Ferri – Acute Glomerulonephritis (AGN)

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Acute Glomerulonephritis (AGN)

  • Rupali Avasare, M.D.

 Basic Information

Definition

Acute glomerulonephritis is an immunologically mediated inflammation of the filtering units of the nephron, the glomeruli. The inflammation may result in damage to the glomerular basement membrane (GBM), mesangium, and/or capillary endothelium.

Synonyms

  1. Acute nephritic syndrome

  2. Glomerulonephritis, acute AGN

ICD-10CM CODES
N00.0 Acute nephritic syndrome with minor glomerular abnormality
N00.1 Acute nephritic syndrome with focal and segmental glomerular lesions
N00.2 Acute nephritic syndrome with diffuse membranous glomerulonephritis
N00.3 Acute nephritic syndrome with diffuse mesangial proliferative glomerulonephritis
N00.4 Acute nephritic syndrome with diffuse endocapillary proliferative glomerulonephritis
N00.5 Acute nephritic syndrome with diffuse mesangiocapillary glomerulonephritis
N00.6 Acute nephritic syndrome with dense deposit disease
N00.7 Acute nephritic syndrome with diffuse crescentic glomerulonephritis
N00.8 Acute nephritic syndrome with other morphologic changes
N00.9 Acute nephritic syndrome with unspecified morphologic changes

Epidemiology & Demographics

  1. •

    Incidence rates of primary glomerulonephritis vary between 0.2/100,000 per year and 2.5/100,000 per year.

  2. •

    Immunoglobulin A (IgA) nephropathy (Berger’s disease) is the most common glomerulonephritis worldwide.

  3. •

    Glomerulonephritis accounts for 23% of end-stage renal disease cases.

  4. •

    Glomerulonephritis affects adults and children.

Physical Findings & Clinical Presentation

  1. •

    Acute onset of hypertension.

  2. •

    Dark, “tea-colored” urine.

  3. •

    Edema (peripheral, periorbital, or pulmonary).

  4. •

    Fatigue.

  5. •

    Concurrent pulmonary hemorrhage and kidney disease may indicate anti-neutrophil cytoplasmic antibody (ANCA) vasculitis or anti-GBM disease.

  6. •

    Joint pains, oral ulcers, and malar rash are frequently seen with systemic lupus erythematosus.

  7. •

    Palpable purpura may be found in patients with systemic vasculitis such as Henoch-Schönlein purpura, ANCA-associated vasculitis, or cryoglobulinemia.

  8. •

    Recent history of endocarditis or cellulitis or preceding pharyngitis may indicate infection-related glomerulonephritis.

  9. •

    Hepatitis C infection may cause membranoproliferative glomerulonephritis (MPGN) with or without cryoglobulinemia.

  10. •

    Concurrent upper respiratory tract infection “synpharyngitic” is commonly associated with flares of IgA nephropathy.

  11. •

    Nonspecific flulike symptoms, fatigue, and myalgias are frequent with ANCA-associated vasculitis.

Etiology

Acute glomerulonephritis may occur as a kidney-limited disease or a systemic disease. The three mechanisms of primary glomerulonephritis are immune-complex deposition, anti-GBM disease antibodies, and vasculitis with minimal immune staining (“pauci-immune” glomerulonephritis). See Table 1.

TABLE1 Mechanisms of Primary Glomerulonephritis
Immune Complex Pauci-Immune Anti–Glomerular Basement Membrane
IgA nephropathy/Henoch-Schönlein purpura (IgA vasculitis) Myeloperoxidase (MPO)–associated vasculitis Goodpasture disease
Lupus nephritis Proteinase 3–associated vasculitis
Infection-related glomerulonephritis, including poststreptococcal GN and endocarditis-associated GN Eosinophilic vasculitis
Membranoproliferative GN
Cryoglobulinemic vasculitis

Pathologic features of immune glomerular disease are summarized in Table 2. Fig. 1 is an algorithm for diagnostic classification of GN that is known or suspected of being mediated by antibodies and complement.

