Diptesh Gupta, Derek S. Larson, and Seth Goldberg
Acute Kidney Injury
GENERAL PRINCIPLES
· Acute kidney injury (AKI) is a clinical syndrome denoted by an abrupt decline (within 48 hours) in glomerular filtration rate (GFR) sufficient to decrease the elimination of nitrogenous waste products (urea and creatinine) and other uremic toxins.1
· Clinically, AKI is often further divided into oliguric or nonoliguric subtypes based on urine flow (500 mL/day or 0.5 mL/kg/hour for 6 hours).2
· AKI is generally a disease of the hospitalized patient with approximately 13% of all hospitalized patients meeting the diagnostic criteria for AKI.3
· AKI needs to be quickly recognized and the underlying etiology determined.
Etiology and Pathophysiology
Prerenal Azotemia
· Prerenal azotemia refers to conditions that lead to impaired renal perfusion with a resultant fall in glomerular capillary filtration pressure. The renal parenchymal function is generally preserved.
· The most common scenario of diminished renal perfusion is in the setting of reduced effective circulating volume, which results in concentrated urine (urine osmolality >500 mOsm/kg) with low urine sodium (<10 mmol/L). Causes include true hypovolemia, decreased cardiac output, and liver cirrhosis.
· However, preferential renal vasoconstriction may lead to a prerenal state in certain situations, even with normal or elevated systemic blood pressure (BP), including NSAIDs and calcineurin inhibitors (e.g., cyclosporine and tacrolimus).
· Radiocontrast agents, which typically occur in patients with underlying renal impairment. Other risk factors include diabetic nephropathy, advanced age (>75 years), heart failure, volume depletion, high or repetitive doses of radiocontrast agent, and high osmolar contrast agents.4 Prophylactic measures include temporarily holding diuretics and administering saline-based fluids.
· Endotoxin associated with bacterial infection is also associated with prerenal AKI.
Intrinsic Renal Causes of Acute Renal Kidney Injury
· The most common cause of AKI due to intrinsic renal disease is acute tubular necrosis (ATN).
o Common causes of ATN are listed in Table 24-1.
o ATN is usually considered to be due to ischemic or nephrotoxic injury.5,6
o The most important toxic materials that lead to ATN are drugs.7
· Other important disease processes such as glomerular disease, acute interstitial nephritis, and small vessel disease (e.g., vasculitis and renal atheroembolism) may also lead to AKI.
TABLE 24-1 Some Causes of Toxic Acute Tubular Necrosis
Postrenal Failure
· Ureteral obstruction (e.g., calculus, tumor, clot, sloughed papillae, and external compression)
· Bladder outlet obstruction (e.g., prostatic hypertrophy, neurogenic bladder, carcinoma, and urethral stricture)
DIAGNOSIS
Clinical Presentation
History
· Urine history
o Establish urine volume and recent trends.
o Elicit any history of hematuria, proteinuria, dysuria, or pyuria.
o Urgency, frequency, dribbling, and incontinence, especially in elderly men, may direct to prostatic disease.
· Drug history
o Look for nephrotoxins such as NSAIDs, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), aminoglycosides, or radiocontrast agents.
o The history should include over-the-counter formulations and herbal remedies or recreational drugs.
· Volume status
o History of thirst or orthostatic lightheadedness may suggest intravascular depletion.
o Weight gain, ankle swelling, orthopnea, or paroxysmal nocturnal dyspnea may signify fluid retention.
o Look for the possible causes of fluid loss.
§ Gastrointestinal: diarrhea, vomiting, and prolonged nasogastric drainage
§ Renal: diuretics and osmotic diuresis in hyperglycemia or hypercalcemia
§ Dermal: burns and extensive sweating
§ Third spacing: acute pancreatitis, ascites, and muscle trauma
· Other potential causes
o Chronic liver disease may cause hepatorenal syndrome.
o Hepatitis C with purpura may suggest cryoglobulinemia.
o Arthralgias, skin rash, and oral ulcers may suggest a connective tissue disorder.
o Sinusitis, cough, and hemoptysis may alert the physician to the possibility of granulomatosis with polyangiitis (formerly Wegener granulomatosis) or Goodpasture syndrome.
o A history of recent sore throat or significant skin infection may suggest acute poststreptococcal glomerulonephritis.
o Low back pain and anemia may suggest multiple myeloma.
o Myalgias, dark-colored urine, and the appropriate clinical scenario (crush injury, exercise, immobilization) may suggest rhabdomyolysis.
Physical Examination
· Orthostatic vital signs, mucous membrane and skin turgor, and examination of jugular veins can assess the patient’s fluid balance. Looking for sacral edema in a supinepositioned patient is also important.
· The presence of an S3, pulmonary crackles, and pitting edema suggests volume overload.
· The presence of an abdominal bruit suggests renovascular disease.
· Pelvic examination in females and rectal examination in both females and males may detect a cause of postrenal obstruction.
· The kidney can be palpable in cases of hydronephrosis or polycystic kidney disease.
Diagnostic Testing
Laboratories
· Routine urinalysis and microscopic analysis of urine should always be done and are often helpful in determining the cause of AKI. Usually, the urine is bland in prerenal and uncomplicated postrenal AKI, while an abnormal urinalysis and active sediment suggest an intrinsic renal cause.
o Prerenal AKI: usually bland, with occasional hyaline casts
o ATN: muddy brown granular casts, epithelial cells, and epithelial cell casts
o Glomerulonephritis: dysmorphic red blood cells (RBCs) and RBC casts
o Acute interstitial nephritis: eosinophils, other white blood cells (WBCs), and WBC casts
· In prerenal states, tubular function is intact, and the kidney avidly retains sodium, usually resulting in low urine sodium and a fractional excretion of sodium (FENa) of <1%. FENa is particularly helpful in oliguric AKI (Table 24-2).
where U = urine, P = plasma, Na = sodium, and Cr = creatinine.
· Because loop diuretics force natriuresis, calculation of FENa is misleading in patients who are taking these agents. The fractional excretion of urea (FEurea) of <30% to 35% is suggestive of prerenal azotemia (Table 24-2).
where Uurea = urine urea, P = plasma, BUN = blood urea nitrogen (mg/dL), and Cr = creatinine.
