Cisplatin
Platinol · Platinum agent
Proximal tubular ATN + magnesium wasting; the archetype.
ATNLYTEPRE
SevereOpen →
Antifolate
Pemetrexed
Alimta · Pem
The slow burn — cumulative tubular toxicity that surfaces after many cycles.
ModerateMultitargeted antifolate · approved 2004
NSCLC (non-squamous)Mesothelioma
Signature kidney injury
Acute Tubular Necrosis
Representative incidence21%
Clinically relevant eGFR decline (≥25%) in ~21%; ~8% discontinue for nephrotoxicity. Cumulative-dose dependent.
Source: de Rouw et al., Lung Cancer 2020
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
0%incidence
SeverityModerate
ReversibilityPartially reversible
Evidence0 refs
Nephron map
Proximal TubuleBulk reabsorption + drug uptake (OCT2, OATs)
Distal Tubule / Collecting DuctFine-tuning of Na, K, Mg, acid & water
Interstitium
Acute Tubular Necrosis
Direct death of tubular epithelial cells — the dose-limiting lesion of the platinums and zoledronate.
Mechanism of kidney injury
Taken up into proximal tubular cells via the reduced folate carrier and organic anion transporters, producing direct tubular toxicity and chronic tubulointerstitial damage that accumulates with prolonged maintenance dosing.
Clinical presentation
Slowly progressive eGFR decline, sometimes renal tubular acidosis, hypophosphatemia and nephrogenic diabetes insipidus — insidious rather than abrupt AKI.
Onset
Delayed / cumulative; risk rises after ~10 cycles.
Reversibility
Partially reversible
Anticancer mechanism
Multitargeted antifolate inhibiting thymidylate synthase, DHFR and GARFT. Non-squamous NSCLC and mesothelioma, often as maintenance therapy.
Management
Discontinue or dose-adjust; supportive care.
Risk factors
- High cumulative dose / prolonged maintenance
- Pre-existing CKD
- Concurrent nephrotoxins
Prevention
- Folic acid + vitamin B12 supplementation
- Renal-function monitoring
- Dose-hold for declining eGFR
Note · Increasingly relevant as immuno-chemotherapy prolongs pemetrexed exposure.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Interstitium
Supporting tissue around the tubules
Injury signatures
Acute Tubular NecrosisElectrolyte Wasting
Beyond the kidney
Class-level context for the major non-renal toxicities of antifolates.
Gastrointestinal
Diarrhea, colitis, mucositis, perforation
- Mucositis and diarrhea
Hepatic / Liver
Transaminitis, hepatitis, VOD/SOS
- Transaminitis (methotrexate)
Hematologic
Cytopenias, thrombosis, TMA
- Myelosuppression
Pulmonary
Pneumonitis, ILD, effusions, hypertension
- Methotrexate / gemcitabine pneumonitis
Evidence
5 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkCumulative pemetrexed dose increases the risk of nephrotoxicity.de Rouw N et al. · Lung Cancer 2020 · PMID 3250507821% develop relevant eGFR decline; 8% discontinue for nephrotoxicity.PMID[Pemetrexed nephrotoxicity].Izzedine H et al. · Bull Cancer 2015 · PMID 25641712Dedicated review of progressive, cumulative pemetrexed renal toxicity.PMIDRenal failure during chemotherapy: renal biopsy for assessing subacute nephrotoxicity of pemetrexed.Assayag M et al. · BMC Cancer 2017 · PMID 29145816Biopsy-documented ATN attributable to pemetrexed.PMIDPemetrexed-induced acute renal failure, nephrogenic diabetes insipidus, and renal tubular acidosis in a patient with non-small cell lung cancer.Vootukuru V et al. · Med Oncol 2006 · PMID 17018900Defines the tubular phenotype (AKI + nephrogenic DI + RTA).PMIDNew drug toxicities in the onco-nephrology world.Perazella MA et al. · Kidney Int 2015 · PMID 25671763Onco-nephrology review covering pemetrexed and newer agents.