Yayoi Shiotsu

Plasma S100A12 Level Is Associated with Cardiovascular Disease in Hemodialysis Patients

BACKGROUND AND OBJECTIVES S100A12 is an endogenous receptor ligand for advanced glycation end products. Cardiovascular disease remains a major cause of morbidity and mortality in patients with chronic kidney disease. In this study, we report cross-sectional data on 550 hemodialysis patients and assess the relationship between plasma S100A12 level and cardiovascular disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A cross-sectional study of 550 maintenance hemodialysis patients was conducted. We investigated the past history of cardiovascular disease and quantified the plasma level of S100A12 protein in all participants. RESULTS Plasma S100A12 level was higher in hemodialysis patients with cardiovascular disease (n=197; 33.8 ± 28.1 ng/ml) than in those without it (n=353; 20.2 ± 16.1 ng/ml; P<0.001). In multivariate logistic regression analysis, the plasma S100A12 level (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.13 to 1.44; P<0.001) was identified as an independent factor associated with the prevalence of cardiovascular disease. The other factors associated with the prevalence of cardiovascular diseases were the presence of diabetes mellitus (OR, 2.81; 95% CI, 1.79 to 4.41; P < 0.001) and high-sensitivity CRP level (OR, 1.02; 95% CI, 1.00 to 1.05; P=0.046). Furthermore, the plasma S100A12 level (OR, 1.30; 95% CI, 1.09 to 1.54; P=0.004) was significantly associated with cardiovascular disease even in hemodialysis patients without diabetes mellitus (n=348). CONCLUSIONS These results suggest that the plasma S100A12 protein level is strongly associated with the prevalence of cardiovascular disease in hemodialysis patients.

The kinase Pyk2 is involved in renal fibrosis by means of mechanical stretch-induced growth factor expression in renal tubules

Unilateral ureteral obstruction is a well-established experimental model of progressive renal fibrosis. We tested whether mechanical stretch and subsequent renal tubular distension might lead to renal fibrosis by first studying renal tubular epithelial cells in culture. We found that mechanical stretch induced reactive oxygen species that in turn activated the cytoplasmic proline-rich tyrosine kinase-2 (Pyk2). This kinase is abundantly expressed in tubular epithelial cells where it is activated by several stimuli. Using mice with deletion of Pyk2 we found that the expression of transforming growth factor-β1 induced by mechanical stretch in renal tubular epithelial cells was significantly reduced. The expression of connective tissue growth factor was also reduced in the Pyk2(-/-) mice. We also found that expression of connective tissue growth factor was independent of transforming growth factor-β1, but dependent on the Rho-associated coiled-coil forming protein kinase pathway. Thus, Pyk2 may be an important initiating factor in renal fibrosis and might be a new therapeutic target for ameliorating renal fibrosis.

Direct Aldosterone Action as a Profibrotic Factor via ROS-Mediated SGK1 in Peritoneal Fibroblasts

Background/Aims: Peritoneal fibrosis leads to discontinuation of peritoneal dialysis. Although aldosterone promotes tissue fibrosis in many organs, its contribution to peritoneal fibrosis and the underlying mechanism are poorly understood. The present study investigated the direct effect of aldosterone on cultured rat peritoneal fibroblasts (RPFs). Methods: The expression of aldosterone synthase (CYP11B2), mineralocorticoid receptors (MRs), 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), serum- and glucocorticoid-inducible protein kinase 1 (SGK1), and connective tissue growth factor (CTGF) mRNA was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR). To determine the role of reactive oxygen species (ROS) induced by aldosterone, an active oxygen assay with several inhibitors was used. The ability of RPFs to produce aldosterone was examined by enzyme immunoassay. Small interfering RNA (siRNA) of SGK1 was transfected into cultured cells using lipofectamine. Results: CYP11B2, MRs, and 11β-HSD2 were expressed in RPFs. The release of aldosterone from RPFs into the culture medium was confirmed. Aldosterone increased the expression of SGK1 mRNA via ROS generation. Spironolactone, apocynin, and tempol significantly reduced SGK1 expression. Aldosterone upregulated CTGF transcripts significantly. SGK1 gene silencing suppressed aldosterone-induced CTGF expression. Conclusion: The local aldosterone system acts directly as a profibrotic factor via ROS-mediated SGK1 in RPFs.

