Ya-Hsueh Shih

Hyperuricemia as an independent risk factor of chronic kidney disease in middle-aged and elderly population.

Introduction:Hyperuricemia in the general population remains controversial, in terms of it being considered a risk factor for chronic kidney disease (CKD). Within this context, we evaluated the effects of hyperuricemia on renal function in older Taiwanese adults. Methods:From January 2002 to December 2006, we conducted a community-based medical screening program involving 31,331 subjects older than 40 years. According to the National Kidney Foundation guidelines, stage 3 to 5 patients with CKD were included for analysis. Age, body mass index, systolic blood pressure, fasting plasma glucose, triglyceride, cholesterol and proteinuria were considered potential confounders. Results:Participants with hyperuricemia tended to have higher systolic blood pressure, sugar levels, body mass index, and cholesterol and triglyceride levels but lower estimated glomerular filtration rate (eGFR) levels; eGFR negatively correlated with serum uric acid level. By using multiple logistic regression models before and after adjusting for any confounding factors, we noted that participants with hyperuricemia had a 4.036-fold (odds ratios = 4.036) and 3.649-fold (odds ratios = 3.649) increased risk for CKD, respectively, compared with the control group. We used multiple linear regression analysis to examine the association of serum uric acid level and eGFR at different stages of CKD; significance was found only in participants with stage 3 CKD and not in participants with stages 4 or 5. Conclusions:Hyperuricemia is an independent risk factor for CKD in middle-aged and elderly Taiwanese adults. Thus, an effective screening program that identifies people with hyperuricemia is warranted.

Hypertriglyceridemia: an independent risk factor of chronic kidney disease in Taiwanese adults.

Background:The prevalence and incidence of chronic kidney disease (CKD) are relatively high in Taiwanese patients than in patients of other countries, particularly in the older age groups. Dyslipidemia in patients with CKD has been recognized as a risk factor for disease progression but the role of triglycerides (TGs) remains controversial. With this regard, we evaluated the effects of hypertriglyceridemia on renal function in Taiwanese adults (aged ≥40 years). Methods:From January 2002 to December 2006, we conducted a community-based medical screening program in Chiayi County with 18,422 subjects (aged ≥40 years). The CKD was defined as an estimated glomerular filtration rate of <60 mL min 1.73 m2. Age, body mass index, systolic blood pressure, fasting plasma glucose, and serum total cholesterol were considered as potential confounders. Result:The CKD was prevalent in 24.2% of the middle-aged and elderly population. By using multiple logistic regression models, we determined that old age and elevated levels of body mass index, systolic blood pressure, fasting plasma glucose, and cholesterol were associated with CKD. The adjusted odds ratios of CKD in participants with serum TG ≧200 mg/dL was 1.901 (95% confidence interval: 1.07–3.36; P < 0.05) and in participants with serum TG > 500 mg/dL it increased to 2.205 (1.33–3.64, P < 0.05). Conclusion:Hypertriglyceridemia is an independent risk factor for CKD in Taiwanese adults. Thus, an effective screening program that identifies people with hypertriglyceridemia is warranted.

Curcumin Rescues Diabetic Renal Fibrosis by Targeting Superoxide-Mediated Wnt Signaling Pathways

