Checkpoint inhibitors (pembrolizumab · nivolumab · ipilimumab)
Immune checkpoint inhibitor
Acute interstitial nephritis with long latency.
AIN
ModerateOpen →
CTLA-4 checkpoint inhibitor
Ipilimumab
Yervoy · Ipi
The first-approved CTLA-4 blocker whose kidney signature is immune-mediated acute interstitial nephritis, classically granulomatous, with markedly higher AKI risk when combined with nivolumab.
SevereCTLA-4 checkpoint inhibitor · approved 2011
Unresectable or metastatic melanoma (monotherapy and with nivolumab)Adjuvant treatment of resected stage III melanomaAdvanced renal cell carcinoma (with nivolumab)Metastatic colorectal cancer that is MSI-H/dMMR (with nivolumab)Unresectable malignant pleural mesothelioma (with nivolumab)Metastatic non-small cell lung cancer (with nivolumab +/- chemotherapy)Hepatocellular carcinoma (with nivolumab)Esophageal squamous cell carcinoma (with nivolumab)
Signature kidney injury
Acute Interstitial Nephritis
Representative incidence2%
Clinically significant kidney injury from ipilimumab monotherapy is uncommon; renal immune-related adverse events are reported in roughly 1-2% of patients on single-agent checkpoint blockade. The dominant driver of elevated incidence is combination therapy: in real-world ICI cohorts any-cause AKI reaches about 16-17%, but only a minority is true immune-mediated nephritis. The combination of ipilimumab plus nivolumab carries a substantially higher and more severe AKI risk than either single agent. In a pooled analysis of biopsy-proven ICI-related acute tubulointerstitial nephritis, all patients on dual ICI blockade developed stage 3 AKI versus about half on a single agent, and complete renal recovery was less likely with dual blockade.
Source: Single-center cohort: 16.5% (51/309) developed AKI, ~2% biopsy/clinically attributed to ICI nephritis (Meraz-Munoz et al., J Immunother Cancer 2020, PMID 32601079); dual-blockade severity from pooled biopsy analysis (Esposito et al., Front Oncol 2023, PMID 37936605).
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
0%incidence
SeveritySevere
ReversibilityPartially reversible
Evidence0 refs
Nephron map
Glomerulus
Vasculature / Endothelium
Distal Tubule / Collecting Duct
InterstitiumSupporting tissue around the tubules
Acute Interstitial Nephritis
Immune-mediated inflammation of the renal interstitium — the signature kidney injury of checkpoint inhibitors.
Mechanism of kidney injury
The signature lesion is immune-mediated acute (tubulo)interstitial nephritis. CTLA-4 blockade removes a checkpoint on T-cell tolerance, and loss of peripheral tolerance is thought to drive an activated, cytotoxic T-cell infiltrate of the interstitium; biopsies show lymphocytic tubulointerstitial inflammation, frequently with granulomatous features and occasionally vasculitis or thrombotic microangiopathy-like changes. A proposed mechanism is reactivation of drug-specific (e.g., PPI, NSAID) memory T cells once the checkpoint brake is lifted. Less commonly, checkpoint blockade is associated with de novo or relapsing glomerular disease (minimal change disease, membranous nephropathy, pauci-immune/ANCA-type and anti-GBM disease have been reported) and rare thrombotic microangiopathy. Combination with nivolumab amplifies the immune activation and is associated with more frequent and more severe kidney injury. Much AKI in these patients is nonetheless prerenal/hemodynamic rather than drug-immune.
Clinical presentation
Usually a subacute, often asymptomatic rise in serum creatinine found on routine labs. Urinalysis may show sterile pyuria, low-grade eosinophiluria, and subnephrotic proteinuria; bland sediment is also common. Overt oliguria is unusual but severe, dialysis-requiring AKI occurs, particularly with combination therapy. A concurrent or preceding extrarenal immune-related adverse event (rash, colitis, hepatitis, thyroiditis, hypophysitis) is a key diagnostic clue and was present before AKI onset in a large share of biopsy series. Glomerular involvement may present with nephrotic-range proteinuria, edema, or hematuria.
Anticancer mechanism
Ipilimumab is a fully human IgG1 monoclonal antibody against cytotoxic T-lymphocyte antigen 4 (CTLA-4), an inhibitory receptor upregulated on activated T cells and constitutively expressed on regulatory T cells. By blocking CTLA-4 engagement of its B7 ligands (CD80/CD86) on antigen-presenting cells, ipilimumab removes an early "checkpoint" brake on T-cell priming in lymph nodes, amplifying antitumor T-cell activation and proliferation and depleting intratumoral regulatory T cells. It was the first immune checkpoint inhibitor to gain FDA approval (2011, advanced melanoma) and is most often used today combined with the PD-1 inhibitor nivolumab.
