Ziv-aflibercept
Zaltrap · VEGF trap
Hypertension and proteinuria like bevacizumab.
HTNGLOMTMA
Moderate#1 · 100% phenotype match
VEGFR Tyrosine Kinase Inhibitors
Sutent · Nexavar · Votrient · Inlyta · VEGFR-TKI
VEGFR TKI · approved 2006 · 8 citations
Recent· through 2024
Deeply sourced7/9 · 6 signals
- Met: 8 citations
- Not met: 12+ references
- Met: Accrued over 10+ years (span: 16y)
- Met: Beyond single case reports
- Met: High-impact journal
- Met: Landmark reference
- Met: Current through 2024
- Not met: Real-world FAERS signal
Describes how this page is sourced, not how dangerous the drug is. Thinly sourced means fewer of the sourcing signals are met — not that the agent is kidney-safe. A rule-based summary, not a formal certainty appraisal.
Hypertension so reliable it doubles as a marker that the drug is working.
ModerateAntiangiogenic TKI
Renal cellHepatocellularGISTThyroidSarcoma
§01
Signature kidney injury
Signature lesion
Representative incidence35%
17–50% range across studies
Hypertension ~17–50%; proteinuria 8–73% across agents (the cited review's ranges; it reports no single pooled proteinuria rate).Source: Semeniuk-Wojtaś et al., Int J Mol Sci 2016
Onset & rechallenge
Time to injurySubacute (~1–6 weeks)
Hypertension within days to weeks; proteinuria over weeks to months.
Distilled from: “Hypertension within days–weeks; proteinuria over weeks–months.”
§02
Renal toxicities, ranked
This agent's kidney lesions ordered by prominence — the #1 signature lesion first, then secondary and rare patterns. Cited incidence is shown where a citable figure exists; otherwise the tier stands qualitatively.
Raised blood pressure — archetypally on-target loss of endothelial nitric oxide from VEGF-pathway blockade, studied as a pharmacodynamic marker of drug exposure. Other agents raise it too: vascular effects of BCR-ABL, BTK and RET inhibitors and of copanlisib; abiraterone's mineralocorticoid excess; androgen suppression or blockade.
Damage to the filtration barrier — podocyte injury, FSGS and protein leak from VEGF and mTOR blockade.
Endothelial injury with microvascular thrombi, hemolysis and thrombocytopenia — gemcitabine, mitomycin C, anti-VEGF.
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
35%incidence
SeverityModerate
ReversibilityReversible
Evidence8 citations
Nephron map
GlomerulusFiltration barrier (podocytes + endothelium)
Vasculature / EndotheliumGlomerular & peritubular capillaries
Hypertension
Raised blood pressure — archetypally on-target loss of endothelial nitric oxide from VEGF-pathway blockade, studied as a pharmacodynamic marker of drug exposure. Other agents raise it too: vascular effects of BCR-ABL, BTK and RET inhibitors and of copanlisib; abiraterone's mineralocorticoid excess; androgen suppression or blockade.
§03
Kidney injury
Mechanism of kidney injury
Intracellular disruption of the same VEGF pathway as bevacizumab: reduced nitric oxide and prostacyclin raise blood pressure, while podocyte and endothelial injury produce proteinuria and occasional TMA or collapsing/FSGS lesions.
Clinical presentation
Early hypertension (first weeks), proteinuria, sometimes microangiopathic hemolysis and a rising creatinine.
Management
Antihypertensives (ACEi/ARB, dihydropyridine CCBs; avoid non-dihydropyridine CCBs that inhibit CYP3A4), dose reduction/hold, discontinue for TMA.Lesion-level management framework
§ Receptor target map
Which kinases VEGFR Tyrosine Kinase Inhibitors blocks — and where the blockade reaches the kidney
VEGFR2 is the target with documented renal consequences across every VEGFR TKI; multi-kinase breadth beyond it (PDGFR-β, FGFR, and off-target receptor kinases) adds further renal and hypertensive liability. Select a lit receptor for its renal consequence.
