Alan H. Lau
KEY CONCEPTS
Glomerulonephritis is a collection of glomerular diseases mediated by different immunologic pathogenic mechanisms, resulting in varied clinical presentation and therapeutic outcomes.
The signs and symptoms associated with glomerulonephritis can be nephritic in nature, characterized by inflammatory injury, or nephrotic in nature, characterized by proteinuria.
In the absence of specific and effective therapy for many types of glomerulonephritis, supportive treatments for edema, hypertension, hyperlipidemia, and intravascular thrombosis play important roles in reducing the complications associated with the disease.
To maximize therapeutic benefits and minimize drug-induced complications, patients have to be monitored closely to assess their therapeutic responses as well as the development of any treatment-induced toxicities.
Among all the types of glomerulonephritis, minimal-change nephropathy is most responsive to treatment. Steroids can induce good responses in most patients during initial treatment as well as relapse.
Because of the lack of consistently effective treatment for primary focal segmental glomerular sclerosis, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are commonly used for patients with mild disease to control symptoms. Steroids and immunosuppressive agents are reserved for patients with severe disease.
The optimal treatment for lupus nephritis depends on the underlying lesion and disease activity, as well as the severity and duration of the clinical presentation.
The treatment of poststreptococcal glomerulonephritis is mainly supportive and symptomatic. Antibiotic therapy does not prevent subsequent diseases but may reduce the severity.
The precise pathogenetic mechanisms of many glomerular diseases remain unknown, and the available therapeutic regimens are still far from optimal. This chapter provides an overview of the primary causes of glomerulonephritis with a focus on their etiology, the pathophysiologic mechanisms responsible for glomerular injury, and the clinical presentation of the eight predominant types of glomerulonephritis. Treatment options and monitoring approaches for each of these types of glomerulonephritis are also discussed. Diabetes mellitus is an important secondary cause of glomerular injury, and a thorough discussion of the pathophysiology and management of this condition can be found in Chapter 57.
NORMAL GLOMERULAR ANATOMY AND FUNCTION
The glomerulus, which is enclosed within the Bowman’s capsule, consists of two important components: the filtration barrier and the mesangium (Fig. 32-1). The capillary wall, which serves as a filtration barrier, consists of three well-defined layers: fenestrated endothelium, glomerular basement membrane (GBM), and epithelial cell layer. The epithelial cells, also known as podocytes, have specialized foot processes embedded in the outer layer of the GBM. It is across this barrier that fluid flows and ultimately becomes the ultrafiltrate. Under normal conditions, the GBM functions as a compact hydrated gel of matrix proteins with a pore-like structure. The mesangium, which consists of mesangial cells embedded in an extracellular matrix, provides support for the glomerular capillaries and also modulates blood flow through the capillaries.
FIGURE 32-1 Microanatomy of the glomerulus.
The unique capillary bed of the glomerulus allows small nonprotein plasma constituents up to the size of inulin, which has a molecular weight of 5.2 kDa, to pass freely while excluding macromolecules equal to or larger than albumin, which has a molecular weight of 69 kDa. The ease of passage of solutes through the glomerular membrane is impacted by both the size and charge of the solute. Fixed, negatively charged sites are found within the glomeruli in all three layers of the capillary wall: the endothelium, the epithelium, and the GBM. The movement of negatively charged molecules is thus restricted more than that of neutral or positively charged molecules. Different glomerular diseases affect this size-and charge-selective barrier to different extents; consequently, glomerulopathies present with varied clinical features and solute-excretion patterns.
Some of the glomerular cells, such as the epithelial cells, have phagocytic function that can remove macromolecules trapped within the filtration barrier. They are also capable of synthesizing the GBM. In contrast, the mesangial cells regulate glomerular hemodynamics in response to angiotensin II and by producing prostaglandins. These cells also synthesize and respond to various cytokines and thus play a key role in immune-mediated glomerular diseases. Resident phagocytes in the mesangium are responsible for moving macromolecules trapped in the basement membrane into the urinary space. They are also involved in the development of both immune and nonimmune glomerular injury.
EPIDEMIOLOGY AND ETIOLOGY
In the United States in 2010, glomerulonephritis was the third most common cause of end-stage renal disease (ESRD), accounting for approximately 15% of all the living ESRD patients. About 7,300 patients (6.4% of all patients) develop stage 5 chronic kidney disease, which is also called ESRD, because of glomerulonephritis each year.1
Humoral and cellular immunologic mechanisms participate in the pathogenesis of most glomerulonephritis. Abnormalities in coagulation and metabolism, as well as hereditary and vascular diseases, also contribute to glomerular damage. The histopathologic manifestations vary substantially among the different types of glomerulonephritis. An overview of the primary pathogenetic mechanisms is presented in this section, and specific abnormalities for each of the primary types of glomerulonephritis are presented in subsequent sections.
PATHOPHYSIOLOGY
The glomerular lesion may be diffuse (involving all glomeruli), focal (involving some but not all glomeruli), or segmental, also known as local (involving part of the individual glomerulus). The pathologic manifestations may also be described as proliferative (overgrowth of epithelium, endothelium, or mesangium), membranous (thickening of GBM), and/or sclerotic.
The glomerular capillary wall is particularly susceptible to immune-mediated injury. Antigens and antibodies tend to localize in the glomerulus, probably because of its high blood flow and capillary hydrostatic pressure. Parenchymal damage can be induced as a result of humoral- and cell-mediated immune reactions. Antibodies and sensitized T lymphocytes are the primary mediators of glomerular injury.2,3
Production of antibodies to endogenous or exogenous antigens that are recognized as foreign by the host is the first step in humoral immunologic damage to the glomerulus. Endogenous antigens may be intrinsic glomerular antigens, such as Heymann antigen on the epithelial cell or Goodpasture antigen on the GBM, or previously sequestered antigens, such as DNA or thyroglobulin. Exogenous antigens are most often viral, bacterial, parasitic, or fungal in origin. Antineutrophil cytoplasmic autoantibodies (ANCAs) (i.e., autoantibodies that react to the cytoplasmic components of neutrophils and monocytes) are found in patients with idiopathic crescentic glomerulonephritis and also in the accompanying vasculitis.
Complexes of antigens and antibodies may be formed in the circulation and then passively entrapped in the glomerular capillary or mesangium. Alternately, experimental antibodies may combine with endogenous glomerular antigens or exogenous antigens entrapped in the glomerulus to form complexes locally, or in situ.3 The type and extent of glomerular damage depend on the location of the immune complex formation and the rate at which it is removed. Impaired removal facilitates the growth of the complex and thus increases the likelihood of glomerular damage.
Subsequent to antigen–antibody formation, a series of biologic events is triggered that ultimately leads to glomerular injury. Noninflammatory lesions can result from the binding of noncomplement-fixing antibody to the glomerular epithelial cell (mechanism 1) or from the activation of the complement system to form the C5b-9 membrane attack complex (mechanism 2).3 Both mechanisms can damage the glomerular epithelial cell and result in capillary wall injury and proteinuria. Inflammatory lesions are induced by glomerular infiltration of circulating inflammatory cells such as neutrophils, monocytes/macrophages, and platelets (mechanism 3) or by proliferation of resident glomerular mesangial cells (mechanism 4), resulting in GBM damage.3 The migration of neutrophils and monocytes to the glomerular tufts is promoted by chemoattractants such as complement fragments (C3a and C5a), platelet-activating factor, interleukin-8, and monocyte chemotactic protein-1.4 Various cytokines, chemokines, and growth factors are then released to participate in the inflammatory process.2
T cells sensitized to glomerular antigen, macrophages, and resident mesangial cells are important participants in cell-mediated injury. Sensitized T cells can cause glomerular hypercellularity in the absence of antibody deposition.2–4 Cytotoxic T cells may bind with the target cells and destroy them. Alternatively, a delayed-type hypersensitivity reaction may be initiated by activated T cells through the release of lymphokines to attract, activate, and transform monocytes into macrophages.3 These humoral and cellular mediators, in conjunction with a host of toxic molecular entities including reactive oxygen species, proteinases, eicosanoids, and procoagulants, which are secreted by neutrophils, macrophages, platelets, and resident glomerular cells, can alter the permeability, blood flow, and function of the glomeruli. Vascular constriction and occlusion follow and result in the eventual destruction of the glomeruli.
Acute forms of glomerular injury frequently lead to chronic and persistent renal dysfunction, even though the original immune factors that induced the initial glomerular injury have resolved. Experimental and clinical investigations suggest that a variety of factors may participate in the progression of renal injury. These factors include systemic and glomerular hypertension, high dietary protein intake, proteinuria, glomerular hypertrophy, hyperlipidemia, activation of the coagulation system, abnormalities of calcium and phosphorus balance, and tubulointerstitial injury. The degree of proteinuria not only is an index of the severity of glomerular disease but also has been associated with an increased rate of progression of renal injury. Heavy proteinuria is an indicator of poor prognosis in various glomerular diseases.
Proteinuria is also accompanied by an increased flux of macromolecules across the mesangium. The mesangial overload may then lead to structural damage. The passage of serum components, such as complement, across the GBM may have a pathophysiologic effect on the glomerular epithelial cells and alter the integrity of the glomerular filtration barrier. The damaging effects of macromolecules other than albumin, such as immunoglobulins, lipoproteins, transferrin, and complement, remain to be characterized.
CLINICAL PRESENTATION
Although patients with glomerular disease may present with an array of signs and symptoms, they are often categorized into one of two broad classifications: nephritic syndrome or nephrotic syndrome (Table 32-1). The unique clinical presentation characteristics of the predominant glomerulopathies are described in the individual disease sections, presented later in the chapter.
TABLE 32-1 Tendencies of Glomerular Diseases to Manifest Nephrotic and Nephritic Features
Nephritic syndrome reflects glomerular inflammation and frequently results in hematuria. White cells and cellular and granular casts are commonly found in the urine. In contrast, nephrotic syndrome reflects noninflammatory injury to the glomerular structures and results in few cells or cellular casts in the urine. Initially, there may be limited or no reduction in renal excretory function.
CLINICAL PRESENTATION Nephritic and Nephrotic Syndromes
General
• The patients are generally not in acute distress
Symptoms
• The patients may not experience any major symptoms
Nephritic Signs
• Hematuria
• Hypertension and edema as renal function declines
Nephrotic Signs
• Edema
• Weight gain
• Fatigue
Laboratory Tests
• Proteinuria up to 3 g/day
• Pus, cellular and granular casts in urine is common
• Hypoproteinemia
• Hypercoagulable state for some patients
• Proteinuria, >3.5 g/day/1.73 m2
• Hyperlipidemia
• Lipiduria
Hematuria occurs when red blood cells leak through the openings of the GBM. The presence of red cell casts is highly indicative of glomerulonephritis or vasculitis. The presence of dysmorphic red blood cells in the urine is suggestive of glomerular disease. The red blood cells are damaged as they pass through the openings in the GBM or the cells may sustain osmotic injury as they travel through the different osmotic environments within the lumen of the kidney tubules.
The presence of proteinuria indicates a defect of the size-and/or charge-selective barriers within the GBM. Normal urinary protein excretion is between 40 and 80 mg/day, with a maximum of 150 mg. Fewer than 20 mg of the excreted proteins are albumin. Most of the albumin that enters the glomerular filtrate is either reabsorbed or catabolized by the tubular epithelium. The dipsticks that are commonly used to identify proteinuria detect only albumin; they become positive when protein excretion is more than 300 to 500 mg/day. They are therefore unable to detect the early stages of renal injury secondary to diabetes mellitus or hypertension, which often result in microalbuminuria with urinary albumin excretion ranges between 30 and 300 mg/day. Chemstrip Micral-Test II (Roche Diagnostics, Indianapolis, IN), a simple immunoassay on a dipstick, permits specific and semiquantitative determination of urinary albumin concentrations at five levels: 0, 10, 20, 50, and 100 mg/L. Another qualitative test, Micro-Bumintest (Bayer Diabetes Care, Mishawaka, IN), registers a positive reading when the urine albumin concentration is greater than 40 mg/L.
Hypertension is common for patients with glomerular diseases, as a result of renal salt retention causing plasma volume expansion. In contrast, increased activity of vasoconstrictors such as angiotensin II is often the cause for patients with chronic glomerular diseases. Scarring of the glomerulus resulting in regional ischemia is thought to be responsible for the hypertension. Activation of the sympathetic nervous system and the release of vasoconstrictor substances may also contribute.
Nephritic Syndrome
Glomerular bleeding resulting in hematuria is typical in nephritic syndrome. Dysmorphic red cells, especially acanthocytes, are a sensitive and specific marker of glomerular bleeding. The presence of pus and cellular and granular casts in the urine is common. The extent of proteinuria is variable. Patients with severe nephritic glomerular injury have renal function impairment because of the reduced glomerular surface area available for filtration, as a result of constriction of the capillary lumen by proliferating mesangial cells or inflammatory cells.
Nephrotic Syndrome
Nephrotic syndrome is characterized by proteinuria greater than 3.5 g/day per 1.73 m2, hypoproteinemia, edema, and hyperlipidemia. A hypercoagulable state may also be present in some patients. The syndrome may be the result of primary diseases of the glomerulus, or be associated with systemic diseases such as diabetes mellitus, lupus, amyloidosis, and preeclampsia. Hypoproteinemia, especially hypoalbuminemia, results from increased urinary loss of albumin and an increased rate of catabolism of filtered albumin by proximal tubular cells. The compensatory increase in hepatic synthesis of albumin is insufficient to replenish the protein loss, probably because of malnutrition.
Edema formation in patients with nephrotic syndrome was traditionally thought to be driven by the reduced plasma oncotic pressure secondary to hypoalbuminemia. If the oncotic pressure is low, the movement of fluid from the vascular space to the interstitial compartment results in a reduction of the plasma volume, which can trigger compensatory renal sodium and water retention through the activation of the renin–angiotensin–aldosterone axis, vasopressin, and the sympathetic nervous system (the “underfill” mechanism). However, experimental data reveal that the plasma volume is actually normal or elevated. Hypoalbuminemia may not cause edema until the serum albumin concentration is less than 2 g/dL (20 g/L). In addition, the transcapillary oncotic pressure gradient is not as high as previously thought because increased lymphatic flow reduces the interstitial oncotic pressure by removing protein and fluid from the interstitium, thereby reducing the transcapillary oncotic pressure gradient.5 Instead, fluid retention is likely mediated by a primary increase in sodium reabsorption at the distal nephron, which is probably caused by tubular resistance to the action of atrial natriuretic peptide (the “overflow” mechanism).6 It is likely that both mechanisms may contribute to nephrotic edema in different patients.6
Albuminuria greater than 3 g daily is associated with a significant increase in serum cholesterol concentrations for patients with primary glomerular disease.7 Hyperlipidemia in nephrotic syndrome is characterized by elevated serum total cholesterol and triglyceride concentrations, with increased very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) cholesterol concentrations. Lipoprotein (a) levels may also be increased. The reduced plasma oncotic pressure as a result of hypoalbuminemia may stimulate hepatic synthesis of lipids and lipoproteins. The increased VLDL production and increased liver cholesterol synthesis, along with a decrease in LDL receptor activity, can then lead to an increase in LDL cholesterol concentrations. In addition, reduced serum albumin or the loss of a liporegulatory substance may result in reduced VLDL clearance.8 Nephrotic patients with hyperlipidemia, especially those with concomitant hypertension, are presumed to have an increased risk for atherosclerotic vascular disease. Hyperlipidemia also promotes the progression of glomerular injury, as evidenced by glomerulosclerosis, mesangial expansion, and hyalinosis.8,9
Many patients with nephrotic syndrome have a hypercoagulable state caused by defects of several control proteins in the coagulation cascade. The concentration of the coagulation inhibitor antithrombin III is reduced because of increased loss in the urine. A reduced amount of the coagulation inhibitors proteins C and S, along with increased concentrations of factors V and VIII, increased fibrinogen concentrations, and abnormal platelet function, may also contribute to the hypercoagulable state. The net result of these alterations in coagulation is an increased risk for arterial and venous thrombosis, especially in the deep veins and renal veins. As many as 25% of patients with membranous nephropathy may have renal vein thrombosis.
