Busulfan
Myleran · Alkylator
Conditioning-regimen TMA risk.
TMA
ModerateOpen →
Pyrimidine analog
5-Fluorouracil
Adrucil · 5-FU
A GI-cancer mainstay that is mostly kidney-safe until it teams up with mitomycin.
MildFluoropyrimidine antimetabolite · approved 1962
Colorectal cancerGastric and pancreatic cancerBreast cancerHead and neck cancer
Signature kidney injury
Thrombotic Microangiopathy
Intrinsic nephrotoxicity is low; the recognized vascular renal complication is thrombotic microangiopathy/hemolytic-uremic syndrome, classically with mitomycin C, with 5-FU as a frequent co-agent. In TTP/HUS series the most common antecedent chemotherapy is mitomycin C plus 5-FU.
Source: Martinez Frances et al., Med Clin (Barc) 1997
Mechanism of kidney injury
5-FU itself is largely renally well tolerated; in combination (especially with mitomycin C) it contributes to chemotherapy-associated thrombotic microangiopathy via endothelial injury, with glomerular capillary fibrin thrombi, microangiopathic hemolysis and progressive renal failure that may appear months into therapy. Severe diarrhea/mucositis can cause prerenal AKI. Preclinically, 5-FU can induce direct renal oxidative/apoptotic tubular injury (p53/Bax/caspase-3, KIM-1), though this is not the dominant clinical lesion. DPD deficiency markedly amplifies systemic (not specifically renal) toxicity.
Clinical presentation
In TMA/HUS: microangiopathic hemolytic anemia (schistocytes, elevated LDH), thrombocytopenia and progressive renal failure, sometimes months after starting therapy and often dose-cumulative with mitomycin; otherwise prerenal azotemia from GI losses.
Onset
TMA often delayed (weeks to months); prerenal effects acute with GI toxicity.
Reversibility
Variable
Anticancer mechanism
Fluoropyrimidine antimetabolite whose active metabolites (FdUMP, FUTP, FdUTP) inhibit thymidylate synthase and incorporate into RNA and DNA, blocking nucleotide synthesis. Catabolized predominantly by dihydropyrimidine dehydrogenase (DPD). Backbone of colorectal, gastric, pancreatic, breast and head and neck regimens.
Management
Discontinue offending agents for TMA/HUS and provide supportive care (the syndrome carries high mortality; plasma exchange has limited efficacy, and complement-directed therapy is used in select cases); rehydrate for prerenal AKI. Renal recovery is variable and may be incomplete in established TMA.
Risk factors
- Concurrent mitomycin C (dominant TMA driver)
- Cumulative mitomycin/fluoropyrimidine exposure
- Volume depletion from diarrhea/mucositis
- DPD (DPYD) deficiency for severe systemic toxicity
Prevention
- Recognize mitomycin as the dominant TMA driver and cap its cumulative dose
- Hydration and prompt management of GI toxicity
- Monitor CBC, LDH, haptoglobin and renal function; consider DPYD genotyping
Note · The TMA signature is driven mainly by the mitomycin partner; single-agent 5-FU is generally renally safe, and the principal independent 5-FU safety lever is DPD-deficiency-related toxicity.
Clinical depth
Renal dose adjustment
No standard CrCl-based dose adjustment for IV 5-FU (catabolism is enzymatic via DPD, not renal); dose by toxicity and consider DPYD-genotype-guided reduction. In significant renal impairment, monitor closely but renal clearance is a minor pathway.
Dialyzability & ESKD dosing
5-FU has a very short half-life and is enzymatically catabolized; it is not managed by dialysis. Its catabolite fluoro-beta-alanine is renally excreted and can accumulate in renal failure but is not the toxic species.
Differential diagnosis
Chemo-associated TMA/HUS (Coombs-negative microangiopathic hemolysis, schistocytes, thrombocytopenia, normal-ish coagulation, often mitomycin-related) vs prerenal azotemia from diarrhea (volume-responsive, low FeNa) vs other causes of AKI. ADAMTS13 is usually not severely deficient, separating it from classic TTP.
Monitoring
- CBC, LDH, haptoglobin and creatinine - rising LDH with thrombocytopenia signals TMA
- Volume/diarrhea status each cycle
- DPYD genotype or phenotype where available before fluoropyrimidine start
Key trials & series
- Mitomycin-5-FU HUS literature (Jain Pathology 1987; Martinez Frances Med Clin 1997 35-patient TTP/HUS series)
- Henricks Lancet Oncol 2018 - prospective DPYD genotype-guided fluoropyrimidine dosing safety study
Clinical pearls
- Single-agent 5-FU is renally benign - when TMA appears, look hard at the mitomycin C in the regimen and its cumulative dose.
- Fluoropyrimidine toxicity is enzymatic (DPD), not renal - DPYD genotyping, not CrCl, is the key safety screen.
- Mitomycin/5-FU TMA can surface months in and is cumulative-dose related; persistent thrombocytopenia plus hemolysis should not be dismissed.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
Thrombotic MicroangiopathyPrerenal / Hemodynamic AKI
Beyond the kidney
Class-level context for the major non-renal toxicities of pyrimidine analogs.
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
7 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkA review of hemolytic uremic syndrome in patients treated with gemcitabine therapy.Fung MC et al. · Cancer 1999 · PMID 10223245Antimetabolite-associated HUS review noting mitomycin-C/5-FU as confounding co-exposures.PMIDMitomycin C associated hemolytic uremic syndrome.Jain S et al. · Pathology 1987 · PMID 3108839Chemotherapy-associated HUS/TMA (mitomycin with 5-FU) with characteristic renal histology.PMIDHigh-dose 5-fluorouracil/folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study.Hofheinz RD et al. · Onkologie 2002 · PMID 12119460Prospective series documenting HUS cases with 5-FU plus mitomycin C.PMID[Mitomycin-induced hemolytic uremia syndrome].Steffens F · Dtsch Med Wochenschr 2004 · PMID 15227598Mitomycin/5-FU-associated hemolytic uremic syndrome case context.PMIDMitigation of 5-Fluorouracil induced renal toxicity by chrysin via targeting oxidative stress and apoptosis in wistar rats.Rashid S et al. · Food Chem Toxicol 2014 · PMID 24486618Preclinical evidence of direct 5-FU renal oxidative/apoptotic tubular injury.PMIDDPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis.Henricks LM et al. · Lancet Oncol 2018 · PMID 30348537DPD-deficiency toxicity context; genotype-guided dosing improves fluoropyrimidine safety.PMIDAnticancer drug-induced kidney disorders.Kintzel PE · Drug Saf 2001 · PMID 11219485Onconephrology review of antimetabolite and TMA/HUS mechanisms.