Kidney Diseases Associated With Anti-Vascular Endothelial Growth Factor (VEGF)

Abstract

Expanded clinical experience with patients taking antiangiogenic compounds has come with increasing recognition of the renal adverse effects. Because renal histology is rarely sought in those patients, the renal consequences are underestimated. Antiangiogenic-treated-cancer patients, who had a renal biopsy for renal adverse effects from 2006 to 2013, were included in the current study. Clinical features and renal histologic findings were reviewed. Our cohort was 100 patients (58 women) with biopsy-proven kidney disease using anti-vascular endothelial growth factor (VEGF) therapy with a mean age of 59.8 years (range, 20–85 yr). Patients were referred for proteinuria, hypertension, and/or renal insufficiency. Kidney biopsy was performed 6.87 ± 7.18 months after the beginning of treatment. Seventy-three patients experienced renal thrombotic microangiopathy (TMA) and 27 patients had variable glomerulopathies, mainly minimal change disease and/or collapsing-like focal segmental glomerulosclerosis (MCN/cFSGS). MCN/cFSGS-like lesions developed mainly with tyrosine-kinase inhibitors, whereas TMA complicated anti-VEGF ligand. Thirty-one percent of TMA patients had proteinuria up to 1 g/24 h. Half of TMA cases are exclusively renal localized. Pathologic TMA features are intraglomerular exclusively. MCN/cFSGS glomeruli displayed a high abundance of KI-67, but synaptopodin was not detected. Conversely, TMA glomeruli exhibited a normal abundance of synaptopodin-like control, whereas KI-67 was absent. Median follow-up was 12 months (range, 1–80 mo). Fifty-four patients died due to cancer progression. Hypertension and proteinuria resolved following drug discontinuation and antihypertensive agents. No patient developed severe renal failure requiring dialysis. Drug continuation or reintroduction resulted in a more severe recurrence of TMA in 3 out of 4 patients requiring maintenance of anti-VEGF agents despite renal TMA. In conclusion, TMA and MCN/cFSGS are the most frequent forms of renal involvement under anti-VEGF therapy. Careful risk-benefit assessment for individual patients should take into account risk factors related to the host and the tumor.

Mechanisms of Hypertension and Renal Injury During Vascular Endothelial Growth Factor Signaling Inhibition

“…61 In rats exposed to the RTKI sunitinib, no evidence for a decrease in peritubular ECs was found, and also in renal biopsies obtained from patients treated with VSP inhibitors, glomerular abnormalities are predominant. 54,[62][63][64] In addition to the mentioned podocyte-glomerular and tubulo-vascular cross talk between VEGF and VEGFR-2, recent evidence indicates an autocrine role of the soluble part of the VEGFR-1 produced by podocytes to maintain the glomerular filtration barrier. 65 Podocyte-specific deletion of the gene encoding VEGFR-1 results in disruption of the glomerular cytoskeletal architecture and heavy proteinuria.…”

“…58,63,64 However, a recent study indicates a more diverse spectrum of renal histological abnormalities after VSP inhibition. 62 Kidney biopsies of 100 patients with proteinuria and renal function impairment during VSP inhibition showed TMA in 73 and minimal change and collapsing-like focal segmental glomerulosclerosis in 27 patients. 62 In 50% of patients with TMA, no systemic hematologic manifestations of TMA were detectable.…”

“…62 Kidney biopsies of 100 patients with proteinuria and renal function impairment during VSP inhibition showed TMA in 73 and minimal change and collapsing-like focal segmental glomerulosclerosis in 27 patients. 62 In 50% of patients with TMA, no systemic hematologic manifestations of TMA were detectable. Almost all patients with TMA were treated with bevacizumab or VEGF-trap, whereas all but one of the patients with minimal change and collapsing-like focal segmental glomerulosclerosis were treated with a RTKI.…”

Pharmacology behind Common Drug Nephrotoxicities

“…In the kidney, VEGF is produced by podocytes and binds glomerular and peritubular capillary endothelial cell VEGF receptors. Glomerular endothelial VEGF receptor binding maintains normal fenestrated endothelial health and is important for normal functioning of the glomerular basement membrane (11,(44)(45)(46)(47). Reduction in VEGF levels or signaling pathways by antiangiogenic drugs promotes loss of the healthy fenestrated endothelial phenotype and promotes microvascular injury and thrombotic microangiopathy, causing proteinuria and AKI.…”

“…Antiangiogenesis therapy with monoclonal antibodies against vascular endothelial growth factor (VEGF), circulating soluble VEGF receptors, and small molecule tyrosine kinase inhibitors that impair intracellular VEGF signaling pathways are associated with various forms of kidney injury (11,(44)(45)(46)(47). In the kidney, VEGF is produced by podocytes and binds glomerular and peritubular capillary endothelial cell VEGF receptors.…”