Is kidney injury from Methotrexate (high-dose) reversible?

Reversible. Typical onset: Acute — within hours to days of infusion..

How should kidney function be monitored during Methotrexate (high-dose) therapy?

Serial plasma MTX concentrations at scheduled intervals (e.g., 24/48/72 h post-infusion) until below the clearance threshold (~0.05-0.1 micromol/L); a rising or plateauing level signals nephrotoxicity and impending delayed clearance.; Serum creatinine/eGFR daily during and after the infusion; a creatinine rise is an early sign of crystal nephropathy and should trigger leucovorin escalation.; Urine pH with every void or bag during HD-MTX, targeting pH >=7.0 to keep MTX and 7-OH-MTX soluble; adjust IV sodium bicarbonate to maintain it.; Strict intake/output and body weight to confirm high urine flow and avoid volume depletion that promotes tubular crystal precipitation.; Review concomitant drugs that delay MTX clearance or displace it (NSAIDs, penicillins, probenecid, PPIs, sulfonamides) and hold them around dosing..

How can kidney injury from Methotrexate (high-dose) be prevented?

Aggressive hydration Urinary alkalinization to pH > 7 Leucovorin rescue Avoid interacting drugs

Who is at higher risk of kidney injury from Methotrexate (high-dose)?

Volume depletion; Acidic urine; Third-spacing (ascites/effusions); Interacting drugs (NSAIDs, PPIs, penicillins).

Back to explorer

Printable monograph

Antifolate

Methotrexate (high-dose)

Trexall · HD-MTX

Antifolate · approved 1953 · 10 citations · FAERS AKI reporting ROR 1.27 (95% CI 1.23–1.31, 4,486 AKI reports)

Up to date· through 2025

Deeply sourced8/9 · 7 signals

Met: 10 citations
Not met: 12+ references
Met: Accrued over 10+ years (span: 15y)
Met: Beyond single case reports
Met: High-impact journal
Met: Landmark reference
Met: Current through 2025
Met: Real-world FAERS signal

Describes how this page is sourced, not how dangerous the drug is. Thinly sourced means fewer of the sourcing signals are met — not that the agent is kidney-safe. A rule-based summary, not a formal certainty appraisal.

The crystal-former — precipitates in acidic urine and clogs the tubule.

ModerateAntifolate antimetabolite

OsteosarcomaALLCNS lymphoma

§01

Signature kidney injury

Signature lesion

Crystal / Obstructive Nephropathy

Representative incidence7%

2–12% range across studies

AKI in ~2–12% of patients and 2–39% of high-dose courses, with severe (AKIN grade ≥2) nephrotoxicity in ~2% of courses.Source: Howard et al., Oncologist 2016

Onset & rechallenge

Time to injuryAcute (~1–7 days)

AKI within hours to days of infusion.

Distilled from: “Acute — within hours to days of infusion.”

RechallengeOften tolerated

High-dose methotrexate has been safely resumed after AKI and glucarpidase rescue in a pediatric series. PMID 22252903 (opens PubMed in a new tab)

Long-term outlook & thresholds

Renal recoveryUsually reversible

HD-MTX crystal nephropathy is characteristically an acute, reversible AKI: once toxic exposure is cleared with intensified hydration/urinary alkalinization, high-dose leucovorin, and glucarpidase, renal function typically recovers, and HD-MTX can often be safely resumed after recovery. The injury is self-amplifying (reduced clearance raises MTX exposure), so prompt rescue is what determines the reversible course.PMID 20679598 (opens PubMed in a new tab)

