Ming-Shiou Wu

Role of NHE3 in Mediating Renal Brush Border Na+-H+ Exchange ADAPTATION TO METABOLIC ACIDOSIS

The aims of the present study were to estimate the fraction of renal brush border membrane Na+-H+ exchange activity mediated by the isoform NHE3 and to evaluate whether the increased brush border Na+-H+ exchange observed in metabolic acidosis is due to increased expression of NHE3 protein. Compared with other isoforms, NHE3 is known to have a unique profile of sensitivity to pharmacologic inhibitors, including relative resistance to amiloride analogs and HOE694. We therefore assessed the inhibitor sensitivity of pH gradient-stimulated 22Na uptake in renal brush border vesicles isolated from normal rats. The I50 values for amiloride (30 μM), dimethylamiloride (10 μM), ethylisopropylamiloride (6 μM), and HOE694 (>100 μM) were markedly dissimilar from those reported for NHE1 and NHE2 but were nearly identical to reported values for NHE3. Na+-H+ exchange activity in renal brush border vesicles isolated from rats with 5 days of NH4Cl-induced metabolic acidosis was increased 1.5-fold compared with control rats, with no change in inhibitor sensitivity. Western blot analysis indicated that NHE3 protein expression was greater in brush border membranes from acidotic compared with control rats. We conclude that virtually all measured Na+-H+ exchange activity in brush border membranes from control and acidotic rats is mediated by NHE3 and that metabolic acidosis causes increased expression of renal brush border NHE3 protein.

Sexual dysfunction in female hemodialysis patients: A multicenter study

BACKGROUND Sexual function is one aspect of physical functioning. Sexual dysfunction, no matter the etiology, could cause distress. In female hemodialysis patients, sexual problems have often been neglected in clinical performance and research. METHODS We conducted this study by use of self-reported questionnaires. A total of 578 female hemodialysis patients in northern Taiwan were included in this study. Demographic data, comorbid diseases, medications in use, biochemical, and hematologic parameters were analyzed. All patients were asked to complete by themselves three questionnaires: (1) the Index of Female Sexual Function (IFSF) to assess sexual function; (2) the Beck Depression Inventory (BDI) (Chinese version) to rate the severity of depressive symptoms; and (3) the 36-item Short Form Health Survey Questionnaire (SF-36, Taiwan Standard Version 1.0) to survey their quality of life. RESULTS A total of 138 female patients were enrolled into further analysis. The mean age was 48.7 +/- 11.2 years old. The mean IFSF score was 24.5 +/- 9.3. Age, BDI score, and serum triglyceride levels were the independent factors of dysfunction in each sexual functional dimension. Patients with higher IFSF scores had significantly higher scores in physical functioning and mental health (P= 0.007 and 0.018, respectively). Patients with higher intercourse satisfaction had significantly higher general health scores (P= 0.001). CONCLUSION Sexual dysfunction is frequent in the female hemodialysis population. It is strongly associated with increasing age, dyslipidemia, and depression. The subjects with sexual dysfunction had poorer quality of life. The diagnosis and treatment of sexual dysfunction should be included in the clinical assessment.

The safety profile of ustekinumab in the treatment of patients with psoriasis and concurrent hepatitis B or C

Ustekinumab, an interleukin (IL)‐12 and IL‐23 blocker, has emerged as a new therapeutic option for patients with psoriasis. It is generally well tolerated but safety data on the use of ustekinumab in patients with viral hepatitis are limited.

Immunochemical characterization of Na+/H+exchanger isoform NHE4

Mammalian Na+/H+exchangers (NHEs) are a family of transport proteins (NHE1-NHE5). To date, the cellular and subcellular localization of NHE4 has not been characterized using immunochemical techniques. We purified a fusion protein containing a portion of rat NHE4 (amino acids 565-675) to use as immunogen. A monoclonal antibody (11H11) was selected by ELISA. It reacted specifically with both the fusion protein and to a 60- to 65-kDa polypeptide expressed in NHE4-transfected LAP1 cells. By Western blot analysis, NHE4 was identified as a 65- to 70-kDa protein that was expressed most abundantly in stomach and in multiple additional epithelial and nonepithelial rat tissues including skeletal muscle, heart, kidney, uterus, and liver. Subcellular localization of NHE4 in the kidney was evaluated by Western blot analysis of membrane fractions isolated by Percoll gradient centrifugation. NHE4 was found to cofractionate with the basolateral markers NHE1 and Na+-K+-ATPase rather than the luminal marker γ-glutamyl transferase. In stomach, NHE4 was detected by immunoperoxidase labeling on the basolateral membrane of cells at the base of the gastric gland. We conclude that NHE4 is a 65- to 70-kDa protein with a broad tissue distribution. In two types of epithelial cells, kidney and stomach, NHE4 is localized to the basolateral membrane.

