Checkpoint inhibitors (pembrolizumab · nivolumab · ipilimumab)
Immune checkpoint inhibitor
Acute interstitial nephritis with long latency.
AIN
ModerateOpen →
PD-1 immune checkpoint inhibitor
Retifanlimab
Zynyz · PD-1 inhibitor
PD-1 blockade — kidney injury is immune-mediated interstitial nephritis, not direct tubular toxicity.
Moderatecheckpoint-immunotherapy · approved 2023
Metastatic or recurrent locally advanced Merkel cell carcinoma (accelerated approval, 2023)Locally recurrent or metastatic squamous cell carcinoma of the anal canal, first-line with carboplatin-paclitaxel (POD1UM-303)
Signature kidney injury
Acute Interstitial Nephritis
Representative incidence2%
Renal immune-related adverse events are uncommon with PD-1 monotherapy. Across the checkpoint-inhibitor class, all-cause AKI occurs in roughly 2-5% of treated patients and biopsy-confirmed immune-related AIN in approximately 1-3%, with higher rates when combined with CTLA-4 blockade or nephritogenic co-medications (PPIs, NSAILs). Retifanlimab's registrational program did not flag nephritis as a prominent signal; in the phase III POD1UM-303 anal-cancer trial the dominant grade ≥3 events were chemotherapy-driven cytopenias (neutropenia 35%, anaemia 20%), not renal events.
Source: Class-level AIN/AKI incidence extrapolated from ICI nephrotoxicity literature (PMID 33162990); retifanlimab-specific safety from POD1UM-303 (PMID 40517007) and POD1UM-202 (PMID 35816951), where renal events were not a leading toxicity.
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
0%incidence
SeverityModerate
ReversibilityPartially reversible
Evidence0 refs
Nephron map
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
Kidney injury is immune-mediated, not a direct toxic effect on tubular cells. PD-1/PD-L1 blockade abrogates peripheral tolerance, allowing reactivation of effector T cells directed against self or drug-hapten antigens within the renal interstitium, producing a T-cell–rich acute tubulointerstitial nephritis. Tubular epithelial PD-L1 expression appears permissive: biopsy series show AIN arises only where tubular PD-L1 and interstitial PD-1–positive inflammatory cells coexist (PMID 35755033, PMID 33552089). Concomitant PPIs, NSAIDs, and antibiotics are frequent co-triggers via the same loss-of-tolerance mechanism.
Clinical presentation
Typically a subacute, often asymptomatic rise in serum creatinine weeks to months into therapy. Urinalysis may show sterile pyuria and subnephrotic proteinuria; eosinophiluria is insensitive. Fever, rash, or eosinophilia accompany a minority. Concurrent extrarenal immune-related adverse events (thyroiditis, colitis, hepatitis, dermatitis) raise suspicion. Hyponatremia and mild electrolyte disturbances may co-occur; lower serum sodium at biopsy has been associated with better renal recovery (PMID 37547603).
Anticancer mechanism
Retifanlimab is a humanized, hinge-stabilized IgG4κ monoclonal antibody that binds programmed cell death protein 1 (PD-1) on T cells and blocks its engagement by PD-L1/PD-L2. This releases the inhibitory checkpoint that tumors exploit, restoring cytotoxic T-cell recognition and killing of malignant cells. The crystal structure (PMID 39632294) shows the epitope partially overlaps the ligand-binding site, reshaping the PD-1 BC, C'D, and FG loops to occlude PD-L1 docking.
Management
Withhold retifanlimab for grade 2 and permanently discontinue for grade 3-4 or recurrent immune-mediated nephritis per label guidance. Exclude prerenal, obstructive, and competing causes; discontinue offending co-medications (PPIs, NSAIDs). For immune-related AIN, start corticosteroids (prednisone ~0.5-1 mg/kg/day, up to 1-2 mg/kg for severe disease) with a slow taper over 4-6+ weeks; consider kidney biopsy to confirm AIN versus ATN before committing to prolonged steroids. Most patients recover at least partial function; steroid dose and chronicity on biopsy did not predict recovery in one cohort, whereas lower serum sodium did (PMID 37547603). Rechallenge is case-by-case after full recovery.
Risk factors
- Concomitant proton pump inhibitors
- Concomitant NSAIDs or recent nephritogenic antibiotics
- Combination with CTLA-4 blockade or other immunotherapy
- Prior immune-related adverse events
- Pre-existing chronic kidney disease or lower baseline eGFR
Prevention
- Review and deprescribe non-essential PPIs and NSAIDs before and during therapy
- Baseline and periodic serum creatinine/eGFR monitoring on each cycle
- Early nephrology referral and low threshold for biopsy when AKI is unexplained
- Screen for and manage concurrent immune-related adverse events
Clinical depth
Renal dose adjustment
No dose adjustment for mild-to-moderate renal impairment; retifanlimab is a monoclonal antibody cleared by reticuloendothelial catabolism, not renal excretion. No studied data in severe impairment or dialysis. Dosing is flat (500 mg IV every 4 weeks), not weight- or GFR-based. Renal management is toxicity-driven (withhold/discontinue) rather than pharmacokinetic dose reduction.
