Anemia associated with chronic kidney disease (CKD) often requires treatment with recombinant human erythropoietin (EPO). Hypoxia-inducible factor-prolyl hydroxylase inhibitors (PHIs) stimulate endogenous EPO synthesis and induce effective erythropoiesis by non-EPO effects. GSK1278863 is an orally administered small-molecule PHI. Multicenter, single-blind, randomized, placebo-controlled, parallel-group study. Anemic non-dialysis-dependent patients with CKD stages 3-5 (CKD-3/4/5 group; n=70) and anemic hemodialysis patients with CKD stage 5D (CKD-5D group; n=37). Patients with CKD-3/4/5 received placebo or GSK1278863 (10, 25, 50, or 100mg), and patients with CKD-5D received placebo or GSK1278863 (10 or 25mg) once daily for 28 days. Primary pharmacokinetic and pharmacodynamic (increase and response rates in achieving the target hemoglobin [Hb] concentration, plasma EPO concentrations, reticulocyte count, and others]) and safety and tolerability end points were obtained. Both CKD-3/4/5 and CKD-5D populations showed a dose-dependent increase in EPO concentrations and consequent increases in reticulocytes and Hb levels. Percentages of GSK1278863 participants with an Hb level increase > 1.0g/dL (CKD-3/4/5) and >0.5g/dL (CKD-5D) were 63% to 91% and 71% to 89%, respectively. Per-protocol-defined criteria, high rate of increase in Hb level, or high absolute Hb value was the main cause for withdrawal (CKD-3/4/5, 30%; CKD-5D, 22%). A dose-dependent decrease in hepcidin levels and increase in total and unsaturated iron binding were observed in all GSK1278863-treated patients. Sparse pharmacokinetic sampling may have limited covariate characterization. EPO concentrations at the last pharmacodynamic sample (5-6 hours) postdose may not represent peak concentrations, which occurred 8 to 10 hours postdose in previous studies. Patients were not stratified by diabetes status, potentially confounding vascular endothelial growth factor and glucose analyses. GSK1278863 induced an effective EPO response and stimulated non-EPO mechanisms for erythropoiesis in anemic non-dialysis-dependent and dialysis-dependent patients with CKD.

Background. Early patient referral correlates with improved patient survival on dialysis. We examine whether early referral and a planned first dialysis affect quality of life (QoL). Methods. All patients commencing dialysis in nine centres in seven European countries between 1 July 1998 and 31 October 1999 were recruited. Definitions: early referral=followed by a nephrologist >1 month before first dialysis (300 µmol/l and non‐urgent first dialysis (early referral and no creatinine >300 µmol/l or urgent first dialysis=unplanned). QoL was measured at 8 weeks using a visual analogue scale (VAS) and Short Form 36 (SF‐36). Results. VAS was significantly higher in early referral patients [mean (SD) 58.4 (20) vs 50.4 (19), P=0.005], particularly if the first dialysis was planned [60.7 (20) vs 54.2 (20), P=0.03]. Planned patients also had higher SF‐36 mental summary scores [45.4 (12) vs 39.7 (11), P=0.003], role emotional scores [58.0 (43) vs 30.9 (38), P=0.003], and mental health scores [63.7 (24) vs 54.6 (22), P=0.01] than unplanned patients. Adjusting for centre and other confounding variables showed that having a planned first dialysis had an independent effect on QoL (VAS, and the SF‐36's mental summary score, physical functioning, role physical, general health, role emotional and mental health). Early referral had no independent effect on QoL. Socio‐economic status had an important positive effect on physical QoL. Conclusions. While the effect of early referral to a nephrologist on QoL appeared centre dependent, a smooth transition onto dialysis was associated with significantly better early QoL, independent of other variables.

