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VEGFR/EGFR/RET TKI

Vandetanib

Caprelsa · Vande

VEGFR/EGFR/RET TKI · approved 2011 · 5 references

A VEGFR/EGFR/RET inhibitor for medullary thyroid cancer whose antiangiogenic action commonly raises blood pressure.

Signature injury
Hypertension
Severity
Moderate
Reversibility
Reversible
Onset
Within the first weeks of therapy.

Signature kidney injury & incidence

Hypertension — representative incidence ~32%.

In the pivotal phase III ZETA trial, any-grade hypertension occurred in about 32% of vandetanib-treated patients versus 5% with placebo; proteinuria occurs as an antiangiogenic class effect.

Source: Wells et al., J Clin Oncol 2012 (ZETA, any-grade hypertension)

Reported injury signatures: Hypertension, Glomerular Injury / Proteinuria, Electrolyte Disturbance.

Renal toxicity profile

  1. HypertensionPrimary
  2. Glomerular Injury / ProteinuriaSecondaryVandetanib significantly increased all-grade proteinuria risk in a VEGFR-TKI meta-analysis (9,446 pts, 20 RCTs; class all-grade RR 2.35, high-grade RR 3.70) — podocyte VEGF-inhibition glomerulopathy.
  3. Electrolyte DisturbanceRare

Onset timing & rechallenge

Subacute (~1–6 weeks) — Within the first weeks of therapy.

Mechanism of kidney injury

VEGFR2 tyrosine kinase inhibition reduces glomerular VEGF and nitric-oxide signaling, increasing vascular tone (hypertension) and potentially injuring the glomerular filtration barrier (proteinuria/podocytopathy). A clinically dominant non-renal hazard is QT prolongation, which interacts with drug-induced electrolyte disturbances (hypokalemia, hypomagnesemia, hypocalcemia) to raise arrhythmia risk.

Clinical presentation

New or worsening hypertension, sometimes with proteinuria; clinicians must also watch for QT prolongation and the electrolyte derangements (hypocalcemia, hypokalemia, hypomagnesemia) that compound cardiac risk.

Management

Antihypertensive therapy (ACE inhibitor/ARB favored); interrupt or dose-reduce per label for grade 3 hypertension or significant proteinuria; aggressively maintain potassium, magnesium and calcium to mitigate QT-related arrhythmia. Hypertension is rarely dose-limiting and improves with treatment.

Risk factors

  • Pre-existing hypertension
  • Baseline proteinuria or CKD
  • Electrolyte abnormalities (QT risk)

Prevention

  • Blood pressure optimization and electrolyte repletion before and during therapy

Renal dose adjustment

Reduce the starting dose to 200 mg for moderate impairment (CrCl 30-49 mL/min); use in severe impairment (CrCl <30 mL/min) is not recommended per label, because vandetanib is partly renally excreted and exposure rises with impairment; titrate with ECG and electrolyte monitoring.

Dialyzability & ESKD dosing

Long half-life (~19 days), large volume of distribution and high protein binding make it essentially non-dialyzable; HD does not provide meaningful removal and is not used for dosing.

Differential diagnosis

VEGFR-TKI hypertension/proteinuria versus baseline nephropathy versus prerenal AKI. Crucially, separate drug-induced electrolyte wasting (which drives QT risk) from other causes, since correcting it is part of safe vandetanib use.

Monitoring

  • Blood pressure regularly
  • ECG (QTc) at baseline, 2-4 and 8-12 weeks, then periodically
  • Serum potassium, magnesium, calcium and TSH
  • Urine protein (dipstick/UPCR) periodically

Key trials & series

  • ZETA phase III trial in advanced medullary thyroid carcinoma (hypertension 32% vs 5% placebo)

Clinical pearls

  • Vandetanib's renal-vascular signal is hypertension, but the safety-defining toxicity is QT prolongation — monitor ECG and electrolytes together.
  • Hypomagnesemia/hypokalemia from VEGFR-TKI effects compound QT risk, so repletion is therapeutic and protective.

