Doxorubicin
Adriamycin · Anthracycline
Experimental podocyte model; clinical proteinuria rare.
GLOMTMA
MildOpen →
VEGFR TKI
Pazopanib
Votrient · Pazo
A VEGFR tyrosine kinase inhibitor that throttles glomerular VEGF housekeeping signaling, producing the class triad of hypertension, proteinuria, and occasional renal-limited thrombotic microangiopathy.
ModerateVEGFR tyrosine kinase inhibitor · approved 2009
Advanced renal cell carcinomaAdvanced soft-tissue sarcoma (after prior chemotherapy)
Signature kidney injury
Glomerular Injury / Proteinuria
Representative incidence15%
Proteinuria is common but usually low-grade. In a pooled secondary analysis of two phase III trials of pazopanib or sunitinib in metastatic RCC (n=1392), any-grade proteinuria occurred in 15.0% and grade 3/4 in 3.7%. A single-center prospective cohort reported proteinuria in 80% of pazopanib-treated patients, most grade 1-2 and managed with continued monitoring. Hypertension is one of the most frequent class effects (grade 3-4 hypertension reported in roughly 15% of VEGFR-TKI-treated RCC patients in BIONIKK). Thrombotic microangiopathy is rare and largely case-level; biopsy-proven renal-limited and systemic TMA/TTP-like presentations have been reported.
Source: Sorich, Br J Cancer 2016 (pooled phase III)
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
0%incidence
SeverityModerate
ReversibilityPartially reversible
Evidence0 refs
Nephron map
GlomerulusFiltration barrier (podocytes + endothelium)
Vasculature / Endothelium
Glomerular Injury / Proteinuria
Damage to the filtration barrier — podocyte injury, FSGS and protein leak from VEGF and mTOR blockade.
Mechanism of kidney injury
Inhibition of VEGFR2 signaling disrupts the constitutive paracrine VEGF-A signal from podocytes to the glomerular endothelium that maintains the fenestrated filtration barrier. Loss of this housekeeping signal causes endothelial dysfunction, reduced nitric oxide and prostacyclin (driving hypertension), podocyte and endothelial injury (proteinuria, sometimes nephrotic-range, with minimal-change/FSGS-like or endotheliosis patterns), and in some patients a localized thrombotic microangiopathy. A biopsy of a pazopanib-treated patient with nephrotic syndrome showed glomerular endothelial injury with podocyte changes that resolved on drug withdrawal.
Clinical presentation
Most often new or worsening hypertension and asymptomatic dipstick/quantified proteinuria detected on routine monitoring; occasionally nephrotic-range proteinuria with edema. TMA may present with a rising creatinine, hypertension, and bland or nephrotic urine, with or without systemic microangiopathic hemolysis (thrombocytopenia, schistocytes); reported cases span renal-limited TMA in a transplant graft to a systemic TTP-like syndrome with acute kidney injury.
Anticancer mechanism
Oral multi-targeted tyrosine kinase inhibitor of VEGFR-1/2/3, PDGFR-alpha/beta, and c-KIT; blocks tumor angiogenesis by interrupting VEGF-driven endothelial proliferation and vascular sprouting.
Management
Manage hypertension proactively per standard antihypertensive guidance (ACE inhibitors/ARBs are commonly favored for concurrent proteinuria). For low-grade proteinuria, continue at the same dose with monitoring; for grade 3-4 or nephrotic-range proteinuria, interrupt, dose-reduce, or discontinue. For suspected TMA, hold/discontinue pazopanib; case reports describe improvement after withdrawal, and ADAMTS13-low presentations have responded to plasma exchange. Discontinuation often leads to partial or full resolution of proteinuria and renal function.Lesion-level management framework
Risk factors
- Pre-existing proteinuria
- Pre-existing/baseline hypertension
- Diabetes
- Prior nephrectomy (common in RCC)
- Asian ethnicity (per pooled analysis)
- Reduced renal reserve / solitary kidney
- Concurrent calcineurin inhibitor or kidney transplant (TMA susceptibility)
Prevention
- Baseline and periodic urine protein (dipstick/UPCR) monitoring
- Baseline and ongoing blood pressure monitoring with early antihypertensive therapy
- Optimize blood pressure before and during treatment
- Quantify and trend nephrotic-range or rising proteinuria
Note · Educational reference, not medical advice. Pazopanib-specific renal evidence is dominated by class-level cohort/trial proteinuria-hypertension data plus biopsy-level case reports for TMA and podocyte/endothelial injury; mechanistic and TMA claims are hedged accordingly.
Clinical depth
Renal dose adjustment
No starting-dose adjustment is generally required for mild-to-moderate renal impairment; data in patients with CrCl <30 mL/min are limited. Pazopanib undergoes predominantly hepatic metabolism (CYP3A4) with minimal renal excretion, so renal impairment is not the principal pharmacokinetic driver; dose modification is guided more by hepatic function and toxicity (including proteinuria) than by GFR.
Dialyzability & ESKD dosing
Not meaningfully dialyzable — pazopanib is highly protein-bound (>99%) and largely hepatically cleared, so hemodialysis is not expected to remove appreciable drug.
Differential diagnosis
Distinguish VEGF-inhibitor effect from pre-existing hypertensive/diabetic nephropathy, RCC-related paraneoplastic glomerulopathy, contrast- or other nephrotoxin-associated AKI, and prerenal azotemia from GI losses. TMA must be separated from primary TTP (ADAMTS13 activity), atypical HUS, and calcineurin-inhibitor-associated TMA in transplant recipients.
