Acute glomerulonephritis and rapidly progressive glomerulonephritis

CHAPTER 14

ACUTE GLOMERULONEPHRITIS AND RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS John R. Sedor

1. What is the syndrome of acute glomerulonephritis? Acute glomerulonephritis is an acute kidney injury (AKI) syndrome characterized by the sudden onset of edema and new-onset or worsening hypertension. Urinalysis demonstrates an active sediment, including abnormal proteinuria (usually .30 mg/dL or 11 on a semiquantitative scale), hematuria, and red cell casts. Patients with acute glomerulonephritis are often azotemic (i.e., they have elevated serum blood urea nitrogen and creatinine concentrations) and occasionally develop severe kidney injury requiring dialysis. Acute glomerulonephritis can be a primary kidney disease, which is usually classified on the basis of kidney histopathology, or can result from a number of systemic diseases. Although this chapter focuses on primary acute glomerulonephritis, the diagnostic and therapeutic approaches for kidney-limited glomerulonephritis and glomerulonephritides associated with systemic diseases are similar. The reader is referred to the sections on primary (Part IV) and secondary (Part V) glomerular disorders for additional information. 2. What are the major causes of acute glomerulonephritis? What approaches should be used to develop an appropriate differential diagnosis? The patient’s history and a physical examination can provide clues to the diagnosis of acute glomerulonephritis. Looking for skin lesions and disease in other organ systems can help determine if the cause of the acute glomerulonephritis syndrome is a result of kidney-limited or systemic disease. A focused laboratory examination, including serologic studies, directed by the findings in the patient’s history and physical examination, can also be useful in establishing a diagnosis. Hematuria with dysmorphic red cell morphology and red cell casts are usually detected on urinalysis. Moderate proteinuria, usually in the non-nephrotic range, is typical. Nephrotic-range proteinuria occurs in ,30% of patients. Mild to severe azotemia is universally present. Table 14.1 presents major causes of acute glomerulonephritis stratified by their association with serum complement levels (low vs. normal or high). Complement levels can help a clinician focus on a differential diagnosis on the most likely causes of the acute glomerulonephritis syndrome. Measuring serum complement levels (C3, C4) and/or activity (CH50) is a somewhat arbitrary choice of initial tests, but they provide a practical approach to further testing and management of the patient with presumptive glomerulonephritis. A kidney biopsy is almost always indicated to establish a definitive diagnosis and direct treatment. The extent of acute inflammation and fibrosis present in the biopsy can provide important data on prognosis and can be used to project responsiveness to therapy. In order to optimize patient care, a standardized kidney biopsy classification system based on current concepts of glomerulonephritis etiology/pathogenesis has been proposed. 3. What are dysmorphic red cells? Phase-contrast morphology can be used to characterize urinary erythrocyte morphology. Glomerular bleeding, a characteristic of glomerulonephritis, causes red cells in the urine to have a non-uniform morphology with irregular outlines and small blebs projecting from their surfaces (i.e., the red cells are “dysmorphic”). Red cells in the urine from non-glomerular bleeding in the urinary tract are uniform in shape and similar in appearance to red cells in the circulation. Urine can be analyzed by the clinical laboratory for the presence of dysmorphic red cells. The sensitivity, specificity, and predicative values for this test are limited, and results need to be interpreted in the context of other clinical and diagnostic data. Clinical labs most often quantify numbers of dysmorphic red cells as a percentage of total red cells, and define the upper limit of normal to aid in the interpretation of the test.

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100  ACUTE KIDNEY INJURY Table 14.1.  Some Causes of Acute Glomerulonephritis (Serologic and Other Tests that Provide Diagnostic Clues) LOW SERUM COMPLEMENT LEVEL

NORMAL SERUM COMPLEMENT LEVEL

Systemic diseases

Systemic lupus erythematosus (ANA1, anti-DNA antibody1) Cryoglobulinemia (cryoglobulin1) Henoch-Schönlein purpura Infectious endocarditis (positive blood cultures) “Shunt” nephritis (positive blood cultures) Infection-associated glomerulonephritis

Microscopic polyangiitis (ANCA1) Granulomatosis with polyangiitis (ANCA1) Goodpasture syndrome (anti-GBM Ab1) Hypersensitivity vasculitis Visceral abscess (positive blood cultures)