VEGFR family
PDGFR
PDGFR-αPDGFR-β
Other receptor kinases
FGFRKITRETMETEGFRFLT3AXLCSF1RTIE2RAF-1/BRAF
VEGFR2 · renal target
Glomerular endothelial VEGFR2: loss of podocyte-derived paracrine VEGF signaling → fenestrae loss, nephrin downregulation, nitric-oxide depletion → hypertension, proteinuria, and thrombotic microangiopathy.
renal consequence (1)targetednot a target
Risk factors
- Pre-existing hypertension / CKD
- Higher-potency agents
- Renal cell carcinoma
Prevention
- Proactive hypertension treatment
Anticancer mechanism· how it treats cancer
Sunitinib, sorafenib, pazopanib and axitinib block the VEGFR (and PDGFR, c-KIT) kinase domains to shut down angiogenesis. Renal cell, hepatocellular, GIST, thyroid and sarcoma.
Note · Hypertension is considered an on-target pharmacodynamic marker.
§04
Clinical depth
Renal dose adjustment
No renal-function-based dose adjustment is required for the oral VEGFR TKIs themselves — they undergo predominantly hepatic (CYP3A4) metabolism with minimal renal excretion, and labels for sunitinib, sorafenib, pazopanib, axitinib, cabozantinib, and lenvatinib state no starting-dose change for mild-to-severe CKD (cabozantinib and lenvatinib carry caution but no defined CrCl threshold). The clinically relevant "adjustment" is for the on-target toxicities: hold or dose-reduce for grade 3+ hypertension or nephrotic-range proteinuria and discontinue for TMA, rather than for measured GFR.
Dialyzability & ESKD dosing
Largely not dialyzable — these agents are small but highly protein-bound and have large volumes of distribution, so hemodialysis is not expected to remove meaningful drug, and no supplemental post-HD dosing is defined. Limited case-series data (chiefly sunitinib and sorafenib) suggest standard dosing can be used in HD patients without dialysis timing changes, though monitoring for amplified toxicity is advised.
Differential diagnosis
VEGFR-TKI hypertension/proteinuria is on-target and class-typical, distinguished from prerenal or ATN by a temporal link to drug start, preserved tubular function, and reversibility on holding the drug. The key mimic is TMA: a falling platelet count, schistocytes, low haptoglobin, and high LDH point to drug-induced TMA (which can be C5/complement-mediated or direct endothelial), whereas isolated nephrotic-range proteinuria without hematologic features suggests a podocytopathy (minimal-change/FSGS-like or membranous-like lesion) — both demand drug interruption rather than immunosuppression first.
Monitoring
- Blood pressure: confirm control at baseline, recheck weekly during the first cycle (the highest-risk window), then at each visit — VEGFR-TKI hypertension can appear within days of starting
- Urine protein: dipstick or spot urine protein-to-creatinine ratio at baseline and periodically; quantify with 24-hour collection or escalate workup if dipstick is 2+ or UPCR rises
- Serum creatinine/eGFR each cycle, with a lower threshold to investigate any rise alongside new/worsening proteinuria
- If TMA is suspected (rising creatinine + new proteinuria + hypertension): check CBC with smear for schistocytes, LDH, haptoglobin, platelets, and bilirubin
- Reassess BP and proteinuria after any dose change or interruption, since both on-target effects are dose-dependent and reversible
Key trials & series
- Motzer et al. (NEJM 2007) — pivotal phase III sunitinib vs interferon-alfa in metastatic RCC; established sunitinib and quantified treatment-emergent hypertension as a class on-target effect
- Sternberg et al. VEG105192 (J Clin Oncol 2010) — registrational phase III of pazopanib in RCC; hypertension and proteinuria were characteristic adverse events
- Eremina et al. (NEJM 2008) — landmark mechanistic series/biopsy correlation showing VEGF pathway inhibition causes glomerular (podocyte) injury and renal thrombotic microangiopathy, the pathophysiologic basis of the class renal signal
- AXIS / Rini et al. (Lancet 2011) — phase III axitinib vs sorafenib in RCC; hypertension and proteinuria differentiated the more potent, selective VEGFR inhibitor
Clinical pearls
- Hypertension here is a mechanistic on-target effect (loss of endothelial VEGF-driven nitric oxide/prostacyclin), and its emergence is often a pharmacodynamic marker of effective VEGF blockade — treat it, do not reflexively stop the drug
- Treat the hypertension aggressively (ACE inhibitors/ARBs are reasonable first-line and may also blunt proteinuria); the goal is to keep the patient on effective anticancer therapy
- New or worsening proteinuria signals podocyte/glomerular injury — check for the hematologic features of TMA before assuming benign drug-related proteinuria
- Renal effects are usually reversible: BP, proteinuria, and most TMA improve after dose reduction or drug withdrawal, unlike fixed structural tubular injury
- Class breadth matters — sunitinib, sorafenib, pazopanib, axitinib, cabozantinib, lenvatinib, regorafenib, and vandetanib all share the hypertension/proteinuria/TMA signature; switching within the class does not eliminate the on-target renal risk
Beyond the kidney — non-renal toxicities· 4 organ systems
Class-level context for the major non-renal toxicities of the VEGFR TKI class.