Management
For immune-mediated nephritis: hold ipilimumab (and nivolumab), exclude prerenal and obstructive causes, and consider kidney biopsy when the diagnosis or lesion is unclear, since management hinges on distinguishing immune nephritis from prerenal AKI. Grade 2-3 nephritis is treated with corticosteroids (e.g., prednisone 0.5-1 mg/kg/day, higher for severe/grade 4) with a slow taper, and discontinuation of offending co-medications (PPIs/NSAIDs). Steroid-refractory cases may need additional immunosuppression. Permanently discontinue for grade 3-4 or recurrent immune-mediated nephritis; cautious rechallenge after resolved low-grade AIN has been done but AKI recurs in a substantial minority (~40% in pooled data). Prerenal AKI is managed with volume optimization and removal of contributing agents, not steroids.Lesion-level management framework
Risk factors
- Combination ipilimumab + nivolumab therapy (strongest risk for incidence and severity)
- Concurrent or prior extrarenal immune-related adverse events
- Pre-existing hypertension
- Concomitant nephritis-associated drugs (PPIs, NSAIDs, antibiotics)
- RAAS inhibitor or diuretic use (predisposes to prerenal AKI)
- Pre-existing chronic kidney disease
- Higher cumulative checkpoint-inhibitor exposure
Prevention
- Baseline and periodic serum creatinine/eGFR and urinalysis throughout therapy
- Review and minimize concomitant AIN-associated drugs (PPIs, NSAIDs) before and during treatment
- Maintain euvolemia; reassess RAAS inhibitors and diuretics
- Heightened renal surveillance when ipilimumab is combined with nivolumab
- Early nephrology referral and low threshold for kidney biopsy when AKI develops
- Hold drug and evaluate before attributing AKI to a benign cause
Note · Ipilimumab monotherapy rarely causes clinically significant kidney injury; the renal story is dominated by combination ipilimumab/nivolumab, where AKI is both more frequent and more severe. The signature lesion is granulomatous-leaning acute interstitial nephritis, distinguishing it somewhat from the more purely lymphocytic AIN of PD-1 monotherapy. This profile reasons from ICI-class biopsy series and cohorts that pool CTLA-4 with PD-1/PD-L1 agents; truly ipilimumab-monotherapy-specific renal incidence figures are limited. Educational reference, not medical advice.
Clinical depth
Renal dose adjustment
No pharmacokinetic dose adjustment for renal impairment. Ipilimumab is dosed by body weight (e.g., 3 mg/kg in melanoma monotherapy; 1 mg/kg every 3 or 6 weeks in nivolumab combinations) and, as a ~150 kDa IgG1 antibody, is cleared by reticuloendothelial proteolysis rather than the kidney, so mild-to-moderate renal impairment does not meaningfully alter exposure. Data in severe impairment and dialysis are limited. Dose modification is event-driven: hold for grade 2-3 nephritis and permanently discontinue for grade 3-4 or recurrent immune-mediated nephritis.
Dialyzability & ESKD dosing
Not dialyzable. Large IgG1 monoclonal antibodies are not removed by hemodialysis or peritoneal dialysis; dosing timing relative to dialysis is irrelevant. Dialysis is used to support patients with severe ICI-AKI, not to clear the drug.
Differential diagnosis
Distinguish true immune-mediated interstitial nephritis from the more common prerenal/hemodynamic AKI (volume depletion, sepsis, contrast, cardiorenal). Other considerations: concomitant PPI/NSAID/antibiotic-induced AIN (which checkpoint blockade may unmask), tumor-related obstruction, hypercalcemia, tumor lysis, and checkpoint-associated glomerular disease (minimal change, membranous, pauci-immune/anti-GBM) or thrombotic microangiopathy. Concurrent extrarenal immune-related adverse events, sterile pyuria, and granulomatous features on biopsy favor ICI nephritis; bland sediment with a clear hemodynamic trigger favors prerenal. Kidney biopsy is the reference standard when the distinction changes management (steroids vs supportive care).
