Pemetrexed

Chronic Interstitial Nephropathy — representative incidence ~21%.

Clinically relevant eGFR decline (≥25%) in ~21%; ~8% discontinue for nephrotoxicity. Cumulative-dose dependent.

Source: de Rouw et al., Lung Cancer 2020

Reported injury signatures: Chronic Interstitial Nephropathy, Acute Tubular Necrosis, Electrolyte Disturbance, SIADH / Hyponatremia.

1. Chronic Interstitial NephropathyPrimary~21%Clinically relevant (≥25%) eGFR decline in 21% during pemetrexed therapy — cumulative and dose-dependent (≥10 cycles: adjusted OR 5.66); a chronic tubulointerstitial injury that is often only partially reversible
2. Acute Tubular NecrosisSecondaryAcute tubular injury/AKI reported in ~21% (6/29) of a single-center NSCLC cohort (baseline eGFR >45); biopsy-documented ATN with interstitial fibrosis in case reports
3. Electrolyte DisturbanceRareTubular electrolyte disturbances (nephrogenic diabetes insipidus, distal renal tubular acidosis, hypophosphatemia/hypokalemia) reported mainly at case level, not systematically quantified
4. SIADH / HyponatremiaRareExposure-correlated severe hyponatremia in a prospective PK cohort, with events during single-agent maintenance.

Delayed (>6 weeks / cumulative) — Cumulative — renal risk rises after roughly 10 cycles of exposure.

• High cumulative dose / prolonged maintenance
• Pre-existing CKD
• Concurrent nephrotoxins

• Folic acid + vitamin B12 supplementation
• Dose-hold for declining eGFR

• Check serum creatinine/eGFR and recalculate CrCl (Cockcroft-Gault) before EVERY cycle; withhold if CrCl falls below 45 mL/min.
• Confirm folic acid and B12 supplementation are in place and adherent before each cycle (under-supplementation predicts severe toxicity).
• Screen and document NSAID and other nephrotoxin exposure at each visit; reinforce the peri-dose NSAID hold window.
• Monitor CBC (nadir counts) and mucositis as surrogate markers of impaired renal clearance, since accumulation manifests first as marrow/mucosal toxicity.
• With prolonged or cumulative (maintenance) exposure, trend eGFR over time and assess electrolytes, urine osmolality and polyuria for tubulopathy (NDI, RTA).

• JMDB (Scagliotti, JCO 2008) — phase III cisplatin plus pemetrexed first-line in advanced NSCLC; the registrational efficacy trial that also established the platinum-doublet renal/toxicity profile requiring CrCl-based dosing.
• EMPHACIS (Vogelzang, JCO 2003) — phase III cisplatin/pemetrexed in mesothelioma; demonstrated that mandatory folic acid and B12 supplementation markedly reduced toxicity, shaping the current supplementation requirement.
• PARAMOUNT (Paz-Ares, Lancet Oncol 2012) — phase III continuation-maintenance pemetrexed in NSCLC; prolonged exposure surfaced cumulative renal/laboratory toxicity informing the chronic-nephrotoxicity concern.

• The hard rule: do not start pemetrexed if CrCl < 45 mL/min — reduced clearance causes life-threatening myelosuppression and mucositis, which are the earliest clinical signals of drug accumulation.
• NSAIDs are the classic avoidable hit — they cut tubular secretion of pemetrexed; observe the peri-dose hold window, especially in any degree of renal impairment.
• Folate/B12 supplementation is non-negotiable and renal-protective in effect; missed supplementation is a leading driver of severe toxicity.
• Cumulative/maintenance dosing can cause an insidious CKD with tubular dysfunction — watch for nephrogenic diabetes insipidus (polyuria) and renal tubular acidosis, which are often only partially reversible after stopping.
• Renal injury is amplified when pemetrexed is paired with cisplatin; aggressive hydration, Mg repletion, and avoiding additional nephrotoxins matter most in the doublet.
• Severe hyponatremia tracks pemetrexed exposure (AUC) in a prospective PK cohort, with urine osmolality exceeding serum suggesting SIADH and further events during single-agent maintenance.

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.

