ICI-Associated Glomerular Diseases: Diagnosis and Management

Frequency of Glomerular Involvement

Cortazar Multicenter Study (2020) — 93 Biopsied ICI-AKI Patients: - Pure AIN: 66/93 (71%) - AIN + glomerular disease: 18/93 (19%) - AIN + TMA: 5/93 (5%) - Pure glomerular disease: 4/93 (4%) - Conclusion: ~27% had glomerular involvement, either as sole lesion or concurrent with AIN [2]

Kitchlu Systematic Review (2021) — Meta-Analysis of ICI-Associated GN: - Total patients: 112 across 40 case reports and small series - Most common glomerular patterns: 1. Pauci-immune GN (ANCA-negative): 28.3% 2. Podocytopathies (minimal change, FSGS): 26.4% 3. Immune-complex GN (lupus-like, membranous): 18.9% 4. Membranoproliferative GN (including C3-GN): 9.8% 5. ANCA-positive vasculitis: 8.0% 6. Other patterns (IgA, antiGBM, etc.): 8.6%

Risk Factors for Glomerular Disease

Clinical/Demographic Factors: - Older age (>60 years): relative risk 2-3× for GN vs. AIN - Female sex: slight predominance in some series - Baseline CKD: may predispose to severe forms

ICI-Related Factors: - Specific drug class: Anti-PD-L1 agents (atezolizumab, avelumab, durvalumab) have slightly higher GN incidence than PD-1 inhibitors - Duration of exposure: GN can develop weeks to years after ICI initiation - Rechallenged patients: GN recurrence possible on second ICI course

Oncologic Factors: - Tumor burden: High burden may correlate with immunologic dysregulation - Specific tumor types: Melanoma, RCC show higher GN rates than NSCLC in some series

Clinical Presentation

Typical Features: - Sudden onset nephrotic syndrome (edema, proteinuria >3.5 g/day) - Typically 2-8 weeks after ICI initiation - Serum creatinine: Often normal or near-normal at onset (distinguishes from AIN) - Urinalysis: Heavy proteinuria, few or no cellular elements, bland sediment - Serologies: Normal complement, negative ANA, ANCA negative

Distinguishing Features from ICI-AIN: - Nephrotic vs. non-nephrotic: MCD causes nephrotic range proteinuria; AIN typically <2 g/day - Hematuria: MCD rarely has hematuria; AIN commonly has WBC/RBC - Renal function: MCD preserves GFR early; AIN causes immediate Cr rise - Speed of onset: MCD rapid (days-weeks); AIN more insidious (weeks-months)

Pathology

Light Microscopy: - Glomeruli appear normal (minimal change) - No proliferation, crescents, or sclerosis - Interstitium: May show minimal inflammation or none

Electron Microscopy (EM): - Widespread podocyte foot process effacement — hallmark finding - Normal glomerular basement membrane - No deposits on EM (pauci-immune)

Immunofluorescence (IF): - Negative or trace staining for immunoglobulins and complement - Minimal IgM occasionally

Pathogenesis of ICI-Associated MCD

Mechanism: 1. ICI blockade restores T-cell function within kidneys 2. T cells infiltrate glomerular region 3. Activated T cells produce lymphokines (IL-4, IL-13) that act on podocytes 4. Podocyte cytoskeleton disrupted → foot process effacement 5. Loss of charge barrier → proteinuria

Podocyte Injury Pathway: - IL-4/IL-13 → STAT6 activation → podocyte actin derangement - TNF-α → podocyte mitochondrial dysfunction - Direct T-cell contact via immune synapse formation

Management of ICI-Associated MCD

ICI Management: - Hold or discontinue ICI (most cases) - Rechallenge rarely attempted (risk of recurrent nephrotic syndrome)

Immunosuppression: - Corticosteroids: Prednisone 0.5-1 mg/kg/day - Expected response: 80% achieve complete remission of proteinuria within 4-8 weeks - Taper: Minimum 6-8 weeks at full dose, then slow taper over 2-3 months

Steroid-Sparing Agents for Steroid-Dependent Cases: - Mycophenolate mofetil: 1-2 g/day PO - Tacrolimus: 0.05-0.1 mg/kg/day (target trough 3-5 ng/mL) - Rituximab: 375 mg/m² weekly × 4 doses (for steroid-dependent patients)

