Is kidney injury from Nirogacestat reversible?

Reversible. Typical onset: During therapy; not well characterized..

How should kidney function be monitored during Nirogacestat therapy?

Serum phosphate, potassium, magnesium and bicarbonate periodically; Stool frequency and volume status during diarrhea.

How can kidney injury from Nirogacestat be prevented?

Oral phosphate/electrolyte repletion as needed Hydration during diarrhea Address contributing GI toxicity early

Who is at higher risk of kidney injury from Nirogacestat?

Baseline electrolyte/phosphate disturbance; Concurrent diarrhea/volume loss; Pre-existing CKD; Poor oral intake.

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Printable monograph

Gamma-secretase inhibitor

Nirogacestat

Ogsiveo · Niro

Gamma-secretase inhibitor · approved 2023 · 7 citations

Recent· through 2024

Fairly sourced5/9 · 5 signals

Met: 7 citations
Not met: 12+ references
Not met: Accrued over 10+ years (span: 7y)
Met: Beyond single case reports
Met: High-impact journal
Met: Landmark reference
Met: Current through 2024
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.

A gamma-secretase inhibitor for desmoid tumors — watch phosphate and electrolytes.

MildGamma-secretase inhibitor

Desmoid tumors (aggressive fibromatosis)

§01

Signature kidney injury

Signature lesion

Electrolyte Disturbance

Representative incidence42%

Hypophosphatemia occurred in 42% of nirogacestat-treated patients in the DeFi trial, alongside other electrolyte disturbances; the characteristic DeFi-trial toxicities were diarrhea, rash, nausea, fatigue and ovarian dysfunction. Beyond the phosphate signal, renal-specific incidence is not well quantified.Source: Gounder et al., N Engl J Med 2023 (DeFi, hypophosphatemia 42%)

Onset & rechallenge

Time to injuryVariable / unpredictable

Occurs during therapy but is not well characterized.

Distilled from: “During therapy; not well characterized.”

§02

Renal toxicities, ranked

This agent's kidney lesions ordered by prominence — the #1 signature lesion first, then secondary and rare patterns. Cited incidence is shown where a citable figure exists; otherwise the tier stands qualitatively.

Electrolyte Disturbance#1 · Signature42%PMID 36884323 (opens PubMed in a new tab)
hypophosphatemia 42% (DeFi phase 3)
Fanconi SyndromeSecondaryqualitative — no citable incidence
Global failure of proximal tubule reabsorption — glucosuria, phosphaturia and acidosis, classically from ifosfamide.

Toxicity fingerprint

Tap a signature to trace where it strikes the nephron.

42%incidence

SeverityMild

ReversibilityReversible

Evidence7 citations

Nephron map

Proximal Tubule

Distal Tubule / Collecting DuctFine-tuning of Na, K, Mg, acid & water

Electrolyte Disturbance

Renal electrolyte derangement — magnesium/potassium/calcium wasting (cisplatin, anti-EGFR antibodies) or retention (FGFR-inhibitor hyperphosphatemia, tumor-lysis hyperkalemia/hyperphosphatemia).

§03

Kidney injury

Mechanism of kidney injury

Gamma-secretase/Notch signaling participates in epithelial differentiation and mineral/phosphate homeostasis; its inhibition is postulated to perturb proximal-tubular electrolyte and phosphate handling, producing hypophosphatemia and other electrolyte shifts (a partial proximal-tubular/Fanconi-like phenotype is the conceptual concern). Robust nephron-level human data are lacking, so characterization is conservative and class/electrolyte-based rather than tied to a defined tubular lesion. Diarrhea-related volume/electrolyte loss can compound the picture.

Clinical presentation

Hypophosphatemia and other electrolyte abnormalities on labs; if a proximal-tubular pattern occurs, low phosphate with phosphaturia and possibly glucosuria/aminoaciduria. Serum creatinine is usually preserved.

Management

Electrolyte and phosphate repletion; supportive care for diarrhea-related losses; dose interruption/modification per label for significant toxicity. No specific renal antidote; abnormalities are generally reversible.Lesion-level management framework

Risk factors

Baseline electrolyte/phosphate disturbance
Concurrent diarrhea/volume loss
Pre-existing CKD
Poor oral intake

Prevention

Oral phosphate/electrolyte repletion as needed
Hydration during diarrhea
Address contributing GI toxicity early

Anticancer mechanism· how it treats cancer

Oral gamma-secretase inhibitor that blocks the regulated intramembrane proteolysis of Notch (and other gamma-secretase substrates), preventing release of the Notch intracellular domain and downstream transcription. In desmoid tumors (aggressive fibromatosis), Notch-pathway suppression drives the antitumor effect.