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
§05
References
5 primary references — trials, cohorts, mechanism, and reviews. Single-patient case reports are listed separately below, graded by strength. Citation metadata via PubMed / NLM.
Evidence accrual
5 references · 2008–2016 · 2 since 2014Primary (non–case-report) references per year — a proxy for how actively the agent's renal literature is accruing. Recent years are highlighted. Reflects curation depth, not a systematic bibliometric count.
- 1.LandmarkVEGF inhibition and renal thrombotic microangiopathy.Eremina V et al. · N Engl J Med · 2008 · PMID 18337603Foundational mechanism for the whole VEGF-blockade class.
- 2.Thrombotic microangiopathy secondary to VEGF pathway inhibition by sunitinib.Bollée G et al. · Nephrol Dial Transplant · 2009 · PMID 19054798First biopsy-proven renal TMA from a VEGFR-TKI.
- 3.Influence of Tyrosine Kinase Inhibitors on Hypertension and Nephrotoxicity in Metastatic Renal Cell Cancer Patients.Semeniuk-Wojtaś A et al. · Int J Mol Sci · 2016 · PMID 27941701Systematic review quantifying hypertension and proteinuria incidence.
- 4.Renal effects of anti-angiogenesis therapy: update for the internist.Gurevich F et al. · Am J Med · 2009 · PMID 19332223Clinical review of anti-VEGF/VEGFR renal effects and mechanisms.
- 5.Renal Toxicities of Targeted Therapies.Abbas A et al. · Target Oncol · 2015 · PMID 25922090Cross-class review of targeted-therapy renal toxicity.
Case reports — ranked by strength· 3
Single-patient and small-series reports, graded by evidentiary strength — A Strong (biopsy-proven plus a series and/or positive rechallenge), B Moderate, and C Limited (a single clinically-diagnosed case). Strongest first. Grades are inferred automatically from each report's abstract and journal — a heuristic ranking aid, not a formal quality appraisal.
CaseB · ModerateSunitinib-induced endocapillary proliferative glomerulonephritis with IgA2 deposit in addition to thrombotic microangiopathy: a case report.Zhang X et al. · BMC Nephrol 2024 · PMID 39215250Metastatic GIST patient on the VEGFR TKI sunitinib developed severe hypertension, nephrotic syndrome and AKI with biopsy-confirmed thrombotic microangiopathy plus endocapillary proliferative glomerulonephritis with IgA2 deposits.CaseB · ModerateRegorafenib-induced renal-limited thrombotic microangiopathy: a case report and review of literatures.Yin Q et al. · BMC Nephrol 2022 · PMID 35305559Patient on the VEGFR TKI regorafenib for metastatic colon cancer presented with nephrotic-range proteinuria and biopsy-confirmed renal-limited thrombotic microangiopathy, the first such reported case.CaseB · ModerateThrombotic Microangiopathy, Podocytopathy, and Damage to the Renal Tubules with Severe Proteinuria and Acute Renal Dysfunction Induced by Lenvatinib.Nakashima S et al. · Intern Med 2022 · PMID 35342129Woman on the VEGFR TKI lenvatinib for HCC developed hypertension, severe proteinuria and renal dysfunction with biopsy-proven thrombotic microangiopathy, podocytopathy and the first reported lenvatinib-induced renal tubular damage.
Guidelines & consensus· 17
Each recommendation below is this atlas's faithful summary of the source, not a quotation from it — follow the PubMed link for the wording the society published. Summaries may be superseded; consult the current full text and individualize to the patient.
