Antifolates & the slow erosion of the tubule
Pemetrexed tubular nephrotoxicity
Pemetrexed leaves the body through the kidney, so the tubule sees the drug at every cycle — and the injury accumulates quietly, cycle by cycle, into a tubulointerstitial scar that often does not heal once the drug is finally stopped.
- 21%
- clinically relevant renal declineShare of 359 pemetrexed-treated patients with a ≥25% fall in eGFR during treatment in a retrospective cohortPMID 32505078
- 5.66×
- risk with cumulative doseAdjusted odds ratio for renal decline once patients pass ≥10 cycles of pemetrexed-based therapy (95% CI 1.73–18.54) — the injury is cumulativePMID 32505078
- 8.1%
- stopped for nephrotoxicityPatients who discontinued pemetrexed-based treatment because of declining renal functionPMID 32505078
- often irreversible
- does not recoverIn a biopsy series of maintenance pemetrexed, kidney function remained impaired but stable after the drug was stopped — the tubulointerstitial injury does not reversePMID 21849225
- 12.6%
- early AKI with immuno-chemoEarly AKI in front-line ICI-based therapy for metastatic NSCLC; highest (16.7%) with pemetrexed + pembrolizumab + carboplatinPMID 40719750
Teaching case · illustrative composite, not a real patient
A 66-year-old man with metastatic non-squamous NSCLC, ten months into maintenance pemetrexed (well past his tenth cycle), is noted to have a serum creatinine that has crept from 0.9 to 1.6 mg/dL over successive cycles. He feels well; the urinalysis is bland, without significant proteinuria, hematuria, or cellular casts, and he has no eosinophilia or rash.
Because the decline is gradual and the sediment is bland, a drug-induced tubular process is suspected. If a kidney biopsy is done it shows tubulointerstitial injury — tubular simplification and loss of brush border with interstitial fibrosis — rather than a florid interstitial nephritis. Pemetrexed is held. Over the following months the creatinine stabilizes but does not return to baseline: he is left with chronic kidney disease.
Teaching point — Pemetrexed nephrotoxicity is insidious and cumulative, not a single dramatic event: watch the eGFR trend across cycles rather than any one value, since risk climbs with cumulative dose. The urine is often bland and the injury is a tubulointerstitial one that frequently does not recover after discontinuation. In combination with a checkpoint inhibitor, the harder question is which drug to blame — chemotherapy tends to cause acute tubular injury, whereas the ICI causes acute tubulointerstitial nephritis, and telling them apart decides which agent to hold.
How it happens
The pathophysiology as a cascade — select a step to follow the mechanism.
Pemetrexed is eliminated largely unchanged by the kidney, so the proximal tubule is exposed to the antifolate at every cycle — the reason adequate renal function is required before dosing and the reason injury accrues with cumulative exposure.
PMID 32505078 (opens PubMed in a new tab)Biopsies of affected patients show tubular simplification, loss of the proximal brush border, and tubular atrophy — a tubulointerstitial injury rather than a glomerular or crystalline one.
PMID 21849225 (opens PubMed in a new tab)In more severe or advanced cases the picture is frank acute tubular necrosis accompanied by interstitial fibrosis — the substrate for the transition from acute injury to chronic kidney disease.
PMID 24424085 (opens PubMed in a new tab)Beyond proximal injury, pemetrexed can impair the distal nephron, manifesting as nephrogenic diabetes insipidus (a concentrating defect) and distal renal tubular acidosis.
PMID 17018900 (opens PubMed in a new tab)Because injury accrues cycle by cycle and the tubulointerstitial scar does not remodel, kidney function typically stabilizes at a lower level rather than recovering once the drug is stopped.
PMID 21849225 (opens PubMed in a new tab)
How we learned it
- 2006
Vootukuru et al. report a patient who developed acute renal failure with nephrogenic diabetes insipidus and distal renal tubular acidosis after pemetrexed, postulating renal tubular toxicity as the unifying lesion.
An early, detailed description that pemetrexed injures the tubule — producing not just azotemia but concentrating and acidification defects.
PMID 17018900 (opens PubMed in a new tab) - 2011
Glezerman et al. biopsy three patients on maintenance pemetrexed and find tubulointerstitial injury with tubular simplification, brush-border loss, and atrophy; function stayed impaired but stable after stopping.
Pathologically defined the lesion as a tubulointerstitial injury and showed it does not reverse on drug withdrawal.
PMID 21849225 (opens PubMed in a new tab) - 2014
Chauvet et al. describe two patients — including one on single-agent pemetrexed — whose AKI progressed to chronic kidney disease, with biopsy showing acute tubular necrosis and interstitial fibrosis.
Confirmed that pemetrexed alone can cause AKI that leaves permanent CKD, decoupling it from co-administered cisplatin.
PMID 24424085 (opens PubMed in a new tab) - 2020
de Rouw et al. show in 359 patients that ≥10 cycles of pemetrexed-based therapy is an independent risk factor for renal decline (adjusted OR 5.66), with 21% declining and 8.1% discontinuing.
Quantified the dose-dependence and flagged that longer survival on immuno-chemotherapy means more cycles — and more nephrotoxicity.
PMID 32505078 (opens PubMed in a new tab) - 2020
Dumoulin et al. lay out how to distinguish chemotherapy-induced acute tubular injury from checkpoint-inhibitor tubulointerstitial nephritis when the two are given together.
Made the combination-era diagnostic problem explicit: which drug injured the kidney determines which one you can safely continue.