Early-detection biomarkers

Serial plasma methotrexate concentration (24/48/72 h post-infusion) — Delayed methotrexate clearance / impending crystal-nephropathy AKI. The drug's own monitoring backbone and earliest signal: a rising or plateauing MTX level (vs the ~0.05-0.1 micromol/L clearance threshold) flags nephrotoxicity and delayed elimination before or alongside a creatinine rise, and drives leucovorin escalation and glucarpidase-rescue thresholds. After glucarpidase, avoid immunoassay: DAMPA cross-reacts and falsely elevates the reading, for about 48 h per this consensus but for 5 days in a published case (Young et al., PMID 31903191).PMID 29079637 (opens PubMed in a new tab)
Urinary KIM-1 and NGAL — Proximal tubular injury. Studied in 86 childhood acute lymphoblastic leukemia (ALL) survivors a median 6.6 years after treatment ended: median creatinine-indexed urinary KIM-1 and NGAL were higher than in 53 healthy peers, consistent with subclinical tubular damage — but neither cumulative methotrexate nor cumulative cyclophosphamide dose predicted the markers, so this is survivor-cohort evidence of late tubular injury after multi-agent therapy rather than a methotrexate-specific signal. Research-grade rather than a validated clinical trigger.PMID 33052454 (opens PubMed in a new tab)
Serum cystatin C (and urinary KIM-1/clusterin) — Early glomerular filtration decline, less confounded by muscle mass than creatinine. Evaluated prospectively as early kidney-injury markers around each HD-MTX dose. Honest caveat: in this pediatric HDMTX cohort the biomarker panel (cystatin C, KIM-1, clusterin, FGF23) did not identify kidney injury more frequently than serum creatinine alone, so cystatin C remains investigational here rather than an established replacement for creatinine-based monitoring.PMID 40549937 (opens PubMed in a new tab)

Long-term outcome and threshold data distilled from the agent's cited literature — educational, not a substitute for the primary sources.

Recovery across agents

Host risk modifiers

Germline / pharmacogenomic variants that shift an individual's risk of this agent's kidney injury. Research-grade — not routine clinical testing.

MTHFRc.677C>T (rs1801133, Ala222Val)
T allele raises risk of high-dose methotrexate renal toxicity (meta-analysis: recessive OR 3.54, 95% CI 1.81-6.90; allelic OR 1.89, 95% CI 1.18-3.02); reduced MTHFR activity is thought to potentiate MTX antifolate/tubular injury PMID 34744734 (opens PubMed in a new tab)
SLCO1B1rs11045879 (intronic; LD with reduced-function c.521T>C/rs4149056)
Low-clearance genotype slows OATP1B1-mediated MTX elimination (genome-wide significant, meta-analysis P=3.13x10^-19), prolonging high plasma MTX exposure - the principal driver of HD-MTX crystal/tubular nephrotoxicity; carriers warrant closer level monitoring and hydration/leucovorin PMID 23233662 (opens PubMed in a new tab)

§02

Renal toxicities, ranked

This agent's kidney lesions ordered by prominence — the #1 signature lesion first, then secondary and rare patterns. Cited incidence is shown where a citable figure exists; otherwise the tier stands qualitatively.

Crystal / Obstructive Nephropathy#1 · Signature1.8%PMID 15139068 (opens PubMed in a new tab)
~1.8% clinically significant (grade >=2) HDMTX nephrotoxicity in a 3887-patient osteosarcoma cohort; any-grade nephrotoxicity reaches ~38% (mostly grade 1-2) and AKI ~9.5% in other series. Crystalline precipitation of MTX and 7-OH-MTX in the acidic tubular lumen is the dominant mechanism.
Acute Tubular NecrosisSecondaryqualitative — no citable incidence
Direct death of tubular epithelial cells — the dose-limiting lesion of the platinums and zoledronate.

Toxicity fingerprint

Tap a signature to trace where it strikes the nephron.

7%incidence

SeverityModerate

ReversibilityReversible

Evidence10 citations

Nephron map

Proximal Tubule

Distal Tubule / Collecting Duct

Tubular LumenThe urine flow path

Crystal / Obstructive Nephropathy

Intratubular precipitation of drug or metabolite — high-dose methotrexate and tumor lysis crystals.

§03

Kidney injury

Deep diveHigh-dose methotrexate crystal nephropathyHigh-dose methotrexate is cleared by the kidney, so when it and its poorly-soluble metabolite crystallize in the acidic tubular lumen the kidney injures itself — and because that same kidney is what clears the drug, injury feeds a spiral of rising levels that leucovorin cannot break but an enzyme can.Appears in 1 documented synergy combination

Mechanism of kidney injury

Methotrexate and its 7-OH metabolite are poorly soluble in acidic urine and precipitate as intratubular crystals, causing obstruction plus direct tubular toxicity. The resulting AKI impairs methotrexate clearance, spiraling into systemic toxicity.

Clinical presentation

Non-oliguric AKI, rising creatinine, markedly delayed methotrexate clearance and crystalluria.

