Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
Topoisomerase I inhibitor
Irinotecan
Camptosar · Irino
A topoisomerase I poison whose severe diarrhea is the real threat to the kidneys.
MildTopoisomerase I inhibitor · approved 1996
Colorectal cancerPancreatic cancerGastric cancer
Signature kidney injury
Prerenal / Hemodynamic AKI
Direct nephrotoxicity is not a recognized feature; the principal renal risk is prerenal AKI from severe early (cholinergic) and delayed diarrhea with volume depletion. Severe (grade 3-4) irinotecan toxicity, mostly diarrhea/neutropenia, occurs in roughly a quarter to a third of patients and is enriched in UGT1A1 poor metabolizers. AKI incidence specifically attributable to irinotecan is not well quantified.
Source: Hulshof et al., Eur J Hum Genet 2022
Mechanism of kidney injury
Volume depletion from profuse SN-38-mediated secretory diarrhea (plus vomiting and poor intake) reduces effective circulating volume and renal perfusion, producing prerenal azotemia that can progress to ischemic ATN if uncorrected. The drug does not directly injure tubular cells at usual exposures; impaired SN-38 glucuronidation (UGT1A1*28/*6/*37) raises active-metabolite exposure and the severity of the diarrhea.
Clinical presentation
Watery diarrhea, orthostasis, decreased urine output, and rising BUN/creatinine with a high BUN:creatinine ratio and bland sediment; urine is concentrated (low FeNa) consistent with prerenal physiology. Early cholinergic syndrome (diaphoresis, cramping, lacrimation) reverses with atropine.
Onset
Acute cholinergic diarrhea within hours of infusion; delayed diarrhea after ~24 hours and over subsequent days, with AKI following cumulative volume loss.
Reversibility
Reversible
Anticancer mechanism
Prodrug converted by carboxylesterases (CES1/CES2) to the active metabolite SN-38, which stabilizes the topoisomerase I-DNA cleavable complex, causing lethal double-strand breaks during DNA replication. Used in colorectal, pancreatic, and other gastrointestinal cancers (FOLFIRI, FOLFIRINOX).
Management
Restore volume with IV crystalloid, control diarrhea, and hold chemotherapy until recovery. Prerenal AKI typically reverses promptly once euvolemia is restored; persistent injury warrants evaluation for ischemic ATN.
Risk factors
- Severe or unmanaged delayed diarrhea
- UGT1A1 poor-metabolizer genotype (*28/*28, *6, *37) - higher SN-38 exposure
- ABCG2 c.421C>A and other transporter variants
- Older age, baseline volume depletion, concurrent diuretics
Prevention
- Aggressive antidiarrheal management (high-dose loperamide for delayed diarrhea; atropine for acute cholinergic symptoms)
- Patient education and early oral/IV rehydration at first loose stools
- Consider UGT1A1 genotyping; reduce starting dose to ~70% in confirmed poor metabolizers
Note · Kidney injury is essentially diarrhea-driven and prerenal; preventing and treating diarrhea is the key renal-protective step.
Clinical depth
Renal dose adjustment
Largely hepatic/biliary elimination, so no formal eGFR-based renal dose table; UGT1A1 poor metabolizers warrant a ~30% starting-dose reduction. Caution and possible reduction in significant hepatic dysfunction (hyperbilirubinemia).
Dialyzability & ESKD dosing
Irinotecan and SN-38 are protein-bound and hepatically/biliary cleared; not effectively removed by dialysis. No HD-timed dosing established.
Differential diagnosis
Diarrhea-driven prerenal AKI (volume signs, low FeNa, bland urine) vs C. difficile or neutropenic enterocolitis vs concurrent nephrotoxin ATN. The temporal link to delayed diarrhea and rapid reversal with fluids is characteristic.
Monitoring
- Stool frequency and hydration status each cycle
- Serum creatinine/BUN and electrolytes with significant diarrhea
- CBC for neutropenia
- UGT1A1 genotype before first dose where available
Key trials & series
- DPWG UGT1A1-irinotecan pharmacogenetic guideline (Hulshof 2022)
- FOLFIRINOX and FOLFIRI registrational regimens
Clinical pearls
- Atropine treats the acute cholinergic diarrhea; loperamide treats the delayed diarrhea - they are different syndromes.
- UGT1A1 poor metabolizers get worse diarrhea and thus more prerenal AKI; genotype-guided dose reduction helps.
- The kidney is collateral damage from gut fluid loss - the renal-protective intervention is controlling diarrhea early.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
Prerenal / Hemodynamic AKI
Beyond the kidney
Class-level context for the major non-renal toxicities of topoisomerase i inhibitors.
Neurologic
Neuropathy, encephalopathy, ICANS, PRES
- Peripheral neuropathy (taxanes, vinca)
Hematologic
Cytopenias, thrombosis, TMA
- Myelosuppression
Immune / Infusion
CRS, infusion reactions, irAEs, anaphylaxis
- Hypersensitivity (taxane vehicles)
Evidence
5 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkDutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between UGT1A1 and irinotecan.Hulshof EC et al. · Eur J Hum Genet 2022 · PMID 36443464Evidence-based guideline linking UGT1A1 deficiency to severe irinotecan toxicity (diarrhea, neutropenia) and recommending dose reduction.PMIDIrinotecan-Induced Toxicity: A Pharmacogenetic Study Beyond UGT1A1.de With M et al. · Clin Pharmacokinet 2023 · PMID 37715926Implicates ABCG2 and CES1 variants in irinotecan toxicity, refining the pharmacogenetic basis of severe diarrhea.PMIDOnconephrology.Kala J et al. · Crit Care Clin 2021 · PMID 33752861Overview of cancer-therapy AKI including prerenal mechanisms from gastrointestinal fluid losses.PMIDOnconephrology: mitigation of renal injury in chemotherapy administration.Selamet U et al. · Curr Opin Nephrol Hypertens 2024 · PMID 38095483Reviews prevention and mitigation of chemotherapy-associated renal injury, including volume management.PMIDOnconephrology: The intersections between the kidney and cancer.Rosner MH et al. · CA Cancer J Clin 2020 · PMID 32853404Authoritative review contextualizing chemotherapy-associated renal effects.
Related agents
Other agents sharing the same signature kidney injury.