Raltitrexed

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. (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 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.

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.

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.Lesion-level management framework

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.

Polyglutamated, tissue-retained antifolate cleared largely by the kidney; not characterized as efficiently dialyzable and not recommended in dialysis-dependent patients.

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.