DIAGNOSTIC CONSIDERATIONS
Patients with suspected glomerular disease should have an extensive medical history obtained to identify potential systemic causes (Table 32-2). Medication, environmental, and occupational histories may also help identify possible exposure to potentially nephrotoxic agents. A carefully conducted physical examination and laboratory evaluation may reveal the presence of systemic diseases that may contribute to the development of glomerular disease (Fig. 32-2). In addition, the patient’s age, gender, and ethnic background may be helpful in pinpointing the specific type of glomerular disease. Many of the conditions are more prevalent in certain age groups, although they may occur at any age. For example, proliferative glomerulonephritis is more common in those younger than 40 years of age, whereas the incidence of membranous glomerulonephritis is dramatically higher in those older than 50 years of age.
TABLE 32-2 Evaluation of Patients Suspected of Having Glomerular Disease
FIGURE 32-2 Clinical presentations of glomerulonephritis. (AP, anaphylactoid purpura; GBM, glomerular basement membrane; GN, glomerulonephritis; HUS, hemolytic uremic syndrome; IgA, immunoglobulin A; MPGN, membranoproliferative glomerulonephritis; SBE, subacute bacterial endocarditis; SLE, systemic lupus erythematosus; TTP, thrombotic thrombocytopenic purpura.)
Laboratory evaluation such as urinalysis can help differentiate the nephrotic or nephritic nature of the disease. The glomerular filtration rate (GFR) may be used to determine the extent of glomerular damage. In the early stages of the disease, the GFR may remain normal. Initial injury to the glomerulus primarily lowers the permeability coefficient (Kf) of the GBM by reducing the surface area available for filtration and/or the unit permeability of the membrane. The reduced permeability is compensated by an elevation in the glomerular capillary hydrostatic pressure through afferent arteriolar dilation and efferent arteriolar constriction. Extensive glomerular damage may therefore be present before a substantial reduction of total GFR is evident.
Although the cause of glomerular disease may be established from clinical and laboratory evaluation, sometimes percutaneous renal biopsy may be needed to provide a definitive diagnosis.
TREATMENT
General Approach to Treatment
The course and prognosis of the different glomerular diseases are extremely variable and depend on the underlying etiology. In glomerular diseases with a secondary cause, such as poststreptococcal glomerulonephritis (PSGN), after the initiating factor is removed, the prognosis of the renal disease is often good. In contrast, the rates of renal function deterioration among the primary glomerulonephritides vary markedly. The majority of patients with minimal-change disease, IgA nephropathy, and membranous nephropathy have a fairly good prognosis. However, those with focal segmental glomerulosclerosis (FSGS) who are resistant to therapy, as well as those with rapidly progressive glomerulonephritis (RPGN) who are untreated, are likely to experience rapid loss of renal function. In some instances, half of the renal function may be lost within a 3-month period. Certain glomerulonephritides, such as minimal-change nephropathy, are very responsive to treatment while patients with membranous proliferative glomerulonephritis are rarely responsive to existing therapies.
Because of the variable courses exhibited by the different glomerulonephritides, specific treatment approaches have been developed for each disease. When natural history of the glomerulonephritis is well delineated, it is more likely that potential regimens can be designed and evaluated from both therapeutic and economic perspectives. The potential therapeutic benefits of treatment regimens should always be weighed against the risks to which the patients are being exposed. It is therefore imperative to identify patients who are most likely to benefit from treatment, especially those who have other risk factors that may contribute to the deterioration of their renal function. In those instances in which satisfactory regimens are not available to treat the primary disease, appropriate supportive measures should be employed. Optimization of systemic and glomerular blood pressure, reducing proteinuria, and possibly controlling hyperlipidemia may all improve the long-term outcome as well as the quality of life of these patients.
KDIGO (Kidney Disease: Improving Global Outcomes) is a global nonprofit foundation dedicated to improving the care and outcomes of kidney disease patients worldwide through promoting coordination, collaboration, and integration of initiatives to develop and implement clinical practice guidelines for many kidney diseases through its work groups of experts.10 The quality of evidence and strength of recommendations were graded. Many of these clinical practice guidelines are referenced in the ensuing sections on the treatment of individual primary glomerular diseases.
Nonpharmacologic Therapy
For patients with nephrotic syndrome, dietary measures involve restriction of sodium intake to 50 to 100 mEq/day (50 to 100 mmol/day),11 protein intake of 0.8 to 1 g/day,11,12 and a low-lipid diet of less than 200 mg cholesterol. Total fat should account for less than 30% of daily total calories.11 Sodium restriction is important not only in the control of edema, but also in the control of hypertension and proteinuria. Similarly, protein restriction not only helps to reduce proteinuria but also has a potential role in retarding the progression of renal disease. Patients should also stop smoking because a dose-dependent increase in risk for developing ESRD was observed in men with primary inflammatory (immunoglobulin A glomerulonephritis) or noninflammatory (polycystic kidney disease) renal diseases.13
Because many immune factors are implicated in the pathogenesis of glomerulonephritis, plasmapheresis may be used to remove these mediators. During the procedure, whole blood is removed from the body and centrifugation is used to separate the cellular elements from the plasma. The cells are then infused back to the patient after resuspension in saline or plasma substitute. The plasma proteins, presumably including the pathogenic immune factors, are thereby removed from the patient.
Pharmacologic Therapy
Immunosuppressive Agents
Immunosuppressive agents, alone or in combination, are commonly used to alter the immune processes that are responsible for the glomerulonephritides. Corticosteroids, in addition to their immunosuppressive effect, also possess antiinflammatory activities. They reduce the production and/or release of many substances that mediate the inflammatory process, such as prostaglandins, leukotrienes, platelet-activating factors, tumor necrosis factors, and interleukin-1 (IL-1). Movement of leukocytes and macrophages to the site of inflammation is also inhibited. The immunosuppressive effects of corticosteroids are mediated through the inhibition of the release of IL-1 and tumor necrosis factor by activated macrophages, and interleukin-2 by activated T cells. In addition, the actions of migration-inhibiting factor and γ-interferon are inhibited. Processing of antigens is thus affected by the presence of corticosteroids. Cytotoxic agents, such as cyclophosphamide, chlorambucil, or azathioprine, are commonly used to treat glomerular diseases. Cyclosporine can reduce lymphokine production by activated T lymphocytes, and it may decrease proteinuria by improving the permselectivity of the GBM. Mycophenolate mofetil is useful in different glomerulonephritides because of its effects on T- and B-cell lymphocytes.
Recently, many novel targets were identified and new agents are being evaluated for their usefulness to control the disease, preserve renal function, and improve patient outcome.14 To stay abreast of the expanding availability of treatment options, one can routinely consult one of the clinical trial registries, such as www.clinicaltrials.gov.
Diuretics
Management of nephrotic edema involves salt restriction, bed rest, and use of support stockings and diuretics. However, severe salt restriction is difficult to achieve and prolonged bed rest can predispose nephrotic patients to thromboembolism. Hence the use of a loop diuretic such as furosemide is frequently required. Although the delivery of diuretic to the kidney tubules is normal, the presence of large amounts of protein in the urine promotes drug binding, and thereby reduces the availability of the diuretic to the luminal receptor sites. In addition, reduced sodium delivery to the distal tubule secondary to decreased glomerular perfusion may also alter diuretic effectiveness. Large doses of the loop diuretic, such as 160 to 480 mg of furosemide, may be needed for patients with moderate edema (see Chap. 34). In some instances, a thiazide diuretic or metolazone may be added to enhance natriuresis.11,15Alternatively, continuous IV infusion of a loop diuretic, such as furosemide 160 to 480 mg/day, may be employed.16For patients with morbid edema, albumin infusion may be used to expand plasma volume and increase diuretic delivery to the renal tubules, thus enhancing diuretic effect. However, it may precipitate congestive heart failure and may also reduce therapeutic response to steroid in minimal-change nephropathy. For patients with significant edema, the goal of treatment should be a daily loss of 1 to 2 lb (0.45 to 0.9 kg) of fluid until the patient’s desired weight has been obtained.
Antihypertensive Agents
Optimal control of hypertension for patients with glomerular disease is important in reducing both the progression of renal disease and the risk for cardiovascular disease12 (see Chaps. 3 and 29). The target blood pressure for patients with chronic kidney disease defined by GFR <60 mL/min (<1 mL/s) or albuminuria >300 mg/day is less than 130/80 mm Hg.17 Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) delay the loss of renal function for patients with diabetic and nondiabetic (primarily glomerulonephritis) renal diseases.18 Nondihydropyridine calcium channel blockers (e.g., diltiazem, verapamil) reduce proteinuria and preserve renal function and could be used as an additional agent. In contrast, the dihydropyridine calcium channel blockers (e.g., nifedipine, amlodipine, or nisoldipine) are effective in lowering blood pressure, but without the benefit of proteinuria reduction.19
Antiproteinuria Agents
Dietary protein restriction reduces proteinuria and may retard renal function deterioration. Secondary analysis of the Modification of Diet in Renal Disease Study for patients with moderate renal insufficiency (GFR of 25 to 55 mL/min/1.73 m2 [0.24 to 0.53 mL/s/m2]) revealed that reduced protein intake (0.66 g/kg/day) delayed the rate of GFR deterioration for patients with severe renal insufficiency (GFR of 13 to 24 mL/min/1.73 m2 [0.13 to 0.23 mL/s/m2]).20 Consequently, modest protein restriction of 0.8 g/kg/day is reasonable for patients with moderate renal insufficiency. Decreasing dietary protein also reduces the intake of phosphorus and potassium. In many instances, the potential benefits of protein restriction have to be balanced against the need for protein intake to overcome nutritional deficiencies. For nondialyzed patients who have GFRs of less than 25 mL/min/1.73 m2 (0.24 mL/s/m2), dietary protein intake should be reduced to 0.6 g/kg/day.13
Angiotensin-Converting Enzyme Inhibitors and Receptor Blockers It is now recognized that proteinuria is an independent risk factor for renal function decline and cardiovascular disease.21 Reducing proteinuria can retard renal function loss and delay the progression to ESRD.22 The antiproteinuric effect of ACEIs is associated with a fall in filtration fraction, suggesting a reduction in intraglomerular pressure. Recent studies show that ACEIs and ARBs may also have direct effects on podocytes, resulting in reduction of proteinuria and glomerular scarring.23 In addition, angiotensin-converting enzyme (ACE) inhibition may also reduce the effect of angiotensin II on renal cell proliferation, thereby reducing sclerosis. These beneficial effects on proteinuria are beyond what can be attributed by the drug’s antihypertensive effects (see Chaps. 3 and 29).24,25
Clinical Controversy…
Differences in the mechanism of action accountable for proteinuria reduction and renal protective effects of ACEs and ARBs have been espoused by some clinicians and thus combination therapy has been recommended. Others believe that at comparable doses their effects are similar and thus there is no benefit of combination therapy.
The combined use of an ACEI and an ARB reduces the rate of renal function decline more than either treatment alone.18 A meta-analysis of 21 randomized, controlled studies revealed that combination therapy enhanced the reduction of proteinuria in both diabetic and nondiabetic patients.26 Combination therapy maximizes blockade of the renin–angiotensin system by counteracting the effects of angiotensin II produced by non-ACE pathways. In addition, with the blockade of the angiotensin II type 1 receptor, the angiotensin II produced by the non-ACE pathways may still act on the angiotensin II type 2 receptors, further facilitating vasodilation.27 An angiotensin II receptor antagonist should therefore be added to the regimen for those patients who do not attain full and persistent remission of proteinuria with an ACEI alone. A thorough review of the combined use of ACEs and ARBs for diabetic nephropathy and proteinuria reduction is found in Chapter 29.
Nonsteroidal Antiinflammatory Agents Nonsteroidal antiinflammatory drugs (NSAIDs) probably reduce proteinuria through prostaglandin E2 inhibition, resulting in a reduction of intraglomerular pressure, a decrease in GFR, and restoration of the barrier size selectivity of the GBM.12 Indomethacin and meclofenamate are the two most evaluated NSAIDs. Their antiproteinuric effect is comparable to that attained with ACEIs, and combined treatment with an ACEI results in additional proteinuria reduction.28 However, adherence to a low-sodium diet or concurrent use of a diuretic is needed to maximize the antiproteinuric effect. Because of their potential for nephrotoxicity, especially for patients with poor renal function, long-term use of an NSAID for renoprotection is not preferred.24
Adrenocorticotropin A synthetic adrenocorticotropin (ACTH) analog has been used in Europe for proteinuria reduction associated with nephrotic syndrome. It was reported to have effects similar to alternating months of steroids and cyclophosphamide.29 Instead of the synthetic analog, a natural, purified ACTH gel is available in the United States and is approved by the FDA for inducing a remission of proteinuria in the nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus. Favorable response was reported in an observation series of 21 patients in the United States.30 However, the authors cautioned the interpretation of the results since the data were not derived from a controlled, randomized study. The patients had different glomerular diseases and the long-term effect was not reported.