Primary kidney diseases

Post-infection glomerulonephritis (b-hemolytic streptococci) C3 glomerulopathy Dense deposit disease Membranoproliferative glomerulonephritis

IgA nephropathy Idiopathic RPGN Type I: Anti-GBM disease (Goodpasture disease; anti-GBM Ab1) Type II: Immune complex/immune deposit disease Type III: Pauci-immune (ANCA1)

ANA, Antinuclear antibody; ANCA, anti-neutrophil cytoplasmic antibodies; GBM, glomerular basement membrane; IgA, immunoglobulin-A; RPGN, rapidly progressive glomerulonephritis. Modified from Manoharon, A., Schelling, J. R., Diamond, M., Chung-Park, M., Madaio, M., & Sedor, J. R. (2013). Immune and inflammatory glomerular diseases. In R. J. Alpern, M. J. Caplan, & O. W. Moe (Eds.), Seldin and Giebisch’s the kidney: Physiology and pathophysiology (pp. 2763–2816). Amsterdam: Elsevier.

4. Describe glomerulonephritis in the setting of infection. Glomerulonephritis associated with infection is varied. Post-infectious glomerulonephritis occurs after an infection and latent period in which the patient returns to her or his baseline health. Beta-hemolytic Streptococcus is almost exclusively the etiology of post-infectious glomerulonephritis. In contrast, infection-associated glomerulonephritis occurs concurrently with the infection. While an active staphylococcal infection is a classically recognized cause of infection-associated glomerulonephritis, it can be caused by many different viruses, bacteria, and fungi. Complement levels, especially C3, are often—but not always—depressed in infection-associated glomerulonephritis. Recognizing the distinction between these clinical presentations is necessary for appropriate clinical management. The management of post-streptococcal glomerulonephritis is supportive, primarily managing hypertension and volume overload. For infection-associated glomerulonephritis, the primary goal is to treat the infection. 5. Define the syndrome of rapidly progressive glomerulonephritis (RPGN). Patients with RPGN have evidence of glomerular disease (proteinuria, hematuria, and red cell casts) accompanied by rapid loss of kidney function over days to weeks. If untreated, RPGN often results in kidney failure. The pathologic hallmark of RPGN is the presence of crescents on kidney biopsy, and RPGN is also described as crescentic nephritis (see later for further discussion). Fortunately, the disorders associated with this syndrome are rare, so that RPGN makes up only 2% to 4% of all cases of glomerulonephritis. Importantly, RPGN is not a specific diagnosis, and multiple different diseases can cause this syndrome. Diagnosis almost always requires a biopsy of the affected tissue if the presentation suggests systemic involvement, or of the kidney if it is kidney-limited. 6. What are crescents in kidney biopsies? Crescent formation is a nonspecific response to severe injury of the glomerular capillary wall. As a result, fibrin leaks into Bowman’s space, causing parietal epithelial cells to proliferate and mononuclear phagocytes to migrate into the glomerular tuft from the circulation. Large crescents can compress glomerular capillaries and impair filtration. Although crescent formation can resolve, some inflammatory chemotactic signals recruit fibroblasts into Bowman’s space, which ultimately can cause both the crescents and glomeruli to scar. Extensive scarring results in end-stage kidney disease (ESKD). Similar to RPGN, crescentic nephritis is not a specific pathologic diagnosis. Crescents can be seen with a number of specific glomerular diseases (see question 9).