PMID 32360753 (opens PubMed in a new tab) - 2025
Li et al. find early AKI in 12.6% of patients on front-line ICI-based therapy (16.7% with pemetrexed + pembrolizumab + carboplatin), associated with worse 12-month survival (HR 1.73).
Linked early renal injury in these regimens to survival, reinforcing close monitoring in the modern combination era.
PMID 40719750 (opens PubMed in a new tab)
The landmark studies
Kidney tubular toxicity of maintenance pemetrexed therapy
Glezerman IG, et al. · Am J Kidney Dis 2011 · PMID 21849225
Kidney biopsies showed tubulointerstitial injury (tubular simplification, brush-border loss, atrophy); renal function remained impaired but stable after stopping the drug.
3/3 with biopsy-proven tubulointerstitial injury; function impaired-but-stable after discontinuation
Pemetrexed-induced acute kidney injury leading to chronic kidney disease
Chauvet S, et al. · Clin Nephrol 2014 · PMID 24424085
AKI after pemetrexed — including as a single agent — progressed to persistent CKD; biopsy showed acute tubular necrosis and interstitial fibrosis.
2/2 with persistent CKD despite discontinuation; ATN + interstitial fibrosis on biopsy
Cumulative pemetrexed dose increases the risk of nephrotoxicity
de Rouw N, et al. · Lung Cancer 2020 · PMID 32505078
A clinically relevant fall in eGFR occurred in 21% of patients and 8.1% discontinued for nephrotoxicity; ≥10 cycles of therapy independently raised the risk.
21% with ≥25% eGFR decline; 8.1% discontinued; ≥10 cycles adjusted OR 5.66 (1.73–18.54)
Early acute kidney injury and its association with survival in metastatic NSCLC on front-line immunotherapy-based therapies
Li M, et al. · Cancer Med 2025 · PMID 40719750
Early AKI occurred in 12.6% of patients (highest with pemetrexed + pembrolizumab + carboplatin) and was associated with reduced 12-month survival.
AKI 12.6% overall, 16.7% with pem/pembro/carbo; HR for death 1.73 (1.06–2.84)
What the data says now
How disproportionately each agent's FAERS reports name these phenotypes vs. all other drugs (reporting odds ratio; significant signals only, 95% CI lower bound > 1; as of 2026-09-01). A reporting signal, not incidence or proven causation. A dash means tested without reaching significance, not a phenotype that never occurs — ATN and AIN undercount badly, most true cases filing as generic “acute kidney injury”. Computed by this atlas on the current snapshot — a published disproportionality analysis will not match cell for cell (different window, different term set).
| Agent | ATN | LYTE |
|---|---|---|
| Pemetrexed | Pemetrexed, Acute Tubular Necrosis: ROR 16.55, 284 reports | Pemetrexed, Electrolyte Disturbance: ROR 3.09, 1,043 reports |
Not in this grid: Chronic Interstitial Nephropathy — this phenotype is outside the clinician-reviewed MedDRA term map behind this grid and never queried. Absence is a boundary of that map, not evidence against the association.
Clinically relevant renal decline
359 pemetrexed-treated patients (≥25% eGFR fall)
PMID 32505078 (opens PubMed in a new tab)Discontinuation for nephrotoxicity
Same pemetrexed cohort
PMID 32505078 (opens PubMed in a new tab)Risk with ≥10 cycles
Cumulative-dose risk analysis (95% CI 1.73–18.54)
PMID 32505078 (opens PubMed in a new tab)Early AKI on front-line ICI-based therapy
310 metastatic NSCLC patients
PMID 40719750 (opens PubMed in a new tab)Recovery after discontinuation
Biopsy case series of 3 patients on maintenance pemetrexed — too few to give a rate
PMID 21849225 (opens PubMed in a new tab)How it's managed
- 1
Track the eGFR trend across cycles, not a single value
Because risk climbs with cumulative dose and longer treatment, monitor renal function every cycle and read the trajectory — a slow, stepwise creep is the characteristic signal.
Cumulative dose (≥10 cycles) an independent risk factor for renal decline · PMID 32505078 (opens PubMed in a new tab)
- 2
Treat a decline as potentially permanent — hold early
Once eGFR falls, the tubulointerstitial injury frequently does not reverse; withholding or stopping pemetrexed to prevent further, permanent loss is the main lever, since there is no specific antidote.
Function impaired-but-stable after discontinuation in biopsy series · PMID 21849225 (opens PubMed in a new tab)
- 3
In combination with a checkpoint inhibitor, identify the culprit
Chemotherapy tends to cause acute tubular injury and the ICI acute tubulointerstitial nephritis; use the clinical, laboratory, and (where needed) biopsy picture to decide which drug to hold — steroids help ICI nephritis but not pemetrexed tubular injury.
Proposed diagnostic/treatment algorithm distinguishing chemo- from ICI-nephrotoxicity · PMID 32360753 (opens PubMed in a new tab)
- 4
Respect the renal-function floor before dosing
Pemetrexed's renal clearance means it is avoided at low creatinine clearance (per label); confirm adequate renal function before each course, and note that folate and B12 supplementation reduce systemic toxicity but do not prevent the renal injury.
Renal elimination requires adequate function; cumulative renal risk · PMID 32505078 (opens PubMed in a new tab)
What the guidelines say
Society and consensus recommendations addressing this syndrome.
Each recommendation below is this atlas's faithful summary of the source, not a quotation from it — follow the PubMed link for the wording the society published. Summaries may be superseded; consult the current full text and individualize to the patient.
Every citation on this page is a real, PubMed-verified reference. The teaching case is an illustrative composite, not a real patient. Medical-education content — not medical advice.