# Nephrotic Nephritic Review

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

### Definition and Clinical Features

RPGN is a clinical syndrome of rapidly worsening kidney function with suspected glomerular inflammation. Evaluate urgently while assessing other causes of AKI. Crescents and necrosis may be found on biopsy, but neither a 50% GFR decline nor a fixed crescent burden is required before urgent assessment.

**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 (strongly support glomerular bleeding; neither their presence nor absence establishes the cause) - 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

1.  **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

1.  **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
2.  **Rituximab**:
    - Alternative to cyclophosphamide for induction
    - 375 mg/m² weekly × 4 or 1g × 2 doses
    - Equal efficacy to cyclophosphamide in trials
3.  **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
4.  **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:**

1.  **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
2.  **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
3.  **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
4.  **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
5.  **Autoimmune Diseases:**
    - Lupus podocytopathy (most common autoimmune etiology)
    - Found in 1-2% of lupus kidney biopsies
    - Meets ACR criteria for SLE with nephrotic syndrome
6.  **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:**

1.  **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)
2.  **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**
3.  **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**
4.  **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)
5.  **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:

1.  **Address underlying cause:**
    - HIV: Antiretroviral therapy
    - Obesity: Weight loss (surgical if necessary)
    - Drug-induced: Discontinue offending agent
    - Hyperfiltration: Reduce single nephron GFR
2.  **Supportive care:**
    - ACE inhibitors or ARBs for proteinuria reduction
    - Blood pressure control
    - Lipid management
    - Dietary protein restriction in advanced CKD
3.  **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

1.  Rosenberg AZ, Kopp JB. Focal Segmental Glomerulosclerosis. Clin J Am Soc Nephrol. 2017;12(3):502-517. PMID: 28242845

2.  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

## Related Notes

- !Changes to Primer - shared tags: ent, kidney
- Edema Index - shared tags: ent, gi
- dialysis student guide - shared tags: kidney, renal
- student cardiorenal report 1 - shared tags: kidney, renal
- cardiorenal disease report - shared tags: clinical-medicine, kidney, renal
- Medication Reconciliation Nephrology Data Complexity - shared tags: kidney, renal
- Nephrotic Diseases hepta - shared tags: clinical-medicine, ent, kidney
- The Temporal Disconnect between Nephrology Consult and Window for Early Intervention in AKI - shared tags: clinical-medicine, kidney, renal
- hepatology report expanded references - shared tags: clinical-medicine, gi, hypertension
- atn loop diuretics report 1 - shared tags: ent, gi, kidney

## Related Notes

- !Changes to Primer - shared tags: ent, kidney
- Edema Index - shared tags: ent, gi
- dialysis student guide - shared tags: kidney, renal
- student cardiorenal report 1 - shared tags: kidney, renal
- cardiorenal disease report - shared tags: clinical-medicine, kidney, renal
- Medication Reconciliation Nephrology Data Complexity - shared tags: kidney, renal
- Nephrotic Diseases hepta - shared tags: clinical-medicine, ent, kidney
- The Temporal Disconnect between Nephrology Consult and Window for Early Intervention in AKI - shared tags: clinical-medicine, kidney, renal
- hepatology report expanded references - shared tags: clinical-medicine, gi, hypertension
- atn loop diuretics report 1 - shared tags: ent, gi, kidney

## 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

### Also on this topic

The same subject at other levels of depth.

- **Primer chapter:** [Chapter 18: Nephritic & Nephrotic Syndromes](https://urinenephrology.org/nephrology-textbook/chapters/chapter-15-nephritic-nephrotic-review.html)


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