What kind of kidney injury does Trifluridine/tipiracil cause?

Prerenal / Hemodynamic AKI — Renal hypoperfusion from capillary leak and cytokine storm — IL-2 and CAR-T cytokine release syndrome.

How should kidney function be monitored during Trifluridine/tipiracil therapy?

Complete blood count before each cycle and at nadir (more often early in renal impairment); Volume status with diarrhea/mucositis; Electrolytes if GI losses are significant.

How can kidney injury from Trifluridine/tipiracil be prevented?

Assess creatinine clearance before starting and reduce dose for severe renal impairment per label Maintain hydration; manage GI losses

Who is at higher risk of kidney injury from Trifluridine/tipiracil?

Moderate-to-severe renal impairment (CrCl < 60 mL/min); Low baseline blood counts; Older age and low body surface area; Volume depletion from diarrhea/poor intake.

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Printable monograph

Oral fluoropyrimidine + TP inhibitor

Trifluridine/tipiracil

Lonsurf · FTD-TPI

Oral fluoropyrimidine + TP inhibitor · approved 2015 · 7 citations

Up to date· through 2025

Deeply sourced7/9 · 6 signals

Met: 7 citations
Not met: 12+ references
Met: Accrued over 10+ years (span: 10y)
Met: Beyond single case reports
Met: High-impact journal
Met: Landmark reference
Met: Current through 2025
Not met: Real-world FAERS signal

Describes how this page is sourced, not how dangerous the drug is. Thinly sourced means fewer of the sourcing signals are met — not that the agent is kidney-safe. A rule-based summary, not a formal certainty appraisal.

An oral fluoropyrimidine combo whose tipiracil component accumulates as the kidney fails — driving cytopenias.

ModerateOral fluoropyrimidine / thymidine-phosphorylase inhibitor

Refractory metastatic colorectal cancerPreviously treated metastatic gastric/gastroesophageal adenocarcinoma

§01

Signature kidney injury

Signature lesion

Prerenal / Hemodynamic AKI

Direct intrinsic nephrotoxicity is not a prominent feature; the renal relevance is pharmacokinetic. The tipiracil component is mainly renally excreted, so its exposure rises with declining GFR: a phase I study found tipiracil AUC increased significantly with renal-impairment severity and required a dose reduction (to 20 mg/m2 twice daily) in severe impairment, while grade >= 3 adverse events — chiefly hematologic (anemia, neutropenia) — were more frequent across the impaired cohorts. Real-world data confirm more early severe neutropenia in patients with reduced creatinine clearance.Source: Saif et al., Cancer Chemother Pharmacol 2021 (renal-impairment phase I); Saito et al., Sci Rep 2024

Onset & rechallenge

Time to injurySubacute (~1–6 weeks)

Prerenal effects tend to emerge within the first one to two treatment cycles, particularly with early severe neutropenia in patients with reduced creatinine clearance.

Distilled from: “Within the first one to two cycles, especially early severe neutropenia in patients with reduced creatinine clearance.”

§02

Renal toxicities, ranked

This agent's defining kidney lesion — its #1 signature. Cited incidence is shown where a citable figure exists; otherwise the tier stands qualitatively.

Prerenal / Hemodynamic AKI#1 · Signaturequalitative — no citable incidence
Renal hypoperfusion from capillary leak and cytokine storm — IL-2 and CAR-T cytokine release syndrome.

§03

Kidney injury

Mechanism of kidney injury

The kidney is the route of elimination rather than the primary target. Tipiracil is predominantly renally cleared; as GFR falls its plasma exposure climbs, prolonging trifluridine's effective exposure and amplifying systemic, principally myelosuppressive, toxicity (neutropenia, anemia). This accumulation can secondarily contribute to volume depletion (mucositis, GI losses) and prerenal/tubular stress. Hematologic and constitutional toxicity dominate; there is no well-characterized direct tubular lesion. The renal management priority is dose reduction to prevent exposure-driven cytopenias.

