Trametinib
Mekinist · MEK inhibitor
MEK inhibitor; hypertension, proteinuria, and combination-therapy AKI.
PREAINGLOM
Moderate#1 · 77% phenotype match
Ibrutinib
Imbruvica · Ibrut
BTK inhibitor · approved 2013 · 9 citations
Up to date· through 2025
Deeply sourced7/9 · 6 signals
- Met: 9 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.
A first-generation BTK inhibitor whose off-target kinase inhibition drives hypertension — and occasionally proteinuria, AIN or AKI.
ModerateBTK inhibitor
CLL/SLLMantle-cell lymphomaWaldenström macroglobulinemiaMarginal-zone lymphomaChronic GVHD
§01
Signature kidney injury
Signature lesion
Representative incidence26%
New or worsened hypertension is common (~26% in a real-world CLL cohort comparing it with acalabrutinib; higher with longer follow-up). AKI at CLL presentation and with tumor lysis is well described. Drug-attributable AKI from interstitial nephritis or glomerular endotheliosis is case-level.Source: Majrashi et al., Pharmacol Res Perspect 2025 (HTN 26.3%)
Onset & rechallenge
Time to injuryVariable / unpredictable
Hypertension over weeks to months; tumor lysis early (first cycle); glomerular/interstitial lesions case-level over weeks to months.
Distilled from: “Hypertension develops over weeks–months (can be early); tumor lysis is early (first cycle); glomerular/interstitial lesions are case-level over weeks to months.”
§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.
Any-grade hypertension in 25.3% of ibrutinib-treated relapsed/refractory CLL/SLL patients (ALPINE, n=325); dedicated cardio-oncology cohorts report new or worsening BP even more often (e.g. a >10 mmHg systolic rise in ~37% by 1 month).
Renal hypoperfusion from capillary leak and cytokine storm — IL-2 and CAR-T cytokine release syndrome.
Damage to the filtration barrier — podocyte injury, FSGS and protein leak from VEGF and mTOR blockade.
Direct death of tubular epithelial cells — the dose-limiting lesion of the platinums and zoledronate.
Immune-mediated inflammation of the renal interstitium — the signature kidney injury of checkpoint inhibitors.
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
26%incidence
SeverityModerate
ReversibilityVariable
Evidence9 citations
Nephron map
GlomerulusFiltration barrier (podocytes + endothelium)
Vasculature / EndotheliumGlomerular & peritubular capillaries
Proximal Tubule
Distal Tubule / Collecting Duct
Interstitium
Hypertension
Raised blood pressure — archetypally on-target loss of endothelial nitric oxide from VEGF-pathway blockade, studied as a pharmacodynamic marker of drug exposure. Other agents raise it too: vascular effects of BCR-ABL, BTK and RET inhibitors and of copanlisib; abiraterone's mineralocorticoid excess; androgen suppression or blockade.
§03
Kidney injury
Mechanism of kidney injury
Beyond BTK, ibrutinib's off-target kinase inhibition (including effects on endothelial nitric-oxide/VEGF signaling) produces hypertension and, in case reports, pre-eclampsia–like glomerular endothelial injury (glomerular endotheliosis) with proteinuria. A cysteine-conjugate (extrahepatic) metabolite can bioactivate in proximal tubular cells, and acute interstitial nephritis has been reported. Rapid CLL/lymphoma cytoreduction can cause tumor lysis, and volume depletion adds prerenal/hemodynamic AKI.
Clinical presentation
Rising blood pressure (often early and substantial), sometimes proteinuria, and acute-on-chronic kidney injury; occasional biopsy-proven glomerular endotheliosis or acute interstitial nephritis. Tumor-lysis labs (hyperuricemia/hyperkalemia/hyperphosphatemia) when bulky disease lyses. Atrial fibrillation and bleeding are the other hallmark off-target toxicities.
Management
Treat hypertension (no single antihypertensive class is clearly superior for BTKi-induced hypertension; control is the goal). Manage tumor lysis with hydration and rasburicase/allopurinol. Investigate unexplained AKI/proteinuria (including biopsy for suspected AIN or glomerular endotheliosis); dose-modify or hold for severe events.Lesion-level management framework
Risk factors
- Bulky/high-burden CLL or lymphoma
- Pre-existing hypertension or CKD
- Volume depletion
- Concurrent nephrotoxins
- Black ancestry and prior arrhythmia (for BTKi hypertension)
Prevention
- Prompt antihypertensive control when blood pressure rises on therapy
- TLS risk assessment with hydration and urate-lowering therapy
Anticancer mechanism· how it treats cancer
Irreversible covalent Bruton tyrosine kinase (BTK) inhibitor that binds cysteine-481, shutting down B-cell receptor signaling and NF-κB–driven survival in chronic lymphocytic leukemia (CLL), mantle-cell lymphoma and Waldenström macroglobulinemia. Its off-target inhibition of other kinases (including TEC, ITK, EGFR and effects on endothelial/VEGF signaling) underlies several toxicities.