Management

Intensify hydration and alkalinization, increase leucovorin, and give glucarpidase (cleaves plasma MTX) for severe AKI. Hemodialysis is relatively ineffective.Lesion-level management framework

Risk factors

Volume depletion
Acidic urine
Third-spacing (ascites/effusions)
Interacting drugs (NSAIDs, PPIs, penicillins)

Prevention

Aggressive hydration
Urinary alkalinization to pH > 7
Leucovorin rescue
Avoid interacting drugs

Anticancer mechanism· how it treats cancer

Inhibits dihydrofolate reductase, blocking purine and thymidylate synthesis. High-dose protocols treat osteosarcoma, ALL and CNS lymphoma.

§04

Clinical depth

Renal dose adjustment

High-dose MTX (>500 mg/m2) is predominantly renally cleared, so it is contraindicated or sharply dose-reduced when CrCl/eGFR is low and is generally withheld until any prior AKI resolves; nephrotoxicity itself is the chief driver of toxic exposure because delayed clearance prolongs systemic MTX and amplifies marrow/mucosal/hepatic toxicity. Rather than a single fixed CrCl band, practice is to confirm adequate baseline renal function, intensify hydration and urinary alkalinization, and titrate leucovorin rescue against serial MTX levels (Bleyer-type nomogram).

Dialyzability & ESKD dosing

Conventional intermittent hemodialysis clears MTX inefficiently and is followed by substantial post-dialysis rebound from tissue redistribution, so it is not a reliable rescue for MTX overexposure; high-flux/high-efficiency HD and continuous modalities (CVVHD) remove somewhat more but still lag far behind enzymatic clearance. Glucarpidase (carboxypeptidase-G2), which cleaves circulating MTX to inactive metabolites within minutes, is the definitive intervention for MTX-induced AKI with toxic levels and largely supplants dialysis.

Differential diagnosis

MTX crystal nephropathy is suggested by AKI arising during or shortly after a HD-MTX infusion together with a rising/plateauing MTX level (delayed clearance), often a relatively bland urinalysis, and an acidic, low-volume urine - distinct from prerenal azotemia (low FeNa, volume-responsive) and from other tubular toxins. Concurrent tumor lysis (uric acid crystals) and contrast or aminoglycoside ATN are the main mimics; the temporal link to MTX dosing and the elevated drug level point to MTX as the culprit.

Monitoring

Serial plasma MTX concentrations at scheduled intervals (e.g., 24/48/72 h post-infusion) until below the clearance threshold (~0.05-0.1 micromol/L); a rising or plateauing level signals nephrotoxicity and impending delayed clearance.
Serum creatinine/eGFR daily during and after the infusion; a creatinine rise is an early sign of crystal nephropathy and should trigger leucovorin escalation.
Urine pH with every void or bag during HD-MTX, targeting pH >=7.0 to keep MTX and 7-OH-MTX soluble; adjust IV sodium bicarbonate to maintain it.
Strict intake/output and body weight to confirm high urine flow and avoid volume depletion that promotes tubular crystal precipitation.
Review concomitant drugs that delay MTX clearance or displace it (NSAIDs, penicillins, probenecid, PPIs, sulfonamides) and hold them around dosing.

Key trials & series

Ramsey et al., Oncologist 2018 - consensus guideline on monitoring, prevention, and management of HD-MTX-induced nephrotoxicity, codifying aggressive hydration/alkalinization, the leucovorin nomogram, and glucarpidase use.
Widemann et al., expanded-access/compassionate-use glucarpidase series - rapid (>97%) reduction in plasma MTX and renal recovery in MTX-induced AKI, supporting glucarpidase (Voraxaze) approval.
Howard et al., Oncologist 2016 ('Preventing and Managing Toxicities of High-Dose Methotrexate') - clinical-review framework for risk stratification, supportive measures, and glucarpidase indications.

Clinical pearls

The lesion is largely a crystal nephropathy: poorly soluble MTX and its metabolite 7-OH-MTX precipitate in acidic distal tubules, so prophylaxis hinges on high urine flow plus alkalinization to pH >=7.0 - solubility of MTX rises several-fold between pH 6 and 7.
Nephrotoxicity is self-amplifying: reduced clearance raises MTX exposure, which worsens marrow, mucosal, hepatic, and renal injury - hence the urgency of serial levels and prompt rescue.
Leucovorin rescues normal tissues but does NOT lower the MTX level; for genuine AKI with toxic concentrations, glucarpidase is the agent that actually reduces drug burden, and leucovorin must be continued (and timed apart from glucarpidase, which also degrades leucovorin).
Avoid measuring MTX by immunoassay after glucarpidase: DAMPA, an inactive cleavage product, cross-reacts and falsely elevates the reported level - for about 48 h per the consensus guideline (Ramsey et al., PMID 29079637), but for 5 days in a published case (Young et al., PMID 31903191); use chromatographic assays.