TABLE 24-2 Laboratory Tests in the Differentiation of Oliguric Prerenal Azotemia from Oliguric Intrinsic Acute Tubular Necrosis
FENa, fractional excretion of sodium; Plasma BUN/Cr, plasma blood urea nitrogen to creatinine ratio; UNa, urine sodium concentration; Uosm, urine osmolality; U/PCr, urine to plasma creatinine ratio.
Imaging
· Ultrasonography exhibits high sensitivity (90% to 98%) but a lower specificity (65% to 84%) for the detection of urinary tract obstruction.5 It can also measure the echotexture (increased echogenicity suggests more chronic damage) and kidney size (a marked difference may suggest renovascular disease).
· Compared with renal ultrasonography, noncontrast CT is superior in the evaluation of ureteral obstruction since it can define the level of obstruction and demarcate retroperitoneal fibrosis or a retroperitoneal mass.
Diagnostic Procedures
Renal biopsy is reserved for patients in whom the cause of intrinsic AKI is unclear or in cases of unexplained proteinuria or hematuria where immunosuppressive therapy is being considered.
TREATMENT
Nondialytic Therapy
· Volume expansion: Prompt and effective restoration of effective circulating volume is the key in prerenal azotemia due to true hypovolemia.
· Avoidance of nephrotoxins: Contrast media should be avoided when possible. ACE inhibitors, ARBs, diuretics, and NSAIDs should be held when there is a sudden decline in renal function.
· Electrolyte management: Hyperkalemia is a potentially lethal complication of AKI. Hyperphosphatemia and hypocalcemia are also common in AKI.
o Rule out pseudohyperkalemia by repeating a whole-blood potassium. Consider drawing the sample without the use of a tourniquet or fist clenching.
o If the patient has thrombocytosis or marked leukocytosis, the sample may be drawn in a heparinized tube.
o Obtain a stat ECG and arterial blood gases (ABG) if acidosis is a concern.
o Review the patient’s medication list and stop all exogenous K+ and potentially offending drugs.
o Acute treatment is necessary for severe hyperkalemia.
o Calcium gluconate 10%, 10 mL IV over 2 to 3 minutes, decreases cardiac membrane excitability but does not alter the potassium concentration. The effect occurs in minutes but lasts only 30 to 60 minutes. It can be repeated after 5 to 10 minutes if the ECG does not change. Use with extreme caution in patients receiving digoxin.
o Insulin, 10 units of regular insulin IV, causes an intracellular shift of K+ in 10 to 30 minutes. The effect lasts for several hours. Glucose, 50 g IV (2 ampules D50), should be administered concurrently to prevent hypoglycemia.
o β2-Adrenergic agonists can be used to cause an intracellular shift of K+.
o Diuretics (e.g., furosemide 40 to 120 mg IV) enhance K+ excretion provided renal function is adequate.
o Cation exchange resins (sodium polystyrene sulfonate, Kayexalate) enhance K+ excretion from the gastrointestinal tract. Kayexalate may be given PO (15 to 30 g) or as a retention enema (30 to 50 g). The effect may not be evident for several hours and lasts 4 to 6 hours. Doses may be repeated every 4 to 6 hours as needed. The oral preparation is preferred given reports of intestinal necrosis in select patients after rectal administration.
o NaHCO3, 1 ampule (50 mEq) IV, can also be used to cause an intracellular shift of K+, and the effect can last several hours. Its effect is minimal in organic acidoses. Patients with end-stage renal disease (ESRD) seldom respond and may not tolerate the Na+ load.
o Dialysis may be necessary for severe hyperkalemia when other measures are ineffective and for patients with renal failure.
· Acid-base disorders: Metabolic acidosis is a common complication of AKI. If severe, alkali therapy may be required.
o Severe acidosis (pH < 7.20) may require treatment with parenteral NaHCO3. Rapid infusion should be considered only for very severe acidosis.
o The bicarbonate deficit may be estimated as follows:
o Overaggressive correction should be avoided to prevent overshoot alkalosis.
o Hypernatremia and fluid overload can occur with NaHCO3 administration.
o Serum electrolytes, including calcium, should be followed closely.
· Nutrition support is an important facet of conservative care.
· Treatment for specific causes of AKI
o Immunosuppressive agents for glomerulonephritis or vasculitis
o Systemic anticoagulation for renal artery or vein thrombosis
o Plasmapheresis for hemolytic-uremic syndrome (HUS)/thrombotic thrombocytopenic purpura
Dialytic Therapy for Acute Renal Failure
Indications for initiation of dialytic support in acute renal failure include the following:
· Severe hyperkalemia, metabolic acidosis, or volume overload refractory to medical therapy
· Uremic syndrome with uremic pericarditis, encephalopathy, or seizures
· Need to start total parental nutrition (volume/solute issues)
· Overdose/intoxications
· Refractory hypercalcemia
· Refractory hyperuricemia
Glomerulopathy
GENERAL PRINCIPLES
· Glomerular diseases are manifestations of primary kidney pathology or representations of kidney involvement of a multisystem disease.
· The etiology of many glomerular diseases remains unknown.
· Glomerular disease may be asymptomatic and found on routine patient evaluation for systemic diseases or in patients noted to have hypertension (HTN), edema, proteinuria, and/or hematuria (Fig. 24-1).1
Figure 24-1 Spectrum of glomerular diseases with nephrotic and nephritic features. FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; GN, glomerulonephritis; strep, streptococcal. (From Khalid SA. Overview and approach to the patient with glomerular disease. In: Cheng S, Vijayan A, eds. The Washington Manual Nephrology Subspecialty Consult, 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012:192.)
DIAGNOSIS
Clinical Presentation
· The presentation of some glomerulopathies can be asymptomatic.
o Isolated proteinuria: A daily protein excretion of >150 mg is abnormal. When proteinuria exceeds 3.5 g/day, it is termed nephrotic range and is highly likely to be caused by a glomerular lesion. Microalbuminuria is excretion of 30 to 300 mg albumin per day and is not typically detected on routine urine dipstick. This test is commonly used in diabetic subjects to help identify patients at risk of developing nephropathy.
o Isolated hematuria is classified as either microscopic, referring to more than two RBCs per high power field (HPF) in spun urine, or macroscopic, referring to visible tea-colored (brown/red) urine. In patients with glomerular disease, macroscopic hematuria is usually not associated with pain. The presence of dysmorphic RBCs and/or RBC casts in the urine sediment would be highly suggestive of a glomerular source of hematuria.
o The presence of proteinuria with hematuria is a stronger indicator of an underlying glomerular disease process.
