Vepdegestrant
Veppanu · PROTAC estrogen-receptor degrader
2026 first PROTAC ER degrader; no meaningful intrinsic renal signal.
PRE
Mild100% phenotype match
Oral selective estrogen-receptor degrader (SERD)
Imlunestrant
Inluriyo · IML
Oral selective estrogen-receptor degrader (SERD) · approved 2025 · 2 citations
Up to date· through 2025
Limited evidence3/9 · 4 signals▾
- 2 citations
- Deep literature (12+ refs)
- Accrued over 1+ years
- Beyond single case reports
- High-impact journal
- Landmark reference
- Registrational / key trials
- Current through 2025
- Real-world FAERS signal
Grades the strength of the evidence base (volume, journal quality, landmark trials, recency, real-world corroboration) — not the drug's severity. A rule-based summary, not a formal certainty appraisal.
An oral, brain-penetrant selective estrogen-receptor degrader that is renally benign on its own — the only kidney wrinkle is the harmless creatinine bump contributed by its abemaciclib partner.
MildOral selective estrogen-receptor degrader (SERD)
ER-positive, HER2-negative advanced or metastatic breast cancer, particularly with ESR1 mutations, after progression on prior endocrine therapyAs monotherapy or in combination with abemaciclib
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Signature kidney injury
Signature lesion
There is no meaningful renal signal for imlunestrant, and no discrete drug-specific incidence of acute kidney injury. In the phase 3 EMBER-3 trial (Jhaveri, N Engl J Med 2024; n=874) grade 3 or higher adverse events occurred in only 17.1% with imlunestrant monotherapy — comparable to standard endocrine therapy (20.7%) — with the toxicity profile of an oral SERD (low-grade fatigue, diarrhea, nausea) rather than a nephrotoxic one. The one renal-relevant nuance is not imlunestrant itself but its combination partner: abemaciclib inhibits the renal tubular transporters (OCT2/MATE) that secrete creatinine, producing an early, benign, non-progressive rise in serum creatinine without a true fall in glomerular filtration — so the imlunestrant-abemaciclib combination (grade 3+ adverse events 48.6%) can show a creatinine bump that must not be mistaken for kidney injury.Source: No meaningful renal signal; grade 3+ AEs 17.1% as monotherapy in EMBER-3 (Jhaveri 2024); the only renal wrinkle is the benign creatinine rise of the abemaciclib partner
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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.
Renal hypoperfusion from capillary leak and cytokine storm — IL-2 and CAR-T cytokine release syndrome.
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Kidney injury
Mechanism of kidney injury
Imlunestrant has no established direct renal toxicity. As an oral SERD it acts on tumor ER and is hepatically metabolized; the kidney is neither a target of injury nor the route of clearance. The only renal-relevant phenomenon in its clinical use is pharmacologic and belongs to its combination partner: abemaciclib competitively inhibits the proximal-tubule organic cation transporters (OCT2) and MATE proteins that secrete creatinine into the urine, so measured serum creatinine rises modestly and early without any true reduction in glomerular filtration — a 'pseudo-AKI' that is reversible and does not reflect nephron injury. Recognizing this prevents unnecessary dose reductions or workups. Beyond this, diarrhea from the combination could in principle contribute mild prerenal physiology if severe, but this is not a characteristic feature.
Clinical presentation
On monotherapy, no characteristic renal presentation — renal function stays stable. On the abemaciclib combination, an asymptomatic, early, mild rise in serum creatinine may be seen that plateaus and does not progress, with a normal cystatin-C-based estimate and no proteinuria or sediment abnormality — the signature of transporter-mediated creatinine handling rather than injury. True AKI in a patient on imlunestrant should prompt a search for another cause.
Management
For imlunestrant monotherapy, no renal-specific management is required. For the abemaciclib combination, the key action is interpretive: confirm that an early, stable creatinine rise reflects blocked tubular creatinine secretion rather than a falling GFR (a cystatin-C-based estimate helps), and avoid reflexive dose reductions or workups. Manage combination diarrhea with hydration and antidiarrheals to prevent any prerenal contribution. Investigate a progressive or large creatinine rise, proteinuria, or an active sediment as a separate, true renal process. No dialysis or drug-specific renal rescue is relevant.Lesion-level management framework
Risk factors
- Use in combination with abemaciclib (for the benign creatinine-secretion effect)
- Baseline CKD (makes any creatinine change harder to interpret)
- Severe combination-related diarrhea causing volume depletion (uncommon, prerenal)
- Concurrent nephrotoxins or true renal insults confounding interpretation
Prevention
- Recognize the abemaciclib-related creatinine rise as benign transporter inhibition, not injury, before altering therapy
- Establish a baseline creatinine so an early combination-related rise is interpreted correctly
- Consider a cystatin-C-based GFR estimate if the creatinine change needs clarification
- Maintain hydration if combination diarrhea occurs
Anticancer mechanism· how it treats cancer
Oral, next-generation, brain-penetrant selective estrogen receptor degrader (SERD) that binds estrogen receptor alpha (ERα) and promotes its degradation, delivering continuous ER inhibition even in tumors bearing ESR1 mutations that confer resistance to aromatase inhibitors. It is used alone or combined with the CDK4/6 inhibitor abemaciclib in ER-positive, HER2-negative advanced breast cancer.
