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Antifolate

Pralatrexate

Folotyn · PDX

Antifolate · approved 2009 · 8 references

A potent antifolate that shares methotrexate's appetite for renal handling and its crystal risk.

Signature injury
Crystal / Obstructive Nephropathy
Severity
Moderate
Reversibility
Partially reversible
Onset
During treatment cycles; exposure-dependent.

Signature kidney injury & incidence

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

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

Renal toxicity profile

  1. Crystal / Obstructive NephropathyPrimary
  2. Acute Tubular NecrosisSecondary

Onset timing & rechallenge

Variable / unpredictable — Occurs during treatment cycles in an exposure-dependent manner.

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.

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

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.

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.

Guidelines & consensus

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
  • 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

References

8 peer-reviewed references. Citation metadata via PubMed / NLM.

  1. 1.Phase 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 27638045
  2. 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 21245435
  3. 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 20739433
  4. 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 20501616
  5. 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 22542448
  6. 6.Preventing and Managing Toxicities of High-Dose Methotrexate.Howard SC et al. · Oncologist · 2016 · PMID 27496039
  7. 7.Acute methotrexate-induced crystal nephropathy.Blum MF et al. · Kidney Int · 2022 · PMID 35065698
  8. 8.Anticancer drug-induced kidney disorders.Kintzel PE · Drug Saf · 2001 · PMID 11219485
Educational monograph from NephTox (nephtox.com). Not medical advice — verify against current guidelines before any clinical decision.