ACUTE GLOMERULONEPHRITIS AND RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS  101 7. Do crescentic nephritis and RPGN describe the same syndrome? Although the terms crescentic nephritis and RPGN are used interchangeably, these diagnoses are not synonymous. RPGN describes a clinical syndrome of rapid loss of kidney function over days to weeks in patients with evidence of glomerulonephritis. In contrast, crescentic nephritis is a histopathologic description of kidney biopsy specimens, which demonstrate the presence of crescents in more than 50% of glomeruli. Biopsies of patients with RPGN very commonly reveal crescentic nephritis. However, RPGN can occur in the absence of crescentic nephritis, and extensive glomerular crescent formation is rarely identified in kidney biopsy specimens from patients without the clinical syndrome of RPGN. 8. How is primary RPGN classified? RPGN can occur as a primary disorder in the absence of other glomerular or systemic diseases. Crescentic nephritis, the pathologic correlate of RPGN, is classified into three types using immunofluorescence microscopy to describe the presence or absence of immune deposits and the character of their distribution within the glomerular basement membrane (GBM; Table 14.1 and Box 14.1): 1. Type I RPGN is characterized by linear deposition of antibodies directed against type IV collagen, a matrix protein that is a constituent of the GBM. These antibodies are commonly referred to as antiGBM antibodies (discussed later). Type I RPGN comprises approximately 10% to 20% of patients with primary RPGN without pulmonary hemorrhage. 2. Type II RPGN is characterized by a granular pattern of immune complex deposition. This is found in 20% to 30% of patients with primary RPGN without pulmonary hemorrhage. 3. Type III RPGN has no immune deposits (“pauci-immune”) in glomeruli using immunofluorescence or electron microscopy, and occurs in 50% to 60% of patients with crescentic glomerulonephritis on kidney biopsy. 9. What glomerular diseases are associated with RPGN? RPGN can complicate the clinical course of some primary glomerular diseases, such as immunoglobulin A (IgA) nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis, and hereditary nephritis (Alport syndrome). In addition, RPGN is associated with infectious and multisystem diseases, including systemic lupus erythematosus, cryoglobulinemia, and systemic vasculitides. Box 14.1 summarizes the kidney-limited and systemic causes of RPGN. Box 14.1.  Classification of RPGN Primary Type I: Anti-GBM antibody disease (Goodpasture disease) Type II: Granular glomerular immune complex association Type III: Pauci-immune glomerulonephritis

Secondary to Systemic Disease Superimposed on a primary glomerular disease Infection related Post-streptococcal and rarely post-viral glomerulonephritis Visceral abscess and other infection-associated Vasculitides: Small Vessel (Pauci-Immune): Microscopic polyangiitis Granulomatosis with polyangiitis (Wegener’s syndrome) Eosinophilic granulomatosis (Churg-Strauss syndrome) Small Vessel (Immune Complex): Systemic lupus erythematosus Henoch-Schönlein purpura Cryoglobulinemia Medium Vessel: Polyarteritis nodosa (rare) Goodpasture syndrome and disease Malignancy-related Medication-associated: ANCA-associated (hydralazine, propylthiouracil, minocycline) Drug-induce lupus

ANCA, Anti-neutrophil cytoplasmic antibodies; GBM, glomerular basement membrane; RPGN, rapidly progressive glomerulonephritis.

