insudative lesions with immune complex deposits. These lesions equate with the hyalinosis seen by light microscopy and result from the accumulation of plasma proteins within sclerotic areas. Thus, if the electron dense material is present in sclerotic but not in non-sclerotic glomerular segments, it should not be considered to be evidence for immune complex mediated glomerular disease. On the other hand, well-defined mesangial or capillary wall electron dense deposits in non-sclerotic segments indicate immune complex-mediated glomerulonephritis with secondary scarring, which should be confirmed and further characterized by immunofluorescence microscopy.
Pathogenesis
The pathogenesis of FSGS remains poorly understood. The advanced segmental lesions are essentially segmental scars composed predominantly of collagen. The pathogenesis must involve an injurious factor (the etiology) that initiates a sequence of events that ultimately causes the segmental glomerular scarring. As with many patterns of glomerular injury, it is likely that multiple different etiologies can initiate shared pathogenic pathways that can ultimately result in segmental glomerular sclerosis. In addition, different sets of etiologic factors may initiate the different pathogenic pathways that lead to the different structural variants of FSGS.
Some of the same pathogenic events that cause segmental scarring secondary to focal glomerular injury caused by a proliferative or necrotizing glomerulonephritis are probably operative in producing the sclerosis of FSGS. In this regard, the overproduction of TGF-β1 in glomeruli due to acute inflammatory lesions may cause glomerular sclerosis.[226] In experimental models of glomerular inflammation, the administration of antibodies to TGF-β or other inhibitors to TGF-β results in a decrease in matrix accumulation and a reduction in the severity of glomerular scarring.[227] Whether these events occur in human disease is yet to be proven, although there is increased expression of TGF-β in many different types of renal disease, including FSGS.[228] Several mechanisms are associated with the fibrosis of renal disease. Extracellular matrix, and proteoglycans such as decorin and biglycan, may have a pathogenic role in fibrosing diseases by regulation of transforming growth factor beta.[229]
Focal segmental glomerulosclerosis also results from the loss of nephrons, which causes compensatory intraglomerular hypertension and hypertrophy in the remaining glomeruli. The compensatory glomerular hypertension results in both epithelial and endothelial cell injury, as well as mesangial alterations that lead to progressive focal and segmental sclerosis. [230] [231] [232] [233] [234] [235] [236] [237] This process, at least in experimental animals, is made worse by increased dietary protein intake and is ameliorated by both protein restriction and antihypertensive therapy. Several other abnormalities also may play a role in the pathogenesis of FSGS, including disorders of lipid metabolism, such as the urinary loss of lecithin-cholesterol acyltransferase, [238] [239] [240] [241] abnormalities of the coagulation pathway, and alterations in T cell function.[242] The role of growth factors in addition to TGF-β and platelet-derived growth factor certainly may participate in these lesions.
Whether the loss of nephron number leads to glomerular sclerosis in humans remains controversial. There are well-documented examples of patients who have had either congenital absence or surgical removal of a kidney prior to the development of FSGS.[243] As expected, patients with a greater loss of renal mass have a greater incidence of secondary FSGS. However, data from long-term studies of individuals donating a kidney for renal transplantation have not demonstrated an increased incidence of hematuria or proteinuria when compared to siblings. [244] [245] Long-term studies of men who have had a unilateral nephrectomy due to trauma indicate that there is only a small increase in mild proteinuria and systolic hypertension when compared to age-matched controls. [246] [247]
Glomerular enlargement accompanied by the development of FSGS occurs in the setting of hypoxemia, for example in patients with sickle cell anemia, congenital pulmonary disease, or cyanotic congenital heart disease. Obesity appears to predispose to FSGS. [248] [249] Weight loss and the administration of an ACE inhibitor decreased protein excretion by 80% to 85%.[250] Patients with sleep apnea may have proteinuria that is more functional in nature, but with little or no evidence of glomerular scarring or epithelial injury observed on biopsy. [251] [252] The association between sleep apnea and proteinuria is questioned by an analysis of 148 patients referred for polysomnography who were not diabetic and had not been treated previously for obstructive sleep apnea.[253] In this patient population, clinically significant proteinuria was uncommon, was associated with older age, hypertension, coronary artery disease, and arousal index by univariate analysis, and only with age and hypertension in multiple regression analysis. Body mass index and apnea hypopnea index were not associated with urine protein-creatinine ratio. The authors concluded that nephrotic-range proteinuria should not be ascribed to sleep apnea and deserves a thorough renal evaluation.
A permeability factor has been described in some patients with FSGS. In a seminal study, 33 patients with recurrent FSGS after transplantation had a higher mean permeability to albumin value than normal subjects.[254] After plasmapheresis, the permeability factor in six patients was reduced and proteinuria significantly decreased. This circulating factor bound to protein A and had an apparent molecular weight of about 50,000D. [255] [256] In a minority of patients with steroid-resistant FSGS in the native kidneys, plasmapheresis may diminish proteinuria and stabilize renal function. In most patients, however, there is no improvement in proteinuria despite loss of the permeability factor after plasmapheresis.[257] An exact description of this permeability factor in the pathogenesis of FSGS remains unknown despite attempts at elucidating its origin.
The past decade has witnessed an explosion of interest in the role of the podocyte in FSGS (see Chapter 39 ). Podocytes are highly differentiated postmitotic cells whose function is based on their architecture. Several proteins have now been detected on the podocyte, and their role in various diseases is becoming clear. Thus, in collapsing forms of focal sclerosis, podocytes undergo irreversible ultrastructural changes. This is in contrast to minimal change disease and membranous nephropathy where mature podocyte markers are retained at normal levels. In collapsing FSGS and HIV nephropathy, all of the podocyte markers disappear, suggesting a dysregulated podocyte phenotype in these diseases. [258] [259] [260] In fact, podocyte proliferation is seen in some examples of FSGS, which may be a consequence of the decrease in cyclin-dependent kinase inhibitors P27 and P57.[261] The effacement of foot processes may be a consequence of the overproduction of oxygen radicals and accumulation of lipid peroxidase.[262] In theory, the loss of visceral epithelial cells could result in focal areas of glomerular basement membrane denudation with diminished barrier function. The concept that podocyte dropout is a major factor in the development of glomerulosclerosis in general, and specifically in the development of collapsing FSGS, has been highly touted. [263] [264] [265] [266] In fact, collapsing FSGS is prototypical of the concept that podocytes become dysregulated and proliferate[267]; however, there have been challenges to the concept. In a mouse model of focal sclerosis, parietal epithelial and not visceral epithelial cells were involved in the proliferative event.[268] In a single patient, it was found that parietal epithelial cells, not the podocyte, were responsible for FSGS, including collapsing FSGS. Which cell(s) are to be the real culprit remains to be determined. It is well established that there are familial forms of FSGS.[269] In a study of 18 families with 45 biopsy-proven cases of FSGS, the disorder appeared to be transmitted in an autosomal dominant pattern. It was associated with HLA alleles, including HLA DR4, HLA-B12, HLA-DRW8, and HLA-DRW5.[270] Even nonfamilial FSGS is associated with specific HLA types. In children of Hispanic origin, FSGS has been linked to HLA DRW8, [271] [272] and B8 is associated with DR3 and DR7 in children of Germanic origin.[273] In adults, FSGS is found with an increased incidence of HLA DR4[274] and HLA BW53 in some patients with FSGS associated with heroin.[275]
Recent genetic case studies of familial FSGS have led to the identification of podocyte proteins and have highlighted the important role of podocyte proteins in the glomerular filtration barrier. For instance, positional cloning has led to the identification of a gene that encodes a podocyte actin-binding protein called α-actin 4 as the cause of autosomal-dominant FSGS.[276] The same strategy has been used to clone two other genes, NPHS1 (encoding the protein nephrin) and NPHS2 (encoding the protein podocin). Mutations in the nephrin gene are responsible for autosomal-recessive congenital nephrotic syndrome of the Finnish type.[277] Earlier familial studies on mutations in NPHS2 described the early childhood onset of proteinuria, rapid progression to end-stage renal disease, and no recurrence after renal transplantation.[278] Further studies have shown that mutations in NPHS2 resulting in familial autosomal recessive FSGS are due to nonsense, missense, frame shift, or premature stop codons.[279] The frequency of podocin mutation varies depending on the population studied. [280] [281] [282] Mutations in podocin are found in familial autosomal recessive FSGS in European children and adolescents with steroid-resistant nephrotic syndrome. One study suggested that children with familial or sporadic FSGS had NPHS2 mutations in 21% of 152 patients. In another study of 338 patients with autosomal-recessive or sporadic steroid-resistant nephrotic syndrome, a number of NPHS2 mutations were found, including 43% in the familial autosomal-recessive group and 10% in the sporadic group. Mutations in α-actinin-4 (ACTN-4) have been described in patients with autosomal-dominant FSGS as well. There are now a total of 5 ACTN-4 genes believed to cause disease 6,[283] and may account for about 4% of familial FSGS. A cautionary note must be made in that most studies of genetic mutations in FSGS have been examined in children. In an adult study[284] of patients with FSGS from 33 sporadic cases in Italy, disease-associated podocin mutation was present but there were no disease-causative ACTN4 genes. Interestingly, the genotype does not necessarily correlate with the phenotype. Some patients appear to be steroid-sensitive, others steroid-resistant, and yet others sensitive to cyclosporine therapy.[285] Two very interesting studies describe the TRPC6 cation channel family in FSGS. In one study,[286] a large family with hereditary FSGS with a missense mutation to the TRPC6 gene caused mutation from an amino acid from proline to glutamine, which enhanced the TRPC6 calcium signal in response to a number of stimuli. Another study[287] found TRPC6 abnormalities in patients with FSGS in 5 families with autosomal-dominant FSGS. How this calcium channel regulates podocyte structure and function remains to be fully elucidated, but it is possible that TRPC6 channel activity in the slit diaphragm is important for podocyte structure. There are a number of other mutations that may be associated with FSGS, including genes for proteins, such as WT-1.[6]
A number of infections cause FSGS. HIV-associated FSGS is pathologically identical to idiopathic collapsing FSGS, except for the presence of endothelial tubuloreticular inclusions in the former but not the latter. This close association of HIV infection with collapsing FSGS, as well as experimental evidence of focal glomerular sclerosis in mice transgenic for HIV type I genes, [209] [215] [226] [228] [243] [288] [289] [290] raise the possibility that the HIV virus can be an etiologic agent of FSGS. Whether other viral diseases, including parvovirus B19, cause the idiopathic collapsing variant of FSGS remains to be elucidated. [291] [292] Parvovirus B19 has been found with greater frequency in patients with idiopathic and collapsing FSGS compared with patients with other diagnoses.[292] The polyomavirus SV40 may also play a role.[293] Focal sclerosis is associated with a number of malignant conditions that have been associated with lymphoproliferative disease. In a recent study,[294] there was an association of FSGS in monoclonal gammopathies of undetermined significance (MGUS) that responded in MGUS or multiple myeloma. When the lymphoproliferative disease was treated, the renal lesion improved.
Clinical Features and Natural History
In all forms of primary FSGS, proteinuria of varying degrees is the hallmark feature. The degree of proteinuria varies from non-nephrotic (1 to 2 grams) to massive proteinuria (over 10 grams) associated with all of the morbid features of the nephrotic syndrome. Hematuria occurs in over half of FSGS patients and approximately one third of patients present with some degree of renal insufficiency. Gross hematuria is more commonly seen in FSGS than in minimal change glomerulopathy.[295] Hypertension is found as a presenting feature in one third of patients. There are differences in the presentation of FSGS in adults and children. [206] [296] [297] [298] Children tend to present with more proteinuria, while hypertension is more common in adults.
Differences in clinical manifestations correlate with different pathologic phenotypes of FSGS.[214] For example, patients with perihilar FSGS accompanied by glomerular hypertrophy more commonly have non-nephrotic-range proteinuria than FSGS patients who do not have glomerular hypertrophy. Additionally there are differences in the clinical presentation of the collapsing variant of FSGS and the glomerular tip lesion variant of FSGS. For example, the collapsing variant often has more severe proteinuria and renal insufficiency but less hypertension than the typical variant, and the glomerular tip lesion variant often presents with rapid onset of edema similar to minimal change glomerulopathy.
Weiss[299] first reported six patients with a collapsing variant of FSGS, and larger series of such patients have subsequently been studied. [210] [211] Patients with collapsing FSGS have substantially more proteinuria, a lower serum albumin, and higher serum creatinine than patients with either perihilar FSGS. The development of proteinuria, edema, or hypoalbuminemia may occur rapidly over the course of days to weeks, in contrast to the more insidious development of proteinuria in most patients with typical FSGS. Moreover, patients with collapsing FSGS more frequently have extrarenal manifestations of disease a few weeks prior to onset of the nephrosis, such as episodes of diarrhea, upper respiratory tract infections, or pneumonic-like symptoms that are usually ascribed to viral or other infectious process. However, the systemic symptoms of fever, malaise, and anorexia occur in less than 20% of patients at the time of onset of nephrosis.
Pamidronate, a bisphosphonate that prevents bone disease in myeloma and metastatic tumors, has been reported to be associated with collapsing FSGS in a number of series. [268] [300] With discontinuation of the drug, kidney function stabilized in all patients except those with collapsing FSGS.
The clinical presentation of glomerular tip lesion differs from that of both perihilar FSGS and the collapsing FSGS.[214] Patients with glomerular tip lesion tend to be older white males, in sharp contrast to the younger black male prevalence in collapsing FSGS. The proteinuria in these patients usually is severe and the onset is abrupt with sudden development of edema and hypoalbuminemia. The rapidity of onset of the disease process is similar to the clinical presentation of minimal change glomerulopathy. [223] [301] [302] Glomerular tip lesion patients may develop reversible acute renal failure, especially at the time of initial presentation when the degree of proteinuria, edema, and hypoalbuminemia are at their peak. This also is similar to minimal change glomerulopathy but rarely occurs with other variants of FSGS.
It is difficult to ascribe a survival by year for the aggregate group of patients with FSGS. In general, patients with perihilar FSGS have a better long-term outcome than those with collapsing FSGS. Because a greater number of patients with glomerular tip lesion respond to corticosteroid therapy, the long-term outcome for patients with this histological variant may be better than that for patients with typical FSGS.[214] Some authorities do not believe there is an association between the pathological variants of FSGS and the long-term course.[303]
The degree of proteinuria is a predictor for the long-term clinical outcome. Non-nephrotic-range proteinuria correlates with a more favorable renal survival of over 80% after 10 years of follow-up. [304] [305] In contrast, patients who have more than 10 grams of proteinuria per day have a very poor long-term renal survival with the majority of patients reaching end-stage renal disease within 3 years. [306] [307] This rapid decline in renal function has been termed “malignant FSGS” due to the morbid nature of the nephrosis and the rapidity of the deterioration in renal function.[305] Patients with FSGS and protein excretion that measures between non-nephrotic range and massive proteinuria have a variable long-term renal outcome. In general, these have a relatively poor outcome, with half of these patients reaching end-stage renal disease by 10 years. [206] [298] [308]
One of the most useful prognostic indicators for patients with FSGS is whether they attain a remission of their nephrotic syndrome.[297] Patients who have a remission of nephrosis have a substantially greater renal survival than those who do not. [297] [304] [305] [309] [310] According to Korbet, [206] [298] less than 15% of patients with complete or partial remission progress to end-stage renal disease within 5 years of follow-up. Up to 50% of patients not attaining remission progress to end-stage disease within 6 years of follow-up.
As in other forms of glomerular injury, entry serum creatinine is associated with a poor long-term renal survival. [304] [306] [311] [312] Patients with a serum creatinine of over 1.3 mg/dL have a poorer renal survival than those with lower serum creatinine, irrespective of the level of proteinuria (10-year renal survival of 27% versus 100%).[206] Entry serum creatinine by multivariate analysis may be more important than proteinuria as a predictor of progression to end-stage renal disease. [304] [305] [307] [308] [311] [312]
Controversy abounds regarding whether there is a poorer long-term prognosis in black patients compared to white patients. In children, Inguli and Tejani noted that within 8.5 years of follow-up, 78% of black patients but only 33% of white patients progressed to end-stage renal disease. [312] [322] The racial predilection for poor long-term prognosis has not been corroborated in adult patients with nephrosis. [304] [305]
Some pathological discriminators correlate with long-term clinical outcome. Neither the degree of scarring within the glomerulus nor the number of glomeruli that are totally obsolescent is predictive of long-term renal outcome. [301] [303] [312] [313] As in most forms of glomerular disease, interstitial fibrosis and tubular atrophy correlate with poor prognosis. Substantial controversy has surrounded the prognostic value of discriminating between different types of focal segmental glomerulosclerosis. Most investigators agree that there is a much more rapid deterioration in renal function with collapsing FSGS than typical FSGS. [207] [210] [314]
Another controversial issue is the prognostic significance of the location of the sclerosis within the glomerular tuft. The original descriptions of the glomerular tip lesion by Howie [222] [223] [224] suggested that this variant of FSGS has a better response to corticosteroid therapy and a more benign clinical course than typical FSGS. Other investigations have not confirmed an improved long-term renal survival with glomerular tip lesion. These latter studies, however, included very few patients with glomerular tip lesions in the cohort of patients who were studied. [225] [301] [303] Thomas and colleagues observed that tip lesion FSGS had a higher rate of remission and a better 3-year renal survival that other pathologic variants of FSGS.[205]
The prognostic significance of mesangial hypercellularity associated with FSGS also is controversial. Some studies have identified a correlation between mesangial hypercellularity and poor outcomes, such as poor response to steroids, [315] [316] more frequent relapses, and more progression of renal insufficiency.[317] However, other studies have not confirmed the more rapid loss of renal function. [225] [301] [303]
Laboratory Findings
Hypoproteinemia is common in patients with FSGS, with total serum protein reduced to varying extents. The serum albumin concentration may fall to below 2 g/dL, especially in patients with the collapsing and glomerular tip variants of FSGS. As in other forms of the nephrotic syndrome, levels of immunoglobulins are typically depressed; and levels of lipids are increased, especially serum cholesterol. Serum complement components are generally in normal range in FSGS. Circulating immune complexes have been detected in patients with FSGS, [154] [318] although their pathogenic significance has not been determined. Serologic testing for HIV infection should be obtained for patients with FSGS, especially those with the collapsing pattern.
Treatment
Other than the study by the ISKD, there have been no prospective randomized treatment trials for focal segmental glomerulosclerosis. Thus, available data are based entirely on anecdotal series using different treatment protocols, different definitions of remission, response, relapse, and resistance, and different lengths of therapy. [297] [304] [309] [319] One review of studies suggested that only 15% of patients with FSGS responded to treatment, in sharp contrast to those with minimal change glomerulopathy.[320] More optimistic reports have been obtained by groups in Toronto and Chicago [297] [298] that suggest that 30% to 40% of adult patients may attain some form of remission with corticosteroid treatment. A compilation of these studies by Korbet and co-workers[206] suggests that of 177 patients who received a variety of different forms of therapy, 45% attained complete remission, 10% attained partial remission, and 45% had no response. [297] [304] [309] [319] [321]
In children, the initial treatment of focal segmental glomerulosclerosis is similar to that of minimal change glomerulopathy, because so many pediatricians treat patients without having histological confirmation of the disease process. Thus, the International Study of Kidney Diseases in Children recommended using an initial course of prednisone of 60 mg/day/M2, up to 80 mg/day for 4 weeks. This should be followed with 40 mg/day/M2, up to 60 mg/day, administered in divided doses for 3 consecutive days of 7, for 4 weeks, and then tapered off for 4 more weeks. Similar to the adult patients with minimal change glomerulopathy, a longer course of therapy at higher doses of prednisone may be necessary to induce remission. Thus, in those series where there is an increased remission rate, [198] [297] [304] [309] [319] [322] [323] prednisone treatment was continued for 16 weeks in order to achieve remission. In adult patients, median time for complete remission was 3 to 4 months.[201]
Among patients with a positive response to corticosteroid treatment, a portion will relapse. Guidelines for re-treatment of this group of patients are similar to those of relapsing minimal change glomerulopathy. In patients whose remission prior to relapse was prolonged (over 6 months), a repeat course of corticosteroid therapy may again induce a remission. In steroid-dependent patients who develop frequent relapses, repeated high-dose corticosteroid therapy results in unacceptable cumulative toxicity. Thus, alternative strategies such as the addition of cyclophosphamide or cyclosporine may be useful. In some individuals, reestablishment of remission may result when cyclophosphamide is administered for 8 to 12 weeks at a dose of 2 mg/kg/day.[298] In patients with the glomerular tip lesion variant of FSGS, a trial of corticosteroids is appropriate because many patients have a decline in protein excretion. [221] [302] [303]
The practice of using higher doses of corticosteroids in order to reach remission has resulted in alternative therapeutic approaches in patients who are resistant to oral prednisone. In these forms of therapy, prednisone-resistant FSGS has been treated with methylprednisolone boluses of 30 mg/kg/day to a maximum of 1 gram given every other day for 6 doses, followed by this same dose on a weekly basis for 10 weeks; subsequently, similar doses are given on a tapering schedule. In addition to these large doses of methylprednisolone, oral prednisone is given. [324] [325] Some patients are also given alkylating agents. With this treatment protocol, 12 of 23 children entered remission, and six had decreased urinary protein losses.
These very high doses of corticosteroids in children, and the duration of daily prednisone for up to 6 to 9 months in adults is not without enormous short- and long-term side effects. In studies in which long-term, high-dose corticosteroids are administered, few analyses have been undertaken of the development of osteoporosis, short- and long-term risk of infection, and the development of cataract, diabetes, or other long-term sequelae. Thus, the available data do not allow for careful understanding of risk-benefit ratios. Until the use of very large dose of Solu-Medrol is subject to controlled clinical trials, the utility of this potential yet dangerous approach must be viewed with caution. There are some authorities who feel that most treatment of FSGS with corticosteroids is hazardous.[326]
Attempts at alternate-day steroid therapy have not been successful except in elderly populations. The Toronto group[327] demonstrated that patients over the age of 60 achieved a 40% remission rate using up to 100 mg of prednisone on alternate days for 3 to 5 months. This therapy was well tolerated in this population without obvious side effects during the study period. Alternate-day prednisone most likely works in this population because of an increased susceptibility to the immunosuppressive effects of corticosteroids and altered glucocorticoid kinetics in the elderly.
Alternatives to Corticosteroid Therapy
Several studies have failed to document the effectiveness of cytotoxic drugs in the treatment of FSGS. [309] [328] In one review, only 23% of 247 children with FSGS were steroid-responsive, and 70 patients were treated with cytotoxic drugs. Of these, 30% responded. In the final analysis, less than 20% of the 247 children were in remission. The use of cytotoxic drugs has been evaluated in only one series of adults.[309] Although their use correlated with longer remissions and fewer relapses, no other study has corroborated these results.
The International Study of Kidney Diseases in Children carefully examined the role of cyclophosphamide in the treatment of children with FSGS. For 3 months, cyclophosphamide was used in combination with a 12-month course of every-other-day prednisone therapy. When this regimen was compared to prednisone alone, there was no improvement in response between patients treated with cyclophosphamide compared to those receiving prednisone alone.[329]
Patients resistant to prednisone may be induced into remission with cyclosporine. A randomized trial demonstrates the utility of cyclosporine in patients with steroid resistance, resulting in remission in the majority of patients.[330]This study compared 46 cyclosporine-treated steroid-resistant FSGS patients to 45 control patients. Of the 46 patients, nine achieved complete remission whereas none of the controls did. Partial remissions were observed in 40% to 70% of the cyclosporine-treated patients, and in 17% to 33% of the control patients. These results are statistically significant when both complete and partial remissions are considered. Withdrawal of treatment results in relapse in over 75% of patients.[320]
How long should patients be treated with cyclosporine? In a study by Meyrier,[201] when patients remained in remis-sion for over 12 months, cyclosporine was slowly tapered and eventually removed without subsequent relapse.[201]Unfortunately, long-term treatment with cyclosporine was associated with increases in tubular atrophy and interstitial fibrosis.[201] The degree of tubulointerstitial disease was positively correlated with the initial serum creatinine, the number of segmental scars on initial biopsy, and on a cyclosporine dose of more than 5.5 mg/kg/day. Thus, there is a clear trade-off in the use of cyclosporine over the long term in the well-established development of interstitial fibrosis and tubular atrophy.
Angiotensin-converting enzyme (ACE) inhibitors angiotensin receptor blockers (ARB) have been evaluated in the treatment of FSGS. ACE inhibitors have been shown to decrease proteinuria and the rate of progression to end-stage renal disease. [331] [332] [333] [334] These results have been obtained not only in the presence of diabetes, but also in cases of non-diabetic renal disease. In patients with sickle cell disease, glomerulomegaly, and FSGS, ACE inhibitors decreased proteinuria acutely while maintaining glomerular filtration rate and renal plasma flow.[335] In general, these studies suggest that angiotensin-converting enzyme inhibitors, and perhaps angiotensin II receptor antagonists would provide a substantial ameliorative effect in nephrotic symptoms of FSGS. In fact, in patients with glomerulomegaly and resultant non-nephrotic-range proteinuria, an ACE inhibitor or angiotensin II receptor antagonist sufficiently decreases proteinuria and potentially decreases hyperlipidemia, edema, and other manifestations of persistent loss of protein in the urine in this population with excellent long-term prognosis. Regardless of other forms of anti-inflammatory or immunosuppressive therapy employed, the beneficial effects of these agents indicates that they should be added, despite the well-known side effects of hyperkalemia and reduction in glomerular filtration rate, especially in patients with serum creatinines of over 3 mg/dL.
Other forms of treatment have been used. Plasmapheresis or protein absorption strategies to remove circulating factors responsible for FSGS have led to remission of recurrent FSGS, but it does not appear to be beneficial in the primary disease. [257] [336] Anecdotal cases suggest that mycophenolate mofetil may be useful in some patients as well.
In summary, patients with primary FSGS remain frustrating patients to treat. Enthusiasm for the use of high-dose, prolonged corticosteroid therapy in adults and children has prompted the use of this therapy in many FSGS patients. Only a prospective randomized trial that carefully evaluates this approach will determine its precise effectiveness. In patients who have protein excretion of less than 3 grams/day or with glomerulomegaly found on biopsy (or both), a trial of angiotensin converting enzyme inhibitors or angiotensin II receptor antagonist is warranted. In those patients who have nephrotic-range proteinuria, careful supportive care and consideration of a trial of oral corticosteroids in adult patients may be an acceptable approach after the patient is carefully informed about the risks and potential benefits of 12 to 16 weeks of daily corticosteroid therapy. Alternating a trial of cyclosporine may be warranted at a dose of 5 mg/kg/day for less than 12 months. In all of these patients, an angiotensin converting enzyme inhibitor may provide a substantial reduction in proteinuria and a potential long-term benefit that may be equal to or greater than that of the immunosuppressive therapy.
C1q Nephropathy
C1q nephropathy is a relatively rare cause for proteinuria and nephrotic syndrome that can mimic FSGS clinically and histologically. [337] [338] The diagnosis is based on the presence of mesangial immune complex deposits that have conspicuous staining for C1q. The C1q staining usually is accompanied by staining for IgG, IgM, and C3. Electron microscopy demonstrates well-defined mesangial immune complex type dense deposits. Light microscopic findings vary from no lesion (mimicking minimal change glomerulopathy), to focal glomerular hypercellularity, to focal segmental sclerosing lesions that may be indistinguishable histologically from FSGS. The findings by immunofluorescence microscopy and electron microscopy, however, readily differentiate C1q nephropathy from minimal change glomerulopathy and FSGS. The pathologic features suggest an immune complex pathogenesis, but the details of the pathogenic mechanism and the etiology are unknown.
Patients with C1q nephropathy are predominantly black and male, with a black to white ratio of 4.7:1 and a male to female ratio of 1.8:1. Patients are usually between the ages of 15 and 30 when diagnosed, and all of them have proteinuria. Almost half have edema, 40% have hypertension, and 30% have hematuria. Interestingly, many patients are relatively asymptomatic, and proteinuria is first detected at the time of a “sports physical” or induction into the armed forces. These patients, by definition, have no clinical or serological evidence of systemic lupus erythematosus, despite the presence of C1q in the renal biopsy. C1q nephropathy may have a spontaneous improvement.[339]
Ninety percent of C1q nephropathy patients followed by the Glomerular Disease Collaborative Network continue to have proteinuria at 2.5 years of follow-up. Whether corticosteroids have a role in the treatment of patients with this disease process is not certain. Life table analysis demonstrates that renal survival at 3 years is 84%, and treatment with corticosteroids had no statistical improvement in proteinuria or preservation of renal function. Yet, there are reports of some patients who have had complete remission with corticosteroids.[340]
Membranous Glomerulopathy
Epidemiology
Idiopathic membranous glomerulopathy is the most common cause for nephrotic syndrome in adults. [211] [221] [222] [223] [224] [225] [230] [231] [232] [233] [234] [235] [236] [237] [239] [240] [241] [242] [256] [295] [297] [299] [302] [305] [306] [309] [324] [341] [342] [343] [344] [345] [346] [347] [348] [349] [350] [351] [352] [353] [354] [355] [356] [357] [358] [359] [360] [361] [362] [363] [364] [365] [366] [367] [368] [369] [370] [371] [372] [373] [374] [375] [376] [377] [378] [379] [380] [381] [382] [383] [384] [385] [386] [387] [388] [389] [390] [391] Membranous glomerulopathy occurs as an idiopathic (primary) or secondary disease. Secondary membranous glomerulopathy is caused by autoimmune diseases (e.g., lupus erythematosus, autoimmune thyroiditis), infection (e.g., hepatitis B, hepatitis C), drugs (e.g., penicillamine, gold), and malignancies (e.g., colon cancer, lung cancer). Secondary membranous glomerulopathy, especially that caused by hepatitis B [380] [381] [392] [393] [394] [395] [396] [397] and lupus, is more frequent in children than adults. In patients over the age of 60, membranous glomerulopathy is associated with a malignancy in from 20% to 30% of patients.[375]
Membranous glomerulopathy is the cause for nephrotic syndrome in approximately 25% of adults. [398] [399] [400] [401] [402] [403] [404] [405] [406] [407] A study of patients with more than 1 gram of proteinuria in the United Kingdom by the Medical Research Council from 1978 to 1990 determined that 20% had membranous glomerulopathy. Membranous glomerulopathy is uncommon in children. The peak incidence of membranous glomerulopathy is in the fourth or fifth decade of life. [401] [408] [409] [410] [411] [412] Membranous glomerulopathy is most common in middle-aged males. In a pooled analysis of patients with idiopathic membranous glomerulopathy derived from articles in North America, Europe, Australia, Asia, and Japan, there was a 2:1 predominance of males (1190 males and 598). [400] [401] [402] [403] [406] [409] [410] [411] [413] [414] [415] [416] [417] [418] [419] [420] [421] [422] [423] [424] [425] [426] [427] [428] [429] [430] [431] [432] [433] The adult-to-child ratio was 26:1 (1734 adults and 67 children), however, this low incidence of membranous glomerulopathy in children was biased by the exclusion of children from some of the studies that were pooled. Membranous glomerulopathy affects all races.