Note · CLL itself causes kidney disease (leukemic infiltration, MPGN, cryoglobulinemia, light-chain effects), so attributing AKI to ibrutinib requires excluding disease-related and tumor-lysis causes. Hypertension precedes and predicts major adverse cardiac events, making BP control clinically important beyond the kidney.
§04
Clinical depth
Renal dose adjustment
No dose adjustment for mild-to-moderate renal impairment (CrCl ≥30 mL/min); severe impairment (CrCl <30) and dialysis are not well studied — use with caution. Ibrutinib is hepatically (CYP3A) cleared, so hepatic impairment, not renal, drives dose reduction; <10% renal excretion of metabolites.
Dialyzability & ESKD dosing
Not meaningfully dialyzable — highly protein-bound (~97%) small molecule with hepatic clearance. No supplemental dosing after HD is needed.
Differential diagnosis
Separate ibrutinib-attributable AKI from CLL-related kidney disease (infiltration, MPGN, cryoglobulinemia), tumor lysis (urate/phosphate profile), prerenal azotemia, drug-induced AIN (sterile pyuria, white-cell casts, biopsy), and glomerular endotheliosis (proteinuria, biopsy). Hypertension is the most consistent and reproducible renal-relevant signal.
Monitoring
- Blood pressure at each visit (and home monitoring) — hypertension is the signature renal-relevant toxicity
- Serum creatinine and urine protein periodically
- Tumor-lysis labs during early cytoreduction in bulky disease
- ECG/clinical assessment for atrial fibrillation (off-target effect)
Key trials & series
- Burger et al., NEJM 2015 — RESONATE-2 first-line CLL registrational trial
- Majrashi et al., Pharmacol Res Perspect 2025 — real-world federated network: hypertension 26.3% (ibrutinib) vs 15% (acalabrutinib)
- Chen et al., J Hematol Oncol 2022 — BTKi hypertension cohort showing HTN precedes major cardiac events
Clinical pearls
- Hypertension is the most reliable ibrutinib renal-system toxicity, is often early, and predicts later cardiovascular events — control it.
- Unexplained proteinuria/AKI on ibrutinib should prompt consideration of glomerular endotheliosis or acute interstitial nephritis, sometimes warranting biopsy.
- Always exclude CLL-intrinsic kidney disease and tumor lysis before blaming the drug.
Beyond the kidney — non-renal toxicities· 2 organ systems
Class-level context for the major non-renal toxicities of the BTK inhibitor class.
Cardiac
Cardiomyopathy, QT, ischemia, myocarditis
- Atrial fibrillation, ventricular arrhythmia
Vascular
Hypertension, VTE/ATE, bleeding, aneurysm
- Bleeding, hypertension
§05
References
8 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
8 references · 2015–2025 · 1 since 2023Primary (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.
- 1.LandmarkIbrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia.Burger JA et al. · N Engl J Med · 2015 · PMID 26639149RESONATE-2 registrational first-line CLL trial establishing the toxicity profile.
- 2.A Comparative Analysis of Cardiovascular Events Associated With Acalabrutinib Versus Ibrutinib in Chronic Lymphocytic Leukemia: Insights From a Global Federated Network.Majrashi A et al. · Pharmacol Res Perspect · 2025 · PMID 40341807Real-world cohort: hypertension 26.3% with ibrutinib vs 15% with acalabrutinib.
- 3.Hypertension and incident cardiovascular events after next-generation BTKi therapy initiation.Chen ST et al. · J Hematol Oncol · 2022 · PMID 35836241BTKi hypertension cohort; SBP rise after initiation predicts major adverse cardiac events; hypertension a class effect.
- 4.Extrahepatic metabolism of ibrutinib.Rood JJM et al. · Invest New Drugs · 2020 · PMID 32623551Mechanistic basis for ibrutinib nephrotoxicity: cysteine-conjugate metabolite bioactivation in proximal tubular cells.
- 5.A case report of pre-eclampsia-like endothelial injury in the kidney of an 85-year-old man treated with ibrutinib.Li A et al. · BMC Nephrol · 2022 · PMID 35870899Biopsy-proven glomerular endotheliosis with proteinuria attributed to ibrutinib's off-target effects.
- 6.Ibrutinib-induced acute kidney injury via interstitial nephritis.Markóth C et al. · Ren Fail · 2021 · PMID 33567947Case of biopsy-proven acute interstitial nephritis attributed to ibrutinib.
- 7.Hypertension and Prohypertensive Antineoplastic Therapies in Cancer Patients.van Dorst DCH et al. · Circ Res · 2021 · PMID 33793337Cardio-onconephrology review covering BTK-inhibitor–associated hypertension mechanisms and management.