Beyond the kidney — non-renal toxicities· 4 organ systems

Class-level context for the major non-renal toxicities of the Antifolate class.

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

§05

References

7 primary references — trials, cohorts, mechanism, and reviews. Single-patient case reports are listed separately below, graded by strength. Citation metadata via PubMed / NLM.

Evidence accrual

7 references · 2010–2025 · 3 since 2023

Primary (non–case-report) references per year — a proxy for how actively the agent's renal literature is accruing. Recent years are highlighted. Reflects curation depth, not a systematic bibliometric count.

Case reports — ranked by strength· 3

Single-patient and small-series reports, graded by evidentiary strength — A Strong (biopsy-proven plus a series and/or positive rechallenge), B Moderate, and C Limited (a single clinically-diagnosed case). Strongest first. Grades are inferred automatically from each report's abstract and journal — a heuristic ranking aid, not a formal quality appraisal.

CaseB · ModerateMethotrexate Crystals on Electron Microscopy of Kidney Biopsy for Acute Kidney Injury.Fang D et al. · Kidney Med 2024 · PMID 39634329Kidney biopsy in a patient with primary CNS lymphoma on high-dose methotrexate showed methotrexate crystals characterized on electron microscopy, demonstrating crystalline (obstructive) nephropathy as the cause of AKI.CaseC · LimitedAcute kidney injury after high-dose methotrexate application - case report.Markova P et al. · Folia Med (Plovdiv) 2025 · PMID 41163608A 13-year-old with osteosarcoma developed grade 4 AKI from high-dose methotrexate via tubular precipitation (crystalline nephropathy) requiring renal replacement therapy, then tolerated dose-escalated re-challenge.CaseC · LimitedCrystalline Nephropathy With High-Dose Methotrexate in a Patient With Primary CNS Lymphoma: A Case Report.Sami FL et al. · Cureus 2022 · PMID 35865443Describes high-dose methotrexate-induced crystalline nephropathy with birefringent needle-shaped urinary crystals and AKI despite hydration and alkalinization, treated with glucarpidase.

Conference abstracts & journal reports· 1 non-PubMed

Non-PubMed sources — conference abstracts (e.g. ASN Kidney Week, badged Abstract) and case reports from non-indexed field journals (e.g. Journal of Onco-Nephrology, badged Journal). Included for completeness; weigh below peer-reviewed PubMed citations.

AbstractDAMPAned Methotrexate Levels: A Case Report of Acute Methotrexate ToxicityASN Kidney Week 2019 2019 · Abstract TH-PO149Severe high-dose-methotrexate crystal/tubular AKI (creatinine to 608 µmol/L) rescued with glucarpidase, achieving full renal recovery without dialysis — with the caveat that DAMPA-metabolite interference made immunoassay MTX levels read falsely high for >5 days after glucarpidase, while mass spectrometry showed the true level.

FDA label — boxed warning & renal dosing· boxed warning · renal impairment

Quoted verbatim from this agent's current FDA label (Sep 2026) — not paraphrased or interpreted. Full label on DailyMed .

Boxed warning

WARNING: EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, BENZYL ALCOHOL TOXICITY, and OTHER SERIOUS ADVERSE REACTIONS Methotrexate Injection can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, Methotrexate Injection is contraindicated in pregnancy. Advise females and males of reproductive potential to use effective contraception [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and Use in Specific Populations ( 8.1 , 8.3 )]. Methotrexate Injection can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, Methotrexate Injection is contraindicated in pregnancy. Advise females and males of reproductive potential to use effective contraception [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and Use in Specific Populations ( 8.1 , 8.3 )]. Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis [see Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )]. Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis [see Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )]. Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis. Use only preservative-free…

Renal impairment — from the label

Methotrexate elimination is reduced in patients with renal impairment [creatinine clearance (CLcr) less than 90 mL/min, calculated using Cockcroft-Gault] [see Clinical Pharmacology ( 12.3 )]. Patients with renal impairment are at increased risk for methotrexate adverse reactions. Follow recommendations to promote methotrexate elimination and decrease risk of acute kidney injury and other methotrexate toxicities in patients who are receiving intermediate- or high-dose regimens [see Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.6 )]. Consider reducing the dose or discontinuing Methotrexate Injection in patients with renal impairment as appropriate.

