Checkpoint inhibitors (pembrolizumab · nivolumab · ipilimumab)
Immune checkpoint inhibitor
Acute interstitial nephritis with long latency.
AIN
ModerateOpen →
PD-1 immune checkpoint inhibitor
Penpulimab
Penpulimab (AK105) · PD-1 inhibitor
Fc-silent PD-1 blocker for nasopharyngeal carcinoma — class-typical, infrequent immune interstitial nephritis
ModeratePD-1/PD-L1 checkpoint-inhibitor era (FDA approval 2025; China approval 2021 for Hodgkin lymphoma) · approved 2025
Recurrent or metastatic nasopharyngeal carcinoma (first-line, in combination with cisplatin/carboplatin plus gemcitabine)Recurrent or metastatic nasopharyngeal carcinoma (later-line monotherapy after platinum-based chemotherapy)Relapsed/refractory classic Hodgkin lymphoma (approved in China)
Signature kidney injury
Acute Interstitial Nephritis
Representative incidence3%
Penpulimab-specific renal data are limited. In the pivotal first-line phase 3 trial (penpulimab plus chemotherapy), grade >=3 immune-related adverse events occurred in only 4.1% of patients, and renal events were not separately prominent; the most common toxicities were hematologic. By class, immune checkpoint inhibitor-associated AKI (predominantly acute tubulointerstitial nephritis) occurs in roughly 2-5% of patients on PD-1 monotherapy, with higher rates when combined with nephrotoxic chemotherapy. Platinum (cisplatin) and gemcitabine in the registrational backbone independently contribute ATN and (rarely) thrombotic microangiopathy risk, so observed kidney injury in this regimen is often multifactorial.
Source: Class incidence of ICI-associated AKI/AIN ~2-5% (Zhou P et al., Front Immunol 2024, PMID 38464524; Miao J et al., Front Nephrol 2022, PMID 37674988). Penpulimab grade >=3 irAEs 4.1% in the first-line phase 3 trial (Huang S et al., Signal Transduct Target Ther 2026, PMID 41946687).
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
0%incidence
SeverityModerate
ReversibilityPartially reversible
Evidence0 refs
Nephron map
Glomerulus
Proximal Tubule
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 dominant kidney lesion is immune-mediated acute tubulointerstitial nephritis: PD-1 blockade lowers peripheral tolerance, allowing reactivation of autoreactive/drug-primed T cells that infiltrate the renal interstitium, with a predominantly CD4+ and CD8+ T-cell infiltrate and occasional granulomas. Loss of PD-1/PD-L1 tolerance to commonly co-administered tubulointerstitial-acting drugs (PPIs, NSAIDs, antibiotics) is a frequent trigger. Less commonly, immune dysregulation produces glomerular lesions (minimal change, podocytopathy, pauci-immune/ANCA-type glomerulonephritis) or electrolyte disturbances. Penpulimab's FcgammaR-silent design is hypothesized to reduce immune-related toxicity overall, but does not eliminate the interstitial-nephritis mechanism. In the platinum/gemcitabine combination, direct tubular toxicity (ATN) and rare TMA are chemotherapy-driven rather than checkpoint-driven.
Clinical presentation
Typically a subacute, asymptomatic rise in serum creatinine detected on routine labs, often without oliguria. Sterile pyuria, white-cell casts, mild sub-nephrotic proteinuria, and occasionally eosinophilia/eosinophiluria may be present but are insensitive. Fever and rash are inconsistent. Extrarenal immune-related adverse events (thyroiditis, hepatitis, colitis, dermatitis) may coexist and raise suspicion. Heavy proteinuria or nephrotic syndrome suggests a coexisting glomerular irAE. Hyponatremia or electrolyte wasting can occur but is less characteristic than with platinum or anti-EGFR agents.
Anticancer mechanism
Penpulimab is a humanized IgG1 monoclonal antibody that binds programmed cell death protein 1 (PD-1) on T cells and blocks engagement with its ligands PD-L1/PD-L2, releasing the inhibitory checkpoint and restoring cytotoxic T-cell anti-tumor activity. It is deliberately engineered to abolish Fc-gamma-receptor (FcgammaR) binding, which is intended to prevent FcgammaR-mediated activation-induced T-cell apoptosis and reduce pro-inflammatory cytokine release while preserving receptor blockade.