Although most patients with membranous glomerulopathy present with the nephrotic syndrome, there may be 10% to 20% of patients who have proteinuria that remains less than 2 g/day.[434] Thus, it is likely that the frequency of membranous glomerulopathy in the general population is underestimated because of individuals who have membranous glomerulopathy that is causing subclinical proteinuria that never prompts renal biopsy.
There are geographic variations in the clinical manifestations of membranous glomerulopathy. Patients in studies from Australia or Japan have lower percentages of the nephrotic syndrome at entry when compared to patients from Europe or North America. The geographic differences may be caused by different frequencies and causes of secondary membranous glomerulopathy in different geographical locations, such as different frequencies of membranous glomerulopathy caused by hepatitis B, malaria, and other infections. [381] [395]
Pathology
Electron Microscopy
The pathologic sine qua non of membranous glomerulopathy is the presence of subepithelial immune complex deposits, or their structural consequences.[435] Electron microscopy provides the most definitive diagnosis of membranous glomerulopathy, although a relatively confident diagnosis can be made based on typical light microscopic and immunofluorescence microscopic findings.
Figure 30-7 depicts the four ultrastructural stages of membranous glomerulopathy as described by Ehrenreich and Churg.[436] The earliest ultrastructural manifestation, stage I, is the presence of scattered or more regularly distributed small immune complex-type electron dense deposits in the subepithelial zone between the basement membrane and the epithelial cell. Epithelial foot process effacement and microvillous transformation occur in all stages of membranous glomerulopathy when there is substantial proteinuria. Stage II is characterized by projections of basement membrane material around the subepithelial deposits. In three dimensions, these projections surround the sides of the deposits, but when observed in cross sections, they appear as spikes extending between the deposits (Figs. 30-7 and 30-8 [7] [8]). In stage III, the new basement membrane material surrounds the deposits and thus in cross-sections there is basement membrane material between the deposits and the epithelial cytoplasm. At this point the deposits are in essence intramembranous rather than subepithelial; however, the ultrastructural appearance allows the inference that they once were subepithelial and thus indicative of membranous glomerulopathy. Stage IV is characterized by loss of the electron density of the deposits, often resulting in irregular electron lucent zones within an irregularly thickened basement membrane. Although not described by Ehrenreich and Churg, some nephropathologists recognize stage V, which is characterized by a repaired outer basement membrane zone with the only residual basement membrane disturbance in the inner aspect of the basement membrane. At the time of renal biopsy, most patients in the United States have stage I or II disease ( Table 30-10 ).
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FIGURE 30-7 Diagram depicting the four ultrastructural stages of membranous glomerulopathy. Stage I has subepithelial dense deposits (arrow) without adjacent basement membrane reaction. Stage II has projections of basement membrane adjacent to deposits. Stage III has deposits surrounded by basement membrane. Stage IV has thickened basement membrane with irregular lucent zones. (Reproduced with permission of J.C. Jennette.) |
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FIGURE 30-8 Electron micrograph of stage II membranous glomerulopathy with numerous subepithelial dense deposits (straight arrows) and adjacent projections of basement membrane material (curved arrows) (magnification ×100). |
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TABLE 30-10 -- Pathologic Features of 350 Consecutive Non-Lupus Membranous Glomerulopathy Renal Biopsy Specimens Evaluated by the UNC Nephropathology Laboratory
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% Positive and Mean Intensity when Positive |
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Immunofluorescence microscopy |
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IgG |
99% (3.5+) |
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IgM |
95% (1.2+) |
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IgA |
84% (1.1+) |
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C3 |
97% (1.6+) |
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C1q |
34% (1.1+) |
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Kappa |
98% (3.1+) |
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Lambda |
98% (2.8+) |
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Electron microscopy |
% with |
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Subepithelial electron dense deposits |
99% |
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Mesangial electron dense deposits |
16% |
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Subendothelial electron dense deposits |
7% |
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Endothelial tubuloreticular inclusions |
3% |
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Stage I |
38% |
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Stage II |
32% |
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Stage III |
6% |
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Stage IV |
5% |
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Stage V |
1% |
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Mixed stage |
20% |
Mesangial dense deposits are rare in idiopathic membranous glomerulopathy but are frequent in secondary membranous glomerulopathy (see Table 30-10 ). This suggests, but does not prove, that idiopathic membranous glomerulopathy is caused by subepithelial in situ immune complex formation with antibodies from the circulation complexing with antigens derived from the capillary wall. Immune complexes formed only at this site could not go against the direction of filtration to reach the mesangium. Secondary forms of membranous glomerulopathy usually are caused by immune complexes that contain antigens that are in the circulation, such as antigens derived from infections (e.g., hepatitis B), tumor antigens (e.g., colon cancer), or autoantigens (e.g., thyroglobulin). With both the antigens and antibodies in the systemic circulation, it is likely that some immune complexes wold form that would localize not only in the subepithelial zone but also in the mesangium or subendothelial zone. This is demonstrated in the secondary form of membranous glomerulopathy that occurs in patients with systemic lupus erythematosus. Over 90% of lupus membranous glomerulopathy specimens have mesangial dense deposits identified by electron microscopy.[437] Therefore, the presence of mesangial dense deposits should raise the index of suspicion for secondary rather than primary membranous glomerulopathy.
Immunofluorescence Microscopy
The characteristic immunofluorescence microscopy finding in membranous glomerulopathy is diffuse global granular capillary wall staining for immunoglobulin and complement ( Fig. 30-9 ).[435] IgG is the most frequent and usually the most intensely staining immunoglobulin, although less staining for IgA and IgM is common (see Table 30-10 ). C3 staining is present over 95% of the time but typically is relatively low intensity. C1q staining is uncommon and of low intensity in idiopathic membranous glomerulopathy but is frequent and of high intensity in lupus membranous glomerulopathy.[437] Although not usually evaluated in routine diagnostic preparations, there is very intense staining of capillary walls for terminal complement components (i.e., components of the membrane attack complex). In the rare patients who have concurrent anti-GBM glomerulonephritis and membranous glomerulopathy, linear staining for IgG can be discerned just below the granular staining.[438]
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FIGURE 30-9 Immunofluorescence micrograph showing global granular capillary wall staining for IgG in a glomerulus with membranous glomerulopathy. (FITC anti-IgG, ×300.) |
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Tubular basement membrane staining for immunoglobulins or complement is rare in idiopathic membranous glomerulopathy, but is common in secondary membranous glomerulopathy, especially lupus membranous glomerulopathy.[437]
Light Microscopy
The characteristic histologic abnormality is diffuse global capillary wall thickening in the absence of significant glomerular hypercellularity.[439] The light microscopic features of membranous glomerulopathy, however, vary with the stage of the disease and with the degree of secondary chronic sclerosing glomerular and tubulointerstitial injury. Mild stage I lesions may not be discernible by light microscopy, especially using only a hematoxylin and eosin stain. Stage II, III, and IV lesions usually have readily discernible thickening of capillary walls.
Masson trichrome stains may demonstrate the subepithelial immune complex deposits as tiny fuchsinophilic (red) grains along the outer aspect of the glomerular basement membranes. However, this is not a sensitive, specific, or technically reliable method for detecting glomerular immune complex deposits. Special stains that accentuate basement membrane material, such as the Jones' silver methenamine stain, may reveal the basement membrane changes that are induced by the subepithelial immune deposits. Spikes along the outer aspect of the glomerular basement membrane usually are seen in stage II lesions ( Fig. 30-10 ). Stage III and IV lesions have irregularly thickened and trabeculated basement membranes, which resemble changes that occur with membranoproliferative glomerulonephritis and chronic thrombotic microangiopathy.
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FIGURE 30-10 Light micrograph of a glomerulus with stage II membranous glomerulopathy demonstrating spikes along the outer aspects of the glomerular basement membrane (cf. Fig. 30-2 ). These correspond to the projections of basement membrane material between the immune deposits. (Jones methenamine silver, ×300.) |
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Overt mesangial hypercellularity is uncommon in idiopathic membranous glomerulopathy, although it is more frequent in secondary membranous glomerulopathy.[437] Crescent formation is rare unless there is concurrent anti-GBM disease or ANCA-disease. [440] [441] [442] [443] [444] [445] [446]
With disease progression, chronic sclerosing glomerular and tubulointerstitial lesions develop. Glomeruli become segmentally and globally sclerotic, and develop adhesions to Bowman capsule. Worsening tubular atrophy, interstitial fibrosis, and interstitial infiltration by mononuclear leukocyte parallels progressive loss of renal function.[447]
Pathogenesis
Membranous glomerulopathy is caused by immune com-plex localization in the subepithelial zone of glomerular capillaries. The pathogenetic mechanisms that lead to this immune complex localization and the subsequent development of a proteinuria remain incompletely understood. The nature of the antigen involved in the immune complex deposits of membranous glomerulopathy and its source remain unknown. In fact, it is apparent that may different antigen-antibody combinations cause membranous glomerulopathy. The nephritogenic antigens can be endogenous to the glomerulus itself or can be exogenous. In the latter case, the antigen may be deposited in the subepithelial zone as part of preformed, circulating, immune complexes, or could be produced in or planted in the subepithelial zone as free antigen to which antibodies bind to form immune complexes in situ.
In rat Heymann nephritis, which closely resembles human idiopathic membranous glomerulopathy, there is convincing evidence that the subepithelial immune deposits form in situ as a result of the binding of antibodies to glycoproteins produced by visceral epithelial cells followed by accumulation of masses of the immune complexes in the subepithelial zone. [448] [449] [450]
If the nephritogenic antigens in human membranous glomerulopathy are intrinsic to the glomerulus, one could postulate that they should be distributed along the lamina rara externa or at the base of the visceral epithelial cells. [451] [452] Antibodies reactive in vitro with normal glomerular capillary walls have only rarely been described in human membranous glomerulopathy. [453] [454] [455] Antibodies to endothelin I and III were unexpectedly found to stain immune deposits in kidneys with idiopathic membranous glomerulonephritis, but not other primary glomerular diseases. As endothelin mRNA was not expressed in renal tissues of patients with membranous glomerulopathy, it was implied that the endothelin found in immune deposits waste of non-renal origin.[456] Identifying the target antigen(s) associated with membranous nephropathy is a key question. A number of antigens have been detected in human membranous nephropathy associated with either infectious disease or cancers. To date, the most convincing identification of a target antigen intrinsic to the normal podocyte membrane comes from the identification of antibodies to neutral endopeptidase in four cases of antenatal membranous nephropathy.[457] Mothers who lack this neural endopeptidase (NEP) and become pregnant with a normal fetus were described to form antibodies to this protein (also expressed on syncytiotrophoblastic cells), which can then cross the placenta and induce typical membranous nephropathy in the fetus.[458] NEP has not been found in the subendothelial immune deposits of patients with idiopathic membranous nephropathy.[459] Nevertheless, these cases of membranous nephropathy caused by alloimmunization to a protein intrinsic to the podocyte foot process raises the possibility that a similar mechanism could be involved in the pathogenesis of adult idiopathic disease.[457]
Regardless of the nature of the immune complex deposits in membranous glomerulopathy, the mechanisms leading to the proteinuric and nephrotic state are somewhat more completely understood. The current understanding of these mechanisms is largely based on data emerging from studies of passive Heyman nephritis. [450] [451] In this model, immune complex formation in the subepithelial zone leads to the activation of the complement pathway leading to the formation of the C5b-C9 membrane attack complex. This results in complement-mediated injury to the epithelial cells. [460] [461] [462] The characteristic findings of a predominance of IgG4 with less IgG3 and no IgG1 in subepithelial deposits, [463] [464] and the paucity of C1q and C4 in these deposits,[465] argues against a predominant role for the classical pathway of complement activation in membranous nephropathy, but rather points to a role of the alternative pathway.[466] The fact that the alternative pathway is spontaneously active in turn points to the likely importance of the complement regulatory proteins. Podocytes primarily rely on membrane complement receptor 1 (CR1) (Crry in rodents), decay accelerating factor (DAF) and have the capability to make their own factor H. The importance of complement-mediated injury (at least in passive Heymann nephritis) comes from the evidence that nephritogenic serum contains antibodies to membrane complement regulatory proteins [Crry]. [467] [468] In a model of active Heymann nephritis, immunization with Fx1A lacking Crry leads to the formation of anti-Fx1A antibodies and subepithelial immune complex deposits, but no complement activation or the development of proteinuria.[469] Conversely, the over-expression of Crry or treatment with exogenous Crry has a salutatory effect on immune complex-mediated glomerulonephritis. [470] [471] Subsequent injury to the epithelial cell membrane and to the glomerular basement membrane is hypothesized to be mediated at least in part by the production of reactive oxygen species and lipid peroxidation of cell membrane proteins and of type IV collagen.[472] Complement activation seems to be involved in the tubular injury as well, which eventually leads to tubulointerstitial atrophy and fibrosis. [473] [474]
The alteration in the glomerular extracellular matrix seen in membranous glomerulopathy may not be mediated entirely by complement activation and formation of the membrane attack complex. This is evidenced by GBM thickening in the autologous immune complex nephritis model but not in passive Heymann nephritis.[472] Recent studies suggest that the thickening of the basement membrane seen in membranous glomerulopathy may be caused at least in part by a decrease in fibrinolytic activity, due to the stabilization of active plasminogen activator inhibitor I (PAI I) in conjunction with vitronectin in the subepithelial deposits.[475]
The human leukocyte antigen (HLA) class II DR3 has been associated with membranous glomerulopathy. [476] [477] [478] [479] [480] [481] [482] [483] [484] [485] [486] [487] [488] In fact, there may be a relative risk of 12 for developing membranous glomerulopathy if HLA DR3 is inherited.[476] In a Japanese population, there is an increased incidence of HLA DR2 [479] [480] and Dqw1.[481] It is possible that a haplotype containing DR3 and specific HLA Class I antigens may be common in these patients as well.[476] For instance, HLA-B18 and HLA DR3 haplotype may confer an even greater risk for the development of membranous glomerulopathy.[482] C4 null alleles are more frequently found in patients with membranous glomerulopathy, especially in Caucasian populations.[483] Whether or not these immunogenetic markers confer at worsening prognosis has been controversial.[393] Despite the relative risk associated with some of these immunogenetic markers, there are relatively few examples of familial membranous glomerulopathy. [484] [485] [486] [487] [488]
Clinical Features and Natural History
Patients with membranous glomerulopathy usually have the nephrotic syndrome with hypoalbuminemia, hyperlipidemia, peripheral edema, and lipiduria. This presentation occurs in 70% to 80% of patients with membranous glomerulopathy. [374] [405] [410] [423] [427] [489] [490] [491] [492] [493] [494] [495] [496] The onset of this nephrotic process is usually not associated with any prodromal disease process or other antecedent infections. Hypertension may be absent at the outset of disease. [401] [403] In most series, the incidence of hypertension at onset varies from 13% to 55%. [400] [401] [402] [403] [406] [409] [410] [411] Most patients present with normal or slightly decreased renal function.
If progressive renal insufficiency develops, it is usually relatively indolent. An abrupt change to more acute renal insufficiency should prompt investigation of a superimposed condition. For instance, crescentic glomerulonephritis has been observed in some patients with membranous glomerulopathy.[497] Most of these patients have an idiopathic cause for the crescentic transformation. One third of these patients have anti-glomerular basement membrane antibodies, and some may have anti-neutrophil cytoplasmic autoantibodies.
Other causes for sudden deterioration of renal function include acute bilateral renal vein thrombosis, and hypovolemia in the setting of massive nephrosis. The incidence of renal vein thrombosis in the setting of membranous glomerulopathy[498] varies from 4% to 52%.[115] The diagnosis of renal vein thrombosis may be clinically apparent based on the sudden development of macroscopic hematuria, flank pain, and reduction in renal function. It is more persistent, and insidious development of renal vein thrombosis is not uncommon. [167] [499] Although ultrasonography with Doppler studies may demonstrate the renal thrombus, intravenous venography with contrast remains the gold standard. Magnetic resonance imaging with gadolinium allows for visualization of clots involving arterial and venous systems and may prove to be a useful diagnostic test.
Drug-induced renal injury is another reason for the sudden deterioration in renal function in a patient with membranous glomerulopathy. The use of non-steroidal anti-inflammatory drugs, diuretics, and anti-microbials is linked with the occurrence of acute interstitial nephritis or acute tubular necrosis.
An estimate of renal survival in patients with membranous glomerulopathy can be obtained from a pooled analysis of outcomes in clinical studies.[500] In this analysis of 1189 pooled patients, [400] [401] [402] [403] [406] [409] [410] [411] [413] [414] [415] [416] [417] [418] [419] [420] [421] [422] [423] [424] [425] [426] [427] [428] [429] [430] [431] [432] [433] [501] [502] [503] the probability of renal survival was 46% in 5 years, 65% in 10 years, and 59% years at 15 years. Although 35% of patients may progress to renal disease at 10 years, 25% may have a complete spontaneous remission of proteinuria within 5 years.[430] In a study from Italy of 100 untreated patients with membranous glomerulopathy who were observed for 10 years, 30% had progressive renal impairment after 8 years of follow-up. On the other hand, of the 62% who presented with nephrotic-range proteinuria, 50% underwent spontaneous remission in 5 years.[426] When pooling data from many studies on membranous glomerulopathy,[500] 10% of non-treated patients are in complete remission at 12 months, 16% at 24 months, and 22% at 36 months. Spontaneous remission may take 36 to 48 months to develop.
Although population studies provide an estimate of the prognosis in patient populations, sequential examination of any given patient over time provides a much stronger predictor of the long-term renal outcome in that individual. Thus, several studies have attempted to estimate the prognosis of patients with membranous glomerulopathy. Patients with overtly declining renal function are at higher risk for progressive renal deterioration.[430] In addition to declining renal function, Pei and colleagues[504] have reported that persistent proteinuria is more predictive of renal insufficiency than proteinuria at a single time point. Thus, persistent proteinuria of ≤8 grams per day for ≤6 months was associated with a 66% probability of progression to chronic renal failure. Patients with at least 6 grams of protein per day for 9 or more months had a 55% probability of developing chronic renal insufficiency. Even moderate levels of persistent proteinuria (≤4 grams/day) for over 18 months were associated with increased risk of chronic renal insufficiency. Although the data of Pei and colleagues described the persistence of proteinuria as a poor long-term prognostic factor, the amount of proteinuria at the time of presentation may also confer some degree of long-term prognostic information. Adults who present with non-nephrotic proteinuria have a more favorable 10-year survival rate than those with advanced proteinuria.[426] In contrast, patients with ≤10 grams or proteinuria per day at the onset of disease have a 60% probability of developing end-stage renal disease during 8 years of follow-up.[432]Despite these assertions, it should be noted that some patients with non-nephrotic proteinuria may develop a more progressive course,[432] and others with massive proteinuria at the time of presentation may have spontaneous remission.
In addition to renal insufficiency and proteinuria, other factors may be associated with an increased risk of progressive renal failure. These include male gender, advanced age (over age 50 years), poorly controlled hypertension, and reduced glomerular filtration rate at the outset of presentation. [409] [424] [426] [430] [432] [494] [504] [505] [506] In addition to the clinical prognostic features, the presence of advanced membranous glomerulopathy on renal biopsy (stage III or IV), tubular atrophy, and interstitial fibrosis can also be associated with increased risk. In fact, chronic interstitial fibrosis and tubular atrophy are shown to be independent predictors of progressive renal failure in idiopathic membranous glomerulopathy. [428] [502] [507] [508] [509] The presence of crescents on renal biopsy may also portend a poor long-term prognosis.
There is considerable controversy regarding the predic-tive value of the stage of glomerular lesions detected by electron microscopy. Some studies [493] [510] [511] suggest that a poor prognosis is associated with stage III or IV lesions. Other studies [400] [418] [424] [428] [432] [502] [512] refute this observation. The presence of frequent mononuclear cells in the interstitium may carry an increased risk of progressive renal failure.[513]
Focal segmental glomerulosclerosis superimposed on membranous has a worse long-term renal prognosis than membranous glomerulopathy without sclerosis. [514] [515] In one study, renal insufficiency in patients with concurrent FSGS and membranous glomerulopathy occurred at a rate of 52% at 5 years compared to 12% at 5 years in patients with membranous glomerulopathy alone.[514]
In summary, strong indicators of progressive disease are persistent moderate proteinuria, impaired renal function, severe proteinuria at presentation, and the presence of substantial interstitial infiltrates on biopsy. Patients with superimposed crescentic glomerulonephritis or segmental sclerosis fare poorly.
Laboratory Findings
Proteinuria is the hallmark of patients with membranous glomerulopathy. Well over 80% have more than 3 grams of protein per 24 hours. In some patients, the amount of proteinuria may exceed 20 grams/day. The MRC study reported 30% of patients had more than 10 grams per day at the time of presentation.[434] Microscopic hematuria is present in 30% to 50% of patients at the time of presentation. [410] [495] [516] Macroscopic hematuria on the other hand, is distinctly uncommon and occurs in less than 4% of adult patients [517] [518] although it may be common in children.[519] Most patients present with either normal or only slightly decreased renal function. In fact, impaired renal function is found in less than 10% of patients at the time of presentation. [423] [495]
In patients with severe nephrosis, hypoalbuminemia is common, as well as the loss of other serum proteins, including IgG. Serum lipoproteins are characteristically elevated, as they are in other forms of the nephrotic syndrome. Elevated LDL and VLDL are common in membranous glomerulopathy. In one study, elevated levels of lipoprotein (A) normalized in those patients who are in remission.[520]
Complement component levels, C3 and C4, are typically normal in patients with membranous glomerulopathy. The complex of terminal complement components known as C5b-9 is found in the urine in some patients with active membranous glomerulopathy. There is increased excretion of this complex in patients with active immune complex formation. The excretion may decrease during disease inactivity. [460] [461] [462] [521] [522] [523] [524] [525] [526]
To exclude common causes of secondary membranous glomerulopathy, one should obtain serologic tests for nephritogenic infections such as hepatitis B, hepatitis C, and syphilis, and tests for immunological disorders such as lupus, mixed connective tissue disease, and cryoglobulinemia. Membranous nephropathy has been associated with graft versus host disease following allogenic stem cell transplant, and this should be considered as well.[527]
Although patients with nephrosis in general appear to be hypercoagulable, this tendency may be enhanced in patients with membranous glomerulopathy. [115] [498] [528] Thus, patients with membranous glomerulopathy have hyperfibrinogenemia with increased circulating pro-coagulants and decreased anti-coagulant factors such as anti-thrombin 3.[529] The thrombotic tendency may be increased by the erythrocytosis that occurs in some patients, as well as by the effect of lipoprotein (a) to retard thrombolysis. Consequently, renal vein thrombosis is reported more frequently in patients with membranous glomerulopathy than in other causes of nephrotic syndrome. [498] [530] [531] [532] [533] The prevalence of renal vein thrombosis in patients with membranous glomerulopathy ranges from approximately 5% to 63%, with an averaged of less than 15%. The prevalence of all forms of deep vein thrombosis in patients with membranous glomerulopathy in general ranges from 9% to 44%. Renal vein thrombosis secondary to membranous glomerulopathy is often silent, pulmonary embolism is typically the phenomenon that presents the first clinical evidence of an underlying thrombotic tendency. It is the concern for the morbidity and, at times, mortality associated with pulmonary embolism that has led to the use of prophylactic anticoagulation for patients of severe nephrotic syndrome and membranous glomerulopathy. A decision analysis suggests the risk of life-threatening complications of pulmonary embolism outweigh the risks associated with anticoagulation.[534]
Treatment
Corticosteroids
Of all glomerular diseases, the management of membranous nephropathy has been most intensively studied, yet remains greatly controversial. The difficulty in the management of membranous glomerulopathy is a consequence of the chronic nature of the disease, the tendency for spontaneous remission and relapse, the variability of clinical severity, and the lack of efficacy of existing treatment protocols. The role of corticosteroids and alkylating agents in the treatment of this disease has been debated for decades. The common therapeutic approaches for new-onset disease include (1) no specific treatment, that is, placebo or supportive care, (2) corticosteroids (usually prednisone or methylprednisolone), and (3) alkylating agents, such as chlorambucil or cyclophosphamide, with or without concurrent corticosteroid treatment. Numerous studies using corticosteroid treatment have demonstrated different outcomes.[400] [401] [402] [403] [406] [409] [410] [411] [413] [414] [415] [416] [417] [418] [419] [420] [421] [422] [423] [424] [425] [426] [427] [428] [429] [430] [431] [432] [433] [501] [502] [503] In a pooled analysis of these studies, corticosteroid therapy resulted in no better probability of renal survival than no treatment.[500]
There have been three large, prospective, randomized trials examining the efficacy of oral corticosteroid therapy in adult patients. [414] [415] [535] These prospective studies have differed in outcome. The US Collaborative Study[405]suggested that 8 weeks of 100 mg to 150 mg of prednisone given on alternate days resulted in a transient decrease in proteinuria to less than 2 grams when compared to placebo. In this trial, prednisone was discontinued after 3 months unless a relapse of proteinuria occurred after either a partial or complete remission. Relapses were treated by reinstitution of high-dose prednisone for 1 month, and then prednisone was tapered. Interestingly, the results of this study suggested that patients who were treated with prednisone were less likely to double their entry serum creatinine, were more likely to experience a transient decrease in proteinuria to less than 2 grams a day, and that even a partial remission of proteinuria was associated with well-preserved, long-term renal function. This seminal study guided treatment for more than a decade, but was criticized because the placebo group faired substantially worse than non-treated patients in several other studies.
The US Collaborative Study prompted other similar prednisone-treatment protocols. For instance, the protocol of Cameron and co-workers[414] for the British Medical Research Council, was similar in a number of ways, except that prednisolone was discontinued after 8 weeks without tapering and without treatment of the relapse of proteinuria. Moreover, patients with lower creatinine clearance (≤30 ml/min) were included in the study. Three to nine months after study entry, there was no improvement in renal function, and the urine protein excretion and albumin level improved only transiently. A third corticosteroid treatment protocol was reported by Cattran.[415] The entry criteria included patients with relatively small amounts of proteinuria (≤0.3 g/day). The prednisone treatment included alternate-day dosage of 45 mg/M2 of body surface area. In this prospective study, prednisone had no effect on either proteinuria or renal function.
Meta-analysis of the US Collaborative study and the studies by Cameron, Cattran, and Kobayashi [400] [414] [415] [416] compared glucocorticoid-treated patients to those not receiving treatment.[500] There was a tendency for patients to achieve complete remission at 24 to 36 months, but this result did not reach statistical significance. A pooled analysis of randomized trials and prospective studies using adjusted values from logistic regression analysis again demonstrated a lack of benefit of corticosteroid therapy in inducing a remission of the nephrotic syndrome. There was no benefit of corticosteroids on renal survival in general.
The issue, then, is whether prednisone has any role in the treatment of patients with idiopathic membranous glomerulopathy. The three studies described above employed relatively short courses of prednisone, anticipating long-term effects. It has been argued by several investigators that higher doses (60 to 200 mg QOD) of prednisone and longer courses of therapy (up to 1 year) are essential for treatment in these patients. [399] [494] The studies of these investigators suffer from the fact that they are retrospective and contain reasonably small numbers of patients. Moreover, the side effects of extended courses of very high dose corticosteroids do not favor the risk/benefit ratio of this form of therapy. [535] [536]
An alternative to oral glucocorticoid therapy has been treatment with pulse methylprednisolone. This approach has been largely aimed at patients with membranous glomerulopathy who have deteriorating renal function. Short and colleagues[537] treated patients with membranous glomerulopathy and renal insufficiency using pulse methylprednisolone at 1 gram/day for 5 days followed by oral prednisone. Improvement in renal function was sustained for 6 months, and there was reduction in proteinuria. Yet, long-term outcomes were discouraging in almost half of these patients, including renal failure in one third and myocardial infarction with renal dysfunction in 13%. A similar study[538] combined pulse methylprednisolone with azathioprine or cyclophosphamide. Although there may have been some improvement in proteinuria and renal function in a minority of patients, substantial side effects afflicted almost the entire study population.
The evidence to date does not support the use of oral corticoids for the treatment of idiopathic membranous glomerulopathy. This said, it should be noted that there is an uncommon group of patients with membranous glomerulopathy who are highly steroid-responsive and have a natural history of response and relapse in a fashion very reminiscent of minimal change glomerulopathy. [172] [173] [539] These patients are rare with respect to the entire spectrum of patients with idiopathic membranous glomerulopathy. [172] [173] [539]
Interestingly, emerging data suggest that ACTH may have a different effect on the nephritic syndrome of membranous nephropathy than high-dose oral glucocorticoids.[540] In a recently published randomized controlled trial which compared treatment with methylprednisolone alternated with a cytotoxic drug every other month for 6 months to intramuscular synthetic adrenocorticotropic hormone administered twice a week for 1 year, the two forms of therapy led to significant and comparable reductions of proteinuria in most patients.[541]
Use of Cyclophosphamide
Cytotoxic drugs, including cyclophosphamide and chlorambucil have been used for the treatment of idiopathic membranous glomerulopathy. In a number of studies, Ponticelli demonstrated that chlorambucil has a salutatory effect in the treatment of membranous glomerulopathy. [418] [502] [510] [512] In these studies, patients with idiopathic membranous glomerulopathy were treated initially with intravenous pulse methylprednisolone at 1 gram per day for the first 3 days of each month, with daily oral glucocorticoid (methylprednisolone at 0.4 mg/kg/day or prednisone 0.5 mg/kg/day) therapy, given on an alternating monthly schedule with chlorambucil at a dose of 0.2 mg/kg/day. Patients randomized to the treatment group had their nephrotic syndrome for a significantly shorter duration of nephrotic syndrome and had a complete or partial remission of proteinuria in 83% of patients compared with 38% of control patients.[512] The slope of the mean reciprocal plasma creatinine remained stable in the treatment group, but declined in the untreated patients beginning at 12 months. At follow-up at 10 years, the probability of a functioning kidney was 92% in the treated patients and 60% in controls. Only 10% of patients were withdrawn from therapy as a consequence of side effects. When compared to treatment with glucocorticoids alone, treatment with a combination of chlorambucil and methylprednisolone was associated with an earlier remission of the nephrotic syndrome, and a greater stability of complete or partial remission of proteinuria.[418] Interestingly, the overall decline in renal function was not different in the two treatment groups. Unfortunately, this difference persisted for the first 3 years of follow-up but was no longer statistically significantly different by 4 years (62% versus 42%, p = 0.102). In a study comparing cyclophosphamide with chlorambucil, cyclophosphamide was found to be at least as effective as chlorambucil when used in a similar dosing protocol, and appeared to have somewhat fewer side effects.[542]
Despite these reported benefits, the salutary effects of alkylating agents combined with prednisone or other agents have not been confirmed in other trials. [417] [429] [433] [503] These conflicting results prompted two meta-analyses of controlled trials of either cyclophosphamide or chlorambucil treatment of membranous glomerulopathy. [500] [543] Both meta-analyses suggested that cytotoxic agents improve the chance of a complete remission of proteinuria by four- to five-fold, but have no long-term protective effect on renal survival. In a recent study comparing patients treated with prednisone tapered over 6 months plus chlorambucil, when compared to conservative treatment of historical controls, patients treated with combined glucocorticoid and chlorambucil regimen did much better over the long term.[544]
Some patients with membranous glomerulopathy present with progressive deterioration of renal function. Several rescue therapies with alkylating agents have been tried. [545] [546] [547] [548] [549] [550] [551] [552] These studies suggest that oral cyclophosphamide or chlorambucil may stabilize renal function and induce a remission of the nephrotic syndrome. Intravenous cyclophosphamide has been shown to be ineffective. [548] [549] These regimens have used large doses of prednisone (60 mg to 100 mg QOD for a year)[547] and oral cyclophosphamide from 1 to 4.5 years. In general, complete or partial remission of proteinuria can be obtained in up to 50% of patients, and stability of renal function in approximately the same number. The risk-to-benefit ratio of these aggressive treatment protocols must be acceptable to the patient. As a consequence, these treatments result in substantial side effects during the study follow up. Recent long-term follow up using prolonged oral cyclophosphamide in patients with Wegener granulomatosis[553] suggests that 15% of patients will develop transitional cell carcinoma of the bladder with a substantial increase in the incidence of lymphomas. The development of bladder cancer may become apparent up to seven years after the cyclophosphamide has been given. Thus, these aggressive salvage strategies for membranous glomerulopathy must be balanced against the immediate and long-term consequences of alkylating agents.
