Soluble Epoxide Hydrolase Activity Determines the Severity of Ischemia-Reperfusion Injury in Kidney

Soluble epoxide hydrolase (sEH) in endothelial cells determines the plasma concentrations of epoxyeicosatrienoic acids (EETs), which may act as vasoactive agents to control vascular tone. We hypothesized that the regulation of sEH activity may have a therapeutic value in preventing acute kidney injury by controlling the concentration of EETs. In this study, we therefore induced ischemia-reperfusion injury (IRI) in C57BL/6 mice and controlled sEH activity by intraperitoneal administration of the sEH inhibitor 12-(3-adamantan-1-ylureido)-dodecanoic acid (AUDA). The deterioration of kidney function induced by IRI was partially moderated and prevented by AUDA treatment. In addition, AUDA treatment significantly attenuated tubular necrosis induced by IRI. Ischemic injury induced the down-regulation of sEH, and AUDA administration had no effect on the expression pattern of sEH induced by IRI. In vivo sEH activity was assessed by measuring the substrate epoxyoctadecenoic acid (EpOME) and its metabolite dihydroxyoctadec-12-enoic acid (DHOME). Ischemic injury had no effects on the plasma concentrations of EpOME and DHOME, but inhibition of sEH by AUDA significantly increased plasma EpOME and the EpOME/DHOME ratio. The protective effect of the sEH inhibitor was achieved by suppression of proinflammatory cytokines and up-regulation of regulatory cytokines. AUDA treatment prevented the intrarenal infiltration of inflammatory cells, but promoted endothelial cell migration and neovascularization. The results of this study suggest that treatment with sEH inhibitors can reduce acute kidney injury

Effects of residential greenness on clinical outcomes of patients with chronic kidney disease: a large-scale observation study

Background: As industrialization and urbanization are accelerating, the distribution of green areas is decreasing, particularly in developing countries. Since the 2000s, the effects of surrounding greenness on self-perceived health, including physical and mental health, longevity, and obesity have been reported. However, the effects of surrounding green space on chronic kidney disease are not well understood. Therefore, we investigated the impact of residential greenness on the mortality of chronic kidney disease patients and progression from chronic kidney disease to end-stage renal disease (ESRD). Methods: Using a large-scale observational study, we recruited chronic kidney disease patients (n = 64,565; mean age, 54.0 years; 49.0% of male) who visited three Korean medical centers between January 2001 and December 2016. We investigated the hazard ratios of clinical outcomes per 0.1-point increment of exposure to greenness using various models. Results: During the mean follow-up of 6.8 +/- 4.6 years, 5,512 chronic kidney disease patients developed ESRD (8.5%) and 8,543 died (13.2%). In addition, a 0.1-point increase in greenness reduced all-cause mortality risk in chronic kidney disease and ESRD patients and progression of chronic kidney disease to ESRD in a fully adjusted model. The association between mortality in ESRD patients and the normalized difference vegetation index was negatively correlated in people aged >65 years, who had normal weight, were nonsmokers, and lived in a nonmetropolitan area. Conclusion: Chronic kidney disease patients who live in areas with higher levels of greenness are at reduced risk of all-cause mortality and progression to ESRD.Y

Factors affecting the long-term outcomes of idiopathic membranous nephropathy

Abstract Background We attempted to describe the clinical features and determine the factors associated with renal survival in idiopathic membranous nephropathy (iMN) patients with nephrotic syndrome (NS) and to determine the factors associated with spontaneous complete remission (sCR) and progression to NS in iMN patients with subnephrotic proteinuria. Methods This retrospective study involved 166 iMN patients with NS and 65 patients with subnephrotic proteinuria. The primary end point was a doubling of serum creatinine or initiation of dialysis. In patients with subnephrotic proteinuria, we determined the factors associated with sCR and factors associated with progression to NS. Results Remission of NS was achieved in 125 out of 166 patients (75.3%). Of those who reached remission, 26 patients (20.8%) experienced relapse that was followed by second remission. The relapse or persistence of proteinuria was associated with the primary end points (hazard ratio [HR] = 12.40, P = 0.037, HR = 173, P < 0.001, respectively). In patients with subnephrotic proteinuria, sCR occurred in 35.4% of the patients. The patients with sCR had lower proteinuria and serum creatinine levels and higher serum albumin concentrations at baseline. The serum albumin level at diagnosis was a prognostic factor for progression to NS (Odds ratio [OR] = 0.015, P < 0.001). Conclusions The occurrence of relapse or persistence of proteinuria had negative effects on renal survival in iMN patients with NS, and low serum albumin levels at baseline were associated with non-achievement of sCR and progression to NS

Dose selection method for pharmacokinetic study in hemodialysis patients using a subpharmacological dose: oseltamivir as a model drug

BACKGROUND: Dose selection is an important step in pharmacokinetic (PK) studies of hemodialysis patients. We propose a simulation-based dose-selection method for PK studies of hemodialysis patients using a subpharmacological dose of oseltamivir as a model drug. METHODS: The concentrations of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were measured by liquid chromatography-tandem mass spectrometry. To determine a low oseltamivir dose exhibiting PK linearity, a pilot low dose determination investigation (n = 4) was performed using a single administration dose-escalation study. After the dose was determined, a low dose study (n = 10) was performed, and the optimal dose required to reach the hypothetical target OC exposure (area under the concentration-time curve [AUC] of 60,000 ng · hr/mL) was simulated using a nonparametric superposition method. Finally, observed PKs at the optimal dose were compared to the simulated PKs to verify PK predictability. RESULTS: In the pilot low dose determination study, 2.5 mg of oseltamivir was determined to be the low dose. Subsequently, we performed a single-dose PK study with the low oseltamivir dose in an additional group of 10 hemodialysis patients. The predicted AUC(last) of OC following continuous oseltamivir doses was simulated, and 35 mg of oseltamivir corresponded to the hypothetical target AUC(last) of OC. The observed PK profiles of OC at a 35-mg oseltamivir dose and the simulated data based on the low dose study were in close alignment. CONCLUSION: The results indicate that the proposed method provides a rational approach to determine the proper PK dose in hemodialysis patients