Statins
An abnormal lipoprotein profile increases the risk of atherosclerosis and coronary heart disease for patients with nephrotic syndrome. It is therefore important to treat patients with persistent nephrotic syndrome and sustained dyslipidemia, especially those with high VLDL and LDL cholesterol levels in the presence of a normal or low high-density lipoprotein cholesterol level (see Chaps. 11 and 29). Therapy is especially needed for those with concurrent atherosclerotic cardiovascular disease, or with additional risk factors for atherosclerosis, such as smoking and hypertension.8
A low-fat diet is usually not sufficient to correct hyperlipoproteinemia.12 β-Hydroxy-β-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as “statins” such as lovastatin, pravastatin, simvastatin, and fluvastatin, are considered the treatment of choice.12 They reduce total plasma cholesterol concentration, LDL cholesterol, and total plasma triglyceride concentrations.8 Aside from the lipid-lowering effects, statins may confer renoprotection through different mechanisms, including reduction of cell proliferation and mesangial matrix accumulation and antiinflammatory and immunomodulatory effects.31 Recent clinical studies show that they can reduce proteinuria and delay renal function loss.32,33 The combined use of an ACEI with a statin may offer additional benefits in controlling nephrotic hyperlipidemia.20
Anticoagulants
Renal vein thrombosis, pulmonary emboli, or other thromboembolic events are serious and common complications of nephrotic syndrome, and are frequently seen in those with membranous nephropathy. Although patients who have documented thromboembolic episodes should be anticoagulated with warfarin until remission of nephrotic syndrome, the use of prophylactic anticoagulation is controversial. A decision analysis study suggested that prophylactic anticoagulation is beneficial for patients with membranous nephropathy.34 Prophylactic anticoagulation is not recommended for all patients; rather, a “selective” approach or individualized assessment should be conducted to identify those at high risk (i.e., those with severe nephrotic syndrome and a serum albumin concentration <2 to 2.5 g/dL [<20 to 25 g/L]).34 Also at risk are those who require prolonged bed rest, those receiving high-dose IV steroid therapy, and individuals who are dehydrated as well as postsurgical patients.12
Evaluation of Therapeutic Outcomes
The management of patients with glomerulonephritis involves specific pharmacologic therapy for the glomerular disease and supportive measures to prevent and/or treat the pathophysiologic sequelae, namely, hypertension, edema, and progression of renal disease. Although the course of the disease, as well as the specific treatment regimens, varies among the different glomerulonephritis, the monitoring parameters for efficacy assessment are similar. For patients with nephrotic syndrome, supportive therapy should also address the management of extrarenal complications of heavy proteinuria, namely, hypoalbuminemia, hyperlipidemia, and thromboembolism. Because patients with significant proteinuria tend to have more rapid decline of renal function, reduction of proteinuria thus becomes critical in delaying the rate of progression toward ESRD.
Patients should be monitored closely for therapeutic response as well as the development of treatment-related toxicities. Although the rate of renal function deterioration is an important indicator of the long-term success of treatment, resolution of nephrotic and nephritic signs and symptoms associated with the glomerulopathies is an important short-term therapeutic target (see Table 32-3).
TABLE 32-3 Monitoring Parameters to Assess Response to Glomerulonephritis Treatment
Serum creatinine concentration as well as creatinine clearance should be evaluated prior to and during treatment; 24-hour urine outflow should be collected to determine the extent of proteinuria. Alternatively, the daily urine protein excretion may be estimated from the urinary total protein-to-creatinine concentration ratio. After establishing the correlation between the 24-hour urinary protein excretion and the protein-to-creatinine ratio, single, random urine specimens may be used in place of a 24-hour urine collection. Blood pressure should be monitored periodically to assess the need for and the adequacy of antihypertensive therapy. The pressures should also be evaluated in conjunction with clinical signs and symptoms of edema and fluid overload to gauge the need for volume control as well as diuretic use. For patients with nephrotic syndrome, serum lipid concentrations should be monitored. If the patient has hematuria, urinalysis and a complete blood count should be obtained. The clinician should also be aware of the patient’s appetite and energy level, because these are indicators of the patient’s overall state of well-being. At times, renal biopsy is needed to assess response to treatment and disease progression, to determine future treatment strategy, and to confirm the initial diagnosis.
Patients receiving cytotoxic drug treatment should be evaluated for drug-related toxicities every week during the initial treatment period. After 1 month of treatment, the frequency of monitoring may be reduced. When the patient is on long-term steroid treatment, monthly visits are often required for assessment of both efficacy and toxicities. If a favorable response is obtained after a course of treatment, the patient may be evaluated every 3 to 4 months. The patient’s renal function, proteinuria, urinalysis, blood pressure, lipid profile, and the overall state of health should be assessed during these regular follow-up visits.
Minimal-Change Nephropathy
Epidemiology and Etiology
Minimal-change nephropathy (also termed nil disease or minimal-change disease) is commonly found in children, accounting for about 85% to 90% of all cases of nephrotic syndrome in children between 1 and 4 years of age. The percentage drops gradually to less than 50% after age 10 years and accounts for less than 20% of all cases of idiopathic nephrotic syndrome in adults. Secondary causes of minimal-change nephropathy include drug administration (e.g., NSAIDs, lithium, interferons), lupus, and various T-cell–related disorders, such as Hodgkin’s disease and leukemias.
Pathophysiology
Minimal-change disease is characterized by the absence of definitive pathologic changes observed under light and immunofluorescence microscopy. The characteristic lesion in patients with minimal-change disease, as visualized under electron microscopy, is the spreading and fusion of the foot processes of epithelial cells over an unchanged GBM. Lipoid nephrosis is another term that has been used to describe this type of glomerular disease because lipids, as well as renal tubular cells, are found in the urine. The pathogenesis of minimal-change disease is unknown. Altered cell-mediated immunologic response, specifically T-cell dysfunction or changes in the T-cell subpopulations, may be responsible. The activated lymphocytes are thought to secrete lymphokines that reduce the production of anions in the GBM. The permeability of the GBM to plasma albumin is increased through a reduction of electrostatic repulsion. The loss of anionic charges also results in fusion of the epithelial cell foot processes. Other vascular permeability factors, such as hemopexin, interleukin-4, and vascular endothelial growth factor, also have been suggested to be responsible.
Clinical Presentation
Most patients present initially with edema, frequently acute in onset, following a nonspecific upper respiratory tract infection, allergic reaction, or vaccinations, which might have activated the T lymphocytes. Nephrotic syndrome with massive proteinuria (substantially more than 40 mg/m2/h for children and >3 to 3.5 g/day for adults), edema, hypoalbuminemia, and hyperlipidemia is common. The patient’s weight may increase dramatically because of sodium and fluid retention. Nephritic features, such as gross hematuria, are uncommon. Hypertension and decreased renal function are uncommon in children but are more common in older adults.35 For some patients, volume depletion may result in mild-to-moderate azotemia.
TREATMENT
Pharmacologic Therapy
Steroids
Minimal-change disease is most responsive to initial treatment with corticosteroids. In children, steroid therapy is expected to reduce proteinuria in approximately 90% of the patients, with >95% 10-year renal survival. Because of the excellent response to initial therapy with steroids and the prevalence of this glomerular disease in children, reduction of proteinuria secondary to steroid treatment is considered diagnostic for minimal-change disease without the need for biopsy. Prednisone is commonly administered at 60 mg/m2 per day initially for 4 to 6 weeks. The dose is then reduced to 40 mg/m2 per day every other day for another 4 to 6 weeks, with or without tapering afterward (Fig. 32-3).36 Proteinuria will disappear in 50% of patients after 1 week and in 90% of patients after 4 weeks of treatment. Different versions of the steroid regimen are available as there is no consensus on the optimal dose and duration. Studies are being conducted to identify the best strategy to induce remission, reduce disease recurrence, and minimize adverse effects of the therapy. Commonly, the initial episode is treated with an extended course (months) of therapy, followed by shorter treatment (weeks) for relapses.37
FIGURE 32-3 Treatment algorithm for minimal-change nephropathy. (Reprinted by permission from Macmillan Publishers Ltd: from reference 36.)
For adults, prednisone 1 mg/kg per day is given initially for 4 weeks with a reduction to 0.75 mg/kg every other day for the next 4 weeks. Proteinuria will disappear in 50% to 60% of patients after 8 weeks of treatment, and complete remission will be attained in 80% of patients after 28 weeks of therapy.35
Relapse As many as 85% of the patients who respond to initial steroid therapy (steroid sensitive) will experience a relapse of proteinuria, mostly within 6 to 12 months after disease onset. The risk of relapse is affected by the duration of initial steroid therapy.12,36 Children who were asymptomatic with proteinuria diagnosed during routine urine screening tend to have less frequent relapses and a more favorable clinical course. In those who relapse, 50% to 65% may have steroid-responsive relapse episodes over the subsequent 3- to 5-year period. The dose and duration of steroid treatment for the relapse do not influence the subsequent rate of relapse.12,36 Commonly, 60 mg/m2 per day of prednisone is given until the urine is free of protein for 3 days, to be followed by 4 weeks of alternate-day prednisone at 40 mg/m2 per dose.36
Frequent Relapse Approximately 10% to 20% of children that are responsive to steroid will experience three or four relapses. Half of them will then relapse frequently and become steroid dependent, requiring continuous low-dose alternate-day prednisone to maintain an extended relapse-free period.36 A small number of patients eventually develop resistance to steroids, and a biopsy done at that time often reveals another pathology such as FSGS. It is controversial whether minimal-change disease progresses into FSGS or whether the glomerulosclerosis that was present at the time of initial diagnosis was inadvertently diagnosed as minimal-change nephropathy because of tissue-sampling error during the renal biopsy.
Cytotoxic Agents
Cytotoxic agents are often considered for patients who are steroid resistant, as well as for those who require large doses of steroids to sustain remission (steroid dependent). These agents are also beneficial for pediatric patients who experience growth inhibition secondary to chronic use of steroids.12 Cytotoxic agents are effective in inducing remission and the duration of remission tends to be longer than that induced by steroids. In those patients who relapse after cytotoxic therapy, they may respond to steroids better than before.
Cyclophosphamide at 2 mg/kg per day for 10 to 12 weeks given alone or with prednisone (50 to 75 mg/m2) is very effective in inducing remission and restoring steroid responsiveness for patients who were previously steroid dependent and then became steroid resistant. Alternatively, chlorambucil at 0.1 to 0.2 mg/kg per day may be used. This agent, however, is associated with more adverse effects than cyclophosphamide. Azathioprine has also been used; however, treatment for 6 to 12 months is often needed before any favorable response is apparent.
The immunosuppressive effect of cytotoxic agents, with or without the concurrent use of steroids, can result in serious infections, which are the primary cause of death for patients with minimal-change nephropathy. Other toxicities associated with cyclophosphamide include gonadal fibrosis, which results in sterility, hemorrhagic cystitis, alopecia, and a potential to develop malignancy in those on long-term treatment.
Calcineurin Inhibitors
Cyclosporine decreases lymphokine production by activated T lymphocytes and thereby reduces proteinuria by reversing the lymphokine-induced alterations in the anionic charge and permeability of the GBM to albumin. For patients with steroid-sensitive or steroid-dependent disease, cyclosporine induces remission in 80% to 85% of patients. However, the disease-free period is not often sustained, and relapse, which is usually not as responsive to cyclosporine retreatment, may occur as soon as the drug is tapered or discontinued. The steroid-sparing effect of cyclosporine is also useful for steroid-dependent patients, especially those who have experienced significant adverse effects.
Dosage The usual starting dose of cyclosporine for remission induction is 5 mg/kg per day for adults and 100 to 150 mg/m2 per day for children. Similar dosages are used to maintain remission long term. The optimal cyclosporine blood concentrations, as well as the need to monitor them, are controversial. No correlation has been found between the severity of the cyclosporine-induced tubulointerstitial lesions and the mean dose or trough drug concentration. However, monitoring of the area under the serum concentration–time curve has been suggested and target exposures have been proposed.38 Testing the in vitro sensitivity of peripheral blood lymphocytes to cyclosporine in the presence of a T-cell mitogen may offer a novel method to predict response and individualize therapy.39
Adverse Events Adverse events such as rise in serum creatinine, hypertrichosis, and gingival hyperplasia are quite common. Long-term therapy may result in persistent hypertension and progressive renal failure. Cyclosporine should not therefore be given for more than 4 months in the absence of any beneficial effect. Consequently, it is indicated for patients (a) who relapse frequently or are steroid dependent, after failing to respond to a course of cyclophosphamide; (b) for whom cyclophosphamide is contraindicated or when gonadal toxicity is a concern; (c) who are steroid dependent when a “steroid holiday” is needed for catch-up growth and puberty; or (d) who have steroid-resistant disease.36
Levamisole
Levamisole, an immunostimulant, can promote the maturation of young T cells and restore the function of T cells and phagocytes when the immune system is depressed. It may also inhibit the production of an immunosuppressive lymphokine. Levamisole was found to have a steroid-sparing effect and was capable of maintaining remission in children who had frequent relapse steroid-dependent nephrotic syndrome.40 In addition, it is as effective as cyclophosphamide in reducing relapse rate and steroid dosages.41 The adverse effect of levamisole are mild neutropenia, which is generally reversible, and GI upsets. At present the drug is no longer available in the United States; however, it is recommended by the KDIGO guidelines as a steroid-sparing agent.10
Mycophenolate Mofetil
Mycophenolate mofetil is an immunosuppressant that can suppress T- and B-cell lymphocyte proliferation, B-lymphocyte antibody production, and expression of adhesion molecules. It is reported to have steroid-sparing effects and is useful in frequently relapsing, steroid-dependent and steroid-resistant patients, as well as in those who fail cytotoxic therapy.42
Rituximab
Rituximab has been observed to induce long-term remission with repeated doses,43 possibly through a direct effect on the podocyte actin cytoskeleton. However, its use is not recommended by the KDIGO clinical practice guidelines due to the lack of randomized trials and risk for serious adverse effects.10
Prognosis
The long-term prognosis of most patients with minimal-change disease is good. The majority of pediatric patients will not experience any relapse of the disease 10 years after the initial onset, and most will be free of the proteinuria after puberty. In adults, an 85% to 90% survival rate is seen 10 years after disease onset. Although this condition may spontaneously remit in up to 70% of untreated adults, life-threatening complications may be associated with untreated nephrotic syndrome. Significant deterioration in renal function is uncommon in both adult and pediatric patients and is observed only in those who are steroid resistant or steroid dependent. Because of the overall favorable outcome of the disease and the relatively uncommon progression into chronic renal failure, aggressive use of cytotoxic agents is not indicated even for most patients with frequent relapses. Toxicities associated with aggressive therapy do not justify the need to induce remission in those patients who fail to respond to steroids and the nonaggressive use of cytotoxic agents. Symptomatic therapy with diuretics to control edema, in conjunction with a low-salt diet and albumin infusion as needed for acute development of anasarca, is often a more rewarding therapeutic approach. NSAIDs and ACEIs may also be used to reduce the proteinuria.
Focal Segmental Glomerulosclerosis
Etiology and Epidemiology
FSGS is a clinicopathologic condition that can be idiopathic (primary) or secondary to a variety of causes. FSGS accounts for less than 20% of the cases of idiopathic nephrotic syndrome in children and approximately 40% in adults44; however, it may account for 36% to 80% of the cases in African Americans. The incidence of FSGS has been rapidly increasing, so that it now is the most common glomerular disease that ultimately leads to ESRD. Conditions such as sickle cell disease, cyanotic congenital heart disease, and morbid obesity can induce hemodynamic stress on an initially normal nephron population and result in FSGS. Severe glomerular injury can also be seen in patients with nephropathy associated with heroin abuse, human immunodeficiency virus (HIV) infection, and genetic mutations involving the podocin and WT1 genes. A recent case series identified the association of FSGS and proteinuria in bodybuilders after long-term anabolic steroid abuse.45 In addition, heroin, pamidronate, and interferon have been associated with FSGS.44 The primary and secondary sclerotic lesions may be morphologically similar, but they represent diseases with different courses and responses to therapy.