Cyclosporine
There has been substantial interest in the use of cyclosporine that has resulted in improvement in proteinuria and stability of renal function in many patients. [554] [555] [556] In most studies however, protein excretion increased in the majority of patients soon after the cessation of cyclosporine therapy. Yet, in one series,[557] improvement in renal function and proteinuria was sustained in 75% of patients for 20 months after cyclosporine was discontinued. Cyclosporine treatment may play a role in patients with steroid-resistant membranous nephropathy. In a randomized, controlled trial comparing 26 weeks of cyclosporine treatment plus low-dose prednisone to placebo plus prednisone, 75% of the treatment group versus 22% of the control group (P < 0.001) had a partial or complete remission of their proteinuria by 26 weeks. Relapse occurred in about 40% of patients achieving remission in either treatment group. The fraction of patients in sustained remission then remained significantly different between the groups until the end of the study (cyclosporine 39%, placebo 13%, P = 0.007). Renal function was unchanged and equal in the two groups over the test medication period.[558] It is interesting to consider how cyclosporine induces a remission of membranous glomerulopathy while the drug is administered, and the repeated observation of relapse after the drug is withdrawn. Some understanding of this issue was obtained examining the effect of three months of cyclosporine and three months of enalapril in a randomized cross-over study.[559] Cyclosporine did improve proteinuria without alterations in glomerular filtration or plasma flow (dextran analysis revealed that cyclosporine improved the size-selective and charge-selective properties of the glomerular capillary wall). These results were not obtained by use of enalapril. However, 75% of these study patients relapsed in the month after stopping cyclosporine. Repeat biopsy of a subset of these patients revealed persistent deposition of immunoglobulin and complement, suggesting that the disease process was ongoing.
Other Forms of Immunosuppressive Therapy
Other forms of therapy have been tried in idiopathic membranous glomerulopathy, with varying results. These include the use of azathioprine, [419] [420] which demonstrated no positive effect of prednisone and azathioprine combinations. Pooled intravenous immunoglobulin[560] was tested in nine patients with resultant decline in proteinuria and stabilization of renal function with minimal side effects. This small case series must be evaluated in a larger prospective trial. In a retrospective analysis of 86 patients with primary MN, 30 patients were non-randomly treated with one to three courses of intravenous immune globulin, (100–150 mg/kg/day) for 6 consecutive days. There was no difference in the initial demographic or clinicopathological states between the two treatment groups. Among patients with homogeneous (“synchronous”) immune complex deposits, treatment with IVIg was associated with earlier remission as compared to patients treated with corticosteroid ± cyclophosphamide alone (57 versus 10% remission at 6 months respectively, P = 0.006). No benefit was demonstrated among patients with heterogeneous immune complex deposits or in the final outcome for all groups.[561]
Mycophenolate mofetil has been tried in the management of membranous nephropathy. In general, patients have been treated with this drug after they have failed ACE inhibitors, ARBs, glucocorticoids, alkylating agents, and even cyclosporine. In a pilot open label study of 16 patients treated for 6 to 16 months, 6 patients had a decrease in proteinuria of >50%, within a period of 6 months.[562] The role (if any) of mycophenolate mofetil in the therapy of membranous nephropathy remains to be elucidated. [562] [563] [564] [565] [566]
The recent years have seen great interest in the use of the anti-CD20 monoclonal antibody rituximab for the management of a number of antibody mediated autoimmune diseases, including membranous nephropathy. In an initial report of eight patients, treatment with rituximab (4 weekly doses of 375 mg/M2 body surface area) was associated with prompt and sustained reduction in proteinuria. [567] [568] There has since been followed an additional open-label study from the same group,[569] but no controlled trial of this agent has been undertaken yet, and its effects on long-term renal outcome are unproven.
Based on the greater appreciation of the role of complement activation and especially that of complement regulatory proteins, in the pathogenesis of membranous nephropathy, a great deal of interest exists in targeting this pathway for therapy. Several compounds are under development. To date human trials were conducted only for eculizumab, a monoclonal antibody directed against the fifth component of complement (C5). In a randomized trial of patients with de novo membranous nephropathy, treatment with eculizumab was not associated with a statistically significant improvement in proteinuria or preservation of renal function. These disappointing results were likely due to insufficient dosing, as only a minority of patients attained consistent inhibition of complement inhibition.[570] Nevertheless, this general approach is thought to hold a great deal of promise based on early animal studies.
In the absence of full understanding of the pathogenesis of membranous glomerulopathy, and thus an effective targeted therapy, the current approach to the treatment of membranous glomerulopathy must rely on risk stratification. The indolent disease process that results in spontaneous remissions in one quarter of patients, coupled with the known adverse consequences of long-term oral glucocorticoids and alkylating agents, should prompt a careful analysis of the risk-benefit ratio in treatment of any given patient. All patients should receive excellent supportive care, including the use of angiotensin converting enzyme inhibitors [331] [571] [572] [573] [574] or angiotensin receptor blockers, therapy using lipid-lowering agents described previously, and perhaps the use of a prophylactic anticoagulant. The usefulness of lipid-lowering therapy in membranous nephropathy may be more than just the diminution of plasma cholesterol. In fact, certain agents, especially probucol, may inhibit the lipid peroxidation, which may alter the composition of the glomerular basement membrane.[575]
Several predictors of a progressive loss of GFR have been described in patients with membranous nephropathy. Both age and gender have been identified as predictors of outcome, with men having a worse prognosis than women.[576] Although older age is associated with a poorer renal outcome, it appears that the rate of decline in renal function is comparable in older and younger patients, however, older patients have a lower creatinine clearance at presentation.[577] Important predictors of progression are the rate of decline in GFR over the an observation period of 6 months[577] and the degree and duration of proteinuria. Patients presenting with non-nephrotic proteinuria have an improved 10-year renal survival rate; whereas those with more than grams of proteinuria have a 60% probability of ESRD at 8 years. In addition, several histologic features on renal biopsy have been associated with a poor outcome, including the severity of tubulointerstitial damage, and vascular sclerosis, the amount of complement deposition on immunofluorescence, the presence of the lesion of focal and segmental glomerulosclerosis and the findings of heterogeneous versus homogeneous (synchronous) morphology of the subepithelial electron-dense deposits. In a recent analysis of renal biopsies of 389 adult patients with membranous nephropathy, associations were tested between these variables and the rate of decline of renal function decline, renal survival, remission in proteinuria, and response to immunosuppression.[578] Although these histologic features were associated with a reduced renal survival, they did not predict this outcome independently of the baseline clinical variables nor did they correlate with the rate of decline in function or with baseline proteinuria. Furthermore, the severity of tubulointerstitial and vascular lesions did not preclude a remission in proteinuria in treated patients. The amount of complement deposition did not predict renal survival, remissions in proteinuria, or response to immunosuppressive drugs, but did correlate with a faster rate of renal function decline.[578] Additional predictors of outcome include the degree of IgG and a(1)microglobulin excretions as reflecting the alteration of permselectivity in the glomerular capillary wall and the reabsorption impairment of low-molecular-weight proteins respectively. Remission was reported in 100% versus 20% in patients with IgG excretion <110 mg/g Cr versus >110 mg/g Cr (P = 0.0001) and 77% versus 17% in patients with a(1)microglobulin excretion <33.5 mg/g Cr versus >33.5 mg/g Cr (P = 0.0009).[579] Similarly urinary β-2-microglobulin has also been found to predict progressive loss of renal function.[580]
Most patients should be observed for the development of adverse prognostic factors or the development of spontaneous remissions. In adult patients with good prognostic features, with less than 4 grams or proteinuria per day and normal renal function should be managed conservatively without the use of glucocorticoid or cytotoxic agents, but with an ACE inhibitor and or an angiotensin receptor blocker. These patients should receive excellent supportive care. Patients at moderate risk (persistent proteinuria between 4 and 6 grams per day after 6 months of conservative therapy and normal renal function) or high risk of progression (persistent proteinuria greater than 8 grams per day with or without renal in-sufficiency) should be considered for immunosuppressive therapy with either the combination of glucocorticoids and cyclophosphamide (or chlorambucil) in alternating monthly pulses (“Ponticelli protocol”); or a regimen consisting of cyclosporine with low-dose glucocorticoids. A current recommendation gives preference for the use a cytotoxic treatment approach in patients with moderate risk of progression, and for the use of cyclosporine in patients at high risk of progression.[581] This decision must be individualized to each patient's comorbidities and assessment of the risk associated with each kind of therapy. Whenever cyclosporine is used, close attention must be given to the consistent use of a same formulation over time, and initiating therapy at a low- to moderate dose (e.g., starting at 2 mg/day to 2.5 mg/day in divided dose of the microemulsion formulation), followed by a dose adjustment with careful evaluation of changes in blood pressure and creatinine clearance. Individuals who have advanced chronic renal failure and in whom serum creatinine exceeds 3 mg/dL to 4 mg/dL are best treated by supportive care awaiting dialysis and renal transplantation. Acute renal insufficiency in this population should prompt evaluation of interstitial nephritis, crescentic nephritis, or renal vein thrombosis.
Membranoproliferative Glomerulonephritis (Mesangial Capillary Glomerulonephritis)
Epidemiology
The majority of patients with membranoproliferative glomerulonephritis (MPGN) are children between the ages of 8 and 16 years.[582] In pediatric populations, 90% of type I MPGN and 70% of type II are found in individuals between the ages of 8 and 16 years. There is nearly an equal proportion of males to females in both type I and type II disease. [583] [584] [585] [586] [587] [588] [589] [590] [591] [592] [593] There was a male to female ratio of 1.2 to 1.0 in the last 248 examples of type I MPGN diagnosed in the UNC Nephropathology Laboratory. MPGN is identified in approximately 10% of renal biopsy specimens. [583] [585] MPGN appears to be decreasing in frequency.[594]
Pathology
Type I Membranoproliferative Glomerulonephritis
Light Microscopy
The most common histologic features of type I MPGN are diffuse global capillary wall thickening and endocapillary hypercellularity. [584] [595] Infiltrating mononuclear leukocytes and neutrophils also contribute to the glomerular hypercellularity. The consolidation of glomerular segments that results from these changes often causes an accentuation of the segmentation referred to as “hypersegmentation” or lobulation. As a consequence, an earlier name for this phenotype of glomerular injury was “lobular glomerulonephritis.” Markedly expanded mesangial regions may develop a nodular appearance with a central zone of sclerosis that may resemble diabetic glomerulosclerosis or light chain deposition disease. However, the integration of light, immunofluorescence, and electron microscopy findings readily differentiates type I MPGN from other diseases that can mimic it by light microscopy.
A distinctive but not completely specific feature of type I MPGN is doubling or more complex replication of glomerular basement membranes that can be seen with stains that highlight basement membranes, such as Jones' silver methenamine stain or periodic acid-Schiff stain ( Fig. 30-11 ). This change is caused by the production of basement membrane material between and around projections of mesangial cytoplasm that extend into an expanded subendothelial zone, probably in response to the presence of subendothelial immune complex deposits ( Fig. 30-12 ). The presence of “hyaline thrombi” within capillary lumens should raise the possibility of cryoglobulinemia or lupus as the cause for the MPGN. Hyaline thrombi are not true thrombi but rather are aggregates of immune complexes filling capillary lumens. A minority of patients with type I MPGN have crescents, but these rarely involve more than 50% of glomeruli. [596] [597] As with other types of glomerulonephritis, substantial crescent formation correlates with a more rapid progression of disease.[595]
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FIGURE 30-11 Light micrograph of a glomerular segment from a patient with type I membranoproliferative glomerulonephritis (MPGN) demonstrating doubling (arrows) and more complex replication of glomerular basement membranes. (Periodic acid-Schiff [PAS], ×1000.) |
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FIGURE 30-12 Diagram depicting the ultrastructural features of type I MPGN. Note the subendothelial dense deposits (straight arrow), subendothelial mesangial cytoplasm interposition (curved arrow), and production of new basement material (asterisk). (Reproduced with permission of J.C. Jennette.) |
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Immunofluorescence Microscopy
The characteristic pattern of staining is peripheral granular to band-like staining for complement, especially C3, and usually immunoglobulins ( Fig. 30-13 ). This corresponds to the prominent subendothelial immune complex localization seen by electron microscopy. The staining pattern is less granular and less symmetrical than that usually seen with membranous glomerulopathy. Mesangial granular staining may be conspicuous or inconspicuous. The hypersegmentation or lobulation that is seen by light microscopy often can be discerned by immunofluorescence microscopy. A minority of patients with type I MPGN have staining of immune complexes along tubular basement membranes or in extraglomerular vessels or both.
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FIGURE 30-13 Immunofluorescence micrograph of a glomerulus with type I MPGN showing global bandlike capillary wall staining for C3, as well as irregular mesangial staining. (FITC anti-C3, ×300.) |
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The composition of the immune deposits is variable, which probably reflects the many different causes of type I MPGN. Most specimens have more intense staining for C3 than for any immunoglobulin, but some specimens have more intense staining for IgG or IgM. Rare specimens have a predominance of IgA and can be considered a MPGN expression of IgA nephropathy. Even when C3 is the most intensely staining immune determinant, most specimens have clear cut staining for IgG or IgM or both. The presence of intracapillary globular structures that stain intensely for immunoglobulin and complement corresponds to the hyaline thrombi seen by light microscopy raise the possibility of MPGN caused by lupus or cryoglobulinemia.
Electron Microscopy
The ultrastructural hallmark of type I MPGN is mesangial interposition into and expanded subendothelial zone that contains electron dense immune complex deposits (Figs. 30-12 and 30-14 [12] [14]). This distinct pattern of mesangial and capillary involvement has prompted a synonym for type I MPGN, “mesangiocapillary glomerulonephritis.” New basement membrane material is formed around the subendothelial deposits and around the projections of mesangial cytoplasm, which is the basis for the basement membrane replication seen by light microscopy (see Fig. 30-11 ). Scattered mesangial dense deposits are usually found in association with mesangial hypercellularity and mesangial matrix expansion. Variable numbers of subepithelial electron dense deposits occur. When they are numerous enough to resemble membranous glomerulopathy, some nephropathologists apply the diagnosis “mixed membranous and proliferative glomerulonephritis” or “type III MPGN” as proposed by Burkholder.[598] The term type III MPGN also has been applied to a very rare pattern of glomerular injury that resembles type I MPGN by light microscopy and immunofluorescence microscopy, but is characterized ultrastructurally by irregularly thickened glomerular basement membranes with numerous intramembranous deposits of variable density. [589] [599]
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FIGURE 30-14 Electron micrograph of a capillary wall from a glomerulus with type I MPGN. The capillary lumen (L) is in the upper left and the urinary space is in the lower right (U). In the subendothelial zone are dense deposits (straight arrow), extensions of mesangial cytoplasm (curved arrow), and new basement membrane material (cf. Fig. 30-12 ) (magnification ×10,000). |
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The hyaline thrombi seen by light microscopy appear as intraluminal spherical densities. When these structures, or any of the other electron dense deposits, have a microtubular substructure, the possibility of cryoglobulinemic glomerulonephritis or immunotactoid glomerulopathy should be considered.
Type II Membranoproliferative Glomerulonephritis
An alternative term for type II MPGN is dense deposit disease.[595] This term emphasizes the pathognomonic feature of type II MPGN, which is the development of discontinuous electron dense bands within glomerular basement membranes (Figs. 30-15 and 30-16 [15] [16]). These are accompanied by spherical to irregular mesangial dense deposits, and occasional subendothelial and subepithelial deposits, some of which may resemble the “humps” of postinfectious glomerulonephritis.
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FIGURE 30-15 Diagram depicting a glomerular capillary loop with features of type II MPGN (dense deposit disease) with bandlike intramembranous dense deposits (arrow) and spherical mesangial dense deposits. (Reproduced with permission of J.C. Jennette.) |
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FIGURE 30-16 Electron micrograph of a glomerular capillary from a patient with type II MPGN showing a bandlike intramembranous dense deposit that has essentially replaced the normal glomerular basement membrane. Also note the endocapillary hypercellularity (magnification ×5000). |
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Immunofluorescence microscopy demonstrates intense capillary wall linear to band-like staining for C3 ( Fig. 30-17 ), with little or no staining for immunoglobulin. [600] [601] The capillary wall staining may have a fine double contour with outlining of the outer and inner aspects of the dense deposits. The mesangial deposits usually appear as scattered spherules or rings, with the latter resulting from staining of the outer surface but not the interior of the spherical deposits.
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FIGURE 30-17 Immunofluorescence micrograph of a portion of a glomerulus with type II MPGN demonstrating discontinuous bandlike capillary wall staining and granular mesangial staining for C3. (FITC anti-C3, ×600.) |
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The light microscopic appearance of type II MPGN is much more variable than that of type I MPGN, and does not always have a membranoproliferative appearance. This has prompted some nephropathologists to prefer the term dense deposit disease rather than type II MPGN.[601] The histologic appearance can be a typical membranoproliferative pattern with thickened capillary walls and marked lobular hypercellularity that closely resembles type I MPGN. However, some specimens have predominantly capillary wall thickening with focal or absent hypercellularity, and some specimens have focal or diffuse hypercellularity without substantial capillary wall thickening. A minority of patients will have crescent formation. Therefore, the histologic appearance of type II MPGN (dense deposit disease) can mimic many other categories of glomerulonephritis and the findings by immunofluorescence and especially electron microscopy are required for accurate diagnosis.
Pathogenesis
Although the pathologic findings indicate that type I MPGN is an immune complex disease, the identity of the nephritogenic antigen is unknown in most patients. In the minority of patients in whom the nature of the antigen is identified, the sources have included infections, neoplasms, hereditary diseases, and autoimmune diseases ( Table 30-11 ). The pathological finding of intense immune complex deposition with hypercellularity suggests that the inflammation caused by the immune complexes has resulted in both proliferation of mesangial and endothelial cells, and the recruitment of inflammatory cells, including neutrophils and monocytes. These leukocytes are attracted to the glomerulus by activation of multiple mediator systems, including the complement system, cytokines, and chemokines.
TABLE 30-11 -- Classification of Membranoproliferative Glomerulonephritis [612] [1019] [1316] [1317] [1318] [1319] [1320] [1321] [1322] [1323]
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Type II MPGN is characterized by deposits of dense material within the basement membranes of glomeruli, Bowman capsule, and tubules. Interestingly, these deposits do not appear to contain immunoglobulins, but seem to activate the alternate pathway of complement. A porcine model of MPGN (porcine-dense deposit disease) suggests that there is massive deposition of C3 and the terminal C5b-9 complement complex (the membrane attack complex). In the circulation, there is extensive complement activation with very low C3 and high circulating terminal complement components. No immune complex deposits were detected in renal tissue. At least in this animal model of type II MPGN, the pathogenetic mechanism does not appear to involve immune complexes, but rather utilizes some other mechanism for the activation of complement and the trapping of activating complement components within the glomerular basement membrane.[602]
Hypocomplementemia is a characteristic feature of all types of MPGN. Complement activation in MPGN type I occurs through the classical pathway initiated by immune complex formation. The hypocomplementemia in MPGN type II is more than likely a consequence of alternate pathway activation. C3 nephritic factor is an antibody that prolongs the half-life of C3 convertase. It does so in one of two ways—by either binding to C3bBb, or IgG-C3b-C3bBb of the assembled convertase. The stabilization of this complex results in perpetual C3 breakdown. It is tempting to impugn this factor as central to the pathogenesis of MPGN. C3 nephritic factor does not always correlate with disease activity and, more importantly, progressive renal damage still occurs in patients who have normal levels of complement. [603] [604] [605] Normal protective, or regulatory, mechanisms control C3bBb levels and complement deposition, of which Factor H is one of the most important. Factor H is a soluble glycoprotein that regulates complement in the fluid phase and on cell surfaces by binding to C3b.[606] Some mutations in Factor H result in MPGN-like diseases.[607] [608]
Clinical Features and Natural History
The clinical features of all forms of membranoproliferative glomerulonephritis are usually that of the nephrotic syndrome. At least half of patients present with all of the components of the nephrotic syndrome, and one quarter of patients present with a combination of asymptomatic hematuria and asymptomatic proteinuria. Finally, one quarter to one third of patients present with the acute nephritic syndrome associated with red cells, red call casts, hypertension, and renal insufficiency. [584] [585] [609] [610] Hypertension is typically mild, although in some cases, especially those with MPGN type II, severe hypertension can occur. Renal dysfunction occurs in at least half of cases. When present at the outset of disease, renal dysfunction portends a poor prognosis. There is an association of respiratory tract infections that may precede cases of MPGN in half of patients.
Membranoproliferative glomerular diseases are also associated with a number of other disease processes (see Table 30-11 ). A wide variety of infectious and autoimmune conditions are associated with MPGN suggesting that, in addition to the known association of hepatitis, infections in and by themselves may present with a pathological presentation of MPGN.
Of note are those patients who have either deficiency of the second or third component of complement with or without partial lipodystrophy. [605] [611] [612] [613] [614] [615] This disease process may have an X-linked transmission and is associated with the systemic manifestations of this disease process.[615] In addition to partial lipodystrophy, congenital complement deficiency states, and deficiency in alpha-1 anti-trypsin also predispose to MPGN type I.
The prognosis for MPGN type I has been reviewed and described in several studies. [584] [585] [616] D'Amico and Ferrario in Italy[585] found a 10-year renal survival of less than 65%. Cameron in the United Kingdom found a 10-year survival of 40% in patients with MPGN type I and persistent nephrosis.[584] Non-nephrotic patients had a 10-year survival of 85%.
The prognosis for type II disease is worse than that for type I. The worsened prognosis is probably because dense deposit disease is frequently associated with crescentic glomerulonephritis and chronic tubulointerstitial nephritis at the time of biopsy. [617] [618] [619] In type II MPGN, clinical remissions are rare, [584] [586] with a clinical remission rate less than 5% in children. Patients generally enter renal failure between years 8 through 12 of their disease. The parameters suggestive of poor prognosis in idiopathic MPGN type I include hypertension, [593] [619] impaired glomerular filtration rate, [593] [619] [620] [621] nephrotic rather than non-nephrotic, [584] [619] [620] [622] and cellular crescents on biopsy. [584] [621] [623]
What differentiates MPGN type I from type II? Do they represent different diseases, or are they a continuum? The argument that they are different diseases is based on the distinct morphologic, histopathologic, and immunopathologic changes differentiating the two types. [586] [592] [624] [625] [626] Type II MPGN tends to present with nephritis whereas MPGN type I presents with more nephrotic features. Type II disease is associated with persistently low serum C3 concentrations. [584] [586] [592] [593] [620] [626] [627] Type II MPGN occurs in individuals who are usually less than 20 years old, although there are occasional exceptions. Type II MPGN recurs in the transplanted kidney much more regularly than type I. [586] [628] [629] [630]
Type III MPGN occurs in a very small number of children and young adults. Regardless of the pathological distinctions of MPGN type III of Burkholder[598] or of Strife,[599] there are few clinical parameters noted on these patients. These patients may have clinical features of disease quite similar to that of MPGN type I, and the long-term, clinical course is quite similar as well. Patients with MPGN described by Strife[589] have low C3 levels in the absence of C3 nephritic factor. Patients with non-nephrotic proteinuria do better patients presenting with nephrotic syndrome. In our own experience, progression to end-stage renal disease is quite variable, but it appears that some patients stabilize or even improve with long-term renal survival.
Laboratory Findings
Hematuria is the hallmark of presentation. Hematuria may be microscopic or macroscopic in nature. Proteinuria can be mild and asymptomatic in 30% of patients, but half of patients may have the nephrotic syndrome. Renal insufficiency occurs in a variable number of cases, but it becomes the most ominous feature of the acute nephritic syndrome. Decreasing glomerular filtration rate associated with retention of salt and water results in hypertension that can occasionally be severe.
Type I MGPN often is secondary to recognizable causes, such as cryoglobulinemia, hepatitis C, hepatitis B, osteomyelitis, subacute bacterial endocarditis, or infected ventriculoatrial shunt. Serologic and clinical evidence of these processes should be sought. The observation that upper respiratory tract infections precede the onset of what is considered idiopathic MPGN in as many as one half of patients[582] raises the possibility that infectious agents contribute to the pathogenesis of many examples of idiopathic type I MPGN.
One of the hallmarks of the laboratory abnormalities in types I and II MPGN is alteration in the complement cascade ( Table 30-12 ). C3 is persistently depressed in approximately 75% of MPGN patients. [584] [585] [609] [610] [631]This is in contrast to post-streptococcal glomerulonephritis in which depressed C3 levels typically return to normal levels within 2 months. [632] [633] [634] The persistent depression of C3 and the nephritic syndrome should suggest type I MPGN. The depression of C3 is a consequence of both the activation of the alternate complement pathway and low synthetic levels. Activation of the alternate pathway is suggested by the observation that in type I MPGN, C3 levels are depressed, whereas classical pathway activator C1q and C4 usually are normal. However, when MPGN is caused by cryoglobulinemia there may be more depression of C4 than C3.[635] In type II MPGN, C3 depression occurs in 80% to 90% of patients and, if anything, C3 levels persist longer in type II disease[432] associated with decrements in terminal complement components C5b-9.
TABLE 30-12 -- Selected Serologic Findings in Patients with Primary Glomerular Disease
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Disease |
C4 |
C3 |
ASO, ADNase B |
Cryo Ig |
aGBM |
ANCA |
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Minimal change glomerulopathy |
N |
N |
— |
— |
— |
— |
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Focal glomerulosclerosis |
N |
N |
— |
— |
— |
— |
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Membranous GN |
N |
N |
— |
— |
— |
— |
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Membranoproliferative GN |
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Type I |
N or ↓↓ |
↓↓ |
+ |
++ |
— |
— |
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Type II |
N |
↓↓↓ |
+ |
— |
— |
— |
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Fibrillary GN |
N |
N |
— |
— |
— |
— |
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IgA nephropathy |
N |
N |
— |
— |
— |
— |
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Acute poststreptococcal GN |
N or ↓ |
↓↓ |
+++ |
++ |
— |
— |
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Crescentic GN |
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Anti-GBM |
N |
N |
— |
— |
+++ |
± |
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Immune complex |
N or ↓ |
N or ↓↓ |
— |
N/++ |
— |
± |
|
ANCA-SVV |
N |
N |
— |
— |
± |
+++ |
|
ADNase B, antideoxyribonuclease B; ANCA, antineutrophil cytoplasmic antibodies; aGBM, anti-glomerular basement membrane antibodies; ASO, antistreptolysin-O; Cryo, cryoglobulins; GN, glomerulonephritis; Ig, immunoglobulins. |
Complement activation is enhanced by C3 nephritic factor (C3 NeF) an autoantibody that reacts with convertase of C3 (C3b Bb). [636] [637] [638] [639] The autoantibody results in the stabilization of C3 convertase resulting in persistent enzyme activity. Thus, C3 cleavage occurs unabated due to the inability of usual inhibitory proteins to degrade the alternative pathway convertase. C3 nephritic factor occurs in over 60% of patients with MPGN type II and may be responsible for the persistently low levels of C3 in these patients. C3 nephritic factor or its analogues are not only found in type II MPGN, but may be found in other glomerular diseases as well, usually those associated with nephritis. [631] [640] Other factors capable of cleaving C3 are not clear, but are found in patients with other acute glomerulonephritis and especially lupus.[632]
Some proportion of type I MPGN is attributable to hepatitis C with or without cryoglobulinemia. The precise percentage of patients with MPGN due to hepatitis C may vary according to geographic area and cultural factors. Consequently, the overall percentage of patients with MPGN type I with hepatitis C across the globe is still unknown. When MPGN is secondary to other disease processes such as malignancy or a rheumatic condition, the laboratory features associated with the systemic disease (for instance SLE) are positive (e.g., antibodies to double-stranded DNA).
Treatment
In general, one third of patients with type I MPGN will have a spontaneous remission, one third will have progressive disease, and one third will have a disease process that will wax and wane but never completely disappear.[585]
The management of type I MPGN is based on the underlying cause of the disease process. Thus, the therapy for MPGN associated with cryoglobulinemia and hepatitis C should be aimed at treating hepatitis C virus infection; whereas, the management of MPGN associated with lupus or with scleroderma should be based on the principles of care of those rheumatological conditions. Most recommendations for the treatment of type I MPGN are limited to studies in children. [641] [642] [643] [644] [645] [646] [647] [648] West and colleagues touted the benefits of prednisone therapy provided on a continuous basis for improved renal survival.[643] Whether the benefit of low-dose prednisone therapy is only seen in children, or whether similar effects are achieved in adults has never been subject to a prospective randomized trial. However, low-dose, alternate-day prednisone may have a salutary effect on improving renal function. [646] [647]
In addition to glucocorticoids, a host of other forms of immunosuppressive and anti-coagulant treatment has been used in the management of type I MPGN. Studies with dipyridamole, aspirin, and warfarin with and without cyclophosphamide have been tried in both controlled and uncontrolled studies. [417] [583] [648] [649] [650] [651] [652] [653] A retrospective study of patients treated with warfarin, dipyridamole, and cyclophosphamide[648] touted a long-term survival of 82% compared to historical untreated controls in which there were no survivors. The reason for the extremely adverse outcome of the historical untreated controls is not clear, and a controlled trial in Canada using this approach[415] did not demonstrate a benefit.
