Methotrexate (high-dose)
Trexall · Antifolate
Crystal nephropathy; glucarpidase rescue.
XTALATN
ModerateOpen →
Antifolate
Pralatrexate
Folotyn · PDX
A potent antifolate that shares methotrexate's appetite for renal handling and its crystal risk.
ModerateAntifolate · approved 2009
Relapsed or refractory peripheral T-cell lymphoma
Signature kidney injury
Crystal / Obstructive Nephropathy
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
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 and markedly higher systemic exposure in severe renal impairment, amplifying mucositis and myelosuppression. 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.
Onset
During treatment cycles; exposure-dependent.
Reversibility
Partially reversible
Anticancer mechanism
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.
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.
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
- Hydration and attention to volume status
- Folic acid and vitamin B12 supplementation per labeling to mitigate toxicity
- Dose reduction/monitoring in renal impairment; avoid additive nephrotoxins
Note · Renal-toxicity reasoning is partly extrapolated from methotrexate-class antifolate behavior; high-quality pralatrexate-specific nephrotoxicity data are sparse, so claims here are deliberately conservative.
Clinical depth
Renal dose adjustment
In the dedicated renal-impairment PK study, severe renal impairment (and ESRD on dialysis) required dose reduction (to ~15 mg/m2) owing to reduced clearance and higher exposure; mild-moderate impairment was tolerated near standard dosing with monitoring. Hold/reduce for grade 3-4 mucositis or cytopenias.
Dialyzability & ESKD dosing
Hemodialysis can lower pralatrexate exposure; in the renal-impairment study, dosing in ESRD patients was reduced and timed around dialysis. It is a small molecule with partial renal handling, so dialysis contributes to clearance but dose reduction remains necessary.
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)
- CBC and serum creatinine each cycle
- 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
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
8 peer-reviewed references. Citation metadata via PubMed / NLM.
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.PMIDPralatrexate 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.PMIDFolotyn (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.PMIDPralatrexate 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.PMIDPralatrexate 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.PMIDPreventing 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.PMIDAcute methotrexate-induced crystal nephropathy.Blum MF et al. · Kidney Int 2022 · PMID 35065698Illustrates intratubular antifolate crystal nephropathy as the class mechanism.PMIDAnticancer drug-induced kidney disorders.Kintzel PE · Drug Saf 2001 · PMID 11219485Onconephrology review of antimetabolite/antifolate renal effects.
Related agents
Other agents sharing the same signature kidney injury.