ICI Nephrotoxicity Management: Grade-Based Treatment and Rechallenge Strategies

CTCAE v5.0 (Common Terminology Criteria for Adverse Events) Grading

The standard oncology grading system for ICI-related kidney injury uses CTCAE v5.0, though KDIGO criteria provide additional clinical context:

Grade 1 (Mild): - Serum creatinine: 1.5-1.9× baseline OR >1.0-1.5 mg/dL absolute increase - Management: Monitor closely, continue ICI with caution

Grade 2 (Moderate): - Serum creatinine: 2.0-2.9× baseline OR >1.5-3.0 mg/dL absolute increase - Management: Consider ICI hold, initiate corticosteroids (0.5-1 mg/kg/day prednisone)

Grade 3 (Severe): - Serum creatinine: ≥3× baseline OR >3.0 mg/dL absolute increase - Management: Hold ICI, high-dose corticosteroids (1-2 mg/kg/day prednisone)

Grade 4 (Life-Threatening): - Acute kidney injury requiring emergency intervention (dialysis-dependent) - Management: Permanent ICI discontinuation, high-dose steroids, intensive immunosuppression

Hybrid Approach: CTCAE + KDIGO Classification

Modern guidelines recommend combining CTCAE grading for oncology communication with KDIGO staging for nephrologic precision:

Grade 1 ICI-Associated Nephrotoxicity

Definition: - Creatinine 1.5-2× baseline - Asymptomatic, no oliguria - Typically diagnosed on routine labs

Initial Management: 1. Continue ICI with intensified monitoring (labs weekly × 4 weeks, then q2 weeks) 2. Optimize baseline therapy: - Hold NSAIDs, ACE inhibitors (controversial—some recommend continuing ACE-I) - Hold diuretics unless clinically necessary - Ensure adequate hydration 3. Hold PPIs if the patient is on them (and if not contraindicated for upper GI disease) 4. Monitor for progression: If Cr stable for 4 weeks → continue ICI with monitoring

Escalation Triggers: - Creatinine rises to Grade 2 → hold ICI, initiate steroids - Symptoms develop (nausea, fatigue worsening) → escalate workup

Expected Course: - 60-70% remain stable at Grade 1 - 20-30% progress to Grade 2-3 - <10% progress to Grade 4

Grade 2 ICI-Associated Nephrotoxicity

Definition: - Creatinine 2-3× baseline (or >1.5-3 mg/dL absolute increase) - Symptomatic in some cases - Productive of AKI on urinalysis (pyuria, casts)

Initial Management:

1. Hold ICI Therapy Immediately
   • Discontinue infusion if next dose is scheduled
   • Notify oncology team of temporary hold
2. Initiate Corticosteroids:
   • Dose: Prednisone (or equivalent) 0.5-1 mg/kg/day PO
   • For severe symptomatic cases: Methylprednisolone 1 g IV daily × 3 days, then transition to PO prednisone
   • Baseline laboratory work: CBC, CMP, LFTs, TB testing (ensure not latent TB before steroids)
   • Consider PPI: Omeprazole or famotidine to reduce GI ulcer risk with high-dose steroids
3. Diagnostic Workup:
   • Urinalysis + urine microscopy
   • Assess FENa, urine osmolality, urine Na
   • Renal ultrasound if obstructive physiology suspected
   • Consider kidney biopsy: MD Anderson advocates biopsies; NCCN permits empiric steroid start
   • Infectious workup if any signs of infection
4. Supportive Care:
   • NPO status if nausea
   • Adjust medication dosing for reduced GFR (renally clear drugs)
   • Monitor fluid balance daily
   • Serial Cr measurements (daily × 3-5 days, then every 2-3 days)

Steroid Taper Schedule: - Continue full dose (0.5-1 mg/kg) for 10-14 days - Reduce by 20 mg every 5-7 days (e.g., 60 mg → 40 mg → 20 mg → 10 mg) - Minimum taper duration: 4-6 weeks total - Critical: Do NOT taper rapidly; rapid tapers increase relapse rate from 10% to 30-40%

Monitoring During Steroid Course: - Labs: Cr, BUN, electrolytes every 3 days - Weight: Daily (assess for fluid retention from steroids) - Blood glucose: Daily if diabetic (steroids worsen glycemic control) - Blood pressure: Daily (steroids increase BP)