Pathophysiology
Sclerotic lesions are characteristically found in some of the glomeruli (focal) and usually involve only a portion of the glomeruli (segmental).44 Similar to minimal-change disease, fusion of foot processes is commonly seen in those glomeruli that are not sclerotic. It is thought that both minimal-change disease and FSGS share similar pathogenetic mechanisms, with FSGS resulting in severe injury to the glomerular epithelial cells. During the early stage of FSGS, only a small number of glomeruli may have the segmental sclerotic lesion, and the disease may be confined to the juxtamedullary region. If an inadequate number of glomeruli are sampled during renal biopsy, the diagnosis of FSGS may be missed, or the patient may be thought to have minimal-change disease. Resistance to steroid therapy may thus be one of the first clues that the patient, indeed, has FSGS rather than minimal-change disease. Alternatively, a patient may have the steroid-sensitive minimal-change disease initially, which subsequently progresses to steroid-resistant FSGS.
Clinical Presentation
Almost all the patients present with proteinuria, and many of them have all the features of nephrotic syndrome. The proteinuria is nonselective, containing albumin and other higher-molecular-weight proteins, and is usually less severe when compared to patients who have minimal-change disease. Hypertension, microscopic hematuria, and renal dysfunction may be seen in up to half of the patients. Reduced renal function becomes more prevalent as the disease progresses.
The presenting clinical features in nephrotic adults with minimal-change nephropathy can be indistinguishable from that of FSGS, and renal biopsy is therefore critical in the diagnosis of adults with nephrotic syndrome. African Americans have a fourfold higher risk of developing FSGS than white or Asian patients. They tend to develop the disease earlier and present with nephrotic range proteinuria more often. They are less responsive to steroids and are more likely to experience a rapid decline in renal function, resulting in ESRD.
TREATMENT
Pharmacologic Therapy
The treatment of FSGS is controversial because of the lack of data from randomized, prospective, controlled trials.
Steroids
A course of prednisone (1 to 2 mg/kg/day) with tapering after 3 to 6 months of treatment is first used for nephrotic patients.44 Urinary protein excretion and serum albumin concentration should be monitored to assess efficacy. The median time to induce complete remission is 3 to 4 months, although 5 to 9 months may be needed in some patients. In general, 30% to 50% of all patients are expected to be resistant to steroids, after at least 4 months of therapy. Patients with diffuse mesangial IgM deposition may be prone for steroid resistance.46
If the patient develops a relapse after an adequate response to the initial treatment, a second course of steroids is generally sufficient. However, if relapse occurs frequently, cytotoxic agents or cyclosporine would be indicated. For patients who are not nephrotic, their relatively favorable prognosis does not support using steroids or other immunosuppressive agents. However, close follow-up and good blood pressure control with ACEIs are necessary to minimize disease progression.44
Most of the studies conducted thus far include mostly white patients. In a retrospective review of 72 patients that included 65 African American patients, steroid use was not associated with renal survival or the induction of proteinuria remission.47 The initial creatinine level, blood pressure, and severity of renal lesions are significant factors for renal survival. About one third of the patients who received steroids developed complications such as diabetes and significant weight gain.
Cytotoxic Agents
When used with steroids during initial therapy, cytotoxic agents were not found to offer any additional beneficial effect.44,48 Randomized clinical trials are not available to support their use as first-line therapy.10
Calcineurin and Rapamycin Inhibitors
In steroid-resistant patients, cyclosporine therapy has produced a complete or partial remission in 70% of patients, with a relapse rate of 47%.49 Tacrolimus may also be used with similar effects.50 Therapy continued for 12 months before slow tapering is more likely to maintain remission. In patients with diabetes, psychiatric disorder, or severe osteoporosis, calcineurin inhibitor may be a first-line therapy due to the concern for steroid side effects.44 The effect of sirolimus on proteinuria has been found to be conflicting; however, it may cause a rapid decline in GFR, and hence its use for FSGS is not recommended.51
Mycophenolate Mofetil
Mycophenolate mofetil has been reported to have favorable effects for patients who were steroid resistant. After inducing remission with high-dose IV methylprednisolone and oral cyclosporine, a combination of cyclosporine and mycophenolate, followed by mycophenolate alone, can sustain long-term remission, preserve renal function, and improve blood pressure control.52 However, due to the varied experiences from different investigators, further studies are needed to define the role of this agent among the various treatment options.
ACEIs and ARBs
Because of the lack of a consistently effective regimen for primary FSGS, many patients with mild disease are treated conservatively. ACEIs and ARBs are effective in reducing proteinuria and stabilizing renal function in many patients with primary or secondary FSGS. Control of blood pressure and hyperlipidemia are important as well.44 For patients who have nephrotic range proteinuria, an elevated serum creatinine concentration, and interstitial scarring on biopsy, corticosteroids with or without immunosuppressive agents are often used.
Prognosis
ESRD develops within 10 years in 10% or less of the 30% to 50% of adults and children who had attained complete remission.49 For those patients who are resistant to therapy, the rate of renal function deterioration to ESRD may be rapid, within 1 year, or slow, over as long as 10 to 20 years; approximately 50% develop ESRD within 10 years. Those patients with severe proteinuria (>10 to 15 g/day), high serum creatinine concentration at diagnosis, initial steroid resistance, or interstitial fibrosis on renal biopsy are likely to have a more rapid decline in renal function. African American patients may also have a higher risk. Kidney transplantation is often indicated for those patients who develop ESRD; however, FSGS has recurred in 40% of the renal allografts soon after transplantation.44 Children, nonblack race, and those with severe disease or rapid progression to ESRD prior to transplantation are more likely to experience a recurrence. The proteinuria may reappear within hours after transplantation, and graft failure may occur in one third to one half of the patients. The median time to recurrence was reported to be 14 days in one study. Although cyclosporine is ineffective in preventing the recurrence of nephrotic syndrome after transplantation, a high dose of the agent (up to 35 mg/kg/day) induces a remission of the recurrent disease. ACEIs and plasmapheresis are also used to prolong graft survival. The effectiveness of these therapies and the rapid recurrence of the disease in the transplanted kidney substantiate the possibility that a circulating humoral mediator is responsible for the nephropathy. Plasmapheresis to remove the mediator was found to be effective in inducing a remission.44
Membranous Nephropathy
Etiology and Epidemiology
Membranous nephropathy is the most common disorder responsible for idiopathic nephrotic syndrome in adults, accounting for about 20% to 25% of cases. It is also a frequent cause of renal failure secondary to glomerulonephritis. The hallmark histologic features of membranous nephropathy are glomerular capillary wall thickening with subepithelial deposits under light and electron microscopy. Autoimmunity is responsible for 70% to 80% of the cases. Autoantibodies toward phospholipase A2 receptor (PLA2R) and neutral endopeptidase (NEP) have been discovered recently.53 The presence of bovine serum albumin (BSA) and anti-BSA antibodies in certain patients suggests that food antigens may be involved in the pathogenesis. Further anti-PLA2R antibodies appear to predict disease activity and response to therapy.53
About 25% of adults and 80% of children have secondary causes.54 In the United States, the most common etiologies are autoimmune diseases (e.g., lupus), infection (e.g., hepatitis B and C), syphilis, neoplasm (e.g., carcinoma of the lung, breast, GI tract, or kidney), and medications (e.g., gold, penicillamine, or captopril). Malaria and schistosomiasis are common causes in other parts of the world. De novo membranous nephropathy can also occur in the allografts of renal transplant patients. Because the responses to therapy as well as the prognosis for idiopathic and secondary membranous nephropathy are different, it is important to identify any potential underlying causes for the nephropathy prior to treatment. Although this glomerular disease can occur at any age, the peak incidence is between ages 30 and 50 years and is especially likely in patients older than age 50 years who present with nephrotic syndrome.54
Pathophysiology
Examination of kidney tissue under light microscopy reveals normal mesangium and normocellularity. The glomerular capillary wall may be thickened in well-developed lesions. In the advanced stage, the epithelial side of the capillary wall is markedly thickened, and intramembranous deposits are found. Progressive changes in capillary lumen patency parallel those in the GBM, resulting in glomerulosclerosis with capillary collapse and tubular atrophy in end-stage membranous nephropathy. Immunofluorescence microscopy shows strong capillary wall staining of IgG and C3 on the epithelial side of the basement membrane. Antibody-mediated immune injury appears to be the main pathogenetic mechanism. The immune complex can be formed in situ or deposited from circulating immune complexes.
Clinical Presentation
Most patients with membranous nephropathy present with heavy proteinuria (exceeding 3.5 g/day). Those patients excreting large amounts of IgG and α1-microglobulin, indicating more significant tubulointerstitial damage, have a lower remission rate, and are more likely to progress toward renal failure.54
The signs and symptoms are usually insidious in onset and may consist of anorexia, malaise, edema, anasarca, or ascites, and pericardial and pleural effusions may also be present. As a result of a hypercoagulable state, pulmonary embolism may develop but rarely results in death. The incidence of renal vein thrombosis varies from 5% to 62%, and membranous nephropathy should be suspected when there is a sudden onset of hematuria, loin pain, pulmonary embolus, fluctuating or worsening proteinuria or GFR, renal tubular acidosis, or an increase in leg edema. Hypertension is found in approximately 30% of patients and is more common with renal insufficiency or in advanced disease.
In addition to heavy proteinuria, urinalysis often reveals lipiduria and oval fat bodies. Microhematuria is seen in fewer than 25% of patients, and gross hematuria and red cell casts are rare. In idiopathic membranous nephropathy, the serum complement concentrations are normal. Low levels of complement should alert one to search for secondary causes, such as lupus, hepatitis B infection, or an alternative diagnosis. Similarly, antinuclear antibodies, anti-DNA antibodies, rheumatoid factor, hepatitis B serologies, and serum cryoglobulins are generally negative in idiopathic membranous nephropathy. Occult malignancy has been found in as many as 10% of elderly patients with membranous nephropathy.
TREATMENT
The treatment of idiopathic membranous nephropathy is controversial and ranges from supportive therapy to immunosuppression. Conservative management of patients with mild disease includes edema control with salt restriction and diuretics5 and reduction of proteinuria with protein restriction and ACEIs (Fig. 32-4).10,55 Management of hypertension and hyperlipidemia is required for most patients, whereas prophylactic anticoagulation, despite having benefits shown to outweigh the risks, is usually given only for patients with renal vein thrombosis or documented pulmonary embolus.34,55
FIGURE 32-4 Treatment algorithm for idiopathic membranous nephropathy. (Adapted from reference 55.)
Pharmacologic Therapy
Steroids
Remission of proteinuria, whether spontaneously or treatment related, may confer a good prognosis. Corticosteroids alone were ineffective in improving proteinuria remission rate in all controlled trials and in preventing progression.56 The result of a meta-analysis also confirmed the lack of efficacy of steroids when used alone.57
Cytotoxic Agents
Cytotoxic agents, when used in conjunction with corticosteroids, are effective in increasing the remission rate of proteinuria and preserving renal function.10 Ponticelli and colleagues devised such a regimen by combining IV methylprednisolone (1 g) for 3 days followed by oral methylprednisolone (0.4 mg/kg) for the subsequent 27 days of months 1, 3, and 5. Oral chlorambucil (0.2 mg/kg) is to be given daily in months 2, 4, and 6.58 The 10-year renal survival was increased to 92% when compared with 60% in the control group. They later substituted cyclophosphamide (2.5 mg/kg/day) for chlorambucil, which resulted in similar rates of proteinuria remission and relapse, but with fewer serious side effects in those who received cyclophosphamide.59
Results from a recent meta-analysis of randomized, controlled trials affirmed that cytotoxic agents, but not steroids, are effective in reducing nephrotic-range proteinuria, with cyclophosphamide having fewer adverse effects than chlorambucil.56
Calcineurin Inhibitors
Cyclosporine is effective in reducing proteinuria and rate of renal function decline as well as inducing remission of nephrotic syndrome. Such effects were observed in patients with preserved, declining, or impaired renal function as well as those who are resistant to other immunosuppressants.56 Results from a retrospective study indicate that using cyclosporine in combination with steroids was more effective in inducing remission than cytotoxic agents with steroids in inducing remission; however, there was more relapse associated with the cyclosporine regimen.56 The concurrent use of small doses of prednisone tend to favor remission and reduce risk of relapse.57 However, long-term use of calcineurin inhibitors may increase blood pressure and result in nephrotoxicity, especially in patients with preexisting renal function impairment.10
Tacrolimus has been studied by several investigators in small, noncontrolled trials and was found to have efficacy similar to cyclosporine.10,56
Alternative Therapeutic Options
Because spontaneous remission is common and only approximately 25% of patients with new-onset idiopathic membranous nephropathy ultimately develop ESRD in 20 to 30 years, it is prudent not to aggressively treat all patients at the onset of the disease. Patients who have a low risk for renal disease progression can be managed with observation and symptomatic therapy. Normalizing the blood pressure and reducing proteinuria with ACEIs and/or ARBs are important as both hypertension and proteinuria are independent risk factors for the progression of renal failure.54 Patients with low risk for renal disease progression include children 2 to 16 years of age, adult males with proteinuria less than 2 g/day, or adult females with proteinuria less than 5 g/day and normal renal function.
In contrast, patients who have a high risk of developing renal failure, including those with proteinuria greater than 10 g/day with or without impaired renal function, and patients with symptomatic nephrotic syndrome with a plasma albumin of less than 2 g/dL (20 g/L) should be aggressively treated to induce remission. An alkylating agent such as cyclophosphamide or chlorambucil, combined with steroids, should be given to induce remission. Recently, rituximab was shown to be effective in several small studies; however, randomized, controlled trials are not available to elucidate its longer-term effects.56,60Treatment decisions should be made in light of the FDA black box warning fort potentially fatal mucocutaneous reactions as well as the risk for severe infection. The effect of eculizumab was evaluated in one trial and was not found to be beneficial.61
Favorable results have been reported for mycophenolate mofetil by some investigators with conflicting efficacy by others.56 However, it might be a reasonable alternative for patients experiencing significant adverse effects from steroids, alkylating agents, or calcineurin inhibitors. Tetracosactide, a synthetic analog of adrenocorticotropic hormone, has also been shown in small studies to offer results superior to the cytotoxic–steroid combination regimen.10,29
The cytotoxic–steroid combination regimen may be effective in inducing remission in the 30% to 40% of the medium-risk patients who relapse within 2 years after treatment discontinuation. Alternately, cyclosporine may be used with similar effectiveness.54 The cyclophosphamide–steroid combination should also be used for relapse in high-risk patients.