Initial reports of a positive response in renal survival were associated with treatment with aspirin and dipyridamole.[583] This approach was widely accepted; however, statistical design flaws resulted in re-analysis of the data revealing no difference in the treatment and control groups with respect to long-term outcome.[609] A subsequent study using acetylsalicylic acid with dipyridamole demonstrated a slight decrease in urine protein excretion by 3 years without differences in renal function.[652]
Type I MPGN is significantly ameliorated by the use of cyclosporine in the very rare condition known as Buckley syndrome. [172] [173] [654] Cyclosporine does seem to have an effect on the long-term outcome of this process.
Unfortunately, there is not a good form of therapy for MPGN type II. This is compounded by the fact that MPGN type II recurs almost invariably in renal transplant patients, especially if crescentic disease is present in the native kidney biopsy. [584] [593] [604] [610] [630] [655] [656] [657] MPGN type I may also recur after transplantation, albeit less frequently.
Glomerulonephritis
The syndrome of glomerulonephritis is characterized by hematuria, red blood cell casts, proteinuria, hypertension, and renal insufficiency. The clinical presentation varies from asymptomatic hematuria or proteinuria (or both) to acute nephritis to rapidly progressive nephritis to chronic nephritis. These varied clinical manifestations are the result of different expressions of inflammatory glomerular injury that ranges from structurally imperceptible abnormalities, to pure mesangial hypercellularity, to endocapillary proliferative glomerulonephritis, to crescentic glomerulonephritis, or to chronic sclerosing glomerulonephritis ( Fig. 30-18 ). These structural categories of glomerulonephritis are not specific diseases, but rather are patterns of glomerular injury that can be caused by many different etiologies and pathogenic mechanisms.[657]
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FIGURE 30-18 Diagram depicting the continuum of structural changes that can be caused by glomerular inflammation (top), the usual clinical syndromes that are caused by each expression of glomerular injury (middle), and the portion of the continuum that is most often attained by several specific categories of glomerular disease (bottom). (From Ferrario F, Kourilsky O, Morel-Maroger L: Acute endocapillary glomerulonephritis in adults: A histologic and clinical comparison between patients with and without initial acute renal failure. Clin Nephrol 19:17–23, 1983, with permission. |
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Acute Post-Streptococcal Glomerulonephritis (PSGN)
Epidemiology
Acute PSGN is a disease that affects primarily children with the peak incidence being between ages of 2 and 6 years. Children younger than age 2 years and adults older than age 40 account for only about 15% of patients affects with acute PSGN. Subclinical, microscopic hematuria may be four times more common as overt acute PSGN, as documented in studies of family members of affected patients. [658] [659] [660] Only rarely do PSGN and rheumatic fever occur concomitantly.[661] Males are more likely than females to have overt nephritis.
Acute PSGN may occur as part of an epidemic or sporadic disease. During epidemic infections of streptococci of proven nephrogenicity, the clinical attack rate appears to be about 12%, [662] [663] [664] but may be as high as 25%.[665] Indeed, the attack rate may be as high as 38% in certain affected families.[660]
Differences in attack rates among different families are used to argue the existence of host factors affecting susceptibility to overt nephritis.[666] An association was found between HLA-DRW4 and acute PSGN in a study of 18 families involving 67 siblings in Venezuela. More recently, Mori and colleagues reported an increased incidence of HLA-DP5 antigen in 58 Japanese patients when compared to 317 healthy unrelated controls.[667] These authors report a statistically significant increase in frequency of HLA-DPA*02-022 and DPB1*05-01; whereas, HLA-DPA*01 and DPA*0201 were significantly decreased when compared to controls.
The attack rate of acute PSGN after sporadic infections with group A streptococci of potentially nephritogenic types is quite variable, [668] [669] again pointing to ill-defined host factors. The minority of streptococcal infections lead to the nephritic syndrome, arguing for the presence of certain nephritogenic “characteristics of the offending agent.” Indeed, Rammelkamp and co-workers identified in the 1950s [668] [669] certain strains of streptococci within the Lancefield group A in particular, type XII that are capable of leading to an acute glomerulonephritis. Other nephritogenic serotypes include M types 1, 2, 3, 4, 18, 25, 49, 55, 57, 59, and 60. Other potential nephritogenic types include types 31, 52, 56, 59, and 61. There are differences among these serotypes in their propensity to be associated with nephritis depending on the site of infection. Certain strains, such as type 2, 49, 55, 57 and 60, are usually associated with nephritis after a pyoderma, [670] [671] whereas M type 49 can lead to nephritis after either a pharyngitis or pyoderma. Besides the group A beta hemolytic streptococci, acute PSGN has also been described after infection with group C streptococci and possibly group G streptococci. [672] [673]
Acute PSGN is on the decline in developed countries, whereas it continues to occur in developing communities.[674] Epidemic PSGN is frequently associated with skin infec-tions as opposed to pharyngitides associated with sporadic PSGN in developed countries. Overt glomerulonephritis is found in about 10% of children at risk, but when one includes subclinical disease as evidenced by microscopic hematuria, about 25% of children at risk are affected.[675] [676] In some developing countries, acute PSGN remains the most common form of acute nephritic syndrome among children. The “attack rate” appears to follow a cyclical pattern every ten years or so.[677] Based on 11 published population-based studies, a recent study estimated the median incidence of post-streptococcal glomerulonephritis in children from less developed country studies or those that included substantial minority populations in more developed countries at 24 cases per 100,000 person-years, whereas the incidence in adults was conservatively estimated at 2 cases per 100,000 person-years in less developed countries and 0.3 cases per 100,000 person-years in more developed countries.[678] These authors estimated that over 470,000 cases of acute post-streptococcal glomerulonephritis occur annually, with approximately 5000 deaths (1% of total cases), 97% of which are in less developed countries.
Pathology
Light Microscopy
The pathologic appearance of acute PSGN varies during the course of the disease. The acute histologic change is influx of neutrophils that results in diffuse global hypercellularity ( Fig. 30-19 ). [679] [680] [681] [682] [683] Endocapillary proliferation of mesangial cells and endothelial cells also contributes to the hypercellularity. The hypercellularity often is very marked and results in enlarged consolidated glomeruli. The descriptive designation acute diffuse proliferative glomerulonephritis often is used as a pathologic designation for this stage of acute PSGN. A minority of patients has crescent formation that usually affects only a small proportion of glomeruli.[684] Extensive crescent formation is rare. [685] [686] Special stains that have differential reactions with immune deposits may demonstrate subepithelial deposits. For example, the subepithelial deposits may stain red (fuchsinophilic) with Masson trichrome stain.
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FIGURE 30-19 Light micrograph of a glomerulus with acute poststreptococcal glomerulonephritis demonstrating marked influx of neutrophils (arrows). (Masson trichrome, ×700.) |
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Interstitial edema and interstitial infiltration of predominantly mononuclear leukocytes usually is present and occasionally is pronounced, especially with unusually severe disease with crescents. Focal tubular epithelial cell simplification (flattening) also may accompany severe disease. Arteries and arterioles typically have no acute changes, although there may be preexisting sclerotic changes in older patients.
During the resolving phase of self-limited PSGN, which usually begins within several weeks of onset, the infiltrating neutrophils disappear and endothelial hypercellularity resolves leaving behind only mesangial hypercellularity.[679] [687] This mesangioproliferative stage often is present in patients with APSG who have had resolution of nephritis but have persistent isolated proteinuria, and may persist for several months in patients who have complete clinical resolution. There may be focal segmental glomerular scarring as sequelae of particularly injurious inflammation, but this is rarely extensive except in the rare patients with crescentic APGN. Ultimately, the pathologic changes of APGN can resolve completely. [687] [688]
Immunofluorescence Microscopy
Immunofluorescence microscopy demonstrates immune glomerular immune complex deposits in PSGN. [680] [682] [683] [689] The pattern and composition of deposits change during the course of PSGN. During the acute diffuse proliferative phase of the disease there is diffuse global coarsely granular capillary wall and mesangial staining that usually is very intense for C3 and of varying degrees for IgG from intense to absent ( Fig. 30-20 ). Staining for IgM and IgA is less frequent and usually less intense. In self-limited disease, biopsy should be performed later in the disease course as it is more likely that the staining will be predominantly or exclusively for C3 with little or no immunoglobulin staining. Because most patients with uncomplicated new onset acute PSGN undergo renal biopsy, most biopsy specimens are obtained later in the course when there is diagnostic uncertainty because of equivocal serologic confirmation, or unusually aggressive or persistent clinical features. At this time, the immunofluorescence microscopy staining is usually predominantly for C3. This may reflect termination of nephritogenic immune complex localization in the kidney with masking of residual complexes by complement. The continued presence of intense staining for IgG a month or more into the course of what otherwise looks like pathologically typical PSGN is cause for concern that the process will not be self-limited.
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FIGURE 30-20 Immunofluorescence micrograph of a glomerular segment from a patient with acute poststreptococcal glomerulonephritis (PSGN) showing coarsely granular capillary wall staining for C3. Compare this to the finely granular capillary wall staining of membranous glomerulopathy in Figure 30-9 . (FITC anti-C3, ×800.) |
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Several patterns of immune staining have been described but are of limited prognostic value. [680] [683] [690] The garland pattern has numerous large closely apposed granular deposits along the capillary walls. Patients with this pattern usually have nephrotic range proteinuria as a component of their disease. The starry sky pattern has more scattered granular staining, which corresponds somewhat to less severe disease. The mesangial pattern, especially when it is predominantly C3 staining, corresponds to the resolving phase with a mesangioproliferative light microscopic appearance.
Electron Microscopy
The hallmark ultrastructural feature of PSGN is the subepithelial hump-like dense deposits (Figs. 30-21 and 30-22 [21] [22]). [682] [687] [688] [689] [691] However, small subendothelial and mesangial dense deposits can usually be identified when carefully observed and theoretically may be more important in the pathogenesis of the disease, especially the neutrophilic influx and endocapillary proliferative response, than the subepithelial humps. The subepithelial humps are covered by effaced epithelial foot processes, which usually contain condensed cytoskeletal filaments (including actin) that form a corona around the immune deposits (see Fig. 30-22 ). During the acute phase, capillary lumens often contain marginated neutrophils, some of which are in direct contact with glomerular basement membranes (see Fig. 30-22 ). Lesser numbers of monocytes and macrophages contribute to the leukocyte influx. Mesangial regions are expanded by increased numbers of mesangial cells and leukocytes as well as increased matrix material and varying amounts of electron dense material.
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FIGURE 30-21 Diagram of the ultrastructural features of acute PSGN. Note the subepithelial humplike dense deposits (straight arrow), subendothelial deposits (curved arrow), and mesangial deposits. There is endocapillary hypercellularity caused by neutrophil infiltration, and endothelial and mesangial proliferation. (Reproduced with permission of J.C. Jennette.) |
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FIGURE 30-22 Electron micrograph of a portion of a glomerular capillary from a patient with acute PSGN showing subepithelial dense deposits (straight arrow), condensation of cytoskeleton in adjacent epithelial cytoplasm (small curved arrow), and a neutrophil (N) marginated against the basement membrane with no intervening endothelial cytoplasm (magnification ×5000). |
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During the resolution phase, usually 6 to 8 weeks into the course, the subepithelial humps disappear, leaving behind only mesangial and sometimes a few scattered subendothelial and intramembranous dense deposits. The subepithelial first become electron lucent and then disappear completely. The humps in peripheral capillary loops disappear before the humps in the subepithelial zone adjacent to the perimesangial basement membrane.
Pathogenesis
Acute post-streptococcal glomerulonephritis is the prototype disease of an acute glomerulonephritis associated with an infectious etiology. The first description of this link dates back to the early 18th century after Scarlet Fever epidemics in Florence and Vienna. Richard Bright first described the association in 1836, reporting that Scarlet Fever was sometimes followed by hematuria and kidney disease.[692] In 1907, Schick described an asymptomatic interval of 12 days to 7 weeks between the onset of streptococcal infection and that of nephritis.[693] In the early 1950s, Rammelkamp and Weaver further refined the association of post-streptococcal glomerulonephritis with specific serotypes of streptococci. [668] [694]
Despite the early recognition of an association between streptococcal infection and an acute glomerulonephritis, the pathogenic mechanism of disease remains incompletely understood. Conceptually, acute post-streptococcal glomerulonephritis (PSGN) could be secondary to either a direct toxic effect on the glomerulus of a streptococcal protein, or the streptococcal product could induce an immune-complex-mediated injury. This could occur by a number of different mechanisms: (1) by introducing an antigen to the glomerulus (planted antigen), (2) by the deposition of circulating immune complexes, (3) by altering a normal renal antigen, causing it to become a self antigen, (4) by inducing an autoimmune response to a self antigen by way of antigenic mimicry. It is conceivable that more than one streptococcal antigen may be involved in the pathogenesis of acute PSGN, and more than one pathogenic mechanism may be at play simultaneously.
Several streptococcal proteins have been implicated in the pathogenesis of acute PSGN.[695] M protein molecules protruding from the surface of group A streptococci contain epitopes which cross-react with glomerular antigens. Shared sequences of M protein types V, VI, and XIX have been shown to elicit antibodies that react with several myocardial and skeletal muscle proteins.[696] Conversely, monoclonal antibodies raised against human renal cortex have been shown to cross-react with types VI and XII M proteins, bringing evidence that certain M proteins may share antigenic determinants between all glomeruli.[697] The renal glomerular cross-reactivity of the amino terminal region of type I M protein was further localized to a tetra peptide sequence at position 23-26.[698] Antibodies raised against amino terminal of type I M protein was shown to cross-react with the cytoskeletal protein of glomerular mesangial cells, namely, the filament protein vimentin.[696]
Currently, the spectrum of infectious agents associated with a post-infectious glomerulonephritis or a peri-infectious glomerulonephritis includes many more bacterial pathogens than streptococci. These include staphylococci, gram negative rods, and intracellular bacteria.[699] Likewise, the population at risk for peri-infectious glomerulonephritis has changed to include alcoholics, intravenous drug users, and patients with ventricular atrial shunts. However, post-streptococcal glomerulonephritis remains the infectious glomerulonephritis, which is the most extensively studied and documented.
Clinical Features and Natural History
Classically, the syndrome of acute PSGN presents abruptly with hematuria, proteinuria, hypertension, and azotemia. This syndrome can present with an entire spectrum of severity from asymptomatic to oliguric acute renal failure.[700] A latent period is present from the onset of pharyngitis to that of nephritis. In post-pharyngitic cases, the latent period averages 10 days after pharyngitis with a range from 7 to 21 days. The latent period may be longer after a skin infection (from 14 to 21 days), although this period is harder to define after impetigo.[701] The latency period can exceed 3 weeks.[702] Conversely, short latency periods of less than one week are suggestive of a “synpharyngitic syndrome” corresponding typically to exacerbation of an underlying IgA nephropathy.
The hematuria is microscopic in more than two-thirds of cases, but may be macroscopic on occasions. Patients commonly report gross hematuria and transient oliguria. Anuria, however, is infrequent and, if persistent, may indicate the development of crescentic glomerulonephritis.
Mild to moderate hypertension occurs in more than 75% of patients that is most evident at the onset of nephritis and typically subsides promptly after diuresis.[661] Antihypertensive treatment is necessary in only about one half of patients. Signs and symptoms of congestive heart failure may occur and, indeed, dominate the clinical picture. These include jugular venous distention, the presence of an S3 gallop, dyspnea, and signs of pulmonary congestion. [702] [703] [704] [705] Frank heart failure may be a complication in as many of 40% of elderly patients with PSGN.
Edema may be the presenting symptom in two thirds of patients, and is present in as many as 90% of patients.[658] The presence of edema is based on primary renal sodium and fluid retention. The edema typically presents in the face and upper extremities. Ascites and anasarca may occur in children.
Encephalopathy presenting as confusion, headache, somnolence, or even convulsion, is not frequent, and may affect children more frequently than adults. This encephalopathy is not always attributable to severe hypertension, but may be the result of CNS vasculitis instead. [702] [704] [705] [706]
The clinical manifestations of acute PSGN typically resolve in 1 to 2 weeks as the edema and hypertension disappear after diuresis, the patient remains typically asymptomatic. Both the hematuria and proteinuria may persist for several months, but are usually resolved within a year. However, proteinuria may persist in those patients who initially presented with nephrotic syndrome.[658] The long-term persistence of proteinuria and, especially albuminuria, may be an indication of persistence of proliferative glomerulonephritis.[664]
Differential diagnosis of acute PSGN includes (1) IgA nephropathy[707] and Henoch-Schönlein purpura, (especially when the acute nephritic syndrome is associated with gross or rusty hematuria), (2) MPGN, or (3) acute crescentic glomerulonephritis (RPGN immune complex mediated, anti-GBM-mediated, or pauci-immune). The occurrence of an acute nephritis in the setting of persistent fever should raise the suspicion of a peri-infectious GN especially with a persistence of an infection such as an occult abscess or infective endocarditis.
Although rheumatic fever and post-streptococcal glomerulonephritis rarely occur concomitantly, their concurrence has recently been described.[708]
Laboratory Findings
Hematuria, microscopic or gross, is nearly always present in acute PSGN. There are, however, rare cases of documented acute PSGN with no associated hematuria. [660] [709] Microscopic examination of urine typically reveals the presence of dysmorphic red blood cells[710] or red blood cell casts. Other findings on microscopy are those of leukocytes, renal tubule epithelial cells, as well as hyaline and granular casts.[661] When the hematuria is macroscopic, the urine typically has a rusty or tea-color.
Proteinuria is nearly always present but typically in the sub-nephrotic range. In half of patients, it may be less than 500 mg per day. [711] [712] Nephrotic-range proteinuria may occur in as many as 20% of patients and is more frequent in the adults than in children.[658] The proteinuria may often con-tain large amounts of fibrin degradation products, and fibrinopeptides. [709] [713]
A pronounced decline in urine glomerular filtration rate (GFR) is common in the elderly population with acute PSGN affecting nearly 60% of patients 55 years of age and older.[704] This profound decrease in GFR is uncommon in children to middle-aged adults. Indeed, because of the accompanying fluid retention and increase in circulatory volumes, a mild decrease in GFR may not be accompanied by an increase in serum creatinine concentration above laboratory limits of normal. Renal plasma flow, tubular reabsorptive capacity, and concentrating ability are typically not affected. On the other hand, urinary sodium excretion and calcium excretion are greatly reduced.[714]
A transient hyporeninemic hypoaldosteronism may lead to mild to moderate hyperkalemia. This may be exacer-bated by a concomitant decrease in GFR and a reduced distal delivery of solute. This type IV renal tubular acidosis may resolve with the resolution of nephritis in the event of diuresis, but may be persistent beyond that point in some patients.[715] The suppressed plasma renin activity may be a consequence of the volume expansion present in those patients.[716]
Throat or skin cultures frequently reveal group A streptococci. [661] [717] The sensitivity and specificity of these tests are likely affected by the methodology of obtaining a throat culture and the test used.[718] Such cultures may be less satisfactory than serologic studies to evaluate the presence of recent streptococcal infection in patients suspected of hav-ing PSGN.[665] The antibodies most commonly studied for the detection of a recent streptococcal infection are anti-streptolysin-O (ASO), anti-streptokinase, anti-hyaluronidase, anti-deoxyribonuclease-B, and anti-nicotinamide adenine dinucleotidase.[719] Of these, the most commonly used test is the ASO. An elevated ASO titer above 200 units may be found in 90% of patients with pharyngeal infection.[661] In the diagnosis of an acute post-streptococcal glomerulonephritis however, a rise in titer is more specific than the absolute level of a titer. The latter is likely affected by the geographic and socioeconomic prevalence of pharyngeal infections with group A streptococci. Increased ASO titers may be present in about two-thirds of patients with upper respiratory tract infection, but in only about one-third of patients following streptococcal impetigo.[658] Serial ASO titer measurements with a two-fold or greater rise in titer are highly indicative of a recent infection. [658] [661]
The streptozyme test combines several anti-streptococcal antibody assays and may be a useful screening test.[720] Because certain strains of type XII group A streptococci do not produce streptolysin S or O and in patients in whom impetigo-associated PSGN is suspected, testing for anti-deoxyribonuclease B and anti-hyaluronidase titers is a useful procedure.[670] Antibodies to other streptococcal cell wall glycoproteins may also increase, including those for endostreptosin. [661] [721] [722] [723] [724] On occasion, autoantibodies to collagen and laminin may be detected. [661] [725] Positive throat cultures or skin cultures may be present in a few as one fourth of patients.
The serial estimation of complement components is important in the diagnosis of PSGN. Early in the acute phase, the levels of hemolytic complement activity (CH-50 and C3) are reduced. These levels return to normal usually within 8 weeks. [661] [702] [726] [727] [728] [729] [730] [731] The reduction in serum C3 levels is especially marked in patients with C3 nephritic factor, which is capable of cleaving native C3. [632] [633] [634] The finding of low properdin and C3 levels, and the concomitant normal to modestly reduced levels of C1q, C2, and C4 [726] [727] [732] all point to the importance of the activation of the alternate pathway of the complement activation cascade.[726] There is some evidence as well for activation via the classic pathway.[733] Other complement level abnormalities include a mild depression of C5 levels, whereas C6 and C7 are most often normal. [632] [661] [732] Plasma level of soluble terminal complement components (C5b-9) rises acutely and then falls to normal.[727] As complement levels typically return to normal within eight weeks, the presence of persistent depression of C3 levels may be indicative of another diagnosis, such as MPGN, endocarditis, occult sepsis, SLE, atheromatous emboli, or congenital chronic state of complement deficiency.[726]
Circulating cryoglobulins, [734] [735] as well as circulating immune complexes [736] [737] [738] [739] may be detected in some patients with PSGN. The pathophysiologic importance of these circulating immune complexes as to the development of acute nephritis is unclear. [738] [739] [740]
Abnormalities in blood coagulation systems may be detected in acute PSGN, thus thrombocytopenia may be seen.[741] Elevated levels of fibrinogen, factor VIII, plasmin activity, and circulating high molecular weight fibrinogen complexes may be seen and correlate with disease activity, and unfavorable prognosis. [742] [743] [744] [745] [746]
Although complement studies suggest that the alternative pathways are primarily involved in acute PSGN, there is some evidence also for activation via the classic pathway.[733]
Treatment
Treatment of acute post-streptococcal glomerulonephritis is largely that of supportive care. Children almost invariably recover from the initial episode. [489] [665] [747] Of concern to clinicians are those patients who present with acute renal failure. An initial episode of acute renal failure is not necessarily associated with a bad prognosis.[700] In a study of 20 adult patients with diffuse proliferative glomerulonephritis, 11 had acute renal failure and 9 had normal or mild renal insufficiency. There were no differences in the clinical, immunological, or histological features between the groups. After 18 months of follow-up, outcome was similar in the two groups. Thus, there is little evidence to suggest the need for any form of immunosuppressive therapy. Because of the profound salt and water retention observed in these patients, and, in some, pulmonary congestion, it is important to use loop diuretics such as furosemide to avoid volume expansion and hypertension. When volume expansion does occur, antihypertensive agents are frequently useful to ameliorate the hypertension. Interestingly, plasma renin levels are reduced; yet, captopril has been shown to lower blood pressure and improve glomerular filtration rate in patients with post-streptococcal glomerulonephritis.[748]
Some patients with substantial volume expansion and marked pulmonary congestion do not respond to diuretics. In those individuals, dialytic support is appropriate, either hemodialysis or continuous venovenous hemofiltration in adults or peritoneal dialysis in children. Some patients develop substantial hyperkalemia. In those patients, exchange resins or dialysis may be useful. Importantly, so-called potassium sparing agents, including triamterene, spironolactone, and amiloride, should not be used in this disease state. Usually, patients undergo a spontaneous diuresis within 7 to 10 days after the onset of their illness and no longer require supportive care. [700] [749] There is no evidence to date that early treatment of streptococcal disease, either pharyngitic or cellulitic, will alter the risk of post-streptococcal glomerulonephritis. It has long been speculated whether penicillin can control the spread of outbreaks of epidemic poststreptococcal glomerulonephritis. In studies from aboriginal communities in Australia, the use of benzathine penicillin prevented new cases of poststreptococcal glomerulonephritis, especially in children with skin sores and household contacts with affected cases.[750]
The long-term prognosis of patients with post-streptococcal glomerulonephritis is not as benign as previously considered. Widespread crescentic glomerulonephritis results in an increased number of obsolescent glomeruli associated with tubulointerstitial disease that results in progressive reduc-tion of the renal mass over time.[751] A proportion of patients with streptococcal glomerulonephritis develop hypertension, proteinuria and renal insufficiency from 10 to 40 years after the illness. [751] [752] [753] Nonetheless, it is most common that the long-term disease process is marked only by mild hypertension.
In some patients, there is evidence to suggest that the original diagnosis of post-streptococcal glomerulonephritis may have been in error. This is especially true for those individuals in whom a renal biopsy was never performed. For instance, a patient who has an upper respiratory tract infection and then develops a glomerulonephritis may be considered to have post-streptococcal glomerulonephritis, when in fact they have another proliferative form of glomerulonephritis. In these patients, lack of resolution of their renal disease should prompt a renal biopsy to elucidate the underlying cause of the glomerular injury.
IgA Nephropathy
Epidemiology
IgA nephropathy remains one of, if not the most common glomerular lesion of all of the forms of glomerulonephritis. Initially described in the late 1960s by Berger and Hinglais, [754] [755] patients were described based on the finding of predominant IgA deposition (and, to a lesser extent other immunoglobulins) in the mesangium with a mesangial proliferation, and with clinical features that span the spectrum from asymptomatic hematuria to rapidly progressive glomerulonephritis. The disease process was initially considered a benign form of hematuria. However, over the past decades, it has become clear that up to 40% of patients may progress to end-stage kidney disease. Moreover, it has become recognized that, in addition to an idiopathic form of disease, IgA nephropathy is also associated with a variety of disease processes ( Table 30-13 ).
TABLE 30-13 -- IgA Nephropathy: The Syndrome [795] [810] [822] [906] [907] [976] [1324] [1325] [1326] [1327] [1328] [1329] [1330] [1331] [1332] [1333] [1334] [1335] [1336] [1337] [1338] [1339] [1340] [1341] [1342] [1343] [1344] [1345] [1346] [1347] [1348] [1349] [1350]
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Primary IgA nephropathy |
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Familial IgA nephropathy |
IgA nephropathy occurs in individuals of all ages, but it is still most common in the second and third decade of life, and it is much more common in males than females ( Table 30-14 ). IgA nephropathy is uncommon in children under 10 years of age. In fact, 80% of patients are between the ages of 16 and 35 at the time of renal biopsy, [756] [757] [758] [759] [760] [761] The male-to-female ratio has been described anywhere from 2:1 to 6:1. [756] [757] [758] [759] [760] [761]
TABLE 30-14 -- Diseases that Cause Glomerulonephritis[*]
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Glomerular Lesion |
N |
Male:Female Ratio |
White:Black Ratio |
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IgA nephropathy |
693 |
2.0:1.0 |
14.0:1.0 |
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MPGN I |
248 |
1.2:1.0 |
3.3:1.0 |
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Anti-GBM |
82 |
1.1:1.0 |
7.9:1.0 |
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ANCA-GN |
257 |
1.0:1.0 |
6.7:1.0 |
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Fibrillary glomerulonephritis |
76 |
1.0:1.2 |
14.3:1.0 |
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* |
Information in this table is from 9605 native kidney biopsies from the UNC Nephropathology Laboratory. This laboratory evaluates kidney biopsies from a base population of approximately 10 million throughout the southeastern United States and centered in North Carolina. The expected white-to-black ratio in this renal biopsy population is approximately 2 : 1. |
The distribution of IgA nephropathy varies in different geographic regions throughout the world.[762] It is the most common form of primary glomerular disease in Asia, accounting for up to 30% to 40% of all biopsies, 20% in Europe, and 10% of all biopsies performed for glomerular disease in North America.[762] The reason for this wide variance in incidence is partly attributable to indications for renal biopsy in Asia compared to those in North America. In Asia, urinalyses are performed routinely on children of school age, and renal biopsies of this population with asymptomatic hematuria may lead to an increased number of patients who have the diagnosis of IgA nephropathy. Genetic issues may also be important in the geographic difference. IgA nephropathy is rare in African Americans (see Table 30-14 ) [763] [764] and quite common in Native Americans of the Zuni and Navajo tribes.[765]The prevalence of IgA in the general population has been estimated to be between 25 and 50 cases per 100,000, [762] [766] although notably, almost 5% of all biopsied patients have at least some IgA deposits in their glomeruli.[767]Population studies in Germany and in France calculated an incidence of 2 cases per 10,000, [768] [769] [770] [771] although autopsy studies performed in Singapore[772] suggested that 2% to 4.8% of the population had IgA deposition in their glomeruli.
Genetics
IgA nephropathy is a histological diagnosis that is unlikely to be due to a single genetic locus. In fact, the genetics of IgA nephropathy likely results from interaction of multiple susceptibility and progression genes in combination with environmental factors.[773] A number of studies suggest that there are genes that render an individual susceptible to IgA nephropathy and genes that portend a more rapid progression of IgA nephropathy. Polymorphism occurs in a number of genes, including the angiotensin converting enzyme, angiotensinogen, angiotensin II receptor, major histocompatibility loci, T cell receptor, interleukin-1 and -6, and interleukin receptor antagonist, transforming growth factor, mannose binding lectin, uteroglobin, nitric oxide synthesis, and tumor necrosis factor. [774] [775] [776] [777] [778] [779] [780] There have been a number of studies examining in the angiotensin converting enzyme (ACE) gene in IgA nephropathy with or without progressive disease. [781] [782] [783] Data obtained[784] in a group of 168 white patients with IgA nephropathy suggest that the angiotensinogen gene and the insertion-deletion polymorphism of the angiotensin converting enzyme were important markers for predicting progression to chronic renal failure.[784] Studies in this arena have been relative small and, as a consequence, definitive statements about these genes in IgA nephropathy are difficult to make.
