Background: Serum total and low-density lipoprotein (LDL) cholesterol levels are elevated in patients with nephrotic syndrome and those with kidney failure treated by peritoneal dialysis (PD), who are characterized by heavy losses of protein in urine and peritoneal dialysate, respectively. Hypercholesterolemia in nephrotic syndrome is associated with and largely due to acquired LDL receptor (LDLR) deficiency. Because PCSK9 (proprotein convertase subtilisin/kexin type 9) promotes degradation of LDLR, we tested the hypothesis that elevation of LDL cholesterol levels in patients with nephrotic syndrome and PD patients may be due to increased PCSK9 levels.Study Design: Cross-sectional study.Setting & Participants: Patients with nephrotic syndrome or treated by PD or hemodialysis and age-and sex-matched healthy Korean individuals (n 5 15 in each group).Predictor: Group and serum total and LDL cholesterol levels.Outcomes: Plasma PCSK9 concentration. Measurements: Concentrations of fasting serum PCSK9, lipids, and albumin, and urine protein excretion.Results: Mean serum total and LDL cholesterol levels in patients with nephrotic syndrome (317.9 6 104.2 [SD] and 205.9 6 91.1 mg/dL) and PD patients (200.0 6 27.6 and 126.7 6 18.5 mg/dL) were significantly (P , 0.05) higher than in hemodialysis patients (140.9 6 22.9 and 79.1 6 19.5 mg/dL) and the control group (166.5 6 26.5 and 95.9 6 25.2 mg/dL). This was associated with significantly (P , 0.05) higher plasma PCSK9 levels in patients with nephrotic syndrome (15.13 6 4.99 ng/mL) and PD patients (13.30 6 1.40 ng/mL) than in the control (9.19 6 0.60 ng/mL) and hemodialysis (7.30 6 0.50 ng/mL) groups. Plasma PCSK9 level was directly related to total and LDL cholesterol concentrations in the study population (r 5 0.559 [P , 0.001] and r 5 0.497 [P , 0.001], respectively).Limitations: Small number of participants may limit generalizability. Conclusions: Nephrotic syndrome and PD are associated with higher plasma PCSK9 concentration, which can contribute to elevation of LDL levels by promoting LDLR deficiency. Am J Kidney Dis. -(-):---. ª 2013 by the National Kidney Foundation, Inc.

Abstract. Hypothyroidism is associated with impaired urinary concentrating ability in humans and animals. The purpose of this study was to examine protein expression of renal sodium chloride and urea transporters and aquaporins in hypothyroid rats (HT) with diminished urinary concentration as compared with euthyroid controls (CTL) and hypothyroid rats replaced with L-thyroxine (HTϩT). Hypothyroidism was induced by aminotriazole administration. Body weight, water intake, urine output, solute and urea excretion, serum and urine osmolality, serum creatinine, 24-h creatinine clearance, and fractional excretion of sodium were comparable among the three groups. However, with 36 h of water deprivation, HT rats demonstrated significantly greater urine flow rates and decreased urine and medullary osmolality as compared with CTL and HTϩT rats at comparable plasma vasopressin concentrations. Western blot analyses revealed decreased renal protein abundance of transporters, including Na-K-2Cl, Na-K-ATPase, and NHE3, in HT rats as compared with CTL and HTϩT rats. Protein abundance of renal AQP1 and urea transporters UTA 1 and UTA 2 did not differ significantly among study groups. There was however a significant decrease in protein abundance of AQP2, AQP3, and AQP4 in HT rats as compared with CTL and HTϩT rats. These findings demonstrate a decrease in the medullary osmotic gradient secondary to impaired countercurrent multiplication and downregulation of aquaporins 2, 3, and 4 as contributors to the urinary concentrating defect in the hypothyroid rat.Hypothyroidism is a very common clinical disorder that is associated with abnormalities in many organs, including the kidney. The ability to conserve water during periods of fluid deprivation is an important function of the kidney. Hypothyroidism has been associated with an impaired urinary concentrating capacity (1,2). However, the mechanisms of this defect at the cellular and molecular level have not been defined.In the present study, the effect of hypothyroidism in rats on the pivotal components of the urinary concentrating mechanism have been examined and compared with euthyroid animals. These components during fluid deprivation include release of the antidiuretic hormone, arginine vasopressin (AVP), and upregulation of the abundance of aquaporin-2 (AQP2) water channels in the principal cells of the collecting duct. Activation of the countercurrent concentrating mechanism, which is initiated by increased sodium-potassium-2 chloride (Na-K-2Cl) co-transporter in the water impermeable ascending limb, creates the osmotic driving force for passive water reabsorption across the collecting duct. There are also roles for other water channels, including aquaporins 1, 3, and 4, and for urea transporters in urinary concentration. The present study was undertaken to define the effect of hypothyroidism on these various molecular events during fluid deprivation in the rat. Materials and Methods Animal ModelThe study protocol was approved by the University of Colorado Institutional Animal Ca...

Levofloxacin (LVFX) has different effects depending on the area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC) ratio. While AUC can be expressed as dose/clearance (CL), we measured serial concentrations of LVFX in Koreans and tried to set a Korean-specific equation, estimating the CL of the antibiotic. In total, 38 patients, aged 18-87 years, received once daily intravenous LVFX doses of 500 mg or 250 mg, depending on their renal function. Four plasma samples were obtained according to a D optimal sampling design. The population pharmacokinetic (PK) parameters of LVFX were estimated using non-linear mixed-effect modeling (NONMEM, ver. 7.2). The CL of LVFX was dependent on creatinine clearance (CLCR) as a covariate. The mean population PK parameters of LVFX in Koreans were as follows: CL (l/hour) = 6.19 ×  (CLCR/75)(1.32). The CL of LVFX in Koreans is expected to be lower than that in Western people.

Volume status is a key parameter for cardiovascular-related mortality in dialysis patients. Although N-terminal pro-B-type natriuretic peptide (NT-proBNP), myeloperoxidase, copeptin, and pro-adrenomedullin have been reported as volume markers, the relationship between body fluid status and volume markers in dialysis patients is uncertain. Therefore, we investigated the utility of volume status biomarkers based on body composition monitor (BCM) analyses. We enrolled pre-dialysis, hemodialysis (HD), and peritoneal dialysis (PD) patients and age- and gender-matched healthy Korean individuals (N = 80). BCM and transthoracic echocardiography were performed and NT-proBNP, myeloperoxidase, copeptin, and pro-adrenomedullin concentrations were measured. Relative hydration status (ΔHS, %) was defined in terms of the hydration status-to-extracellular water ratio with a cutoff of 15%, and hyperhydrated status was defined as ΔHS > 15%. Although there were no significant differences in total body water, extracellular water, or intracellular water among groups, mean amount of volume overload and hyperhydrated status were significantly higher in HD and PD patients compared with control and pre-dialysis patients. Mean amount of volume overload and hyperhydrated status were also significantly associated with higher NT-proBNP and pro-adrenomedullin levels in HD and PD patients, although not with myeloperoxidase or copeptin levels. Furthermore, they were significantly associated with cardiac markers (left ventricular mass index, ejection fraction, and left atrial diameter) in HD and PD patients compared with those in the control and pre-dialysis groups. On the basis of increased plasma NT-proBNP and pro-adrenomedullin concentrations, we might be able to make predictions regarding the volume overload status of dialysis patients, and thereby reduce cardiovascular-related mortality through appropriate early volume control.

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