The 90-day mortality and the subsequent renal recovery in critically ill surgical patients requiring acute renal replacement therapy.

BACKGROUND Particular attention should be paid to postoperative patients that suffer from severe acute kidney injury (AKI) requiring renal replacement therapy (RRT). METHODS This multicenter prospective observational study included 342 patients with postoperative AKI requiring RRT from January 2002 to December 2006. RESULTS There were 137 (40%) survivors at 90 days after the commencement of RRT. Independent predictors of 90-day mortality were older age, presence of sepsis, status post-cardiopulmonary resuscitation, necessity of continuous renal replacement therapy (CRRT), requirement of total parenteral nutrition, lower body mass index, higher Sequential Organ Failure Assessment score, and higher serum lactate level at the commencement of RRT. Further analysis among the survivors showed that lower serum creatinine at intensive care unit admission, lower Simplified Acute Physiology Score II and inotropic equivalent score at the commencement of RRT, and using CRRT were independent predictors for subsequent renal recovery. CONCLUSIONS The development of AKI requiring RRT in postoperative critical patients represents a substantial risk for mortality and morbidity.

Comparison of residual renal function in patients undergoing twice-weekly versus three-times-weekly haemodialysis

Aim:  Patients with end‐stage renal disease (ESRD) often start long‐term haemodialysis (HD) thrice weekly, regardless of the level of residual renal function (RRF). In this study, we investigated whether ESRD patients having sufficient RRF can be maintained on twice‐weekly HD, and how they fare compared to patients without RRF on thrice‐weekly HD.

Repetitive Hypoxic Preconditioning Attenuates Renal Ischemia/reperfusion Induced Oxidative Injury via Upregulating Hif-1α–dependent bcl-2 Signaling

Background. In response to ischemic/hypoxic preconditioning, tissues/organs exhibit protective responses to subsequent and severe ischemic stress. We hypothesized that repetitive hypoxic preconditioning (RHP) may provide long-lasting protection than single preconditioning against ischemia/reperfusion injury in rat kidneys through hypoxia-induced factor (HIF)-1-dependent pathway. Methods. For RHP induction, female Wistar rats were subjected to intermittent hypoxic exposure (380 Torr) 15 hr/day for 28 days. Results. RHP increased renal HIF-1&agr; mRNA and protein expression and triggered HIF-1&agr;-dependent renal Bcl-2 protein expression in a time-dependent manner. When returning to normoxia, increased RHP exposure prolonged renal Bcl-2 expression. Forty-five minutes of renal ischemia with 4 hr of reperfusion enhanced O2−· levels and proapoptotic mechanisms, including enhanced cytosolic Bax translocation to mitochondria, release of cytochrome c to cytosol, activation of caspase 3, poly-(ADP-ribose)-polymerase fragments, tubular apoptosis, blood urea nitrogen, and creatinine level. RHP treatment depressed renal O2−· production, mitochondrial Bax translocation and cytochrome c release, and tubular apoptosis. In the primary tubular cultures from RHP-treated kidneys, antisense oligodeoxyribonucleotides of bcl-2 abrogated this protection. Conclusions. RHP activates an HIF-1&agr;-dependent signaling cascade leading to an increase in Bcl-2 protein expression, an inhibition in cytosolic Bax and mitochondrial cytochrome c translocation, and a hypoxic/ischemia tolerance against renal ischemia/reperfusion injury.