A familial form of IgA nephropathy has also been described. [785] [786] [787] [788] [789] IgA has been described in siblings and in twins. In some kindred, it may be associated with deafness. Familial IgA nephropathy must be differentiated from Alport syndrome. In Italy, the familial IgA nephropathy was linked in 60% of case to 6q22-23 locus and was associated with poor prognosis. The 20-year renal survival in these families was only 41% versus the 20-year renal survival in sporadic cases of 94%.[790] Ghavari[791] studied 30 kindred with IgA nephropathy and found a strong linkage on chromosome 6q22-23 with a load score of 5.6. This was not linked to a major histocompatibility locus, uteroglobin, the IgA Fc receptor, or galactosyl transferase. Uteroglobin is an antiinflammatory protein that binds to IgA fibronectin complexes, thereby reducing their inflammatory potential. Interestingly, uteroglobin knockout mice develop IgA nephropathy. Some Japanese patients with IgA nephropathy are homozygous for muta-tions of uteroglobin and have low uteroglobin plasma levels.[777] Italian patients with IgA nephropathy have an in-creased amount of uteroglobin bound to IgA fibronectin complexes.[792]
The prevailing hypothesis pertaining to the pathogenesis of IgA nephropathy pertains to defects in protein glycosylation, particularly in B cells secreting IgA1. It has been difficult, however, to demonstrate consistent defects in the β-1,3-galactosyltransferase enzyme that places galactose on O-linked carbohydrate side chains of the IgA1 molecule. Recently, the gene responsible for protein glycosylation of the Tn antigen on red blood cells in patients with the autoimmune disease known as Tn syndrome has been discovered.[793] This gene, known as Cosmc, is located on the X chromosome and is a molecular chaperone for an enzyme T-synthase that glycosylates the Tn antigen on defective red blood cells in the Tn syndrome. This defect was similarly found in B cells from IgA nephropathy.[794] The defect in IgA nephropathy may be due to an improper folding of the β-1,3-galactosyltransferase enzyme, reducing its activity in B cells in patients with IgA nephropathy.
Pathology
Immunofluorescence Microscopy
IgA nephropathy can only be definitively diagnosed by the immunohistologic demonstration of glomerular immune deposits that stain dominantly or co-dominantly for IgA compared to staining for IgG and IgM ( Fig. 30-23 ). [795] [796] [797] [798] The staining is usually exclusively or predominantly mesangial, although a minority of specimens, especially from patients with severe disease, will have substantial capillary wall staining. By definition, 100% of IgA nephropathy specimens stain for IgA. On a scale of 0 to 4+, the mean intensity of IgA staining is approximately 3+.[797] IgM staining is observed in 84% of specimens with a mean intensity (when present) of only approximately 1+. IgG staining is observed in 62% of specimens, also with a mean intensity (when present) of approximately 1+. Early studies of IgA nephropathy described more frequent and more intense IgG staining than is seen today, but this probably was caused by less specific antibodies that cross reacted between IgA and IgG. Almost all IgA nephropathy specimens have substantial staining for C3 but staining for C1q is rare and weak when present. If there is intense staining in a specimen that has substantial IgA and IgG, the possibility of lupus nephritis rather than IgA nephropathy should be considered.[797] An additional relatively distinctive feature of IgA nephropathy is that, unlike any other glomerular immune complex disease, the immune deposits usually have more intense staining for lambda light chains than kappa light chains. [795] [797]
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FIGURE 30-23 Immunofluorescence micrograph of a glomerulus with IgA nephropathy showing intense mesangial staining for IgA. (FITC anti-IgA, ×300.) |
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Electron Microscopy
The ubiquitous ultrastructural finding is mesangial electron dense deposits that correspond to the immune deposits seen by immunohistology (Figs. 30-24 and 30-25 [24] [25]).[796] The mesangial deposits often are immediately beneath the perimesangial basement membrane. They are accompanied by varying degrees of mesangial matrix expansion and hypercellularity. Most specimens do not have capillary wall deposits, but a minority, especially from patients with more severe disease, will have scattered subendothelial dense deposits or subepithelial dense deposits or both. The extent of endocapillary proliferation and leukocyte infiltration parallel the pattern of injury observed by light microscopy. Epithelial foot process effacement is observed in those patients with substantial proteinuria.
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FIGURE 30-24 Diagram depicting the ultrastructural features of IgA nephropathy. Note the mesangial dense deposits (straight arrow) and mesangial hypercellularity. (Reproduced with permission of J.C. Jennette.) |
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FIGURE 30-25 Electron micrograph of a capillary and adjacent mesangium from a patient with IgA nephropathy showing mesangial dense deposits immediately beneath the paramesangial basement membrane (magnification ×7000). |
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Light Microscopy
IgA nephropathy can cause any of the light microscopic phenotypes of proliferative glomerulonephritis ( Fig. 30-26 ) or may cause no discernible histologic changes. [796] [797] [798] [799] [800] [801] [802] [803] As depicted in Figure 30-18 , this spectrum of glomerular inflammatory responses is shared by a variety of glomerulonephritides that have different etiologies but induce similar or identical light microscopic alterations in glomeruli. Figure 30-18 also depicts the most frequent clinical manifesta-tions of the different histologic phenotypes of glomerulonephritis, all of which can be caused by IgA nephropathy. At the time of biopsy, IgA nephropathy usually manifests as a focal or diffuse, mesangioproliferative or proliferative glomerulonephritis, although a few patients will have no lesion by light microscopy, a few patients will have aggressive disease with crescents, and occasional patients will already have chronic sclerosing disease. Different criteria for renal biopsy result in different frequencies of the various phenotypes of IgA nephropathy among different series of patients. If nephrologists who are contributing patients to series have liberal criteria, for example performing biopsies on patients with hematuria, normal renal function and little or no proteinuria, the phenotypes of IgA nephropathy will be skewed to the left of the diagram in Figure 30-18 . Alternatively, if the contributing nephrologists reserve biopsy only for patients with some degree of renal insufficiency or substantial proteinuria, the IgA nephropathy phenotypes will be skewed to the right. Of 668 consecutive native kidney IgA nephropathy specimens diagnosed in the UNC Nephropathology Laboratory, 4% had no lesion by light microscopy, 13% had exclusively mesangioproliferative glomerulonephritis, 37% had focal proliferative glomerulonephritis (25% of these had <50% crescents), 28% had diffuse proliferative glomerulonephritis (45% of these had <50% crescents), 4% had crescentic glomerulonephritis (50% or more crescents), 6% had focal sclerosing glomerulonephritis without residual proliferative activity, 6% had diffuse chronic sclerosing glomerulonephritis, and 2% had lesions that did not fall within this categorization.
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FIGURE 30-26 Light micrograph of a glomerulus with IgA nephropathy showing segmental mesangial matrix expansion and hypercellularity (straight arrow), and an adhesion to the Bowman capsule (curved arrow). (PAS, ×300.) |
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The mildest light microscopic expression of IgA nephropathy, other than no discernible lesion, is focal or diffuse mesangial hypercellularity without more complex endocapillary hypercellularity, such as endothelial proliferation or influx of leukocytes. This is analogous to class II lupus nephritis. More severe inflammatory injury causes focal (involving less than 50% of glomeruli) or diffuse proliferative glomerulonephritis as the pathologic expression of IgA nephropathy, which is pathologically analogous to class III and class IV lupus nephritis. The lesions are characterized by not only mesangial hypercellularity but also some degree of endothelial proliferation or leukocyte infiltration that distorts or obliterates some capillary lumens. Extensive necrosis is rare in IgA nephropathy, although slight focal segmental necrosis with karyorrhexis often occurs in severely inflamed glomeruli. With time, destructive glomerular inflammatory lesions progress to sclerotic lesions that may form adhesions to Bowman capsule. Occasional patients with IgA nephropathy will have focal glomerular sclerosis by light microscopy that is indistinguishable from focal segmental glomerulosclerosis until the immunofluorescence microscopy is taken into consideration. Because of the episodic nature of IgA nephropathy, many patients will have combinations of focal sclerotic lesions and focal active proliferative lesions. Patients with the most severe IgA nephropathy have crescent formation because of extensive disruption of capillaries.[803] Advanced chronic disease is characterized by extensive glomerular sclerosis associated with marked tubular atrophy, interstitial fibrosis, and interstitial infiltration by mononuclear leukocytes.
Pathogenesis
Thirty years after the first description of IgA nephropathy, the pathogenesis of this disease is becoming clearer. [661] [804] The characteristic pathologic finding by immunofluorescence microscopy of granular deposits of IgA and C3 in the glomerular mesangium, and in the case of Henoch-Schönlein purpura, in dermal capillaries suggests that this disease is the result of the deposition of circulating immune complexes leading to the activation of the complement cascade via the alternate pathway. The deposited IgA is predominantly polymeric IgA-1. [805] [806] [807] [808] The fact that polymeric IgA-1 is usually derived mainly from the mucosal immune system, and the association of some cases of IgA nephropathy with syndromes that affect the respiratory tract or gastrointestinal tract, has led to the suggestion that IgA nephropathy is a disease of the mucosal immune system.[809] This concept was supported by the finding in some patients with IgA nephropathy of Ig antibodies to dietary antigens or various infectious agents, both viral and bacterial. [810] [811] [812] [813] [814] [815] [816] [817] [818] [819] [820] [821] [822] [823] This concept is also supported by the clinical observations that in some patients with IgA nephropathy, the hematuria increases acutely at the time of upper respiratory tract or gastrointestinal infections. However, it has now been determined that the increased polymeric IgA-1 antibody synthesis is reduced from the mucosa but is increased after systemic immunization. [806] [824] [825] In addition, increase in IgA secreting B cells was documented both from the peripheral blood of patients[826] and in the bone marrow.[827] It is unlikely that the pathogenesis of IgA nephropathy is related to a quantitative increase in serum levels of polymeric IgA-1, as those are only modestly increased, [806] [828] and the occurrence of IgA nephropathy in patients with IgA myeloma or AIDS is decreased despite very high levels of circulating IgA in these diseases.[828] In addition, the inability to identify a consistent antigen associated with IgA deposition in IgAN argues against the concept that this disease is primarily due to the deposition of circulating immune complexes. Alternatively, the deposition of IgA in IgAN may occur by mechanisms other than classical antigen antibody interactions.[806]
It has been suggested that rather than a quantitative abnormality in IgA antibodies in this disease, the anomaly may be in the IgA molecule itself, namely in its glycosylation.[829] In humans, the heavy chain of IgA-1, but not IgA-2, contains a hinge region which includes five serine residues. To these serine residues, are O-linked mono- or oligosaccharides consisting of N-acetylgalactosamine (GalNac). This GalNac is usually substituted with a terminal galactose.[830] It has been demonstrated by lectin-binding studies and by carbohydrate composition that the IgA-1 in patients with IgA nephropathy contains less terminal galactose than that of healthy controls. [806] [831] As IgA-1 is normally cleared from the circulation by the liver via the asialoglycoprotein receptor (ASGPR), [832] [833] [834] it is thought that the defective galactosylation of the hinge region in IgA-1 may lead to decreased clearance of IgA-1 molecule in patients with IgA nephropathy. [835] [836] This altered galactosylation also leads to an increased binding of polymeric IgA-1 in the kidney. [829] [836] [837] This defect in IgA-1 glycosylation is thought to be synthetic rather than degradative.[838] It has now been demonstrated that there is a reduced activity of the beta-1,3 galactosyl transferase (beta-1, 3GT), (the specific enzyme responsible for galactosylation of olein sugars), in B cells of patients with IgA nephropathy. However, the activity of that enzyme in other cells is maintained intact compared to normal controls. [806] [839]
The pathogenesis of IgA nephropathy is most likely a consequence of defective mucosal immunity.[840] As a consequence of this abnormality, there is exposure to any number of environmental antigens that may stimulate IgA-1 B cells. Defective beta-1,3 galactosyltransferase in these B cells results in exaggerated synthesis of galactose deficient IgA-1 molecules in the circulation. [831] [839] [841] Autoantibody response to galactose deficient IgA-1 molecule results in circulating immune complexes that are poorly removed by the reticuloendothelial system.[842] Galactose-deficient IgA-1 molecules also deposit in the mesangium where they induce a variety of phlogistic mediators including cytokines, chemokines, and growth factors. [843] [844] [845] A mesangial receptor for IgA immune complexes has now been identified.[846] In addition, IgA1-containing immune complexes alter the proliferation of mesangial cells as well.[847]
The existence, nature, and role of other autoantibodies in IgA nephropathy is also a hypothesis under investigation. A number of autoantibodies to various putative autoantigens have been described in IgA nephropathy and have recently been reviewed.[848] Such autoantigens include a mesangial cell membrane antigen,[849] endothelial cells (human umbilical vein endothelial cells), [811] [848] single-stranded DNA,[811] cardiolipin, [811] [850] and antibodies to galactose deficient IgA-1 models. Most of these autoantibodies were found in a subset of patients rarely exceeding 3% of patients with IgA nephropathy and may sometimes be the result of high circulating levels of IgA in these patients.[850] The presence of IgG anti-neutrophil cytoplasmic autoantibodies has been described to occur in a minority of patients with IgA nephropathy.[851] In addition, IgA ANCA have been rarely associated with a systemic vasculitis of the Henoch-Schönlein purpura type. [852] [853] [854] In the setting of IgA ANCA, the autoantigen seems to be different from the major ANCA autoantigens, namely myeloperoxidase (MPO) and proteinase 3 (PR3). Circulating IgA-fibronectin complexes have also been described in the circulation of patients with IgA nephropathy and HIV infection.[855] The fibronectin in these complexes may then mediate binding to collagen. However, these complexes may not be true immune complexes and once again may be directly related to increased IgA levels in patients with IgA nephropathy.[856] Lastly, IgA rheumatoid factor has been described in about 50% of patients with IgA nephropathy [857] [858] and may have a functional role in the impaired solubilization of antigen antibody complexes.[859]
An alternative hypothesis as to the increased levels of serum IgA in patients with IgAN is that of increased production of IgA antibodies rather than a decrease in the hepatic clearance due to abnormal glycosylation. Previous studies have suggested increases in circulating IgA-bearing cells in peripheral blood[860] as well as an increase in the in vitro production of IgA by peripheral blood lymphocytes. [861] [862] [863] More recent data suggests that polymorphisms in the regulatory region of the I alpha-1 gene may account for the hypersynthesis of IgA in patients with IgA nephropathy. [864] [865]
Regardless of the mechanism leading to the increased deposition of IgA or IgA-containing immune complexes in the glomeruli, the mechanisms responsible for the glomerular injury remains poorly understood, especially when one keeps in mind the poor phlogistic nature of IgA and its inability to activate complement. Despite the demonstration of a specific IgA receptor on mesangial cells[866] and in the glomerulus of patients with IgA nephropathy,[867]studies of the expression of Fc-alpha R on peripheral blood mononuclear cells and granulocytes led to conflicting results. [867] [868] IgAN may be linked to the expression of an IgAN-specific variant of Fc alpha R receptor on monocytes.[869] The role, if any, of Fc alpha R in the pathogenesis of IgA nephropathy remains to be elucidated. Alternatively, IgA-IgG immune aggregates have been hypothesized to activate C3 by the IgG contained in those aggregates.[870]
Clinical Features and Natural History
Approximately 40% to 50% of patients present with macroscopic hematuria at the time of their initial presentation. The episodes tend to occur with a close temporal relationship to upper respiratory infection, including tonsillitis or pharyngitis. This synchronous association of pharyngitis and macroscopic hematuria has been give the name “synpharyngitic” nephritis. Much less commonly, episodes of macroscopic hematuria may follow infections that involve the urinary tract or gastroenteritis. Macroscopic hematuria may be entirely asymptomatic, but more often is associated with dysuria that may prompt the treating physician to consider bacterial cystitis. Systemic symptoms are frequently found, including nonspecific symptoms such as malaise, fatigue, muscle aches and pains, and fever. Some patients present with abdominal or flank pain. [871] [872] In a minority of patients (<5%), malignant hypertension may be an associated presenting feature.[873] In the most severe cases (less than 10%), acute glomerulonephritis results in acute renal insufficiency and failure. [874] [875] Recovery typically occurs with resolution of symptoms, even in those patients who have been temporarily dialysis dependent.[875]
Macroscopic hematuria due to IgA nephropathy occurs more often in children than young adults. When it occurs in older individuals, it should raise the possibility of the more common causes of urinary tract bleeding, such as stones or malignancy.
The second most common presentation is that of microscopic hematuria, occurring in 30% to 40% of patients. Patients with IgA nephropathy present for evaluation of asymptomatic hematuria with or without the presence of proteinuria. In addition to glomerulonephritis, these patients may commonly have hypertension. In fact, in white patients with hypertension and hematuria, IgA nephropathy is the most common form of hematuria.[876] Intermittent macroscopic hematuria occurs in 25% of these patients. Microscopic hematuria and proteinuria persist between episodes of macroscopic hematuria.
Approximately one third of patients with IgA nephropathy present with macroscopic hematuria, one third present with microscopic hematuria (with or without proteinuria) and the final one third of patients have a variety of presentations, including the nephrotic syndrome or chronic glomerular disease.
Patients presenting with the nephrotic syndrome may have a widespread proliferative glomerulonephritis, or coexisting of IgA nephropathy and minimal change glomerulopathy.[877] Finally, some patients with IgA nephropathy have reached end-stage renal disease at the time of their first presentation. These individuals typically have had asymptomatic microscopic hematuria and proteinuria that has remained undetected.[874]
In addition to idiopathic IgA nephropathy, IgA nephropathy may be the glomerular expression of a systemic disease (see Table 30-13 ). For example, patients with Henoch-Schönlein purpura have abdominal pain, arthritis, a vasculitic rash, and a glomerulonephritis that is indistinguishable from primary IgA nephropathy. This condition is discussed more fully in the next chapter.
Although IgA nephropathy was thought to carry a relatively benign prognosis, it is estimated that 1% to 2% of all patients with IgA nephropathy will develop end-stage renal failure each year from the time of diagnosis. In a study of 1900 patients derived from 11 separate series, the long-term renal survival was estimated to be 78% to 87% within a decade of the presentation.[878] Similarly, European studies have suggested that renal insufficiency may occur in 20% to 30% of patients within two decades of the original presentation.[760] In a study from Hong Kong, patients with mild IgA nephropathy were followed prospectively. Significant proteinuria or renal insufficiency was found in a number of patients, suggesting that, even in patients presenting with milder forms of disease, there is a significant risk of progression.
Nonetheless, there are patients in whom there is no tendency toward progressive disease, whereas other patients have a fulminate course resulting in a rapid progression to end-stage renal disease.[879] Several studies have assessed features that predict a poor prognosis. Sustained hypertension, persistent proteinuria (especially proteinuria over 1 gram), impaired renal function, and the nephrotic syndrome, constitute poor prognostic markers. [798] [880] [881] [882]Male gender and an older age at the onset of disease may also connote a poor prognosis. [881] [883] [884] [885] [886] [887] Controversy persists with respect to the issue of recurring bouts of macroscopic hematuria.[888] It is possible that macroscopic hematuria is an overt manifestation of disease and, therefore, identifies patients earlier in the course of their disease. Alternatively, macroscopic hematuria may represent an episodic process that results in self-limited inflammation, in contrast to persistent hematuria that represents ongoing, low-grade inflammation. In general, persistent microscopic hematuria is associated with a poor prognosis.[889] It is important to note that acute renal failure associated with macroscopic hematuria does not affect long-term prognosis. The fact that acute renal failure does occur during gross episodes of hematuria has been confirmed. [890] [891] [892] In these patients, the acute renal failure is most likely associated with acute tubular damage and not too crescentic disease. After the episodes of gross hematuria, renal function typically returns to baseline and the long-term prognosis is good. The degree of proteinuria is more than likely an additional marker of glomerular disease. Whether this is a consequence of the relationship between proteinuria and tubular dysfunction found in many forms of glomerular disease or specific to IgA nephropathy is not clear. In a study by Chen,[893] mice that had been proteinuric by various methods had enhanced deposition of administered IgA immune complexes. This suggests that these complexes might be more easily deposited in proteinuric states. More importantly, the amount of protein excretion one year after diagnosis was highly predictive of the development of end-stage renal disease within 7 years of subsequent follow-up. Individuals with less than 500 mg/dL per 24 hours had no renal failure within 7 years whereas those with over 3 g had approximately 60% chance of end-stage renal disease.[894]
Histological features that are associated with progression to end-stage renal disease include interstitial fibrosis, tubular atrophy, and glomerular scarring. Presence or absence of immune deposits in capillary loops and the mesangium, and crescent formation have also been correlated with disease. Whether crescents found on renal biopsy constitute a poor prognostic factor has also been a controversial issue. Crescentic glomerulonephritis is most likely to occur in patients who have macroscopic hematuria. Thus, it is not clear whether the presence of crescentic disease can be separately associated with a poor prognosis. However, in IgA as in other forms of glomerular disease, the severity of tubulointerstitial nephritis appears to correlate more closely with the risk of progression than with glomerular damage.
Women with IgA tolerate pregnancy well. Only those women with uncontrolled hypertension, a glomerular filtration rate less than 70 ml/min, or severe arteriolar or interstitial damage on renal biopsy are at risk for renal dysfunction.[895] [896] Pregnant women with creatinine levels greater than 1.4 mg/dL have a higher propensity for hypertension and a progressive increase in creatinine during the course or pregnancy, and pregnancy-related loss of maternal renal function occurs in 43% of patients. The infant survival rate was 93% in this study, and pre-term delivery occurred in almost two thirds, and growth retardation in one third of infants.[897]
Laboratory Findings
To date, there are no specific serologic/laboratory tests diagnostic of IgA nephropathy or Henoch-Schönlein purpura. Although the serum IgA levels are elevated in up to 50% of patients, the presence of elevated IgA in the circulation is not specific for IgA nephropathy. The detection of IgA-fibronectin complexes was initially thought to be a marker in patients with IgA nephropathy. [898] [899] [900] This was not proven a clinically significant test. In our own experience, some patients with IgA nephropathy have elevated IgA-fibronectin levels that are maintained throughout the course of their disease, whereas in other patients, IgA fibronectin levels are never discovered. Polymeric IgA also appears to be found in some patients with IgA nephropathy. [805] [901] [902] [903] [904] [905] The polymeric IgA itself appears to be that of the IgA1 subclass. IgA may also be contained in circulating immune complexes that are non-complement binding. Similar immune complexes have been described in Henoch-Schönlein purpura. [906] [907] [908] [909] [910] [911] [912] [913] [914] [915] [916] [917] [918] [919] [920] [921] [922] [923] The level of circulating immune complexes wax and wane and may sometimes correlate with episodes of macroscopic hematuria. In one interesting study, the level of circulating immune complexes was increased after patients drank cow's milk. This phenomenon occurred in 10% to 15% of patients, possibly suggesting sensitivity to bovine serum albumin. Unfortunately, none of these findings is pathognomonic of IgA nephropathy.
Some patients with IgA nephropathy have antibodies to the glomerular basement membrane,[924] the mesangium, [925] [926] glomerular endothelial cells,[810] and IgA rheumatoid factor. [857] [858] The IgA rheumatoid factor has been found and may participate in the pathogenetic process. [857] [858] Others have found antibodies to anti-neutrophil cytoplasmic constituents, [812] [813] although it is possible that the IgA ANCA are a laboratory artifact.[858]Antibodies to infectious agents such as herpes, Haemophilus parainfluenza, and normal pathogens found in both the respiratory tract as well as in the gut have been described, as well as antibodies to both bovine serum proteins and soy proteins. [815] [816] [817] [818] [819] [820] [821] [822] [927] [928] Until studies demonstrate that certain patients have sensitivity to a particular pathogen or food allergen, it is difficult to know whether to obtain antibody testing to eliminate certain foods from the patient's diet. None of these antibody tests has been standardized well enough in large patient populations to make their study in all patients with IgA nephropathy meaningful.
Complement levels such as C3 and C4 are typically normal and, in some patients, even elevated,[929] as are complement components C1q, C2-C9. [758] [906] [907] [929] [930] The fact that these complement levels are normal may belie the fact that either the alternate or the classical pathway of complement may be activated. In this regard, C3 fragments are increased in 50% to 75% of patients, [931] [932] as well as C4 binding protein concentrations.[930]
A typical finding is microscopic hematuria on urinalysis that may persist, even at very low levels of macroscopic hematuria. The finding of dysmorphic erythrocytes in the urine is typical.[933] Proteinuria is found in many patients with IgA nephropathy, although the majority of them have less than one gram of protein per day. Patients who have a more persistent course or a more aggressive diffuse proliferative glomerulonephritis may have a greater amount of proteinuria. Other factors found in the urine of patients with IgA nephropathy include platelet-derived growth factor and interleukin-6. The initial interest in elevated urinary interleukin-6 is tempered by the fact that this same protein is found in association with urinary tract infections. [934] [935] [936]
A frequently asked question is whether skin biopsy provides any diagnostic utility in patients with IgA nephropathy. In one study, the sensitivity of finding dermal capillary IgA deposits in the skin of patients with IgA nephropathy was found to be 75% with a specificity of 88%.[937] When the IgA is present along the dermal capillaries, it is also accompanied by C3, properdin, and fibrin deposits. [937] [938] [939] [940] In these biopsies, it is important to note that IgG or IgM should not be found in the dermal vasculature. If they are, other diagnoses, such as systemic lupus erythematosus, should be considered. The value of skin biopsy in recurrent episodes of macroscopic hematuria has not gained widespread acceptance, largely because of the substantial variation in sensitivity and specificity of skin biopsies in finding IgA in patients with nephropathy.[940]
Treatment
Without a clear understanding of the pathogenesis of IgA nephropathy, it is difficult to describe precise treatment for this condition. As in any form of chronic renal insufficiency, antihypertensive therapy may ameliorate a possibility of secondary glomerular damage. The angiotensin converting enzyme inhibitors have been demonstrated to be beneficial in IgA in reducing proteinuria, even in normotensive patients with IgAN nephropathy.[941] A report by Woo suggests that in patients with normal renal function and mild proteinuria (<500 mg/day), blood pressure should be controlled with an ACE inhibitors or angiotensin receptor blockers.[942] These agents may also improve proteinuria due to altering glomerular size selectivity.[943] In a retrospective analysis, ACE inhibitors were compared to other anti-hypertensive medicines. The ACE-inhibitor treated group experienced a slower loss of renal function and a higher percentage of remission of proteinuria than the no treatment group.[944] These agents have been similarly demonstrated to decrease the deterioration in renal function when compared to beta blockers.[945] In the ACE gene DD genotype, anti-proteinuric effects of the ACE inhibitor were more profound in patients with the DD genotype than in other patients with IgA nephropathy.[781] The combined effects of ACE-inhibitors and angiotensin receptor blocker (ARB) was assessed in a large controlled trial in which 263 patients with non-diabetic kidney disease were randomized to trandolapril alone, losartan alone or both drugs.[946] Fifty percent of enrolled patients had IgA nephropathy. All patients received other antihypertensive medications to maintain a target blood pressure <130/80 mm Hg. Compared to either agent alone, the combination of trandolapril and losartan resulted in a significantly greater reduction in proteinuria and decreased likelihood of reaching the combined primary endpoint of time to doubling of serum creatinine or reaching end stage kidney disease. The combination therapy was not associated with a higher frequency of side effects (including hyperkalemia).
Therapy with glucocorticoids for IgA nephropathy has generated substantial controversy. While prednisone was initially considered to be without effect,[947] some cohort studies suggest that corticosteroids may have an important effect, [948] [949] Recently, a randomized trial demonstrated that glucocorticoids may be useful in patients with IgA nephropathy and well-preserved renal function (serum creatinine <1.5 mg/dL and proteinuria between 1 and 3.5 gm/day).[950] Patients were treated with IV methylprednisolone for three consecutive days in months 1, 3, and 5 and oral prednisone given at a dose of 0.5 mg/kg qod for months 1 to 6, compared to standard therapy. After a 5-year follow-up, the risk of a doubling in plasma creatinine was significantly lower in the corticosteroid-treated patients, who also showed a significant decrease in mean urinary protein excretion after 1 year that persisted throughout the follow-up.[950] This beneficial effect was maintained after 10 years of follow up as reflected by a renal survival (failure to double the serum creatinine) of 97% in the treated group as compared to 53% (log rank test P = 0.0003) in the placebo group.[951] On the other hand, in the multicenter, randomized controlled trial conducted by the Southwest Pediatric Nephrology Study Group,[952] there was no statistically significant improvement in the rate of renal failure (defined as a 60% decrease in GFR) among patients who were treated with an alternate day regime of high dose prednisone (60 mg/M2 every other day for 3 months, then 40 mg/M2 every other day for 9 months, then 30 mg/M2 every other day for 12 months) when compared to placebo. This negative result is however mitigated by the fact that patients in the placebo group had a statistically significantly lower degree of proteinuria at baseline. The potential role of corticosteroids in the management of IgA nephropathy was also evaluated in a metaanalysis of six randomized trials in which various regimen were compared to placebo or dipyridamole and encompassing a total or 181 patients.[953] This analysis did not include the study by the Southwest Pediatric Nephrology Study Group.[952] Based on this analysis, the use of corticosteroids was associated with a decreased risk of doubling serum creatinine (RR 0.45; 95% CI 0.29, 0.69) or reaching ESKD (RR 0.44; 95% CI 0.25, 0.80).
Another circumstance in which prednisone has a demonstrated substantial beneficial effect is in the treatment of patients with IgA nephropathy and concurrent minimal change glomerulopathy. These patients have nephrotic-range proteinuria and diffuse foot process fusion. They respond to prednisone in a manner very similar to that of patients with minimal change glomerulopathy. [194] [877] [954] However, the nephrotic syndrome might also be a consequence of advanced glomerular scarring or diffuse proliferative glomerulonephritis. In these patients, resolution of the nephrotic syndrome by corticosteroids is not as forthcoming.
More aggressive treatment may be appropriate in patients with progressive IgA nephropathy. In a randomized, controlled trial, patients with a serum creatinine >1.5 mg/dL and a GFR declining at a rate >15% per year received either no immunosuppression or were treated with oral prednisolone (initially at 40 mg/day) and cyclophosphamide (at 1.5 mg/kg/day) for 3 months followed by 2 years of azathioprine (1.5 mg/kg/day).[955] Over a follow-up of 2 to 6 years, treated patients had 72% 5-year renal survival, versus only 6% in untreated patients.[955] This approach of prednisone coupled with oral azathioprine for 2 years in patients with over 2.5 g of proteinuria was also observed in a retrospective survey by Goumenos. [956] [957]
In patients who have rapidly progressive glomerulonephritis with widespread crescentic transformation, there are reports on the use of pulse methylprednisolone, oral prednisone, and/or cyclophosphamide. [958] [959] [960] It is reasonable to treat crescentic disease in IgA nephropathy in a manner similar to other forms of crescentic glomerulonephritis (e.g., ANCA glomerulonephritis). Of concern, however, was the finding in 12 patients of the persistence of crescents on repeat biopsy, despite the early and aggressive treatment with pulse methylprednisolone and oral prednisone, and a short-term reversal of the acute crescentic glomerulonephritis.[960] This study suggests that there was only a diminution in the rate of progression to end-stage renal disease.