TABLE2 Pathologic Features of Immune Glomerular DiseasesFrom McPherson RA, Pincus MR: Henry’s clinical diagnosis and management by laboratory methods, ed 23, Philadelphia, 2017, Elsevier.
Disease Pathogenesis LM IF EM
Membranous In situ immune complex deposition (PLA2R is antigen) Capillary wall thickening Capillary wall granular IgG and C3 Subepithelial deposits
IgA nephropathy Abnormal IgA glycosylation Mesangial hypercellularity Mesangial dominant IgA (and some C3) Mesangial deposits
Membranoproliferative glomerulonephritis (MPGN) Immune complex deposition Endocapillary hypercellularity, mesangial sclerosis, “double contouring” Capillary wall IgG (less IgM) and C3 Subendothelial deposits
C3 glomerulonephritis (C3GN) Dysregulation of alternative pathway of complement Variable features, but often similar to MPGN Capillary wall dominant C3 (less or no Igs) Variable, but subendothelial deposits
Dense deposit disease (DDD) Dysregulation of alternative pathway of complement Variable, but often similar to MPGN or mesangial cell hypercellularity Capillary wall dominant C3 (less or no Igs) Dense deposits in GBM
Postinfectious glomerulonephritis Immune complex deposition, planted or circulating antigen Endocapillary hypercellularity Capillary wall IgG and C3 Subepithelial “hump” deposits
Anti-GBM disease Circulating anti-GBM antibodies (antigen is α3 chain of COL4) Capillary wall necrosis and crescents Capillary wall linear IgG and C3 No deposits, GBM ruptures
Pauci-immune glomerulonephritis ANCAs (antineutrophil cytoplasmic antibodies) Capillary wall necrosis and crescents No or sparse Ig/C3 staining No or sparse deposits
Lupus nephritis (Class I-VI) Immune complex deposition Variable, class-dependent “Full-house” staining for all Igs, C3, and C1q Numerous deposits typically (location is class-dependent)

COL4, Type IV collagen; EM, electron microscopy; IF, immunofluorescence; Igs, immunoglobulins; LM, light microscopy.
FIG.1

Algorithm for diagnostic classification of glomerulonephritis (GN) that is known

Diagnosis

Differential Diagnosis

  1. •

    Cirrhosis with edema and ascites.

  2. •

    Congestive heart failure.

  3. •

    Acute interstitial nephritis.

  4. •

    Acute tubular necrosis.

  5. •

    Thrombotic microangiopathy.

  6. •

    Nephrotic syndrome.

  7. •

    Hereditary nephritis.

  8. •

    Nephrolithiasis.

Workup

Initial evaluation of suspected glomerulonephritis consists of laboratory testing.

Laboratory Tests

  1. •

    Urinalysis (hematuria [dysmorphic erythrocytes and red cell casts], proteinuria).

  2. •

    Blood urea nitrogen and serum creatinine (to estimate glomerular filtration rate [GFR]).

  3. •

    24-hour urine for protein excretion and creatinine clearance (to document degree of renal dysfunction and amount of proteinuria). Random urine (spot specimen) protein-to-creatinine ratio is also acceptable instead of a 24-hour collection. Proteinuria in acute glomerulonephritis typically ranges from 500 mg/day to 3 g/day, but nephrotic-range proteinuria (>3.5 g/day) may be present.

  4. •

    Streptococcal tests (Streptozyme), antistreptolysin O (ASO) quantitative titer (highest in 3 to 5 weeks); ASO titer, however, is not related to severity of renal disease, duration, or prognosis.

  5. •

    Additional serologic testing: anti-DNA antibodies (rule out SLE), C3, C4, cryoglobulins, rheumatoid factor, hepatitis B and C serologies, antineutrophil cytoplasmic antibodies (MPO and PR3), and anti–glomerular basement membrane antibodies, serum and urine protein electrophoresis, and serum kappa and lambda free light chains. Table 3 describes selected serologic findings in patients with primary glomerular disease.

