Muscle wasting or sarcopenia contributes to morbidity and mortality in patients with cancer, renal failure, or heart failure, and in elderly individuals. Na+-K+-2Cl− cotransporter 1 (NKCC1) is highly expressed in mammalian skeletal muscle, where it contributes to the generation of membrane ion currents and potential. However, the physiologic function of NKCC1 in myogenesis is unclear. We investigated this issue using the NKCC1 inhibitors bumetanide and furosemide, which are commonly used loop diuretics. NKCC1 protein levels increased during C2C12 murine skeletal myoblast differentiation, similarly to those of the myogenic markers myogenin and myosin heavy chain (MHC). NKCC1 inhibitors markedly suppressed myoblast fusion into myotubes and the expression of myogenin and MHC. Furthermore, phosphorylated and total NKCC1 levels were elevated in mouse skeletal muscles after 6 weeks’ voluntary wheel running. Immunofluorescence analyses of myofiber cross-sections revealed more large myofibers after exercise, but this was impaired by daily intraperitoneal bumetanide injections (0.2 or 10 mg/kg/day). NKCC1 plays an essential role in myogenesis and exercise-induced skeletal muscle hypertrophy, and sarcopenia in patients with renal or heart failure may be attributable to treatment with loop diuretics.

KLHL3 expression was decreased in CUL3 mice. However, expression levels of other KLHL family proteins were comparable between the wild-type and mutant mice. These findings indicate that the decreased abundance of KLHL3 is a specific phenomenon caused by mutant CUL3 (Δexon9). Our findings would improve our understanding of the pathogenesis of PHAII caused by CUL3 mutation in vivo.

BackgroundHyponatremia is associated with increased mortality in chronic kidney disease with and without end-stage renal disease (ESRD). Increasing evidence suggests that hyponatremia is not only a marker of severe underlying disease, but also a direct contributor to mortality. However, specific pathogenesis or diseases contributing to mortality in the hyponatremic population are unknown. This study aimed to clarify the relationship between serum sodium level (sNa) and infection risk in ESRD patients.MethodsThis observational cohort study included 332 patients on maintenance hemodialysis in our dialysis unit in May 2009. The mean of 3 monthly measurements of glucose-corrected sNa before each dialysis session in May, June, and July 2009 was applied as baseline sNa. The primary endpoint was first infection-related hospitalization (IRH), and the secondary endpoint was death of any cause. Data were analyzed using Cox hazards modeling, adjusted for baseline demographics and characteristics, or laboratory data. Patients were followed until transfer, kidney transplantation, death, or study end on January 31, 2013.ResultsMean sNa was 138.9 mEq/L (1st tertile: <138.0, n = 104; 2nd tertile: 138.0–140.0, n = 116; 3rd tertile: >140.0, n = 112). During 39.5 months’ mean follow-up, 57 patients experienced IRH (56.4/1,000 patient-years overall; 89.7/1,000 in 1st tertile; 57.9/1,000 in 2nd tertile; 28.0/1,000 in 3rd tertile), and 68 patients died. The hazard ratio (HR) for IRH was higher for the 1st and 2nd tertiles than the 3rd tertile (unadjusted HR, 3.20; 95% confidence interval (CI), 1.54–6.64; p = 0.002; adjusted HR, 2.36; 95% CI, 1.10–5.04; p = 0.027; and unadjusted HR, 2.07; 95% CI, 0.98–4.40; p = 0.058; adjusted HR, 2.11; 95% CI, 0.99–4.51; p = 0.054 respectively). In a continuous model, higher sNa was associated with lower risk of IRH (adjusted HR, 0.90; 95% CI, 0.81–0.99; p = 0.040), and lower all-cause mortality (adjusted HR, 0.91; 95% CI, 0.83–1.00; p = 0.049).ConclusionsLower sNa is an independent predictor of higher risk for infection-related hospitalization in maintenance hemodialysis patients. Infectious disease may partially account for the increased mortality observed in the hyponatremic population with ESRD.

The study results suggest that hyporesponsiveness to ESA after the first 12-week administration as well as after 12 weeks is a risk for RD in pre-dialysis CKD patients. Furthermore, hyperphosphatemia and diabetic nephropathy are risk factors for RD.

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