Methotrexate (high-dose)

Crystal / Obstructive Nephropathy — representative incidence ~7% (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

Reported injury signatures: Crystal / Obstructive Nephropathy, Acute Tubular Necrosis.

1. Crystal / Obstructive NephropathyPrimary~1.8%~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.
2. Acute Tubular NecrosisSecondary

Acute (~1–7 days) — AKI within hours to days of infusion.

Rechallenge: Often tolerated — High-dose methotrexate has been safely resumed after AKI and glucarpidase rescue in a pediatric series.

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

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

• 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.

• 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.

• 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.

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
• Intl. Expert Panel (2018) — Consensus Guideline for Use of Glucarpidase in Patients with High-Dose Methotrexate Induced Acute Kidney Injury and Delayed Methotrexate ClearanceFor 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.Oncologist · PMID 29079637
• 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