Checkpoint inhibitors (pembrolizumab · nivolumab · ipilimumab)
Immune checkpoint inhibitor
Acute interstitial nephritis with long latency.
AIN
ModerateOpen →
Immune checkpoint inhibitor (anti-LAG-3)
Relatlimab
Opdualag · Rela
An anti-LAG-3 checkpoint inhibitor whose kidney risk is the class lesion — immune-mediated acute interstitial nephritis, amplified in combination with nivolumab.
ModerateImmune checkpoint inhibitor (anti-LAG-3) · approved 2022
Unresectable or metastatic melanoma (with nivolumab)
Signature kidney injury
Acute Interstitial Nephritis
LAG-3-specific renal literature is thin: dedicated searches return no relatlimab AKI cohort or case series, and the pivotal RELATIVITY-047 trial reported aggregate grade 3/4 treatment-related adverse events (about 18.9% with the combination vs 9.7% with nivolumab alone) without an isolated nephritis rate. The renal signal is therefore class-based — immune checkpoint inhibitors cause acute interstitial nephritis, the dominant lesion in 80–90%+ of biopsied ICI-AKI cases, with combination immunotherapy a recognized risk factor.
Source: Tawbi et al., NEJM 2022 (RELATIVITY-047); Cortazar et al., JASN 2020 (ICI-AKI biopsy series)
Mechanism of kidney injury
By analogy to the established immune-checkpoint-inhibitor mechanism, LAG-3 blockade (combined with PD-1 blockade) disrupts peripheral immune tolerance and permits T-cell-mediated tubulointerstitial inflammation — acute interstitial nephritis. Multicenter ICI-AKI series show acute tubulointerstitial nephritis as the predominant biopsy lesion (>80–90%), often with a long latency and frequently potentiated by concomitant AIN-associated drugs (PPIs, NSAIDs). Combination checkpoint blockade (as in Opdualag) increases the risk relative to single-agent PD-1 therapy. A direct relatlimab-specific renal lesion has not been separately characterized.
Clinical presentation
A subacute creatinine rise (often weeks to months into therapy), sometimes with sterile pyuria, white-cell casts, low-grade tubular proteinuria and occasionally eosinophilia/eosinophiluria; extrarenal immune-related adverse events may coexist. Nephrotic-range proteinuria is uncommon and suggests an alternative glomerular irAE.
Onset
Delayed — typically weeks to months after initiation (long latency is characteristic of ICI-AIN).
Reversibility
Partially reversible
Anticancer mechanism
Monoclonal antibody against lymphocyte-activation gene-3 (LAG-3), an inhibitory immune checkpoint on T cells. Blocking LAG-3 restores T-cell activation; given as a fixed-dose combination with the anti-PD-1 antibody nivolumab (Opdualag) for unresectable or metastatic melanoma.
Management
Hold the drug and exclude alternative causes; treat suspected ICI-AIN with corticosteroids (early initiation improves renal recovery in multicenter cohorts), with biopsy when feasible to confirm. Discontinue contributing AIN-associated drugs. Rechallenge decisions are individualized, weighing recurrence risk; corticosteroid duration influences recurrence.
Risk factors
- Combination checkpoint blockade (relatlimab + nivolumab)
- Concurrent AIN-associated drugs (PPIs, NSAIDs, antibiotics)
- Prior immune-related adverse events
- Pre-existing CKD
Prevention
- Baseline and periodic creatinine monitoring
- Review and minimize concomitant AIN-associated drugs
- Early nephrology referral for unexplained creatinine rise
- Patient education on irAE symptoms
Note · Relatlimab-specific renal data are thin — the AIN signature is inferred from the broader ICI class literature (where acute tubulointerstitial nephritis dominates) and from the combination's higher overall irAE rate. No relatlimab-specific AIN incidence is quantified, so incidencePct is null.
Clinical depth
Renal dose adjustment
No renal dose adjustment is established (monoclonal antibody, not renally cleared); mild–moderate impairment does not require change. The actionable step is holding the drug and steroid treatment for immune-mediated AIN rather than dose modification.
Dialyzability & ESKD dosing
The IgG antibodies are not dialyzable and are cleared by proteolysis; no ESKD dose change is expected. Dialysis supports severe AKI management, not drug removal.
Differential diagnosis
ICI-associated acute interstitial nephritis (subacute creatinine rise, sterile pyuria/WBC casts, long latency, steroid-responsive) vs prerenal AKI vs a glomerular irAE (heavy proteinuria) vs drug AIN from co-medications; biopsy and the temporal/medication context discriminate, and combination therapy raises pre-test probability.
Monitoring
- Serum creatinine before each cycle and periodically
- Urinalysis if creatinine rises (pyuria/WBC casts/tubular proteinuria)
- Review of concomitant AIN-associated drugs
- Surveillance for extrarenal immune-related adverse events
Key trials & series
- RELATIVITY-047 (Tawbi NEJM 2022) — pivotal phase 2/3 combination trial
- Cortazar JASN 2020 and Gupta J Immunother Cancer 2021 — multicenter ICI-AKI biopsy series (class evidence)
Clinical pearls
- Think AIN: as part of a checkpoint-inhibitor combination, relatlimab's signature renal lesion is immune-mediated acute interstitial nephritis.
- Latency is long — a creatinine rise weeks to months in, often with sterile pyuria, should trigger drug-hold and nephrology referral, not just dose-reduction.
- Concomitant PPIs/NSAIDs potentiate ICI-AIN — review and stop where possible.
- Early corticosteroids improve renal recovery; relatlimab-specific incidence is not quantified, so lean on class evidence.
Where it strikes
Nephron segments
Interstitium
Supporting tissue around the tubules
Injury signatures
Acute Interstitial Nephritis
Beyond the kidney
Class-level context for the major non-renal toxicities of immune checkpoint inhibitor (anti-lag-3)s.
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.
LandmarkRelatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma.Tawbi HA et al. · N Engl J Med 2022 · PMID 34986285RELATIVITY-047 pivotal trial establishing nivolumab+relatlimab; higher grade 3/4 treatment-related AEs than nivolumab alone (no isolated nephritis rate reported).LandmarkClinical Features and Outcomes of Immune Checkpoint Inhibitor-Associated AKI: A Multicenter Study.Cortazar FB et al. · J Am Soc Nephrol 2020 · PMID 31896554Landmark multicenter ICI-AKI cohort; acute tubulointerstitial nephritis the dominant biopsy lesion and combination ICI a risk factor — class basis for relatlimab AIN.PMIDAcute kidney injury in patients treated with immune checkpoint inhibitors.Gupta S et al. · J Immunother Cancer 2021 · PMID 34625513Largest ICI-AKI multicenter study; acute tubulointerstitial nephritis in 82.7% of biopsies and early steroids improve recovery.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 33162990Authoritative review of ICI nephrotoxicity mechanisms (AIN predominant), risk factors and management — applies to the anti-LAG-3 class by extension.PMIDThe introduction of LAG-3 checkpoint blockade in melanoma: immunotherapy landscape beyond PD-1 and CTLA-4 inhibition.Kreidieh FY et al. · Ther Adv Med Oncol 2023 · PMID 37484526LAG-3-specific review contextualizing relatlimab's irAE/toxicity profile relative to PD-1/CTLA-4 blockade.