Methotrexate (high-dose)
Trexall · Antifolate
Crystal nephropathy; glucarpidase rescue.
XTALATN
Moderate#1 · 89% phenotype match
Pralatrexate
Folotyn · PDX
Antifolate · approved 2009 · 8 citations
Aging evidence· through 2022
Fairly sourced6/9 · 5 signals
- Met: 8 citations
- Not met: 12+ references
- Met: Accrued over 10+ years (span: 21y)
- Met: Beyond single case reports
- Met: High-impact journal
- Met: Landmark reference
- Not met: Current through 2022
- Not 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.
A potent antifolate that shares methotrexate's appetite for renal handling and its crystal risk.
ModerateAntifolate
Relapsed or refractory peripheral T-cell lymphoma
§01
Signature kidney injury
Signature lesion
Drug-specific renal-injury rates are not well quantified; renal handling resembles methotrexate, and severe renal impairment substantially increases pralatrexate exposure and toxicity (more cytopenias/mucositis). Antifolate crystal-related tubular injury is therefore a class-based, conservative concern rather than a measured rate.Source: Kelly et al., Cancer Chemother Pharmacol 2016
Onset & rechallenge
Time to injuryVariable / unpredictable
Occurs during treatment cycles in an exposure-dependent manner.
Distilled from: “During treatment cycles; exposure-dependent.”
§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.
Intratubular precipitation of drug or metabolite — high-dose methotrexate and tumor lysis crystals.
Direct death of tubular epithelial cells — the dose-limiting lesion of the platinums and zoledronate.
§03
Kidney injury
Mechanism of kidney injury
By analogy to methotrexate, a renally cleared antifolate can precipitate in the acidic distal tubular lumen, causing intratubular crystal deposition with direct tubular toxicity - a vicious cycle in which falling clearance prolongs toxic exposure. Pralatrexate is partly renally excreted, and PK studies show reduced renal clearance of its diastereomers in renal impairment; systemic exposure was not markedly increased once the dose was reduced in severe impairment, though cytopenias were more frequent, so dose reduction is advised in severe renal impairment. High-affinity RFC-1 uptake and polyglutamation underlie potency and the methotrexate-like handling.
Clinical presentation
Rising creatinine with possible tubular injury; systemically, dose-limiting mucositis/stomatitis and myelosuppression that worsen with reduced clearance. Renal-specific histologic findings are not well characterized in published series.
Management
Hold/reduce dose for renal dysfunction or significant mucositis/cytopenias; supportive hydration and electrolyte correction. Manage analogous to antifolate toxicity, recognizing limited drug-specific evidence.Lesion-level management framework
Risk factors
- Renal impairment (increased exposure; severe RI requires dose reduction)
- Volume depletion and aciduria
- Inadequate folate/B12 supplementation
- Concurrent nephrotoxins or drugs affecting folate handling
Prevention
- Folic acid and vitamin B12 supplementation per labeling to mitigate toxicity
- Dose reduction/monitoring in renal impairment; avoid additive nephrotoxins
Anticancer mechanism· how it treats cancer
Folate analog metabolic inhibitor engineered for high affinity to the reduced folate carrier (RFC-1) and efficient polyglutamation by folylpolyglutamate synthetase, depleting reduced folates and inhibiting dihydrofolate reductase and de novo DNA synthesis. Approved for relapsed/refractory peripheral T-cell lymphoma.
§04
Clinical depth
Renal dose adjustment
In the dedicated renal-impairment PK study, severe renal impairment (eGFR 15-29) requires dose reduction to 15 mg/m2 owing to reduced clearance and higher exposure, while ESRD (eGFR <15, with or without dialysis) is best avoided given serious adverse reactions (reduce only if benefit justifies risk); mild-moderate impairment (eGFR 30-59) is tolerated near standard dosing with monitoring. Hold/reduce for grade 3-4 mucositis or cytopenias.
Dialyzability & ESKD dosing
Pralatrexate is partly renally handled, so some dialytic removal is expected pharmacologically, but no study has characterized it and no post-HD supplemental dose is defined; the dedicated renal-impairment study enrolled no ESRD or dialysis cohort, and the label advises avoiding ESRD (eGFR <15, with or without dialysis) unless the benefit justifies the risk, reserving the reduced 15 mg/m2 dose for severe impairment (eGFR 15-29).
Differential diagnosis
Antifolate crystal/tubular nephropathy (rising creatinine with reduced clearance, mucositis as a parallel toxicity) is inferred by analogy to methotrexate; distinguish from prerenal azotemia (volume-responsive) and from disease-related renal involvement. Pralatrexate-specific biopsy data are limited, so attribution rests on temporality and the exposure-toxicity relationship.