Monitoring
- Serum creatinine/eGFR at baseline and before each cycle
- Urinalysis for proteinuria, pyuria, eosinophiluria, and hematuria
- Surveillance for concurrent immune-related adverse events (skin, GI, hepatic, thyroid, pituitary)
- Quantify proteinuria (urine protein:creatinine ratio) if glomerular involvement suspected
- Electrolytes including potassium and magnesium
- Trend creatinine after any drug hold or steroid course to confirm recovery
Key trials & series
- CheckMate 067 (NCT01844505): phase 3 nivolumab + ipilimumab vs nivolumab vs ipilimumab in advanced melanoma; established the combination but with markedly higher grade 3-4 immune-related toxicity
- CheckMate 214 (NCT02231749): nivolumab + ipilimumab vs sunitinib in advanced renal cell carcinoma
- CheckMate 9LA / CheckMate 743: ipilimumab + nivolumab combinations in NSCLC and pleural mesothelioma
Clinical pearls
- Ipilimumab monotherapy rarely hurts the kidney; the renal risk surges when it is paired with nivolumab - dual blockade drives both higher incidence and more stage 3/dialysis-requiring AKI.
- The CTLA-4 nephritis lesion leans granulomatous, a histologic tilt distinct from the more purely lymphocytic AIN of PD-1 monotherapy.
- ICI nephritis is a delayed, slow-burn diagnosis (median ~3 months) - it does not behave like classic days-after-drug allergic AIN.
- An extrarenal immune-related adverse event (rash, colitis, hepatitis, thyroiditis) often precedes the creatinine rise - treat it as a renal early-warning sign.
- Co-prescribed PPIs and NSAIDs are frequent cofactors; checkpoint blockade can unmask T-cell reactivity to them, so review and stop them when nephritis is suspected.
- Most AKI on these agents is still prerenal/hemodynamic, not drug-immune - reserve high-dose steroids for genuine immune nephritis and consider biopsy when uncertain.
Beyond the kidney — non-renal toxicities· 5 organ systems
Class-level context for the major non-renal toxicities of ctla-4 checkpoint inhibitors.
Endocrine
Thyroiditis, hypophysitis, diabetes
- Thyroiditis, hypophysitis, type-1 diabetes
Gastrointestinal
Diarrhea, colitis, mucositis, perforation
- Immune colitis
Hepatic / Liver
Transaminitis, hepatitis, VOD/SOS
- Immune hepatitis
Pulmonary
Pneumonitis, ILD, effusions, hypertension
- Pneumonitis
Dermatologic
Rash, HFS, SJS/TEN, vitiligo
- Rash, vitiligo, rarely SJS/TEN
Evidence
8 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkClinicopathological features of acute kidney injury associated with immune checkpoint inhibitors.Cortazar FB, Marrone KA, Troxell ML, et al. · Kidney International 2016 · PMID 27282937Landmark multicenter biopsy series of 13 CPI-induced AKI cases (including ipilimumab and combinations); defined acute tubulointerstitial nephritis as the prevalent lesion, with granulomatous features in some and one TMA, a long ~91-day latency, and steroid responsiveness.PMIDAcute kidney injury associated with immune checkpoint inhibitor therapy: incidence, risk factors and outcomes.Meraz-Munoz A, Amir E, Ng P, et al. · Journal for ImmunoTherapy of Cancer 2020 · PMID 32601079Cohort of 309 ICI patients (including ipilimumab/nivolumab) anchoring the incidence figures: 16.5% developed AKI but only ~2% had biopsy/clinically attributed ICI nephritis; identified concurrent irAE and hypertension as independent risk factors.PMIDBiopsy-proven acute tubulointerstitial nephritis in patients treated with immune checkpoint inhibitors: a pooled analysis of case reports.Esposito P, Bottini A, Lecini E, et al. · Frontiers in Oncology 2023 · PMID 37936605Pooled analysis of 85 biopsy-proven ICI-ATIN cases quantifying the dual-blockade danger: all dual-ICI patients developed stage 3 AKI vs ~half on single agents, with lower complete recovery and ~40% AKI recurrence on rechallenge.PMIDHistological diagnosis of immune checkpoint inhibitor induced acute renal injury in patients with metastatic melanoma: a retrospective case series report.Hultin S, Nahar K, Menzies AM, et al. · BMC Nephrology 2020 · PMID 32894101Melanoma-specific renal irAE series (n=23, mostly combination ipilimumab/nivolumab); median onset 4 months, acute tubulointerstitial nephritis in 92%, one anti-GBM case, and documented persisting renal dysfunction at 12 months.PMIDSevere Acute Kidney Injury Due to Nivolumab/Ipilimumab-induced Granulomatosis and Fibrinoid Vascular Necrosis.Person F, Chahoud-Schriefer T, Fehrle W, et al. · Journal of Immunotherapy 2020 · PMID 31567702Case report of fulminant dialysis-requiring AKI on combination ipilimumab/nivolumab with biopsy showing granulomatous