What gets reported — FAERS

Everything below is FAERS — adverse events someone chose to report, about 489,788 of them for this agent. Nobody counts the patients who were fine, so none of these numbers is an incidence, a risk, or a rate: they describe what gets reported, shaped by a drug's fame, its indication, and who was watching. How these numbers work.

Reporting odds ratio (ROR) — is kidney injury named in this agent's reports more often than in every other drug's? Above 1 means yes, disproportionately.
Renal phenotypes — the same question asked separately for each kind of kidney injury, so the ratios differ from the overall one and from each other.
Outcomes — a share of this agent's own reports, not of patients: how many were filed as involving a death or a hospitalization. Not a case-fatality rate.

FAERS reported renal phenotypes· 6 signals

Only significant signals appear (95% CI lower bound above 1) — a phenotype missing here was tested and did not reach significance, except Prerenal / Hemodynamic AKI, Pseudo-AKI, Renal Cysts, Chronic Interstitial Nephropathy — outside the clinician-reviewed MedDRA term map, never queried — and ATN and AIN, queried but biopsy-bound: real cases are filed as generic “acute kidney injury”, so their absence is not a negative. As of 2026-10-01.

What reporting says about this profile's documented lesions

Crystal / Obstructive Nephropathycorroborated · ROR 2.07
Acute Tubular Necrosiscorroborated · ROR 1.14

Thrombotic Microangiopathy

ROR 2.9195% CI 2.73–3.10· 1,004 reports

Hemorrhagic Cystitis

ROR 2.2595% CI 2.17–2.33· 3,523 reports

Hypertension

ROR 2.2395% CI 2.20–2.26· 19,098 reports

Crystal / Obstructive Nephropathy

ROR 2.0795% CI 1.99–2.16· 2,624 reports

Acute Tubular Necrosis

ROR 1.1495% CI 1.01–1.29· 262 reports

Glomerular Injury / Proteinuria

ROR 1.1295% CI 1.04–1.21· 761 reports

FAERS outcomes & reporting trend· 7.7% of reports w/ death · 27.2% w/ hospitalization

7.7%

Reported with a death outcome

37,720 of 489,788 reports

27.2%

Reported with hospitalization

133,305 of 489,788 reports

Reports per year

Yearly FAERS report volume · most recent year is partial.

FAERS adverse-event signal — all organ systems· 7 systems · 489,788 reports

Bars rank systems by summed reaction-term mentions (a report counts once per term it names) — an ordinal “more vs less reported” cue, not a tally of distinct reports. Renal & urinary first. As of 2026-10-01.

Disproportionality (acute kidney injury):ROR 1.2795% CI 1.23–1.31· 4,486 AKI reports ·AKI is reported disproportionately more often than for other drugs (CI entirely above 1) — a hypothesis-generating signal, not proof of causation.

Musculoskeletal

Rheumatoid Arthritis42,798Arthralgia40,826Joint Swelling25,029Pain In Extremity20,089Musculoskeletal Stiffness14,826

General / constitutional

Pain39,717Fatigue33,048Pyrexia18,945Malaise17,518Peripheral Swelling15,007

Gastrointestinal

Nausea29,000Diarrhoea20,863Vomiting17,469Abdominal Discomfort16,222

Immune / infection

Drug Hypersensitivity19,662Pneumonia18,284Nasopharyngitis15,599Infection15,227

Skin

Rash22,473Alopecia17,463

Nervous system

Headache23,433

Respiratory

Dyspnoea16,359

Guidelines & consensus· 15

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.

ADQIConventional cytotoxic chemotherapy-associated nephrotoxicity: consensus report of the 34th Acute Disease Quality Initiative (ADQI) WorkgroupKidney Int 2026 · PMID 41881107Cisplatin 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.Intl. Expert PanelConsensus Guideline for Use of Glucarpidase in Patients with High-Dose Methotrexate Induced Acute Kidney Injury and Delayed Methotrexate ClearanceOncologist 2018 · PMID 29079637For HDMTX infusions <=24 h, glucarpidase may be indicated when the methotrexate concentration is >30 uM at 36 h, >10 uM at 42 h, or >5 uM at 48 h together with a significantly elevated serum creatinine (indicating HDMTX-induced AKI); administer optimally within 48-60 h of infusion start, as it is far less effective beyond 60 h.