Other Modalities
It is reasonably clear that treatment with the combination of oral cyclophosphamide, dipyridamole, and low-dose warfarin[961] has very little long-term benefit in patients with IgA nephropathy. At 8 years, there was no difference between placebo and control patients, and 25% to 30% of patients in both groups had progressed to end-stage renal disease.
Whether mycophenolate mofetil is useful in the treat-ment of IgA nephropathy has not been established. Four randomized trials of MMF have been published with conflicting results. [962] [963] [964] [965] The studies based in China and Hong Kong report a beneficial effect of MMF on proteinuria and hyperlipidemia [962] [963] without an effect on renal function.[962] On the other hand the two placebo controlled studies of MMF in white populations of 32 and 34 patients failed to demonstrate a benefit of MMF on proteinuria or the preservation of renal function. [964] [965] It is noteworthy however that in one study,[964] patients had relatively advanced renal insufficiency (mean serum creatinine of 2.4 mg/dL). Collectively, these underpowered studies fail to establish a role for MMF in IgA nephropathy and raise the question as to whether certain ethnic groups (Asians) may be more responsive to this form of therapy. MMF is currently the focus of a large randomized placebo-controlled trial in the United States.[966]
Intravenous immunoglobulins have been used in at least one study for IgA nephropathy.[967] Treatment of 9 patients with IgA nephropathy produced some favorable results, including a reduction in proteinuria, hematuria, and leukocyturia. There was a decrease in the progressive decline in renal function. The conclusions of these studies must be tempered by the relatively small numbers of patients enrolled in any of them, and the absence of appropriate control populations.
There has been much discussion in the literature about the use of tonsillectomy in IgA nephropathy. The results of the retrospective trials are inconsistent. [968] [969] [970] Based on a retrospective multivariate analysis 969 of large cohort of patients (329 patients) from Japan, treatment with tonsillectomy and pulse glucocorticoid therapy (methylprednisolone [0.5 g/day for 3 days for three courses] followed by oral prednisolone at an initial dose of 0.6 mg/kg on alternate days, with a decrease of 0.1 mg/kg every 2 months) was associated with clinical remission. Similarly, a multivariate analysis[971] of the focusing on the subgroup of patients 70 patients from the same cohort with a baseline serum creatinine >1.5 mg/dL, treatment with the combination of tonsillectomy and pulse glucocorticoids was associated with improved long-term renal survival. Another retrospective analysis[968] however, showed no benefit of tonsillectomy on the clinical course of IgA nephropathy. No study has yet demonstrated a superiority of tonsillectomy alone, or superiority over similar course of pulse glucocorticoids, and no randomized controlled trials assessing the value of tonsillectomy has been performed. At this point, there is therefore no convincing evidence in support for tonsillectomy in the treatment of IgA nephropathy. Such measure could however be beneficial in patients with recurrent tonsillitis.
Fish Oil
The advent of treatment of IgA nephropathy with fish oil has led to substantial difficulties in treatment of the individual patient with IgA nephropathy. Because of the widespread publicity of the potential beneficial effect of omega-3 fatty acids and IgA nephropathy, [972] [973] [974] it has been difficult to avoid this form of treatment in patients who have learned about it either from the news media or the Internet. A study by the Mayo Clinic[973] randomized 106 patients to either 12 grams of fish oil containing N-3 fatty acids or olive oil for 2 years. Only 6% of patients treated with fish oil had a doubling of their plasma creatinine concentration when compared to 33% of those treated with olive oil. In the fish oil-treated patients, only 14% excreted over 3.5 grams of protein per day, in contrast to 65% of those treated with olive oil. Impressively, the incidence of death or end-stage renal disease by 4 years of follow-up was 10% in the fish oil group and 40% in the olive oil-treated group. There was no difference between the two groups with respect to blood pressure control. The fish oil was apparently well tolerated. The enthusiasm for this approach must be tempered by two other much smaller trials that showed absolutely no benefit of fish oil therapy. [972] [975] A meta-analysis of the available trials suggested that some of the differences in the positive versus negative trials were a consequence of differences in follow-up time.[974] When all studies were combined, there was not a statistically significant benefit of fish oil therapy, although there was at least a minor beneficial effect. If any effect was to be observed with fish oil therapy, it was found in those individuals who had more proteinuria. In the multicenter, randomized controlled trial conducted by the Southwest Pediatric Nephrology Study Group,[952] treatment with Omacor 4 gm/day for 2 years was not associated with a statistically significant improvement in the rate of renal failure (defined as a 60% decrease in GFR) when compared to placebo. This negative result is however mitigated by the fact that patients in the placebo group had a statistically significantly lower degree of proteinuria at baseline.
Dietary Modification
If IgA nephropathy is a consequence of the mucosal immune reaction to certain dietary products, then a diet avoiding these products may have a salutary effect. In a study from Italy, a low antigen diet was used to treat 51 patients with IgA nephropathy. In these patients, a diet was selected to avoid most meats, all dairy products, eggs, and gluten. In this group of 21 patients, proteinuria fell in 12 whose baseline protein excretion was greater than 1 gram/day. A subsequent post-treatment biopsy suggested that there was a reduction in mesangial immunoglobulin deposition, C5 deposition, and fibrin. Similar results were described in an uncontrolled study of a gluten-free diet. These dietary modification studies must be subjected to a longer clinical trial.
There have been reports on a variety of potential mechanisms to decrease the level of IgA or to alter dietary anti-gen exposure. These include tonsillectomy,[976] antibiotics,[977] sodium cromoglycate,[978] or dietary manipulation.[979] [980] At-tempts at decreasing IgA production have been explored by using phenytoin. [981] [982] None of these approaches has been widely tested, nor are they considered approved treatment modalities.
In summary, patients with IgA nephropathy should be treated with an ACE inhibitor or angiotensin receptor blocker.[983] The use of the combination of an angiotensin receptor blocker and ACE inhibitor should be attempted especially in hypertensive patients who have substantial proteinuria. [946] [984] [985] This may occur without further decline in blood pressure. [986] [987] Patients with significant proteinuria and microscopic hematuria that persists over time should be considered for treatment with alternate month intravenous methylprednisolone and alternate-day corticosteroids. In those patients with progressive renal insufficiency, the use of prednisone and cyclophosphamide followed by azathioprine should be considered.[955] High-dose corticosteroids and/or cyclophosphamide should also be considered for patients with widespread crescentic glomerulonephritis, whereas patients with acute renal failure associated with tubular necrosis and little glomerular damage should be treated conservatively, as these individuals have an excellent long-term response. Although there is still no conclusive evidence of efficacy, the relatively benign side effect profile of omega-3 fatty acids warrants its use in patients who have an unfavorable prognosis. Those patients with the nephrotic syndrome and minimal change glomerulopathy may benefit from oral glucocorticoids. If there is a clear sensitivity to certain types of dietary products, it is useful to attempt an antigen-free diet.
Other Glomerular Diseases that Cause Hematuria
The clinical designation of benign familial hematuria often refers to thin basement membrane nephropathy. The prevalence of thin basement membrane nephropathy in the general population has been estimated from morphometry studies in transplant and allografts to be approximately 5.2% to 9.2%.[988] Similarly, of over 1078 native kidney biopsies, thin basement membrane nephropathy was found in 5% of patients.
Males and females are equally effected patients and are typically found to have microscopic hematuria when they are adolescents or young adults. The majority of patients have microscopic hematuria at presentation. Many have had previous urological examinations in search of a lower urinary tract source of bleeding, including cystoscopy and IVP or ultrasound. The presence of dysmorphic red cells or red cell casts may make the diagnosis of thin basement membrane nephropathy more readily apparent. Unlike IgA nephropathy, however, macroscopic hematuria is uncommon. [747] [989] Similarly, unlike many patients with IgA nephropathy, most have no proteinuria, although some may have mild to moderate proteinuria, usually less than 1 to 2 grams. [30] [990] [991] The pattern of hematuria is sometimes familial, and assessing the urine of family members can further complement a diagnosis. In some patients, there is no obvious pattern of inheritance. [30] [989] [992] [993] [994] In a search for hematuria in first-degree relatives, approximately one half of those undiagnosed patients may have hematuria. [993] [995] Father-to-son transmission, not found in X-linked hereditary nephritis, may be found in thin basement membrane nephropathy. It has long been known that Alport syndrome is a consequence of molecular defect in the COL-413/4 genes. Mutations within the COL-4A3 gene have been described in patients with familial hematuria.[996]
The long-term course of patients with thin basement membrane nephropathy is thought to be excellent. [30] [990] [997] In a study of 19 normotensive adults with normal renal function and hematuria, all patients had thin basement membrane nephropathy on biopsy. These patients were followed for a mean of 12 years. The incidence of hypertension in this population was 35% and was statistically more common than in healthy controls. Although thin basement membrane nephropathy has been thought to be of long-term benign prognosis, it is important to note that in this population, some patients have premature glomerular obsolescence, increased incidence of hypertension, and potential late onset of renal insufficiency. In this same study,[998] 6 of 89 first-degree elderly relatives had renal failure compared to only 1 of 129 relatives with IgA nephropathy. At the end of 12 years of follow-up, 3 of 7 subjects over the age of 50 had a slight decline in glomerular filtration rate.
Persistent isolated hematuria is also present in hereditary nephritis associated with Alport syndrome. [29] [999] [1000] By examining the urine of asymptomatic family members, it may be possible to elicit a hereditary cause. By history, hereditary nephritis is usually associated with an x-linked dominant form of inheritance[1001] and is associated with hearing loss and ocular abnormalities in many cases. It may be possible to differentiate thin basement membrane nephropathy from Alport disease by skin biopsy using an antibody to the alpha-5 chain of type IV collagen. In males with hereditary nephritis, there was no staining with this antibody along the epidermal basement membrane and, interestingly, there was discontinuous staining in female carriers who had no urinary abnormalities. In contrast, there was normal staining of this antibody in control patients.[1002]
The syndrome of loin pain hematuria is another condition causing hematuria. This uncommon syndrome occurs primarily in young women. [1003] [1004] [1005] Oral contraceptives have been associated with this condition. [1003] [1004] [1005] [1006] The clinical picture is reminiscent of that of IgA nephropathy. There are recurrent episodes of gross hematuria, usually with flank pain that is typically described as dull or aching. Patients sometimes have fever, malaise, and anorexia. Hypertension and proteinuria are uncommon. It has been suggested that the cause of the pain is due to small vessel thrombi resulting in infarction of the kidney. Thus, arteriograms have been performed which occasionally reveal narrowing of intrarenal vessels.[1005] In the few renal biopsies that have been performed, normal glomeruli have been demonstrated, [640] [1006] [1007] although C3 and IgM deposits have been found. Some patients have a substantial psychological overlay. Continued pain may lead to narcotics addiction.[1006] The treatment of loin pain hematuria usually begins with cessation of the oral contraceptives, [640] [1003] [1004] [1005] [1006] or treatment with anticoagulant drugs. There have been reports of a renal denervation by autotransplantation of the kidney,[1008] but 30% of these patients have recurrence of their symptoms. In a study by Lucas,[1009] 15 patients with loin pain hematuria were compared to 10 with nephrolithiasis and flank pain. Patients with loin pain hematuria syndrome tended to have somatic symptoms, adverse psychological events, and a history of analgesic ingestion to a greater degree than those patients with nephrolithiasis.[1005]
Fibrillary Glomerulonephritis and Immunotactoid Glomerulopathy
Nomenclature
Fibrillary glomerulonephritis and immunotactoid glomerulopathy are glomerular diseases that are characterized by patterned deposits seen by electron microscopy (Figs. 30-27 and 30-28 [27] [28]). [1010] [1011] [1012] [1013] [1014] [1015] [1016] [1017] There is controversy over how to categorize these diseases. Most renal pathologists prefer to distinguish fibrillary glomerulonephritis from immunotactoid glomerulopathy based on the presence of fibrils of approximately 20 nm diameter in the former and larger 30 nm to 40 nm diameter microtubular structures in the latter [1010] [1012] [1013] [1014] [1015] (see Figs. 30-27 and 30-28 [27] [28]). A minority of pathologists, however, advocate grouping glomerular diseases with either fibrillary deposits or microtubular deposits under the term immunotactoid glomerulopathy. [1014] [1017]
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FIGURE 30-27 Electron micrographs showing the glomerular deposits of fibrillary glomerulonephritis (A) and immunotactoid glomerulopathy (B). Note the random orientation of the former, and the microtubular appearance and greater organization of the latter (magnification ×20,000). |
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FIGURE 30-28 Algorithm for the pathologic categorization of glomerular diseases with patterned or organized deposits. The first dichotomy is into amyloid versus nonamyloid disease, and the second is into diseases caused by immunoglobulin molecule deposition versus those that are not. By the approach illustrated, fibrillary glomerulonephritis is distinguished from immunotactoid glomerulopathy based on the ultrastructural characteristics of the deposits. |
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Pathology
Electron Microscopy
The diagnosis of fibrillary glomerulonephritis requires the identification by electron microscopy of irregular accumulation of randomly arranged non-branching fibrils of approximately 20 nm diameter in glomerular mesangium or capillary walls or both [1010] [1011] [1012] [1013] [1014] [1015] [1016] [1018] ( Fig. 30-27A ). In capillary walls, the fibrillary deposits can be subepithelial, subendothelial, or intramembranous. The fibrillary deposits often contain blotchy electron dense material, but only rarely have associated well-defined electron dense deposits. The fibrils are distinctly larger than the actin filaments in adjacent cells, which is a useful observation that helps distinguish the fibrils of fibrillary glomerulonephritis from those of amyloidosis, which are only slightly larger than actin. The fibrils of fibrillary glomerulonephritis are not as large as the microtubular deposits of immunotactoid glomerulopathy or cryoglobulinemia, and they do not have the “fingerprint” configuration occasionally observed in lupus nephritis dense deposits. Most patients with fibrillary glomerulonephritis have substantial proteinuria and therefore there usually is extensive effacement of visceral epithelial foot processes.
The tubular substructure of the deposits of immunotactoid glomerulopathy is readily discerned at 5000 to 10,000 magnification ( Fig. 30-27B ). At this magnification, the deposits of fibrillary glomerulonephritis have no tubular structure. The microtubules of immunotactoid glomerulopathy also have a greater tendency to align in parallel arrays whereas the fibrils of fibrillary glomerulonephritis always are randomly distributed.[1018] The ultrastructural deposits of im-munotactoid glomerulonephritis resemble those seen with cryoglobulinemic glomerulonephritis, and thus the latter must be ruled out before making a diagnosis of immunotactoid glomerulopathy.
Light Microscopy
In fibrillary glomerulonephritis, extensive localization of fibrils in capillary walls causes capillary wall thickening. Mesangial localization causes increased mesangial matrix and usually stimulates mesangial hypercellularity. Varying distributions of the fibrillary deposits causes the light microscopic appearance of fibrillary glomerulonephritis to be extremely variable. [1010] [1011] [1012] [1013] [1014] [1015] [1016] Therefore, fibrillary glomerulonephritis can mimic the light microscopic appearance of membranoproliferative glomerulonephritis, proliferative glomerulonephritis, or membranous glomerulopathy. Crescents occur in the most aggressive phenotypes. Of 74 sequential fibrillary glomerulonephritis specimens evaluated at UNC, 28% had crescents with an average involvement of 29% of glomeruli (range 5% to 80%). The fibrillary deposits typically have a moth-eaten appearance when stained with a Jones silver methenamine stain. They are negative with Congo red staining, which distinguishes them from amyloid deposits. Immunotactoid glomerulopathy also has a varied light microscopic appearance. Combined capillary wall thickening and mesangial expansion is most common, often giving a membranoproliferative appearance.
Immunofluorescence Microscopy
The deposits of fibrillary glomerulonephritis almost always stain more intensely for IgG than for IgM or IgA, and many specimens have little of no staining for IgM and IgA. [1010] [1011] [1012] [1013] [1014] [1015] [1016] IgG4 is the dominant subclass. Only rare specimens have staining for only one light chain type. C3 staining usually is intense. The immunofluorescence staining pattern of fibrillary glomerulonephritis is relatively distinctive ( Fig. 30-29 ). It is not granular or linear, but rather has an irregular band-like appearance in capillary walls and an irregular shaggy appearance in the mesangium.
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FIGURE 30-29 Immunofluorescence micrograph of a glomerulus with fibrillary glomerulonephritis showing mesangial and bandlike capillary wall staining for IgG. (FITC anti-IgG, ×300.) |
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The deposits of immunotactoid glomerulopathy usually are IgG dominant with staining for both kappa and lambda light chains. Some investigators conclude that the immunoglobulin in the deposits of immunotactoid glomerulopathy more often is monoclonal than in fibrillary glomerulonephritis.[1012]
Pathogenesis
The etiology and pathogenesis of fibrillary glomerulone-phritis and immunotactoid glomerulopathy are not known. Fibrillary glomerulonephritis and immunotactoid glomerulonephritis have been associated with lymphoproliferative disease (for instance with chronic lymphocytic leukemia or B-cell lymphomas). [1012] [1018] [1019] In fact, the treatment of some patients with chemotherapy has caused improvement in renal function and reduction in proteinuria. The possible oligoclonal character of the deposits of fibrillary glomerulonephritis may facilitate self-association and fibrillar organization in an analogous fashion to the monoclonal light chains of AL amyloidosis.[1015] The resemblance of immunotactoid deposits to those of cryoglobulinemia, which often contain a monoclonal component, also raises the possibility that the presence of some type of uniformity of the immunoglobulin in the deposits may be causing the patterned organization in immunotactoid glomerulopathy.
Epidemiology and Clinical Features
An analysis of 9085 consecutive native kidney biopsies evaluated in the UNC Nephropathology laboratory reveals a frequency of fibrillary glomerulonephritis of 0.8%, compared to 14.5% for membranous glomerulopathy, 7.5% for IgA nephropathy, 2.6% for type I MPGN I, 1.5% for amyloidosis, 0.8% for anti-GBM glomerulonephritis, 0.2% for type II, and 0.1% for immunotactoid glomerulonephritis. Thus, fibrillary glomerulonephritis is about as common as anti-GBM glomerulonephritis and much more frequent than immunotactoid glomerulopathy.
Patients with fibrillary glomerulonephritis present with a mixture of the nephrotic and nephritic syndrome features. [1013] [1015] [1018] Patients may have microscopic or macroscopic hematuria, renal insufficiency (including RPGN in a few patients), hypertension, and proteinuria, which may be nephrotic range. In a series of 28 patients with fibrillary glomerulonephritis, the mean age was 49 years, with a range of 21 to 75. The ratio of males to females was 1:1.8, and the ratio of whites to blacks was 8.3:1, suggesting a predilection for whites over blacks.[1015] The mean amount of proteinuria was 6 grams/day. Unfortunately, after 24 months of follow-up, renal survival was only 48%.[1015]Renal insufficiency is common at the time of presentation, as are hematuria and hypertension. Patients with these disorders must not have cryoglobulinemia, lupus, or paraproteinemia. Some controversy exists as to whether patients with immunotactoid glomerular disease should be separate from those with fibrillary glomerulopathy. Fibrillary glomerulopathy have microfibrils less than 30 nm, whereas those with immunotactoid have microfibrils greater than 30 nm. Most investigators suggest there is a difference, in that patients with immunotactoid glomerular disease are more likely to have a lymphoproliferative disorder. Such patients have progressive renal failure in less than 5 years, although long-term patient survival is greater than 80% at 5 years. [1020] [1021]
In a group of six patients with immunotactoid glomerulopathy, the mean age was 62, suggesting that patients with immunotactoid glomerulopathy may be significantly older than those with fibrillary glomerulonephritis.[1013] On clinical presentation, these patients look very much like those with fibrillary glomerulonephritis with proteinuria, hematuria and renal insufficiency. Importantly, those patients with immunotactoid glomerular disease are more likely to have an associated hematopoietic process and poor long-term survival.[1013] In a review study of patients presenting with fibrillary glomerulopathy or immunotactoid glomerulopathy, 161 patients were observed. Those who had fibrillary glomerulopathy, all patients had proteinuria and three quarters of both types of presentations had the nephrotic syndrome. Hematuria occurred in approximately two-thirds of patients and hypertension in half to two thirds. Renal insufficiency was discovered in half the patient population. There were no real statistical differences in the clinical presentation of either the fibrillary glomerular disease group or those with immunotactoid glomerulopathy. The patients who had a more rapid progression to end-stage renal disease had a higher incidence of nephrosis and hypertension than those with milder disease. Four patients eventually received transplants and recurrent disease was found in three of five allografts, although there was a slower rate of deterioration of renal function in the allograft.[1022] In fibronectin glomerulonephritis, patients present with proteinuria in adolescence and the clinical course is characterized by proteinuria with hematuria in one half of these patients. The few patients that have been reported either have stable renal function, yet some have persistent decline in renal function.[1023]
In one report of extrarenal manifestations of fibrillary glomerulonephritis, there was evidence of pulmonary hemorrhage[1024] and in one patient with immunotactoid glomerulopathy, there were extrarenal deposits in both the liver and bone.[1025]
Treatment
At this time, there is no convincingly effective form of treatment for patients with either fibrillary glomerulonephritis or immunotactoid glomerulopathy.[1018] The dismal prognosis in patients with either of these diseases prompts physicians to search for some immunosuppressive form of treatment. Fully 40% to 50% of patients with these diseases develop end-stage renal disease within 6 years of presentation. [1010] [1011] [1013] [1015] Efforts for treatment with either glucocorticoids or alkylating agents such as cyclophosphamide have typically shown either no response or, at best, some amelioration of proteinuria.[1026] In our own experience, prednisone therapy alone has had no benefit at all. Efforts at treatment with colchicine therapy in a fashion analogous to treatment of systemic amyloidosis have also not provided any substantial beneficial effect. Nonetheless, in fibrillary glomerulonephritis or other forms of glomerulonephritis associated with chronic lymphocytic leukemia or other forms of lymphocytic lymphoma, there is a report of improvement in a minority of patients treated with chlorambucil. Thus, it is possible that the treatment of the underlying malignancy if one is detected may make the glomerulonephritis better.[1019]
There is only one report in the literature[1022] that describes the predictors of disease progression in transplantation in fibrillary glomerulopathy. Four patients received five renal allografts followed for four to eleven years. Recurrence of fibrillary glomerulonephritis was documented in three of these allografts, although the rate of deterioration in the allograft was slower.
Rapidly Progressive Glomerulonephritis and Crescentic Glomerulonephritis
Nomenclature and Categorization
The term rapidly progressive glomerulonephritis (RPGN) refers to a clinical syndrome characterized by a rapid loss of renal function, often accompanied by oliguria or anuria, and with features of glomerulonephritis, including dysmorphic erythrocyturia, erythrocyte cylindruria, and glomerular proteinuria.[1027] Aggressive glomerulonephritis that causes RPGN usually has extensive crescent formation.[1028] For this reason, the clinical term RPGN is sometimes used interchangeably with pathologic term crescentic glomerulonephritis. Crescentic glomerulonephritis is the most aggressive structural phenotype in the continuum of injury that results from glomerular inflammation (see Fig. 30-18 ). The crescent formation results from disruption of glomerular capillaries that allows inflammatory mediators and leukocytes to enter Bowman space where they induce epithelial cell proliferation and macrophage maturation that together produce cellular crescents ( Fig. 30-30 ). [1029] [1030] [1031] Therefore, a ubiquitous pathologic feature of crescentic glomerulonephritis is focal rupture of glomerular capillary walls that can be seen by light microscopy and electron microscopy. [1028] [1032] [1033]
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FIGURE 30-30 Light micrograph showing a large cellular crescent (magnification ×500). |
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Renal diseases other than crescentic glomerulonephritis can cause the sign and symptoms of RPGN. Two examples are acute thrombotic microangiopathy and atheroembolic renal disease. Although acute tubular necrosis and acute tubulointerstitial nephritis may cause rapid loss renal function and oliguria, these processes typically do not cause dysmorphic erythrocyturia, erythrocyte cylindruria, or substantial proteinuria.
A small minority of all patients with glomerulonephritis develops RPGN. The incidence of the clinical syndrome has been estimated to be as low as seven cases per million population per year. [661] [1034] The three major immunopathologic categories of crescentic glomerulonephritis have different frequencies in different age groups ( Table 30-15 ). [1027] [1028] [1032] [1035] In a patient who has RPGN clinically and crescentic glomerulonephritis identified light microscopy of a renal biopsy specimen, the precise diagnostic categorization of the disease requires integration of clinical, serologic, immunohistologic, and electron microscopic data ( Fig. 30-31 ).
TABLE 30-15 -- Frequency of Immunopathologic Categories of Glomerulonephritis in over 3000 Consecutive Non-Transplant Renal Biopsies Evaluated by Immunofluorescence Microscopy in the University of North Carolina Nephropathology Laboratory
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Immunohistology |
All Proliferative GN (n = 1093) |
Any Crescents (n = 540) |
>50% Crescents (n = 195) |
Arteritis in Biopsy (n = 37) |
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Pauci-immune (<2+ Ig) |
45% (496/1093) |
51% (227/540) |
61% (118/195)[*] |
84% (31/37) |
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Immune Complex (≥2+ Ig) |
52% (570/1093) |
44% (238/540) |
29% (56/195) |
14% (5/37)[‡] |
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Anti-GBM |
3% (27/1093) |
5% (25/540)[†] |
11% (21/195) |
3% (1/37)[¶] |
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Derived from Jennette JC, Falk RJ: The pathology of vasculitis involving the kidney. Am J Kidney Dis 24:130–141, 1994. |
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70 of 77 patients tested for ANCA were positive (91%) (44 P-ANCA and 26 C-ANCA). |
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3 of 19 patients tested for ANCA were positive (16%) (2 P-ANCA and 1 C-ANCA). |
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4 patients had lupus and 1 post-streptococcal glomerulonephritis. |
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This patient also had a P-ANCA (MPO-ANCA). |
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FIGURE 30-31 Algorithm for categorizing glomerulonephritis that is known or suspected of being mediated by antibodies. This categorization applies to glomerulone-phritis with crescents as well as to glomerulonephritis without crescents. The diseases with stars beneath them can be considered primary glomerular diseases, whereas those without stars are secondary to (components of) systemic diseases. |
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Immune complex crescentic glomerulonephritis is caused by immune complex localization within glomeruli. It is the most common cause for RPGN in children ( Table 30-16 ).[1028] The major clinical differential diagnosis in children is hemolytic uremic syndrome, which also can cause rapid loss of renal function, hypertension, hematuria, and proteinuria. The presence of microangiopathic hemolytic anemia and thrombocytopenia are indicators that the rapid loss of renal function is more likely caused by hemolytic uremic syndrome than crescentic glomerulonephritis. Pauci-immune crescentic glomerulonephritis, which has no evidence for immune complex or anti-GBM localization in glomeruli and is usually associated with ANCA, is the most common cause for RPGN and crescentic glomerulonephritis in adults, especially older adults (Tables 30-16 and 30-17 [16] [17]). [1027] [1035] [1036] In most patients, pauci-immune crescentic glomerulonephritis is a component of a systemic small-vessel vasculitis, such as Wegener granulomatosis or microscopic polyangiitis, however, some patients have renal-limited (primary) disease.[1028] [1037] [1038] [1039] This entity will be more fully discussed in Chapter 33 . Anti-GBM disease is the least frequent cause for crescentic glomerulonephritis (see Tables 30-16 and 30-17 [16] [17]). [1027] [1028] [1035] [1036] It is most frequent in young males and older females, but is not common in any setting.
TABLE 30-16 -- Relative Frequency of Immunopathologic Categories of Crescentic Glomerulonephritis in Different Age Groups[*]
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Categories of CGN |
Age in Years |
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1–100 (n = 632) |
1–20 (n = 73) |
21–60 (n = 303) |
>60(n = 256) |
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Anti-GBM CGN |
15% |
12% |
15% |
15% |
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Immune complex CGN |
24% |
45% |
35% |
6% |
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Pauci-immune CGN[†] |
60% |
42% |
48% |
79% |
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Other |
1% |
0% |
3% |
0% |
Derived from Jennette JC, Nickeleit V: Anti-glomerular basement membrane glomerulonephritis and Good-pasture's syndrome. In Jennette JC, Olson JL, Schwartz MM, Silva FG (eds): Heptinstall's Pathology of the Kidney, 6th ed. Philadelphia, Lippincott Williams & Wilkins, 2006, pp 613–642.
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ANCA, antineutrophil cytoplasmic antibodies; CGN, crescentic glomerulonephritis. |
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CGN is defined as >50% of glomeruli with crescents. |
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Approximately 90% associated with ANCA. Frequency is determined with respect to age in patients whose renal biopsies were evaluated in the University of North Carolina Nephropathology Laboratory. Notice the very high frequency of pauci-immune (usually ANCA-associated) disease in the elderly. |
Immune Complex-Mediated Crescentic Glomerulonephritis
Epidemiology
Most patients with immune complex crescentic glomerulonephritis have clinical or pathologic evidence for a specific category of primary glomerulonephritis, such as IgA nephropathy, post-infectious glomerulonephritis, or membranoproliferative glomerulonephritis, or they have glomerulonephritis that is a component of a systemic immune complex disease, such as systemic lupus erythematosus, cryoglobulinemia, or Henoch-Schönlein purpura. A minority of patients with immune complex crescentic glomerulonephritis, however, do not have patterns of immune complex localization that readily fit into the specific categories of immune complex glomerulonephritis.[1040] This category is sometimes called idiopathic crescentic immune complex glomerulonephritis.
Immune complex crescentic GN accounts for the majority of crescentic glomerulonephritides in children, but accounts for only a minority of crescentic glomerulonephritis in the elderly (see Table 30-16 ). The higher frequency in children reflects the general trend for many types of immune complex glomerulonephritis to be more frequent in younger individuals, for example, IgA nephropathy, poststreptococcal glomerulonephritis, membranoproliferative glomerulonephritis type I and II, and lupus nephritis.
Data in Table 30-17 demonstrate that immune complex glomerulonephritis less often has crescent formation, and, when crescents are present, they involve a smaller proportion of glomeruli than is the case with anti-GBM glomerulonephritis or ANCA glomerulonephritis. The data in Table 30-17 overestimate the extent of crescent formation in immune complex glomerulonephritis because patients with severe disease are more likely to undergo renal biopsy than patients with less severe disease. For example the frequency of glomerular crescents in all patients with post-streptococcal glomerulonephritis or IgA nephropathy is likely much lower than the frequency shown in Table 30-17 because of the bias in the patients selected for renal biopsy. Nevertheless, the data show the much greater propensity for crescent formation in anti-GBM and ANCA glomerulonephritis compared with immune complex glomerulonephritis.
