Nephrotic Nephritic Review — Medical Education Handout

7. Rapidly Progressive Glomerulonephritis (RPGN): Diagnosis and Treatment

Definition and Clinical Features

Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome characterized by a rapid decline in glomerular filtration rate (GFR) of at least 50% over days to 3 months, often progressing to kidney failure without prompt treatment. RPGN is relatively uncommon, with incidence varying by the cause of glomerulonephritis. The pathological hallmark is extensive glomerular crescent formation (>50% of glomeruli).

Clinical Presentation: - Rapid loss of renal function (days to weeks) - Nephritic urine analysis: microscopic or macroscopic hematuria, dysmorphic RBCs, RBC casts, proteinuria - Edema (less prominent than nephrotic syndrome) - Hypertension - Constitutional symptoms may include fever, malaise, arthralgias

Classification

RPGN is classified into three main categories based on immunofluorescence patterns:

Type I: Anti-GBM Disease (Linear Pattern) - ~10% of RPGN cases - Linear IgG deposition on immunofluorescence - May present as: - Anti-GBM nephritis (kidney-limited) - Goodpasture syndrome (kidney + lung involvement) - Peak incidence in 20s (predominantly males) and 60s (equal sex distribution)

Type II: Immune Complex Disease (Granular Pattern) - ~40% of RPGN cases - Associated conditions: - Systemic lupus erythematosus - IgA nephropathy - Post-infectious glomerulonephritis - Cryoglobulinemia - Endocarditis

Type III: Pauci-Immune Disease - ~50% of RPGN cases - Almost all patients have elevated antineutrophil cytoplasmic antibodies (ANCAs) - Usually associated with systemic vasculitis: - Microscopic polyangiitis (P-ANCA/MPO) - Granulomatosis with polyangiitis (C-ANCA/PR3)

Type IV: Double Antibody Positive - Rare variant with both ANCA and anti-GBM antibodies - Associated with worse prognosis

Diagnostic Approach

Laboratory Evaluation

Essential Tests: 1. Serum creatinine and eGFR: Document rapid decline 2. Urinalysis with microscopy: - RBC casts (pathognomonic for glomerulonephritis) - Dysmorphic RBCs - Proteinuria (variable, may be nephrotic range) 3. Serologic workup: - Anti-GBM antibodies - ANCA (both immunofluorescence and antigen-specific assays) - ANA, anti-dsDNA - Complement levels (C3, C4) - Cryoglobulins - Hepatitis B and C serologies - ASO titers 4. CBC: Anemia common 5. Inflammatory markers: ESR, CRP often elevated

ANCA Testing Interpretation: - The positive predictive value (PPV) of a positive ANCA result in a patient with classic features of RPGN is 95% - Combined immunofluorescence and ELISA testing maximizes sensitivity and specificity - Negative predictive value is greater than 95%

Renal Biopsy

Indications: - Essential for diagnosis unless contraindicated - Determines disease activity and chronicity - Guides treatment decisions

Findings: - Cellular crescents (indicate active disease) - Fibrous crescents (indicate chronic damage) - Immunofluorescence pattern distinguishes types - Degree of interstitial fibrosis predicts prognosis

Treatment Approach

Treatment must be initiated urgently, often before biopsy results are available. The approach depends on the underlying etiology:

Type I: Anti-GBM Disease

Induction Therapy: 1. Plasmapheresis: - Daily exchanges for 14 days or until anti-GBM antibodies undetectable - Essential for antibody removal - Most effective if started before serum creatinine >5.7 mg/dL

Immunosuppression:
- IV methylprednisolone 1g daily × 3 days
- Then oral prednisone 1 mg/kg/day
- Cyclophosphamide 2 mg/kg/day (oral) or IV monthly pulses

Prognosis: - Patient survival is greatly improved with treatment and is as high as 90% - Renal recovery depends on initial severity - Dialysis dependence at presentation predicts poor renal recovery

Type II: Immune Complex Disease

Treatment varies by underlying cause:

Post-streptococcal GN: - Usually self-limiting - Supportive care in most cases - Corticosteroids for severe crescentic disease

Lupus nephritis: - Corticosteroids plus cyclophosphamide or mycophenolate mofetil - See lupus nephritis guidelines for specific protocols

IgA nephropathy with crescents: - Corticosteroids if <25% crescents - Add cyclophosphamide if >25% crescents

Type III: Pauci-Immune (ANCA-Associated)

Induction Therapy: 1. Corticosteroids: - IV methylprednisolone 0.5 to 1 g/d for 3 days followed by oral prednisone 1 mg/kg for 1 month and then tapered over 3 to 4 months

