Early biomarkers of nephrotoxicity associated with the use of anti‑VEGF drugs

Abstract

Anti-angiogenic anticancer drugs that block vascular endothelial growth factor (VEGF) can cause kidney damage. An early assessment of the risk of nephrotoxicity would allow the development of optimal treatment approaches and allow for relatively safer therapeutic regimens. The aim of this study was to assess the utility of neutrophilic gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), hypoxia inducible factor-1α (HIF-1α) and nephrin levels in urine as early biomarkers for the nephrotoxicity of anti-VEGF drugs. The study included 50 patients who received anti-VEGF drugs (aflibercept, bevacizumab or ramucirumab) for 8 weeks. The levels of KIM-1, NGAL, HIF-1α and nephrin in urine samples were determined by ELISA before treatment and after 1, 2, 4 and 8 weeks of treatment. To assess risk factors for nephrotoxicity, a logistic regression analysis was performed with the inclusion of the primary clinical and laboratory parameters. The primary outcome measure was a decrease in glomerular filtration rate (GFR) to <60 ml/min/1.73 m 2 at 8 weeks, and nephrotoxicity resulting in discontinuation within 9 months. The primary outcome goal was achieved in 21 (42%) patients treated with anti-VEGF drugs. Increased NGAL, KIM-1, HIF-1α and nephrin levels in urine at 1 week of treatment predicted the development of nephrotoxicity. High sensitivity and specificity of these urinary biomarkers were established by ROC analysis: KIM-1 [area under the curve (AUC) 0.69], NGAL (AUC 0.7), HIF-1α (AUC 0.7) and nephrin (AUC 0.7). The unfavorable predictors of nephrotoxicity were an initial decrease in estimated GFR, a history of arterial hypertension, and an increase in urinary concentration KIM-1 OR of 1.1 [CI 95% 1.02-1.183], and HIF-1α OR of 5.6 [CI 95% 3.601-8.949] (P<0,05) at 1 and 2 weeks of treatment. Urinary NGAL, KIM-1, HIF-1α and nephrin are early biomarkers of nephrotoxicity following treatment with anti-VEGF anticancer drugs. The independent risk factors for nephrotoxicity are the initial decrease in GFR, arterial hypertension, and an increase in the concentration of KIM-1 and HIF-1α in the urine in the early stages of therapy.

Cardiac and Nephrological Complications Related to the Use of Antiangiogenic and Anti-Programmed Cell Death Protein 1 Receptor/Programmed Cell Death Protein 1 Ligand Therapy

“…Their consequence may be a decrease in the glomerular filtration rate up to the development of acute kidney damage. In some cases, therapy with anti-VEGF drugs may lead to gradual but irreversible changes in renal function, up to end-stage renal disease [11]. The incidence of renal-related hypertension, depending on the source, ranges from 23 to 41% for bevacizumab, approximately 17-55% for sorafenib, 22-60% for sunitinib therapy and 40-52% for pazopanib [46].…”

“…Cardiac toxicity related to the use of therapy manifests itself mainly in the form of hypertension, thromboembolic episodes and ischemic heart disease [10]. In the case of renal complications, the most frequently observed are renal arterial hypertension, proteinuria and microangiopathy [11]. Also, the use of PD-1 inhibitors may result in kidney and heart damage.…”