Dialyzability & ESKD dosing
Not dialyzable. As a ~150 kDa IgG4 monoclonal antibody it is not removed by hemodialysis or peritoneal dialysis; no supplemental dosing needed around dialysis sessions.
Differential diagnosis
Distinguish immune-related AIN from prerenal azotemia (volume depletion, chemotherapy-associated emesis/diarrhea in the anal-cancer regimen), contrast or platinum-related ATN from concurrent carboplatin, obstruction, and drug-induced AIN from co-prescribed PPIs/NSAIDs/antibiotics. Biopsy is the discriminator: ICI-AIN shows T-cell–rich interstitial infiltrate with tubular PD-L1 positivity, versus tubular necrosis in ATN. TMA and glomerular lesions are rare with PD-1 agents and should prompt a search for alternative causes.
Monitoring
- Serum creatinine/eGFR at baseline and before each cycle
- Urinalysis with protein and sediment when creatinine rises
- Serum electrolytes including sodium, potassium, magnesium
- Surveillance for concurrent immune-related adverse events (TSH, LFTs, symptoms)
Key trials & series
- POD1UM-303/InterAACT-2 (NCT04472429) — phase III, first-line anal SCC, retifanlimab + carboplatin-paclitaxel improved PFS (9.3 vs 7.4 mo, HR 0.63); PMID 40517007
- POD1UM-202 (NCT03597295) — phase II, previously treated advanced anal SCC, ORR 13.8%; PMID 35816951
- POD1UM-201 — phase II in metastatic Merkel cell carcinoma, basis for accelerated approval
Clinical pearls
- PD-1 inhibitors do not directly poison tubules — kidney injury is an immune-mediated interstitial nephritis driven by loss of peripheral tolerance.
- AIN is often clinically silent; a subacute creatinine rise weeks-to-months in, with sterile pyuria, is the classic clue.
- Always hunt for a concomitant PPI or NSAID — they are frequent co-triggers and the easiest modifiable risk factor.
- The antibody is renally inert pharmacokinetically: no GFR-based dose adjustment and not dialyzable; manage the kidney by withholding/steroids, not dose reduction.
- Lower serum sodium at the time of biopsy has been associated with better renal recovery in ICI-AIN — a counterintuitive prognostic signal.
Beyond the kidney
Class-level context for the major non-renal toxicities of pd-1 immune 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
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkRetifanlimab with carboplatin and paclitaxel for locally recurrent or metastatic squamous cell carcinoma of the anal canal (POD1UM-303/InterAACT-2): a global, phase 3 randomised controlled trial.Rao S et al. · Lancet 2025 · PMID 40517007Pivotal phase III registrational trial; defines the contemporary safety profile, where dominant grade ≥3 events were chemotherapy cytopenias rather than renal toxicity.PMIDA phase II study of retifanlimab (INCMGA00012) in patients with squamous carcinoma of the anal canal who have progressed following platinum-based chemotherapy (POD1UM-202).Rao S et al. · ESMO Open 2022 · PMID 35816951Phase II monotherapy safety/efficacy; safety stated as consistent with the PD-(L)1 inhibitor class, supporting the low renal-event characterization.PMIDIn brief: Retifanlimab (Zynyz) for Merkel cell carcinoma.The Medical Letter · Med Lett Drugs Ther 2023 · PMID 37039620Concise label-level review of the FDA-approved indication, dosing, and adverse-effect framing for Merkel cell carcinoma.PMIDThe Use of Immune Checkpoint Inhibitors in Oncology and the Occurrence of AKI: Where Do We Stand?Franzin R et al. · Front Immunol 2020 · PMID 33162990Class-level review of ICI-associated AKI/AIN incidence and mechanism, the basis for extrapolating retifanlimab's renal risk.PMIDCompartmentalization of Intrarenal Programmed Cell Death Protein 1-Ligand 1 and Its Receptor in Kidney Injury Related to Immune Checkpoint Inhibitor Nephrotoxicity.Tampe D et al. · Front Med (Lausanne) 2022 · PMID 35755033Biopsy-based mechanistic evidence that ICI-AIN requires coexisting tubular PD-L1 and interstitial PD-1 positivity.PMIDSerum sodium levels associate with recovery of kidney function in immune checkpoint inhibitor nephrotoxicity.Tampe D et al. · Front Med (Lausanne) 2023 · PMID 37547603Renal-specific outcome data: lower serum sodium at biopsy predicts recovery in ICI-AIN, informing prognosis and monitoring.