Supportive Care: - ACE inhibitor/ARB for proteinuria reduction (use cautiously if significant proteinuria-related Cr elevation) - Diuretics for edema management - Sodium restriction (<2 g/day) - Monitor for hypoalbuminemia complications (thrombosis risk, infection)

Prognosis

• Complete remission: 80-90%
• Steroid-dependent relapse: 10-20%
• ESRD progression: <5%
• Time to remission: 4-12 weeks typical

Clinical Presentation

Typical Features: - Systemic manifestations: Joint pain, rash, fever (not always present) - Hematuria (both dysmorphic RBCs and RBC casts) with proteinuria - Serum creatinine: Variable rise, ranges from minimal to severe - Serologies: ANA-negative or low-titer (KEY DIFFERENCE from primary SLE) - Anti-dsDNA antibodies: Usually absent or low-titer - Complement C3/C4: Normal or only mildly low

When to Suspect ICI-Lupus: - ICI-treated patient with proteinuria + hematuria - Features of lupus nephritis (RBC casts, dysmorphic RBCs) BUT - ANA negative or minimal serologic markers of SLE

Pathology

Light Microscopy: - Class III or Class IV lupus nephritis pattern (WHO classification) - Endocapillary or membranoproliferative proliferation - Wire-loop lesions (subendothelial deposits) - Hyaline thrombi - Interstitial involvement: Often AIN component concurrent

Electron Microscopy: - Subendothelial electron-dense deposits (characteristic of lupus) - Subepithelial deposits possible

Immunofluorescence: - Full house pattern: IgG + IgA + IgM + C3 + C1q (diagnostic of lupus) - Or predominant IgG + C3

Pathogenesis

Mechanism: 1. PD-1 checkpoint blockade impairs Treg function 2. Loss of tolerance to nuclear autoantigens (dsDNA, nucleosomes) 3. Germinal center hyperplasia in secondary lymphoid organs 4. Breaching of B-cell tolerance → autoantibody production 5. Immune complex formation and glomerular deposition 6. Lupus nephritis pathology identical to primary SLE

Why Seronegativity? - ICI-lupus may represent early/evolving disease - Different B-cell epitope recognition than primary SLE - Rapid development prevents extensive antibody maturation

Management of ICI-Associated Lupus Nephritis

ICI Management: - Permanent discontinuation (do NOT rechallenge) - Switching to alternative ICI not recommended (cross-reactivity likely)

Immunosuppression (Intensity Based on Pathology):

Class III (Focal Proliferative): - Prednisone 0.5-1 mg/kg/day - Plus mycophenolate mofetil 1-2 g/day (preferred) OR cyclophosphamide 500-750 mg/m² IV monthly

Class IV (Diffuse Proliferative — most common with ICI): - Prednisone 1-2 mg/kg/day (may use IV methylprednisolone 1 g daily × 3 days initially) - PLUS Induction Regimen: - Option A: Mycophenolate 1-3 g/day × 6 months → maintenance MMF - Option B: Cyclophosphamide 500-750 mg/m² IV monthly × 6 months (with mesna prophylaxis) - Rituximab increasingly used: 375 mg/m² IV weekly × 4, especially if crescents present

Maintenance (after 6-month induction): - Low-dose prednisone 5-10 mg/day - Mycophenolate mofetil 1-2 g/day or azathioprine 1-2 mg/kg/day - Continue ACE-I/ARB for proteinuria reduction

Monitoring: - Monthly labs during induction: CBC, CMP, UA with protein - Quarterly labs during maintenance - Repeat renal biopsy at 6 months if not improved - Screen for GBM antibodies if new hematuria develops

Prognosis

• Complete renal remission: 50-70% (lower than primary SLE due to ICI-continued immune dysregulation)
• Partial remission: 20-30%
• ESRD progression: 10-20%
• Lupus flare after ICI discontinuation: Rare (unlike ICI-AIN recurrence with rechallenge)