• ADQI (2026) — Conventional cytotoxic chemotherapy-associated nephrotoxicity: consensus report of the 34th Acute Disease Quality Initiative (ADQI) WorkgroupCisplatin is identified as a leading cytotoxic nephrotoxin; the workgroup details preventive measures (adequate isotonic hydration, correction of volume depletion, avoidance of concurrent nephrotoxins, attention to electrolyte/magnesium wasting) and management of cisplatin-associated AKI, with a research agenda for knowledge gaps.Kidney Int · PMID 41881107
• ADQI (2026) — The nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupProvides expert-based statements (modified Delphi) on preventing and managing cisplatin/platinum-associated AKI, including isotonic IV hydration, attention to volume status and concomitant nephrotoxins, and incorporates evidence that IV magnesium supplementation may reduce cisplatin-associated AKI; emphasizes risk stratification and standardized AKI definitions.Nat Rev Nephrol · PMID 41361704
• SIRM (2022) — SIRM-SIN-AIOM: appropriateness criteria for evaluation and prevention of renal damage in the patient undergoing contrast medium examinations-consensus statements from Italian College of Radiology (SIRM), Italian College of Nephrology (SIN) and Italian Association of Medical Oncology (AIOM)Recommends eGFR-based renal risk assessment and pre/post-contrast isotonic saline or sodium bicarbonate hydration; advises maintaining a 5-7 day interval between iodinated contrast administration and cisplatin in cancer patients to reduce additive nephrotoxicity.Radiol Med · PMID 35303246
• KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerIdentifies platinum compounds (especially cisplatin) as leading cytotoxic causes of acute tubular injury, AKI, and electrolyte/magnesium wasting; calls for interdisciplinary onco-nephrology care, accurate GFR estimation, and individualized drug dosing in patients with reduced kidney function.Kidney Int · PMID 33126977
• KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationAddresses chemotherapy-associated AKI/CKD in hematologic cancer, GFR estimation and chemotherapy dosing in patients with reduced kidney function, and management priorities and research gaps for onco-nephrology care.Kidney Int · PMID 33276867
• ADDIKD (2025) — Integrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceProvides GRADE-based, drug-specific dose-adjustment recommendations for anticancer agents in kidney dysfunction (illustrated for methotrexate, cisplatin, carboplatin and nivolumab); the recommendations build on Part 1's standardised CKD-EPI eGFR assessment rather than Cockcroft-Gault creatinine clearance.EClinicalMedicine · PMID 40290844
• ADDIKD (2025) — Aligning kidney function assessment in patients with cancer to global practices in internal medicineThree consensus recommendations: assess kidney function by GFR (measured GFR or CKD-EPI eGFR), classify it using KDIGO categories, and use this uniform approach to dose anticancer drugs — moving cancer medicine away from Cockcroft-Gault estimated creatinine clearance.EClinicalMedicine · PMID 40290845
• ADDIKD (2025) — A methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEstablishes that, where RCT evidence is lacking, anticancer drug dosing recommendations in kidney dysfunction should be derived by critically appraising observational literature via GRADE combined with structured international multidisciplinary consensus voting.EClinicalMedicine · PMID 40290846
• KDIGO (2013) — Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Defines/stages AKI by serum creatinine and urine output; emphasizes avoiding nephrotoxins, maintaining euvolemia/perfusion, dose-adjusting drugs to kidney function, and monitoring high-risk patients — the framework applied to nephrotoxic anti-cancer agents.Crit Care · PMID 23394211
• KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknownsEvaluate and risk-stratify CKD, manage to delay progression and its complications, and practise explicit medication management and drug stewardship — the framework the atlas's G1–G5 eGFR banding and every renal dose-adjustment recommendation sit inside. Because the guideline excludes dialysis and transplant recipients by its own statement of scope, its recommendations do not carry to those settings, where this atlas's dialyzability and post-transplant guidance rests on other sources.Kidney Int · PMID 38519239
• KDIGO (2021) — Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesProvides the staging/treatment framework for drug-associated glomerular lesions (e.g., bisphosphonate- and interferon-related collapsing FSGS, VEGF-inhibitor podocytopathy/proteinuria), including immunosuppression and supportive RAAS-blockade strategies.Kidney Int · PMID 34556300
• KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisUpdates immunosuppressive induction (rituximab/cyclophosphamide), incorporates avacopan and lower-dose or glucocorticoid-sparing regimens — the management framework for drug- and checkpoint-inhibitor-associated ANCA/pauci-immune glomerulonephritis.Kidney Int · PMID 38388147
• KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisUpdates first-line lupus nephritis therapy to combination immunosuppression with the addition of belimumab or a calcineurin inhibitor (voclosporin) — informs management of immune-complex/lupus-like glomerulonephritis encountered with immunotherapy.Kidney Int · PMID 38182299
• KDIGO (2025) — Executive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Encourages liberal kidney biopsy and stricter proteinuria control (<0.5 g/d, ideally <0.3 g/d) with RAAS blockers, SGLT2 inhibitors, and targeted-release budesonide — the framework for IgA-dominant glomerular lesions, including those triggered by immune-modulating cancer therapy.Kidney Int · PMID 40975525