Clinical presentation

Predominantly hematologic toxicity (neutropenia in roughly a third, leukopenia, anemia, occasional febrile neutropenia) and GI effects, amplified in renal impairment. Electrolyte disturbances and a creatinine rise can accompany severe GI losses; a discrete intrinsic renal lesion is not characteristic.

Management

Manage toxicity by dose interruption and reduction; supportive care for cytopenias (growth factors, transfusion) and hydration for GI losses. In severe renal impairment use the reduced starting dose; reassess renal function and counts each cycle.Lesion-level management framework

Risk factors

Moderate-to-severe renal impairment (CrCl < 60 mL/min)
Low baseline blood counts
Older age and low body surface area
Volume depletion from diarrhea/poor intake

Prevention

Assess creatinine clearance before starting and reduce dose for severe renal impairment per label
Maintain hydration; manage GI losses

Anticancer mechanism· how it treats cancer

Oral combination of trifluridine (FTD), a thymidine-based nucleoside analog incorporated into DNA to cause dysfunction, and tipiracil (TPI), a thymidine-phosphorylase inhibitor that blocks FTD degradation and raises its systemic exposure. Approved for refractory metastatic colorectal cancer and for previously treated metastatic gastric/gastroesophageal cancer.

Note · The renal signal is exposure/accumulation (tipiracil is renally cleared), not a primary tubular toxin. The actionable issue is reduced starting dose and intensified count monitoring in renal impairment; no dosing data exist for end-stage renal disease.

§04

Clinical depth

Renal dose adjustment

No starting-dose adjustment for mild (CrCl 60-89 mL/min) or moderate (CrCl 30-59) renal impairment — the full 35 mg/m2 twice daily is tolerated; for severe impairment (CrCl 15-29) reduce to 20 mg/m2 twice daily per the label and PK study. Not studied in ESKD/dialysis — avoid or use with extreme caution.

Dialyzability & ESKD dosing

Tipiracil is renally cleared and its dialyzability is not well characterized; no established dosing in dialysis-dependent patients.

Differential diagnosis

Distinguish exposure-driven cytopenias plus prerenal AKI (GI losses) from an intrinsic nephropathy; a creatinine rise here usually reflects volume depletion or unrecognized CKD increasing tipiracil exposure rather than a direct renal lesion.

Monitoring

Complete blood count before each cycle and at nadir (more often early in renal impairment)
Volume status with diarrhea/mucositis
Electrolytes if GI losses are significant

Key trials & series

RECOURSE (Mayer NEJM 2015) pivotal colorectal trial
Saif Cancer Chemother Pharmacol 2021 renal-impairment phase I PK/dosing study
Saito Sci Rep 2024 real-world early-neutropenia analysis

Clinical pearls

Early severe neutropenia in the first cycle is the tell-tale of overexposure in a patient with reduced kidney function.
No ESKD dosing exists; avoid in dialysis-dependent patients.

Where it strikes· nephron segments & injury signatures

Nephron segments

Vasculature / Endothelium

Glomerular & peritubular capillaries

Injury signatures

Prerenal / Hemodynamic AKI

Beyond the kidney — non-renal toxicities· 4 organ systems

Class-level context for the major non-renal toxicities of the Oral fluoropyrimidine + TP inhibitor class.

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

§05

References

4 primary references — trials, cohorts, mechanism, and reviews. Single-patient case reports are listed separately below, graded by strength. Citation metadata via PubMed / NLM.

Evidence accrual

4 references · 2015–2024 · 1 since 2022

Primary (non–case-report) references per year — a proxy for how actively the agent's renal literature is accruing. Recent years are highlighted. Reflects curation depth, not a systematic bibliometric count.

Case reports — ranked by strength· 3

Single-patient and small-series reports, graded by evidentiary strength — A Strong (biopsy-proven plus a series and/or positive rechallenge), B Moderate, and C Limited (a single clinically-diagnosed case). Strongest first. Grades are inferred automatically from each report's abstract and journal — a heuristic ranking aid, not a formal quality appraisal.