Clinical Presentation and Distinguishing Features

Typical Features: - Rapid onset AKI (days to weeks) - Heavy proteinuria (often nephrotic range) - Hematuria with dysmorphic RBCs and RBC casts (suggests glomerular origin) - Serum creatinine: Rising rapidly (>0.3 mg/dL/day) - Serologies: ANCA-NEGATIVE, ANA-negative, ANCA-PR3 and ANCA-MPO negative - Complement: Usually normal C3/C4

Why “ANCA-Negative”? - Pathologically identical to ANCA-positive vasculitis (pauci-immune crescents, no deposits) - But patient seronegative for MPO and PR3 antibodies - ICI-induced autoreactivity doesn’t target these classic ANCA antigens

When to Suspect: - Rapidly progressive AKI with dysmorphic hematuria on ICI - Serological workup shows normal complement, negative ANCA, negative ANA - Biopsy shows crescentic GN with ANCA-negative pattern

Pathology

Light Microscopy: - Necrotizing crescents: Acute necrosis of glomerular capillary wall - Fibrinoid necrosis - Crescent formation (cells filling Bowman’s space) - Segmental necrosis (not all glomeruli involved) - NO immune deposits (hence “pauci-immune”) - Interstitial inflammation, often with AIN component

Electron Microscopy: - Pauci-immune: <5% of glomerular area with electron-dense deposits - Foot process effacement variable - GBM breaks in areas of necrosis

Immunofluorescence: - Negative or trace for IgG, IgA, IgM, C3 - Negative for ANCA (classic distinction from ANCA-positive vasculitis)

Severity Grading: - Percent of glomeruli with crescents - Degree of global sclerosis (worse prognosis if >50%) - Severity of tubular atrophy

Pathogenesis

Mechanism: 1. ICI blocks PD-1 or CTLA-4 checkpoints 2. Autoreactive T cells restored (CD8+ cytotoxic T cells predominate) 3. Infiltration of kidney with necrotizing inflammatory response 4. Direct endothelial cell injury → capillary necrosis 5. Crescent formation from proliferating parietal cells in Bowman’s space

Why No Antibodies? - T-cell mediated rather than immune-complex disease - Some ICI-ANCA cases may have delayed antibody development (repeat serology in weeks helpful)

Management of ICI-Associated Pauci-Immune Crescentic GN

ICI Management: - Immediate and permanent discontinuation (do NOT rechallenge) - Risk of further crescentic progression with continued ICI exposure

Kidney Biopsy: - Mandatory to confirm diagnosis and assess severity - Percent of crescents, global sclerosis critical for prognostication - If <50% global sclerosis: Aggressive therapy warranted (good recovery potential) - If >50% global sclerosis: Prognosis poor; consider discussion of futility

Immunosuppression (Intensive — this is RPGN):

Induction (6 months): - Prednisone: 1-2 mg/kg/day (0.5-1 mg/kg/day if milder presentation) - PLUS one of the following: - Rituximab (preferred): 375 mg/m² IV weekly × 4 doses - Cyclophosphamide: 500-750 mg/m² IV monthly × 6 doses (with mesna) - IV methylprednisolone pulse (optional): 1 g daily × 3 days at initiation for severe cases

Plasma Exchange: - Consider if severe renal dysfunction (Cr >5 mg/dL) or oliguria at presentation - Not universally recommended; center-dependent - May improve outcomes in severe crescentic disease

Maintenance (year 2+): - Low-dose prednisone 5-10 mg/day - Azathioprine 1-2 mg/kg/day OR mycophenolate 1-2 g/day - Continue minimum 18-24 months

Monitoring: - Urinalysis: Track hematuria and proteinuria resolution - ANCA serologies: Recheck at weeks 4-8 (seroconversion to ANCA-positive possible but uncommon) - Renal function: Close monitoring during induction; aim for stabilization by 3-4 months - Repeat biopsy: Consider at 6 months if no improvement in function/proteinuria

Prognosis

• Complete renal remission (Cr return to baseline): 40-50%
• Partial remission (improved but not baseline Cr): 30-40%
• ESRD progression: 15-25%
• Long-term dialysis: 10-15%
• Mortality (at 2 years): 5-10% (reflects cancer outcomes, not renal disease alone)

Predictors of Poor Prognosis: - Severe renal dysfunction at presentation (Cr >3 mg/dL) - Oliguria - >50% global sclerosis on biopsy - Delayed diagnosis and treatment initiation