Monitoring
- Mucositis/stomatitis grade before each weekly dose (dose-limiting)
- Homocysteine/methylmalonic acid or documented folate-B12 supplementation
Key trials & series
- PROPEL (O'Connor JCO 2011) - pivotal phase II registration trial in relapsed/refractory PTCL
- Kelly Cancer Chemother Pharmacol 2016 - phase I PK across mild/moderate/severe renal impairment driving dose reduction
- FDA accelerated-approval summary (Malik Clin Cancer Res 2010)
Clinical pearls
- Think methotrexate: pralatrexate is renally handled, so renal impairment sharply raises exposure and mucositis/myelosuppression.
- Folate and B12 supplementation are not optional - they materially reduce mucositis and hematologic toxicity.
- Severe renal impairment mandates dose reduction (around 15 mg/m2) - do not give full dose and watch.
Where it strikes· nephron segments & injury signatures
Nephron segments
Tubular Lumen
The urine flow path
Injury signatures
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
8 primary references — trials, cohorts, mechanism, and reviews. Citation metadata via PubMed / NLM.
Evidence accrual
8 references · 2001–2022 · 1 since 2020Primary (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.
- 1.LandmarkPhase 1 study evaluating the safety and pharmacokinetics of pralatrexate in relapsed/refractory advanced solid tumors and lymphoma patients with mild, moderate, and severe renal impairment.Kelly KR et al. · Cancer Chemother Pharmacol · 2016 · PMID 27638045Key renal-impairment PK study; reduced clearance and dose reduction (to ~15 mg/m2) in severe RI/ESRD.
- 2.Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study.O'Connor OA et al. · J Clin Oncol · 2011 · PMID 21245435Pivotal registration trial defining the efficacy and dose-limiting mucositis toxicity profile.
- 3.Folotyn (pralatrexate injection) for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma: U.S. Food and Drug Administration drug approval summary.Malik SM et al. · Clin Cancer Res · 2010 · PMID 20739433FDA approval summary: pharmacology, dosing and folate/B12 supplementation requirements.
- 4.Pralatrexate is synergistic with the proteasome inhibitor bortezomib in in vitro and in vivo models of T-cell lymphoid malignancies.Marchi E et al. · Clin Cancer Res · 2010 · PMID 20501616Mechanism: enhanced RFC-1 uptake and polyglutamation underpinning methotrexate-like renal handling.
- 5.Pralatrexate is an effective treatment for relapsed or refractory transformed mycosis fungoides: a subgroup efficacy analysis from the PROPEL study.Foss F et al. · Clin Lymphoma Myeloma Leuk · 2012 · PMID 22542448PROPEL subgroup with tolerability/toxicity data relevant to dosing.
- 6.Preventing and Managing Toxicities of High-Dose Methotrexate.Howard SC et al. · Oncologist · 2016 · PMID 27496039Defines the antifolate crystal-nephropathy/tubular-toxicity paradigm relevant to pralatrexate's handling.
- 7.Acute methotrexate-induced crystal nephropathy.Blum MF et al. · Kidney Int · 2022 · PMID 35065698Illustrates intratubular antifolate crystal nephropathy as the class mechanism.
- 8.Anticancer drug-induced kidney disorders.Kintzel PE · Drug Saf · 2001 · PMID 11219485Onconephrology review of antimetabolite/antifolate renal effects.
FDA label — boxed warning & renal dosing· renal impairment
Quoted verbatim from this agent's current FDA label (Aug 2025) — not paraphrased or interpreted. Full label on DailyMed .
Renal impairment — from the label
No dosage modification is recommended for patients with mild or moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m 2 based on MDRD). For patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m 2 ), reduce the recommended dose of pralatrexate injection [ see Dosage and Administration (2.3) ] . Serious adverse drug reactions, including TEN and mucositis, have been reported in patients with ESRD undergoing dialysis. Avoid the use of pralatrexate injection in patients with ESRD with or without dialysis. If the potential benefit of administration justifies the potential risk, monitor renal function and reduce the pralatrexate injection dose based on adverse reactions [ see Dosage and Administration (2.3) , Warnings and Precautions (5.6) ] .
What gets reported — FAERS
Everything below is FAERS — adverse events someone chose to report, about 205 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· 3 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 NephropathyNo disproportionate reporting — This phenotype IS reportable and this agent has enough reports, yet the reporting is not disproportionate — the one genuinely informative negative of the four.
- Acute Tubular NecrosisNot measurable in reporting — Reporters cannot reliably name this lesion, so its absence from FAERS is expected and is not evidence against the documented injury.
