Ramucirumab
Cyramza · Anti-VEGFR2 antibody
Hypertension and proteinuria, class effect.
HTNGLOMTMA
ModerateOpen →
Androgen-receptor inhibitor
Enzalutamide
Xtandi · Enza
Androgen-receptor blockade with a real hypertension signal but minimal direct nephrotoxicity.
MildAndrogen-receptor signaling inhibitor · approved 2012
Castration-resistant prostate cancerCastration-sensitive prostate cancerNon-metastatic CRPC
Signature kidney injury
Hypertension
Hypertension is the dominant renovascular signal. A 2024 JAMA Oncology meta-analysis of androgen-receptor signaling inhibitors found a markedly increased risk of grade ≥3 hypertension (relative risk ~2.25); an earlier meta-analysis showed the same for enzalutamide specifically. Direct intrinsic kidney injury is uncommon; rare hyponatremia appears mainly in combination regimens.
Source: El-Taji et al., JAMA Oncol 2024
Mechanism of kidney injury
Androgen-receptor signaling inhibition exerts a class effect on the vasculature — reduced endothelial nitric-oxide-mediated vasodilation, plus sympathetic/RAAS contributions — raising systemic blood pressure. Unlike abiraterone, enzalutamide does not redirect steroidogenesis, so it lacks a strong mineralocorticoid-excess electrolyte syndrome; sustained uncontrolled hypertension is the mechanism by which renovascular/cardiovascular injury can accrue over time. Hyponatremia is occasionally reported, largely in combination settings.
Clinical presentation
New or worsened hypertension is the usual finding; serum creatinine is generally stable. Occasional electrolyte abnormalities (including hyponatremia) chiefly in combination therapy. Seizure risk (CNS penetration) is a separate non-renal concern.
Onset
Hypertension emerges over weeks to months of therapy.
Reversibility
Reversible
Anticancer mechanism
Potent second-generation androgen-receptor inhibitor that blocks androgen binding to the receptor, nuclear translocation of the receptor, and receptor–DNA binding/coactivator recruitment. Used across castration-sensitive, non-metastatic and metastatic castration-resistant prostate cancer.
Management
Standard antihypertensive treatment to target; intensify rather than interrupt for most hypertension. Rarely requires dose change for renal reasons. Manage combination-related hyponatremia by addressing the contributing agent.
Risk factors
- Baseline hypertension
- Established cardiovascular disease
- Older age
- Concurrent ADT and/or combination regimens
Prevention
- Baseline and on-treatment blood-pressure monitoring
- Optimize antihypertensive therapy proactively
- Global cardiovascular risk-factor management
Note · Unlike abiraterone, enzalutamide raises blood pressure without a mineralocorticoid-excess hypokalemia/alkalosis syndrome; hyponatremia reports are mostly from combination settings. It is a strong CYP3A4 inducer — watch interactions with renally relevant co-medications.
Clinical depth
Renal dose adjustment
No dose adjustment for mild–moderate renal impairment; severe impairment and ESKD have not been formally studied. Reduce dose in concomitant strong CYP2C8 inhibitors and for hepatic impairment per label.
Dialyzability & ESKD dosing
Highly protein-bound and hepatically metabolized; not expected to be dialyzable. No established ESKD dosing — use clinical judgment and blood-pressure-directed care.
Differential diagnosis
Hypertension from ARSI vs essential/poorly controlled baseline hypertension vs VEGF-inhibitor hypertension (if on combination antiangiogenics); a rising creatinine should prompt search for a separate prerenal or obstructive cause rather than attribution to the drug.
Monitoring
- Blood pressure at each visit and at home early in therapy
- Serum sodium if combination therapy or symptoms
- Cardiovascular risk reassessment periodically
Key trials & series
- PREVAIL and AFFIRM (mCRPC)
- PROSPER (nmCRPC)
- ARCHES / ENZAMET (castration-sensitive)
- El-Taji JAMA Oncol 2024 ARSI cardiovascular meta-analysis
Clinical pearls
- Treat the blood pressure, don't stop the drug — enzalutamide hypertension is manageable with standard agents.
- No mineralocorticoid syndrome: enzalutamide lacks abiraterone's hypokalemia/alkalosis because it does not shunt steroidogenesis.
- It is a potent CYP3A4 inducer — re-check levels of narrow-therapeutic-index co-meds.
- An unexplained creatinine rise is rarely the drug itself; look elsewhere.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
HypertensionElectrolyte Wasting
Beyond the kidney
Class-level context for the major non-renal toxicities of androgen-receptor inhibitors.
Cardiac
Cardiomyopathy, QT, ischemia, myocarditis
- QT, hypertension, fluid retention
Musculoskeletal
Myalgia, myositis, rhabdomyolysis, ONJ
- Bone loss, fatigue, hot flashes
Hepatic / Liver
Transaminitis, hepatitis, VOD/SOS
- Transaminitis (abiraterone)
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkCardiovascular Events and Androgen Receptor Signaling Inhibitors in Advanced Prostate Cancer: A Systematic Review and Meta-Analysis.El-Taji O et al. · JAMA Oncol 2024 · PMID 38842801Large meta-analysis: ARSIs increase grade ≥3 hypertension (RR ~2.25) across the disease spectrum.PMIDThe Cardiovascular Toxicity of Abiraterone and Enzalutamide in Prostate Cancer.Iacovelli R et al. · Clin Genitourin Cancer 2017 · PMID 29339044Meta-analysis: enzalutamide significantly increases hypertension risk.PMIDEnzalutamide in metastatic prostate cancer before chemotherapy.Beer TM et al. · N Engl J Med 2014 · PMID 24881730PREVAIL pivotal trial: fatigue and hypertension the most common clinically relevant adverse events.PMIDEnzalutamide in Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study.Beer TM et al. · Eur Urol 2016 · PMID 27477525Final PREVAIL analysis confirming the hypertension/fatigue safety signature with longer follow-up.PMIDPhase 1 trial of enzalutamide in combination with gemcitabine and nab-paclitaxel for the treatment of advanced pancreatic cancer.Mahipal A et al. · Invest New Drugs 2018 · PMID 30298303Combination-regimen experience including hyponatremia among adverse events.PMIDConventional Chemotherapy Nephrotoxicity.Gupta S et al. · Adv Chronic Kidney Dis 2021 · PMID 35190107Onconephrology reference framing drug-related hypertension and electrolyte effects.
Related agents
Other agents sharing the same signature kidney injury.