TABLE 30-17 -- Patients with Various Glomerular Diseases who Have Crescent Formation Based on Analysis of over 6000 Native Kidney Biopsies[*]
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Disease |
Pts. with Crescents (%) |
Pts. with ≥50% Crescents |
Avg. % of Glomeruli with Crescents |
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Anti-GBM antibody-mediated glomerulonephritis |
97 |
85 |
77 |
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ANCA-associated glomerulonephritis |
90 |
50 |
49 |
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Immune complex-mediated glomerulonephritis |
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Lupus glomerulonephritis (classes III and IV) |
56 |
13 |
27 |
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Henoch-Schönlein purpura glomerulonephritis[†] |
61 |
10 |
27 |
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IgA nephropathy[†] |
32 |
4 |
21 |
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Acute postinfectious glomerulonephritis[†] |
33 |
3 |
19 |
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Fibrillary glomerulonephritis |
23 |
5 |
26 |
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Type I membranoproliferative glomerulonephritis |
24 |
5 |
25 |
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Membranous lupus glomerulonephritis (class V) |
12 |
1 |
17 |
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Membranous glomerulonephritis (non-lupus) |
3 |
0 |
15 |
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Derived from Jennette JC: Rapidly progressive crescentic glomerulonephritis. Kidney Int 63:1164–1177, 2003. |
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* |
Evaluated in the University of North Carolina Nephropathology Laboratory. In general, diseases that most often have crescents also have the largest percentage of glomeruli involved by crescents when they are present. |
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† |
Because more severe examples of IgA nephropathy and postinfectious glomerulonephritis are more often evaluated by renal biopsy, the extent of crescent formation in the biopsied patients shown in this table is higher than in all patients with these diseases. |
Pathology
Light Microscopy
The light microscopic appearance of crescentic immune complex glomerulonephritis depends upon the underlying category of glomerulonephritis, for example, in their most aggressive expressions, membranoproliferative glomerulonephritis, membranous glomerulopathy, acute postinfectious glomerulonephritis, or proliferative glomerulonephritis, including IgA nephropathy, can all have crescent formation. [440] [441] [442] [443] [444] [445] [596] [697] [680] [685] [686] [708] [800] [802] [803] [960] [1034] [1041] [1042] [1043] [1044] [1045] [1046] [1047] [1048] [1049] [1050] [1051] [1052] This underlying phenotype of immune complex glomerulonephritis is recognized best in the intact glomeruli or glomerular segments. There usually are varying combinations of capillary wall thickening and endocapillary hypercellularity in the intact glomeruli. This is in contrast to anti-GBM glomerulonephritis and ANCA-glomerulonephritis, which tend to have surprisingly little alteration in intact glomeruli and segments in spite of the severe necrotizing injury in involved glomeruli and segments. In glomerular segments adjacent to crescents in immune complex glomerulonephritis, there usually is some degree of necrosis with karyorrhexis; however, the necrosis rarely is as extensive as that typically seen with anti-GBM or ANCA-glomerulonephritis. In addition, there is less destruction of Bowman capsule associated with crescents in immune complex glomerulonephritis, as well as less pronounced periglomerular tubulointerstitial inflammation. Crescents in immune complex glomerulonephritis have a higher proportion of epithelial cells to macrophages than crescents in anti-GBM or ANCA glomerulonephritis, which may be related to the less severe disruption of Bowman capsule and thus less opportunity for macrophages to migrate in from the interstitium.[1040]
Immunofluorescence Microscopy
Immunofluorescence microscopy, as well as electron microscopy, provides the evidence that crescentic glomerulone-phritis is immune complex mediated versus anti-GBM antibody mediated versus likely to be ANCA-associated. The pattern and composition of immunoglobulin and complement staining depends on the underlying category of immune complex glomerulonephritis that has induced crescent formation. [441] [619] [623] [684] [685] [800] [1027] [1044] [1046] [1052] [1053] [1054] For example, crescentic glomerulonephritis with predominantly mesangial IgA-dominant deposits is indicative of crescentic IgA nephropathy, C3-dominant deposits with peripheral band-like configurations suggest crescentic membranoproliferative glomerulonephritis, coarsely granular capillary wall deposits raise the possibility of crescentic post-infectious glomerulonephritis, and finely granular IgG-dominant capillary wall deposits suggest crescentic membranous glomerulopathy. The latter may be a result of concurrent anti-GBM disease, which will also cause linear GBM staining beneath the granular staining, or concurrent ANCA disease, which can be documented serologically. About a quarter of all patients with crescentic immune complex glomerulonephritis are ANCA-positive, whereas less than 5% of patients with non-crescentic immune complex glomerulonephritis are ANCA-positive. This suggests that the presence of ACA in patients with immune complex glomerulonephritis may predispose to disease that is more aggressive.
Electron Microscopy
As with the immunofluorescence microscopy, the findings by electron microscopy in patients with crescentic immune complex glomerulonephritis are dependent upon the type of immune complex disease that has induced crescent formation. The hallmark ultrastructural finding is immune complex-type electron dense deposits. These can be mesangial, subendothelial, intramembranous, subepithelial, or any combinations of these. The pattern and distribution of deposits may indicate a particular phenotype of primary crescentic immune complex glomerulonephritis, such as postinfectious, membranous, or membranoproliferative type I or II. [441] [685] [1052] Ultrastructural findings also may suggest that the disease is secondary to some unrecognized systemic process. For example, endothelial tubuloreticular inclusions suggest lupus nephritis, and microtubular configurations in immune deposits suggest cryoglobulinemia.
As with all types of crescentic glomerulonephritis, breaks in glomerular basement membranes usually can be identified if looked for carefully, especially in glomerular segments adjacent to crescents. Dense fibrin tactoids occur in thrombosed capillaries, in sites of fibrinoid necrosis, and in the interstices between the cells in crescents. In general, the extent of fibrin tactoid formation in areas of fibrinoid necrosis is less conspicuous in crescentic immune complex glomerulonephritis than in crescentic anti-GBM or ANCA glomerulonephritis.
Pathogenesis
Crescentic glomerulonephritis is the result of a final common pathway of glomerular injury that results in crescent formation. Multiple etiologies and pathogenic mechanisms can lead to the final common pathway, including many types of immune complex disease. The general dogma is that immune complex localization in glomerular capillary walls and mesangium, by either deposition or in situ formation or both, activates multiple inflammatory mediator systems. [237] [1027] [1028] This includes humoral mediator systems, such as the coagulation system, kinin system, and complement system, as well as phlogogenic cells, such as neutrophils, monocytes/macrophages, platelets, lymphocytes, endothelial cells, and mesangial cells. The activated cells also release soluble mediators, such as cytokines and chemokines. If the resultant inflammation is contained within the glomerular basement membrane, a proliferative or membranoproliferative phenotype of injury ensues with only endocapillary hypercellularity. However, if the inflammation breaks through capillary walls into Bowman space, extracapillary hypercellularity (crescent formation) results.
Complement activation has often been considered a major mediator of injury in immune complex glomerulonephritis, however, experimental data indicate the importance of Fc receptors in immune complex mediated injury. [1055] [1056] For example, mice deficient for the Fc gamma R1 and Fc gamma R3 receptors have a markedly reduced capacity to develop immune complex glomerulonephritis. [1057] [1058]
Treatment
The therapy for crescentic immune complex glomerulonephritis is influenced by the nature of the underlying cate-gory of immune complex glomerulonephritis. For example, acute post-streptococcal glomerulonephritis with 50% crescents might not prompt the same therapy as IgA nephropathy with 50% crescents. However, there are inadequate controlled prospective studies to guide therapy for most forms of crescentic immune complex glomerulonephritis. Some nephrologists extrapolate from the lupus nephritis experience and choose to treat patients with crescentic immune complex disease with immunosuppressive drugs which they would not use if the glomerular lesions appeared less aggressive. For example, there are advocates for treating crescentic IgA nephropathy with immunosuppressive drugs and even plasmapheresis who would not recommend such treatment for patients without crescents.[960] For the minority of patients who have idiopathic immune complex crescentic glomerulonephritis, the most common treatment is immunosuppressive therapy with pulse methylprednisolone followed by prednisone at a dose of 1 mg/kg daily, and then tapered over the second to third month to an alternate-day regimen until completely discontinued. [661] [1059] [1060] [1061] In patients with a rapid decline in renal function, cytotoxic agents in addition to corticosteroids may be considered. As with anti-GBM and ANCA disease, institution of immunotherapy should occur as early as possible during the course of crescentic immune complex glomerulonephritis to reduce the likelihood of reaching the irreversible stage of advanced scarring. There is evidence, however, that crescentic glomerulonephritis with an underlying immune complex proliferative glomerulonephritis is less responsive to aggressive immunosuppressive therapy than is anti-GBM or ANCA crescentic glomerulonephritis. [960] [1040]
Anti-Glomerular Basement Membrane Glomerulonephritis
Epidemiology
Anti-GBM disease accounts for about 10% to 20% of crescentic glomerulonephritides. [661] [1038] This disease is characterized by circulating antibodies to the glomerular basement membrane (anti-GBM) and deposition of IgG or rarely IgA along glomerular basement membranes. [661] [1040] [1062] [1063] [1064] [1065] [1066] [1067] [1068] [1069] [1070] [1071] [1072] [1073] [1074] Anti-GBM antibodies may be eluted from renal tissue samples from pa-tients with anti-GBM disease, thus allowing verification that the antibodies are specific to the glomerular basement membrane. [661] [1068] [1072] The antibodies eluted from renal tissue bind to the same epitope of type IV collagen as the circulating anti-GBM antibodies from the same patient.[1075]
Anti-GBM disease occurs as a renal-limited disease (anti-GBM glomerulonephritis) and as a pulmonary-renal vasculitic syndrome (Goodpasture syndrome). [661] [1040] [1062] [1063] [1064] [1065] [1066] [1067] [1068] [1069] [1070] [1071] [1072] [1073] [1074] [1076] The incidence of anti-GBM disease has two peaks with respect to age. The first peak is in the second and third decade of life and the second peak is in the sixth and seventh decade. The first peak has a male preponderance and higher frequency of pulmonary hemorrhage (Goodpasture syndrome), whereas the second peak has a predominance of women who more often have renal-limited disease.
Genetic susceptibility to anti-GBM disease is associated with HLA DR2 specificity.[1077] Further analysis of the association with HLA DR2 reveals an association with the DRB1 alleles, DRB1*1501 and DQB*0602. [1078] [1079] [1080] [1081] Further refinement of this association showed that polymorphic residues in the second peptide-binding region of the HLA class II antigen segregated with disease, supporting the hypothesis that the HLA association in GBM disease reflects the ability of certain class II molecules to bind and present anti-GBM peptides to T helper cells.[1078] This concept is further supported by mouse models of anti-GBM disease in which crescentic glomerulonephritis and lung hemorrhage are restricted to only certain MHC haplotypes, despite the ability of mice of all haplotypes to produce anti-alpha 3 NC1 antibodies.[1082]
Pathology
Immunofluorescence Microscopy
The pathologic finding of linear staining of the glomerular basement membranes for immunoglobulin is indicative of anti-GBM glomerulonephritis ( Fig. 30-32 ). [1069] [1072] [1073] [1083] [1084] [1085] [1086] This is predominantly IgG, however, rare patients with IgA-dominant anti-GBM glomerulonephritis have also been reported. [1070] [1087] Linear staining for both kappa and lambda light chains typically accompanies the staining for gamma heavy chains. Linear staining for gamma heavy chains alone indicates gamma heavy chain deposition disease. Most specimens with anti-GBM glomerulonephritis have discontinuous linear to granular capillary wall staining for C3, but a minority has little or no C3 staining. Linear staining for IgG may also occur along tubular basement membranes.[1073]
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FIGURE 30-32 Immunofluorescence micrograph of a portion of a glomerulus with anti-GBM glomerulonephritis showing linear staining of glomerular basement membranes for IgG. (FITC anti-IgG, ×600.) (Modified from Ferrario F, Kourilsky O, Morel-Maroger L: Acute endocapillary glomerulonephritis in adults: A histologic and clinical comparison between patients with and without initial acute renal failure. Clin Nephrol 19:17–23, 1983, with permission.) |
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The linear IgG staining of glomerular basement membranes frequently seen in patients with diabetic glomerulosclerosis and the less intense linear staining seen in older patients with hypertensive vascular disease must not be confused with anti-GBM disease. The clinical data and light microscopic findings should help make this distinction. Serologic confirmation should always be obtained to substantiate the diagnosis of anti-GBM disease.
Serologic testing for ANCA should be ordered simultaneously because a quarter to a third of patients with anti-GBM disease are also ANCA-positive, and this may modify the prognosis and the likelihood of systemic small-vessel vasculitis. [1038] [1088]
Light Microscopy
At the time of biopsy, 95% of patients have some degree of crescent formation and 81% have crescents in 50% or more of glomeruli (see Table 30-17 ). [1028] [1083] On average, 77% of glomeruli have crescents. Glomeruli with crescents typically have fibrinoid necrosis in adjacent glomerular segments. Non-necrotic segments may look entirely normal by light microscopy, or may have slight infiltration by neutrophils or mononuclear leukocytes. This differs from crescentic immune complex glomerulonephritis, which typically has capillary wall thickening and endocapillary hypercellularity in the intact glomeruli. Special stains that outline basement membranes, such a Jones silver methenamine or periodic acid-Schiff stains, often demonstrate focal breaks in glomerular basement membranes in areas of necrosis, and also show focal breaks in Bowman capsule. The most severely injured glomeruli have global glomerular necrosis, circumferential cellular crescents, and extensive disruption of Bowman capsule.
The acute necrotizing glomerular lesions and the cellular crescents evolve into glomerular sclerosis and fibrotic crescents, respectively.[1083] If the renal biopsy specimen is obtained several weeks into the course of anti-GBM disease, the only lesions may be these chronic sclerotic lesions. There may be a mixture of acute and chronic lesions; however, the glomerular lesions of anti-GBM glomerulonephritis tend to be more in synchrony than those of ANCA-glomerulonephritis, which more often show admixtures of acute and chronic injury.
Tubulointerstitial changers are commensurate with the degree of glomerular injury. Glomeruli with extensive necrosis and disruption of Bowman capsule typically have intense periglomerular inflammation, including occasional multinucleated giant cells. There also is focal tubular epithelial acute simplification or atrophy, focal interstitial edema and fibrosis, and focal interstitial infiltration of predominantly mononuclear leukocytes. There are no specific changes in arteries or arterioles. If necrotizing inflammation is observed in arteries or arterioles, the possibility of concurrent anti-GBM and ANCA disease should be considered.
Electron Microscopy
The findings by electron microscopy reflect those seen by light microscopy. [1083] [1089] In acute disease, there is focal glomerular necrosis with disruption of capillary walls. Bowman capsule also may have focal gaps. Leukocytes, including neutrophils and monocytes, often are present at sites of necrosis, but are uncommon in intact glomerular segments. Fibrin tactoids, which are electron dense curvilinear accumulations of polymerized fibrin, accumulate at sites of coagulation system activation, including sites capillary thrombosis, fibrinoid necrosis and fibrin formation in Bowman space ( Fig. 30-33 ). Cellular crescents contain cells with ultrastructural features of macrophages and epithelial cells. An important negative observation is the absence of immune complex type electron dense deposits. These occur only in anti-GBM disease patients who have concurrent immune complex disease. Glomerular segments that do not have necrosis may appear remarkably normal, with only focal effacement of visceral epithelial foot processes. There may be slight lucent expansion of the lamina rara interna, but this is an inconstant and nonspecific feature. In chronic lesions, amorphous and banded collagen deposition distorts or replaces the normal architecture.
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FIGURE 30-33 Electron micrograph of a portion of a glomerular capillary wall and adjacent urinary space from a patient with anti-GBM glomerulonephritis. Note the fibrin tactoids within a capillary thrombus (straight arrow) and in the Bowman space (curved arrow) between the cells of a crescent. Also note the absence of immune complex-type electron dense deposits in the capillary wall (magnification ×6000). |
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Pathogenesis
The landmark studies opening the way to the understanding of the pathogenesis of anti-GBM disease were those of Lerner, Glassock and Dixon.[1068] In these studies, antibodies eluted from nephritic kidneys of patients with Goodpasture syndrome and injected in monkeys led to the induction of fulminant glomerulonephritis, proteinuria, renal failure, and pulmonary hemorrhage along with intense staining of the glomerular basement membrane for human IgG.
The antigen to which anti-GBM antibodies react was initially found to be in the collagenase-resistant part of type IV collagen, the “non-collagenous domain,” or NC1 domain. [1090] [1091] [1092] [1093] The antigenic epitopes found in the NC1 domain is in a cryptic form as evidenced by the fact that little reactivity is found against the native hexameric structure of the NC1 domain. However, when the hexameric NC1 domain is denatured and dissociates into dimers and monomers, the reactivity of antibodies increases 15-fold.[1093] On the other hand, if the antigen is reduced and alkylated, antibody binding to such denatured NC1 domain almost disappears.[1094] About 90% of anti-type IV collagen antibodies are directed against the alpha-3 chain of type IV collagen. [1060] [1095] Furthermore, the majority of patients express antibody to two major conformational epitopes (EA and EB) located within the carboxyterminal non-collagenous (NC1) domain of the alpha-3 chain of type IV collagen. [1096] [1097] This is further supported by inhibition assays using the monoclonal antibody to an antigenic epitope on alpha-3 (IV collagen),[1098] or with the use of a polyclonal anti-idiotype to anti-alpha-3 IV NC1 antibodies.[1099] The Goodpasture epitopes in the native autoantigen are sequestered within the NC1 hexamers of the α3a4a5(IV) collagen network. The crypticity of the target epitopes is a feature of the quaternary structure of two distinct subsets of α3a4a5(IV) NC1 hexamers. Goodpasture antibodies only breach the quaternary structure of hexamers containing only monomer subunits, whereas hexamers composed of both dimer and monomer subunits (D-hexamers) are resistant to autoantibodies under native conditions. The epitopes of D-hexamers are structurally sequestered by dimer reinforcement of the quaternary complex.[1100] It is presumed that environmental factors, such as exposure to hydrocarbons,[1101] tobacco smoke,[1102] and endogenous oxidants[1103] can also expose the cryptic Goodpasture epitopes. In patients with anti-GBM disease who do not have antibodies to the classic epitope on the alpha 3 chain, antibodies to entactin have been detected.[1104] A small percentage of patients with anti-GBM disease may additionally have limited reactivity with the NC1 domains of the alpha-1 or alpha-4 chains of type IV collagen. These additional reactivities seem to be more frequent in patients with anti-GBM mediated glomerulonephritis alone.[1105] Up to one third of patients with anti-GBM disease have circulating ANCA. [1045] [1088] [1098] [1105] [1106] Both anti-myeloperoxidase specific P-ANCA and anti-proteinase 3 specific C-ANCA can occur in patients with anti-GBM disease. Interestingly, no differences in the antigenic specificity of anti-GBM antibodies were detected between sera with or without concurrent expression of ANCA.[1098] Coexistence of ANCA in patients with anti-GBM antibodies is associated with small-vessel vasculitis in organs in addition to lung and kidney. In experimental models, antibodies to myeloperoxidase (MPO) aggravate experimental anti-GBM disease. [1088] [1107] In a recent study comparing patients with anti-GBM, MPO-ANCA and both, patients with both anti-GBM and anti-MPO autoantibodies had a similar renal outcome as patients with anti-GBM alone, and both groups had a significantly worse renal survival than patients with MPO-ANCA alone.[1108] Patient survival at one year was best among patients with MPO-ANCA alone, although the differences did not reach statistical significance.
A number of animal models of anti-GBM disease have been developed over the years. These have been based on the immunization of animals with heterologous or homologous glomerular basement membrane as exemplified in the Steblay nephritis model.[1109] Alternatively, anti-GBM antibody induced injury has been experimentally induced passively by the intravenous injection of heterologous anti-GBM antibodies. This leads to two phases of injury. The first, or so-called heterologous phase, occurs in the first 24 hours and is mediated by the direct deposition of the heterologous antibodies on the glomerular basement membrane with subsequent recruitment of neutrophils. This is usually followed by an autologous phase, depending on the host's immune response to the heterologous immunoglobulin bound to the GBM.[1109] The rat model induced by injection of heterologous anti-GBM has permitted the study of the roles of various inflammatory mediators in the development of anti-GBM disease. [1110] [1111] [1112] [1113] The more recent development of analogous murine models of anti-GBM disease opens the way for more specific evaluations of the inflammatory processes with the use of strains of mice with specific gene “knockouts”.[1082] For example, this approach has been used to assess the role of T cells in the development of anti-GBM disease. When mice of eight different strains representing the major histocompatibility complex haplotypes were immunized with purified bovine alpha-3 (IV) NC1 dimers, this led to the production of anti-alpha-3 IV NC1 antibodies in all strains of mice. However, only a subset of strains developed nephritis and lung hemorrhage. The novelty of this new murine model is that it is derived by direct immunization of mice with bovine alpha-3 chain of type IV collagen as opposed to being induced by the passive transfer of heterologous anti-GBM antibodies from other animal species or strains.
A role for T cells in the initiation or pathogenesis of anti-GBM disease is suggested by the increased susceptibility to the disease in the setting of the HLA class II antigens of the DR2 family, and more specifically, with the DRB1 alleles mentioned earlier.[1078] Further evidence of the involvement of T cell activation in the development of the autoimmune response to the NC1 domain of the alpha-3 chain of type IV collagen comes from studies of T cell proliferation in response to other monomeric components of the glomerular basement membrane[1114] and synthetic oligopeptides.[1115] Only the mouse strains capable of mounting a Th1 type response developed nephritis.[1082]The role of T cells in this model was further documented by the fact that passive transfer of lymphocytes or antibodies from nephritogenic strains to syngenetic recipients led to the development of nephritis, whereas the passive transfer of antigen antibodies to T cell receptor deficient mice failed to do so. In fact, special T cell repertoires capable of generating nephritogenic lymphocytes are critical in the development of anti-glomerular basement membrane disease.[1082]
Both TH2 and TH1 responses may occur, depending upon the host response. In TH2 prone animals, glomerular injury results because of antibody deposition, complement activation and neutrophil infiltration, whereas immune responses to the same antigen in TH1 prone mice result in a delayed hypersensitivity reaction.[1116]
The study of the role of complement activation in anti-GBM disease is largely from studies of passive injection of heterologous antibodies to GBM. This model suggests that the terminal components of the complement system are not involved in the pathogenesis of this model.[1117] Further studies in rabbits that are congenitally deficient in the sixth component of complement also suggested that the terminal compo-nents of complement do not play a major part in the pathogenesis of the disease except in leucocyte-depleted animals. [1118] [1119] The role of complement cascade activation in a murine model of heterologous anti-GBM has previously led to conflicting results as to the role of complement activation in this model.[1120] More recent data using the same model in mice rendered completely deficient of complement components C3 or C4 revealed a protective effect of C3 deficiency more than that of C4 deficiency. Both the protective effects could be overcome if the dose of nephritogenic antibodies was increased.[1121] The role of complement activation in the human disease is poorly understood although it is usually along with the immunoglobulin deposits along the basement membrane.
The role of the Fc receptor in mediating glomerulonephritis has been debated. There are various Fc gamma receptors, some of which appear injurious and others protective. For instance, the Fc gamma receptor 2b is the central regulatory receptor for immunoglobulin antibody expression and function. Mice that are deficient in this receptor develop massive pulmonary hemorrhage when immunized with anti-glomerular basement membrane antibodies.[1122]In others, Fc gamma receptors give mice anti-glomerular basement membrane disease. [1123] [1124]
The role of nitric oxide radicals has been investigated in many glomerular diseases, especially anti-GBM disease. Nitrous oxide radicals generated by endothelial nitric oxide synthetase are involved in the regulation of vascular tone and inhibition of platelet aggregation and leukocyte adhesion to the endothelium. Consequently, they have an anti-inflammatory effect. In animals deficient in eNOS, glomerulonephritis is more severe, especially with capillary thrombosis and neutrophil accumulation.[1125]
In the model of heterologous transfer of anti-GBM disease, the role of macrophage infiltration in anti-GBM disease seems to be species dependent. [1126] [1127] [1128] Finally, many drugs that influence T cell mediated autoimmune responses have been tried in animal models of anti-GBM disease.[1129] Nonetheless, macrophage infiltration occurs in many types of progressive renal diseases. Macrophages produce interleukin-1 beta, TNF alpha, and, in appropriate conditions, transforming growth factor beta TGF beta. Coordinated upregulation of several molecules results in additional macrophage recruitment and activation.[1130] In contrast, interleukin-10 inhibits macrophage induced glomerular injury that may attenuate macrophage-mediated glomerular disease.[1131]
Conclusions about the pathogenesis of human anti-GBM disease that are drawn from these animal models must be tempered by the realization that the animal models may not be exact replicas of the human disease.
Clinical Features and Natural History
The onset of renal anti-GBM disease is typically characterized by an abrupt, acute glomerulonephritis with severe oliguria or anuria. There is a high risk of progression to end stage renal disease if appropriate therapy is not instituted promptly. Prompt treatment with plasmapheresis, corticosteroids, and cyclophosphamide results in patient survival of approximately 85% and renal survival of approximately 60%. [1059] [1132] [1133] [1134] [1135] [1136]
Rarely, patients have a more insidious onset that remains essentially asymptomatic until the development of uremic symptoms and fluid retention. [661] [1076] [1086] [1137] The onset of disease may be associated with arthralgias, fever, myalgias, and abdominal pain; however, gastrointestinal complaints or neurologic disturbances are rare.
Goodpasture syndrome is characterized by the presence of pulmonary hemorrhage concurrent with glomerulonephritis. In some patients, the pulmonary involvement may be, however, the usual pulmonary manifestation is sever pulmonary hemorrhage that may be life threatening. Pulmonary bleeding can be demonstrated early in the course of disease by the finding of unexplained anemia, careful inspection of high-quality radiographs, observation of expectorated sputum looking for the presence of hemosiderin-laden macrophages, and the serial measurement of the alveolar arterial oxygen gradient. [661] [1069] In patients with anti-GBM disease, the occurrence of pulmonary hemorrhage is far more common in smokers than non-smokers.[1138] Pulmonary hemorrhage may be associated with environmental exposures to hydrocarbons [1138] [1139] [1140] [1141] or other exposures, such as cocaine or upper respiratory tract infections.[1142] Occupational exposure to petroleum-based mineral oils is a risk factor for the development of anti-GBM antibodies per se.[1143] The association of pulmonary hemorrhage with environmental exposures and infection raises the theoretical possibility of exposure of the cryptic antigen in the alveolar basement membrane thus allowing for recognition by circulating anti-basement membrane antibodies.
Laboratory Findings
Renal involvement by anti-GBM disease typically causes an acute nephritic syndrome with hematuria including dysmorphic erythrocyturia and red blood cells casts. Although nephrotic-range proteinuria may occur, a full nephrotic syndrome is rarely seen. [1073] [1076] [1083] [1086] [1137]
The diagnostic laboratory finding in anti-GBM disease is detection of circulating antibodies to glomerular basement membrane, and specifically to the alpha-3 chain of type IV collagen. These antibodies are detected by radioimmuno-assay or enzyme immunoassay in approximately 90% of patients. Indirect immunofluorescence microscopy assays are not sensitive enough to be adequate serologic tests for anti-GBM antibodies. The anti-GBM antibodies are most often of the IgG1 subclass, but may also be of IgG4 subclass, the latter being more often seen in females.[1144]
Treatment
The standard treatment for anti-GBM disease includes intensive plasmapheresis combined with corticosteroids and cyclophosphamide or azathioprine. [1059] [1133] [1145] [1146] [1147] [1148] Plasmapheresis consists of removal of two to four liters of plasma with replacement with a 5% albumin solution continued on a daily basis until circulating antibody levels become undetectable. In those patients with pulmonary hemorrhage, clotting factors should be replaced by administering fresh-frozen plasma at the end of each treatment. Prednisone should be administered at a dose of 1 mg/kg of body weight for at least the first month and then tapered to alternate-day therapy during the second and third months of treatment. Cyclophosphamide is administered either orally (at a dose of 2 mg/kg/day) or intravenous cyclophosphamide is used at a starting dose of 0.5 grams/M2 of body surface area. The dose of cyclophosphamide must be adjusted with consideration for the degree of impairment of renal function and the white blood cell count. Cytotoxic therapy is usually continued for about six to twelve months with the possibility of switching cyclophosphamide to azathioprine after three to four months in selected patients. The role of high-dose intravenous methylprednisolone pulses remains unproven in the treatment of anti-GBM disease. [1149] [1150] [1151] [1152] [1153] Nonetheless, the urgent nature of the clinical process prompts some nephrologists to administer methylprednisolone as part of induction therapy in this and other forms of crescentic glomerulonephritis. A dose of 7 mg/kg of methylprednisolone given on a daily basis for three consecutive days is usually sufficient.
Using the regimen of aggressive plasmapheresis with corticosteroids and cyclophosphamide, patient survival is approximately 85% with 40% progression to end-stage renal disease. [1059] [1132] [1133] [1134] [1135] [1136] [1137] These results are better than those before the introduction of plasmapheresis are when patient survival was less than 50% with a near 90% rate of end-stage renal disease. In a recent study from the Hammersmith Hospital in the United Kingdom, Pusey and colleagues have demonstrated that aggressive plasmapheresis, even in patients with severe renal insufficiency, may have an ameliorative effect, and provide improved long-term patient and renal survival.[1154]In that cohort, patients who presented with a creatinine concentration of 500 mmol/L or more (>5.7 mg/dL) but did not require immediate dialysis, patient and renal survival were 83% and 82% at 1 year and 62% and 69% at last follow-up. The renal prognosis of patients who presented with dialysis-dependent renal failure was however very poor at only 8% at 1 year. All patients who required immediate dialysis and had 100% crescents on renal biopsy remained dialysis dependent.[1155]
The major prognostic marker for the progression to end-stage renal disease is the serum creatinine at the time of initiation of treatment. Patients with a serum creatinine above 7 mg/dL are unlikely to recover sufficient renal function to discontinue renal replacement therapy.[1071] At issue is whether and for how long aggressive immunosuppression should persist in dialysis-dependent patients. Aggressive immunosuppression and plasmapheresis are warranted in patients with pulmonary hemorrhage. Aggressive immunosuppression should be withheld in patients with disease limited to the kidney who present with widespread glomerular and interstitial scarring on renal biopsy and a serum creatinine greater than 7 mg/dL. In such patients, the risks of therapy outweigh the potential benefits. In those patients in whom the serum creatinine is elevated, yet on biopsy there is active crescentic glomerulonephritis, aggressive treatment should continue for at least 4 weeks. If there is no restoration of renal function by 4 to 8 weeks, and in the absence of pulmonary bleeding, immunosuppression should be discontinued.
In patients who have both circulating anti-GBM and ANCA, the chance of recovery of renal function may be better than that of patients with anti-GBM alone. In these patients, immunosuppressive therapy should not be withheld, even with serum creatinine levels above 7 mg/dL, as the concomitant presence of ANCA was associated with a more favorable renal outcome in some [1153] [1156] but not all studies.[1108]
The adjunctive use of anti-coagulant therapy in addition to corticosteroids and cytotoxic agents has been considered, in part because of the pathologic finding of fibrin in the glomerular lesions. There are currently no proven benefits of such treatment. In fact, the use of heparin or warfarin may be associated with increased of pulmonary hemorrhage and its inherent morbidity and mortality.