SIADH / Hyponatremia
ROR 7.8295% CI 3.47–17.62· 6 reports
Electrolyte Disturbance
ROR 5.5895% CI 2.95–10.53· 10 reports
Hemorrhagic Cystitis
ROR 4.4895% CI 1.43–14.01· 3 reports
FAERS outcomes & reporting trend· 18% of reports w/ death · 40.5% w/ hospitalization
18%
Reported with a death outcome
37 of 205 reports
40.5%
Reported with hospitalization
83 of 205 reports
Reports per year
- 2015: 6 reports
- 2016: 12 reports
- 2017: 7 reports
- 2018: 5 reports
- 2019: 10 reports
- 2020: 23 reports
- 2021: 20 reports
- 2022: 16 reports
- 2023: 22 reports
- 2024: 20 reports
- 2025: 29 reports
- 2026: 5 reports
Yearly FAERS report volume · most recent year is partial.
FAERS adverse-event signal — all organ systems· 7 systems · 205 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 0.6795% CI 0.09–4.78· 1 AKI reports ·no disproportionate AKI reporting signal (CI spans 1).
Blood & lymphatic
Anaemia18Neutropenia18Febrile Neutropenia17Thrombocytopenia17Neutropenic Sepsis14
Gastrointestinal
Mucosal Inflammation18Stomatitis17Diarrhoea14Nausea12
General / constitutional
Pyrexia21Fatigue12
Nervous system
Generalised Tonic-Clonic Seizure13
Immune / infection
Sepsis10
Metabolic & electrolyte
Decreased Appetite9
Respiratory
Dyspnoea9
Guidelines & consensus· 14
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.
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 Pralatrexate 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.
Phenotype-similar agents· the numbered markers on the map above
Profile
Raltitrexed
Tomudex · Antifolate (TS inhibitor)
Renally cleared antifolate; exposure ~doubles in renal impairment; forerunner CB3717 withdrawn for crystal nephrotoxicity.
ATNXTAL
Moderate#2 · 88% phenotype match
CAR-T cell therapy
Kymriah · Yescarta · CAR-T cell therapy
CRS-driven prerenal AKI and tumor lysis.
PREATNXTAL
Moderate#3 · 58% phenotype match
Lurbinectedin
Zepzelca · Marine alkylating agent
Rhabdomyolysis risk in small-cell lung cancer.
ATNLYTEXTAL
Mild#4 · 53% phenotype match
Clofarabine
Clolar · Purine analog
Capillary-leak / SIRS-like AKI and tumor lysis.
PREATNGLOM
Moderate#5 · 53% phenotype match
Fludarabine
Fludara · Purine analog
Tumor lysis; accumulates in renal impairment.
XTALPRELYTE
Moderate#6 · 53% phenotype match
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.
- 1CapecitabinePRE — Prerenal / Hemodynamic AKIMild
- 2CladribineXTAL — Crystal / Obstructive NephropathyMild
- 35-FluorouracilTMA — Thrombotic MicroangiopathyFAERS AKIMild
- 4HydroxyureaXTAL — Crystal / Obstructive NephropathyFAERS AKIMild
- 5NelarabineXTAL — Crystal / Obstructive NephropathyFAERS AKIMild
- 6DecitabineXTAL — Crystal / Obstructive NephropathyFAERS AKIMild
- 7Trifluridine/tipiracilPRE — Prerenal / Hemodynamic AKIModerate
- 8Pralatrexate· this agentXTAL — Crystal / Obstructive NephropathyModerate
- 9RaltitrexedATN — Acute Tubular NecrosisModerate
- 10Carmofur (HCFU)TMA — Thrombotic MicroangiopathyModerate
- 11DoxifluridineTMA — Thrombotic MicroangiopathyModerate
- 12PentostatinATN — Acute Tubular NecrosisModerate
- 13Methotrexate (high-dose)XTAL — Crystal / Obstructive NephropathyFAERS AKIModerate
- 14FludarabineXTAL — Crystal / Obstructive NephropathyFAERS AKIModerate
- 15AzacitidineFANC — Fanconi SyndromeFAERS AKIModerate
- 16ClofarabinePRE — Prerenal / Hemodynamic AKIFAERS AKIModerate
- 17CytarabineXTAL — Crystal / Obstructive NephropathyFAERS AKIModerate
- 18PemetrexedCIN — Chronic Interstitial NephropathyFAERS AKIModerate
- 19Tegafur-uracil (UFT)TMA — Thrombotic MicroangiopathySevere
- 20GemcitabineTMA — Thrombotic MicroangiopathyFAERS AKISevere
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.