Prognosis
The natural course of idiopathic membranous nephropathy is variable. Up to 30% of the patients experience spontaneous remission, commonly within 2 years of disease onset. Half of the remaining patients have persistent proteinuria with long-term preservation of renal function, while the other half has gradual loss of renal function.54 Heavy proteinuria (>10 g/day), male gender, elevated serum creatinine concentration at the time of presentation; poorly controlled hypertension, advanced age at onset of disease, non-Asian race, certain human leukocyte antigen phenotypes, and tubulointerstitial fibrosis on initial renal biopsy are associated with progressive renal disease.54 A predictive algorithm, incorporating the level of proteinuria, initial creatinine clearance, as well as the slope of renal function decline over 6 months, has been developed to determine the risk for disease progression.54
In general, patients with idiopathic membranous nephropathy have a relatively benign course with mean 10-year survival of approximately 70%. Those who present with persistent nonnephrotic proteinuria seldom develop renal insufficiency and have a normal life expectancy. Fewer than 10% of patients develop a remitting and relapsing course.54 The prognosis for secondary membranous nephropathy depends on the underlying cause. Remission occurs when the infection resolves or when the causative medication is withdrawn. For patients with a transplanted kidney, both de novo and recurrent membranous nephropathy may occur. Patients with primary membranous nephropathy are more at risk. Recurrence is typically associated with nephrotic syndrome and a high risk of allograft failure from disease and/or rejection.
Membranoproliferative Glomerulonephritis
Etiology and Epidemiology
Membranoproliferative glomerulonephritis (MPGN) is one of the least-common renal morphologic entities that occur in older children and adults. Although it accounts for 7% to 10% of all case of biopsy-confirmed glomerulonephritis, MPGN is the third or fourth leading cause of ESRD among the primary glomerular diseases.62 For some unclear reason, the incidence of MPGN has been decreasing over the past few decades in the United States and Europe. However, in Africa and Asia, idiopathic MPGN is still common, perhaps secondary to exposure to unrecognized infectious and parasitic agents.
Pathophysiology
MPGN is a “pattern of injury,” rather than a specific disease, caused by many disorders.10 The several types of MPGN are classified according to the pathologic features. Type I MPGN, also known as mesangiocapillary glomerulonephritis, is characterized by diffuse thickening of glomerular capillary walls and mesangial hypercellularity. Immune complexes are presumed to have a major role in the pathogenesis of type I MPGN, which is the most common type of primary, idiopathic MPGN.
Type II MPGN is also known as dense-deposit disease (DDD) because of the presence of dense deposits of C3 within the GBM, which gives rise to a ribbon-like appearance. Other variants of the disease include type III MPGN, which is seen rarely and consists of subendothelial and subepithelial deposits with lamination and disruption of the lamina densa of the GBM.
Clinical Presentation
Nephrotic syndrome is the most common presenting condition although some patients may also have a nephritic component (hematuria), hypertension, and progressive renal impairment. Hypocomplementemia is commonly seen.
TREATMENT
Pharmacological Treatment
Steroids and Cytotoxic Agents
Results from small uncontrolled studies suggest that certain patients may benefit from various immunosuppressive regimens. However, the lack of randomized, controlled studies makes it difficult to make strong treatment recommendations.62 For patients with idiopathic MPGN, nephrotic syndrome, and progressive decline of kidney function, the KDIGO guidelines recommend using oral cyclophosphamide or mycophenolate plus low-dose alternate-day or daily steroids for initial therapy trial of no longer than 6 months.10
In those with normal kidney function, no active urinary sediment, and nonnephrotic range proteinuria, one may use ACEIs to control blood pressure and reduce proteinuria in light of the favorable long-term outcomes.62 Patients with secondary MPGN should receive therapy directed against the primary etiology. Figure 32-5 presents an algorithm for a general approach for treatment and follow-up of MPGN.
FIGURE 32-5 Treatment algorithm for membranoproliferative glomerulonephritis.
Antiplatelet Agents
Although several studies have shown dipyridamole and aspirin to reduce proteinuria, reduction of GFR decline was not generally observed.63 Consequently, the efficacy of antiplatelet therapy for idiopathic MPGN remains in doubt.10 Similarly, the ability of heparin and warfarin, in combination with steroids and cytotoxic agents, to reduce renal function decline was not confirmed to be sustained.
Alternative Therapeutic Agents
Since steroids are not known to be effective for type II disease other yet-to-be-proven strategies such as rituximab, eculizumab, sulodexide, and plasma infusion or exchange may be considered.64 It is difficult to conduct large-scale controlled trials for MPGN because of the low incidence of the disease. Based on the available studies, many of the drugs evaluated do not have any consistent, beneficial effect on renal function and proteinuria. Renal transplantation is an alternative; however, the recurrence rate is close to 100% for type II MPGN and is approximately 20% to 30% for type I MPGN. Half of the allografts ultimately fail.
Prognosis
Type I MPGN is a slowly progressive disease that accounts for 80% of all MPGN, but only 5% to 15% of all cases of nephrotic syndrome seen in pediatric and adult patients. It occurs most frequently for patients between 5 and 30 years of age, and because remissions are rare, many patients eventually develop ESRD. The renal survival is 60% to 65% at 10 years, and the presence of nephrotic syndrome, interstitial disease, and hypertension are poor prognostic indicators.64 Type II MPGN is a more aggressive disease that constitutes approximately 15% of all patients with MPGN. Only 20% of patients remain stable for more than a few years, and the median time before the development of ESRD is 7 years.
Immunoglobulin A Nephropathy
Etiology and Epidemiology
IgA nephropathy, also known as Berger’s disease, was first described by Jean Berger in France in 1968. It now is the most common primary glomerulonephritis in the world and accounts for 10% of patients with ESRD in many countries. The prevalence among patients with glomerulonephritis or patients who had kidney biopsy varies from 30% to 35% or as high as 45% in Asia to 30% to 40% in Europe. In the United States, the overall prevalence is approximately 10% to 15% but is as high as 35% among Native Americans living in New Mexico.65 These differences in prevalence may reflect variations in genetic predisposition, as well as the criteria used for urinary screening and kidney biopsy. The high biopsy rate tends to correlate with high frequency of the disease.
IgA nephropathy is the most common primary glomerulapathy in young adult Caucasians10 and is two to six times more common in males than in females. It is uncommon in blacks, both in the United States and in Africa.65 IgA nephropathy was once thought to be a benign disease presenting with asymptomatic hematuria; however, its ability to present with any clinical syndrome associated with glomerular disease is now recognized. Some patients will develop ESRD over variable periods of time.
Pathophysiology
Primary IgA nephropathy is an immune-complex–mediated disease in which IgA deposits and other pathologic lesions are found in kidney tissues. In contrast, Henoch–Schönlein purpura, a systemic disease that is believed to be closely linked to IgA nephropathy, shares similar immunohistologic findings in the kidneys. Both typically have vasculitis affecting the joints, skin, and GI tract, which may result from the same pathologic process of IgA nephropathy. The diagnosis of IgA nephropathy is established by the presence of mesangial IgA deposits upon immunofluorescence examination of the kidney biopsy. The IgA immune complex, composed of IgA antibody bound with an environmental antigen, such as a virus, bacteria, or food substances, is presumed deposited from the systemic circulation. Alternately, the complex may be formed in situ, with the IgA antibody bound with an endogenous antigen in the mesangium. In the mesangium, IgA can bind with receptors on the mesangial cells to induce proliferation and cytokine production. In addition, IgA can activate complement through the alternate pathway to induce glomerular damage. The extent of the injury depends on the characteristics of the IgA that favor mesangial deposition, the susceptibility of the mesangium toward deposition, the ability of the patient to mount an inflammatory response to the deposits, and the response of the kidney to the injury in a way that favors progressive renal damage. The key abnormalities and their implications on treatment was reviewed recently by Boyd et al.66
The Oxford histologic classification system has been developed to provide a uniform approach to biopsy evaluation and disease classification.66,67 Further studies are needed to elucidate its ability to predict renal function loss and response to treatment.
Clinical Presentation
IgA nephropathy commonly presents in the second and third decades of life, but it can occur at any age. Many patients have microscopic hematuria and proteinuria for years, persistently or intermittently, during the early stages of the disease. About half of the patients present with gross hematuria concurrent with an infection, commonly in the upper respiratory tract.65 The hematuria may occur 1 to 2 days after the onset of infection symptoms, which is different from the 10- to 14-day delay seen after the pharyngitis in PSGN. Proteinuria is common, and nephrotic range often indicates advanced disease. Hypertension and edema are infrequent but are common in PSGN.
Renal dysfunction is uncommon at the initial presentation; however, approximately 10% to 20% of the patients develop ESRD within 10 years, and 30% develop it after 20 years. The extent of proteinuria is one of the strongest predictors of poor long-term outcomes.68 Uncontrolled hypertension, GFR reduction at disease presentation, and obesity are additional risk factors for developing renal failure.10,68
TREATMENT
General Approach to Treatment
Normotensive patients with normal renal function, isolated microhematuria, and minor proteinuria should be observed closely without specific treatment (Fig. 32-6).68 Patients with minimal proteinuria of 0.5 to 1 g/day should receive optimized supportive therapy, using ACEI or ARB to attain BP of <103/80 mm Hg and urinary protein excretion of <500 mg/day.25 Combined ACEI and ARB seems to be more effective than monotherapy. For patients with persistent proteinuria ≥1 g/day, steroid therapy for 6 months should be used after 3 to 6 months of optimized supportive care. Fish oil may be used if desired. Immunosuppression should not be used for patients with GFR <30 to 50 mL/min because of the lack of trials to demonstrate beneficial effects.68 Comprehensive support must be continued in these patients in an attempt to stabilize the renal function.
FIGURE 32-6 Treatment algorithm for biopsy-proven IgA nephropathy. (Adapted from reference 68.)
Nonpharmacologic Therapy
Low-Gluten Diet and Tonsillectomy
Restriction of dietary gluten is effective for patients with celiac disease but not for patients with no identifiable nephritogenic antigens. Removal of the tonsils, which produce IgA1 and may contribute to IgA nephropathy, may reduce proteinuria and hematuria, as shown in several small, nonrandomized trials in Japan.66 However, such benefits were not seen in studies in Caucasians. Results from recent meta-analysis does not reveal efficacy when used alone.69The KDIGO guidelines therefore do not suggest using tonsillectomy for IgA nephropathy.10 However, it may be helpful for patients who developed recurrent macroscopic hematuria as provoked by bacterial tonsillitis.
Pharmacological Therapy
Steroids
Corticosteroids with or without immunosuppressive agents have been used to treat IgA nephropathy for many years. A recent meta-analysis showed that steroid therapy is associated with reduction in proteinuria, risk for progression to ESRD, as well as the rate of renal function deterioration.70 However, optimal antiproteinuric and antihypertensive therapy were not given in some of the studies.10 Low-dose, short-term (<3 months) steroid therapy is not expected to yield favorable results. In contrast, larger doses of steroids (IV methylprednisolone 1 g/day for 3 days at months 1, 3, and 5 and oral prednisone 0.5 mg/kg every other day for 6 months) were able to reduce proteinuria and renal function deterioration.71 However, the risk for toxicity with such high doses of steroid might be considered high by some, yet the side effects were reported as minor.71 The KDIGO guidelines therefore suggest a 6-month course of steroid for patients with persistent proteinuria ≥1 g/day, despite 3 to 6 months of optimized supportive care and GFR of >50 mL/min per 1.73 m2.10
Cytotoxic Agents and Mycophenolate Mofetil
Several studies have evaluated the efficacy of azathioprine and cyclophosphamide. In some of the studies, cyclophosphamide was used in conjunction with dipyridamole, heparin, and warfarin. It is difficult to assess which of these agents contributed to the limited favorable effects observed. In addition, in many of these studies, blood pressure control and ACE inhibition were not always optimal. At present, there is no clear evidence to support the use of these cytotoxic agents for IgA nephropathy.68 The KDIGO guidelines do not therefore suggest using these agents.10
Clinical Controversy…
Fish oil has been recommended by some while others have advocated the first-line use of mycophenolate mofetil for the management of patients with IgA nephropathy.
Mycophenolate mofetil have been evaluated for treating IgA nephropathy on the premise that it may reduce IgA synthesis and mesangial uptake and/or suppress the effects of proinflammatory or profibrogenic mediators.72Favorable results were observed in two studies in China; however, no such beneficial effects were seen in studies in Belgium and in the United States.10,69 These heterogeneous results and the potential for adverse effects preclude recommendation to use mycophenolate for IgA nephropathy.10
Fish Oil
The third approach is to reduce glomerular inflammation and glomerulosclerosis induced by IgA deposits. Antiinflammatory agents, antiplatelet drugs, and anticoagulants have been tried without success to decrease the production or action of mediators responsible for IgA immune-complex–induced glomerular damage. However, the n-3 fatty acids in fish oil reduce the production or action of prostaglandins and leukotrienes, thus limiting the renal damage caused by inflammation, platelet aggregation, and vasoconstriction.25 In a controlled trial on patients with heavy proteinuria and mildly impaired renal function, daily use of fish oil delayed the progression of renal failure with modest reduction in proteinuria.73 A meta-analysis of five controlled studies indicated that a minor, but not statistically significant, beneficial effect on renal function may be observed.74 Results from several recent studies failed to confirm the beneficial effects reported earlier, and further studies are needed to confirm the role as well as the optimal dose. In many of the studies, 4 to 12 g/day were given for two or more years. Some of the fish oil preparations are rich in cholesterol; thus, it is appropriate to monitor the LDL cholesterol levels for patients receiving therapy. In view of the conflicting study results and the very low-risk profile, the KDIGO guidelines suggest using fish oil for patients with persistent proteinuria of ≥1 g/day, despite 3 to 6 months of optimized supportive care that includes ACEI or ARB and blood pressure control.10
ACEIs and ARBs
Because hypertension is a negative prognostic indicator of IgA nephropathy and many of these patients already have left ventricular diastolic malfunction despite being normotensive, early antihypertensive intervention with ACEIs or ARBs is important.65 Indeed, the KDIGO guidelines recommend using ACEI or ARBs for reducing proteinuria and blood pressure control.10,68 Randomized controlled trials have shown that ACEIs and ARBs can reduce proteinuria and improve kidney function. However, the optimal duration of therapy for reducing the risk for ESRD is unknown. There are also no data to support if there is preference of ACEI over ARB, except perhaps a better side effect profile for ARB when compared with ACEI.10 There are limited data to suggest that the combined use of ACEI with ARB may offer greater proteinuria reduction than monotherapy. However, further studies are needed to affirm such benefits for the combination therapy.
Alternative Therapeutic Approaches
Patients with IgA nephropathy have abnormal production of IgA and several different immunoglobulins. Immunoglobulins, administered IV initially and then intramuscularly, may have beneficial effects through immunomodulation, increased catabolism of auto-antibodies, and blockade of receptors.75 While favorable results were reported in one trial, large randomized controlled trials are needed to substantiate its efficacy.
Urokinase, danazol, dapsone, sodium cromoglycate, and plasma exchange have also been evaluated, but none is consistently effective nor shown to affect renal function. Cyclosporine, tacrolimus, sirolimus, and mizoribine have been evaluated in a limited number of studies; available results do not support its use for IgA nephropathy.