· The nephritic syndrome presents with proteinuria <3.5 g/day, edema, hematuria with dysmorphic RBC and/or casts, renal failure with or without oliguria, and HTN.
· The nephrotic syndrome is characterized by presence of proteinuria >3.5 g/day, hypoalbuminemia <3.5 g/dL, hyperlipidemia, lipiduria, and edema. It is associated with an increased risk of:
o Atherosclerosis and hyperlipidemia.
o Thromboembolic events due to underlying hypercoagulability secondary to urinary loss of antithrombotic proteins, including proteins C and S, and antithrombin III. Venous thromboembolic disease is more common than arterial thrombosis.
o Infection due to urinary loss of immunoglobulins.
· Rapidly progressive glomerulonephritis (RPGN) is an acute presentation of glomerular injury leading to renal failure, which develops in days to weeks. This is a severe manifestation of the nephritic syndrome. The key pathologic finding in RPGN is formation of cellular crescents within the Bowman space. When this involves more than 50% of the glomeruli, it is commonly referred to as crescentic GN.
· Chronic glomerulonephritis is a slowly progressive glomerular disease that leads to renal failure over a period of months to years. It is suggested by HTN, proteinuria >3 g/day, chronic renal insufficiency, and small atrophic kidneys.
History
· Ask about symptoms like joint pain, rash, peripheral and/or periorbital edema, foamy urine, and hematuria. Patients with RPGN may have in addition symptoms of fever, nose bleeds, hemoptysis or vague symptoms of hair loss, fatigue, and weight loss.
· Past history focuses on history of malignancies and infections. Timing of infection can be very helpful. IgA nephropathy will have hematuria within 1 to 3 days after onset of respiratory symptoms as opposed to postinfectious GN, which develops 1 to 3 weeks after a streptococcal upper respiratory tract infection and 5 to 6 weeks after a skin infection.
· Some GN have a familial nature like Alport syndrome (renal failure associated with hearing loss), thin basement membrane disease, IgA nephropathy, focal segmental glomerulosclerosis (FSGS), and atypical HUS.
· Medication use including prescription, over-the-counter medications, and herbal supplements should be evaluated. Many drugs and toxins may be associated with glomerular disease.
o NSAIDs are associated with minimal change disease.
o Penicillamine, gold, NSAIDs, and mercury are associated with membranous nephropathy.
o Heroin has previously been associated with FSGS.
o Cyclosporine, tacrolimus, and mitomycin C are associated with thrombotic microangiopathy.
o Various malignancies are associated with glomerular disease.
· Review of systems should cover multisystem diseases associated with glomerular disease such as HTN, diabetes mellitus (DM), systemic lupus erythematosus (SLE), amyloid, and vasculitis.
Physical Examination
· Periorbital edema in the mornings is a highly suggestive feature of the nephrotic syndrome. Facial edema is most often absent in heart failure or in patients with liver cirrhosis due to the inability of these patients to lie flat.
· Xanthelasmas may be present due to hyperlipidemia associated with nephrotic syndrome.
· Muehrcke bands (white bands in fingernails parallel to the lunula) may also be present from hypoalbuminemia in patients with nephrotic syndrome.8
· Palpable purpura may be seen in cryoglobulinemia, vasculitis, or SLE.
· Malar rash can be seen in patients with SLE.
· Evaluation for piercing and skin tattoos may give a clue to underlying hepatitis or HIV, both of which can be associated with glomerular disease.
Differential Diagnosis
Minimal Change Disease
· Minimal change disease (MCD) is defined by the presence of nephrotic syndrome, the absence of histologic glomerular abnormality by light microscopy, and evidence of podocyte foot process effacement by electron microscopy.
· Most commonly presents in children between ages of 2 and 7 years, but the disease may occur at any age.
· Most cases are idiopathic. However, in a number of patients, the onset is preceded by allergic reaction, vaccination, or viral infection. Around 20% of the patients have a history of atopy.9 Secondary causes include the following:
o Drugs: NSAIDs, lithium, interferon-α
o Infections: HIV, syphilis
o Malignancies: Hodgkin lymphoma, rarely non-Hodgkin lymphoma, and solid tumors
· Onset of nephrotic syndrome is typically abrupt. Creatinine is generally normal at presentation but can be elevated in some adults.
· Urine sediment is usually bland. Complement levels are normal. Renal biopsy is required for diagnosis. Glomeruli appear normal on light microscopy, with no immunoglobulin or complement deposition on immunofluorescence. Presence of foot process effacement is seen on electron microscopy.
· Complications of MCD include infection, peritonitis, thromboembolism, and acute renal failure, especially in the setting of hypovolemia.
Focal and Segmental Glomerulosclerosis
· FSGS is defined by glomerular lesions characterized by segments of sclerosis in only a portion (segmental) of some glomeruli (focal). FSGS has become an important form of glomerular disease in the US due to its increasing cause of ESRD.10 It can be classified as primary or secondary FSGS.
· Primary idiopathic FSGS
o The most common cause of idiopathic nephrotic syndrome in adults. The disease is markedly more common in African Americans.
o Pathogenesis remains unclear, but the presence of a circulating permeability factor called soluble urokinase plasminogen activator receptor (suPAR) has been seen in nearly 60% to 80% of adult patients with primary FSGS.11 Circulating suPAR affects podocyte maturation and function thereby leading to damage at the glomerular filtration barrier.
o FSGS presents most often as nephrotic syndrome but may also present in 20% to 30% as persistent nonnephrotic range proteinuria, HTN, microscopic hematuria, and renal insufficiency.
o There is frequent progression to ESRD, up to 50% at 10 years.
o Diagnosis requires renal biopsy. Multiple histologic variants of FSGS have been described. The so-called tip lesion variant has a better prognosis, while the collapsing variant is associated with worse outcomes.