Hypoxic preconditioning enhances renal superoxide dismutase levels in rats

Renal ischaemia releases reactive oxygen species (ROS) in the kidneys. We hypothesized that the kidneys are more resistant to the insult of ROS in chronically hypoxic rats. We thus compared rats kept at sea level (SL) and those that had been adapted to hypoxia (hypoxia adapted, HA) by exposure to an altitude of 5500 m in an altitude chamber for 15 h day−1 for 4 weeks. Xanthine (X, 0.75 mg kg−1) and xanthine oxidase (XO, 24.8 mU kg−1) were injected intrarenally. A lucigenin‐enhanced chemiluminescence method was employed to detect the amount of free radicals in renal venous blood samples and on the kidney surface. In the renal venous blood samples, 26.05 (± 4.36) × 104 and 10.98 (± 1.79) × 104 counts were detected in the SL and HA rats, respectively, after X‐XO treatment; these figures were significantly different. On the kidney surface of the SL rats, the free radical count amounted to 12.77 (± 1.64) × 104, while that in the HA rats was 8.47 (± 0.42) × 104; these figures were also significantly different. There was a significant increase in urine volume and urinary excretion of Na+, K+ and protein after X‐XO administration in both groups of rats. However, the effect was greater for the SL rats than for the HA rats. The lipid peroxidation of the kidneys was not significantly different in the two groups of rats. Finally, we found that the activity of superoxide dismutase (SOD) and SOD mRNA were higher in the renal tissue of HA rats. We conclude that the renal response to free radicals is attenuated after chronic hypoxia in rats, and that SOD might play an important role in protecting HA rats from oxidative stress.

Sustained low-efficiency dialysis versus continuous veno-venous hemofiltration for postsurgical acute renal failure

BACKGROUND In postsurgical acute renal failure patients with moderate unstable hemodynamics or fluid overload, the choice of dialysis modality is difficult. This study was performed to compare the outcomes between the sustained low-efficiency dialysis (SLED) and continuous veno-venous hemofiltration (CVVH) in these patients. METHODS Sequential postsurgical acute renal failure patients undergoing acute dialysis with CVVH (2002-2003), or SLED (2004-2005) as a result of severe fluid overload or moderately unstable hemodynamics were analyzed. Multivariate analyses of comorbidity, disease severity before initiating dialysis, biochemical measurements, and hemodynamic parameters for 3 days after the first dialysis session were performed by fitting multiple logistic regression models to predict patients 30-day after hospital discharge (AHD) mortality. RESULTS Among the 101 recruited patients, 38 received SLED and the rest received CVVH. The 30-day AHD mortality was 62.4%. The independent risk factors of 30-day AHD mortality included older age (P = .008), lower first postdialysis mean arterial pressure (MAP) (P = .021), higher first postdialysis blood urea nitrogen level (P = .009), and absence of a history of hypertension (P = .002). A further linear regression analysis found that dialysis using SLED was associated with higher first postdialysis MAP (P = .003). CONCLUSIONS Among the postsurgical patients requiring acute dialysis with severe fluid overload or moderately unstable hemodynamics, the patients treated with SLED had a higher first postdialysis MAP than those treated with CVVH, which led to lower mortality. Further multicenter randomized clinical trials of larger sample size are needed to compare the effects of SLED and CVVH on the outcomes of postsurgical acute dialysis patients.

Advanced age affects the outcome-predictive power of RIFLE classification in geriatric patients with acute kidney injury.

The RIFLE (risk, injury, failure, loss, and end-stage) classification is widely used to gauge the severity of acute kidney injury, but its efficacy has not been formally tested in geriatric patients. To correct this we conducted a prospective observational study in a multicenter cohort of 3931 elderly patients (65 years of age or older) who developed acute kidney injury in accordance with the RIFLE creatinine criteria after major surgery. We studied the predictive power of the RIFLE classification for in-hospital mortality and investigated the potential interaction between age and RIFLE classification. In general, the survivors were significantly younger than the nonsurvivors and more likely to have hypertension. In patients 76 years of age and younger, RIFLE-R, -I, or -F classifications were significantly associated with increased hospital mortality in a stepwise manner. There was no significant difference, however, in hospital mortality in those over 76 years of age between patients with RIFLE-R and RIFLE-I, although RIFLE-F patients had significantly higher mortality than both groups. Thus, the less severe categorizations of acute kidney injury per RIFLE classification may not truly reflect the adverse impact on elderly patients.