Antiplatelet agents are commonly used in Japan and rarely outside of Asia for IgA nephropathy.76 A recent meta-analysis of seven trials (four in Japan and three in Hong Kong) revealed that these agents reduced proteinuria and stabilized renal function.74 In view of the different agents and concurrent immunosuppressive regimens used among the trials, it would not be possible to derive a recommendation and the KDIGO guidelines do not recommend using these agents.10
Prognosis
The majority of the patients with IgA nephropathy have a clinically inconspicuous course and some may experience spontaneous remission. However, others may have an increase in proteinuria and decline in renal function. It is therefore important to follow the patients over a long period of time since progressive disease may appear in 30% of the patients.68 Spontaneous remission is seen in only 10% to 25% of children and 5% to 7.5% of adults. Unfortunately, no therapy is known to be consistently effective for the treatment of IgA nephropathy. Because of the slow progression of the disease to ESRD, it is very difficult to conduct trials to evaluate the long-term effectiveness of specific treatments. Since the pathophysiological mechanisms of this disease are not well defined, it has been difficult to design and evaluate results of clinical trials.66
Urinary protein excretion and the mean arterial blood pressure at follow-up correlate well with the progression of disease. The risk of developing ESRD is proportional to the amount of proteinuria, under the influence of ACEI and ARB therapy, after 1 year of follow-up.77 For those patients who develop end-stage renal failure, transplantation is appropriate, especially for young adults. Recurrence of IgA mesangial deposits in the renal allograft may occur in up to 50% of patients in 5 years and be universally present at 10 years or more posttransplant, but the recurrence of clinical disease is only approximately 10% to 15%.65 There is also no correlation between the aggressiveness of the primary disease and the rate of recurrence.65 Use of ACEI may improve graft survival78 while immunosuppression with corticosteroids, azathioprine, and/or cyclosporine is not expected to prevent the recurrent nephropathy.68
Lupus Nephritis
Etiology and Epidemiology
Glomerulonephritis is one of the most serious complications of systemic lupus erythematosus (SLE) and accounts for much of the morbidity and mortality of patients afflicted with the disease. SLE predominantly affects young women between 15 and 40 years of age, with an incidence of 1 in 2,000 women in the United States. African Americans are more susceptible; they develop the disease at a younger age, have nephritis earlier in the course, and are more likely to progress to end-stage kidney disease.
The renal manifestations of lupus nephritis (LN) are variable and encompass a wide spectrum of histopathologic lesions.79 The underlying histopathology is associated with different prognoses and responses to therapy, which cannot be predicted solely based on clinical manifestations. Thus, a renal biopsy is required to assess the severity of the disease and to predict the short-term and long-term outcomes associated with therapy. Drugs, such as hydralazine and procainamide, are known to precipitate a lupus syndrome; however, they are unlikely to cause disease that affects the kidney.
Pathophysiology
Immune complex deposits, whether formed in the circulation or in situ, can be found in various regions of the glomerulus, as well as the peritubular interstitium and vasculature outside the glomerulus. Based on light, immunofluorescence, and electron microscopy findings, LN can be categorized into six ISN/RPS (International Society of Nephrology/Renal Pathology Society) classifications: I, minimal-mesangial LN; II, mesangial-proliferative LN; III, focal LN; IV, diffuse LN; V, membranous LN; and VI, advanced sclerosing LN.80
The hallmark feature in the pathogenesis of SLE is B-cell hyperactivity and the dysregulated production of autoantibodies against multiple antigens in the body, including DNA and various ribonucleoproteins.79,81 The size and location of the immune complexes in the glomerulus correlate with the nature and severity of renal injury. Deposition of small numbers of stable immune complexes of intermediate size in the mesangium tends to produce less severe inflammation in the glomerulus. The sequestration of the immune complexes in the mesangium prevents them from activating inflammatory mediators. Hence, the lesion is noninflammatory in nature. In contrast, large numbers of intermediate-sized or large immune complexes result in infiltration of inflammatory cells and release of necrotizing enzymes. In addition, the kidney may also sustain damage through mechanisms related to thrombotic microangiopathy.
Clinical Presentation
Females have a higher risk for developing lupus, especially in the adult years. Nephritis is commonly seen within the first 4 years of diagnosis of SLE but may also be the first manifestation of the disease. The clinical presentation ranges from minimal hematuria and proteinuria to severe, rapidly progressive diffuse glomerulonephritis. Proteinuria is very common, and nephrotic syndrome is seen in most patients with membranous lesions. Microscopic hematuria is almost always present, whereas macroscopic hematuria, which commonly indicates severe renal involvement, is rare. Active urinary sediments (red cell casts, dysmorphic red cells, and hematuria) are suggestive of the diffuse proliferative lesion.79 Hypertension is present in 25% to 45% of patients and is associated with a worse prognosis. Poor prognosis and higher risk for renal involvement were observed among African American, Hispanic, and Asian patients, compared with white and Puerto Rican–Hispanic patients.10,82 Other conditions found to be associated with poor prognosis include elevated serum creatinine concentration, heavy proteinuria, anemia (hematocrit <26% [<0.26]), and disease onset during childhood or in those >60 years of age. Most patients have hypocomplementemia and increased antibody titers for anti-double-stranded DNA, particularly those with focal or diffuse proliferative lesions. Serum creatinine concentration at the time of diagnosis is most predictive of short-term outcome.
TREATMENT
General Approach to Treatment
The choice of therapy depends on the underlying lesion and the activity, as well as the chronicity indices. Acute life-threatening disease involving multiple organs requires induction treatment that can suppress the disease promptly. In contrast, long-term management of chronic indolent disease requires therapy with more acceptable side-effect profiles. Corticosteroids are the cornerstone of therapy. However, for severe LN, primarily the diffuse proliferative type, alkylating agents may be needed to reduce or prevent the progression to ESRD. Newer alternatives with fewer side effects are now available.
Optimal blood pressure control is important. ACEIs or ARBs are commonly used to reduce proteinuria and blood pressure. It may also slow disease progression through reduction of inflammation and glomerular injury.83 Patients with normal renal function and nonnephrotic range proteinuria (class I LN and II LN) typically do not require therapy, except for the management of extrarenal lupus manifestations.10,83 The prognosis of these patients is generally good, and renal biopsy can be delayed. However, close follow-up of renal function and urinalysis is required.
Acute Induction Treatment
Steroids and Cytotoxic Agents
Patients with nephrotic range proteinuria, deteriorating renal function, and/or active urinary sediments require a renal biopsy to define the underlying lesion and determine the activity and chronicity of disease. Patients with class III LN and class IV LN should be treated with steroids: oral prednisone of up to 1 mg/kg, followed by tapering over 6 to 12 months or pulse IV methylprednisolone followed by low-dose oral steroids.10
Cyclophosphamide is used concurrently because it is a powerful B-cell inhibitor and can suppress the resynthesis of autoantibodies to normal levels. Combined use of IV cyclophosphamide and methylprednisolone is more effective than either agent alone in inducing remission.10,84 Alternately, cyclophosphamide may be given orally, but it results in more adverse effects because of higher cumulative exposure.83 It is uncertain whether IV administration or oral therapy is more effective. Azathioprine has also been used instead; however, it was reported to result in higher relapse rate and renal function decline.10 The risk for adverse events, such as infection, gonadal damage, amenorrhea, and cervical dysplasia, and malignancy is increased with the cytotoxic regimens.81
Mycophenolate Mofetil
Several trials have found that mycophenolate mofetil with concurrent steroid therapy is an effective agent for induction therapy.85 It was as effective as cyclophosphamide in inducing remission but with fewer side effects. A recent meta-analysis of the literature corroborates to the fact that it is an excellent agent for the induction of remission and that continued use may reduce risk for death or development of ESRD.82 Several recent trials that included African Americans, who are known to have a poorer prognosis, also show that mycophenolate mofetil was more efficacious than IV cyclophosphamide and resulted in fewer adverse effects.83,86 Based on these data, mycophenolate mofetil is now considered an alternative to cyclophosphamide as initial therapy for patients with class III LN and class IV LN. However, cyclophosphamide may be preferred for severe class III/IV LN since the long-term outcome may be more favorable than mycophenolate10 (Fig. 32-7).
FIGURE 32-7 Treatment algorithm for class III (focal) and class IV (diffuse) lupus nephritis
Clinical Controversy…
Is mycophenolate mofetil preferred over cyclophosphamide for acute induction treatment of LN?
Chronic Maintenance Treatment
Steroids and Cytotoxic Agents
Oral steroid is commonly used as a component of maintenance treatment (≤10 mg/day prednisolone).10,83 Alternate-day regimens are often used in children to minimize growth retardation. Monthly pulse IV steroids in conjunction with cyclophosphamide resulted in more sustained remission, fewer relapses, and no significant increase in side effects.87 Meta-analysis shows this combination to be more beneficial than steroid or cyclophosphamide alone. Cyclophosphamide, because of its bladder and gonadal toxicity, has been given as monthly and then bimonthly IV injection, instead of daily administration, for two or more years. However, toxicity is still a concern.
The efficacy of mycophenolate or azathioprine as maintenance therapy was evaluated against cyclophosphamide. Patients receiving mycophenolate or azathioprine were found to have better outcome and fewer side effects than cyclophosphamide. They are recommended by the KDIGO guidelines for maintenance therapy.10 Depending on the study, mycophenolate was found to be either equivalent or better than azathioprine.88,89 However, the drug should not be used during pregnancy since many lupus patients are women of child-bearing age.
Calcineurin Inhibitors
Cyclosporine may reduce proteinuria and lupus activity, stabilize renal function, and improve kidney morphology. It has been shown to have comparable efficacy and safety with azathioprine in preventing relapse for patients with diffuse proliferative LN.90 It is recommended by the KDIGO guidelines for those intolerant of the side effects of azathioprine or mycophenolate.
Hydroxychloroquine
The antimalarial agent hydroxychloroquine can inhibit the toll-like receptors that contribute to autoimmunity. It was reported to be protective against the onset of LN, relapse of the disease, development of ESRD, venous thrombosis, and also a beneficial effect on lipid profiles.10 Hydroxychloroquine is recommended by KDIGO guidelines for all patients of any class for patients receiving the drug should have annual eye examination for possible retinal toxicity, especially after 5 years of continuous use.
Alternative Therapeutic Agents
Many new agents have been developed to target the various pathways, costimulatory molecules, and immune mediators responsible for the pathologic autoantibody production.82 Ocrelizumab is an anti-CD20 monoclonal antibody being evaluated as an adjunctive induction agent.83 Abatacept, a selective T-cell co-stimulation modulator, is being studied as add-on induction therapy to cyclophosphamide or mycophenolate regimens. Belimumab, a monoclonal antibody that inhibits B-lymphocyte stimulating protein, appears to be efficacious for SLE treatment but not for LN.91 Also being studied are acthar gel, an ACTH formulation29 and laquinimod (TV-5600 or ABR-215062), a oral immunomodulator that is a quinoline-3-carboxamide derivative.83
Prognosis
The prognosis of patients with class II disease is generally good, and often no specific treatment is needed. For patients with class V disease, steroids alone commonly induce partial or complete remission. Immunosuppressive agents can be used for those who are not responsive to steroids. The survival of patients with classes III and IV disease has improved during the last two to three decades to approximately 74% to 80% at 10 years.79 With the recent use of mycophenolate mofetil, better understanding of the optimal cytotoxic regimens, the use of lower steroid dosages, and better management of complications such as hypertension, infections, hyperlipidemia, and other metabolic complications of the disease, the long-term outcome has become more favorable. Lupus patients with end-stage kidney disease on dialysis fare as well as those with nonlupus-related renal disease. In those patients who received a renal transplant, the allograft outcome of patients with LN is favorable and comparable to those without lupus. Recurrence of lupus in the renal allograft can occur but is usually of minor clinical importance.
Rapidly Progressive Glomerulonephritis
Etiology and Epidemiology
RPGN describes a clinicopathologic syndrome of rapid loss of renal function—usually a greater than 50% decrement of the GFR within 3 months. The predominant histologic finding of RPGN is extensive crescent formation, usually in more than 50% of the glomeruli. Hence, it is also known as crescentic glomerulonephritis. RPGN accounts for 2% to 7% of all renal biopsy findings and is responsible for up to 5% of patients with end-stage kidney disease. The age ranges of susceptible patients vary with the type of RPGN. For example, types I and II RPGN are more common in younger patients, whereas type III is seen more frequently in older individuals.
RPGN is not a single disease entity. A variety of glomerulonephritides with or without systemic diseases may present as RPGN, including anti-GBM glomerulonephritis, Goodpasture’s syndrome, LN, PSGN, MPGN, IgA nephropathy, polyarteritis nodosa, Wegener’s granulomatosis, and idiopathic crescentic glomerulonephritis.
Primary RPGN is categorized according to the immunofluorescence microscopic findings, indicating different immunopathogenesis, therapeutic approaches, and clinical outcomes. Type I is characterized by the linear localization of immunoglobulins, mainly IgG, along the GBM, signifying anti-GBM antibody-induced injury. Type II is defined by the coarse granular deposition of immunoglobulins and complement within the capillary walls and mesangium, indicating immune-complex–mediated injury. Type III is characterized by scanty or complete lack of immune complex deposits; consequently, it is also known as pauci-immune RPGN. Circulating ANCAs are often detected in type III RPGN.
Pathophysiology
Different etiologic factors are implicated as the cause of RPGN: toxins, drugs, viral and bacterial infections, neoplasms, autoimmune mechanisms, and various immunogenetic factors.92 Regardless of the etiology and type of RPGN, damage in the glomerular capillary wall by both humoral and cellular pathways of inflammation is common. Activation of the terminal C5b-9 (membrane-attacking complex) of the complement system produces severe capillary wall injury. Proteinases and reactive oxygen species released by neutrophils and macrophages may result in severe glomerular injury. Platelets and the coagulation system are activated and result in capillary thrombosis. The ruptured capillaries release fibrinogen and procoagulants that may come into contact with thrombogenic tissue debris and lead to fibrinoid changes. In anti-GBM glomerulonephritis, the direct attack of the anti-GBM antibody on the GBM is responsible for the capillary wall injury.92 For patients with ANCA-associated disease, the interaction of ANCAs with neutrophils and monocytes, which have been primed by concurrent infections or inflammatory processes, can lead to activation of these leukocytes and release of toxic oxygen species and lytic enzymes, resulting in vascular injury.
The disruption of the capillary wall allows movement of macrophages and other plasma constituents into Bowman’s space and stimulates the formation of crescents, which are composed mainly of parietal epithelial cells, as well as macrophages and fibroblasts. Crescent formation indicates the severity of the glomerular capillary disease but not its pathogenesis.