ABSTRACT The purposes of this study were to investigate whether curcumin can weaken diabetic nephropathy by modulating both oxidative stress and renal injury from Wnt signaling mediation. Wnt5a/&bgr;‐catenin depression and induction of superoxide synthesis are associated with high glucose (HG) induced transforming growth factor (TGF)‐&bgr;1 and fibronectin expression in mesangial cells. Curcumin resumes HG depression of Wnt/&bgr;‐catenin signaling and alleviates HG induction of superoxide, TGF‐&bgr;1 and fibronectin expression in renal mesangial cell. Exogenous curcumin alleviated urinary total proteinuria and serum superoxide level in diabetic rats. Based on laser‐captured microdissection for quantitative real‐time polymerase chain reaction, it was found that diabetes significantly increased TGF‐&bgr;1 and fibronectin expression in line with depressed Wnt5a expression. Curcumin treatment reduced the TGF‐&bgr;1 and fibronectin activation and the inhibiting effect of diabetes on Wnt5a/&bgr;‐catenin expression in renal glomeruli. Immunohistochemistry showed that curcumin treatment significantly reduced 8‐hydroxy‐2′‐deoxyguanosine, TGF‐&bgr;1 and fibronectin, and was in line with the restoration of the suppressed Wnt5a expression immunoreactivities in glomeruli of diabetic rats. Curcumin alleviated extracellular matrix accumulation in diabetic nephropathy by not only preventing the diabetes‐mediated superoxide synthesis but also resuming downregulation of Wnt/&bgr;‐catenin signaling. These findings suggest that regulation of Wnt activity by curcumin is a feasible alternative strategy to rescue diabetic renal injury.

Induction of Proteinuria by Cannabinoid Receptors 1 Signaling Activation in CB1 Transgenic Mice

Abstract:Proteinuria is not only a sign of kidney damage but is also involved in the progression of renal disease as an independent pathologic factor. Although patients with mutated type 1 cannabinoid receptors (CB1) polymorphism are associated with renal microvascular damage, the biologic role of CB1 signaling in proteinuria remains uncharacterized till now. Herein, we investigate whether CB1 participates in glomerular proteinuria in CB1 transgenic mice and treatment with CB1 agonist WIN55212-2 rat, neither of which are diabetic models. The CB1 transgenic mice and rats treated with CB1 agonist WIN55212-2 had higher kidney weight and urinary protein concentrations but not blood glucose levels compared with the wild-type group. A combination of laser-capture microsdissection, quantitative reverse transcription–polymerase chain reaction, immunoblotting and immunohistochemical validation revealed that CB1 transgenic mice and rats treated with CB1 agonist WIN55212-2 had higher vascular endothelial growth factor (VEGF) expression in renal glomeruli than that of the wild-type group. Geneticorpharmacological activation of CB1 by transgenic CB1 mice or treatment with WIN55212-2 reduced nephrin expression in the renal glomeruli compared with that of the wild-type group in the glomerular mesanglium. Taken together, CB1 transgenic mice and rats treated with CB1 agonist WIN55212-2 induced proteinuria with upregulation of CB1 resulting in impaired nephrin expression, by inducing excess VEGF reaction in the renal glomeruli. Genetic and pharmacological manipulation of CB1 signaling revealed VEGF-dependent nephrin depression of glomerulopathy. Controlling CB1 activity can be used an alternative strategy for sustaining renal function in the presence of CB1 activation.

Protective effects of miR-29a on diabetic glomerular dysfunction by modulation of DKK1/Wnt/β-catenin signaling

Dysregulation of specific microRNAs or Wnt/β-catenin signaling pathway is critically implicated in the pathogenesis of various renal diseases. However, the relationship between microRNAs and Wnt/β-catenin signaling in diabetes-induced glomerular sclerosis remains unknown. Here, we found that decreased miR-29a expression and attenuated Wnt/β-catenin signaling were concomitantly detected in glomeruli of streptozotocin-induced diabetic mice. Gain of miR-29a function in diabetic mice substantially increased the expression of β-catenin and blocked the expressions of profibrotic gene markers, including DKK1 (a Wnt antagonist), TGF-β1 and fibronectin, in glomerular mesangium. Moreover, in the normal mice treated with miR-29a inhibitor, renal fibrosis was induced with an attenuated Wnt/β-catenin signaling activity. Consistently, the constructed miR-29a transgenic mice that supported sustained Wnt/β-catenin signaling had the ability to block the expressions of profibrotic genes after induction of diabetes. We also demonstrated that miR-29a acts as a positive regulator of Wnt/β-catenin signaling in cultured mesangial cells and functions to protect cell apoptosis and fibrosis. Importantly, we showed that activation of Wnt/β-catenin signaling in cultured mesangial cells by transfecting the β-catenin (Δ45) mutant or by a GSK-3β inhibitor reversely upregulated miR29a. Our findings suggest that the reciprocal relationship between miR-29a and DKK1/Wnt/β-catenin signaling may play an important part in protecting renal fibrogenesis.