102  ACUTE KIDNEY INJURY 10. Aside from urinalysis, which other laboratory tests are useful in determining the etiology of acute glomerulonephritis? Certain serologic studies or other laboratory tests may be useful in narrowing the differential diagnosis, but ordering these labs should be guided by the patient’s history and clinical presentation. Complement levels (C3, C4) are usually normal in patients with either primary RPGN or RPGN associated with systemic diseases (see Table 14.1). Lupus is an exception, as these patients usually have depressed C3 and C4 levels. In almost all patients, an antinuclear antibody level is a useful screen for lupus or other connective tissue diseases. Identification of anti-GBM antibodies and anti-neutrophil cytoplasmic antibodies (ANCA) can be useful in establishing a diagnosis in patients with RPGN. Patients who are ANCA antibody positive frequently have a primary small vessel vasculitis. The patient’s clinical presentation determines the predictive value of ANCA testing. For example, the predictive value of a positive ANCA test is lower in a patient who presents with hematuria, proteinuria, and a normal creatinine than in a patient with similar urinalysis findings in the presence of azotemia. Laboratory testing to identify infections with Streptococcus, hepatitis, or HIV, or causes of autoimmune diseases in addition to lupus and ANCA vasculitis, may be indicated. Antibodies to phospholipase A2 receptor (PLA2R) are found in 70% of cases of idiopathic membranous nephropathy. Testing for anti-PLA2R antibodies is reasonable in selected patients with RPGN syndromes. 11. What are anti-GBM antibodies? Anti-GBM antibodies are targeted toward the noncollagenous domain 1 (NC1) domain of the a3 chain of type IV collagen, which is a component of the GBM. Formation of the type IV collagen network in normal GBM sequesters these epitopes from the immune system, preventing tolerance during fetal development. Anti-GBM-associated disease occurs after the kidney is injured in a manner that exposes these regions of the collagen molecule; the collagen is not recognized as “self” and generates an immune response. AntiGBM antibodies are found in 90% to 95% of patients with Goodpasture disease and are deposited in the GBM. On kidney biopsy immunofluorescence, they form linear deposits of immunoglobulin along the basement membranes. 12. Are Goodpasture syndrome and anti-GBM glomerulonephritis (Goodpasture disease) the same? No. Although both disease entities result from circulating anti-GBM antibodies, Goodpasture syndrome describes a systemic disease with a clinical constellation of pulmonary hemorrhage, circulating antiGBM antibodies, and glomerulonephritis. Anti-GBM glomerulonephritis, or Goodpasture disease, is kidney-limited and describes a proliferative glomerulonephritis, which results from the deposition of anti-GBM antibodies. Anti-GBM antibodies are the same in patients with Goodpasture syndrome and Goodpasture disease. Because alveolar basement membrane contains the epitope of type IV collagen that is recognized by anti-GBM antibodies, the variable presence of pulmonary disease seems to reflect whether alveolar basement membrane epitope is accessible to the circulating anti-GBM antibodies. Alveolar injury from infections, smoking, toxins, or other underlying lung disease may predispose the lungs to the deposition of anti-GBM antibodies. 13. What are ANCA? Kidney biopsies from patients with type III RPGN have no immune deposits, but type III RPGN usually results from small-vessel vasculitides associated with circulating ANCA. The ANCA-associated small vessel vasculitides are: • Granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis) • Microscopic polyangiitis (MPA; systemic and kidney-limited) • Eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome) These are usually systemic diseases but can be limited to the kidney. ANCA are directed against neutrophil proteinase 3 (PR3) or myeloperoxidase (MPO). Screening for ANCA uses an indirect immunofluorescence examination of normal neutrophils, which, if positive, demonstrates a staining pattern characteristic of the target antigen (cytoplasmic for ANCA [C-ANCA] against PR3 and perinuclear for anti-MPO ANCA [P-ANCA]). The P-ANCA screening test has low specificity because other anti-neutrophil antibodies give a similar pattern by indirect immunofluorescence. A screening test that is positive for either C-ANCA or P-ANCA needs confirmation with an antigen-specific technique. C-ANCA positivity is associated with active GPA, and P-ANCA positivity is associated with active MPA and less so EGPA. However, ANCA testing results have to be interpreted in the context of the clinical presentation, and the diagnosis of a vasculitis or glomerulonephritis often requires a tissue biopsy. ANCA antibodies can be present in patients with non-vasculitic rheumatologic diseases, infections, and autoimmune gastrointestinal diseases, and can co-occur with other types of acute glomerulonephritis (e.g., anti-GBM disease). 14. What is the treatment for acute glomerulonephritis? The treatment for acute glomerulonephritis is primarily supportive: diuretics to reduce the edema and antihypertensive drugs to reduce elevated blood pressure. Anti-inflammatory therapy with corticosteroids,