· Secondary FSGS occurs as an adaptive response to glomerular hyperfiltration or podocyte injury. Podocyte injury can be caused by many factors like viral infection, drugs, or genetic mutation affecting the structural integrity of the podocytes.
o HIV-associated nephropathy: Up to 95% of cases occur in African Americans. Renal ultrasound shows enlarged kidneys with increased echogenicity. The collapsing form of FSGS is most notably associated with HIV.
o Reduced renal mass (unilateral renal agenesis, renal ablation, and renal allograft): This initially leads to an adaptive hyperfiltration, which over time causes glomerular HTN and FSGS.
o Hypoxemia in the setting of sickle cell anemia, congenital pulmonary disease, or cyanotic congenital heart disease leads to glomerular enlargement and subsequently causes FSGS.
o Toxins from impurities in heroin have been known to cause podocyte damage and an FSGS pattern.
o Chronic vesicoureteral reflux.
o Morbid obesity.
o Genetic forms of FSGS occur due to mutations in genes affecting podocyte and slit diaphragm structures. Variation in the APOL1 gene, (codes for apolipoprotein L-1), a protective mechanism against Trypanosoma brucei brucei, has been associated with FSGS in the presence of HTN among African Americans.12
Membranous Nephropathy
· Membranous nephropathy (MN) is a glomerular disease characterized by subepithelial immune deposits of IgG and complement along the glomerular basement membrane with characteristic spike pattern seen on methenamine silver staining.
· MN represents the most common cause of idiopathic nephrotic syndrome in adults >60 years of age and the second most common cause (after FSGS) of the nephrotic syndrome in all adults.
· The pathogenesis of MN remains unclear, but recent experiments have identified circulating antibodies to the M-type phospholipase A2 receptor (anti-PLA2R antibody) in 70% of patients with idiopathic MN.13 Another antibody targeting neutral endopeptidase (NEP) has been attributed to the development of congenital MN. Secondary causes of MN include the following:
o Malignancies (colon, kidney, lung) account for the majority of secondary MN. Nephrotic syndrome may precede clinical manifestations of malignancy by up to 2 years.1
o Autoimmune diseases including SLE, type 1 DM, rheumatoid arthritis, and myasthenia gravis.
o Infections such as hepatitis B, hepatitis C, and syphilis.
o Drugs including NSAIDs, gold, and penicillamine.
· About 80% of patients with MN present with overt nephrotic syndrome. Microscopic hematuria may be seen in up to 50% of adults. Serum complement levels are normal in idiopathic MN.
· Deep vein thrombosis, especially renal vein thrombosis, is more common in MN than in other forms of nephrotic syndrome.
Membranoproliferative Glomerulonephritis
· Histopathologically, membranoproliferative glomerulonephritis (MPGN) is characterized by diffuse mesangial proliferation, thickening of the capillary loops due to reduplication of glomerular capillary basement membrane (double-contour or tram track), subendothelial immune deposits, and mesangial hypercellularity. Most cases are associated with circulating immune complexes and low serum complements.9
· Based on the histomorphologic pattern, there are three types of MPGN.14
o Type 1: discrete immune deposits in the mesangium and subendothelial space. This is frequently associated with hepatitis C infection, cryoglobulinemia, or endocarditis.
o Type 2: continuous, intramembranous, ribbon-like deposits. It is often called dense-deposit disease. This can be associated with partial lipodystrophy, C3 nephritic factor, and factor H or I deficiency with complement consumption.9
o Type 3: diffuse subepithelial and subendothelial deposits within the glomerular basement membrane.
· MPGN can manifest as microscopic hematuria and proteinuria, nephritic syndrome, nephrotic syndrome, or chronic progressive GN. The majority of patients have HTN.
· MPGN almost always is associated with low serum C3 and/or C4 levels.
· Primary MPGN is a diagnosis of exclusion after potential secondary causes like hepatitis infection, HIV/AIDS, infective endocarditis, collagen vascular disease, malignancy, or chronic liver disease have been excluded.
IgA Nephropathy and Henoch-Schönlein Purpura
· IgA nephropathy (also known as Berger disease) is a mesangial proliferative GN characterized by diffuse mesangial deposition of IgA.
· IgA nephropathy is the most common primary GN globally.
· There is a higher incidence in Asia and Europe, which may be due to difference in biopsy practices for isolated microscopic hematuria.
· Pathogenesis of IgA nephropathy remains unclear. Half of the patients have a preceding infection. There is reduced galactosylation of the O-linked hinge region sugar of circulating IgA1. This leads to production of IgG antibodies against the circulating abnormal IgA predisposing to formation of immune complexes and mesangial deposition.15
· IgA nephropathy can present as episodic hematuria, asymptomatic microscopic hematuria with variable degrees of proteinuria, or uncommonly as a rapidly progressive crescentic disease. Hematuria is seen within 1 to 3 days following upper respiratory infection. This distinguishes IgA nephropathy from poststreptococcal GN, in which the hematuria is delayed by 1 to 3 weeks.
· ESRD develops in 25% to 30% of patients within 20 years of diagnosis. Presence of uncontrolled HTN, persistent proteinuria >1 g/day, impaired renal function, and older age at diagnosis are risk factors for progression.16
· Approximately 30% to 50% of patients have increased serum IgA levels, but levels do not correlate with disease activity. Complement levels are usually normal.
· Henoch-Schönlein purpura is a syndrome with IgA nephropathy and systemic small vessel vasculitis caused by IgA deposits. It presents with arthralgia, purpuric skin rash, abdominal pain, or gastrointestinal bleeding. It predominantly affects children.
Glomerulonephritis in Multisystem Disorders
· Systemic lupus erythematosus
o Lupus nephritis is an immune complex–mediated complication of SLE that presents with various histologic patterns described by the 2003 International Society of Nephrology and Renal Pathology Society, based on the degree of glomerular involvement (Table 24-3).
o Renal biopsy plays a critical role in diagnosis and management of patients with lupus nephritis but remains a topic of controversy in predicting outcomes and prognosis.17 Classically, the proliferative forms of SLE (Classes III and IV) are associated with an increased risk of renal failure.
o About 50% to 60% of patients with lupus have renal involvement during their disease course. Lupus nephritis may manifest as benign asymptomatic hematuria, proteinuria, or even fulminant renal failure.1
o Serum complement levels are usually low in the majority of patients because of classic complement pathway activation.18
· Pauci-immune glomerulonephritis is a group of small vessel vasculitides characterized by the presence of necrotizing crescents with minimal or no immune complex deposits.
o The majority (80%) of the patients have positive circulating antineutrophil cytoplasmic antibodies (ANCA) and hence are also called ANCA-associated vasculitis.
o Pauci-immune GN includes granulomatosis with polyangiitis (GPA, formerly called as Wegener granulomatosis), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA, formerly called Churg-Strauss syndrome), and renal limited vasculitis.19
o Patients can present with nonspecific symptoms of malaise, weight loss, fever, and arthralgia.
o Renal manifestations include hematuria, varying degrees of proteinuria, and dysmorphic RBCs with RBC casts.
o Disease-specific manifestations:
§ GPA: sinusitis, nasopharyngeal mucosal ulceration, hemoptysis, purpura, and renal involvement. C-ANCA and proteinase 3 (PR3) are positive in 65% to 90% of patients with active disease. Serum complement levels are normal.