Expected Course: - 85-90% show improvement in Cr within 10-14 days of steroid initiation - Median time to Cr plateau: 14 days - Complete Cr recovery to baseline: ~50% by 8-12 weeks - Partial recovery (Cr 1.2-1.5× baseline): ~40% - No recovery: ~10%

Progression to Grade 3 Triggers: - Cr continues rising despite steroids (>25% daily rise) - Development of oliguria - Rising potassium - → Escalate to Grade 3 management protocol

Grade 3 ICI-Associated Nephrotoxicity

Definition: - Creatinine ≥3× baseline or >3 mg/dL absolute increase - Often accompanied by oliguria or nausea/vomiting - May develop AKI-related hyperkalemia, hyperphosphatemia - High-risk for progression to dialysis-dependent AKI

Initial Management:

1. Immediate ICI Discontinuation
   • Permanent hold; no reinfusion without nephrology/oncology consensus
2. High-Dose Corticosteroids:
   • IV methylprednisolone: 1 g IV daily × 3 days
   • Transition to prednisone 1-2 mg/kg/day (60-120 mg/day typical)
   • Plus PPI coverage (omeprazole 40 mg daily) + H2 blocker if on other GI drugs
   • Baseline labs: TB testing, CBC, CMP, LFTs (glucose control critical)
3. Nephrology Consultation (Mandatory)
   • Establish baseline renal function and trajectory
   • Assess need for dialysis initiation
   • Evaluate hypertension, electrolyte abnormalities, acidosis
4. Consider Kidney Biopsy
   • Strongly recommended at Grade 3 AKI
   • Guides immunosuppression intensity
   • If crescentic GN or pauci-immune pattern on biopsy → escalate to steroid-sparing agents immediately
5. Intensive Monitoring:
   • Daily labs: Cr, BUN, electrolytes, phosphate
   • Daily weights, vital signs
   • Fluid balance sheet (careful intake/output)
   • ECG if K >5.5 mEq/L (assess for peaked T waves)

High-Dose Steroid Taper: - 1 g IV methylprednisolone daily × 3 days - Transition to prednisone 1-2 mg/kg/day (60-120 mg) for 7-14 days at full dose - Then reduce by 10 mg per week for 4-6 weeks minimum - Total minimum duration: 8-12 weeks

Steroid-Refractory ICI-AKI (Defined Below): - If no improvement in Cr after 3-5 days of high-dose IV steroids, escalate to steroid-sparing agents

Dialysis Consideration: - Initiate renal replacement therapy if: - K >6.0 mEq/L refractory to medical therapy - pH <7.2 (severe metabolic acidosis) - Fluid overload with hypoxia - Uremic symptoms (pericarditis, encephalopathy) - Modality: CRRT preferred in unstable patients, intermittent hemodialysis if stable - Duration: 50-60% of Grade 3-4 patients recover off dialysis within 4-6 weeks

Expected Outcomes: - 70-80% show Cr improvement within 7-10 days of high-dose steroids - Complete recovery: ~30% - Partial recovery: ~50% - Progression to dialysis: ~15-20% - Death from unrelated causes: ~5% (reflects advanced cancer cohort)

Grade 4 ICI-Associated Nephrotoxicity (Dialysis-Dependent AKI)

Definition: - Creatinine ≥3× baseline with oliguria or anuria - Acute kidney injury requiring emergency dialysis initiation - Life-threatening electrolyte abnormalities or volume overload

Management:

1. Permanent ICI Discontinuation
   • No rechallenge consideration at this stage
   • Document in medical record and communicate to patient/oncology
2. Intensive Renal Support:
   • Initiate dialysis immediately (CRRT preferred for hemodynamic stability)
   • Frequency: CRRT 24-48 hours daily vs. IHD every 24-48 hours based on stability
   • Goal: Normalize electrolytes, manage acidosis, control volume
3. Maximum Immunosuppression:
   • IV methylprednisolone 1 g daily × 5 days
   • Add steroid-sparing agent: MMF 1-2 g/day divided, OR rituximab 375 mg/m² weekly × 4 doses, OR cyclophosphamide 500-750 mg/m² monthly
4. Mandatory Kidney Biopsy
   • Essential to guide immunosuppression
   • Crescentic GN (especially ANCA-negative pauci-immune) requires aggressive multi-agent therapy
   • Results determine whether to escalate to cyclophosphamide + plasmapheresis
5. Multidisciplinary Team:
   • Daily rounds: Nephrology + Oncology + ICU
   • Assess for competing causes (infection, sepsis, TLS, cardiac ischemia)
   • Prognostic counseling with patient/family regarding renal recovery likelihood
6. Steroid-Sparing Agent Selection:
   • MMF (mycophenolate mofetil): 500 mg PO q6h (target 2-3 g/day) — preferred for GN, contraindicated if GI complications
   • Rituximab: 375 mg/m² IV weekly × 4 doses — excellent for crescentic GN, cost higher
   • Infliximab: 5 mg/kg IV at weeks 0, 2, 6 then q8 weeks — CAUTION: Never use with PD-L1 inhibitors (additive immunosuppression risk)
   • Azathioprine: 1-2 mg/kg/day PO — slower acting, alternative if above unavailable
   • Cyclophosphamide: 0.5-0.75 g/m² IV monthly — reserved for crescentic GN, requires prophylaxis (mesna, hydration) and monthly labs

Prognosis: - ~50% recover off dialysis within 4-12 weeks - ~30% progress to ESRD (chronic dialysis/transplant) - ~20% expire from cancer progression or other complications

Diagnostic Workup for Steroid-Refractory Cases

1. Confirm Diagnosis:
   • Review pathology if biopsy performed (ensure AIN, not misdiagnosed GN)
   • Rule out competing/additional causes: infection, TLS, TRALI, medication error
2. Assess Compliance:
   • Verify patient actually taking prescribed steroids
   • Check pharmacy records for medication fills
   • Assess GI absorption (vomiting, diarrhea)
3. Evaluate ICI Dosing/Schedule:
   • Ongoing ICI still circulating? (half-life 2-3 weeks for most agents)
   • Consider plasma exchange if urgently needed to remove circulating ICI? (Not standard, experimental)

Steroid-Sparing Agent Additions

Option 1: Mycophenolate Mofetil (MMF) - Dose: 500 mg q6h PO (target 2-3 g/day total) - Mechanism: Inosine monophosphate dehydrogenase (IMPDH) inhibitor; depletes guanine nucleotides in lymphocytes - Onset: 1-2 weeks - Efficacy in ICI-AKI: ~70% show improvement when added to steroids for steroid-refractory cases - Advantages: Oral, well-tolerated, no need for monitoring labs as intense as cyclophosphamide - Disadvantages: Diarrhea (20-30%), GI intolerance common; lower efficacy than rituximab for crescentic GN - Labs: CBC, CMP at baseline and q4 weeks (for neutropenia, kidney function)

Option 2: Rituximab - Dose: 375 mg/m² IV weekly × 4 weeks (maximum 4 doses in most protocols) - Mechanism: CD20+ B cell depletion; reduces autoantibody production and T-cell help - Onset: 2-4 weeks for full effect - Efficacy in ICI-AKI: ~80% show Cr improvement; especially effective for crescentic GN - Advantages: Single mechanism targeting B cells; well-established in AIN and GN - Disadvantages: Cost (expensive), risk of hepatitis B reactivation, infusion reactions - Contraindications: Active infection, moderate-severe immunosuppression already - Monitoring: CBC before each dose, HBsAg/HBcAb screening before therapy

Option 3: Infliximab (TNF-α Inhibitor) - Dose: 5 mg/kg IV at weeks 0, 2, 6, then every 8 weeks - Mechanism: Blocks TNF-α signaling; reduces inflammatory cytokine production - Efficacy in ICI-AKI: ~60-70% show improvement - Advantages: Reduces systemic inflammatory burden; potential synergy with steroids - Disadvantages: Significant infection risk; reactivates latent TB - CRITICAL CONTRAINDICATION: Do NOT use with PD-L1 inhibitors (atezolizumab, avelumab, durvalumab). TNF inhibitors increase PD-L1 expression and theoretically worsen PD-L1 blockade toxicity - Acceptable with: PD-1 inhibitors (nivolumab, pembrolizumab) — less contraindicated, but still caution