- 8.Renal involvement in chronic lymphocytic leukemia.Wanchoo R et al. · Clin Kidney J · 2018 · PMID 30288263Onconephrology review of CLL-related kidney disease and therapy-associated tumor lysis (mimics of drug AKI).
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.
What gets reported — FAERS
Everything below is FAERS — adverse events someone chose to report, about 80,310 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· 5 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
- Hypertensioncorroborated · ROR 1.52 — on the terms that name the lesion (ROR 1.81)
- Prerenal / Hemodynamic AKINot queried in FAERS — No MedDRA term set is defined for this phenotype, so FAERS was never asked about it.
- Glomerular Injury / ProteinuriaNo 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.
- Acute Tubular NecrosisNot measurable in reporting — Reporters cannot reliably name this lesion, so its absence from FAERS is expected and is not evidence against the documented injury.
- Acute Interstitial NephritisNot measurable in reporting — Reporters cannot reliably name this lesion, so its absence from FAERS is expected and is not evidence against the documented injury.
Hemorrhagic Cystitis
ROR 3.0895% CI 2.87–3.30· 805 reports
Crystal / Obstructive Nephropathy
ROR 1.9395% CI 1.75–2.13· 409 reports
Hypertension
ROR 1.5295% CI 1.45–1.58· 2,213 reports
SIADH / Hyponatremia
ROR 1.5195% CI 1.38–1.65· 463 reports
Electrolyte Disturbance
ROR 1.3295% CI 1.23–1.40· 959 reports
FAERS outcomes & reporting trend· 17.1% of reports w/ death · 33.3% w/ hospitalization
17.1%
Reported with a death outcome
13,715 of 80,310 reports
33.3%
Reported with hospitalization
26,719 of 80,310 reports
Reports per year
- 2015: 4,210 reports
- 2016: 4,326 reports
- 2017: 5,376 reports
- 2018: 7,196 reports
- 2019: 8,568 reports
- 2020: 10,342 reports
- 2021: 7,680 reports
- 2022: 13,527 reports
- 2023: 8,225 reports
- 2024: 4,440 reports
- 2025: 3,591 reports
- 2026: 1,474 reports
Yearly FAERS report volume · most recent year is partial.
FAERS adverse-event signal — all organ systems· 10 systems · 80,310 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 1.0295% CI 0.94–1.10· 592 AKI reports ·no disproportionate AKI reporting signal (CI spans 1).
General / constitutional
Fatigue4,752Fall2,527Asthenia2,358Pyrexia1,855Pain1,642
Immune / infection
Pneumonia3,263Covid-191,745Infection1,510
Gastrointestinal
Diarrhoea4,191Nausea2,317
Musculoskeletal
Arthralgia2,209Muscle Spasms1,780
Cardiac
Atrial Fibrillation3,894
Blood & lymphatic
Anaemia1,715Platelet Count Decreased1,651
Nervous system
Dizziness1,729Headache1,539
Skin
Rash2,147
Vascular
Haemorrhage2,015
Respiratory
Dyspnoea1,673
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 Ibrutinib 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.
Phenotype-similar agents· the numbered markers on the map above
Profile
Ivonescimab
AK112 (Akeso/Summit) · PD-1 x VEGF bispecific antibody
Two nephrotoxic pathways in one molecule: VEGF-blockade glomerular injury plus checkpoint-inhibitor interstitial nephritis.
GLOMHTNAIN
Moderate#2 · 70% phenotype match
Sunitinib
Sutent · VEGFR TKI
VEGFR-TKI; hypertension and proteinuria, TMA reported.
HTNGLOMTMA
Moderate#3 · 56% phenotype match
Sacituzumab govitecan
Trodelvy · Antibody-drug conjugate (Trop-2/SN-38)
Diarrhea-driven prerenal AKI; emerging direct signals.
PREAINATN
Moderate#4 · 55% phenotype match
Tislelizumab
Tevimbra · PD-1 immune checkpoint inhibitor
A PD-1 blocker whose kidney risk is the class-typical rare immune-mediated interstitial nephritis.
AINPRETMA
Moderate#5 · 54% phenotype match
Ipilimumab
Yervoy · CTLA-4 checkpoint inhibitor
CTLA-4 inhibitor; immune (often granulomatous) interstitial nephritis.
AINCINGLOM
Severe#6 · 54% 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.
Kidney risk across BTK inhibitors
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.
- 1AcalabrutinibHTN — HypertensionMild
- 2ZanubrutinibPRE — Prerenal / Hemodynamic AKIMild
- 3PirtobrutinibXTAL — Crystal / Obstructive NephropathyFAERS AKIMild
- 4Ibrutinib· this agentHTN — HypertensionModerate
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.