Clinical Presentation
Among the crescentic glomerulonephritides, the pauci-immune RPGN (type III) is the most frequent, accounting for more than 50% of cases, whereas the anti-GBM antibody-mediated RPGN (type I) is the least frequent, occurring in roughly 10% to 20% of patients. Of patients with type I RPGN, 60% to 70% may have concurrent pulmonary hemorrhage and Goodpasture’s syndrome, which is caused by antibodies directed against the pulmonary alveolar basement membrane. Most patients with immune-complex–mediated RPGN (type II) have collagen vascular disease, systemic infections, or a severe form of primary glomerular disease. Approximately 70% of patients with type III RPGN also present with evidence of systemic vasculitis, such as Wegener’s granulomatosis and polyarteritis nodosa. Some patients have only renal manifestations and are said to have idiopathic crescentic glomerulonephritis or renal vasculitis.
The clinical presentation is dominated by progressive renal insufficiency with complaints of tea-colored urine, malaise, anorexia, low-grade fever, and migratory polyarthropathy. Type I RPGN is more common in younger patients, whereas patients with ANCA-mediated disease tend to be older.93 Urinalysis commonly shows nephritic sediments with hematuria, erythrocyte casts, and proteinuria. However, overt nephrotic syndrome is rare.
Serologic analysis is very useful in distinguishing the different types of RPGN. The detection of serum anti-GBM antibodies with the appropriate clinical presentation confirms the diagnosis of anti-GBM glomerulonephritis. More than 80% of patients with pauci-immune or idiopathic crescentic glomerulonephritis have circulating ANCAs. ANCAs are autoantibodies specific for the cytoplasmic constituents of neutrophil granules and monocyte lysosomes. Patients with ANCA-associated disease limited to renal involvement often have P-ANCA (perinuclear staining), whereas patients with Wegener’s granulomatosis tend to have C-ANCA (cytoplasmic staining). Both the anti-GBM antibody and the ANCAs are absent in patients with type II RPGN. Measurements of circulating immune complexes are not useful for making a specific diagnosis, but detection of specific serum antibodies known to mediate immune-complex–associated nephritis is helpful, using anti-DNA antibody as a marker for LN and elevated antistreptolysin O (ASO) titers for PSGN.
TREATMENT
General Approach to Treatment
Early aggressive therapy has improved the renal prognosis of patients with crescentic glomerulonephritis. The rapid deterioration of renal function and the paucity of a large number of patients make randomized controlled studies very difficult to conduct. Based on the available data, immunosuppressive therapy alone appears to be ineffective for type I RPGN, while types II and III RPGN respond well to high-dose steroid therapy.92,94 Because of the differences in response, the therapeutic approaches for each type of RPGN are presented separately below.
Specific Approaches to Treatment
Antiglomerular Basement Membrane Glomerulonephritis (Type I)
Steroids and cyclophosphamide, in conjunction with plasma exchange, are recommended by the KDIGO guidelines in all patients with anti-GBM glomerulonephritis except those who are dialysis-dependent, have 100% crescent in biopsy sample, and do not have pulmonary hemorrhage.10 Plasma exchanges remove the pathogenic anti-GBM antibodies in circulation and are conducted for 2 weeks or until the antibodies disappear. Steroids (prednisolone 1 mg/kg/day, tapered over 6 months) and cyclophosphamide (2 to 3 mg/kg/day for 3 months) are then given to prevent new antibody production.93,94 Patients with mild disease generally respond well to plasma exchange alone or immunosuppression (steroid and/or cytotoxic agents). For patients with severe disease (poor renal function and extensive crescent formation), most are expected to respond to the combination of plasma exchange and steroid/cytotoxic drug therapy. Pulse IV administration of corticosteroids (methylprednisolone 30 mg/kg/day for 3 days) has been used successfully to alleviate pulmonary hemorrhage, but the results are not as convincing for glomerulonephritis.92,94 Because of the rapid decline in renal function, diagnosis should be established early so that therapy can proceed without delay. When the serum creatinine concentration is 6 mg/dL (530 μmol/L) or above or the patient is oliguric or requires dialysis, the response to therapy is usually poor, and the patient should be treated conservatively.93,94 Poor response should also be expected when crescents are found in more than 85% of the glomeruli.
Immune-Complex–Mediated Glomerulonephritis (Type II)
Patients with postinfectious RPGN generally have a favorable prognosis even without treatment. Complete spontaneous recovery occurs in 50% of cases, whereas chronic renal failure develops in 32%.92Pulse doses of methylprednisolone (30 mg/kg/day, every other day × 3), followed by oral prednisone (1 mg/kg/day, tapered over several months) and then tapering, are beneficial in type II RPGN, with a response rate of 85% for patients with acute disease and 70% in those with more chronic disease.92,94 Plasmapheresis does not appear to provide any additional benefit.94
Antineutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis (Type III)
Combined use of high-dose corticosteroids and cyclophosphamide induces remission in more than 90% of patients.95 IV cyclophosphamide, possibly because of the lower cumulative dose administered, is associated with fewer infectious complications while being as effective as the oral route in inducing remission; however, the risk of relapse may be higher.96 Because approximately 30% of the patients may relapse, cyclophosphamide also has been used for maintenance therapy. Rituximab and corticosteroids are recommended by the KIDGO guidelines as an alternative initial treatment in patients without severe disease or in whom cyclophosphamide is contraindicated.10
Maintenance therapy, using azathioprine or mycophenolate mofetil, is recommended for at least 18 months in patients who remain in remission, except those who are dialysis-dependent and have no extrarenal manifestation of disease.10 Trimethoprim–sulfamethoxazole is suggested to be used as an adjunct in patients with upper respiratory disease. However, etanercept is not recommended.
Mycophenolate mofetil and methotrexate are also being used, and they have been shown in limited studies to be effective.94,96 Plasmapheresis is indicated for those with advanced kidney failure or diffuse pulmonary hemorrhage. However, its benefits for patients with better kidney function and mild to moderate disease is not clear.10,96
Renal Transplantation
Anti-GBM nephritis may recur in up to 55% of patients who received a renal transplant. However, only 25% of these patients showed clinical disease activity, with rare allograft failure. Because the frequency of recurrence and its severity are related to the presence of circulating anti-GBM antibody, it is recommended that transplantation should not be performed until the anti-GBM antibody is undetectable for at least 6 to 12 months. The recurrence rate of ANCA-associated nephritis is 17%, with the average time to relapse from transplantation of 31 months.97
Prognosis
Regardless of the type of RPGN, poor response to therapy and an ominous renal survival are expected if the patient presents with oliguria, has a serum creatinine concentration greater than 6 or 7 mg/dL (530 or 619 μmol/L), is dialysis dependent, or has a renal biopsy showing advanced chronic parenchymal disease.95 For those patients who had received kidney transplant, recurrence of the disease is common.
Poststreptococcal Glomerulonephritis
Etiology and Epidemiology
PSGN and glomerulonephritis caused by other infectious agents, such as bacteria, viruses, and parasites, were once common. Improved sanitation, personal hygiene, medical care, and public health measures helped to decrease the incidence of group A streptococcal infection both in the United States and in other developed countries, resulting in a decline of PSGN. In contrast, glomerulonephritis secondary to other infectious agents, such as hepatitis C and HIV, is seen with increasing frequency.
PSGN is now the most common form of glomerulonephritis in children but is less common than the other types of glomerulonephritis in adults. PSGN is seen mostly in children aged between 5 and 15 years and is uncommon in children younger than 2 years of age and in adults older than 50 years of age. It normally follows pharyngeal or skin infection caused by the nephritogenic strains of group A streptococci; however, other strains of streptococci, such as groups C and G, have also been reported to cause PSGN. Streptococcal pharyngitis is more common in winter and early spring, whereas skin infection is frequently found in the summer. The risk for developing acute glomerulonephritis secondary to the nephritogenic strains of bacteria is approximately 10% to 15% for infected patients. However, three to four times more patients may experience a subclinical form of the disease.
Pathophysiology
Streptococcal antigens may induce changes in the glomerular components rendering them immunogenic or autologous IgG may be altered to become antigenic. Alternately, the streptococcal antigens may induce antibodies that react with glomerular antigens. In situ immune complexes are then formed and result in a complement-mediated inflammatory response. The kinin and coagulation cascades are activated, and chemotactic factors are released to recruit neutrophils and monocytes, resulting in acute glomerular lesions.
Examination of the acute PSGN kidneys reveals hypercellular glomeruli with proliferation of mesangial and endothelial cells. Infiltration of neutrophils, monocytes, and eosinophils is apparent within the capillary lumen and also in the mesangial areas. Crescent formation may be seen for patients with severe disease, and if found in more than 30% of the glomeruli, RPGN may be present concurrently.98 The prognosis is generally poor for these patients, and complete recovery is unlikely. Immunofluorescence examination reveals diffuse granular deposits of IgG and C3 along the GBM and also in the mesangium.
Clinical Presentation
The nephritis is preceded by a latent period following a streptococcal infection. The latent period is commonly 7 to 14 days for pharyngitis and 14 to 28 days for skin infection. An acute nephritic syndrome then develops, commonly with hematuria and edema. Gross hematuria is seen in 70% of patients, and microscopic hematuria can be found in all patients. Hypertension is usually mild to moderate and results from sodium and water retention. Many patients have signs and symptoms associated with volume overload, which include dyspnea, orthopnea, and cough. Urinalysis of patients with PSGN reveals hematuria, dysmorphic red blood cells, and red cell casts. Proteinuria is common but often not in the nephrotic range. Renal function is frequently mildly impaired.
Throat or skin culture may be positive for group A streptococci, despite the latent period following the initial infection. However, antibiotic therapy may render the culture result negative. Serologic measurements of antibodies to different streptococcal antigens can confirm recent exposure to the infection. Titers that can be measured include ASO, antistreptokinase, antihyaluronidase (AHase), antideoxyribonuclease B (ADNase B), and antinicotyladenine dinucleotidase (NADase).99 For most patients with streptococcal pharyngitis, the ASO titers begin to rise about 10 to 14 days later, peak at 3 to 4 weeks, and persist for several months before decreasing. The rise in ASO titers can be reduced by antibiotic treatment and may not be seen for patients with streptococcal skin infection in whom the streptolysin may be bound to skin lipids. ADNase B and AHase titers should be used instead because they are specific and are positive in the majority of patients. The streptozyme test is a combined assay for ASO, ADNase B, NADase, and AHase. Antibodies to other antigens such as zymogen, streptococcal cationic proteinase exotoxin B (SPEB), and plasmin receptor (Plr) were evaluated recently.100
Serum complement levels are often decreased for patients with PSGN. If the C3 level is depressed for more than 6 to 8 weeks, MPGN, LN, or glomerulonephritis related to endocarditis or occult visceral abscess should be suspected. Renal biopsy is not normally indicated unless the patient has prolonged hematuria, proteinuria, or depressed C3 level. Renal biopsy is needed to detect other types of glomerulonephritis such as lupus, RPGN, or MPGN.
TREATMENT
General Approach to Treatment
The treatment of PSGN is mainly supportive and symptomatic. Early antibiotic therapy does not prevent subsequent PSGN, but it may reduce the severity of the disease. It can, however, prevent the spread of the streptococcal infection to other family members. Antibiotic prophylaxis is not recommended because infected patients will develop long-lasting, often lifelong immunity against the strain of streptococci. Exposure to another nephritogenic strain of streptococci is possible, but unlikely.
Supportive measures should be used to control fluid volume and blood pressure. Because the hypertension is of the low-renin type, ACEIs and β-blockers are not expected to be useful. If the patient has crescentic disease, use of pulse steroids and/or immunosuppressive agents can be considered; however, the efficacy and safety of these agents have not been established for this condition.
Prognosis
The acute manifestations of PSGN are normally self-limited, and for more than 95% of patients renal function has returned to baseline within 3 to 6 weeks. Diuresis usually begins 7 to 10 days after onset of the acute episode, whereas hypertension and azotemia resolve in 1 to 2 weeks. Gross hematuria lasts for 1 to 2 weeks, and proteinuria usually resolves within 6 months in more than 90% of children. However, microscopic hematuria may persist for up to 2 years. In general, children have more rapid recovery than adults. Prognosis is often better when PSGN occurs during an epidemic than in cases found sporadically. Most of the children will recover fully and be free from chronic complications of PSGN if they have no preexisting renal disorder, heavy proteinuria, or crescentic glomerular lesions or did not require hospitalization during the acute episode. In contrast, adult patients have a less favorable long-term outcome. As many as 50% of the patients may develop persistent proteinuria, hypertension, and renal insufficiency, with some resulting in end-stage renal failure.
CLINICAL BOTTOM LINE
A better understanding of the pathogenetic mechanisms leading to glomerular injury has led to marked improvements in the treatment of glomerulonephritis. However, the glomerulopathies are a heterogeneous group of immune disorders with different clinical courses, prognoses, and responses to current immunologic and non-immunologic therapies. The clinician should understand the natural history and prognosis of each subgroup of glomerulonephritis, the efficacy of different immunomodulation regimens in inducing disease remission and preserving renal function, and the characteristics of at-risk patients who warrant aggressive therapy. Judicious use of immunosuppressive agents with careful monitoring of their adverse effects cannot be overemphasized. In addition, treatment of the disease complications and control of factors that lead to progression of renal disease are important in reducing the morbidity and mortality of patients with glomerulonephritis. The KDIGO guidelines for the first time offer clinicians many evidence-based recommendations that are useful for making individual patient treatment decisions.
ABBREVIATIONS
REFERENCES
1. U.S. Renal Data System 2012 Annual Data Report. Minneapolis, MN: USRDS Coordinating Center, 2012, http://www.usrds.org.
2. Schena FP, Gesualdo L, Grandaliano G, Montinaro V. Progression of renal damage in human glomerulonephritides: Is there sleight of hand in winning the game? Kidney Int 1997;52:1439–1457.
3. Couser WG. Mediation of immune glomerular injury. J Am Soc Nephrol 1990;1:13–29.
4. Remuzzi G, Zoja C, Perico N. Proinflammatory mediators of glomerular injury and mechanisms of activation of autoreactive T cells. Kidney Int Suppl 1994;44:S8–S16.
5. Humphreys MH. Mechanisms and management of nephrotic edema. Kidney Int 1994;45:266–281.
6. Schrier RW, Fassett RG. A critique of the overfill hypothesis of sodium and water retention in the nephrotic syndrome. Kidney Int 1998;53:1111–1117.
7. Warwick GL, Fox JG, Boulton-Jones JM. The relationship between urinary albumin excretion rate and serum cholesterol in primary glomerular disease. Clin Nephrol 1994;41:135–137.
8. Wheeler DC, Bernard DB. Lipid abnormalities in the nephrotic syndrome: Causes, consequences, and treatment. Am J Kidney Dis 1994;23:331–346.
9. Kaysen GA, De Sain-van der Verlden M. New insights into lipid metabolism in the nephrotic syndrome. Kidney Int Suppl 1999;71:S18–S21.
10. Cattran DC, Feehally J, et al. KDIGO clinical practice guidelines for glomerulonephritis. Kidney Int Suppl 2012;2:139–274.