CaseB · ModerateNephrotic syndrome after switching from irinotecan, S-1, and bevacizumab combination to trifluridine/tipiracil.Takami J et al. · CEN Case Rep 2025 · PMID 40637925A 74-year-old man on FTD/TPI developed nephrotic syndrome with hematuria; renal biopsy showed IgA nephropathy with glomerular microangiopathy, improving on steroids.CaseC · LimitedIgA Nephropathy Associated with Trifluridine/Tipiracil: A Case Report.Desbuissons G et al. · Nephron 2020 · PMID 32799198Severe IgA nephropathy requiring hemodialysis emerged weeks after starting trifluridine/tipiracil for refractory metastatic digestive cancer.CaseC · LimitedLeukocytoclastic vasculitis with late-onset Henoch-Schönlein purpura after trifluridine/tipiracil treatment.Aria AB et al. · Dermatol Online J 2018 · PMID 30677817FTD/TPI-induced leukocytoclastic vasculitis progressed to Henoch-Schönlein purpura with rapidly progressive crescentic IgA glomerulonephritis, hematuria, proteinuria, and acute renal failure.

FDA label — boxed warning & renal dosing· renal impairment

Quoted verbatim from this agent's current FDA label (Nov 2025) — not paraphrased or interpreted. Full label on DailyMed .

Renal impairment — from the label

Reduce LONSURF dose in patients with severe renal impairment. ( 8.6 )

What gets reported — FAERS

Everything below is FAERS — adverse events someone chose to report, about 11,088 of them for this agent. Nobody counts the patients who were fine, so none of these numbers is an incidence, a risk, or a rate: they describe what gets reported, shaped by a drug's fame, its indication, and who was watching. How these numbers work.

Reporting odds ratio (ROR) — is kidney injury named in this agent's reports more often than in every other drug's? Above 1 means yes, disproportionately.
Renal phenotypes — the same question asked separately for each kind of kidney injury, so the ratios differ from the overall one and from each other.
Outcomes — a share of this agent's own reports, not of patients: how many were filed as involving a death or a hospitalization. Not a case-fatality rate.

FAERS reported renal phenotypes· 4 signals

Only significant signals appear (95% CI lower bound above 1) — a phenotype missing here was tested and did not reach significance, except Prerenal / Hemodynamic AKI, Pseudo-AKI, Renal Cysts, Chronic Interstitial Nephropathy — outside the clinician-reviewed MedDRA term map, never queried — and ATN and AIN, queried but biopsy-bound: real cases are filed as generic “acute kidney injury”, so their absence is not a negative. As of 2026-10-01.

What reporting says about this profile's documented lesions

Prerenal / Hemodynamic AKINot queried in FAERS — No MedDRA term set is defined for this phenotype, so FAERS was never asked about it.

Glomerular Injury / Proteinuria

ROR 3.0095% CI 2.25–4.01· 46 reports

Crystal / Obstructive Nephropathy

ROR 2.4295% CI 1.92–3.06· 71 reports

Hemorrhagic Cystitis

ROR 1.3495% CI 1.01–1.77· 49 reports

Electrolyte Disturbance

ROR 1.2795% CI 1.07–1.51· 128 reports

FAERS outcomes & reporting trend· 38.6% of reports w/ death · 27.4% w/ hospitalization

38.6%

Reported with a death outcome

4,280 of 11,088 reports

27.4%

Reported with hospitalization

3,037 of 11,088 reports

Reports per year

Yearly FAERS report volume · most recent year is partial.

FAERS adverse-event signal — all organ systems· 7 systems · 11,088 reports

Bars rank systems by summed reaction-term mentions (a report counts once per term it names) — an ordinal “more vs less reported” cue, not a tally of distinct reports. Renal & urinary first. As of 2026-10-01.

Disproportionality (acute kidney injury):ROR 1.1995% CI 0.98–1.46· 96 AKI reports ·no disproportionate AKI reporting signal (CI spans 1).

