Cisplatin
Platinol · Platinum agent
Proximal tubular ATN + magnesium wasting; the archetype.
ATNLYTEPRE
SevereOpen →
Antifolate (TS inhibitor)
Raltitrexed
Tomudex · Ralti
A renally-cleared antifolate whose grandparent compound (CB3717) was withdrawn for crystal nephrotoxicity.
ModerateThymidylate synthase inhibitor (antifolate) · approved 1996
Advanced colorectal cancerMalignant pleural mesothelioma
Signature kidney injury
Acute Tubular Necrosis
Not well quantified as a discrete renal endpoint. Raltitrexed is substantially renally eliminated: in a dedicated pharmacokinetic study, mild-to-moderate renal impairment roughly doubled drug exposure (AUC ratio ~2.0) and nearly doubled terminal half-life, with severe/grade 3-4 toxicity and adverse-event hospitalizations more frequent in the impaired group. The class precedent CB3717, raltitrexed's quinazoline antifolate forerunner, was withdrawn from development specifically because of crystal-related nephrotoxicity.
Source: Judson et al., Br J Cancer 1998 (AUC ratio ~2.0 in renal impairment)
Mechanism of kidney injury
Two linked mechanisms. (1) Because the drug and its active polyglutamates are cleared substantially by the kidney, impaired renal function causes drug accumulation that amplifies systemic antifolate toxicity (myelosuppression, mucositis, hepatic and constitutional effects) and can secondarily worsen renal function through volume depletion and tubular stress — a vicious accumulation cycle. (2) By analogy to its quinazoline antifolate forerunner CB3717 (N10-propargyl-5,8-dideazafolic acid), which precipitated in the renal tubule and caused crystal nephropathy leading to its withdrawal, the structural class carries an intrinsic risk of intratubular crystal deposition and proximal tubular injury. Raltitrexed was specifically engineered to be more water-soluble and less nephrotoxic than CB3717, so clinical crystal nephropathy is uncommon, but the accumulation-toxicity relationship in renal impairment is well documented.
Clinical presentation
Most commonly a creatinine rise in the setting of severe systemic antifolate toxicity (cytopenias, mucositis, diarrhea, transaminitis) when given to a patient with unrecognized renal impairment. Direct tubular/crystal injury would present as a subacute creatinine rise with bland-to-granular sediment; the precursor-class lesion was crystalline. Reduced thymidine-rescue effectiveness if AKI is severe.
Onset
Within the first one to two cycles, often heralded by exaggerated systemic toxicity in patients with reduced GFR.
Reversibility
Partially reversible
Anticancer mechanism
Quinazoline folate-based, direct and specific inhibitor of thymidylate synthase (TS). After transport via the reduced-folate carrier it is polyglutamated intracellularly to highly potent, long-retained forms that block TS, depleting thymidine triphosphate and arresting DNA synthesis. Used mainly for advanced colorectal cancer (notably where fluoropyrimidines are not tolerated) and malignant mesothelioma.
Management
Hold for AKI or for exaggerated systemic toxicity; supportive care with hydration and management of cytopenias/mucositis. Folinic acid (leucovorin) rescue is used for overdose or severe toxicity. Re-dose only after renal recovery with appropriate reduction.
Risk factors
- Pre-existing renal impairment (CrCl < 65 mL/min)
- Volume depletion
- Concurrent nephrotoxins
- Failure to dose-reduce/extend interval for renal function
Prevention
- Measure creatinine clearance before each cycle and dose-reduce or extend the interval for impaired GFR per label
- Avoid in severe renal impairment
- Maintain hydration
- Avoid concurrent nephrotoxins and folate-pathway interacting drugs
Note · The actionable issue is renal clearance: impaired GFR sharply raises exposure and toxicity, so renal dosing is mandatory. Frank crystal nephropathy is a class-precedent (CB3717) risk rather than a common raltitrexed event; language here is deliberately conservative.
Clinical depth
Renal dose adjustment
Dose by creatinine clearance: full dose for CrCl >= 65 mL/min; reduce dose and lengthen the dosing interval for CrCl 25-65 mL/min (e.g., reduced dose every 4 weeks); not recommended for CrCl < 25 mL/min. Always recalculate GFR before each cycle.
Dialyzability & ESKD dosing
Polyglutamated, tissue-retained antifolate cleared largely by the kidney; not characterized as efficiently dialyzable and not recommended in dialysis-dependent patients. Use in ESKD is generally avoided.
Differential diagnosis
Distinguish accumulation-driven systemic antifolate toxicity with secondary renal stress from intrinsic tubular/crystal injury; the precursor CB3717 lesion was crystalline. A patient presenting with severe pancytopenia/mucositis and a creatinine bump usually has under-recognized baseline renal impairment driving overexposure.
Monitoring
- Creatinine clearance/eGFR before every cycle
- Complete blood count (nadir myelosuppression)
- Liver function tests
- Mucositis/diarrhea assessment
Key trials & series
- Judson Br J Cancer 1998 renal-impairment pharmacokinetic study
- Pivotal Tomudex colorectal-cancer registration program
Clinical pearls
- Check the GFR before every dose — raltitrexed is renally cleared and accumulates dangerously when CrCl falls, doubling exposure in mild-moderate impairment.
- Its forerunner CB3717 was abandoned for crystal nephrotoxicity; raltitrexed was redesigned to be more soluble, but the class still warrants renal caution.
- Severe pancytopenia plus a creatinine rise after one cycle should prompt folinic-acid rescue and a hunt for unrecognized CKD.
- Avoid in severe renal impairment and in dialysis patients.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Tubular Lumen
The urine flow path
Injury signatures
Acute Tubular NecrosisCrystal / Obstructive Nephropathy
Beyond the kidney
Class-level context for the major non-renal toxicities of antifolate (ts inhibitor)s.
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
4 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkEffects of impaired renal function on the pharmacokinetics of raltitrexed (Tomudex ZD1694).Judson I et al. · Br J Cancer 1998 · PMID 9820178Dedicated PK study: mild-moderate renal impairment roughly doubled raltitrexed AUC and half-life, with more frequent severe toxicity — basis for renal dosing.PMIDFolate-based thymidylate synthase inhibitors as anticancer drugs.Jackman AL et al. · Ann Oncol 1995 · PMID 8624289Reviews the quinazoline antifolate class and notes that the forerunner CB3717 was withdrawn from clinical study for serious nephrotoxicity, motivating more water-soluble analogues like raltitrexed.LandmarkConventional Chemotherapy Nephrotoxicity.Gupta S et al. · Adv Chronic Kidney Dis 2021 · PMID 35190107Onconephrology reference framing antifolate nephrotoxicity, crystal/tubular injury, and renal dose modification principles.PMIDAcute Kidney Injury in Patients with Cancer.Rosner MH et al. · N Engl J Med 2017 · PMID 28467867Authoritative review of cancer-associated AKI including antimetabolite mechanisms and renal-clearance-driven toxicity.