Ramucirumab
Cyramza · Anti-VEGFR2 antibody
Hypertension and proteinuria, class effect.
HTNGLOMTMA
ModerateOpen →
VEGFR TKI
Lenvatinib
Lenvima · Lenva
A multi-target VEGFR TKI ranked among the most hypertensive, frequently spilling protein into the urine.
ModerateVEGFR multikinase inhibitor · approved 2015
Differentiated thyroid cancerHepatocellular carcinomaRenal cell carcinoma (with everolimus or pembrolizumab)Endometrial carcinoma (with pembrolizumab)
Signature kidney injury
Hypertension
Hypertension is among the most common adverse events; in the SELECT thyroid-cancer trial hypertension occurred in about 68% (grade >=3 ~42%) and proteinuria in roughly 31%. In KEYNOTE-B61 (lenvatinib plus pembrolizumab) grade 3-4 hypertension occurred in ~23%. Proteinuria is a frequent renal AE with lenvatinib.
Source: Albiges et al., Lancet Oncol 2023 (KEYNOTE-B61 combination grade 3-4 hypertension); SELECT (Schlumberger, NEJM 2015) — single-agent renal rate not cleanly separable
Mechanism of kidney injury
VEGFR tyrosine kinase inhibition reduces glomerular endothelial VEGF signaling and nitric-oxide-mediated vasodilation, raising blood pressure and injuring podocytes and glomerular endothelium. Unlike ligand-trapping antibodies, receptor-blocking TKIs preferentially produce podocytopathies — minimal change disease and focal segmental glomerulosclerosis (biopsy-proven with lenvatinib) — driven in part by podocyte c-mip overexpression and dysregulation, in addition to proteinuria and occasional TMA.
Clinical presentation
New or worsening hypertension (often within days to weeks) and proteinuria; occasionally nephrotic-range proteinuria with edema, hypoalbuminemia and a creatinine rise. Biopsy may show FSGS/MCD-like podocytopathy.
Onset
Within the first weeks of therapy (hypertension early; proteinuria over weeks).
Reversibility
Reversible
Anticancer mechanism
Oral multikinase inhibitor of VEGFR1-3, FGFR1-4, PDGFR-alpha, RET and KIT (with a distinctive type V binding mode), suppressing tumor angiogenesis and proliferation. Used in differentiated thyroid cancer, hepatocellular carcinoma, and renal cell and endometrial carcinoma (the latter two with pembrolizumab).
Management
Antihypertensive therapy (ACE inhibitor/ARB favored for concurrent proteinuria); interrupt or dose-reduce per label for grade 3 hypertension or significant proteinuria (>=2 g/24 h) and discontinue for nephrotic syndrome or life-threatening hypertension. Switching to a less nephrotoxic VEGFR-TKI (e.g., sorafenib) has improved lenvatinib-induced nephrotic syndrome while preserving disease control in reported cases. Effects usually improve with dose modification or withdrawal, though FSGS can leave residual CKD.
Risk factors
- Pre-existing hypertension
- Baseline proteinuria or CKD
- Diabetes
Prevention
- Baseline and ongoing blood pressure and urine protein monitoring
- Pre-emptive optimization of blood pressure control (target well-controlled BP before starting)
Note · Headline percentage is grade 3-4 hypertension from a combination regimen; single-agent thyroid-cancer rates of all-grade hypertension and proteinuria are higher. Lenvatinib is consistently ranked among the most hypertensive TKIs.
Clinical depth
Renal dose adjustment
Reduce the starting dose for severe renal impairment (CrCl < 30 mL/min) per label (e.g., a lower mg starting dose in thyroid/RCC indications); no adjustment for mild-moderate impairment. Lenvatinib is mainly hepatically metabolized (CYP3A and aldehyde oxidase), so hepatic impairment also drives dose reduction.
Dialyzability & ESKD dosing
Highly protein-bound (~98-99%) and hepatically cleared, so it is not appreciably removed by hemodialysis; dosing in ESKD follows the severe-renal-impairment reduction with toxicity-guided titration.