§ EGPA: asthma, peripheral eosinophilia, and renal involvement. P-ANCA and myeloperoxidase (MPO) are associated with EGPA.
§ MPA: generally associated with renal involvement and absence of granulomas.
· Goodpasture disease is suggested by the presence of antiglomerular basement membrane (anti-GBM) antibody along with a clinical presentation of pulmonary-renal syndrome consisting of hemoptysis, pulmonary infiltrates, and/or RPGN.
o Anti-GBM antibodies are directed against the noncollagenous-1 domain of the α-3 chain of type IV collagen.
o This disease is characterized by focal necrotizing crescentic GN in association with circulating anti-GBM antibodies in the blood and linear staining of IgG along the glomerular basement membrane.
o Approximately 30% of patients with Goodpasture disease are P-ANCA positive.
· Poststreptococcal glomerulonephritis (PSGN) is an immune complex–mediated GN characterized by renal deposition of complement C3 and IgG as subepithelial humps on electron microscopy. It is associated with low serum C3 and CH50 and occurs following an infection with nephritogenic strains of group A or, sometimes, group C streptococci.
o PSGN is principally a disease of children, but has been increasingly reported in older patients occurring 1 to 3 weeks after pharyngitis or 5 to 6 weeks after impetigo. Incidence of PSGN has progressively declined in the industrialized countries.
o Clinical presentation consists of hematuria manifesting as tea-colored urine, edema, HTN, and oliguria. Prognosis is excellent in children and less favorable in adults.
o Laboratory tests include antibodies to streptococcal antigens (antistreptolysin-O and anti-DNase B) and hypocomplementemia.
o Atypical postinfectious GN is increasingly reported following staphylococcal and gram-negative infections. It is more commonly seen in patients with underlying diabetes. Clinical presentation is more severe than PSGN with a greater number of patients progressing to ESRD. Predominance of IgA deposition and C3 can be seen on renal biopsy with no subepithelial humps.9
· Thrombotic microangiopathies (TMA) is a syndrome characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and varying degrees of organ dysfunction.
o TMA can be seen in a variety of clinical conditions including thrombotic thrombocytopenic purpura (TTP), HUS, malignant HTN, scleroderma, antiphospholipid syndrome (APLA), HIV infection, and secondary to medications like calcineurin inhibitors and clopidogrel.
o Diagnostic criteria for TTP include MAHA, thrombocytopenia, fever, neurologic signs, and renal failure. Low circulating levels or antibodies against ADAMTS13 lead to increased circulating ultralarge vWF (ULvWF) consequently causing platelet activation and aggregation.
o HUS is classically associated with diarrheal infection caused by exotoxins produced by Escherichia coli (O157:H7 serotype) or Shigella dysenteriae type 1.
o Atypical HUS (aHUS) is caused by dysregulation of the complement system.20 Absence of diarrhea and leukocytosis with clinical features of HUS and hypocomplementemia should raise the suspicion of aHUS.9
· Amyloidosis is characterized by the deposition of extracellular, insoluble, polymeric protein fibrils.
o Classification is based on the type of protein precursor that forms the amyloid fibril. Renal involvement is most often seen in primary amyloidosis (AL) and systemic secondary (AA) amyloidosis.
o Protein precursor for AL amyloid is light chain and hence can be seen in patients with multiple myeloma.
o Clinical features include proteinuria with or without microscopic hematuria and renal insufficiency. Monoclonal light chains can be detected by measuring serum free light chains (SFLC) and serum or urine protein electrophoresis with immunofixation.21
o Congo red stain will show an apple-green birefringence if AL amyloid is present on biopsy specimen.
o Prognosis of AL amyloidosis is poor with a median survival of <2 years.
TABLE 24-3 Abbreviated (ISN/RPS) Classification of Lupus Nephritis (2003)
Indicate and grade (mild, moderate, severe) tubular atrophy, interstitial inflammation and fibrosis, severity of arteriosclerosis, or other vascular lesions.
a Indicate the proportion of glomeruli with active and with sclerotic lesions.
b Indicate the proportion of glomeruli with fibrinoid necrosis and cellular crescents.
c Class V may occur in combination with class III or IV in which case both will be diagnosed.
ISN/RPS, International Society of Nephrology/Renal Pathology Society.
Diagnostic Testing
Laboratories
· Tests should include assessment of renal function (blood urea nitrogen [BUN], serum Cr), urinalysis, and microscopic examination of the urine sediment.
· The amount of urine protein should be quantified. A spot urine protein to creatinine ratio can give a rough estimation of 24-hour urine protein excretion when the creatinine is at a stable baseline. A 24-hour urine collection for protein provides a more accurate estimate especially in patients with acute renal failure.
· Presence or absence of RBC casts or dysmorphic RBCs aids in making the diagnosis of glomerular disease.
· Certain serologic tests should be considered (Table 24-4).
· Measurement of C3, C4, and CH50 is particularly helpful in limiting the differential diagnosis (Table 24-5).
TABLE 24-4 Serologic Tests for Glomerulonephritis
ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; GBM, glomerular basement membrane; GN, glomerulonephritis; HIV, human immunodeficiency virus; MPGN, membranoproliferative glomerulonephritis; MPO, myeloperoxidase; PR3, proteinase 3; sFLC, serum free light chain.
TABLE 24-5 Complement Measurements in Glomerulonephritis
GN, glomerulonephritis; HUS, hemolytic-uremic syndrome; MPGN, membranoproliferative glomerulonephritis.