ACUTE GLOMERULONEPHRITIS AND RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS  103 cytotoxic agents, and other classes of immunosuppressive agents is used for some etiologies of acute glomerulonephritis. Therapeutic approaches for acute glomerulonephritis due to systemic lupus nephritis and the pauci-immune vasculitides have been extensively studied, and reasonable evidence from multicenter trials is available to guide treatment for these diseases. Treatment strategies for other etiologies of acute glomerulonephritis are often based on observational studies of small numbers of patients. Approaches to therapy in children and adults with the same etiology of acute glomerulonephritis are not always identical. 15. What are the treatment options for patients with RPGN? RPGN needs to be treated aggressively and early in its course to reduce the likelihood of ESKD. Glucocorticoid and immunosuppressive regimens are the mainstay of RPGN treatment. The benefit of these agents is greatest in patients with ANCA-associated vasculitis. The most common complications of therapy are infections. Hemorrhagic cystitis, a complication of cyclophosphamide therapy, occurs less commonly with use of aggressive intravenous saline infusions to promote the excretion of metabolites toxic to bladder epithelial cells. In addition, 2-mercaptoethanesulfonate (MESNA), an agent that binds and sequesters the metabolite responsible for injury to the uroepithelia, is often given with cyclophosphamide. Malignancies, especially bladder cancers and leukemias, can occur decades after treatment of GPA with cyclophosphamide. Randomized, clinical trials continue to be performed in order to determine optimal therapy for patients with either ANCA-associated vasculitis or lupus nephritis. The reader is encouraged to review the most current literature and expert opinion to develop treatment regimens for patients with these diseases. The most current immunosuppressive protocols include several different immunosuppressive agents directed at different molecular targets to induce and maintain a remission. Therapy with these agents is often prolonged, lasting months to more than 1 year, necessitating the need for expert diagnosis and almost always biopsy confirmation. Of course, all treatment protocols have significant risk for adverse events, and patients require close monitoring and drug dose adjustments to reduce drug toxicity. Consultation with an expert in the treatment of these patients is highly recommended. 16. Should treatment for RPGN be initiated prior to definitive diagnosis? Yes. Data obtained in experimental animal models of acute glomerulonephritis/crescentic nephritis show that fibrosis begins within days after disease initiation. Because patients usually present with evidence of active kidney inflammation and are often azotemic, significant kidney scarring has likely occurred by the time patients receive medical attention. Starting treatment should be viewed as urgent. Patients can be treated with corticosteroids until kidney biopsy results are available and treatment can be directed by the results (see next question). While some experts do treat patients based on clinical diagnosis alone, the toxicities and duration of the immunosuppressive therapies used to treat RPGN make a compelling rationale for biopsy confirmation of the diagnosis. Before initiating any immunosuppressive therapies, the treating physician must rule out infection. 17. What is appropriate empiric therapy for patients with acute glomerulonephritis or RPGN? Kidney biopsy should be performed expeditiously and appropriate laboratory studies should be sent when the patient presents. While waiting for these results, the initiation of steroid therapy—the mainstay inductive anti-inflammatory therapy for most acute inflammatory glomerular diseases—is reasonable. Toxicities from high-dose steroid therapy are minimal and manageable during this short “window” between patient presentation and obtaining diagnostic test results. The initiation of cytotoxic or other immuno­ suppressive treatments, which consolidate treatment response to steroids, or plasma exchange, should wait until a definitive diagnosis is established. Analysis of clinical trial outcomes for some glomerular diseases suggests that benefit from cytotoxic drugs occurs well after disease onset, and most experts feel that the use of these agents can be delayed until diagnosis is established. Dosing for cyclophosphamide must be adjusted in the patient with altered kidney function to avoid leukopenia. The spectrum of agents used in modern protocols has expanded greatly to include biologics as well as additional classes of nonspecific immunosuppressive drugs, such as calcineurin inhibitors and mycophenolate. 18. Is there any role for plasma exchange in the therapy for RPGN? Plasma exchange is thought to remove circulating pathogenic autoantibodies from the circulation. Trials evaluating efficacy of plasma exchange for all causes of RPGN have included only small numbers of patients. However, plasma exchange is a safe procedure in experienced centers and may be an appropriate therapeutic modality for subsets of patients with RPGN, in view of the high risk of kidney failure with this syndrome. The European Vasculitis Study Group published a randomized trial that demonstrated that adjunctive plasma exchange improved kidney outcomes in patients with severe kidney failure (serum creatinine .2.3 mg/dL) and active ANCA vasculitis. In addition, the prompt initiation of plasma exchange and aggressive immunosuppression with corticosteroids and