Management
Grade the AKI and exclude pre-renal and obstructive causes. For suspected immune-related AIN: hold penpulimab, discontinue contributing AIN-associated drugs, and start corticosteroids (typically prednisone ~0.5-1 mg/kg/day, up to 1-2 mg/kg/day for higher-grade injury) with a taper over weeks once renal function improves. Kidney biopsy confirms AIN and excludes ATN/glomerular lesions when the diagnosis is uncertain or steroids fail. Most patients recover at least partially. Permanent discontinuation is warranted for grade 3-4 or recurrent nephritis; rechallenge after lower-grade, fully recovered AIN may be considered cautiously with monitoring. For chemotherapy-driven ATN/TMA in the combination regimen, manage supportively and adjust the platinum/gemcitabine component. Penpulimab itself, as an IgG monoclonal antibody, is not renally cleared and needs no dose change for renal impairment.Lesion-level management framework
Risk factors
- Concurrent use of other AIN-associated drugs (proton-pump inhibitors, NSAIDs, antibiotics)
- Combination with nephrotoxic chemotherapy (cisplatin/carboplatin plus gemcitabine) in the registrational regimen
- Prior or concurrent extrarenal immune-related adverse events
- Lower baseline eGFR / pre-existing chronic kidney disease
- Combination immunotherapy (e.g., dual checkpoint or PD-1 plus TIM-3 blockade under study)
- Volume depletion and intercurrent illness
Prevention
- Check baseline and serial serum creatinine and urinalysis before and during each cycle
- Review and minimize concomitant nephritis-associated drugs (PPIs, NSAIDs)
- Maintain euvolemia and adequate hydration, especially around platinum/gemcitabine cycles
- Early nephrology referral and consideration of kidney biopsy for unexplained AKI
- Hold the drug and evaluate promptly for any unexplained creatinine rise rather than attributing it to pre-renal causes alone
Clinical depth
Renal dose adjustment
No pharmacokinetic dose adjustment for renal impairment: penpulimab is a ~150 kDa IgG1 monoclonal antibody eliminated by reticuloendothelial catabolism, not by glomerular filtration or tubular secretion. Dosing is fixed (200 mg IV every 2 or 3 weeks depending on regimen). Modifications are driven by immune-related toxicity grade (hold/discontinue and add steroids) rather than by eGFR. The cisplatin component of the combination regimen does require renal dosing/eligibility consideration, and carboplatin substitution is used for patients unable to tolerate cisplatin.
Dialyzability & ESKD dosing
Not dialyzable. As a large IgG monoclonal antibody, penpulimab is not removed by hemodialysis or peritoneal dialysis; timing relative to dialysis sessions is irrelevant. No data establish its use in dialysis-dependent patients, but pharmacokinetics are not expected to be altered by renal replacement therapy.
Differential diagnosis
Distinguish immune-related AIN from: (1) cisplatin/gemcitabine-induced ATN (earlier, peri-infusion, often with classic muddy-brown casts); (2) pre-renal azotemia from poor intake, vomiting, or diarrhea; (3) gemcitabine- or platinum-associated thrombotic microangiopathy (hemolysis, thrombocytopenia, schistocytes, hypertension); (4) contrast-associated AKI from staging imaging; (5) obstructive uropathy from tumor; (6) a glomerular irAE (heavy proteinuria, hematuria). Coexisting extrarenal irAEs and sterile pyuria favor checkpoint-related AIN; kidney biopsy is the definitive arbiter.
