Although elevated serum levels of uric acid are common in patients with kidney disease or in those receiving maintenance dialysis therapy, the clinical impact of uric acid on mortality in haemodialysis (HD) patients remains unclear. This work was designed to explore the predictive value of serum uric acid levels on all-cause mortality of HD patients. We retrospectively analysed mortality rates in 146 chronic HD patients that were treated with HD three times per week at our HD unit for a period of one full year. The analysed parameters included demographic characteristics, aetiology of end-stage renal disease, co-morbid conditions, duration (at least 1 year) and delivered dose of HD, normalized protein catabolic rate, serum albumin concentration, haematocrit, serum uric acid (UA) levels and other laboratory parameters. A multivariate Cox proportional hazards model, which included adjustment for the above factors, was applied to identify the predictive value of UA levels on patient mortality. A Cox proportional hazards model revealed that decreased serum albumin, underlying diabetic nephropathy (DMN) and UA groups (< or =20th, 20-80th and > or =80th percentiles; P = 0.016) were all significant, independent predictors of all-cause mortality in HD patients. The hazard ratios of death were: serum albumin (per 0.5 g/dl decrease), 3.10 [95% confidence interval (95% CI), 1.80-5.34, P < 0.001]; DMN (vs non-DMN), 3.47 (95% CI, 1.25-9.59, P = 0.017); and UA groups (vs 20th to 80th percentile): < or =20th percentile, 2.98 (95% CI, 0.82-10.90, P = 0.099); > or = 80th percentile, 5.67 (95% CI, 1.71-18.78, P = 0.004). These preliminary observations suggest that HD patients in the lowest and highest quintiles of UA levels would face higher risk of mortality. Further studies with larger sample sizes will be needed to confirm these findings.

Endoplasmic reticulum (ER) stress-associated apoptosis plays a role in organ remodeling after insult. The effect of ER stress on renal tubular damage and fibrosis remains controversial. This study aims to investigate whether ER stress is involved in tubular destruction and interstitial fibrosis in vivo. Renal cell apoptosis was proven by terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) stain and poly-ADP ribose polymerase expression in the unilateral ureteral obstruction (UUO) kidney. ER stress was evoked and confirmed by the upregulation of glucose-regulated protein 78 (GRP78) and the common Lys-Asp-Glu-Leu (KDEL) motif of ER retention proteins after UUO. ER stress-associated proapoptotic signals, including B-cell chronic lymphocytic leukemia (CLL)/lymphoma 2-associated × protein (BAX) expression, caspase-12 and c-Jun N-terminal kinase (JNK) phosphorylation, were activated in the UUO kidney. Prolonged ER stress attenuated both unsplicing and splicing X-box binding protein 1 (XBP-1) protein expression, but continued to activate inositol-requiring 1α (IRE1α)-JNK phosphorylation, protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2α subunit (eIF2α), activating transcription factor (ATF)-4, CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) and cleavage activating transcription factor 6 (cATF6)-CHOP signals, which induce ER stress-related apoptosis but attenuate adaptive unfolded protein responses in UUO kidneys. However, renal apoptosis and fibrosis were attenuated in candesartan-treated UUO kidney. Candesartan was associated with maintenance of XBP-1 expression and attenuated ATF4, cATF6 and CHOP protein expression. Taken together, results show that overwhelming ER stress leads to renal cell apoptosis and subsequent fibrosis; and candesartan, at least in part, restores renal integrity by blocking ER stress-related apoptosis. Reducing ER stress may present a way to attenuate renal fibrosis.

Advanced chronic kidney disease (CKD) patients encounter anemia through insufficient erythropoietin (EPO) production by peritubular fibroblasts. Recent studies showed an increase in EPO production by pharmacological activation of hypoxia-inducible transcription factors (HIFs) in dialysis patients, suggesting that desensitization of the oxygen-sensing mechanism is responsible for the development of renal anemia. Our recent work demonstrated that indoxyl sulfate (IS), a uremic toxin, dysregulates oxygen metabolism in tubular cells. Here we provide evidence of an additional property that IS impairs oxygen sensing in EPO-producing cells. HepG2 cells were stimulated with cobalt chloride (CoCl₂) or hypoxia under varying concentrations of IS. EPO mRNA was evaluated by quantitative PCR. Nuclear accumulation of HIF-α was evaluated by western blotting. Transcriptional activity of HIF was checked by hypoxia-responsive element (HRE)-luciferase reporter assay. The impact of IS was further evaluated in vivo by administering rats with indole, a metabolic precursor of IS, and subjecting them to CoCl₂ stimulation, in which renal EPO mRNA as well as plasma EPO levels were measured by quantitative PCR and enzyme-linked immunosorbent assay, respectively. Although IS induced cellular toxicity at relatively high concentrations (2.5 mM), EPO mRNA expression was significantly suppressed by IS at concentrations below cytotoxic ranges. In HepG2 cells, IS treatment decreased nuclear accumulation of HIF-α proteins and suppressed HRE-luciferase activity following hypoxia. Furthermore, administration of rats with indole suppressed renal EPO mRNA expression and plasma EPO levels, corroborating in vitro findings. Results of the present study provide a possible connection between a uremic toxin and the desensitization of the oxygen-sensing mechanism in EPO-producing cells, which may partly explain inadequate EPO production in hypoxic kidneys of CKD patients.

Context: Studies addressing the association of metabolic syndrome and insulin resistance with the risks of incident chronic kidney disease (CKD) and the progression of renal function were either lacking or inconclusive. Objective: The aim of this study was to define the effect of metabolic syndrome and insulin resistance on the development of new CKD and the decline in renal function. Design and Setting: A prospective cohort study was conducted at a tertiary university-based hospital in Taiwan. Patients and Other Participants: We studied a total of 1456 Asians 65 or older who were followed for an average of 3.15 yr. Within the cohort, we measured insulin resistance using the homeostasis model assessment formula in 652 nondiabetic participants. Interventions: There were no interventions. Main Outcome Measures: We measured the prevalence and incidence of CKD and the annual decline of the estimated glomerular filtration rate. Results: We found that the adjusted odds ratio for prevalent CKD in association with metabolic syndrome was 1.778 (95% confidence interval, 1.188 to 2.465), the hazard ratio for rapid decline in renal function was 1.042 (0.802–1.355), and the hazard ratio for incident CKD was 1.931 (1.175–3.174). With each one-unit increment of insulin resistance, the odds ratio of prevalent CKD and proteinuria were raised 1.312-fold (1.114 to 1.545) and 1.278-fold (1.098 to 1.488), respectively. Insulin resistance was not associated with incident CKD. Increment of insulin resistance per unit was associated with 1.16-fold (1.06 to 1.26) elevation in the hazard ratios of the decline in renal function. Conclusions: Metabolic syndrome predicts the risks of prevalent and incident CKD, whereas insulin resistance is associated with prevalent CKD and rapid decline in renal function in elderly individuals.