Clinical Presentation

Typical Features: - Nephrotic syndrome: Heavy proteinuria (often >8-10 g/day), edema, hypoalbuminemia - Serum creatinine: Usually normal at onset (preserve GFR unless severe proteinuria) - Urinalysis: Heavy proteinuria, minimal hematuria (unlike lupus or ANCA-GN) - Key serologic feature: PLA2R-negative (distinguishes from primary membranous where 70% PLA2R-positive) - ANA, ANCA negative - Thrombosis risk: Hypercoagulability from nephrotic syndrome and membranous disease

Pathology

Light Microscopy: - Thickened glomerular basement membrane - Subepithelial “spike” lesions (hematoxylin and eosin) - Stage I: GBM basement membrane thickening only - Stage II: GBM thickening + early subepithelial deposits - Stage III: GBM thickening + subepithelial deposits with GBM interposition (classic spike-and-dome)

Electron Microscopy (diagnostic): - Subepithelial electron-dense deposits (pathognomonic) - Foot process effacement - Deposits often large and numerous

Immunofluorescence: - Granular IgG + C3 along GBM (IgG more prominent than C3) - No full-house pattern (distinguishes from lupus)

Management of ICI-Associated Membranous Nephropathy

ICI Management: - Hold ICI; consider permanent discontinuation - Rechallenge very risky (recurrent nephrotic syndrome likely)

Treatment Goals: - Achieve remission of nephrotic syndrome (goal <3-4 g/day proteinuria) - Preserve renal function - Prevent thrombotic complications

Immunosuppression:

Option 1 (Preferred): Rituximab-Based - Rituximab 375 mg/m² IV weekly × 4 doses - Continue ACE-I/ARB at maximal tolerated dose - Consider low-dose prednisone (0.25-0.5 mg/kg) for first 3 months - Response rate: 50-70% achieve partial remission

Option 2: Corticosteroid-Based - Prednisone 0.5-1 mg/kg/day × 4 weeks, then taper - Plus mycophenolate mofetil 1-2 g/day × 6 months - Response rate: 40-50%

Option 3: Cyclophosphamide - Reserved for treatment-resistant cases - Cyclophosphamide 500-750 mg/m² IV monthly × 6 months with mesna

Supportive Care: - ACE-I/ARB: Essential for proteinuria reduction (target proteinuria <3 g/day) - Anticoagulation consideration: If nephrotic syndrome with Alb <2.5 g/dL, consider anticoagulation (warfarin or DOAC) to prevent thrombosis - Sodium restriction, diuretics for edema - Statin therapy if dyslipidemia

Monitoring: - Urinary protein: Quantitate monthly (24-hour or UP/Cr ratio) - Serum albumin, lipids monthly - Renal function every 3 months - Thrombosis screening: DVT/PE symptoms, consider ultrasound if high-risk features

Prognosis

• Complete remission (proteinuria <0.5 g/day): 30-40%
• Partial remission (proteinuria 0.5-3 g/day): 30-40%
• Stable disease without remission: 20%
• Progressive CKD: 10-20%
• ESRD at 5 years: 5-10% (lower than pauci-immune GN)

Clinical Presentation

Typical Features: - Hematuria (often microscopic, can be gross) - Proteinuria (usually non-nephrotic, <3 g/day) - Serum creatinine: Variable rise, mild to moderate AKI - Hypertension - Key feature: Normal complement levels (C3/C4 normal) — distinguishes from post-streptococcal GN - Negative ANCA, ANA, anti-GBM

Pathology

Light Microscopy: - Proliferative GN (endocapillary or membranoproliferative) - Variable severity; can range from mild to severe with crescents (rare) - Interstitial inflammation with AIN component common

Immunofluorescence (diagnostic): - C3-dominant staining: C3 ≥2+ with immunoglobulin staining absent or <1+ (key finding) - Distinguishes from immune-complex disease

Electron Microscopy: - Subepithelial humps (dense deposits) in some cases - But C3 predominance without significant Ig deposits - Consistent with complement-mediated injury

