Ramucirumab
Cyramza · Anti-VEGFR2 antibody
Hypertension and proteinuria, class effect.
HTNGLOMTMA
ModerateOpen →
BTK inhibitor
Ibrutinib
Imbruvica · Ibrut
A first-generation BTK inhibitor whose off-target kinase inhibition drives hypertension — and occasionally proteinuria, AIN or AKI.
ModerateBTK inhibitor · approved 2013
CLL/SLLMantle-cell lymphomaWaldenström macroglobulinemiaMarginal-zone lymphomaChronic GVHD
Signature kidney injury
Hypertension
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%)
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
0%incidence
SeverityModerate
ReversibilityVariable
Evidence0 refs
Nephron map
GlomerulusFiltration barrier (podocytes + endothelium)
Vasculature / EndotheliumGlomerular & peritubular capillaries
Proximal Tubule
Distal Tubule / Collecting Duct
Interstitium
Hypertension
On-target loss of endothelial nitric oxide from VEGF-pathway blockade — so consistent it marks drug activity.
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.
Onset
Hypertension develops over weeks–months (can be early); tumor lysis is early (first cycle); glomerular/interstitial lesions are case-level over weeks to months.
Reversibility
Variable
Anticancer mechanism
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.
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.
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
- Baseline and serial blood-pressure monitoring with prompt antihypertensive control
- TLS risk assessment with hydration and urate-lowering therapy
- Monitor creatinine and urine protein
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.
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 dialyzable in any meaningful sense — 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 (eosinophiluria, 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.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Glomerulus
Filtration barrier (podocytes + endothelium)
Interstitium
Supporting tissue around the tubules
Injury signatures
Prerenal / Hemodynamic AKIHypertensionGlomerular Injury / ProteinuriaAcute Tubular NecrosisAcute Interstitial Nephritis
Beyond the kidney
Class-level context for the major non-renal toxicities of btk inhibitors.
Cardiac
Cardiomyopathy, QT, ischemia, myocarditis
- Atrial fibrillation, ventricular arrhythmia
Vascular
Hypertension, VTE/ATE, bleeding, aneurysm
- Bleeding, hypertension
Evidence
8 peer-reviewed references. Citation metadata via PubMed / NLM.
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.PMIDA 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.PMIDHypertension 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.PMIDExtrahepatic 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.PMIDA 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.PMIDIbrutinib-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.PMIDHypertension 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.PMIDRenal 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).
Related agents
Other agents sharing the same signature kidney injury.