CD44 Expression in Renal Tissue Is Associated with an Increase in Urinary Levels of Complement Components in Chronic Glomerulopathies.

It is suggested that activated CD44+ cells play a profibrogenic role in the pathogenesis of active glomerulopathies. Complement activation is also involved in renal fibrogenesis. The aim of the study was to evaluate the role of the activation of CD44+ cells in the kidney tissue and complement components' filtration to the urine as factors of renal tissue fibrosis in patients with glomerulopathies. In total, 60 patients with active glomerulopathies were included in our study: 29 patients with focal segmental glomerulosclerosis (FSGS), 10 patients with minimal change disease (MCD), 10 patients with membranous nephropathy (MN), and 11 patients with IgA nephropathy. The immunohistochemical peroxidase method was used to study the expression of CD44+ in kidney biopsies. Components of complement were analyzed in urine by the multiple reaction monitoring (MRM) approach using liquid chromatography. Strong CD44 expression was noted predominantly in PEC and mesangial cells (MC) in patients with FSGS, and to a lesser extent, in patients with MN and IgA nephropathy, and it was absent in patients with MCD. Expression of profibrogenic CD44+ in glomeruli correlated with the levels of proteinuria and complement C2, C3, and C9 components, and CFB and CFI in urine. The CD44+ expression scores in the renal interstitium correlated with the level of C3 and C9 components of complement in the urine and the area of tubulo-interstitial fibrosis. The strongest expression of CD44+ was found in the glomeruli (MC, PEC, and podocytes) of patients with FSGS compared with other glomerulopathies. The CD44 expression score in the glomeruli and interstitium is associated with high levels of complement components in the urine and renal fibrosis.

Early biomarkers of nephrotoxicity associated with the use of anti-VEGF drugs.

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 m2 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.