Note · Renal involvement is limited to electrolyte/phosphate disturbance; there is no established intrinsic nephrotoxic lesion. The phosphate signal warrants periodic monitoring even though a defined Fanconi syndrome has not been characterized for this agent.

§04

Clinical depth

Renal dose adjustment

No established renal dose adjustment; not studied in significant renal impairment. Modify dose for GI/dermatologic toxicity per label rather than for GFR. CYP3A interactions apply.

Dialyzability & ESKD dosing

Hepatically metabolized small molecule; dialyzability not characterized and not the management focus. In advanced CKD, monitor and replete electrolytes/phosphate.

Differential diagnosis

Drug-related hypophosphatemia/electrolyte shift vs diarrhea-driven losses vs a true proximal-tubular (Fanconi) pattern (which would add glucosuria/aminoaciduria/normoglycemic phosphaturia); urine studies clarify if creatinine or phosphate handling is unexpectedly abnormal.

Monitoring

Serum phosphate, potassium, magnesium and bicarbonate periodically
Stool frequency and volume status during diarrhea

Key trials & series

DeFi (Gounder NEJM 2023) phase III in progressing desmoid tumors

Clinical pearls

Monitor phosphate — hypophosphatemia is the most consistent renal-relevant lab finding with this gamma-secretase inhibitor.
There is no defined nephrotoxic lesion; the kidney shows up as electrolyte/phosphate disturbance, often reversible with repletion.
Diarrhea is common — distinguish GI-driven electrolyte loss from a primary tubular effect.
Ovarian dysfunction and skin/GI toxicity dominate the overall profile; renal issues are secondary.

§05

References

6 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

6 references · 2017–2024 · 3 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· 1

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.

CaseC · LimitedNirogacestat and Hypophosphatemia.Gudsoorkar P et al. · Kidney Int Rep 2023 · PMID 37441471Nephrology-focused correspondence describing nirogacestat-associated renal phosphate (electrolyte) wasting causing hypophosphatemia.

What gets reported — FAERS

Everything below is FAERS — adverse events someone chose to report, about 838 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· 1 signal

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

Electrolyte Disturbancecorroborated · ROR 3.9 — but the naming terms alone are not disproportionate, so this rests on terms merely consistent with the lesion
Fanconi SyndromeNo disproportionate reporting — This phenotype IS reportable and this agent has enough reports, yet the reporting is not disproportionate — the one genuinely informative negative of the four.

Electrolyte Disturbance

ROR 3.9095% CI 2.69–5.65· 29 reports

FAERS outcomes & reporting trend· 1% of reports w/ death · 13.5% w/ hospitalization

Reported with a death outcome

8 of 838 reports

13.5%

Reported with hospitalization

113 of 838 reports

Reports per year

Yearly FAERS report volume · most recent year is partial.

FAERS adverse-event signal — all organ systems· 9 systems · 838 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 0.8295% CI 0.34–1.98· 5 AKI reports ·no disproportionate AKI reporting signal (CI spans 1).

Gastrointestinal

Diarrhoea305Nausea193Vomiting75Stomatitis59Abdominal Discomfort39

General / constitutional

Fatigue163Pyrexia33Pain31Asthenia28Oropharyngeal Pain27

Skin

Rash109Pruritus44Alopecia42

Nervous system

Headache87Dizziness28

Vascular

Epistaxis37Hot Flush35

Metabolic & electrolyte

Dehydration35Decreased Appetite32

Respiratory

Cough47

Psychiatric

Insomnia28

Immune / infection

Nasopharyngitis24

Guidelines & consensus· 13

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.

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 Nirogacestat 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

Imatinib

Gleevec · BCR-ABL TKI

Profile

Fluid retention; rare Fanconi and AKI.

LYTEFANCATN

Mild#1 · 70% phenotype match

Trastuzumab deruxtecan

Enhertu · Antibody-drug conjugate (HER2/DXd)

Profile

Emerging AKI/proteinuria reports — under-published.

ATNFANCLYTE

Moderate#2 · 64% phenotype match

Streptozocin

Zanosar · Nitrosourea alkylator

Profile

Classic proximal tubular toxin → Fanconi and dose-limiting AKI.

FANCATNLYTE

Severe#3 · 59% phenotype match

Azacitidine

Vidaza · Hypomethylating agent

Profile

Proximal (type 2) RTA / Fanconi-like tubulopathy; overt AKI uncommon.

FANCATNLYTE

Moderate#4 · 56% phenotype match

Erdafitinib

Balversa · FGFR inhibitor

Profile

Hyperphosphatemia is an on-target class effect.

LYTE

Moderate#5 · 56% phenotype match

Futibatinib

Lytgobi · FGFR inhibitor

Profile

Hyperphosphatemia, class effect.

LYTE

Moderate#6 · 56% phenotype match

Compare Nirogacestat 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 Other targeted agents

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.