    TABLE3 Selected Serologic Findings in Patients with Primary Glomerular DiseaseFrom Skorecki K, Chertow GM, Marsden PA, et al.: Brenner & Rector’s the kidney, ed 10, Philadelphia, 2016, Elsevier.
    Disease C4 C3 ASO, ADNase B Cryo Ig Anti-GBM ANCA
    Minimal change disease N N — — — —
    Focal glomerulosclerosis N N — — — —
    Membranous nephropathy N N — — — —
    Membranoproliferative GN∗
    Type I N or ↓↓ ↓↓ + ++ — —
    Type II N ↓↓↓ + — — —
    Fibrillary GN N N — — — —
    IgA nephropathy N N — — — —
    Acute poststreptococcal GN N or ↓ ↓↓ +++ ++ — —
    Crescentic GN
    Anti-GBM N N — — +++ ±
    Immune complex N or ↓ N or ↓↓ — N/++ — ±
    ANCA small vessel vasculitis N N — — ± +++

    ANCA, Antineutrophil cytoplasmic autoantibody; ADNase B, anti–deoxyribonuclease B; ASO, anti–streptolysin O; cryo Ig, cryoglobulins; GBM, glomerular basement membrane; GN, glomerulonephritis; N, normal levels.
  6. •

    Hematocrit and platelet count (decreased in thrombotic microangiopathy).

  7. •

    Blood cultures are indicated in all febrile patients.

  8. •

    Antigens identified in glomerulonephritis are described in Table 4.

    TABLE4 Antigens Identified in GlomerulonephritisFrom Floege J et al: Comprehensive clinical nephrology, ed 4, Philadelphia, 2010, Saunders.
    Poststreptococcal GN Streptococcal pyrogenic exotoxin B, plasmin receptor
    Anti-GBM disease α3 type IV collagen (likely induced by molecular mimicry)
    IgA nephropathy Possibly no antigen but rather polymerized polyclonal IgA (?superantigen driven)
    Membranous nephropathy Phospholipase A2 receptor (idiopathic), neutral endopeptidase in podocyte (congenital), HBeAg (hepatitis associated)
    Staphylococcus aureus–associated GN Staphylococcus superantigens induce polyclonal response; not necessarily antigen in glomeruli
    Membranoproliferative GN HCV and HBsAg in hepatitis-associated MPGN
    ANCA-associated vasculitis Proteinase 3 (c-ANCA) and myeloperoxidase (p-ANCA) in neutrophils; antibodies to lysosome-associated membrane protein 2 on endothelial cells (likely induced by molecular mimicry to fimbriated bacterial antigens)

    ANCA, Antineutrophil cytoplasmic antibody; GBM, glomerular basement membrane; GN, glomerulonephritis; HBeAg, hepatitis B virus early antigen; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; IgA, immunoglobulin A; MPGN, membranoproliferative glomerulonephritis.

Imaging Studies

  1. •

    Chest x-ray: Pulmonary involvement may be seen in ANCA-associated vasculitis and Goodpasture syndrome.

  2. •

    Renal ultrasound to evaluate renal size. A kidney size of <9 cm is suggestive of extensive scarring and low likelihood of reversibility.

  3. •

    Echocardiogram in patients with new cardiac murmurs or positive blood cultures to rule out endocarditis and pericardial effusion.

  4. •

    Renal biopsy with light, electron, and immunofluorescence microscopy to confirm diagnosis.

  5. •

    Biopsy of other affected organs if systemic vasculitis is suspected.

Treatment

Nonpharmacologic Therapy

  1. •

    Low-salt diet if edema or hypertension is present.

  2. •

    Avoidance of high-potassium foods if patient is hyperkalemic.

Acute General Rx

  1. •

    Diuretics in patients with significant edema or hypertension.

  2. •

    Correction of electrolyte abnormalities (hypocalcemia, hyperkalemia) and acidosis.

  3. •

    High-dose steroids for rapidly progressive glomerulonephritis.

  4. •

    Additional immunosuppressive treatment with alkylating agents, calcineurin inhibitors, or biologic agents (e.g., rituximab) may be necessary depending on the underlying disease.

  5. •

    Treatment of streptococcal infection with penicillin (or erythromycin in penicillin-allergic patients). Hemodialysis in patients with diuretic-resistant volume overload, hyperkalemia, uremic symptoms, and encephalopathy. Plasma exchange therapy for concurrent diffuse alveolar hemorrhage or rapidly progressive glomerulonephritis with a low GFR.

  6. •

    Treatment of hepatitis C-associated glomerulonephritis is rapidly changing due to the introduction of direct-acting antiviral agents.

  7. •

    Table 5 summarizes suggested management of idiopathic MPGN.

