Ramucirumab
Cyramza · Anti-VEGFR2 antibody
Hypertension and proteinuria, class effect.
HTNGLOMTMA
ModerateOpen →
VEGFR/FGFR/PDGFR TKI
Nintedanib
Ofev · Ninte
An antifibrotic VEGFR/FGFR/PDGFR TKI that can rarely cross into the kidney as proteinuria or thrombotic microangiopathy.
MildVEGFR/FGFR/PDGFR inhibitor · approved 2014
Non-small-cell lung cancer (adenocarcinoma, with docetaxel)Idiopathic pulmonary fibrosis (non-oncologic)
Signature kidney injury
Hypertension
Renal effects are uncommon; proteinuria and rare biopsy-proven renal thrombotic microangiopathy have been reported, consistent with VEGF-pathway inhibition. Renal incidence is not well quantified (case-level), and much of the published renal experience comes from pulmonary-fibrosis rather than oncology cohorts.
Source: Fujita et al., Case Rep Nephrol Dial 2021 (TMA case)
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
Incidence not quantified
SeverityMild
ReversibilityReversible
Evidence0 refs
Nephron map
GlomerulusFiltration barrier (podocytes + endothelium)
Vasculature / EndotheliumGlomerular & peritubular capillaries
Hypertension
On-target loss of endothelial nitric oxide from VEGF-pathway blockade — so consistent it marks drug activity.
Mechanism of kidney injury
VEGFR inhibition reduces glomerular endothelial VEGF signaling, which can injure the fenestrated endothelium and filtration barrier, producing proteinuria/hypertension and, in rare reported cases, a dose-dependent and reversible renal thrombotic microangiopathy with microaneurysms, glomerular basement-membrane double contours and intracapillary foam cells. The added FGFR/PDGFR activity does not clearly amplify the renal lesion.
Clinical presentation
Proteinuria and reduced kidney function, sometimes with hypertension; biopsy in reported TMA cases shows microaneurysms filled with pale material, segmental GBM double contours and intracapillary foam cells. Diarrhea and hepatotoxicity are the more common general toxicities.
Onset
Over months of therapy in reported cases.
Reversibility
Reversible
Anticancer mechanism
Oral intracellular inhibitor of VEGFR1-3, FGFR1-3 and PDGFR-alpha/beta (plus Src-family kinases). In oncology it is combined with docetaxel for non-small-cell lung adenocarcinoma; it is also widely used as an antifibrotic in idiopathic pulmonary fibrosis and other progressive fibrosing interstitial lung diseases.
Management
Dose-reduce or discontinue for proteinuria/renal dysfunction; reported renal TMA improved after discontinuation (and partially with dose reduction). Control blood pressure (ACE inhibitor/ARB) and provide supportive care.
Risk factors
- Higher dose / cumulative exposure
- Pre-existing hypertension or CKD
Prevention
- Monitor blood pressure, urine protein and renal function
- Dose reduction for emerging renal or other toxicity
Note · Renal toxicity is rare and case-level; the TMA signal reflects its VEGFR-inhibitor activity. Most published renal experience is in pulmonary fibrosis rather than oncology, so the oncology renal evidence is genuinely thin and class-based.
Clinical depth
Renal dose adjustment
No dose adjustment for mild-to-moderate renal impairment; <1% is excreted renally and nintedanib is predominantly cleared by hydrolytic ester cleavage and biliary/fecal excretion. It has not been studied in severe renal impairment (CrCl < 30 mL/min). Dose reduction is driven by hepatotoxicity (transaminitis) more than by renal function.
Dialyzability & ESKD dosing
Highly protein-bound (~98%) with biliary/fecal elimination, so it is not meaningfully dialyzable; no supplemental dosing for HD. ESKD data are essentially absent.
Differential diagnosis
Nintedanib-associated renal TMA/proteinuria (biopsy microaneurysms, double contours) versus other anti-VEGF-pathway TMA, versus baseline hypertensive/diabetic nephropathy, and — in lung-cancer patients — versus concurrent cisplatin/other nephrotoxins or paraneoplastic glomerulopathy.
Monitoring
- Blood pressure and urine protein periodically
- Serum creatinine; CBC/LDH and smear if TMA suspected
- Liver enzymes (the more common dose-limiting toxicity)
Key trials & series
- LUME-Lung 1 phase III trial (docetaxel +/- nintedanib in previously treated NSCLC) — registrational oncology trial
- INPULSIS trials (IPF) — large antifibrotic safety database from which much renal experience derives
Clinical pearls
- Nintedanib is mostly an antifibrotic in practice, so its renal literature comes largely from IPF, not oncology — treat the renal evidence as thin and class-based.
- Its dominant dose-limiting toxicity is hepatotoxicity, not nephrotoxicity; renal TMA is rare and reversible.
- Negligible renal excretion means no renal dose adjustment, but it is also non-dialyzable.
Where it strikes
Nephron segments
Glomerulus
Filtration barrier (podocytes + endothelium)
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
HypertensionThrombotic MicroangiopathyGlomerular Injury / Proteinuria
Beyond the kidney
Class-level context for the major non-renal toxicities of vegfr/fgfr/pdgfr 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.
LandmarkNintedanib-Induced Renal Thrombotic Microangiopathy.Fujita T et al. · Case Rep Nephrol Dial 2021 · PMID 34414215Biopsy-proven, reversible, dose-related nintedanib-associated renal TMA with literature review.PMIDDocetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial.Reck M et al. · Lancet Oncol 2014 · PMID 24411639Registrational oncology trial defining the nintedanib + docetaxel safety profile.PMIDTherapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities.Estrada CC et al. · J Am Soc Nephrol 2019 · PMID 30642877Mechanistic review of VEGF-pathway inhibition causing proteinuria and renal TMA.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 applicable to nintedanib.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 and hypertension.
Related agents
Other agents sharing the same signature kidney injury.