KDIGOManagement of Blood Pressure in Patients With Chronic Kidney Disease Not Receiving Dialysis: Synopsis of the 2021 KDIGO Clinical Practice GuidelineAnn Intern Med 2021 · PMID 34152826Recommends standardized office BP measurement and a target systolic BP <120 mm Hg for most CKD patients, with RAAS inhibitors first-line when albuminuria is present — the BP-management basis for anti-VEGF/TKI-induced hypertension and proteinuria.ESC2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS)Eur Heart J 2022 · PMID 36017568For VEGF/VEGFR inhibitors, perform baseline cardiovascular risk assessment, monitor blood pressure (weekly during the first cycle, then regularly) and treat to a target <140/90 mmHg with ACE inhibitors/ARBs and dihydropyridine calcium-channel blockers; manage VEGFi-associated hypertension and proteinuria with interruption/dose modification when severe.ESCEuropean Society of Cardiology quality indicators for the prevention and management of cancer therapy-related cardiovascular toxicity in cancer treatmentEur Heart J Qual Care Clin Outcomes 2022 · PMID 36316010Adherence quality indicators require documented baseline cardiovascular risk assessment and structured monitoring of cardiovascular complications (including hypertension) during cancer therapy such as VEGF-pathway inhibitors.UK Consensus PanelUsing bevacizumab to treat metastatic cancer: UK consensus guidelinesBr J Hosp Med (Lond) 2010 · PMID 21135762Assess and monitor blood pressure and proteinuria during bevacizumab therapy; treat emergent hypertension to standard targets and interrupt/discontinue the drug for uncontrolled hypertension, nephrotic-range proteinuria or other severe vascular toxicity.
General onco-nephrology references
ADQIThe nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupNat Rev Nephrol 2026 · PMID 41361704Provides expert-based statements (modified Delphi) on preventing and managing cisplatin/platinum-associated AKI, including isotonic IV hydration, attention to volume status and concomitant nephrotoxins, and incorporates evidence that IV magnesium supplementation may reduce cisplatin-associated AKI; emphasizes risk stratification and standardized AKI definitions.SIRMSIRM-SIN-AIOM: appropriateness criteria for evaluation and prevention of renal damage in the patient undergoing contrast medium examinations-consensus statements from Italian College of Radiology (SIRM), Italian College of Nephrology (SIN) and Italian Association of Medical Oncology (AIOM)Radiol Med 2022 · PMID 35303246Recommends eGFR-based renal risk assessment and pre/post-contrast isotonic saline or sodium bicarbonate hydration; advises maintaining a 5-7 day interval between iodinated contrast administration and cisplatin in cancer patients to reduce additive nephrotoxicity.KDIGOKDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerKidney Int 2020 · PMID 33126977Identifies platinum compounds (especially cisplatin) as leading cytotoxic causes of acute tubular injury, AKI, and electrolyte/magnesium wasting; calls for interdisciplinary onco-nephrology care, accurate GFR estimation, and individualized drug dosing in patients with reduced kidney function.KDIGOKDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationKidney Int 2020 · PMID 33276867Addresses chemotherapy-associated AKI/CKD in hematologic cancer, GFR estimation and chemotherapy dosing in patients with reduced kidney function, and management priorities and research gaps for onco-nephrology care.ADDIKDIntegrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceEClinicalMedicine 2025 · PMID 40290844Provides GRADE-based, drug-specific dose-adjustment recommendations for anticancer agents in kidney dysfunction (illustrated for methotrexate, cisplatin, carboplatin and nivolumab); the recommendations build on Part 1's standardised CKD-EPI eGFR assessment rather than Cockcroft-Gault creatinine clearance.ADDIKDAligning kidney function assessment in patients with cancer to global practices in internal medicineEClinicalMedicine 2025 · PMID 40290845Three consensus recommendations: assess kidney function by GFR (measured GFR or CKD-EPI eGFR), classify it using KDIGO categories, and use this uniform approach to dose anticancer drugs — moving cancer medicine away from Cockcroft-Gault estimated creatinine clearance.ADDIKDA methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEClinicalMedicine 2025 · PMID 40290846Establishes that, where RCT evidence is lacking, anticancer drug dosing recommendations in kidney dysfunction should be derived by critically appraising observational literature via GRADE combined with structured international multidisciplinary consensus voting.KDIGODiagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Crit Care 2013 · PMID 23394211Defines/stages AKI by serum creatinine and urine output; emphasizes avoiding nephrotoxins, maintaining euvolemia/perfusion, dose-adjusting drugs to kidney function, and monitoring high-risk patients — the framework applied to nephrotoxic anti-cancer agents.