Data from Floege J, Johnson RJ, Feehally J. Comprehensive Clinical Nephrology, 4th ed. Philadelphia, PA: Mosby; 2010.
Imaging
· Renal ultrasound has a role in the workup of glomerulopathy including confirming the presence of two kidneys, ruling out obstruction or anatomic abnormalities, and assessing kidney size.
· Atrophic small kidneys (<9 cm) suggest chronic kidney disease (CKD) and should limit the use of kidney biopsy or aggressive immunosuppressive therapies.
· Large kidneys (>14 cm) can be seen in nephrotic syndrome associated with diabetes, HIV infection, or deposition disorders such as amyloidosis.
Diagnostic Procedures
Renal biopsy is usually required to establish a definitive diagnosis. This can be done with the help of ultrasound, CT guidance, or rarely via a transjugular approach.
TREATMENT
· General treatment of glomerular disease addresses control of proteinuria, edema, HTN, and hyperlipidemia.
· Patients with proteinuria should be treated with ACE inhibitors or ARBs to a goal proteinuria of <1 g/day. Side effects with these agents include hyperkalemia and rising serum Cr (elevation ≤30% is acceptable).
· Aggressive HTN control is essential for patients with glomerular disease. BP goals are <135/80 mm Hg and can be achieved with a combination of diuretics and the above agents.
· Edema is controlled with dietary sodium restriction and judicious use of diuretics.
· Treatment of hyperlipidemia consists of the use of statins.
· Identification and treatment of the secondary cause of the glomerulopathy is very important.
· Specific treatments of the primary glomerulopathies are complex and require a nephrology consultation.
o MCD: Corticosteroids are the first-line agents, with adults typically requiring a longer course (up to 16 weeks) to achieve remission.
o Primary FSGS: High-dose daily or alternate day steroids for 8 to 16 weeks. Cyclosporine is used in patients with steroid-resistant cases. Secondary FSGS is not responsive to immunosuppressive therapy, and treatment is directed at the underlying condition. The use of antiviral HIV therapy has significantly reduced the incidence of HIV-associated nephropathy.
o MN: Indolent cases may only require conservative antiproteinuric therapy with ACE inhibitors or ARBs. When immunosuppressive therapy is required, corticosteroids with daily cytotoxic therapy (e.g., cyclophosphamide) are used most commonly. Rituximab has also been used for treatment.
o MPGN: Corticosteroids, with or without cytotoxic therapy, can be used in primary cases. MPGN associated with hepatitis C is responsive to antiviral therapy.
o IgA nephropathy: Therapy is based on severity of hematuria and proteinuria, GFR, and histopathology. Fish oil and immune-modulating agents have been used with varying degrees of success in patients with refractory proteinuria.
o PSGN: Therapy is generally supportive. Treatment of streptococcal infection with penicillin should be included even if no persistent infection is present in order to decrease antigenic load.
o Lupus nephritis: Management is highly dependent on the type and severity. Classes I and II generally do not require specific therapy for renal manifestations. Treatment for classes III, IV, and V typically includes corticosteroids and cytotoxic immunosuppressive therapy.
o Pauci-immune GN: Corticosteroids and cytotoxic agents are commonly used. Plasmapheresis is used if patients have associated pulmonary hemorrhage or are dialysis dependent.
o Goodpasture and anti-GBM disease: Plasmapheresis along with corticosteroids and cytotoxic agents are generally indicated when renal function can be salvaged.
o TTP: Plasmapheresis remains the first-line therapy. Corticosteroids are helpful in patients suspected to have antibodies against ADAMTS13.
o HUS: Treatment is supportive in diarrheal cases of typical HUS. Antibiotics are not recommended.
o AL amyloid: Treatment is directed at the underlying disease and may involve melphalan and corticosteroids.
Chronic Kidney Disease
GENERAL PRINCIPLES
· According to current estimates, approximately 26 million American adults have chronic kidney diseases (CKD). The most common causes of CKD and ESRD are DM and HTN.
· Risk factors for CKD include the following: advanced age, low income/education, US ethnic minority status (African American, Native American, Hispanic, Asian, or Pacific Islander), family history of CKD, DM, HTN, autoimmune diseases, systemic infections, urinary tract abnormalities, cancer, prior AKI, reduction in kidney mass, and exposure to certain drugs and toxins.22
· Identifying and treating CKD early is critical, as disease progression is associated with increased mortality, hospitalization, and cardiovascular events.
· Most patients with CKD have a fairly constant progressive decline in GFR over time. However, some patients may experience stabilization or remission.
· The rate of decline for an individual patient can be somewhat difficult to predict but is known to be dependent on the type of kidney disease. Other factors associated with a faster rate of decline include African American race, lower baseline kidney function, male gender, and older age.17
· Acute declines in GFR are not unusual in the course of CKD and may be caused by factors such as volume depletion, radiocontrast, NSAIDs, some antimicrobials (e.g., aminoglycosides, amphotericin B), cyclosporine, tacrolimus, and urinary tract obstruction.
· There is a strong association between CKD and cardiovascular disease. Modifiable risk factors (e.g., HTN, dyslipidemia, DM, and tobacco use) should be treated aggressively.
Definition
· According to the 2003 National Kidney Foundation guidelines on Chronic Kidney Disease, CKD is defined as either kidney damage or decreased GFR for at least 3 months’ duration.22
· Markers of kidney damage include proteinuria, urinary tract abnormalities on imaging, and abnormal urinary sediment or urinary chemistries.
Classification
· The National Kidney Foundation staging for CKD is presented in Table 24-6.22
· The goals of management of CKD evolve as the severity progresses.
o Stages 1 and 2 CKD: preventing disease progression and treating underlying etiologies of kidney damage
o Stage 3 CKD: managing complications that present at this level of dysfunction
o Stage 4 CKD: treating complications of CKD and planning for initiation of renal replacement therapy
· As discussed in Chapter 23, various equations can be used to estimate the GFR when the creatinine is at a stable baseline.
TABLE 24-6 Staging of Chronic Kidney Disease
GFR, glomerular filtration rate.
Modified from National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39(2 suppl 1): S1–S266.
DIAGNOSIS
· The basic diagnostic evaluation is discussed in detail in Chapter 23 and in the preceding sections of this chapter.