Option 4: Cyclophosphamide - Dose: 500-750 mg/m² IV monthly (adjust for renal function, age) - Mechanism: Alkylating agent; direct DNA cross-linking in lymphocytes - Onset: 1-2 weeks - Efficacy in ICI-AKI: ~85% show improvement; most effective for crescentic GN with necrotizing lesions - Advantages: Highest efficacy; can achieve rapid remission in severe GN - Disadvantages: Teratogenic, hemorrhagic cystitis, infertility risk, secondary malignancies; requires extensive monitoring - Monitoring: Monthly labs (CBC, CMP, UA for hematuria), mesna prophylaxis mandatory, aggressive IV hydration - Reserved for: Crescentic GN with >30% global sclerosis, or failure of MMF + rituximab

Typical Steroid-Sparing Escalation Sequence

Step 1 (Day 3-5 of high-dose steroids if no improvement): - Add MMF 500 mg q6h - Continue IV methylprednisolone or transition to PO prednisone 1 mg/kg

Step 2 (Week 1-2 if still no improvement): - Add rituximab 375 mg/m² IV weekly × 4 - Continue MMF + steroids

Step 3 (Week 3-4 if crescentic GN on biopsy with >30% fibrosis): - Transition to cyclophosphamide 500-750 mg/m² IV monthly (with mesna) - Continue rituximab + steroids

Endpoint: Cr stable or improving for 2-4 weeks → continue current regimen, then slow steroid taper

Rechallenge Candidacy: Inclusion Criteria

Appropriate for Rechallenge: 1. Grade 1-2 ICI-AKI at initial event 2. Complete or near-complete Cr recovery (Cr ≤1.2× baseline) 3. Histology (if available) shows pure AIN without extensive glomerular disease 4. ≥2 months have elapsed since ICI discontinuation 5. No steroid-refractory disease 6. Patient and oncology agree rechallenge is beneficial for cancer control

NOT Appropriate for Rechallenge: 1. Grade 3-4 ICI-AKI at initial event 2. Dialysis-dependent AKI 3. Crescentic GN or other severe glomerular pattern on biopsy 4. Steroid-refractory disease requiring multiple immunosuppressive agents 5. Recurrent AKI within 2 months of first AKI episode (suggests true ICI hypersensitivity)

Cortazar Rechallenge Data

The landmark Cortazar et al. 2020 study included 138 ICI-AKI patients, of whom 30 (22%) underwent rechallenge [1].

Key Findings: - Overall rechallenge success: 77% (23/30) had no recurrent AKI - Recurrent AKI rate: 23% (7/30) - Response to steroids in recurrent cases: 100% responded to second-course steroids (except 1 patient) - Predictors of successful rechallenge: - Pure AIN on biopsy (vs. glomerular disease) - Grade 1-2 initial AKI (vs. Grade 3) - Complete Cr recovery before rechallenge

Key Finding: Even patients with recurrent AKI responded to steroids again, suggesting that ICI-AKI is a treatable toxicity rather than true ICI hypersensitivity.

Rechallenge Strategies

Strategy 1: Same ICI at Full Dose (Most Common)

Oncology, nephrology, and patient choose to rechallenge with the original ICI (e.g., if Grade 2 AKI on nivolumab, retry nivolumab after 2+ months).

• Rationale: Proven benefit in cancer; similar AKI risk as before
• Monitoring: Weekly labs × 4 weeks, then q2 weeks × 8 weeks, then monthly if stable
• Success rate: 77% in Cortazar series
• Action if AKI recurs: Hold ICI, initiate steroids immediately (lower threshold than first time)

Strategy 2: Same ICI at Reduced Dosing Interval

Extend dosing interval (e.g., nivolumab 240 mg IV q3 weeks → q4 weeks, pembrolizumab 200 mg q3 weeks → q4-6 weeks).

• Rationale: Lower cumulative drug exposure, theoretical reduction in immune activation
• Evidence: Limited; some centers use empirically
• Efficacy for cancer: Uncertain; may reduce efficacy vs. standard dosing
• Monitoring: Same as full-dose rechallenge

Strategy 3: Switch to Alternative ICI with Same Target

If Grade 2-3 AKI on nivolumab (PD-1 inhibitor), switch to pembrolizumab (PD-1 inhibitor) or atezolizumab (PD-L1 inhibitor).