Monitoring
- Serum creatinine/eGFR before each cycle and periodically during maintenance
- Urinalysis with microscopy (sterile pyuria, white-cell casts, proteinuria)
- Spot urine protein-to-creatinine ratio if proteinuria develops
- Serum electrolytes including sodium, potassium, magnesium (combination chemotherapy)
- Surveillance for extrarenal immune-related adverse events (thyroid, liver, GI, skin)
- Blood pressure and CBC/peripheral smear if TMA is suspected with the platinum/gemcitabine backbone
Key trials & series
- AK105-304 / NCT04974398: randomized double-blind phase 3 of penpulimab plus cisplatin-or-carboplatin/gemcitabine vs placebo plus chemotherapy, first-line R/M NPC (n=291); median PFS 9.63 vs 7.00 months, HR 0.45; grade >=3 irAEs 4.1% (PMID 41946687)
- Single-arm phase 2 of penpulimab monotherapy in heavily pretreated metastatic NPC (n=130); ORR 28.0%, grade >=3 irAEs 7.6% (PMID 38890298)
- Phase 2 exploratory study of penpulimab/gemcitabine with or without anlotinib in metastatic NPC (PMID 42093316)
Clinical pearls
- Kidney injury from penpulimab is class-typical immune AIN, not a direct tubular toxin — treat suspected cases with drug hold plus corticosteroids, not just hydration.
- An unexplained creatinine rise in a patient on a checkpoint inhibitor is AIN until proven otherwise; do not anchor on pre-renal causes.
- In the registrational regimen the kidney sees three potential hits at once — penpulimab (AIN), cisplatin (ATN), and gemcitabine (rare TMA) — so always parse the timing and urine sediment.
- Penpulimab's Fc-silent IgG1 design is intended to lower immune-related toxicity (grade >=3 irAEs were only ~4% in the phase 3 trial), but interstitial nephritis can still occur.
- Penpulimab is not renally cleared and is not dialyzable — no eGFR-based dose change is needed; toxicity management is steroid- and grade-driven.
- Co-prescribed PPIs and NSAIDs are common AIN co-triggers under PD-1 blockade — deprescribe them when feasible.
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
5 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkAnti-PD-1 antibody penpulimab plus chemotherapy for recurrent or metastatic nasopharyngeal carcinoma: a randomized, double-blind phase 3 study.Huang S, Liu F, Qu S, et al. · Signal Transduction and Targeted Therapy 2026 · PMID 41946687Pivotal first-line registrational phase 3 trial (AK105-304/NCT04974398) establishing efficacy and the overall safety profile, including grade >=3 immune-related adverse events of 4.1%; primary source for headline irAE/renal-risk framing.PMIDPenpulimab, an anti-PD-1 antibody, for heavily pretreated metastatic nasopharyngeal carcinoma: a single-arm phase II study.Chen X, Wang W, Zou Q, et al. · Signal Transduction and Targeted Therapy 2024 · PMID 38890298Monotherapy phase 2 efficacy/safety in metastatic NPC (ORR 28.0%, grade >=3 irAEs 7.6%); supports the single-agent immune-toxicity profile separate from chemotherapy confounders.PMIDToripalimab and Penpulimab: Targeting PD-1 in Recurrent or Metastatic Nasopharyngeal Carcinoma.Hockett JJ, Keller ME, Reeves DJ. · Annals of Pharmacotherapy 2025 · PMID 41321253Clinical review of penpulimab in R/M NPC summarizing approval status, efficacy, and the immune-related adverse-event profile; supports drug-class and indication framing.PMIDImmune checkpoint inhibitors and acute kidney injury.Zhou P, Gao Y, Kong Z, et al. · Frontiers in Immunology 2024 · PMID 38464524Class review of ICI-associated AKI: confirms acute tubulointerstitial nephritis as the dominant lesion, ~2-5% incidence, risk factors, mechanism, and steroid-based management used to reason about penpulimab's renal signature.PMIDImmune checkpoint inhibitor related nephrotoxicity: Advances in clinicopathologic features, noninvasive approaches, and therapeutic strategy and rechallenge.Miao J, Sise ME, Herrmann SM. · Frontiers in Nephrology 2022 · PMID 37674988Detailed clinicopathologic review of ICI nephrotoxicity (AIN plus glomerular/electrolyte patterns), diagnosis, corticosteroid therapy, and rechallenge — basis for the differential, monitoring, and management fields.