# ICI Nephrotoxicity Management: Grade-Based Treatment and Rechallenge Strategies

## Overview: Multidisciplinary Management of ICI-Associated Nephrotoxicity

The management of ICI-associated kidney injury (ICI-AKI) is fundamentally different from other drug-induced nephrotoxicities. Unlike traditional nephrotoxins where avoidance is the primary strategy, ICI-AKI often improves with immunosuppression—specifically corticosteroids—and successful rechallenge with the offending ICI is possible in select cases. This creates a unique management tension between treating life-threatening cancer and preserving kidney function \[1\].

The standard of care requires collaboration among oncology, nephrology, and pathology. Major centers like MD Anderson Cancer Center have developed algorithmic approaches to ICI-AKI grading and management that balance efficacy of cancer therapy with nephroprotection.

Key Point ICI-AKI is NOT a contraindication to continued ICI therapy. Rather, it is a toxicity that can be managed with immunosuppression, monitoring, and in select cases, careful ICI rechallenge. The goal is renal recovery + cancer control, not automatic permanent ICI discontinuation.

------------------------------------------------------------------------

## ASCO/NCCN Immune-Related Adverse Event Grading System for Nephrotoxicity

### 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:

| **CTCAE Grade** | **Creatinine Change** | **KDIGO Stage** | **Urine Output** |
|----|----|----|----|
| Grade 1 | 1.5-2× baseline | Stage 1 | \>0.5 mL/kg/hr |
| Grade 2 | 2-3× baseline | Stage 2 | 0.5-1 mL/kg/hr |
| Grade 3 | ≥3× baseline | Stage 3 | \<0.5 mL/kg/hr or \<0.3 mL/kg/hr |
| Grade 4 | Dialysis-dependent | Stage 3 (dialysis) | Anuric |

High-Yield Board Point NCCN and ASCO differ on Grade 3-4 ICI rechallenge: ASCO recommends permanent discontinuation, while NCCN permits rechallenge with appropriate monitoring. MD Anderson and most major academic centers follow NCCN’s more nuanced approach.

------------------------------------------------------------------------

## Grade-Based Management Algorithm

### 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

------------------------------------------------------------------------

## Steroid-Refractory ICI-Associated Nephrotoxicity

**Definition:** No improvement in serum creatinine or worsening Cr despite ≥3-5 days of high-dose corticosteroids (IV methylprednisolone 1 g daily or equivalent).

### 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

Clinical Pearl The “sweet spot” for steroid-sparing addition is day 3-5 of high-dose steroids. Waiting \>7-10 days delays needed immune control; adding too early (day 1-2) prevents identifying true steroid responders who improve dramatically with steroids alone.

------------------------------------------------------------------------

## ICI Rechallenge: When and How

One of the most important management decisions is whether to rechallenge a patient with ICI after resolution of ICI-associated nephrotoxicity. Unlike drug-induced liver injury, where rechallenge is contraindicated, ICI-AKI can often be successfully rechallenged.

### 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

High-Yield Board Point Successful rechallenge after Grade 2 ICI-AKI occurs in ~77% of cases (Cortazar), demonstrating that ICI-AKI is NOT a permanent contraindication to ICI therapy. However, each rechallenge carries significant recurrence risk and requires careful shared decision-making with patient and oncologist.

------------------------------------------------------------------------

## Special Populations and Considerations

### 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

------------------------------------------------------------------------

## Long-Term Renal Outcomes After ICI-AKI

### 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

------------------------------------------------------------------------

## Management of Concomitant Nephrotoxins

### 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

1.  **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.

------------------------------------------------------------------------

## Related Obsidian Vault Resources

- AKI Hub — KDIGO staging, management of prerenal vs. intrinsic AKI
- AIN Hub — detailed treatment of non-ICI-related AIN
- Glomerulonephritis Hub — ANCA vasculitis, lupus nephritis management
- ICI Fundamentals: Mechanisms & Targets
- ICI Kidney Injury: Diagnosis & Pathology
- ICI-Associated Glomerular Diseases

------------------------------------------------------------------------

## Related Resources: Onconephrology Files

- ICI Fundamentals: Mechanisms and Targets
- ICI Kidney Injury: Diagnosis and Pathology
- ICI-Associated Glomerular Diseases

------------------------------------------------------------------------

## References

\[1\] Cortazar FB, Marrone KA, Troxell ML, et al. Clinicopathological features of kidney injury associated with immune checkpoint inhibitors. *Kidney Int*. 2020;98(2):326-339. doi:10.1016/j.kint.2020.01.035. [PMID: 31896554](https://pubmed.ncbi.nlm.nih.gov/31896554/) (corrected — the original Cortazar 2020 ICI multicenter paper is in *J Am Soc Nephrol* 2020;31(3):435-446, doi:10.1681/ASN.2019070676 — not Kidney Int as cited above).

\[2\] Herrmann SM, Perazella MA. Diagnosis and management of immune checkpoint inhibitor-associated acute kidney injury. *Kidney Int*. 2025;107(1):21-32. doi:10.1016/j.kint.2024.09.017. PMID: 39455026.

\[3\] National Comprehensive Cancer Network. Management of Immunotherapy-Related Toxicities. NCCN Clinical Practice Guidelines in Oncology. [Official guideline (current version; registration may be required)](https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf). Published guideline counterpart: Thompson JA, Schneider BJ, Brahmer J, et al. Management of Immunotherapy-Related Toxicities, Version 1.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(4):387. [PubMed](https://pubmed.ncbi.nlm.nih.gov/35390769/)

\[4\] Schneider BJ, Naidoo J, Santomasso BD, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. *J Clin Oncol*. 2021;39(36):4073-4126. [DOI](https://doi.org/10.1200/JCO.21.01440) \| [PubMed](https://pubmed.ncbi.nlm.nih.gov/34724392/) .

\[5\] Perazella MA, Shirali AC. Immune checkpoint inhibitor nephrotoxicity: what do we know and what should we do? *Kidney Int*. 2020;97(1):62-74. doi:10.1016/j.kint.2019.07.022. [PMID: 31685311](https://pubmed.ncbi.nlm.nih.gov/31685311/).

\[6\] Kitchlu A, Jhaveri KD, Wadhwani S, et al. A systematic review of immune checkpoint inhibitor-associated glomerular disease. *Kidney Int Rep*. 2021;6(2):309-323. doi:10.1016/j.ekir.2020.11.010. PMID: 33426386.

\[7\] Wanchoo R, Karam S, Uppal NN, et al. Adverse renal effects of immune checkpoint inhibitors: a narrative review. *Am J Nephrol*. 2017;45(2):160-169. doi:10.1159/000455014. PMID: 28076863.

------------------------------------------------------------------------

*Document created: 2026-02-28 \| Last updated: 2026-02-28 \| Category: Clinical Medicine / Onconephrology*


---

[Website version](https://urinenephrology.org/mastery/onconephrology/ici-nephrotoxicity-treatment-md-anderson-review.html) · Markdown synchronized October 3, 2026.