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknownsKidney Int 2024 · PMID 38519239Evaluate and risk-stratify CKD, manage to delay progression and its complications, and practise explicit medication management and drug stewardship — the framework the atlas's G1–G5 eGFR banding and every renal dose-adjustment recommendation sit inside. Because the guideline excludes dialysis and transplant recipients by its own statement of scope, its recommendations do not carry to those settings, where this atlas's dialyzability and post-transplant guidance rests on other sources.KDIGOExecutive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesKidney Int 2021 · PMID 34556300Provides the staging/treatment framework for drug-associated glomerular lesions (e.g., bisphosphonate- and interferon-related collapsing FSGS, VEGF-inhibitor podocytopathy/proteinuria), including immunosuppression and supportive RAAS-blockade strategies.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisKidney Int 2024 · PMID 38388147Updates immunosuppressive induction (rituximab/cyclophosphamide), incorporates avacopan and lower-dose or glucocorticoid-sparing regimens — the management framework for drug- and checkpoint-inhibitor-associated ANCA/pauci-immune glomerulonephritis.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisKidney Int 2024 · PMID 38182299Updates first-line lupus nephritis therapy to combination immunosuppression with the addition of belimumab or a calcineurin inhibitor (voclosporin) — informs management of immune-complex/lupus-like glomerulonephritis encountered with immunotherapy.KDIGOExecutive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Kidney Int 2025 · PMID 40975525Encourages liberal kidney biopsy and stricter proteinuria control (<0.5 g/d, ideally <0.3 g/d) with RAAS blockers, SGLT2 inhibitors, and targeted-release budesonide — the framework for IgA-dominant glomerular lesions, including those triggered by immune-modulating cancer therapy.
Where VEGFR Tyrosine Kinase Inhibitors sits in nephrotoxicity space — each dot is an anti-cancer agent, positioned so neighbors share a kidney-injury phenotype. Its 6 closest are filled and lead to a numbered marker, matching the numbered cards below.
Phenotype-similar agents· the numbered markers on the map above
Profile
Bevacizumab
Avastin · Anti-VEGF antibody
Proteinuria, hypertension, glomerular TMA.
GLOMHTNTMA
Moderate#2 · 100% phenotype match
Ramucirumab
Cyramza · Anti-VEGFR2 antibody
Hypertension and proteinuria, class effect.
HTNGLOMTMA
Moderate#3 · 100% phenotype match
Pazopanib
Votrient · VEGFR TKI
VEGFR-TKI; hypertension, proteinuria, TMA.
GLOMHTNTMA
Moderate#4 · 98% phenotype match
Axitinib
Inlyta · VEGFR TKI
Potent VEGFR-TKI; hypertension and proteinuria dominate.
HTNGLOMTMA
Moderate#5 · 98% phenotype match
Nintedanib
Ofev · VEGFR/FGFR/PDGFR TKI
Proteinuria and rare TMA.
HTNTMAGLOM
Mild#6 · 95% phenotype match
Nearest agents by kidney-injury phenotype (shared injuries, nephron target, severity, class) — a similarity approximation, not a claim of shared drug identity or mechanism.
Kidney risk across Anti-angiogenic (VEGF)
Same-class agents ordered by their documented kidney-injury profile — atlas severity, an acute-kidney-injury FAERS signal, and how many injury types each is documented to cause. Agents nearer the top carry the lighter documented renal profile.
- 1NintedanibHTN — HypertensionMild
- 2CabozantinibHTN — HypertensionModerate
- 3RegorafenibHTN — HypertensionModerate
- 4TivozanibHTN — HypertensionModerate
- 5FruquintinibHTN — HypertensionModerate
- 6PazopanibGLOM — Glomerular Injury / ProteinuriaModerate
- 7RamucirumabHTN — HypertensionModerate
- 8VandetanibHTN — HypertensionModerate
- 9VEGFR Tyrosine Kinase Inhibitors· this agentHTN — HypertensionModerate
- 10Ziv-afliberceptHTN — HypertensionModerate
- 11SorafenibHTN — HypertensionModerate
- 12SunitinibHTN — HypertensionModerate
- 13LenvatinibHTN — HypertensionFAERS AKIModerate
- 14AxitinibHTN — HypertensionFAERS AKIModerate
- 15BevacizumabGLOM — Glomerular Injury / ProteinuriaFAERS AKIModerate
A comparison of documented kidney-injury data within one drug class — not a substitution recommendation. Efficacy, indication, and non-renal toxicity differ between these agents and are out of scope here. Educational only, not medical advice.