Differential diagnosis
VEGFR-TKI podocytopathy (MCD/FSGS, heavy proteinuria, hypertension) versus anti-VEGF-antibody TMA versus prerenal AKI versus diabetic/hypertensive nephropathy at baseline. Biopsy distinguishes the FSGS/MCD pattern; the temporal link to drug initiation and accompanying hypertension support attribution.
Monitoring
- Blood pressure weekly for the first 1-2 months, then with each visit (home BP encouraged)
- Urine protein (dipstick/UPCR) before each cycle; quantify if >=2+
- Serum creatinine and electrolytes periodically
Key trials & series
- SELECT phase III in radioiodine-refractory differentiated thyroid cancer (hypertension ~68%, proteinuria ~31%)
- KEYNOTE-B61 lenvatinib + pembrolizumab in non-clear-cell RCC (grade 3-4 hypertension ~23%)
- REFLECT phase III in hepatocellular carcinoma (hypertension a leading AE)
Clinical pearls
- Lenvatinib is a top-tier cause of TKI hypertension — have an antihypertensive plan before the first dose.
- Its glomerular lesion is typically a podocytopathy (FSGS/MCD), which can leave residual CKD even after stopping.
- Switching to sorafenib is a documented strategy to keep treating the cancer while improving lenvatinib-induced nephrotic syndrome.
Where it strikes
Nephron segments
Glomerulus
Filtration barrier (podocytes + endothelium)
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
HypertensionGlomerular Injury / Proteinuria
Beyond the kidney
Class-level context for the major non-renal toxicities of vegfr tkis.
Vascular
Hypertension, VTE/ATE, bleeding, aneurysm
- Hypertension, arterial/venous thrombosis, bleeding, impaired wound healing
Cardiac
Cardiomyopathy, QT, ischemia, myocarditis
- LV dysfunction; QT (some TKIs)
Gastrointestinal
Diarrhea, colitis, mucositis, perforation
- Diarrhea, perforation/fistula
Dermatologic
Rash, HFS, SJS/TEN, vitiligo
- Hand-foot skin reaction
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
PMIDPembrolizumab plus lenvatinib as first-line therapy for advanced non-clear-cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial.Albiges L et al. · Lancet Oncol 2023 · PMID 37451291Reports grade 3-4 hypertension (~23%) and proteinuria with lenvatinib-containing therapy.LandmarkNephrotoxicity in advanced thyroid cancer treated with tyrosine kinase inhibitors: An update.Nervo A et al. · Crit Rev Oncol Hematol 2021 · PMID 34801702Highlights proteinuria as the most frequent renal AE, especially with lenvatinib and cabozantinib.PMIDFocal segmental glomerulosclerosis lesion associated with inhibition of tyrosine kinases by lenvatinib: a case report.Furuto Y et al. · BMC Nephrol 2018 · PMID 30340546First biopsy-proven lenvatinib-induced FSGS, implicating podocyte c-mip and a TKI-specific mechanism.PMIDImprovement of lenvatinib-induced nephrotic syndrome after adaptation to sorafenib in thyroid cancer: A case report.Yang CH et al. · World J Clin Cases 2020 · PMID 33195657Demonstrates switching from lenvatinib to sorafenib to resolve nephrotic syndrome while maintaining cancer control.PMIDTherapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities.Estrada CC et al. · J Am Soc Nephrol 2019 · PMID 30642877Mechanistic review linking VEGFR TKIs to glomerulopathies (MCD/FSGS) and hypertension.PMIDThe Role of Angiogenesis Inhibitors in Hypertension: Following "Ariadne's Thread".Sanidas E et al. · Am J Hypertens 2018 · PMID 29788148Reviews mechanisms and management of antiangiogenic hypertension applicable to lenvatinib.
Related agents
Other agents sharing the same signature kidney injury.