Pralatrexate
Folotyn · Antifolate
Antifolate with MTX-like renal handling.
XTALATN
ModerateOpen →
Antifolate
Methotrexate (high-dose)
Trexall · HD-MTX
The crystal-former — precipitates in acidic urine and clogs the tubule.
ModerateAntifolate antimetabolite · approved 1953
OsteosarcomaALLCNS lymphoma
Signature kidney injury
Crystal / Obstructive Nephropathy
Representative incidence7%
AKI in ~2–12% of high-dose courses.
Source: Howard et al., Oncologist 2016
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
0%incidence
SeverityModerate
ReversibilityReversible
Evidence0 refs
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.
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.
Onset
Acute — within hours to days of infusion.
Reversibility
Reversible
Anticancer mechanism
Inhibits dihydrofolate reductase, blocking purine and thymidylate synthesis. High-dose protocols treat osteosarcoma, ALL and CNS lymphoma.
Management
Intensify hydration and alkalinization, increase leucovorin, and give glucarpidase (cleaves plasma MTX) for severe AKI. Hemodialysis is relatively ineffective.
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
- Monitor MTX levels
Note · Glucarpidase is the key rescue antidote for delayed clearance.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Tubular Lumen
The urine flow path
Injury signatures
Crystal / Obstructive NephropathyAcute Tubular Necrosis
Beyond the kidney
Class-level context for the major non-renal toxicities of antifolates.
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
Evidence
5 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkPreventing and Managing Toxicities of High-Dose Methotrexate.Howard SC et al. · Oncologist 2016 · PMID 27496039Crystal nephropathy mechanism, 2–12% AKI incidence and prevention.PMIDConsensus Guideline for Use of Glucarpidase in Patients with High-Dose Methotrexate Induced Acute Kidney Injury and Delayed Methotrexate Clearance.Ramsey LB et al. · Oncologist 2017 · PMID 29079637Expert thresholds for glucarpidase rescue.LandmarkGlucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome.Widemann BC et al. · J Clin Oncol 2010 · PMID 20679598Glucarpidase cuts plasma MTX 98.7% in 15 minutes.PMIDResumption of high-dose methotrexate after acute kidney injury and glucarpidase use in pediatric oncology patients.Christensen AM et al. · Cancer 2012 · PMID 22252903St. Jude series quantifying glucarpidase use and safe rechallenge.PMIDThe use of glucarpidase as a rescue therapy for high dose methotrexate toxicity - a review of pharmacological and clinical data.Kielbowski K et al. · Expert Opin Drug Metab Toxicol 2023 · PMID 37846862Recent review of glucarpidase pharmacology and efficacy.
Related agents
Other agents sharing the same signature kidney injury.