• Rationale: Different checkpoint mechanism or different drug within same class; may reduce cross-reactivity
• Evidence: Case series suggest ~50-60% avoid recurrent AKI; not prospectively studied
• Risk: Patient thought they were ICI-intolerant when they were actually drug-intolerant
• Monitoring: Intensive (weekly labs × 4 weeks)

Strategy 4: Combination Rechallenge After Grade 2 Monotherapy AKI

Patient had Grade 2 AKI on single-agent ICI, now wants combination ICI (e.g., ipilimumab + nivolumab) for better cancer control.

• Rationale: Combination offers superior efficacy in some cancers; may be worth risk
• Risk: Combination ICIs carry 8-10% nephrotoxicity risk; if patient already had AKI on single agent, risk of recurrence likely higher
• Evidence: NOT well-studied; generally NOT recommended
• Recommendation: Use single-agent rechallenge first; if tolerated, can consider future combination if needed

Rechallenge Preparation Protocol

Weeks -4 to -2 (Before Planned Rechallenge): 1. Confirm Cr at baseline (ideally ≤1.2× original baseline) 2. Verify urine sediment is benign (no WBC casts, pyuria resolved) 3. Obtain baseline labs: CBC, CMP, LFTs 4. Hold PPIs and NSAIDs 5. Verify no active infection, normal BP control

Day of Rechallenge: 1. Detailed review with patient of AKI risk (20% risk of recurrence) 2. Verify informed consent 3. Administer ICI at planned dose 4. Observe for acute hypersensitivity reaction (rare but possible)

Week 1-4 Post-Rechallenge: 1. Labs weekly: Cr, BUN, K, electrolytes 2. Urinalysis at weeks 1 and 4 3. Physician assessment: Any symptoms? Cr trending? 4. Notify patient of action plan: “If Cr rises >20%, call immediately”

Week 5-12: 1. Labs every 2 weeks 2. Assess for any irAEs (colitis, hepatitis, etc.) 3. Monthly physician reassessment

If Recurrent AKI Develops: 1. Hold ICI immediately 2. Initiate prednisone 0.5-1 mg/kg (same as first episode) 3. Consider kidney biopsy to confirm AIN recurrence 4. Permanent ICI discontinuation if Grade 3 recurrence

ICI in Transplant Recipients

Background: Kidney transplant recipients are increasingly treated with ICI for cancer, creating a unique challenge of balancing cancer control with transplant rejection risk.

Pathophysiology: - ICIs restore immune recognition of foreign antigen (cancer) but also of allograft antigen - Risk of rejection: 10-20× higher than background population - ICI-associated AKI can trigger allograft-specific immune response

Management: - Consider enhanced baseline immunosuppression (increase CNI levels, add MMF) - Intensive monitoring: Weekly labs including donor-specific antibodies (DSAs) - Consider biopsy if AKI develops to distinguish ICI-AKI from rejection vs. both - Coordination with transplant team mandatory; not for nephrologists alone

Rechallenge: Generally NOT recommended in transplant recipients unless cancer extremely aggressive and graft expendable

ICI in ESRD or Dialysis Patients

Background: Increasing numbers of dialysis patients developing cancer and receiving ICI.

Special Considerations: - Dosing adjustments: Most ICIs cleared via MPS, not renal function—standard dosing appropriate - Antibody responses: Uremia may impair immune responses; question of ICI efficacy in ESRD - Infectious risk: Already high in dialysis; ICI increases further - irAE severity: Some data suggest milder irAEs in dialysis patients (paradoxical)

ICI-AKI in ESRD: - Not truly “acute kidney injury” since already on dialysis - Manifests as acute rise in non-renal clearance drugs, need for increased dialysis - Biopsy findings (if native kidneys): same AIN pattern as non-dialysis patients - Management: Same steroid protocols apply - Prognosis for native kidney recovery: Poor if already ESRD; unlikely to recover off dialysis

ICI in CKD (Stage 3-4)

Special Consideration: Patients with baseline CKD are at higher risk for rapid functional decline with ICI-AKI.