Gastrointestinal

Nausea1,206Diarrhoea1,064Vomiting653Constipation348Abdominal Pain326

General / constitutional

Fatigue1,426Asthenia502Weight Decreased342Pain292Malaise266

Blood & lymphatic

White Blood Cell Count Decreased492Anaemia382Neutropenia367Platelet Count Decreased235Haemoglobin Decreased194

Metabolic & electrolyte

Decreased Appetite692Dehydration332

Respiratory

Dyspnoea223

Nervous system

Dizziness191

Skin

Alopecia176

Guidelines & consensus· 14

Each recommendation below is this atlas's faithful summary of the source, not a quotation from it — follow the PubMed link for the wording the society published. Summaries may be superseded; consult the current full text and individualize to the patient.

ADQIConventional cytotoxic chemotherapy-associated nephrotoxicity: consensus report of the 34th Acute Disease Quality Initiative (ADQI) WorkgroupKidney Int 2026 · PMID 41881107Cisplatin is identified as a leading cytotoxic nephrotoxin; the workgroup details preventive measures (adequate isotonic hydration, correction of volume depletion, avoidance of concurrent nephrotoxins, attention to electrolyte/magnesium wasting) and management of cisplatin-associated AKI, with a research agenda for knowledge gaps.

General onco-nephrology references

ADQIThe nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupNat Rev Nephrol 2026 · PMID 41361704Provides expert-based statements (modified Delphi) on preventing and managing cisplatin/platinum-associated AKI, including isotonic IV hydration, attention to volume status and concomitant nephrotoxins, and incorporates evidence that IV magnesium supplementation may reduce cisplatin-associated AKI; emphasizes risk stratification and standardized AKI definitions.SIRMSIRM-SIN-AIOM: appropriateness criteria for evaluation and prevention of renal damage in the patient undergoing contrast medium examinations-consensus statements from Italian College of Radiology (SIRM), Italian College of Nephrology (SIN) and Italian Association of Medical Oncology (AIOM)Radiol Med 2022 · PMID 35303246Recommends eGFR-based renal risk assessment and pre/post-contrast isotonic saline or sodium bicarbonate hydration; advises maintaining a 5-7 day interval between iodinated contrast administration and cisplatin in cancer patients to reduce additive nephrotoxicity.KDIGOKDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerKidney Int 2020 · PMID 33126977Identifies platinum compounds (especially cisplatin) as leading cytotoxic causes of acute tubular injury, AKI, and electrolyte/magnesium wasting; calls for interdisciplinary onco-nephrology care, accurate GFR estimation, and individualized drug dosing in patients with reduced kidney function.KDIGOKDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationKidney Int 2020 · PMID 33276867Addresses chemotherapy-associated AKI/CKD in hematologic cancer, GFR estimation and chemotherapy dosing in patients with reduced kidney function, and management priorities and research gaps for onco-nephrology care.ADDIKDIntegrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceEClinicalMedicine 2025 · PMID 40290844Provides GRADE-based, drug-specific dose-adjustment recommendations for anticancer agents in kidney dysfunction (illustrated for methotrexate, cisplatin, carboplatin and nivolumab); the recommendations build on Part 1's standardised CKD-EPI eGFR assessment rather than Cockcroft-Gault creatinine clearance.ADDIKDAligning kidney function assessment in patients with cancer to global practices in internal medicineEClinicalMedicine 2025 · PMID 40290845Three consensus recommendations: assess kidney function by GFR (measured GFR or CKD-EPI eGFR), classify it using KDIGO categories, and use this uniform approach to dose anticancer drugs — moving cancer medicine away from Cockcroft-Gault estimated creatinine clearance.ADDIKDA methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEClinicalMedicine 2025 · PMID 40290846Establishes that, where RCT evidence is lacking, anticancer drug dosing recommendations in kidney dysfunction should be derived by critically appraising observational literature via GRADE combined with structured international multidisciplinary consensus voting.KDIGODiagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Crit Care 2013 · PMID 23394211Defines/stages AKI by serum creatinine and urine output; emphasizes avoiding nephrotoxins, maintaining euvolemia/perfusion, dose-adjusting drugs to kidney function, and monitoring high-risk patients — the framework applied to nephrotoxic anti-cancer agents.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknownsKidney Int 2024 · PMID 38519239Evaluate and risk-stratify CKD, manage to delay progression and its complications, and practise explicit medication management and drug stewardship — the framework the atlas's G1–G5 eGFR banding and every renal dose-adjustment recommendation sit inside. Because the guideline excludes dialysis and transplant recipients by its own statement of scope, its recommendations do not carry to those settings, where this atlas's dialyzability and post-transplant guidance rests on other sources.KDIGOExecutive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesKidney Int 2021 · PMID 34556300Provides the staging/treatment framework for drug-associated glomerular lesions (e.g., bisphosphonate- and interferon-related collapsing FSGS, VEGF-inhibitor podocytopathy/proteinuria), including immunosuppression and supportive RAAS-blockade strategies.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisKidney Int 2024 · PMID 38388147Updates immunosuppressive induction (rituximab/cyclophosphamide), incorporates avacopan and lower-dose or glucocorticoid-sparing regimens — the management framework for drug- and checkpoint-inhibitor-associated ANCA/pauci-immune glomerulonephritis.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisKidney Int 2024 · PMID 38182299Updates first-line lupus nephritis therapy to combination immunosuppression with the addition of belimumab or a calcineurin inhibitor (voclosporin) — informs management of immune-complex/lupus-like glomerulonephritis encountered with immunotherapy.KDIGOExecutive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Kidney Int 2025 · PMID 40975525Encourages liberal kidney biopsy and stricter proteinuria control (<0.5 g/d, ideally <0.3 g/d) with RAAS blockers, SGLT2 inhibitors, and targeted-release budesonide — the framework for IgA-dominant glomerular lesions, including those triggered by immune-modulating cancer therapy.