Cyclophosphamide:
- IV 15 mg/kg initially every 2 weeks or daily orally 1.5 to 2 mg/kg
- Duration: 3-6 months
- IV route may have fewer adverse effects but higher relapse rates
Rituximab:
- Alternative to cyclophosphamide for induction
- 375 mg/m² weekly × 4 or 1g × 2 doses
- Equal efficacy to cyclophosphamide in trials
Plasmapheresis:
- Recommended at diagnosis if there is a rapid decline in kidney function or severe involvement of renal
- Indications:
  - Serum creatinine >4 mg/dL
  - Dialysis dependence
  - Pulmonary hemorrhage
  - Concomitant anti-GBM antibodies
Avacopan:
- In 2021, the medication avacopan (Tavneos®) was approved by the FDA as an adjunctive treatment in adults for severe active ANCA-associated vasculitis
- Complement C5a receptor antagonist
- Used with standard immunosuppression

Maintenance Therapy: - Azathioprine 2 mg/kg/day - Mycophenolate mofetil 1g twice daily - Rituximab 500mg every 6 months - Low-dose prednisone (controversial) - Duration: minimum 18-24 months

Monitoring and Prognosis

Monitoring: - Weekly creatinine initially - ANCA titers (controversial for guiding therapy) - Monitor for treatment complications: - Infections (especially with cyclophosphamide) - Bone marrow suppression - Hemorrhagic cystitis

Prognostic Factors: - Initial serum creatinine level - Dialysis requirement at presentation - Percentage of normal glomeruli on biopsy - Degree of interstitial fibrosis - Patient age

Outcomes: - Mortality in untreated pauci-immune vasculitis is 90% without therapy, although treatment is effective and has reduced mortality to between 10% and 20% - Permanent renal replacement is required in 20% to 40% of patients - Relapses occur in 30-50% of ANCA-associated disease

Special Considerations

Japanese Guidelines: - The Research Committee of Progressive Glomerular Disease of the Ministry of Health, Labor and Welfare of Japan defined RPGN as rapidly progressing renal failure within several weeks to several months - Emphasize early referral and aggressive treatment - MPO-ANCA predominance in Japanese population

Renal-Limited Disease: - May present without systemic features - Requires same aggressive treatment as systemic disease - Regular monitoring for systemic involvement

8. Secondary Causes of Glomerular Diseases

Secondary Causes of Minimal Change Disease

While the majority of MCD cases are idiopathic (primary), approximately 10-20% may have an identifiable secondary cause. Recognition of secondary causes is important as treatment may differ from primary MCD.

Secondary Causes of MCD:

Hematologic Malignancies:
- Hodgkin lymphoma (most common association)
- Non-Hodgkin lymphoma
- Other lymphoproliferative disorders: mycosis fungoides, Waldenstrom’s macroglobulinemia, Kimura disease
- Solid tumors (rare): lung, pancreatic, colon, urothelial, renal cell, prostate carcinomas, thymoma, mesothelioma
Medications:
- NSAIDs (most common drug association)
- Antibiotics: ampicillin, cephalosporins, rifampin
- Lithium
- Interferon (alpha and gamma)
- Immune checkpoint inhibitors
- Others: methimazole, tamoxifen, enalapril, penicillamine, gold salts, probenecid
- Mercury-containing cosmetic skin cream
Infections:
- HIV (can present as MCD or more commonly FSGS)
- Tuberculosis
- Syphilis
- Infectious mononucleosis (EBV)
- Parasitic: schistosomiasis, hydatid disease (echinococcal infection)
- Mycoplasma, ehrlichiosis
- Hepatitis C virus
Atopic/Allergic Conditions:
- Bee and jellyfish stings
- Environmental allergens: dust, pollen, poison ivy, poison oak
- Food allergens: pork, dairy products
- Cat fur, fungi, ragweed pollen
- Often IgE-mediated hypersensitivity mechanism
Autoimmune Diseases:
- Lupus podocytopathy (most common autoimmune etiology)
- Found in 1-2% of lupus kidney biopsies
- Meets ACR criteria for SLE with nephrotic syndrome
Other Associations:
- Recent immunizations (delayed hypersensitivity response)
- Type 1 diabetes mellitus
- IgA nephropathy (can coexist)
- COVID-19 vaccination (case reports of new-onset and relapsing MCD)

Diagnostic Approach for Secondary Causes:

When evaluating MCD, especially in adults or those with atypical features, consider screening for secondary causes: - Complete blood count with differential - HIV testing - Hepatitis B and C serologies - Syphilis testing (RPR/VDRL) - ANA and complement levels (to rule out lupus) - Age-appropriate cancer screening - Medication history review - Serum and urine protein electrophoresis (if suspicion for lymphoma)

Treatment Considerations for Secondary MCD: - Drug-induced: Discontinuation of offending agent often leads to remission - Malignancy-associated: Treatment of underlying malignancy; eradication of tumor leads to improvement of proteinuria - Infection-related: Treatment of underlying infection - Allergen-induced: Allergen avoidance associated with remission

Secondary Causes of Focal Segmental Glomerulosclerosis

Secondary FSGS represents a significant proportion of all FSGS cases and has different treatment implications compared to primary FSGS. Secondary FSGS is caused by identifiable stress or toxin that injures podocytes.

Major Categories of Secondary FSGS:

Viral Infections:
- HIV-associated nephropathy (HIVAN):
  - Collapsing variant most common
  - Predominantly affects individuals of African descent
  - Treatment: HAART plus ACE inhibitors/ARBs
- Parvovirus B19
- CMV
- EBV
- Hepatitis B and C (rare)
Drugs and Toxins:
- Heroin nephropathy:
  - Historically common in IV drug users
  - May be related to adulterants rather than heroin itself
- Anabolic steroids
- Pamidronate/bisphosphonates
- Lithium
- Interferon
- Sirolimus/mTOR inhibitors
- NSAIDs (rare)
- Mercury
Adaptive/Hyperfiltration FSGS:
- Obesity-related glomerulopathy:
  - Glomerulomegaly prominent feature
  - Often perihilar variant
  - Less likely to present with full nephrotic syndrome
- Solitary kidney or renal agenesis
- Reflux nephropathy
- Low nephron mass:
  - Prematurity/low birth weight
  - Oligomeganephronia
- Prior kidney disease with nephron loss
- Sickle cell disease
- Cyanotic congenital heart disease
Genetic/Familial FSGS:
- Podocin (NPHS2) mutations
- Nephrin (NPHS1) mutations
- WT1 mutations
- TRPC6 mutations
- ACTN4 mutations
- INF2 mutations
- APOL1 risk variants (G1/G2 alleles in African Americans)
Other Secondary Causes:
- Alport syndrome
- Systemic lupus erythematosus
- Lymphomas
- Hypertensive nephrosclerosis (superimposed FSGS)

Distinguishing Primary from Secondary FSGS:

Clinical features suggesting secondary FSGS: - Absence of full nephrotic syndrome (proteinuria often <3.5 g/day) - Less peripheral edema relative to proteinuria - Normal serum albumin despite significant proteinuria - Slower progression to ESRD - Identifiable causative factor

Histologic features suggesting secondary FSGS: - Glomerulomegaly in adaptive FSGS - Perihilar variant in obesity/hyperfiltration - Collapsing variant in HIV - Less foot process effacement on electron microscopy - Absence of IgM and C3 deposits

Treatment Approach for Secondary FSGS:

Unlike primary FSGS, secondary forms typically do not respond to immunosuppression. Treatment focuses on:

Address underlying cause:
- HIV: Antiretroviral therapy
- Obesity: Weight loss (surgical if necessary)
- Drug-induced: Discontinue offending agent
- Hyperfiltration: Reduce single nephron GFR
Supportive care:
- ACE inhibitors or ARBs for proteinuria reduction
- Blood pressure control
- Lipid management
- Dietary protein restriction in advanced CKD
Monitoring:
- Regular assessment of proteinuria and kidney function
- Adjust therapy based on response to underlying cause treatment

Prognosis: Secondary FSGS generally has better prognosis than primary FSGS if the underlying cause can be addressed. However, some forms (HIV-associated, heroin nephropathy) can progress rapidly without appropriate treatment.

Updated References

References

Rosenberg AZ, Kopp JB. Focal Segmental Glomerulosclerosis. Clin J Am Soc Nephrol. 2017;12(3):502-517. PMID: 28242845
Shabaka A, Tato Ribera A, Fernández-Juárez G. Focal Segmental Glomerulosclerosis: State-of-the-Art and Clinical Perspective. Nephron. 2020;144(9):413-427. PMID: 32721952

Educational Resources

Student Guide: Comprehensive Nephrology Review Nephritc Nephrotic — PA/medical student educational guide
Student Guide: Dipstick Proteinuria — PA/medical student educational guide
Student Handout: Nephritic Nephrotic — PA/medical student educational guide

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The same subject at other levels of depth.

Primer chapter: Chapter 18: Nephritic & Nephrotic Syndromes