interstitial nephritis, vasculitis, and TMA-like lesions - illustrating the granulomatous and vascular end of the spectrum.PMIDNephrotic syndrome with acute kidney injury due to combination therapy of immune checkpoint inhibitors: a case report and review of the literature.Saiki R, Katayama K, Saiki H, et al. · BMC Nephrology 2024 · PMID 38336610Case plus literature review documenting the rarer glomerular phenotype - minimal change disease/nephrotic syndrome with concurrent AIN after combination nivolumab + ipilimumab, supporting glomerular injury as part of the profile.PMIDSevere acute interstitial nephritis after combination immune-checkpoint inhibitor therapy for metastatic melanoma.Murakami N, Borges TJ, Yamashita M, Riella LV. · Clinical Kidney Journal 2016 · PMID 27274826Detailed case of severe AIN after only two doses of nivolumab + ipilimumab with rash, showing highly proliferative cytotoxic T-cell features - supports the early-onset, T-cell-mediated mechanism with combination therapy.PMIDAcute Kidney Injury Induced by Immune Checkpoint Inhibitors.Tian R, Liang J, Li R, Zhou X. · Kidney Diseases (Basel) 2022 · PMID 35702709Review of ICI-AKI (naming ipilimumab) summarizing acute interstitial nephritis as the most frequent renal complication, mechanisms of toxicity, and KDIGO-aligned management with drug withdrawal and glucocorticoids.
Guidelines & consensus· 19
ASONDiagnosis and management of immune checkpoint inhibitor-associated nephrotoxicity: a position statement from the American Society of Onco-nephrologyKidney Int 2025 · PMID 39455026ICI-AKI most commonly presents as acute interstitial nephritis; nephrology consultation and kidney biopsy should be considered for stage 2 or higher AKI or suspected glomerular disease, but where biopsy is not feasible, prompt empiric corticosteroids (prednisone ~1 mg/kg/day) should be started for clinically suspected ICI-AKI since early steroids improve renal recovery, with cautious individualized consideration of ICI rechallenge after recovery.ASCOManagement of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline UpdateJ Clin Oncol 2021 · PMID 34724392For grade 2 or higher ICI-related nephritis/AKI, hold the ICI, exclude alternative causes, and initiate corticosteroids (prednisone 0.5-1 mg/kg/day for grade 2, 1-2 mg/kg/day for grade 3-4) tapered over 4-6 weeks once creatinine improves; permanently discontinue for grade 4 toxicity.ESMOManagement of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-upAnn Oncol 2022 · PMID 36270461For ICI-related AKI, exclude alternative etiologies and stop concomitant nephrotoxins (PPIs, NSAIDs); ESMO permits continuing the ICI for stage 1 AKI with monitoring, but recommends withholding the ICI and starting corticosteroids for stage 2 or higher nephritis, escalating immunosuppression for steroid-refractory disease.SITCSociety for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse eventsJ Immunother Cancer 2021 · PMID 34172516Grade ICI-related AKI by CTCAE; for persistent grade 2 or higher renal toxicity, discontinue the ICI, exclude other causes, and treat with corticosteroids with a taper begun once creatinine improves toward grade 1, considering kidney biopsy and additional immunosuppression for refractory cases.ASCOManagement of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice GuidelineJ Clin Oncol 2018 · PMID 29442540Withhold the checkpoint inhibitor and start corticosteroids for grade 2 or higher immune-related renal toxicity after excluding other causes of AKI, with steroid taper as renal function recovers and permanent discontinuation for severe (grade 4) events.ASCOManagement of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T-Cell Therapy: ASCO GuidelineJ Clin Oncol 2021 · PMID 34724386Grade toxicities by ASTCT criteria; manage CRS with supportive care escalating to tocilizumab with or without corticosteroids, and manage moderate-to-severe ICANS with corticosteroids and supportive care given potential for rapid decline.Peking Union Medical College Hospital expert panelClinical recommendations on diagnosis and treatment of immune checkpoint inhibitor-induced renal immune-related adverse eventsThorac Cancer 2020 · PMID 32232975Screen and monitor with serum creatinine, urinalysis/sediment, and 24-hour urine protein; strongly recommend kidney biopsy to confirm ICI-related ATIN and exclude other AKI causes, withdraw nephrotoxins (PPIs, NSAIDs), and initiate corticosteroids when a grade 2 or higher renal irAE is highly suspected, with multidisciplinary decisions on ICI withdrawal and rechallenge.