11. Ponticelli C, Passerini P. Treatment of the nephrotic syndrome associated with primary glomerulonephritis. Kidney Int 1994;46:595–604.
12. Klahr S, Levey A, Beck G, et al. The effects of dietary protein restriction and blood pressure control on the progression of chronic renal disease. N Engl J Med 1994;330:877–884.
13. Orth SR, Stockmann A, Conradt C, et al. Smoking as a risk factor for end-stage renal failure in men with primary renal disease. Kidney Int 1998;54:926–931.
14. Nachman PH, Martin J. Developments in the immunotherapy of glomerular disease. J Pharm Pract 2002;15:472–489.
15. Fliser D, Schroter M, Neubeck M. Coadministration of thiazides increases the efficacy of loop diuretics even in patients with advanced renal failure. Kidney Int 1994;46:482–488.
16. Rudy DW, Voelker JR, Greene PK, et al. Loop diuretics for chronic renal insufficiency: A continuous infusion is more efficacious than bolus therapy. Ann Intern Med 1991;115:360–366.
17. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the joint national committee on prevention, detection, evaluation and treatment of high blood pressure: The JNC 7 report. JAMA 2003;289:2560–2572.
18. Ruggenenti P, Remuzzi G. Is therapy with combined ACE inhibitor and angiotensin receptor antagonist the new gold standard of treatment for nondiabetic, chronic proteinuric nephropathies? NephSAP 2003;2:235–237.
19. Gashti CN, Bakris GL. The role of calcium antagonists in chronic kidney disease. Curr Opin Nephrol Hypertens 2004;18:155–161.
20. Levey AS, Adler S, Caggiula AW, et al. Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease Study. Am J Kidney Dis 1996;27:652–663.
21. Toto R. Proteinuria reduction: Mandatory consideration or option when selecting an antihypertensive agent? Curr Hypertens Rep 2005;7:374–378.
22. The GISEN group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Randomized placebo-controlled trial effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997;349:1857–1863.
23. Jefferson JA, Shank SJ. Glomerular disease: The podocyte is ready for prime time and may already be center stage. NephSAP 2006;331–338.
24. Vogt L, Navis G, de Zeeuw D. Renoprotection: A matter of blood pressure reduction or agent-characteristics? J Am Soc Nephrol 2002;13(Suppl 3):S202–S207.
25. Alexopoulos E. Treatment of primary IgA nephropathy. Kidney Int 2004;65:341–355.
26. MacKinnon M, Shurraw S, Akbari A, Knoll GA, Jaffey J, Clark HD. Combination therapy with an angiotensin receptor blocker and an ACE inhibitor in proteinuric renal disease: A systematic review of the efficacy and safety data. Am J Kidney Dis 2006;48:8–20.
27. Taal MV, Brenner BM. Combination ACEI and ARB therapy: Additional benefit in renoprotection? Curr Opin Nephrol Hypertens 2002;11:377–381.
28. Perico N, Remuzzi A, Sangalli F, et al. The antiproteinuric antagonism in human IgA nephropathy is potentiated by indomethacin. J Am Soc Nephrol 1998;9:2308–2317.
29. Ponticelli C, Passerini P, Salvadori M, et al. A randomized pilot trial comparing methylprednisolone plus a cytotoxic agent versus synthetic adrenocorticotropic hormone in idiopathic membranous nephropathy. Am J Kidney Dis 2006;47:233–240.
30. Bomback AS, Tumlin JA, Baranski J, et al. Treatment of nephrotic syndrome with adrenocorticotropic hormone (ACTH) gel. Drug Des Devel Ther 2011;5:147–153.
31. Oda H, Keane WF. Recent advances in statins and the kidney. Kidney Int Suppl 1999;71:S2–S5.
32. Tonelli M, Moyé L, Sacks FM. Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease. J Am Soc Nephrol 2003;14:1605–1613.
33. Agarwal R. Effects of statins on renal function. Am J Cardiol 2006;97:748–755.
34. Glassock RJ. Prophylactic anticoagulation in nephrotic syndrome: A clinical conundrum. J Am Soc Nephrol 2007;18:2221–2225.
35. Nolasco F, Cameron JS, Heywood EF, et al. Adult-onset minimal-change nephrotic syndrome: A long-term follow-up. Kidney Int 1986;29:1215–1223.
36. Bargman JM. Management of minimal lesion glomerulonephritis: Evidence-based recommendations. Kidney Int Suppl 1999;70:S3–S16.
37. Tune BM, Mendoza SA. Treatment of the idiopathic nephrotic syndrome: Regimens and outcomes in children and adults. J Am Soc Nephrol 1997;8:824–832.
38. Rinaldi S, Sesto A, Barsotti P, Faraggiana T, Sera F, Rizzoni G. Cyclosporine therapy monitored with abbreviated area under curve in nephrotic syndrome. Pediatr Nephrol 2005;20:25–29.
39. Yoshida M, Yoshikawa N, Akashi M, et al. Lymphocyte drug sensitivity is useful for prediction of the antiproteinuric effect and relapse rate in cyclosporine treatment for frequent-relapse minimal change nephrotic syndrome. Kidney Blood Press Res 2005;28:226–229.
40. Fu LS, Shien CY, Chi CS. Levamisole in steroid-sensitive nephrotic syndrome children with frequent relapses and/or steroid dependency: Comparison of daily and every-other-day usage. Nephron Clin Pract 2004;97:c137–c141.
41. Alsaran K, Grisaru S, Stephens D, et al. Levamisole vs. cyclophosphamide for frequently-relapsing steroid-dependent nephrotic syndrome. Clin Nephrol 2001;56:289–294.
42. Li Z, Duan C, He J, et al. Mycohenolate mofetil therapy for children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 2010;25:883–888.
43. Kemper MJ, Gellermann J, Habbig S, et al. Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome. Nephrol Dial Transplant 2012;27:1910–1915.
44. D’Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med 2011;365:2398–2411.
45. Herlitz LC, Markowitz GS, Farris AB, et al. Development of focal segmental glomerulosclerosis after anabolic steroid abuse. J Am Soc Nephrol 2010;21:163–172.
46. Mubarak M, Kazi JI, Shakeel S, et al. Clinicopathologic characteristics and steroid response of IgM nephropathy in children presenting with idiopathic nephritic syndrome. APMIS 2011;119:180–186.
47. Crook ED, Habeeb D, Gowdy O, et al. Effects of steroids in focal segmental glomerulosclerosis in a predominantly African-American population. Am J Med Sci 2005;330:19–24.
48. Goumenos DS, Tsagalis G, El Nahas AM, et al. Immunosuppressive treatment of idiopathic focal segmental glomerulosclerosis: A five-year follow-up study. Nephron Clin Pract 2006;104:c75–c82.
49. Frassinetti Castelo Branco Camurça Fernandes P, Bezerra Da Silva G Jr, De Sousa Barros FA, et al. Treatment of steroid-resistant nephrotic syndrome with cyclosporine: Study of 17 cases and a literature review. J Nephrol 2005;18:711–720.
50. Roberti I, Vyas S. Long-term outcome of children with steroid-resistant nephrotic syndrome treated with tacrolimus. Pediatr Nephrol 2010;25:1117–1124.
51. Cho ME, Hurley JK, Kopp JB. Sirolimus therapy of focal segmental glomerulosclerosis is associated with nephrotoxicity. Am J Kidney Dis 2007;49:310–317.
52. Gellermann J, Ehrich JH, Querfeld U, et al. Sequential maintenance therapy with cyclosporin A and mycophenolate mofetil for sustained remission of childhood steroid-resistant nephrotic syndrome. Nephrol Dial Transplant 2012;27:1970–1978.
53. Herrmann SMS, Sethi S, Fervenza FC. Membranous nephropathy: The start of a paradigm shift. Curr Opin Nephrol Hypertens 2012;21:203–210.
54. Cattran D. Management of membranous nephropathy: When and what for treatment. J Am Soc Nephrol 2005;16:1188–1194.
55. Geddes CC, Cattran DC. The treatment of idiopathic membranous nephropathy. Semin Nephrol 2000;20:299–308.
56. Waldman M, Austin III HA. Controversies in the treatment of idiopathic membranous nephropathy. Nat Rev Nephrol 2009;5:469–479.
57. Ponticelli C, Passerini P. Management of idiopathic membranous nephropathy. Expert Opin Pharmacother 2010;11:2163–2175.
58. Ponticelli C, Zucchelli P, Passerini P, et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int 1995;48:1600–1604.
59. Ponticelli C, Altieri P, Scolari F, et al. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol 1998;9:444–450.
60. Jayne D. Role of Rituximab therapy in glomerulonephritis. J Am Soc Nephrol 2010;21:14–17.
61. Appel G, Nachman P, Hogan S, et al. Eculizumab (C5 complement inhibitor) in the treatment of idiopathic membranous nephropathy [abstract]. J Am Soc Nephrol 2002;13:668A.
62. Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis—A new look at an old entity. New Engl J Med 2012; 366:1119–1131.
63. Levin A. Management of membranoproliferative glomerulonephritis: Evidence-based recommendations. Kidney Int Suppl 1999;70:S41–S46.
64. Smith RJ, Alexander J, Barlow PN, et al. New approaches to the treatment of dense deposit disease. J Am Soc Nephrol 2007;18:2447–2456.
65. Donadio JV, Grande JP. Immunoglobulin A nephropathy. N Engl J Med 2002;347:738–748.
66. Boyd JK, Cheung CK, Molyneux K, et al. An update on the pathogenesis and treatment of IgA nephropathy. Kidney Int 2012;81:831–843.
67. Barbour SJ, Reich HN. Risk stratification of patients with IgA nephropathy. Am J Kidney Dis 2012;59:865–873.
68. Floege J, Eitner F. Current therapy for IgA nephropathy. J Am Soc Nephrol 2011;22:1785–1794.
69. Wang Y, Chen J, Wang Y, et al. A meta-analysis of the clinical remission rate and long-term efficacy of tonsillectomy in patients with IgA nephropathy. Nephrol Dial Transplant 2011;26:1923–1931.
70. Samuels JA, Strippoli GF, Craig JC, et al. Immunosuppressive treatments for immunoglobulin A nephropathy: A meta-analysis of randomized controlled trials. Nephrology (Carlton) 2004;9:177–185.
71. Pozzi C, Andrulli S, Del Vecchio L, et al. Corticosteroids effectiveness in IgA nephropathy: Long-term results of a randomized, controlled trial. J Am Soc Nephrol 2004;15:157–163.
72. Lai KN. Future directions in the treatment of IgA nephropathy. Nephron 2002;92:263–270.
73. Donadio JV Jr, Grande JP, Bergstralh EJ, et al. The long-term outcome of patients with IgA nephropathy treated with fish oil in a controlled trial. Mayo Nephrology Collaborative Group. J Am Soc Nephrol 1999;10:1772–1777.
74. Dillon JJ. Fish oil therapy for IgA nephropathy: Efficacy and interstudy variability. J Am Soc Nephrol 1997;8:1739–1744.
75. Rasche FM, Keller E, Lepper PM, et al. High-dose intravenous immunoglobulin pulse therapy in patients with progressive immunoglobulin A nephropathy: A long-term follow-up. Clin Exp Immunol 2006;146:47–53.
76. Taji Y, Kuwahara T, Shikata S, et al. Meta-analysis of antiplatelet therapy for IgA nephropathy. Clin Exp Nephrol 2006;10:268–273.
77. Donadio JV, Bergstralh EJ, Grande JP, et al. Proteinuria patterns and their association with subsequent end-stage renal disease in IgA nephropathy. Nephrol Dial Transplant 2002;17:1197–1203.
78. Courtney AE, McNamee PT, Nelson WE, Maxwell AP. Does angiotensin blockade influence graft outcome in renal transplant recipients with IgA nephropathy? Nephrol Dial Transplant 2006;21:3550–3554.
79. Contreras G, Roth D, Pardo V, et al. Lupus nephritis: A clinical review for practicing nephrologists. Clin Nephrol 2002;57:95–107.
80. Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 2004;65:521–530.
81. Waldman M, Appel GB. Update on the treatment of lupus nephritis. Kidney Int 2006;70:1403–1412.
82. Tsokos G. Systemic lupus erythematous. New Engl J Med 2011;365:2110–2121.
83. Bomback AS, Appel GB. Updates on the treatment of lupus nephritis. J Am Soc Nephrol 2010;21:2028–2035.
84. Gourley MF, Austin HA, Scott D, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med 1996;125:549–557.
85. Walsh M, James M, Jayne D, Tonelli M, Manns BJ, Hemmelgarn BR. Mycophenolate mofetil for induction therapy of lupus nephritis: A systematic review and meta-analysis. Clin J Am Soc Nephrol 2007;2:968–975.
86. Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol 2009;20:1103–1112.
87. Illei GG, Austin HA, Crane M, et al. Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med 2001;135:248–257.
88. Houssiau FA, D’Cruz D, Sangle S. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: Results from the MAINTAIN Nephritis Trial. Ann Rheum Dis 2010;69:2083–2089.
89. Dooley MA, Jayne D, Ginzler EM. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med 2011;365:1886–1895.
90. Griffiths B, Emery P, Ryan V. The BILAG multi-centre open randomized controlled trial comparing ciclosporin vs azathioprine in patients with severe SLE. Rheumatology (Oxford) 2010;49:723–732.
91. Boyce EG, Fusco BE. Belimumab: Review of use in systemic lupus erythematous. Clin Ther 2012;34(5): 1006–1022.
92. Couser WG. Rapidly progressive glomerulonephritis: Classification, pathogenetic mechanisms, and therapy. Am J Kidney Dis 1988;11:449–464.
93. Little MA, Pusey CD. Rapidly progressive glomerulonephritis: Current and evolving treatment strategies. J Nephrol 2004;17:10–19.
94. Bolton WK. Treatment of glomerular disease: ANCA-negative RPGN. Semin Nephrol 2000;20:244–255.
95. Jennette JC. Rapidly progressive crescentic glomerulonephritis. Kidney Int 2003;63:1164–1177.
96. de Groot K, Adu D, Savage CO. The value of pulse cyclophosphamide in ANCA-associated vasculitis: Meta-analysis and critical review. Nephrol Dial Transplant 2001;16:2018–2027.
97. Nachman PH, Segelmark M, Westman K, et al. Recurrent ANCA-associated small-vessel vasculitis after transplantation: A pooled analysis. Kidney Int 1999;56:1544–1550.
98. Couser WG, Johnson RJ. Postinfective glomerulonephritis. In: Neilson EG, Couser WG, eds. Immunologic Renal Diseases, 2nd ed. Philadelphia, PA: Lippincott-Raven, 2001:899–929.
99. Rodriguez-Iturbe B, Parra G. Glomerulonephritis associated with infection: Poststreptococcal glomerulonephritis. In: Massry SG, Glas-sock RJ, eds. Massry & Glassock’s Textbook of Nephrology, 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2001:667–671.
100. Rodriguez-Iturbe B. Nephritis-associated streptococcal antigens: Where are we now? J Am Soc Nephrol 2004;15:1961–1962.