Background: Arterial hypertension (AH) is associated with heart and chronic kidney disease (CKD). However, the precise mechanisms of myocardial remodeling (MR) in the settings of CKD remain elusive. We hypothesized that TRPC6, calcineurin/NFAT, and Wnt/β-catenin signaling pathways are involved in the development of MR in the background of CKD and AH. Methods: Early CKD was induced by performing a 5/6 nephrectomy (5/6NE) in spontaneously hypertensive rats (SHR-NE). Sham-operated (SO) SHR (SHR-SO) and Wistar Kyoto (WKY-SO) rats served as controls. Systolic blood pressure (SBP), heart rate, myocardial mass index (MMI), serum creatinine, cardiomyocyte diameter (dCM), myocardial fibrosis (MF), serum and kidney α-Klotho levels, myocardial expression of calcineurin (CaN), TRPC6, and β-catenin were measured two months after 5/6NE or SO. Results: NE-induced kidney dysfunction corresponded to mild-to-moderate human CKD and was associated with an increase in FGF23 and a decrease in renal α-Klotho. The levels of SBP, MMI, dCM, and MF were higher in SHRs compared to WKY-SO as well as in SHR-NE vs. SHR-SO. The MR was associated with increased cardiomyocyte expression of CaN/NFAT and β-catenin along with its intracellular re-distribution. TRPC6 protein levels were substantially elevated in both SHR groups with higher Trpc6 mRNA expression in SHR-NE. Conclusions: The Wnt/β-catenin and TRPC6/CaN/NFAT hypertrophic signaling pathways seem to be involved in myocardial remodeling in the settings of AH and CKD and might be mediated by FGF23 and α-Klotho axis.

Type 2 diabetes (DM2) could be reproduced in rats with alimentary obesity by using low doses of streptozotocin (LD-STZ) as well as STZ in high doses with preliminary nicotinamide (NA) administration. However, STZ could induce tubulotoxicity.Aim. To develop rat model of DN in NA-STZ-induced DM2 and compare it with LD-STZ-model in order to choose the most relevant approach for reproducing renal glomerular and tubular morphofunctional diabetic changes. Starting at 3 weeks after uninephrectomy, adult male Wistar rats were fed five-week high-fat diet and then received intraperitoneally either LD-STZ (40 mg/kg) or NA (230 mg/kg) followed by STZ (65 mg/kg). Control uninephrectomized vehicle-injected rats received normal chow. At weeks 10, 20, and 30 (the end of the study), metabolic parameters, creatinine clearance, albuminuria, and urinary tubular injury markers (NGAL, KIM-1) were evaluated as well as renal ultrastructural and light microscopic changes at weeks 20 and 30. NA-STZ-group showed higher reproducibility and stability of metabolic parameters. By week 10, in NA-STZ-group NGAL level was significantly lower compared to LD-STZ-group. By week 30, diabetic groups showed early features of DN. However, morphofunctional changes in NA-STZ-group appeared to be more pronounced than those in STZ-group despite lower levels of KIM-1 and NGAL. We proposed a new rat model of DM2 with DN characterized by stable metabolic disorders, typical renal lesions, and lower levels of tubular injury markers as compared to LD-STZ-induced diabetes.

Background Renal transplant glomerulitis (G) is associated with acute antibody-mediated rejection (ABMR) in the presence of donor-specific antibodies. However, the long-term prognosis of isolated G (isG) in the absence of donor-specific antibodies or G in combination with T cell–mediated rejection (TCMR) remains unexplored. Methods Seventy recipients with G were included in this retrospective study and subdivided into 3 groups: isG, G with TCMR (G + TCMR), and G with acute ABMR. The control groups were: patients with TCMR Banff type I or II without G (TCMR) and patients without rejection (NR). Kaplan-Meier death-censored survival plots and Cox regression were used to analyze graft survival. The combined graft survival endpoint was defined as a return to dialysis or estimated glomerular filtration rate less than 15 mL/min/1.73 m². The median follow-up was 37 (14; 77) months from biopsy. Results Graft survival was significantly lower in patients with G than in the NR and TCMR groups. No significant differences were observed among the isG, G + TCMR, and ABMR groups. Graft survival was lower in the G + TCMR group than in the TCMR group. Glomerulitis was independently associated with the risk of adverse graft outcome in a multivariate Cox regression model adjusted for other confounders (hazard ratio, 4.52 [95% confidence interval, 2.37-8.68] vs controls; P < 0.001). Conclusions Glomerulitis is strongly associated with increased risk of graft failure. Graft survival in patients with isG that do not meet the Banff criteria for acute/active ABMR and in patients with G accompanying TCMR is comparable to the ABMR group.

Пароксизмальная ночная гемоглобинурия у детей и взрослых: сравнительный клинический профиль и долгосрочный прогноз