Checkpoint inhibitors (pembrolizumab · nivolumab · ipilimumab)
Immune checkpoint inhibitor
Acute interstitial nephritis with long latency.
AIN
ModerateOpen →
PD-1 checkpoint inhibitor
Pembrolizumab
Keytruda · Pembro
The archetypal checkpoint-inhibitor kidney injury: a delayed, often PPI-associated acute interstitial nephritis that usually responds to drug withdrawal and steroids.
ModeratePD-1 checkpoint inhibitor · approved 2014
MelanomaNon-small cell lung cancerRenal cell carcinomaHead and neck squamous cell carcinomaUrothelial carcinomaMSI-high / dMMR solid tumorsHodgkin lymphomaTriple-negative breast cancer
Signature kidney injury
Acute Interstitial Nephritis
Representative incidence3.6%
In real-world cohorts of patients receiving immune checkpoint inhibitors, any AKI is common (roughly 16-18%), but AKI attributable to the checkpoint inhibitor itself (ICPi-AKI) is less frequent. A single-center cohort reported AKI in 16.5% of ICI-treated patients with checkpoint-attributable nephrotoxicity in a minority, while a larger real-world study found ICPi-AKI in about 3.6%. Acute interstitial nephritis is the dominant biopsy lesion (>80% in the largest multicenter series). These figures are pooled across PD-1/PD-L1/CTLA-4 agents rather than pembrolizumab-specific.
Source: Lumlertgul, Eur J Cancer 2023
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
0%incidence
SeverityModerate
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
ICI-AKI is thought to be an off-target, T-cell-mediated immune reaction within the kidney rather than direct tubular toxicity. Loss of PD-1-mediated peripheral tolerance is thought to permit reactivation of drug-specific effector T cells (for example, against PPIs, NSAIDs, or antibiotics acting as haptens), producing acute interstitial nephritis with a lymphohistiocytic interstitial infiltrate. Less commonly, the same dysregulated immunity is reported to drive podocytopathy (minimal change disease), other glomerular lesions, thrombotic microangiopathy, or tubular dysfunction manifesting as distal renal tubular acidosis with hypokalemic non-anion-gap metabolic acidosis.
Clinical presentation
Typically a subacute, asymptomatic rise in serum creatinine detected on routine labs. Urinalysis is often bland or shows modest sterile pyuria and subnephrotic proteinuria; eosinophiluria is neither sensitive nor specific. Concurrent extrarenal immune-related adverse events (rash, colitis, thyroiditis, hepatitis) are common clues. Glomerular variants (minimal change disease) can present with abrupt edema, weight gain, and nephrotic-range proteinuria. Renal tubular acidosis variants present with hypokalemia and a non-anion-gap metabolic acidosis.
Anticancer mechanism
Humanized IgG4 monoclonal antibody against PD-1 that blocks the PD-1/PD-L1 inhibitory axis, releasing the brakes on T cells and restoring antitumor immunity. The same loss of peripheral tolerance that drives efficacy also underlies its immune-related adverse events, including the kidney.
Management
Hold pembrolizumab and evaluate for and remove competing AIN culprits (PPIs, NSAIDs). Kidney biopsy is often used to confirm the lesion and exclude alternative causes. Corticosteroids are the mainstay for moderate-to-severe ICPi-AKI; in the largest cohort, corticosteroid treatment - and earlier initiation (within 3 days) - was associated with higher odds of renal recovery. About two-thirds of patients recover kidney function. Rechallenge can be considered after recovery but carries a recurrent-AKI risk (~16% in cohort data); decisions should weigh oncologic need against renal risk. Electrolyte/RTA variants require alkali and potassium repletion alongside steroids.Lesion-level management framework
Risk factors
- Concurrent proton pump inhibitor use
- Lower baseline eGFR / pre-existing CKD
- Other (extrarenal) immune-related adverse events
- Concomitant NSAIDs or antibiotics (potential hapten triggers)
- Combination checkpoint blockade (e.g., added CTLA-4 inhibitor)
Prevention
- Review and discontinue non-essential PPIs and other AIN-associated drugs before/during therapy
- Baseline and periodic serum creatinine and electrolyte monitoring
- Early nephrology referral and low threshold for kidney biopsy when AKI develops
- Track and act on extrarenal irAEs as potential heralds
Note · Most quantitative incidence and outcome data come from pooled ICI cohorts (PD-1/PD-L1/CTLA-4), not pembrolizumab-only series; the qualitative lesion spectrum (AIN-dominant, with glomerular and tubular variants) is well supported for pembrolizumab specifically via biopsy-proven case reports. Educational content, not medical advice.
Clinical depth
Renal dose adjustment
No pharmacokinetic renal dose adjustment is required - pembrolizumab is a monoclonal antibody cleared by catabolism, not renal excretion, and no adjustment is needed across the spectrum of renal impairment. Management is immunologic (hold drug, grade the irAE, treat) rather than dose-based: per standard irAE grading, grade 2 nephritis prompts holding the drug and corticosteroids, and grade 3-4 prompts permanent discontinuation.
Dialyzability & ESKD dosing
Not dialyzable - as a ~149 kDa IgG4 monoclonal antibody it is not removed by hemodialysis. Patients on dialysis can receive pembrolizumab without dose change; dialysis does not mitigate the immune-mediated nephritis.
Differential diagnosis
Distinguish ICI-attributable AIN from prerenal azotemia, contrast- or chemotherapy-associated ATN, obstruction, and AIN from concurrent drugs (PPIs, NSAIDs, antibiotics) - these often coexist. Bland urinalysis with a slow creatinine rise and concurrent extrarenal irAEs favors ICI-AIN; abrupt nephrotic syndrome suggests a glomerular (minimal-change) variant; non-anion-gap hypokalemic acidosis suggests distal RTA. Kidney biopsy is frequently needed because clinical features are nonspecific. Pseudo-AKI (a creatinine rise from another mechanism, not true injury) should be considered before attributing every rise to the drug.