104  ACUTE KIDNEY INJURY cyclophosphamide can be lifesaving in patients with ANCA vasculitis and diffuse alveolar hemorrhage. Patients who are dialysis-dependent with ANCA vasculitis can respond to treatment (see question 19). Plasma exchange and immunosuppressive therapy are standard treatments for patients with anti-GBM antibody disease. Most evidence supporting the use of plasma exchange in anti-GBM-associated diseases is from case reports, although one small, randomized, controlled trial demonstrated a non-significant trend toward improved outcome in patients treated with plasma exchange. Patients who are dialysis-dependent with anti-GBM disease are unlikely to respond to aggressive treatment, and the potential benefit of treatment does not outweigh the risk in these individuals (see question 19). 19. What is the prognosis of RPGN? The prognosis and response to treatment in patients with anti-GBM antibody or Goodpasture disease have not been studied in large trials. Data from a number of small case series with similar, but not identical, treatment strategies suggest that patient survivals are high (70% to 90%). Overall, only 40% of patients remain off dialysis 1 year after presentation. However, patients who do not require dialysis and who are treated with immunosuppression and plasma exchange have 1-year kidney survivals of approximately 70% to 75%, even if kidney failure is severe. In contrast, kidney survival is poor in patients with anti-GBM antibody-associated disease, who require dialysis within 72 hours of presentation. Aggressive therapy with immunosuppressive drugs and plasma exchange may not be appropriate in this subgroup of anti-GBM antibody patients, unless significant acute tubular necrosis, in addition to crescentic nephritis, is demonstrated on kidney biopsy. Clinical, laboratory, and pathologic parameters do not have sufficient predictive value for kidney outcomes to be used in an individual patient. Although data on patients with kidney-limited, ANCA-positive RPGN are limited, treatment responses have been recently reported in several cohorts of patients with ANCA-associated necrotizing glomerulonephritis and either GPA or MPA. Many patients (approximately 75%) achieve remission after induction therapy, but only 40% to 50% remain in long-term remission after 4 to 10 years. Serum creatinine at presentation is the strongest predictor of kidney survival in patients who are ANCA positive. In contrast to patients with anti-GBM glomerulonephritis, patients with ANCA-associated glomerulonephritis can respond to therapy even if they have already required the initiation of dialysis.

KEY PO I N T S 1. Acute glomerulonephritis is a kidney injury syndrome characterized by the sudden onset of edema, new or worsening hypertension, and an active urinary sediment. 2. Rapidly progressive glomerulonephritis is a clinical syndrome characterized by rapid loss of kidney function that often results in ESKD. 3. Acute glomerulonephritis and rapidly progressive glomerulonephritis (RPGN) are not specific diagnoses. Kidney biopsy is almost always required for definitive diagnosis and patient management. 4. If you think a patient has either acute glomerulonephritis or RPGN, expeditious diagnosis and initiation of therapy is vital because early intervention is associated with better outcomes. 5. Optimal patient management often requires referral to an expert in the care of patients with these diseases. Bibliography Beck, L. H., Jr., & Salant, D. J. (2014). Membranous nephropathy: From models to man. Journal of Clinical Investigation, 124(6), 2307–2314. Cattran, D. C., & Brenchley, P. E. (2017). Membranous nephropathy: Integrating basic science into improved clinical management. Kidney International, 91(3), 566–574. Glassock, R. J., Alvarado, A., Prosek, J., Hebert, C., Parikh, S., Satoskar, A., . . . Hebert, L. A. (2015). Staphylococcusrelated glomerulonephritis and poststreptococcal glomerulonephritis: Why defining “post” is important in understanding and treating infection-related glomerulonephritis. American Journal of Kidney Diseases, 65(6), 826–832. Glassock, R. J., & Rovin, B. H. (2016). Primary and secondary glomerular diseases. Nephrology Self-Assessment Program, 15(3), 1–346. Manoharon, A., Schelling, J. R., Diamond, M., Chung-Park, M., Madaio, M., & Sedor, J. R. (2013). Immune and inflammatory glomerular diseases. In R. J. Alpern, M. J. Caplan, & O. W. Moe (Eds.), Seldin and Giebisch’s the kidney: Physiology and pathophysiology (pp. 2763–2816). Amsterdam: Elsevier. Nasr, S. H., Radhakrishnan, J., & D’Agati, V. D. (2013). Bacterial infection-related glomerulonephritis in adults. Kidney International, 83(5), 792–803. Sethi, S., Haas, M., Markowitz, G. S., D’Agati, V. D., Rennke, H. G., Jennette, J. C., . . . Fervenza, F. C. (2016). Mayo clinic/ renal pathology society consensus report on pathologic classification, diagnosis, and reporting of GN. Journal of the American Society of Nephrology, 27(5), 1278–1287.