Nitric oxide donors rescue diabetic nephropathy through oxidative-stress- and nitrosative-stress-mediated Wnt signaling pathways

The role of the renal nitric oxide (NO) system in the pathophysiology of diabetic nephropathy constitutes a very challenging and fertile field for future investigation. The purpose of the present study was to investigate whether NO donors can attenuate diabetic renal fibrosis and apoptosis through modulating oxidative‐ and nitrosative‐stress, and Wnt signaling using in vivo diabetic models.

Analgesic use, parents' clan, and coffee intake are three independent risk factors of chronic kidney disease in middle and elderly-aged population: a community-based study.

Abstract Chronic kidney disease (CKD) is a world-wide public health problem. The purpose of this study was to identify the role of some controversial potential risk factors in development of CKD. “Community Complex Health Screening” is a large-scale, free, health program for individuals ≥40 years of age that has been available since January 2002 in Chiayi County, Taiwan. A questionnaire was administered to study participants, collecting information on ethnicity, use of analgesics, and life habits. Age, sex, and blood biochemical analyses were considered as potential confounders. A high prevalence and low awareness of CKD were noted in this population. Females with CKD had a lower awareness of their illness than males. Analgesic users had a significantly lower estimated glomerular filtration rate (eGFR). Age (OR = 1.095), females (OR = 0.348), fasting plasma glucose (OR = 1.005), level of uric acid (UA) (OR = 1.517), and analgesic usage (OR = 1.512) remained independent predictors of CKD. Multivariate linear regression found that use of analgesics, father’ clan from Fujian, mother’ clan from Fujian, and coffee intake were independent determinants of renal outcome with coefficient of regression (β) of −0.102, −0.192, 0.210 and 0.88, respectively. The prevalence of CKD decreased with advanced education. Further, there was no significant difference between education background and analgesics use. In conclusion, analgesic use, parents’ clan, and coffee intake were independent risk factors for CKD in middle-aged and elderly Taiwanese. Thus, an effective educational program that increases the awareness of such individuals residing in rural counties is warranted.

Educational Intervention in CKD Retards Disease Progression and Reduces Medical Costs for Patients with Stage 5 CKD

Background: Nephrologist-based multidisciplinary care (MDC) has a positive impact on slowing chronic kidney disease (CKD) progression. However, the benefits of MDC in patients with stage 5 CKD remain unclear. Methods: Stage 5 CKD patients who visited the Chang Gung Memorial Hospital, Chiayi, Taiwan during the period of 2002–2008 were enrolled. The incident dialysis and medical cost were compared between MDC recipients and nonrecipients. The MDC recipients were divided into two groups by educational duration to observe the clinical renal outcome and medical care expenses. The effect of MDC on renal disease progression was also compared in MDC recipients with and without diabetes. Results: Out of 307 patients, 171 received MDC. For MDC recipients, the temporary usage of catheter was reduced (54.7% vs. 79.4%, p < 0.001), the hospital stay was shorter (18.64 ± 1.20 vs. 24.63 ± 1.22 months, p = 0.001), and the total medical cost was lower [New Taiwan dollars (NTD) 105,948.54 ± 9,967.22 vs. NTD 160,388.61 ± 16,373.97, p = 0.005] than for nonrecipients. Out of the 171 MDC recipients, those with MDC for more than 1 year had slower renal disease progression (0.76 ± 0.27 mL/min per 1.73 m2 per year) and had an estimated per- capita annual cost savings of about NTD 336,500.66. MDC recipients with diabetes had a higher risk of requiring dialysis than those without diabetes. Conclusions: MDC could significantly reduce temporary use of the catheter, hospital stay, and total medical costs in patients with stage 5 CKD. Furthermore, longer (>1 year) MDC could preserve renal function and deliver annual medical cost savings.