Anticancer mechanism

Oral inhibitor of RET, VEGFR2 (and other VEGFRs) and EGFR signaling, blocking angiogenesis and oncogenic RET-driven proliferation. Approved for advanced/metastatic medullary thyroid carcinoma.

Note

Hypertension is the principal renal-vascular signal; proteinuria is a class effect, and QT prolongation (a boxed warning) is the key non-renal safety concern that is amplified by renal electrolyte losses.

Guidelines & consensus

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.

  • KDIGO (2021) — Management of Blood Pressure in Patients With Chronic Kidney Disease Not Receiving Dialysis: Synopsis of the 2021 KDIGO Clinical Practice GuidelineRecommends 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.Ann Intern Med · PMID 34152826
  • ESC (2022) — 2022 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)For 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.Eur Heart J · PMID 36017568
  • ESC (2022) — European Society of Cardiology quality indicators for the prevention and management of cancer therapy-related cardiovascular toxicity in cancer treatmentAdherence quality indicators require documented baseline cardiovascular risk assessment and structured monitoring of cardiovascular complications (including hypertension) during cancer therapy such as VEGF-pathway inhibitors.Eur Heart J Qual Care Clin Outcomes · PMID 36316010
  • UK Consensus Panel (2010) — Using bevacizumab to treat metastatic cancer: UK consensus guidelinesAssess 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.Br J Hosp Med (Lond) · PMID 21135762
  • ADQI (2026) — The nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupProvides 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.Nat Rev Nephrol · PMID 41361704
  • SIRM (2022) — SIRM-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)Recommends 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.Radiol Med · PMID 35303246
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerIdentifies 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.Kidney Int · PMID 33126977
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationAddresses 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.Kidney Int · PMID 33276867
  • ADDIKD (2025) — Integrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceProvides 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.EClinicalMedicine · PMID 40290844
  • ADDIKD (2025) — Aligning kidney function assessment in patients with cancer to global practices in internal medicineThree 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.EClinicalMedicine · PMID 40290845
  • ADDIKD (2025) — A methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEstablishes 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.EClinicalMedicine · PMID 40290846
  • KDIGO (2013) — Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Defines/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.Crit Care · PMID 23394211
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknownsEvaluate 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.Kidney Int · PMID 38519239
  • KDIGO (2021) — Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesProvides 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.Kidney Int · PMID 34556300
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisUpdates 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.Kidney Int · PMID 38388147
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisUpdates 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.Kidney Int · PMID 38182299
  • KDIGO (2025) — Executive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Encourages 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.Kidney Int · PMID 40975525

References

5 peer-reviewed references. Citation metadata via PubMed / NLM.

  1. 1.Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial.Wells SA et al. · J Clin Oncol · 2012 · PMID 22025146
  2. 2.Cabozantinib, Vandetanib, Pralsetinib and Selpercatinib as Treatment for Progressed Medullary Thyroid Cancer with a Main Focus on Hypertension as Adverse Effect.Hojer Wang L et al. · Int J Mol Sci · 2023 · PMID 36768635
  3. 3.Nephrotoxicity in advanced thyroid cancer treated with tyrosine kinase inhibitors: An update.Nervo A et al. · Crit Rev Oncol Hematol · 2021 · PMID 34801702
  4. 4.Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities.Estrada CC et al. · J Am Soc Nephrol · 2019 · PMID 30642877
  5. 5.The Role of Angiogenesis Inhibitors in Hypertension: Following "Ariadne's Thread".Sanidas E et al. · Am J Hypertens · 2018 · PMID 29788148

Case reports & series (1)

The weakest rung of clinical evidence — single-patient and small-series reports, strongest first. Each carries a heuristic strength grade (A Strong / B Moderate / C Limited) inferred from its abstract and journal, not a formal appraisal. Weigh well below the primary references above.

  1. C1.[C · Limited]Acute tubulointerstitial nephritis induced by the tyrosine kinase inhibitor vandetanib.Pilco Teran M et al. · Invest New Drugs · 2021 · PMID 32648118
Educational monograph from NephTox (nephtox.com). Not medical advice — verify against current guidelines before any clinical decision.