General onco-nephrology references
Acute Disease Quality InitiativeThe nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupNat Rev Nephrol 2026 · PMID 41361704Provides expert-based statements (modified Delphi) on preventing and managing cisplatin/platinum-associated AKI, including isotonic IV hydration, attention to volume status and concomitant nephrotoxins, and incorporates evidence that IV magnesium supplementation may reduce cisplatin-associated AKI; emphasizes risk stratification and standardized AKI definitions.SIRMSIRM-SIN-AIOM: appropriateness criteria for evaluation and prevention of renal damage in the patient undergoing contrast medium examinations-consensus statements from Italian College of Radiology (SIRM), Italian College of Nephrology (SIN) and Italian Association of Medical Oncology (AIOM)Radiol Med 2022 · PMID 35303246Recommends eGFR-based renal risk assessment and pre/post-contrast isotonic saline or sodium bicarbonate hydration; advises maintaining a 5-7 day interval between iodinated contrast administration and cisplatin in cancer patients to reduce additive nephrotoxicity.KDIGOKDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerKidney Int 2020 · PMID 33126977Identifies platinum compounds (especially cisplatin) as leading cytotoxic causes of acute tubular injury, AKI, and electrolyte/magnesium wasting; calls for interdisciplinary onco-nephrology care, accurate GFR estimation, and individualized drug dosing in patients with reduced kidney function.KDIGOKDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationKidney Int 2020 · PMID 33276867Addresses chemotherapy-associated AKI/CKD in hematologic cancer, GFR estimation and chemotherapy dosing in patients with reduced kidney function, and management priorities and research gaps for onco-nephrology care.Cancer Institute NSWIntegrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceEClinicalMedicine 2025 · PMID 40290844Provides GRADE-based, drug-specific dose-adjustment recommendations for anticancer agents in kidney dysfunction (illustrated for methotrexate, cisplatin, carboplatin and nivolumab); the recommendations build on Part 1's standardised CKD-EPI eGFR assessment rather than Cockcroft-Gault creatinine clearance.Cancer Institute NSWAligning kidney function assessment in patients with cancer to global practices in internal medicineEClinicalMedicine 2025 · PMID 40290845Three consensus recommendations: assess kidney function by GFR (measured GFR or CKD-EPI eGFR), classify it using KDIGO categories, and use this uniform approach to dose anticancer drugs — moving cancer medicine away from Cockcroft-Gault estimated creatinine clearance.Cancer Institute NSWA methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEClinicalMedicine 2025 · PMID 40290846Establishes that, where RCT evidence is lacking, anticancer drug dosing recommendations in kidney dysfunction should be derived by critically appraising observational literature via GRADE combined with structured international multidisciplinary consensus voting.KDIGODiagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Crit Care 2013 · PMID 23394211Defines/stages AKI by serum creatinine and urine output; emphasizes avoiding nephrotoxins, maintaining euvolemia/perfusion, dose-adjusting drugs to kidney function, and monitoring high-risk patients — the framework applied to nephrotoxic anti-cancer agents.KDIGOExecutive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesKidney Int 2021 · PMID 34556300Provides the staging/treatment framework for drug-associated glomerular lesions (e.g., bisphosphonate- and interferon-related collapsing FSGS, VEGF-inhibitor podocytopathy/proteinuria), including immunosuppression and supportive RAAS-blockade strategies.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisKidney Int 2024 · PMID 38388147Updates immunosuppressive induction (rituximab/cyclophosphamide), incorporates avacopan and lower-dose or glucocorticoid-sparing regimens — the management framework for drug- and checkpoint-inhibitor-associated ANCA/pauci-immune glomerulonephritis.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisKidney Int 2024 · PMID 38182299Updates first-line lupus nephritis therapy to combination immunosuppression with the addition of belimumab or a calcineurin inhibitor (voclosporin) — informs management of immune-complex/lupus-like glomerulonephritis encountered with immunotherapy.KDIGOExecutive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Kidney Int 2025 · PMID 40975525Encourages liberal kidney biopsy and stricter proteinuria control (<0.5 g/d, ideally <0.3 g/d) with RAAS blockers, SGLT2 inhibitors, and targeted-release budesonide — the framework for IgA-dominant glomerular lesions, including those triggered by immune-modulating cancer therapy.