Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
Pyrimidine analog (oral 5-FU)
Capecitabine
Xeloda · Cape
Oral 5-FU whose diarrhea, more than any tubular toxin, is what dents the kidney.
MildFluoropyrimidine antimetabolite (oral) · approved 1998
Colorectal cancerBreast cancerGastric/gastroesophageal cancer
Signature kidney injury
Prerenal / Hemodynamic AKI
Intrinsic nephrotoxicity is uncommon; the main renal issue is prerenal AKI from drug-induced diarrhea and volume depletion. Renal impairment increases toxicity - in the PK study, all patients with severe impairment (CrCl <30) had grade 3-4 adverse events - so labeling mandates dose adjustment by creatinine clearance and contraindicates severe impairment.
Source: Poole et al., Cancer Chemother Pharmacol 2002
Mechanism of kidney injury
Severe diarrhea, nausea and reduced intake cause volume depletion and prerenal azotemia; because the 5-FU catabolites are renally cleared, impaired kidney function increases systemic exposure and toxicity (the basis for CrCl-based dosing). Rare thrombotic microangiopathy/HUS can occur as with other fluoropyrimidines, particularly in mitomycin-containing or high-risk settings, and is occasionally managed with complement blockade. DPD (DPYD) deficiency markedly increases systemic toxicity.
Clinical presentation
Prerenal azotemia (elevated BUN:creatinine, low urine sodium) in the setting of diarrhea/dehydration; enhanced systemic toxicity (hand-foot syndrome, mucositis, cytopenias) when clearance is reduced. Rarely, microangiopathic hemolysis with thrombocytopenia and AKI.
Onset
Acute, during cycles with GI toxicity; TMA delayed and rare.
Reversibility
Reversible
Anticancer mechanism
Oral fluoropyrimidine prodrug converted in three enzymatic steps (carboxylesterase, cytidine deaminase, then tumor-enriched thymidine phosphorylase) to 5-fluorouracil, inhibiting thymidylate synthase. Used in colorectal, breast and gastric/gastroesophageal cancers.
Management
Hold drug and rehydrate for prerenal AKI and significant diarrhea; correct electrolytes and resume at an adjusted dose. For rare TMA, discontinue and provide supportive/complement-directed care. Prerenal injury reverses with volume restoration.
Risk factors
- Reduced creatinine clearance (dose-adjust; contraindicated if CrCl <30)
- Severe diarrhea/dehydration
- Older age and DPD (DPYD) deficiency
- Concurrent mitomycin (TMA risk)
Prevention
- Dose by creatinine clearance per labeling (75% dose for CrCl 30-50); avoid if CrCl <30
- Early aggressive management of diarrhea and hydration
- Monitor renal function across cycles; consider DPYD genotyping
Note · Renal dosing matters chiefly because reduced clearance amplifies systemic toxicity; direct tubular nephrotoxicity is not characteristic.
Clinical depth
Renal dose adjustment
Per labeling/PK data: no adjustment for mild impairment (CrCl 51-80); reduce to 75% of starting dose for moderate impairment (CrCl 30-50); contraindicated for severe impairment (CrCl <30), where all patients experienced grade 3-4 toxicity.
Dialyzability & ESKD dosing
Capecitabine and 5-FU have short half-lives and are not managed by dialysis; the renally cleared catabolites (e.g., fluoro-beta-alanine) accumulate in renal failure, which is why severe impairment is contraindicated rather than dialysis-supported.
Differential diagnosis
Prerenal azotemia from diarrhea (low FeNa, volume-responsive, BUN:Cr elevated) is the usual picture; distinguish from rare fluoropyrimidine TMA (microangiopathic hemolysis, thrombocytopenia) and from amplified systemic toxicity due to unrecognized renal impairment or DPD deficiency. Pseudo-AKI is not the issue here - it is real volume-driven prerenal injury.
Monitoring
- Serum creatinine/CrCl at baseline and across cycles (drives dosing)
- Diarrhea grade and volume status each cycle
- CBC, LDH/haptoglobin if TMA suspected; DPYD status where available
Key trials & series
- Poole Cancer Chemother Pharmacol 2002 - the renal-impairment PK study underpinning CrCl-based dosing and the <30 contraindication
- Cassidy Ann Oncol 2002 - phase III safety supporting higher toxicity at CrCl 30-50
- Henricks Lancet Oncol 2018 - DPYD genotype-guided dosing safety
Clinical pearls
- The kidney lever for capecitabine is dosing, not toxicity surveillance: 75% dose at CrCl 30-50 and do not use below 30.
- Most capecitabine AKI is prerenal from diarrhea - hydrate, hold, and it reverses.
- Unexpectedly severe hand-foot syndrome/mucositis/cytopenias should prompt checks for occult renal impairment or DPD deficiency.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
Prerenal / Hemodynamic AKIThrombotic Microangiopathy
Beyond the kidney
Class-level context for the major non-renal toxicities of pyrimidine analog (oral 5-fu)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
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkEffect of renal impairment on the pharmacokinetics and tolerability of capecitabine (Xeloda) in cancer patients.Poole C et al. · Cancer Chemother Pharmacol 2002 · PMID 11935215Defines CrCl-based dosing: 75% dose in moderate impairment, contraindication if CrCl <30.PMIDFirst-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin.Cassidy J et al. · Ann Oncol 2002 · PMID 12056707Phase III safety supporting higher grade 3-4 toxicity at reduced creatinine clearance.PMIDSafety of capecitabine: a review.Mikhail SE et al. · Expert Opin Drug Saf 2010 · PMID 20722491Safety review covering renal-dysfunction dosing and special populations.PMIDEffect of Pretreatment Renal Function on Treatment and Clinical Outcomes in the Adjuvant Treatment of Older Women With Breast Cancer: Alliance A171201, an Ancillary Study of CALGB/CTSU 49907.Lichtman SM et al. · J Clin Oncol 2016 · PMID 26755510Capecitabine dosing adjusted for renal function; higher toxicity risk with renal impairment.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 for capecitabine; genotype-guided dosing improves safety.PMIDAnticancer drug-induced kidney disorders.Kintzel PE · Drug Saf 2001 · PMID 11219485Onconephrology context for prerenal and fluoropyrimidine-related renal effects.
Related agents
Other agents sharing the same signature kidney injury.