Ramucirumab
Cyramza · Anti-VEGFR2 antibody
Hypertension and proteinuria, class effect.
HTNGLOMTMA
ModerateOpen →
VEGFR TKI
Regorafenib
Stivarga · Rego
An oral multikinase inhibitor that delivers the familiar antiangiogenic toll of hypertension and proteinuria.
ModerateVEGFR multikinase inhibitor · approved 2012
Metastatic colorectal cancerGastrointestinal stromal tumorHepatocellular carcinoma
Signature kidney injury
Hypertension
Hypertension is a common, frequently grade 3 adverse event (in the CORRECT trial hypertension occurred in about 28%, grade 3 ~7%); proteinuria also occurs as a VEGF-pathway class effect. Drug-specific quantitative renal data are otherwise limited.
Source: Grothey et al., CORRECT (Lancet 2013); Estrada et al., J Am Soc Nephrol 2019
Mechanism of kidney injury
VEGFR tyrosine kinase inhibition lowers glomerular VEGF and nitric-oxide signaling, raising vascular tone (hypertension) and injuring the glomerular filtration barrier (proteinuria), with potential for a podocytopathy (FSGS/MCD pattern) and, less commonly, renal TMA.
Clinical presentation
New or worsening hypertension and proteinuria, typically within the first weeks; creatinine may rise in more severe cases. Hand-foot skin reaction and transaminitis commonly co-occur and help flag class toxicity.
Onset
Within the first weeks of therapy.
Reversibility
Reversible
Anticancer mechanism
Oral multikinase inhibitor (a fluorinated sorafenib analog) targeting VEGFR1-3, TIE2, KIT, RET, RAF-1, BRAF and PDGFR, simultaneously inhibiting angiogenic, stromal and oncogenic signaling. Used in metastatic colorectal cancer, gastrointestinal stromal tumor and hepatocellular carcinoma.
Management
Antihypertensive therapy (ACE inhibitor/ARB favored); interrupt or dose-reduce per label for grade 3 hypertension or significant proteinuria; discontinue for nephrotic syndrome, hypertensive crisis or TMA. Effects generally improve with dose modification or withdrawal.
Risk factors
- Pre-existing hypertension
- Baseline proteinuria or CKD
Prevention
- Baseline and periodic blood pressure and urine protein monitoring
- Blood pressure control before and during therapy
Note · Renal effects mirror the VEGF-pathway class; quantitative renal data specific to regorafenib are limited and largely extrapolated from the class and from trial adverse-event tables.
Clinical depth
Renal dose adjustment
No dose adjustment for renal impairment is recommended; regorafenib is hepatically metabolized (CYP3A4 and UGT1A9) with biliary excretion, so it carries hepatotoxicity warnings rather than renal dosing rules. Renal impairment does not require dose change.
Dialyzability & ESKD dosing
Highly protein-bound (~99.5%) and hepatically/biliary cleared; not appreciably dialyzable, so no supplemental dosing for HD. Data in ESKD are limited.
Differential diagnosis
VEGFR-TKI hypertension/proteinuria/podocytopathy versus prerenal AKI versus baseline nephropathy. Within the colorectal-cancer setting, also consider overlapping toxicity from concurrent or prior antiangiogenic therapy (bevacizumab/aflibercept).
Monitoring
- Blood pressure weekly for the first cycle, then regularly
- Urine protein (dipstick/UPCR) before each cycle
- Liver enzymes/bilirubin (boxed hepatotoxicity warning) and serum creatinine
Key trials & series
- CORRECT phase III (regorafenib in refractory metastatic colorectal cancer) — hypertension a leading AE
- GRID (GIST) and RESORCE (HCC) — hypertension/proteinuria safety signals
Clinical pearls
- Regorafenib's renal toxicity is a class effect; expect early hypertension and watch urine protein.
- Its boxed warning is hepatotoxicity — liver monitoring is as important as renal monitoring.
- No renal dose adjustment is needed, but grade 3 hypertension or heavy proteinuria should trigger interruption/dose reduction.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Glomerulus
Filtration barrier (podocytes + endothelium)
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
5 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkTherapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities.Estrada CC et al. · J Am Soc Nephrol 2019 · PMID 30642877Mechanistic basis of VEGFR-TKI hypertension, proteinuria and glomerulopathy.PMID[Regorafenib versus S-1 plus Bevacizumab for Metastatic Colorectal Cancer as Salvage Line-A Phase II Study (OGSG1301)].Kodama H et al. · Gan To Kagaku Ryoho 2021 · PMID 34657055Trial documenting grade 3-4 hypertension and proteinuria among regorafenib adverse events.PMIDThe Role of Angiogenesis Inhibitors in Hypertension: Following "Ariadne's Thread".Sanidas E et al. · Am J Hypertens 2018 · PMID 29788148Reviews antiangiogenic hypertension pathophysiology and management.PMIDProteinuria and hypertension in patients treated with inhibitors of the VEGF signalling pathway--incidence, mechanisms and management.Tesarova P et al. · Folia Biol (Praha) 2013 · PMID 23537524Class review of anti-VEGF proteinuria/hypertension incidence, mechanisms and management.PMID[Nephrotoxicity of anti-angiogenesis drugs].Grechukhina KS et al. · Ter Arkh 2020 · PMID 33346501Review of antiangiogenic-drug nephrotoxicity including multikinase inhibitors.
Related agents
Other agents sharing the same signature kidney injury.