· The specific type of kidney disease dictates its treatment and prognosis.
· Renal function should be assessed to determine the stage of disease. The rate of decline of renal function can be assessed by ongoing measurements of serum Cr (e.g., plotting the inverse of serum Cr against time). The rate of decline can subsequently be used to estimate the interval to the onset of kidney failure.22
· Comorbidities that can accelerate the rate of decline of renal function should be identified and treated (e.g., DM, HTN).
· Patients with diabetes should be screened annually for albuminuric kidney disease.
· Screening should consist of spot urine albumin/Cr ratio, serum Cr, and estimation of GFR.
· Microalbuminuria is defined as an albumin/Cr ratio of 30 to 300 mg/g.23
· Macroalbuminuria is defined as an albumin/Cr ratio of >300 mg/g.
· Symptoms and signs of the complications of renal dysfunction must be identified.
o Uncontrolled HTN can accelerate decline in renal function by increasing intraglomerular pressure. Furthermore, inappropriate sodium retention exacerbates preexisting HTN in patients with CKD.
o Anemia of CKD is due to decreased erythropoietin production that usually occurs once GFR is <30 mL/minute/1.73 m2. Anemia is associated with poorer outcomes in CKD.24
o Secondary hyperparathyroidism occurs as an adaptation to (a) active vitamin D deficiency, (b) phosphorus retention due to decreased GFR, and (c) hypocalcemia due to reduced active vitamin D. Elevated parathyroid hormone (PTH) can result in increased bone turnover, placing patients at high risk for fractures. Serum levels of calcium, phosphorus, and intact plasma PTH should be measured in all patients with CKD and GFR <60 mL/minute/1.73 m2.
o Metabolic acidosis may develop with decreasing GFR as the kidney is less effective in excreting acid loads. Acidosis is present in most patients when the estimated GFR is below 30 mL/minute/1.73 m2. Deleterious effects of metabolic acidosis include bone demineralization, insulin resistance, and increased protein catabolism. Serum bicarbonate is used as a surrogate marker of acidosis and should be measured every 3 to 6 months as CKD progresses.25
· Because of the strong association between CKD and cardiovascular disease, modifiable risk factors (e.g., HTN, dyslipidemia, DM, tobacco use) should be identified.
o Dyslipidemia is common in CKD, and patients should be screened with a fasting lipid profile annually.26
o Those with hyperlipidemia should be evaluated for potential causes such as nephrosis, hypothyroidism, excess alcohol consumption, chronic liver disease, and medications.
TREATMENT
Treatment of CKD is multifaceted and includes the following:
· Specific therapy directed at the etiology of the kidney disease (see above)
· Slowing the loss of kidney function
· Treatment of the complications of loss of kidney function
· Prevention and treatment of cardiovascular disease and its risk factors
· Preparation for renal replacement therapy
· Renal replacement therapy (hemodialysis, peritoneal dialysis, transplantation)
Hypertension
· Lifestyle modifications are usually insufficient to achieve BP goals in CKD, and multiple antihypertensives are often required.
· Control of HTN is particularly important in patients with diabetes.
· The Eighth Report of the Joint National Committee (JNC 8) BP goal for patients with CKD is the same as for the general population, <140/90.27
· The Kidney Disease: Improving Global Outcomes (KDIGO) Working Group, however, recommends a more strict goal of <130/80 for patients with CKD not on dialysis and with albuminuria ≥30 mg/day (or albumin/creatinine ratio ≥30 mg/g or proteinuria ≥150 mg/day). Data most strongly supports this goal for those with albuminuria ≥300 mg/day. The more lenient goal of <140/90 is recommended by KDIGO when albuminuria is <30 mg/day.28
· The National Kidney Foundation accepts these recommendations as reasonable but points out the lack of quality supporting data for the more stringent goals, particularly in those with moderate albuminuria (i.e., 30 to 300 mg/g).29
· KDIGO recommends that an ACE inhibitor or an ARB are first-line therapy in patients with albuminuria ≥30 mg/day (or albumin/creatinine ratio ≥30mg/g), particularly in those with concurrent DM.28The data most strongly supports this recommendation in those with albuminuria ≥300 mg/day.
· They reduce intraglomerular pressures and hence slow the progression of renal dysfunction.
· After starting ACE inhibitors or ARBs, serum K+ and Cr levels should be checked within 1-2 weeks. An increase in creatinine of up to 30% is acceptable after starting these agents. Repeat measurements after dose adjustments.
· Diuretics are often effective adjuvant agents for BP control.
o Thiazide diuretics are ineffective once GFR is <30 mL/minute/1.73 m2, while higher doses of loop diuretics can reduce BP.
o Reasonable starting doses include furosemide 40 mg PO bid or bumetanide 1 mg PO bid.
Diabetes Mellitus
· In patients with type 1 and type 2 diabetes mellitus (DM), lowering the A1C levels to approximately 7.0% will delay progression of the microvascular complications of diabetes, including diabetic kidney disease.23
· Reducing the A1C to approximately 7.0% may also reduce the rate of decline of GFR.
· Refer to the Chapter 20 for details regarding the treatment of DM.
Dyslipidemia
· Treatment of dyslipidemia in CKD should follow the 2013 guidelines of the American College of Cardiology (ACC) and the American Heart Association (AHA).30
· Currently, many consider ESRD to be a coronary artery disease equivalent.
· Lowering low-density lipoprotein cholesterol (LDL-C) with statin-based therapies reduces the risk of major atherosclerotic events, but not all-cause mortality, in patients with CKD including those with diabetes.23
· Refer to the Chapter 11 for details on the treatment of dyslipidemia.
Anemia
· The goal hemoglobin (Hgb) range is 10 to 11 g/dL. Recent studies have demonstrated that artificially increasing the Hgb above 13 g/dL in patients with CKD may result in increased risk of myocardial ischemia, stroke, blood clots, and death.24,31
· Iron stores should be repleted before initiating therapy with erythropoiesis-stimulating agents (ESAs) and should be monitored every 3 months during ESA therapy.
o Transferrin saturation should be corrected to levels >25% to 30%.24
o Iron can be given for ferritin levels <1,200 ng/dL if there is no evidence of iron overload.
o Repletion can be in oral or IV form. Ferrous sulfate 325 mg PO bid to tid can be attempted. Oral formulations are best absorbed in an acid environment on an empty stomach; hence, patients on antireflux medications may require increased doses.
o If response to oral iron is inadequate, or if patients cannot tolerate oral iron, then iron dextran may be given intravenously. This is usually prescribed in a nephrologist’s office, with a 25-mg test dose given first to monitor for adverse events. If tolerated, 1,000 mg can be given IV. Other IV preparations such as iron sucrose or sodium ferric gluconate can also be used, but these require several smaller doses over several days to total 1 g of iron.