Once remission of anti-GBM disease is achieved with immunosuppressive therapy, recurrent disease occurs only rarely. [1157] [1158] [1159] [1160] Similarly, the recurrence of anti-GBM disease after renal transplantation is also rare, especially when transplantation is delayed until after disappearance or substantial diminution of anti-GBM antibody in the circulation.[1161]
Pauci-Immune Crescentic Glomerulonephritis
Epidemiology
The characteristic feature of the glomerular lesion in this category of disease is focal necrotizing and crescentic glomerulonephritis with little or no glomerular staining for immunoglobulin by immunofluorescence microscopy. [1028] [1063] [1146] [1148] [1162] Pauci-immune crescentic glomerulonephritis usually is a component of a systemic small-vessel vasculitis, however, some patients have renal-limited (primary) pauci-immune crescentic glomerulonephritis.[1028] [1037] [1038] [1163] ANCA-associated small-vessel vasculitis is discussed in more detail in Chapter 33 . Pauci-immune crescentic glomerulonephritis, including that accompanying small-vessel vasculitis, is the most common category of RPGN in adults (see Table 30-15 ), especially older adults (see Table 30-16 ). There is a predilection for whites compared to blacks (see Table 30-14 ). There is no sex preference (see Table 30-14 ).
Pathology
Light Microscopy
The light microscopic appearance of ANCA-associated pauci-immune crescentic glomerulonephritis is indistinguishable from that of anti-GBM crescentic glomerulonephritis. [441] [684] [1032] [1039] [1040] [1163] [1164] [1165] Renal-limited (primary) pauci-immune crescentic glomerulonephritis also is indistinguishable from pauci-immune crescentic glomerulonephritis that occurs as a component of a systemic small-vessel vasculitis, such as Wegener granulomatosis, microscopic polyangiitis, or Churg-Strauss syndrome. As illustrated in Figure 30-18 , ANCA glomerulonephritis and anti-GBM glomerulonephritis most often manifest as crescentic glomerulonephritis.
At the time of biopsy, approximately 90% of renal biopsy specimens with ANCA-associated pauci-immune glomerulonephritis have some degree of crescent formation, and approximately half of the specimens have crescents involving 50% or more of glomeruli (see Table 30-17 ). Over 90% of specimens have focal segmental to global fibrinoid necrosis ( Fig. 30-34 ). As with anti-GBM disease, the intact glomerular segments often have no light microscopic abnormalities. The most severely injured glomeruli have not only extensive necrosis of glomerular tufts but also extensive lysis of Bowman capsule with resultant periglomerular inflammation. The periglomerular inflammation contains varying mixtures of neutrophils, eosinophils, lymphocytes, monocytes and macrophages, including occasional multinucleated giant cells. This periglomerular inflammation may have a granulomatous appearance, especially when the glomerulus that was the nidus of inflammation has been destroyed or is not in the plane of section. This granulomatous appearance is a result of the periglomerular reaction to extensive glomerular necrosis and is not specific for a particular category of necrotizing glomerulonephritis. This pattern of injury can be seen with anti-GBM glomerulonephritis, renal-limited pauci-immune crescentic glomerulonephritis, and crescentic glomerulonephritis secondary to microscopic polyangiitis, Wegener granulomatosis, and Churg-Strauss syndrome. Necrotizing granulomatous inflammation that is not centered on a glomerulus, but rather is in the interstitium or centered on an artery raises the possibility of Wegener granulomatosis or Churg-Strauss syndrome. The presence of arteritis in a biopsy specimen that has pauci-immune crescentic glomerulonephritis indicates that the glomerulonephritis is a component of a more widespread vasculitis, such as microscopic polyangiitis, Wegener granulomatosis, or Churg-Strauss syndrome.
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FIGURE 30-34 Light micrograph showing segmental fibrinoid necrosis in a glomerulus from a patient with antineutrophil cytoplasmic antibody-associated pauci-immune crescentic glomerulonephritis. (PAS, ×300.) |
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The acute necrotizing glomerular lesions evolve into sclerotic lesions. During completely quiescent phases, a renal biopsy specimen may have only focal sclerotic lesions that may mimic focal segmental glomerulosclerosis. ANCA-associated glomerulonephritis often has many recurrent bouts of exacerbation. Therefore, combinations of active acute necrotizing glomerular lesions and chronic sclerotic lesions often occur in the same renal biopsy specimen.
Immunofluorescence Microscopy
By definition, the distinguishing pathologic difference between pauci-immune crescentic glomerulonephritis and anti-GBM and immune complex crescentic glomerulonephritis is the absence or paucity of glomerular staining for immunoglobulins. How pauci-immune is pauci-immune crescentic glomerulonephritis? One basis for the categorization as pauci-immune crescentic glomerulonephritis is to identify pa-tients who are likely to be ANCA-positive, which increases the likelihood of certain systemic small-vessel vasculitides. [446] [1037] [1038] [1163] The likelihood of a positive ANCA is inversely proportional to the intensity of glomerular immunoglobulin staining by immunofluorescence microscopy in a specimen with crescentic glomerulonephritis.[1165] The likelihood of a positive ANCA serologic assay is approximately 90% if there is no staining for immunoglobulin, approximately 80% if there is trace to 1+ staining (on a scale of 0 to 4+), approximately 50% if there is 2+ staining, approximately 30% if there is 3+ staining, and less than 10% if there is 4+ staining. Therefore, even patients with definite evidence for immune complex glomerulonephritis have a higher than expected frequency of ANCA, but the highest frequency is in those patients with little or no evidence for immune complex or anti-GBM mediated disease. The presence of ANCA at higher than expected frequency in immune complex disease is intriguing, and raises the possibility that ANCA is contributing to the pathogenesis of not only pauci-immune crescentic glomerulonephritis but also the most severe examples of immune complex disease.[446] Looking at this issue from a different perspective, approximately 25% of patients with idiopathic immune complex crescentic glomerulonephritis (i.e., immune complex glomerulonephritis that does not fit well into one of the categories of primary or secondary immune complex disease) are ANCA positive, compared to less than 5% of patients who have idiopathic immune complex glomerulonephritis with no crescents.[446]
Glomerular capillary wall or mesangial staining usually accompanies immunoglobulin staining and is present in occasional specimens that do not have immunoglobulin staining. There is irregular staining for fibrin at sites of intraglomerular fibrinoid necrosis and capillary thrombosis, and in the interstices of crescents. Foci of glomerular necrosis and sclerosis also may have irregular staining for C3 and IgM.
Electron Microscopy
The findings by electron microscopy are indistinguishable from those described earlier for anti-GBM glomerulonephritis.[1089] Specimens with pure pauci-immune crescentic glomerulonephritis have no immune complex type electron dense deposits. Foci of glomerular necrosis have leukocyte influx, breaks in glomerular basement membranes, and fibrin tactoids in capillary thrombi and sites of fibrinoid necrosis. Sclerotic areas have effacement by amorphous of banded collagen.
Pathogenesis
The pathogenesis of pauci-immune crescentic glomerulonephritis is currently not fully understood. [1166] [1167] In the absence or paucity of immune complex deposition within glomeruli or other vessels, it is difficult to implicate classic mechanisms of immune complex mediated damage in the pathogenesis of pauci-immune crescentic glomerulonephritis. On the other hand, the substantial accumulation of polymorphonuclear leukocytes at the sites of vascular necrosis has led to the study of the role of neutrophil activation in this disease. There is now convincing evidence that ANCA are directly involved in the pathogenesis of pauci-immune small-vessel vasculitis or glomerulonephritis. Substantial in vitro data implicates a pathogenic role for ANCA based on the demonstration that these autoantibodies activate normal human polymorphonuclear leukocytes. [1165] [1166] [1168] In order for anti-MPO, anti-PR3, or autoantibodies to other neutrophil antigens contained within the azurophilic granules[1169] to interact with their corresponding antigens, the antibodies have either to penetrate the cell or alternatively those antigens must translocate to the cell surface. Indeed, small amounts of cytokine (e.g., TNF and interleukin-1) at concentrations too low to cause full neutrophil activation, are capable of inducing such a translocation of ANCA antigens to the cell surface.[1170]This translocation of ANCA antigens to the cell surface has been demonstrated in vivo on the neutrophils of patients with Wegener granulomatosis or in patients with sepsis. [1171] [1172] [1173] In the presence of circulating ANCA, the interaction of the autoantibody with their externalized antigen results in full activation of the neutrophil leading to the respiratory burst and degranulation of primary and secondary granule constituents. [1173] [1174] The current hypothesis stipulates that ANCA induce a premature degranulation and activation of neutrophil at the time of their margination and diapedesis, leading to the release of lytic enzymes and toxic oxygen metabolites at the site of the vessel wall, thus producing a necrotizing inflammatory injury. This paradigm is supported by in vitro studies demonstrating that neutrophils activated by ANCA lead to the damage and destruction of human umbilical vein endothelial cells in culture. [1175] [1176]
In addition to direct damage of the endothelium by neutrophil degranulation, ANCA antigens released from neutrophils and monocytes enter endothelial cells and cause cell damage. PR3 can enter the endothelial cells by a receptor-mediated process [1177] [1178] [1179] and result in the production of IL-8 production[1180] and chemoattractant protein-1. PR3 also induces an apoptotic event from both proteolytic and non-proteolytic mechanisms. [1181] [1182]Similarly, MPO enters endothelial cells by an energy-dependent process,[1183] and transcytoses intact endothelium to localize within the extracellular matrix. There, in the presence of the substrates H2O2 and NO2-, MPO catalyzes nitration of tyrosine residues on extracellular matrix proteins,[1184] resulting in the fragmentation of extracellular matrix protein.[1185] However, a recent study suggests that endothelial cells inhibit superoxide generation by ANCA-activated neutrophils, and that serine proteases may play a more important role than reactive oxygen species as mediators of endothelial injury during ANCA-associated systemic vasculitis.[1186]
Neutrophil activation by ANCA is likely mediated by both the antigen binding portion of the autoantibodies (F(ab’)2) and by the engagement of their Fc fraction to Fc gamma receptors on the surface of neutrophils. [1169] [1176] [1187] [1188] Human neutrophils constitutively express the IgG receptors Fc gamma RIIa and Fc gamma RIIIb.[1189] Engagement of the Fc receptors results in a number of neutrophil-activation events, including respiratory burst, degranulation, phagocytosis, cytokine production, and upregulation of adhesion molecules. ANCA have been shown to engage both types of receptors. [1176] [1190] In particular, FcgammaRIIa engagement by ANCA appears to increase neutrophil actin polymerization leading to distortion in their shape and possibly decreasing their ability to pass through capillaries (the primary site of injury in ANCA vasculitis).[1191] Furthermore, polymorphisms of the Fc gamma RIIIb receptors [1192] [1193] (but not of Fc gammaRII [1194] [1195]) appear to influence the severity of ANCA-vasculitis. In addition to the Fc receptor-mediated mechanism, substantial data supports a role for the F(ab’)2portion of the antibody molecule in leukocyte activation. ANCA F(ab’)2 induce oxygen radical production[1188] and the transcription of cytokine genes in normal human neutrophils and monocytes. Microarray gene chip analysis showed that ANCA IgG and ANCA-F(ab’)2 stimulate transcription of a distinct subset of genes, some unique to whole IgG, some unique to F(ab’)2 fragments, and some common to both.[1196] It is most likely that F(ab’)2 portions of ANCA are capable of low-level neutrophil and monocyte activation.[1188] The Fc portion of the molecule almost certainly causes leukocyte activation once the F(ab’)2 portion of the immunoglobulin has interacted with the antigen, either on the cell surface or in the microenvironment.[1176] Recently, the signal transduction pathways of F(ab’)2 and Fc receptor activation through a specific p21ras (Kristen-ras) pathway were elucidated.[1197]
The role of T cells in the pathogenesis of pauci-immune necrotizing small-vessel vasculitis or glomerulonephritis, although suspected, [1198] [1199] is less well-defined. This role is suggested by the presence of CD4 positive T cells in the granulomatous[1200] and active vasculitic lesions, [1201] [1202] [1203] [1204] [1205] and by some correlation of soluble markers of T cell activation with disease activity, [1200] [1206] specifically, soluble interleukin-2 receptor and sCD3. [1207] [1208] Also, leukocytes isolated from patients with Wegener granulomatosis and anti-PR3 antibodies have been shown to proliferate in response to crude neutrophil extracts that contain PR3 or to purified PR3, [1208] [1209] [1210] [1211] [1212] whereas T cells from patients with MPO-ANCA did not have a similar proliferative response to MPO.[1213]
Further establishment of a pathogenetic role between ANCA and the development of pauci-immune necrotizing glomerulonephritis and small-vessel vasculitis greatly benefited from the development of animal models of this disease.
Early models of disease were based on the finding of circulating anti-MPO antibodies in 20% of female MRL/lpr/lpr mice,[1214] and in an inbred strain of mice, SCG/Kj, derived from the MRL/lpr mice and BXSB strains that develop a severe form of crescentic glomerulonephritis and a systemic necrotizing vasculitis.[1215] Anti-MPO antibodies have been isolated from these strains of mice. Treatment of rats with mercuric chloride led to the development of widespread inflammation, including necrotizing vasculitis in the presence of anti-MPO antibodies and anti-GBM antibodies.[1216] A more convincing model implicates a pathogenetic role for ANCA. Aggravation of a mild anti-glomerular basement membrane mediated glomerulonephritis in the rat when the animals were previously immunized with myeloperoxidase[1107] suggests that minor pro-inflammatory events could be driven to severe necrotizing processes in the presence of ANCA.
Compelling models for ANCA small-vessel vasculitis were recently described. Myeloperoxidase knockout mice were immunized with murine myeloperoxidase. Splenocytes from these mice were transferred to immunoincompetent Rag’2 resulting in the development of anti-MPO antibodies, a severe necrotizing and crescentic glomerulonephritis and, in some animals, vasculitis in the lung and other organ systems. In a separate but similar set of experiments, anti-MPO antibodies alone (not splenocytes) were transferred into Rag’2-/- mice. These mice developed a pauci-immune necrotizing and crescentic glomerulonephritis.[1217] These studies indicate that anti-MPO antibodies cause pauci-immune necrotizing disease. This disease process occurred without antigen-driven T cells.[1218] The glomerulonephritis induced by anti-MPO antibodies is aggravated by the administration of LPS into recipient mice.[1219]Conversely, the disease was abrogated when the neutrophils of anti-MPO recipient mice were depleted by a selective anti-neutrophil monoclonal antibody (NIMP-R14).[1220] In experiments to assess the role of T cells using this animal model, the transfer of T cell enriched splenocytes (>99% T cells) did not cause glomerular crescent formation or vascular necrosis. These data do not support a pathogenic role for anti-MPO T cells in the induction of acute injury.[1221]
The pathogenic role of anti-MPO antibodies is also documented in a second animal model whereby rats immunized with human MPO developed anti-rat-MPO antibodies and a necrotizing and crescentic glomerulonephritis, as well as pulmonary capillaritis.[1222] These two animal models document that anti-MPO antibodies are capable of causing a necrotizing and crescentic glomerulonephritis and a widespread systemic vasculitis. A model of anti-PR3-induced vascular injury was developed in proteinase 3/neutrophil elastase-deficient mice whereby the passive transfer of murine anti-mouse PR3 was associated with a stronger localized cutaneous inflammation and perivascular infiltrates were observed around cutaneous vessels at the sites of intradermal injection of tumor necrosis factor alpha. [1221] [1223] In summary, these animal studies document that both anti-MPO and proteinase-3 antibodies are capable of causing disease.
As is true for most autoimmune responses, the inciting events in the breakdown of tolerance and the generation of anti-MPO or anti-PR3 antibodies are not known. Although genetic predispositions,[1224] environmental exposure to foreign pathogens,[1225] and notably to silica [1226] [1227] have been implicated, no direct link between these exposure and the formation of ANCA has been established. A serendipitous finding in ANCA vasculitis has spawned a theory of autoantigen complementarity. [1228] [1229] This theory rests on evidence that proteins transcribed and translated from the sense strand of DNA bind to proteins that are transcribed and translated from the anti-sense strand of DNA. It has been recently demonstrated that some patients with PR3-ANCA harbor antibodies to an antigen complementary to the middle portion of PR3. These anti-complementary PR3 antibodies form an anti-idiotypic pair with PR3-ANCA. Moreover, cloned complementary PR3 proteins bind to PR3 and function as a serine proteinase inhibitor. Preliminary data suggest that the complementary PR3 antigens are found on a variety of microbes, some of which have been associated with ANCA vasculitis and also found in the genome of some patients with both PR3- and MPO-ANCA.[1229] While these studies need to be confirmed and expanded to determine the source of the complementary PR3 antigen and their role (if any) in inducing vasculitis, these observations may provide a promising avenue for the detection of the proximate cause of the ANCA autoimmune response.
Clinical Features and Natural History
The majority of patients with pauci-immune necrotizing crescentic glomerulonephritis and ANCA have glomerular disease as part of a systemic small-vessel vasculitis. The disease is clinically limited to the kidney in about one-third of patients.[1230] When both renal-limited and vasculitis-associated pauci-immune crescentic glomerulonephritis are considered, this category of crescentic glomerulonephritis is the most common cause of rapidly progressive glomerulonephritis in adults. [1028] [1034] [1038] [1230] [1231] When part of a syste-mic vasculitis, patients may present with a pulmonary-renal, dermal-renal, or a multisystem disease. Frequent sites of involvement include the lungs, upper airways, sinuses, ears, eyes, gastrointestinal tract, skin, peripheral nerves, joints, and central nervous system. The three major ANCA-associated syndromes are microscopic polyangiitis, Wegener granulomatosis, and the Churg-Strauss syndrome. [1039] [1050] [1232] Even when the patients have no clinical evidence of extra renal manifestation of active vasculitis, systemic symptoms consisting of fever, fatigue, myalgias and arthralgias are common.
Although most patients with ANCA-associated pauci-immune necrotizing glomerulonephritis have RPGN with rapid loss of renal function associated with hematuria, proteinuria, and hypertension, some patients follow a more indolent course of slow decline in function and less active urine sediment. In the latter group of patients, episodes of focal necrosis and hematuria resolve with focal glomerular scarring. Subsequent relapses result in cumulative damage to glomeruli.
It is important to note that patients presenting with pauci-immune crescentic glomerulonephritis alone may later develop signs and symptoms of systemic disease with involvement of extra renal organ systems.[1233] An autopsy study was conducted in patients with ANCA-associated vasculitis. This study revealed the widespread presence of glomerulonephritis, but also demonstrated the finding of clinically silent extrarenal vasculitis. Eight percent of patients died either from septic infections or from progressive recurrent vasculitis.[1233]
No studies currently available specifically examine the prognostic factors of pauci-immune crescentic glomerulonephritis in the absence of extra-renal manifestations of disease. In studies addressing the question of prognosis of patients with ANCA small-vessel vasculitis in general, [1037] [1233] [1234] the presence of pulmonary hemorrhage was the most important determinant of patient survival. With respect to the risk of end-stage renal disease, the most important predictor of outcome is the entry serum creatinine at the time of initiation of treatment.[1234] This parameter remained the most important predictive factor of renal outcome in a multivariate analysis correcting for such variables as the presence or absence of extra-renal disease. Treatment resistance and progression to end-stage kidney disease is also predicted by the presence of greater disease chronicity and vascular sclerosis on renal biopsy (presence of glomerular sclerosis, interstitial infiltrates, tubular necrosis, and atrophy,[1235] and clinical markers of chronic disease including cumulative organ damage (measured by the Vasculitis Damage Index).[1236] Vascular sclerosis on biopsy was also found to be an independent predictor of treatment resistance[1237] and may be a reflection of chronic renal damage due to hypertension or other atherosclerotic processes, with ANCA-associated nephritis inducing an additional insult. The impact of renal damage as a predictor of resistance emphasizes the importance of early diagnosis and prompt institution of therapy. It is important to note that while the entry serum creatinine is the most important predictor of renal outcome, there is no threshold of renal dysfunction for which treatment is deemed futile, as more than half the patients presenting with a GFR less than 10 ml/min may reach a remission and have a substantial improvement in renal function. Therefore, aggressive immunosuppressive therapy in all newly diagnosed patients is warranted.[1237] However, the risk of progression to ESKD is also determined by the change in GFR within the first 4 months of treatment. In the absence of other disease manifestations, the decision to continue immunosuppressive therapy among patients with sharply declining GFR should be weighed against the diminishing chance of renal recovery.[1237]
Relapses of ANCA small-vessel vasculitis occurs in up to 40% of patients. Based on a large cohort study of patients, the risk of relapse appears to be predicted by the presence of PR3-ANCA (as opposed to MPO-ANCA) and the presence of upper-respiratory tract or lung involvement.[1237] Patients with glomerulonephritis alone, who predominantly have an MPO-ANCA would therefore belong to the subgroup of patients with a relatively low risk of relapse—with a rate of relapse around 25% in a median of 62 months.
Pauci-immune necrotizing glomerulonephritis and small-vessel vasculitis may recur after renal transplantation. [1238] [1239] The rate of recurrence for ANCA small-vessel vasculitis in general, including pauci-immune necrotizing glomerulonephritis alone, is about 20%.[1240] The rate of recurrence in the subset of patients who have pauci-immune necrotizing glomerulonephritis alone without systemic vasculitis is unknown, but may be lower than 20%. A positive ANCA test at the time of transplantation does not seem to be associated with an increased risk of recurrent disease.
Laboratory Findings
Approximately 80% to 90% of patients with pauci-immune necrotizing and crescentic glomerulonephritis will have circulating ANCA. [446] [1037] [1050] [1167] [1241] [1242] [1243] By indirect immunofluorescence microscopy on alcohol fixed neutrophils, ANCA cause two patterns of staining; perinuclear (P-ANCA) and cytoplasmic (C-ANCA). [1167] [1243] The two major antigen specificities for ANCA are myeloperoxidase (MPO) and proteinase 3 (PR3). [1163] [1243] [1244] [1245] [1246] [1247] Both proteins are found in the primary granules of neutrophils and the lysosomes of monocytes. With rare exceptions, anti-MPO antibodies produce a P-ANCA pattern of staining on indirect immunofluorescence microscopy, whereas anti-PR3 antibodies cause a C-ANCA pattern of staining. About two-thirds of patients with pauci-immune necrotizing crescentic glomerulonephritis without clinical evidence of systemic vasculitis will have MPO-ANCA or P-ANCA, and approximately 30% will have PR3-ANCA or C-ANCA. [1039] [1248] The relative frequency of MPO-ANCA to PR3-ANCA is higher in patients with renal-limited disease than in patients with microscopic polyangiitis or Wegener granulomatosis.[1039] As mentioned previously, about one third of patients with anti-GBM disease and approximately a quarter of patients with idiopathic immune complex crescent glomerulonephritis are ANCA positive, therefore, ANCA-positivity is not completely specific for pauci-immune crescentic glomerulonephritis.[446] Maximal sensitivity and specificity with ANCA testing is best performed when both immunofluorescence and antigen-specific assays are performed. Antigen-specific assays may be either an ELISA or radioimmune assay. A variety of commercial tests are now available, and their diagnostic specificity ranges from 70% to 90%, and sensitivity from 81% to 91%. [446] [1249] Tests still do not provide the necessary sensitivity/specificity and predictive power to use them as the basis for initiating or altering cytotoxic therapy.
The positive predictive value (PPV) of a positive ANCA result (i.e., the percent of positive patients who have pauci-immune crescentic glomerulonephritis) depends on the signs and symptoms of disease in the patient who is tested. The signs and symptoms indicate the pretest likelihood of pauci-immune crescentic glomerulonephritis (predicted prevalence), which greatly influences predictive value. The PPV of a positive ANCA result in a patient with classic features of RPGN is 95%.[446] In patients with hematuria and proteinuria, the PPV of a positive ANCA result is 84% if the serum creatinine is >3 mg/dL, 60% if the serum creatinine is 1.5 to 3.0 mg/dL, and only 29% if the serum creatinine is less than 1 mg/dL.[1250] Although the PPV is not good in this last setting, the negative predictive value is greater than 95% and thus a negative result can allay any concerns that the patient has early or mild pauci-immune necrotizing glomerulonephritis.
Urinalysis findings in pauci-immune crescentic glomerulonephritis include hematuria with dysmorphic red blood cells, with or without red cell casts, and proteinuria. The proteinuria ranges from 1 gram/24 hours to as much as 16 grams/24 hours. [1233] [1251] Serum creatinine usually is elevated at the time of diagnosis and rising, although a minority of patients will have relatively indolent disease. ESR and C-reactive protein are elevated during active disease. Serum complement component levels are typically within normal limits.
Whether a renal biopsy is essential for the management of ANCA-associated pauci-immune glomerulonephritis depends on a number of factors, including the diagnostic accuracy of ANCA testing, the pre-test probability of finding pauci-immune glomerulonephritis, the value of knowing the activity and chronicity of the renal lesions, and the risk associated with immunotherapy of ANCA pauci-immune necrotizing glomerulonephritis. Based on a study of 1000 patients with proliferative and/or necrotizing glomerulonephritis and a positive test for either PR3-ANCA or MPO-ANCA, the positive predictive value of ANCA testing was found to be 86% with a false positive rate of 14% and a false negative rate of 16%. Considering the serious risks inherent to treatment with high-dose corticosteroids and cytotoxic agents, it is prudent to confirm the diagnosis and characterize the activity and chronicity of ANCA-associated pauci-immune crescentic glomerulonephritis by renal biopsy unless the patient is too ill to tolerate the procedure.[1250]
Treatment
The treatment of pauci-immune crescentic glomerulonephritis remains varying regimens of corticosteroids and cyclophosphamide. [1234] [1252] [1253] In view of the potential explosive and fulminant nature of this disease, induction therapy should be instituted using pulse methylprednisolone at a dose of 7 mg/kg/day for three consecutive days in an attempt to halt the aggressive, destructive, inflammatory process. This is followed by the institution of daily oral prednisone, as well as cyclophosphamide, either orally or intravenously. Prednisone is usually started at a dose of 1 mg/kg/day for the first month, then tapered to an alternate-day regimen, and then discontinued by the end of the third to fourth month of treatment. When a regimen of monthly intravenous doses of cyclophosphamide is used, the starting dose should be about 0.5 grams/M2 and adjusted upward to 1 gram/M2 based on the two-week leukocyte count nadir. [1216] [1253] A regimen based on daily oral cyclophosphamide should begin at a dose of 2 mg/kg/day[1252] and is adjusted downward as needed to keep a nadir leukocyte count above 3000 cells/mm3.
The optimal length of therapy with cyclophosphamide remains to be determined. Typically, patients are treated for 6 to 12 months, at which time it is reasonable to discontinue the cyclophosphamide in patients who are in remission. For patients who have not achieved the remission by that time, continuing a longer duration is a reasonable approach. In some patients, the monthly intravenous regimen is not sufficiently immunosuppressive necessitating daily oral cyclophosphamide treatment (which results in a higher cumulative dosage). For patients who attain an early complete remission with cyclophosphamide, it is possible to switch therapy after three months to Azathioprine, 2 mg/kg/day for an additional eighteen months.[1110] This approach appears as effective as 12 months of oral cyclophosphamide followed by 12 months of azathioprine based on renal function, and the frequency of relapse.
In three randomized control trials addressing the role of plasmapheresis in the treatment of ANCA-associated small-vessel vasculitis and glomerulonephritis, [1254] [1255] [1256] plasmapheresis was not found to provide any added benefit over immunosuppressive treatment alone in patients with renal limited disease or in patients with mild to moderate renal dysfunction. However, the use of plasmapheresis in addition to immunosuppressive therapy appears to be beneficial in the subset of patients who require dialysis at the time of presentation. [1256] [1257] In a study performed by a European vasculitis study group, the use of pulse plasma exchange was found to be superior to pulse methylprednisolone in recovery of renal function among patients with severe renal dysfunction at the time of entry into study (serum creatinine >500 micromols [5.7 mg/dl]).[1258] Patients who eventually come off dialysis usually do so within twelve weeks of initiation of therapy.[1216] For this reason, continuing immunosuppressive therapy beyond twelve weeks in a patient who is still on dialysis is unlikely to be of added benefit (unless they continue to have extra-renal manifestations of vasculitis). Because of the clinically observed increased risk of severe bone marrow suppression with the use of cyclophosphamide in patients on dialysis, such treatment should be pursued with extreme caution.
Although high-dose intravenous pooled immunoglobulin has been used in the treatment of systemic vasculitis resistant to usual immunosuppressive treatment, [1259] [1260] [1261] [1262] [1263] [1264] there are no published reports of its use in patients with pauci-immune crescentic glomerulonephritis alone without systemic involvement.
Trimethoprim sulfamethoxazole has been suggested to be of benefit in the treatment of patients with Wegener granulomatosis. [1265] [1266] Such beneficial effects, if any, seem to be limited to the upper respiratory tract and this antibiotic are unlikely to have a role in the treatment of pauci-immune crescentic glomerulonephritis alone. Methotrexate has been used in the treatment of patients with Wegener granulomatosis who did not have immediately life-threatening pulmonary or renal disease. [1267] [1268] The dose of methotrexate must be reduced in patients whose creatinine clearance is less than 80 ml/min, and its use is contraindicated when creatinine clearances are less than 10 ml/min. Moreover, in our experience there are patients on methotrexate who have progressive glomerulonephritis. Methotrexate is, therefore, unlikely to have any role in the treatment of pauci-immune crescentic glomerulonephritis alone.
Recently, other agents including rituximab, [1269] [1270] [1271] [1272] alemtuzumab (Campath H1),[1273] and infliximab [1274] [1275] [1276] [1277] have been evaluated in small studies for the management of patients resistant to conventional therapy with glucocorticoids and cyclophosphamide. These studies were performed among patients with Wegener granulomatosis or microscopic polyangiitis rather than patients with isolated pauci-immune necrotizing glomerulonephritis alone. Whether the use of such agents is indicated or beneficial among patients with glomerulonephritis is currently unknown. Similarly, the studies pertaining to maintenance immunosuppression for the prevention of relapse are primarily geared to patients with Wegener granulomatosis or microscopic polyangiitis. Current data suggest that patients with pauci-immune glomerulonephritis alone and MPO-ANCA are at a relatively low risk of relapse. The value of prolonged maintenance immunosuppression in this group of patients is unknown, and any benefit in preventing a relapse would have to be weighed against the potential toxicity and risks associated with immunosuppressive agents.
The diagnosis and management of ANCA-associated small-vessel vasculitis is discussed in more detail in Chapter 31 .
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