    TABLE5 Suggested Management of Membranoproliferative GlomerulonephritisFrom Floege J et al.: Comprehensive clinical nephrology, ed 4, Philadelphia, 2010, Saunders.
    Type Treatment
    All types Supportive therapy following the recommendations discussed in text
    Idiopathic MPGN in children Non-nephrotic proteinuria, normal renal function: follow with 3-month visits
    Normal renal function and moderate proteinuria (>3 g/day): prednisone 40 mg/m2 on alternate days for 3 months
    Nephrotic or impaired renal function: prednisone 40 mg/m2 on alternate days (80 mg maximum) for 2 years, tapering to 20 mg on alternate days for 3-10 years
    Idiopathic MPGN in adults Non-nephrotic, normal renal function: follow with 3-month visits
    Nephrotic or impaired renal function: 6-month course of corticosteroid with/without cytotoxic agents (cyclophosphamide) or other drugs used: cyclosporine, tacrolimus, mycophenolate mofetil
    Rapidly progressive renal failure with diffuse crescents: treat as for idiopathic rapidly progressive glomerulonephritis. In the presence of chronic renal failure or nephrotic proteinuria: angiotensin-converting enzyme inhibitors

    MPGN, Membranoproliferative glomerulonephritis.

Chronic Rx

  1. •

    Frequent monitoring of blood pressure, urinalysis, serum creatinine, serum albumin, and random urine protein-to-creatinine ratio.

  2. •

    Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor II blockers (ARBs) are used in patients with persistent proteinuria.

  3. •

    Lipid management with statins and fibrates as indicated.

  4. •

    Monitoring for side effects related to immunosuppression, such as infections, leukopenia and anemia, osteoporosis or osteopenia, gastrointestinal ulcers, high blood pressure, and tumors.

  5. •

    Routine health maintenance with vaccinations for influenza and pneumococcal pneumonia, age-appropriate vaccinations, as well as age-appropriate malignancy screening. Live vaccines are contraindicated in patients on immunosuppression.

Disposition

  1. •

    Prognosis is generally related to the initial serum creatinine and degree of fibrosis on biopsy.

  2. •

    In general, prognosis is worse in patients with heavy proteinuria, low GFR at presentation, severe hypertension, and crescentic glomerulonephritis.

  3. •

    Recovery of renal function occurs within 8 to 12 weeks in 95% of patients with poststreptococcal glomerulonephritis.

Referral

  1. •

    Nephrology consultation for all patients with suspected glomerulonephritis. Urgent consultation is recommended if GFR is significantly abnormal or rapidly deteriorating or if the patient has systemic symptoms.

Pearls & Considerations

Comments

  1. •

    Diagnosis of glomerulonephritis is made on kidney biopsy. Kidney biopsy is necessary when the histologic diagnosis will alter the treatment plan, which is usually the case in patients with systemic illnesses, significant proteinuria (>500 mg to 1 g per day), or rising serum creatinine. Not all patients with suspected glomerulonephritis require a kidney biopsy because of success with supportive therapies (e.g., infection-related GN). A search for systemic illness, including infections, autoimmune disease, and malignancy is needed with careful history, physical examination, and serologic tests.

  2. •

    Nephrology consultation is necessary before initiation of immunosuppressive therapy. In the absence of contraindications to their use, ACE inhibitor or ARB therapy is essential for proteinuria reduction. Aldosterone receptor antagonists may be used for additional reduction in proteinuria.

  3. •

    Monitoring of lipids and aggressive treatment of hyperlipidemia is recommended when persistent disease is present.

  4. •

    Close monitoring of side effects of immunosuppressive drugs and complications of corticosteroids is necessary.

Suggested Readings

  • T.M. Chan: Treatment of severe lupus nephritis: the new horizon. Nat Rev Nephrol. 11:46–61 2015 25421826

  • A. Gupta, et al.: Glomerular diseases associated with hepatitis B and C. Adv Chronic Kidney Dis. 22 (5):343–351 2015 26311595

  • S. Nasr, et al.: Bacterial infection-related glomerulonephritis in adults. Kidney Int. 83:792–803 2013 23302723

  • I.S.D. Roberts: Pathology of IgA nephropathy. Nat Rev Nephrol. 10:445–454 2014 24861083

  • U. Schönermarck, et al.: Treatment of ANCA-associated vasculitis. Nat Rev Nephrol. 10:25–36 2014 24189648

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  2. Acute Kidney Injury (Related Key Topic)

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