Pathogenesis

Mechanism: - ICI-induced dysregulation of alternative complement pathway - Loss of complement regulation (factor H, factor I) or gain-of-function mutations in complement components - C3 activation and amplification loop - Less common mechanism than T-cell mediated disease in ICI context

Management of ICI-Associated C3-GN

ICI Management: - Hold ICI; rechallenge controversial (some success reported)

Immunosuppression: - Mild disease: ACE-I/ARB + supportive care alone - Progressive disease: Prednisone 0.5 mg/kg/day × 4-8 weeks

Complement-Directed Therapy (Emerging): - Eculizumab (C5 inhibitor): 600 mg weekly × 4 weeks, then 900 mg at week 5, then 900 mg Q2 weeks - Evidence base: Case reports, limited series - May be considered if progressive C3-GN despite steroids - Cost: Very expensive ($>400,000/year)

• Pegcetacoplan (Factor B inhibitor): Newer agent targeting alternative pathway
  • IV infusion 2× weekly
  • Even more expensive; investigational in C3-GN

Standard Immunosuppression if Complement Therapy Unavailable: - Mycophenolate mofetil 1-2 g/day - Consider rituximab for severe cases - Avoid aggressive cyclophosphamide (lower efficacy in C3-GN vs. ANCA-GN)

Prognosis

• Complete remission: 50-60%
• Partial remission: 20-30%
• ESRD progression: 10-20%
• (Generally better than pauci-immune crescentic GN)

Epidemiology and Presentation

Rarity: Extremely uncommon with ICI; <2% of ICI-associated GN cases [1]

Presentation: - Hematuria + proteinuria - Mild AKI - Normal complement

Pathology: - IgA-dominant immunofluorescence on biopsy - Mesangial proliferation on light microscopy - Treated similarly to primary IgA nephropathy

Rare but Reported

Case Reports: - Lapman et al. (2020) described 3 patients who developed biopsy-proven amyloid A amyloidosis while on checkpoint inhibitors [3]

Mechanism: - Chronic systemic inflammation from persistent ICI-induced immune activation - Sustained IL-6 production drives hepatic SAA synthesis - Misfolded SAA deposits in glomeruli and vessels

Pathology: - Amyloid deposits (Congo Red positive, apple-green birefringence) - A-chain composition

Management: - Discontinue ICI - Anti-inflammatory therapy to reduce SAA: Colchicine, IL-6 inhibitors under investigation - Prognosis: Poor; amyloidosis tends to progress despite immunosuppression

Diagnostic Features Favoring Glomerular Disease

Clinical Features: - Proteinuria >3 g/day (especially if nephrotic range >3.5 g/day) - Significant hematuria (>10 RBC/hpf) or RBC casts - Preserved or minimally elevated Cr at onset (suggests glomerular primary, not AIN) - Rapid progression (Cr rising >0.3 mg/dL/day) - Systemic features: Joint pain, rash, fever (lupus-like)

Laboratory Features: - Serologies positive: ANA, ANCA, anti-GBM (if present) - Dysmorph hematuria: RBC casts, dysmorphic RBCs (vs. isomorphic RBCs in AIN)

Urinalysis Distinctions:

Treatment Approach for Mixed Lesions

If AIN >70% and glomerular component minor: - Treat primarily as AIN - Steroids 0.5-1 mg/kg/day - Add MMF if steroid-sparing indicated

If AIN and glomerular equally significant: - Higher-dose steroids: 1-2 mg/kg/day - Mandatory steroid-sparing agent: Rituximab preferred, MMF alternative

If Glomerular >70% of biopsy: - Treat as primary GN - High-dose steroids + aggressive steroid-sparing - Rituximab or cyclophosphamide based on pattern severity

Long-Term Follow-Up (Year 1+)

Frequency: - Months 1-3: Monthly renal function, urinalysis - Months 3-6: Bimonthly labs - Month 6+: Quarterly or biannual labs (depending on baseline renal function)

Assessments: - Serum creatinine and eGFR - Urinalysis (proteinuria, hematuria, casts) - Serum albumin if nephrotic disease - Repeat serologies if applicable (ANCA, ANA) at 6 and 12 months

CKD Progression: - 30-40% develop progressive CKD over 2-3 years post-GN - Younger age and early complete remission predict better outcomes - ACE-I/ARB continuation essential for renal protection