· Treatment with ESAs can be initiated if the Hgb level remains <10 g/dL after iron deficiency has been corrected.
o Initial treatment options include epoetin alfa at 50 to 100 units/kg SC three times per week or darbepoetin alfa 0.45 µg/kg SC every 1 to 2 weeks. Subsequent dosing should be guided by Hgb levels.
o Rates of Hgb increase are dose dependent, usually <1 g Hgb/week.
· Hgb should be measured at least monthly during ESA treatment to prevent fluctuation outside the goal range.
Secondary Hyperparathyroidism
· Treatment of secondary hyperparathyroidism is approached in a stepwise fashion by (a) reducing phosphorus intake, (b) supplementing nutritional vitamin D (25-OH), and (c) treating with vitamin D analogue (1,25-OH2). Target levels for PTH can be found in Table 24-7.
· Phosphorus intake can be reduced by either dietary restriction or phosphate binders.25
o Dietary intake should be limited to 800 to 1,000 mg/day.
o Calcium-based binders (calcium carbonate and calcium acetate) may be used if dietary restriction of phosphate is insufficient.
o The total dose of elemental calcium provided by the calcium-based phosphate binders should not exceed 1,500 mg/day.
· Nutritional vitamin D (25-OH) deficiency should be corrected.25
o If the serum level is <30 ng/mL, supplementation with ergocalciferol should be initiated.
o Vitamin D insufficiency (16 to 30 ng/mL) is treated with ergocalciferol 50,000 IU PO monthly for 3 months.
o Mild deficiency (5 to 15 ng/mL) is treated with ergocalciferol 50,000 IU PO every other week for 3 months.
o Severe deficiency (<5 ng/mL) is treated with ergocalciferol 50,000 IU PO weekly for 3 months.
o Vitamin D levels should be reassessed at the conclusion of treatment.
o Once the patient is replete, continue supplementation with either monthly ergocalciferol 50,000 IU or vitamin D 1,000 to 2,000 IU daily.
o If the serum levels of corrected total calcium exceed the upper limit of the normal range, vitamin D therapy should be temporarily discontinued.
· If PTH levels remain above goal (Table 24-7) after vitamin D levels are replete, active vitamin D treatment can be used to further reduce PTH levels.25
o Therapy with an active oral vitamin D sterol (e.g., calcitriol) is indicated when serum levels of 25-OH vitamin D are >30 ng/mL and plasma levels of intact PTH are above the target range for the CKD stage. The typical starting dose of calcitriol is 0.25 μg PO daily.
o Vitamin D sterol should be given only to patients with serum levels of corrected total calcium <9.5 mg/dL and serum phosphorus <4.6 mg/dL.
o During treatment, serum levels of calcium and phosphorus should be monitored at least every month for the first 3 months and then every 3 months thereafter. Plasma PTH levels should be measured at least every 3 months. Active vitamin D therapy should be held if PTH falls below the target range, calcium is >9.5 mg/dL, or phosphorus is >4.6 mg/dL.
o Vitamin D sterol treatment is also indicated for dialysis patients with PTH >300 pg/mL. Overcorrection of the intact PTH should be avoided, as this may result in adynamic bone disease.
TABLE 24-7 Target PTH Goals in CKD
CKD, chronic kidney disease; PTH, parathyroid hormone.
Modified from National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003;42(4 suppl 3): S1–S201.
Metabolic Acidosis
In stage 3, 4, and 5 CKD, the goal serum bicarbonate is ≥22 mEq/L.25 When the serum bicarbonate level is <20 mEq/L, alkali salts, such as sodium bicarbonate 650 to 1,300 mg PO bid to tid, may be started.
Nutrition
· Patients with stage 3 and stage 4 CKD may benefit from nutritional consultation.
· Nutritional goals are summarized in Table 24-8, but individualized patient therapy is most appropriate.
· While current recommendations suggest reducing dietary protein intake to minimize urea production, patients with CKD are at increased risk of malnutrition. Hypoalbuminemia is a marker of increased mortality in ESRD patients, and low serum albumin is a contraindication to peritoneal dialysis. Current guidelines recommend measuring albumin every 1 to 3 months.32
TABLE 24-8 Nutrition Goals for Patients with Stage 3 and 4 CKD
Data from K/DOQI, National Kidney Foundation. Clinical practice guidelines for nutrition in chronic renal failure. Am J Kidney Dis 2000;35(6 suppl 2):S1–S140.
REFERRAL
· Patient referral to a nephrologist should occur once the GFR is <30 mL/minute/1.73 m2; furthermore, referral may also be appropriate in patients with stage 3 CKD in whom further decline is anticipated.
· Late nephrology referral is associated with poorer outcomes and increased cost of care.
· Patients with stage 4 CKD should be referred for early vascular access for hemodialysis.
o Arteriovenous fistulas are preferred for hemodialysis, as they have lower risks of infection, lower incidence of thrombosis, and higher flow rates than arteriovenous grafts (AVGs). Arteriovenous fistulas require an average of 3 to 4 months to mature after placement.
o AVGs are preferred to indwelling catheters, as these have lower risks of infection and better flow rates compared with catheters. AVGs require approximately 3 to 6 weeks to mature before use.
· Nephrology consultation may aid in guiding the decision to initiate renal replacement therapy.
o Patients with eGFR below 15 mL/minute/1.73 m2 should be monitored regularly and dialysis started when symptoms of uremia develop. A higher threshold may be used in diabetics, as they tend to tolerate uremia poorly and are frequently troubled by sodium retention and fluid overload.
o Signs and symptoms of uremia, HTN, refractory metabolic disturbances, and volume overload may contribute to a decision to initiate dialysis at higher GFR.
o Malnutrition in the setting of a higher GFR may drive the decision to initiate dialysis even in the absence of severe electrolyte abnormalities.
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