Monitoring
- Serum creatinine/eGFR before each cycle
- Serum electrolytes and bicarbonate (for RTA/hypokalemia)
- Urinalysis with protein quantification when AKI or edema develops
- Surveillance for concurrent extrarenal immune-related adverse events
Key trials & series
- KEYNOTE-021 (NSCLC; AKI reported as a treatment-related adverse event in the pembrolizumab-chemotherapy arm)
- Gupta et al. 30-site international ICPi-AKI cohort (J Immunother Cancer 2021)
- Meraz-Munoz/Kitchlu single-center ICPi-AKI cohort (J Immunother Cancer 2020)
Clinical pearls
- AIN is by far the most common ICI kidney lesion - >80% of biopsies in the largest cohort.
- PPI co-exposure is a recurring, modifiable risk factor; deprescribe when possible.
- Onset is famously delayed and variable - weeks to many months - so keep ICI-AIN on the differential long after starting therapy.
- Earlier steroids (within ~3 days of AKI) were associated with better renal recovery.
- Rechallenge is feasible but recurrent AKI occurs in roughly 1 in 6.
- Watch for the rarer faces: minimal change disease with nephrotic syndrome, and distal RTA with hypokalemic non-gap acidosis.
Beyond the kidney — non-renal toxicities· 5 organ systems
Class-level context for the major non-renal toxicities of pd-1 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.
LandmarkAcute kidney injury in patients treated with immune checkpoint inhibitors.Gupta S, Short SAP, Sise ME, et al. · J Immunother Cancer 2021 · PMID 34625513Largest (30-site, 10-country) ICPi-AKI cohort: acute tubulointerstitial nephritis in 82.7% of biopsies, median onset ~16 weeks, PPI and extrarenal irAEs as risk factors, ~64% renal recovery, and better recovery with early corticosteroids. Anchors the AIN-dominant signature, onset, risk factors, and management. DOI 10.1136/jitc-2021-003467PMIDAcute kidney injury associated with immune checkpoint inhibitor therapy: incidence, risk factors and outcomes.Meraz-Munoz A, Amir E, Ng P, et al. · J Immunother Cancer 2020 · PMID 32601079Single-center cohort of 309 ICI patients: AKI in 16.5%; biopsy/clinical attribution included interstitial nephritis, membranous nephropathy, minimal change disease, and TMA; recurrent AKI in 8.3% of those rechallenged. Supports incidence and lesion spectrum. DOI 10.1136/jitc-2019-000467PMIDAcute kidney injury in patients receiving immune checkpoint inhibitors: a retrospective real-world study.Lumlertgul N, Vassallo P, Tydeman F, et al. · Eur J Cancer 2023 · PMID 37499561Real-world cohort of 1037 ICI patients: any AKI 18.2%, ICPi-AKI 3.6%, with worse kidney recovery for ICPi-AKI than other-cause AKI. Source of the headline checkpoint-attributable incidence figure. DOI 10.1016/j.ejca.2023.112967PMIDAcute Tubulointerstitial Nephritis: A Case Report on Rare Adverse Effect of Pembrolizumab.Basnet S, Dhital R, Tharu B. · Medicina (Kaunas) 2019 · PMID 31117208Biopsy-proven pembrolizumab-associated acute tubulointerstitial nephritis with partial recovery after drug discontinuation and a steroid taper; pembrolizumab-specific evidence for the signature lesion. DOI 10.3390/medicina55050176PMIDPembrolizumab-associated minimal change disease in a patient with malignant pleural mesothelioma.Bickel A, Koneth I, Enzler-Tschudy A, et al. · BMC Cancer 2016 · PMID 27543082First report of pembrolizumab-associated minimal change disease (electron-microscopy confirmed) presenting as nephrotic syndrome and AKI with full recovery on steroids - documents the glomerular (podocytopathy) variant. DOI 10.1186/s12885-016-2718-yPMIDRenal Tubular Acidosis and Immune Checkpoint Inhibitor Therapy: An Immune-Related Adverse Event of PD-1 Inhibitor-A Report of 3 Cases.Herrmann SM, Alexander MP, Romero MF, Zand L. · Kidney Med 2020 · PMID 33089143Three PD-1-treated patients with distal renal tubular acidosis (non-gap acidosis plus hypokalemia) as an immune-related adverse event; supports the electrolyte/distal-RTA tubular variant and its distal-nephron localization. DOI 10.1016/j.xkme.2020.05.015PMIDAcute interstitial nephritis and PR3-ANCA following reintroduction of pembrolizumab: a case report.Mulroy M, Ghafouri S, Sisk A, et al. · Immunotherapy 2021 · PMID 33397120Pembrolizumab-associated AIN recurring on rechallenge (with high PR3-ANCA), improving with steroids and discontinuation; supports recurrence-on-rechallenge and the variable-onset/treatable-entity messaging. DOI 10.2217/imt-2020-0223PMIDImmune Checkpoint Inhibitor-Associated AKI: Debates in Diagnosis, Management, and Rechallenge.Seethapathy H, Herrmann SM, Rashidi A. · Semin Nephrol 2023 · PMID 37137187Review framing AIN as the major ICI kidney lesion alongside electrolyte abnormalities and RTA, and summarizing diagnosis, corticosteroid management, biomarkers, and rechallenge - supports mechanism, differential, and management narrative. DOI 10.1016/j.semnephrol.2023.151346
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.