Baseline eGFR 30-44 (CKD Stage 3b): - Baseline Cr already elevated; relative rise in AKI grading may be modest - Consider using KDIGO staging rather than CTCAE grading (more accurate for CKD baseline) - Escalate monitoring: Monthly labs even if Grade 1 changes

Baseline eGFR <30 (CKD Stage 4): - Use with caution; consider alternative therapy if available - Enhanced monitoring: Biweekly labs at minimum - ICI rechallenge: Generally NOT recommended given limited renal reserve

Chronic Kidney Disease Progression

Natural History: - 30-40% develop CKD progression 6-12 months post-ICI-AKI - 10-15% progress to ESRD within 2 years - Risk factors for progression: Older age, baseline CKD, multiagent immunosuppression needed, crescentic GN

Mechanisms of Progression: 1. Interstitial fibrosis: Prolonged inflammation and scarring from severe AIN 2. Vascular disease: Possible endothelial dysfunction from immune activation 3. Chronic glomerulonephritis: If glomerular disease component at onset 4. Recurrent AKI: Multiple episodes of ICI rechallenge-related AKI

Monitoring Recommendations Post-AKI

First Year: - Monthly Cr and eGFR assessment - Quarterly urinalysis - Annual renal ultrasound (assess for atrophy, fibrosis)

Year 1+: - Biannual Cr, eGFR, urinalysis - Annual nephrology check-in if baseline CKD - Long-term ACE inhibitor/ARB if proteinuria >0.5 g/day (renal protective)

Prognostication: - If Cr recovers to ≤1.2× baseline by 3 months: ~80% remain stable long-term - If Cr only partially recovers (1.5-2× baseline) by 3 months: ~40% progress to CKD Stage 4+ by 2 years

Proton Pump Inhibitors (PPIs) — Mandatory Cessation

Rationale: - PPIs themselves cause AIN; concurrent PPI + ICI multiplicatively increases risk - Cortazar study: PPI use was independent risk factor for ICI-AKI (OR 2.1)

Management: 1. Immediately discontinue PPI if patient develops Grade 1+ AKI on ICI 2. Assess GI indication: Is PPI truly necessary? - If GERD: Switch to H2 blocker (famotidine 20 mg q12h) or antacid - If GI prophylaxis on NSAIDs: Stop NSAIDs too (both cardiotoxic and nephrotoxic with ICI) - If history of peptic ulcer disease: Famotidine + avoid NSAIDs

3. In the future: Avoid PPIs at ICI initiation; use H2 blockers instead for GI prophylaxis

NSAIDs — Mandatory Avoidance

Rationale: - NSAIDs cause hemodynamic AKI; additive with ICI-AKI mechanism - Increased risk of both AKI and AKI severity

Management: 1. Discontinue all NSAIDs at ICI initiation (not just during AKI) 2. Pain management alternatives: - Acetaminophen (up to 3 g/day) — safe in AKI if dose-adjusted for renal function - Topical NSAIDs (diclofenac patch) — minimal systemic absorption - Opioids if needed for cancer-related pain - Physical therapy, heat therapy for musculoskeletal pain

ACE Inhibitors/ARBs — Context-Dependent

Controversy: - Traditional nephrology: ACE-I/ARB held in AKI to avoid hyperkalemia and overcorrection - Modern onconephrology: Some argue continuing ACE-I/ARB despite mild AKI provides renal protection

Current Recommendations: - Hold ACE-I/ARB temporarily if: - AKI Grade ≥2 (Cr >2× baseline) - Potassium >5.0 mEq/L - Systolic BP <90 mmHg

• Can continue ACE-I/ARB cautiously if:
  • Grade 1 AKI only
  • Potassium normal
  • Adequate BP
  • Monitor closely; resume if AKI plateaus/improves
• Definitely continue ACE-I/ARB if:
  • Baseline proteinuria >0.5 g/day
  • Baseline CKD requiring renal protection
  • After AKI recovery (restore for chronic renal protection)

Diuretics

Hold all diuretics during active ICI-AKI (pre-renal component should be minimized). Reassess after AKI resolves and Cr stabilizes.