Where Trifluridine/tipiracil sits in nephrotoxicity space — each dot is an anti-cancer agent, positioned so neighbors share a kidney-injury phenotype. Its 6 closest are filled and lead to a numbered marker, matching the numbered cards below.

Position is a 2-D projection (MDS) of each agent's injury signature, nephron target, severity, and class, so two dots can sit close on the page while differing on an axis the projection flattened — the numbered ranking is computed from the full metric, not from the distance you see. Open the full map.

Phenotype-similar agents· the numbered markers on the map above

Tebentafusp

Kimmtrak · Bispecific T-cell engager (gp100×CD3 ImmTAC)

Profile

CRS-driven hypotension → prerenal AKI early in dosing; uveal melanoma.

PRE

Moderate#1 · 88% phenotype match

Denileukin diftitox

Lymphir · Immunotoxin (IL-2–diphtheria)

Profile

Capillary-leak syndrome → prerenal AKI.

PRE

Moderate#2 · 88% phenotype match

Zolbetuximab

Vyloy · Anti-Claudin-18.2 monoclonal antibody

Profile

2024 gastric mAb; severe on-target nausea/vomiting → volume-depletion prerenal AKI.

PRE

Moderate#3 · 88% phenotype match

Elotuzumab

Empliciti · Anti-SLAMF7 mAb

Profile

Kidney-neutral antibody; unchanged PK in severe impairment and dialysis; no renal dose adjustment.

PRE

Mild#4 · 84% phenotype match

Radium-223 dichloride

Xofigo · Radiopharmaceutical (alpha-emitter)

Profile

Bone-seeking alpha emitter; minimal direct renal toxicity.

PRE

Mild#5 · 83% phenotype match

Pexidartinib

Turalio · CSF1R inhibitor

Profile

Boxed hepatotoxicity; secondary renal effects.

PRE

Mild#6 · 83% phenotype match

Compare Trifluridine/tipiracil with its nearest agents

Nearest agents by kidney-injury phenotype (shared injuries, nephron target, severity, class) — a similarity approximation, not a claim of shared drug identity or mechanism.

Kidney risk across Antimetabolites

Same-class agents ordered by their documented kidney-injury profile — atlas severity, an acute-kidney-injury FAERS signal, and how many injury types each is documented to cause. Agents nearer the top carry the lighter documented renal profile.

A comparison of documented kidney-injury data within one drug class — not a substitution recommendation. Efficacy, indication, and non-renal toxicity differ between these agents and are out of scope here. Educational only, not medical advice.