Monitoring
- Urinalysis / urine protein-to-creatinine ratio at baseline and periodically
- Blood pressure (often weekly early, then routinely)
- Serum creatinine / eGFR
- CBC with smear and LDH/haptoglobin if TMA suspected
Key trials & series
- VEG105192 / COMPARZ-era phase III RCC programs (pooled for proteinuria risk analysis, Sorich 2016)
- BIONIKK phase II (VEGFR-TKI arm including pazopanib; grade 3-4 hypertension and a TMA death noted in TKI recipients)
Clinical pearls
- The hypertension-proteinuria pairing is a direct on-target marker of effective VEGF pathway blockade, not an idiosyncratic reaction.
- Most pazopanib proteinuria is grade 1-2 and can be monitored without dose change; reserve interruption/discontinuation for grade 3-4 or nephrotic-range disease.
- On-therapy proteinuria was associated with improved overall survival in the pooled mRCC analysis — a possible pharmacodynamic signal, not a reason to ignore it.
- Renal TMA can be biopsy-proven and renal-limited (normal platelets/smear) — a rising creatinine on a VEGFR-TKI warrants suspicion even without systemic hemolysis.
- A pazopanib-associated TTP-like case had transiently undetectable ADAMTS13 that normalized after plasma exchange, blurring the TMA/TTP boundary.
- Because clearance is mainly hepatic, GFR rarely dictates dosing — proteinuria, hypertension, and LFTs drive modification.
Beyond the kidney — non-renal toxicities· 4 organ systems
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
8 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkTherapeutic Inhibition of VEGF Signaling and Associated NephrotoxicitiesEstrada CC, Maldonado A, Mallipattu SK · J Am Soc Nephrol 2019 · PMID 30642877Authoritative mechanistic review establishing that VEGFR tyrosine kinase inhibition preferentially causes glomerulopathy (minimal change/FSGS) plus hypertension and proteinuria, with TMA also described — the mechanistic backbone for this profile.PMIDRisk factors of proteinuria in renal cell carcinoma patients treated with VEGF inhibitors: a secondary analysis of pooled clinical trial dataSorich MJ, Rowland A, Kichenadasse G, Woodman RJ, Mangoni AA · Br J Cancer 2016 · PMID 27228299Pooled phase III data (n=1392, pazopanib or sunitinib) quantifying any-grade proteinuria at 15.0% and grade 3/4 at 3.7%, defining risk factors and the survival association — source of the headline incidence.PMIDProteinuria with first-line therapy of metastatic renal cell cancerLand JD, Chen AH, Atkinson BJ, Cauley DH, Tannir NM · J Oncol Pharm Pract 2016 · PMID 25505255Prospective cohort reporting proteinuria in 80% of pazopanib-treated mRCC patients, mostly low-grade and managed with continued monitoring — supports incidence and management framing.PMIDPazopanib-induced Endothelial Injury with Podocyte ChangesMaruyama K, Nakagawa N, Suzuki A, Kabara M, Matsuki M, Shindo M, Ogawa Y, Hasebe N · Intern Med 2017 · PMID 29269661Biopsy-proven case of pazopanib nephrotic syndrome showing glomerular endothelial injury with podocyte changes that resolved on withdrawal — direct histologic basis for the glomerular signature mechanism.PMIDThrombotic Microangiopathy Associated with Pazopanib in a Kidney Transplant RecipientKalla S, Ellis RJ, Campbell SB, Doucet B, Isbel N, Tie B, Jegatheesan D · J Kidney Cancer VHL 2021 · PMID 33850692First reported biopsy-proven case of pazopanib-attributed renal TMA (in a transplant graft), with nephrotic-range proteinuria and graft dysfunction improving after drug cessation — supports the TMA signature.PMIDThrombotic Thrombocytopenic Purpura Associated with PazopanibSyed U, Wahlberg KJ, Douce DR, Sprague JR · Case Rep Hematol 2018 · PMID 30057830Case of pazopanib-associated systemic TMA/TTP-like syndrome with AKI, schistocytes, and transiently undetectable ADAMTS13 responding to plasma exchange — illustrates the systemic end of the TMA spectrum.PMIDA case of pazopanib-induced acute kidney injury, reversible hair depigmentation and radiation recall dermatitisLi J, Li Z, Su T · Ren Fail 2023 · PMID 37264782Case report documenting pazopanib-associated acute kidney injury, supporting the broader renal-injury spectrum beyond proteinuria/hypertension.PMIDOcular and systemic vascular endothelial growth factor ligand inhibitor use and nephrotoxicity: an updateRangaswamy D, Nagaraju SP, Bhojaraja MV, Swaminathan SM, Prabhu RA, Rao IR, Shenoy SV · Int Urol Nephrol 2024 · PMID 38498275Recent comprehensive review of VEGF-inhibitor renal adverse effects (hypertension, proteinuria, renal dysfunction, TMA, electrolyte disturbances) contextualizing pazopanib within the class.
Guidelines & consensus· 16
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 expert oncology/cardiology 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
Acute Disease Quality InitiativeThe 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.Cancer Institute NSWIntegrating 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.Cancer Institute NSWAligning 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.Cancer Institute NSWA 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 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.