Plasma S100A12 Levels and Peripheral Arterial Disease in End-Stage Renal Disease

Background: S100A12 is an endogenous ligand of the receptor for advanced glycation end products (RAGE). Plasma S100A12 levels are high in end-stage renal disease (ESRD) patients undergoing maintenance hemodialysis (HD). Peripheral arterial disease (PAD) is common in HD patients and is associated with increased cardiovascular morbidity and mortality rates in this population. To date, however, no study has specifically assessed the relationship between plasma S100A12 and PAD in HD patients. Methods: We conducted a cross-sectional study of 152 HD patients in our affiliated hospital. We investigated PAD history and patient characteristics and quantified plasma S100A12 levels in all participants. Results: HD patients with PAD (n = 26; 21.9 [13.6–33.4] ng/ml) showed significantly higher plasma S100A12 levels than HD patients without PAD (n = 126; 11.8 [7.5–17.6]ng/ml; p < 0.001). In multivariate logistic regression analysis, the plasma S100A12 level (odds ratio [OR] 5.71; 95% confidence interval [CI] 1.29–25.3; p = 0.022) was identified as an independent factor associated with PAD prevalence. Another factor associated with PAD prevalence was the ankle-brachial index (OR 0.54; 95% CI 0.40–0.74; p < 0.001). Conclusion: These results suggest that plasma S100A12 levels are strongly associated with PAD prevalence in ESRD patients undergoing HD.

Prognostic utility of plasma S100A12 levels to establish a novel scoring system for predicting mortality in maintenance hemodialysis patients: a two-year prospective observational study in Japan

BackgroundS100A12 protein is an endogenous receptor ligand for advanced glycation end products. In this study, the plasma S100A12 level was assessed as an independent predictor of mortality, and its utility in clinical settings was examined.MethodsIn a previous cross-sectional study, plasma S100A12 levels were measured in 550 maintenance hemodialysis patients to determine the association between S100A12 and the prevalence of cardiovascular diseases (CVD). In this prospective study, the risk of mortality within a two-year period was determined. An integer scoring system was developed to predict mortality on the basis of the plasma S100A12 levels.ResultsHigher plasma S100A12 levels (≥18.79 ng/mL) were more closely associated with higher all-cause mortality than lower plasma S100A12 levels (<18.79 ng/mL; P = 0.001). Multivariate Cox proportional hazards analysis revealed higher plasma S100A12 levels [hazard ratio (HR), 2.267; 95% confidence interval (CI), 1.195–4.302; P = 0.012], age ≥65 years (HR, 1.961; 95%CI, 1.017–3.781; P = 0.044), serum albumin levels <3.5 g/dL (HR, 2.198; 95%CI, 1.218–3.968; P = 0.012), and history of CVD (HR, 2.068; 95%CI, 1.146–3.732; P = 0.016) to be independent predictors of two-year all-cause mortality. The integer score was derived by assigning points to these factors and determining total scores. The scoring system revealed trends across increasing scores for predicting the all-cause mortality [c-statistic = 0.730 (0.656–0.804)]. The resulting model demonstrated good discriminative power for distinguishing the validation population of 303 hemodialysis patients [c-statistic = 0.721 (0.627–0.815)].ConclusionThe results indicate that plasma S100A12 level is an independent predictor for two-year all-cause mortality. A simple integer scoring system was therefore established for predicting mortality on the basis of plasma S100A12 levels.

A Japanese Family Suffering from Familial Juvenile Hyperuricemic Nephropathy due to a Rare Mutation of the Uromodulin Gene.

We report the case of a Japanese family suffering from familial juvenile hyperuricemic nephropathy (FJHN) due to a rare missense mutation of the uromodulin (UMOD) gene. An 18-year-old male presented with gout, hyperuricemia, and stage 3 chronic kidney disease. Mostly, FJHN is caused by a mutation altering the cystine residue of UMOD/Tamm-Horsfall protein. However, in the present case, a T688C mutation was identified in exon 4, resulting in amino acid substitution with arginine replacing tryptophan at position 230 (Trp230Arg). This mutation was also found in his brother and father with the same phenotype, indicating autosomal dominant inheritance. The affected amino acid was conserved in 200 healthy Japanese controls. Therefore, mutation T688C most likely causes rare structural and/or functional abnormalities in UMOD/Tamm-Horsfall protein.