General onco-nephrology references

ADQIThe nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupNat Rev Nephrol 2026 · PMID 41361704Provides 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.SIRMSIRM-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)Radiol Med 2022 · PMID 35303246Recommends 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.KDIGOKDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerKidney Int 2020 · PMID 33126977Identifies 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.KDIGOKDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationKidney Int 2020 · PMID 33276867Addresses 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.ADDIKDIntegrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceEClinicalMedicine 2025 · PMID 40290844Provides 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.ADDIKDAligning kidney function assessment in patients with cancer to global practices in internal medicineEClinicalMedicine 2025 · PMID 40290845Three 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.ADDIKDA methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEClinicalMedicine 2025 · PMID 40290846Establishes 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.KDIGODiagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Crit Care 2013 · PMID 23394211Defines/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.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknownsKidney Int 2024 · PMID 38519239Evaluate 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.KDIGOExecutive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesKidney Int 2021 · PMID 34556300Provides 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.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisKidney Int 2024 · PMID 38388147Updates 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.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisKidney Int 2024 · PMID 38182299Updates 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.KDIGOExecutive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Kidney Int 2025 · PMID 40975525Encourages 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.

Where Methotrexate (high-dose) sits in nephrotoxicity space — each dot is an anti-cancer agent, positioned so neighbors share a kidney-injury phenotype. Its 6 closest are filled and lead to a numbered marker, matching the numbered cards below.

Position is a 2-D projection (MDS) of each agent's injury signature, nephron target, severity, and class, so two dots can sit close on the page while differing on an axis the projection flattened — the numbered ranking is computed from the full metric, not from the distance you see. Open the full map.

Phenotype-similar agents· the numbered markers on the map above

Raltitrexed

Tomudex · Antifolate (TS inhibitor)

Profile

Renally cleared antifolate; exposure ~doubles in renal impairment; forerunner CB3717 withdrawn for crystal nephrotoxicity.

ATNXTAL

Moderate#1 · 99% phenotype match

Pralatrexate

Folotyn · Antifolate

Profile

Antifolate with MTX-like renal handling.

XTALATN

Moderate#2 · 89% phenotype match

CAR-T cell therapy

Kymriah · Yescarta · CAR-T cell therapy

Profile

CRS-driven prerenal AKI and tumor lysis.

PREATNXTAL

Moderate#3 · 65% phenotype match

Lurbinectedin

Zepzelca · Marine alkylating agent

Profile

Rhabdomyolysis risk in small-cell lung cancer.

ATNLYTEXTAL

Mild#4 · 65% phenotype match

Clofarabine

Clolar · Purine analog

Profile

Capillary-leak / SIRS-like AKI and tumor lysis.

PREATNGLOM

Moderate#5 · 59% phenotype match

Blinatumomab

Blincyto · BiTE (CD19×CD3)

Profile

CRS and tumor lysis → AKI.

PREATNXTAL

Moderate#6 · 58% phenotype match

Compare Methotrexate (high-dose) with its nearest agents

Nearest agents by kidney-injury phenotype (shared injuries, nephron target, severity, class) — a similarity approximation, not a claim of shared drug identity or mechanism.

Kidney risk across Antimetabolites

Same-class agents ordered by their documented kidney-injury profile — atlas severity, an acute-kidney-injury FAERS signal, and how many injury types each is documented to cause. Agents nearer the top carry the lighter documented renal profile.

A comparison of documented kidney-injury data within one drug class — not a substitution recommendation. Efficacy, indication, and non-renal toxicity differ between these agents and are out of scope here. Educational only, not medical advice.

Who studies this

The leading contributors to Methotrexate (high-dose)’s clinical kidney literature on PubMed, ranked by a blend of publication volume and citation impact — filtered toward clinical work via the PubMed Humans heading and clinical publication types (trials, cohorts, case reports, guidelines, reviews). Names link to that author’s work on Methotrexate (high-dose); the PMIDs beside each name are up to three of their most recent papers on it, not the full count.

Ranked by a 50/50 blend of publication volume and a position-weighted, capped Relative Citation Ratio (NIH iCite) on this agent’s renal literature; the citation count shown is the raw total, not the ranking score — counted over the 184 clinical records among the 300 most-relevant of 1,317 PubMed matches, so counts are within-sample — bibliometric context, not an endorsement or a measure of clinical authority.