Association of Adiponectin with High-Sensitivity C-Reactive Protein and Clinical Outcomes in Peritoneal Dialysis Patients: A 3.5-Year Follow-Up Study.

Introduction Adiponectin (ADPN), one of most abundant fat-derived biologically active substances, plays an important role in anti-atherosclerotic process. There are conflicting results about the impact of ADPN on cardiovascular (CV) outcomes and mortality, particularly in patients undergoing peritoneal dialysis (PD). Moreover, the relationship between ADPN and inflammatory mediators has been seldom explored in this population. Therefore, we examined the relationship between ADPN and longitudinal high-sensitivity C-reactive protein (hs-CRP) changes and investigated whether ADPN or hs-CRP levels could predict CV outcomes and mortality in prevalent PD patients after comprehensive adjustment of possible confounders. Methods In this prospective cohort study, 78 PD patients were enrolled and followed from February 2009 to August 2012. During follow-up, CV events and all-cause mortality were recorded. Results The mean baseline ADPN value was 29.46±18.01 μg/ml and duration of PD treatment was 37.76±36.96 months. In multiple linear regression analysis, plasma ADPN levels positively correlated with high-density lipoprotein and negatively associated with hs-CRP, body mass index, D4/D0 glucose, triglyceride, and duration of PD treatment. After stratified by genders, the inverse association between baseline ADPN and hs-CRP was more significant in the female group. The hs-CRP levels were followed up annually and remained significantly lower in the high ADPN group in the first 2 years. Patients were then stratified into two groups according to the median ADPN value (23.8 μg/ml). The results of Kaplan-Meier survival analysis demonstrated less CV events and better survival in high ADPN group. On multivariate Cox regression analysis, only ADPN level (HR: 0.93, 95% CI: 0.88–0.98, p = 0.02), age and history of CV diseases were independent risk factors for future CV events. Furthermore, hs-CRP (HR: 1.11, 95% CI:1.001–1.22, p = 0.04) was identified as independent predictor of all-cause mortality. Conclusions Serum hs-CRP levels were consistently lower in the high ADPN group during 2-year follow-up. We also demonstrated the importance of ADPN and hs-CRP in predicting CV events and all-cause mortality in PD population during 3.5-year follow-up.

Trichostatin A ameliorates renal tubulointerstitial fibrosis through modulation of the JNK-dependent Notch-2 signaling pathway

Renal fibrosis is the final common pathological feature in a variety of chronic kidney disease. Trichostatin A (TSA), a histone deacetylase inhibitor, reportedly attenuates renal fibrosis in various kidney disease models. However, the detailed molecular action of TSA in ameliorating renal fibrotic injury is not yet fully understood. In a cultured renal fibroblastic cell model, we showed that TGF-β1 triggers upregulation of α-SMA and fibronectin, two hallmarks of myofibroblastic activation. During the course of TGF-β1 treatment, activation of Smad2/3, p38, ERK, JNK and Notch-2 was also detected. Under the conditions, administration of TSA significantly decreased TGF-β1-stimulated expression of α-SMA, fibronectin, phospho-JNK, and cleaved Notch-2; however, the levels of phospho-Smad2/3, phospho-p38 and phospho-ERK remained unchanged. Pharmacological inhibition of different signaling pathways and genetic knockdown of Notch-2 further revealed JNK as an upstream effector of Notch-2 in TGF-β1-mediated renal fibrosis. Consistently, we also demonstrated that administration of TSA or a γ-secretase inhibitor RO4929097 in the mouse model of unilateral ureteral obstruction significantly ameliorated renal fibrosis through suppression of the JNK/Notch-2 signaling activation. Taken together, our findings provide further insights into the crosstalk among different signaling pathways in renal fibrosis, and elucidate the molecular action of TSA in attenuating fibrogenesis.