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Clinical depth
Renal dose adjustment
No renal-impairment dose adjustment is established for imlunestrant; it is an orally administered, hepatically handled SERD and EMBER-3 required adequate organ function. GFR does not drive its exposure, and dose modification is based on tolerability (GI, hepatic) rather than kidney function. The main renal caveat is interpretive — do not down-titrate for the benign abemaciclib creatinine rise.
Dialyzability & ESKD dosing
Not characterized as dialyzable and not clinically relevant: as a protein-bound, hepatically metabolized oral SERD, imlunestrant is not expected to be removed by hemodialysis, and there is no renal-elimination or drug-removal scenario in which dialysis matters for this agent.
Differential diagnosis
The key distinction is benign creatinine-secretion inhibition versus true AKI. The abemaciclib-combination effect is early, small, stable, non-progressive, and unaccompanied by proteinuria or an active sediment, with a preserved cystatin-C-based GFR — not injury. A larger, progressive, or symptomatic creatinine rise, or one with an abnormal sediment or proteinuria, indicates a separate cause (volume depletion, nephrotoxin, obstruction, disease) and should be worked up as such. Imlunestrant itself is not a tubular or glomerular toxin.
Monitoring
- Baseline creatinine to anchor interpretation, then routine chemistry
- On the abemaciclib combination, expect and correctly interpret an early, stable creatinine rise (consider cystatin C if unclear)
- Volume status if combination diarrhea is significant
- Standard tolerability monitoring (GI, hepatic) that drives dose changes
Key trials & series
- EMBER-3 (Jhaveri, N Engl J Med 2024) — phase 3 trial in ER-positive, HER2-negative advanced breast cancer (n=874); imlunestrant improved progression-free survival versus standard endocrine therapy in ESR1-mutant disease and the imlunestrant-abemaciclib combination improved it further, with grade 3+ adverse events of 17.1% (monotherapy) versus 48.6% (combination) — establishing a benign renal profile for imlunestrant and locating the creatinine effect in the abemaciclib partner.
Clinical pearls
- Imlunestrant is a kidney-safe oral SERD — the renal story is really about its abemaciclib partner.
- Know the abemaciclib creatinine trick: blocked tubular secretion (OCT2/MATE) raises measured creatinine without lowering true GFR — don't reduce the dose for it.
- A cystatin-C-based GFR cuts through the confusion when the creatinine rises on the combination.
- A progressive or heavy creatinine rise, proteinuria, or an active sediment is a different problem — investigate it separately.
- Being brain-penetrant is about CNS efficacy, not a renal concern.
Where it strikes· nephron segments & injury signatures
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
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References
2 peer-reviewed references. Citation metadata via PubMed / NLM.
Evidence accrual
2 references · 2024–2025 · 2 since 2023Citations per year in this profile — a proxy for how actively the agent's renal literature is accruing. Recent years are highlighted. Reflects curation depth, not a systematic bibliometric count.
- 1.LandmarkImlunestrant with or without Abemaciclib in Advanced Breast Cancer.Jhaveri KL, Neven P, Casalnuovo ML, et al. · N Engl J Med · 2024 · PMID 39660834Phase 3 EMBER-3 registrational trial establishing imlunestrant's efficacy and its benign toxicity profile (grade 3+ AEs 17.1% as monotherapy), with the higher-toxicity combination arm framing where the creatinine effect (the abemaciclib partner) comes from.
- 2.Renal adverse events associated with cyclin-dependent kinase 4/6 inhibitors.Izzedine H, Wanchoo R, Sharma R, Jhaveri KD. · Cancer Treat Rev · 2025 · PMID 41385991Reviews the renal effects of CDK4/6 inhibitors: abemaciclib carries the highest risk and characteristically causes a 'pseudo-AKI' — a creatinine rise from inhibiting tubular OCT2/MATE creatinine secretion without a true GFR decline (hence the value of cystatin C) — the source of the only renal-relevant finding in the imlunestrant-abemaciclib combination.
Guidelines & consensus· 12
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 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 Imlunestrant sits in nephrotoxicity space — each dot is an anti-cancer agent, positioned so neighbors share a kidney-injury phenotype.
Phenotype-similar agents· nearest neighbors in nephrotoxicity space
Profile
Elacestrant
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PRE
Mild100% phenotype match
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Mild89% phenotype match
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Mild89% phenotype match
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Mild88% phenotype match
Nearest agents by kidney-injury phenotype (shared injuries, nephron target, severity, class) — a similarity approximation, not a claim of shared drug identity or mechanism.