Comprehensive renoprotective effects of ipragliflozin on early diabetic nephropathy in mice

Clinical and experimental studies have shown that sodium glucose co-transporter 2 inhibitors (SGLT2i) contribute to the prevention of diabetic kidney disease progression. In order to clarify its pharmacological effects on the molecular mechanisms underlying the development of diabetic kidney disease, we administered different doses of the SGLT2i, ipragliflozin, to type 2 diabetic mice. A high-dose ipragliflozin treatment for 8 weeks lowered blood glucose levels and reduced urinary albumin excretion. High- and low-dose ipragliflozin both inhibited renal and glomerular hypertrophy, and reduced NADPH oxidase 4 expression and subsequent oxidative stress. Analysis of glomerular phenotypes using glomeruli isolation demonstrated that ipragliflozin preserved podocyte integrity and reduced oxidative stress. Regarding renal tissue hypoxia, a short-term ipragliflozin treatment improved oxygen tension in the kidney cortex, in which SGLT2 is predominantly expressed. We then administered ipragliflozin to type 1 diabetic mice and found that high- and low-dose ipragliflozin both reduced urinary albumin excretion. In conclusion, we confirmed dose-dependent differences in the effects of ipragliflozin on early diabetic nephropathy in vivo. Even low-dose ipragliflozin reduced renal cortical hypoxia and abnormal hemodynamics in early diabetic nephropathy. In addition to these effects, high-dose ipragliflozin exerted renoprotective effects by reducing oxidative stress in tubular epithelia and glomerular podocytes.

Unusual Proliferative Glomerulonephritis in a Patient Diagnosed to Have Hypoparathyroidism, Sensorineural Deafness, and Renal Dysplasia (HDR) Syndrome with a Novel Mutation in the GATA3 Gene.

Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome is a rare autosomal dominant disease caused by GATA3 mutations. Although several cases with variable renal features have been reported, the presence of histological changes within the glomeruli in adult patients is unclear. We herein report an adult case of HDR syndrome with a novel p.C288W (TGC>TGG) missense mutation in GATA3. His renal histology showed a membranoproliferative glomerulonephritis-like glomerular lesion. Additional renal histological analyses of HDR syndrome patients will be needed to clarify the role of GATA3 in both the developing and adult kidney.

Association between Hemoglobin Concentration and the Progression or Development of Albuminuria in Diabetic Kidney Disease

Aims Anemia, which might contribute to pathogenesis of kidney dysfunction, is a common finding in patients with type 2 diabetes. The aim of this study was to investigate if hemoglobin concentration is associated with the degree of change in urinary albumin-creatinine ratio or the development of albuminuria in patients with type 2 diabetes. Methods We measured hemoglobin concentration in 470 (296 men and 174 women) consecutive type 2 diabetic patients without albuminuria. We performed a follow-up study to assess the progression or development of albuminuria, the interval of which was 3.0 years. Then we evaluated relationships between hemoglobin concentration and albuminuria, using multivariate linear regression analyses and logistic regression analyses. Results Eighty four patients developed albuminuria during follow-up duration. In multivariate analyses, hemoglobin concentration was negatively associated with a change in urinary albumin-creatinine ratio in men (ß = -0.259, P = 0.0002) and women (ß = -0.194, P = 0.030). Moreover, multivariate adjusted odds ratio associated with 1 g/L in hemoglobin for the development of albuminuria was 0.93 (95% confidence interval; 0.89-0.96) in men and 0.94 (95% confidence interval; 0.88-0.99) in women, respectively. And, multivariate analyses revealed that adjusted odds ratios for the development of albuminuria were 4.78 (95% confidence interval; 1.65-13.91) in men and 4.62 (95% confidence interval; 1.34-16.68) in women with anemia (hemoglobin < 130 g/L for men and < 120 g/L for women), which were higher than those without anemia. Conclusions Low hemoglobin concentration could be a predictor for the progression and development of albuminuria in patients with type 2 diabetes.

Cerebral Salt-wasting Syndrome and Inappropriate Antidiuretic Hormone Syndrome after Subarachnoid Hemorrhaging

Hyponatremia is a common finding after subarachnoid hemorrhaging (SAH) and can be caused by either cerebral salt-wasting syndrome (CSWS) or syndrome of inappropriate antidiuretic hormone (SIADH). Distinguishing between these two entities can be difficult because they have similar manifestations, including hyponatremia, serum hypo-osmolality, and high urine osmolality. We herein report the case of a 60-year-old man who suffered from SAH complicated by hyponatremia. During his initial hospitalization, he was diagnosed with CSWS. He was readmitted one week later with hyponatremia and was diagnosed with SIADH. This is the first report of SAH causing CSWS followed by SIADH. These two different sources of hyponatremia require different treatments.