Hung-Chun Chen

Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells

Advanced glycation end‐product (AGE) is important in the pathogenesis of diabetic nephropathy (DN), and captopril (an angiotensin converting enzyme inhibitor) is effective in treating this disorder. We have shown that the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) cascade is responsible for AGE‐induced mitogenesis in NRK‐49F (normal rat kidney fibroblast) cells, but its role in renal fibrosis in DN remains unknown. Therefore, we have sought to determine whether JAK/STAT is involved in AGE‐regulated collagen production in NRK‐49F cells. We found that AGE time (1–7 days) and dose (10–200 μg/ml)‐dependently increased collagen production in these cells. Additionally, AGE increased RAGE (receptor for AGE) protein expression. AGE‐induced RAGE expression was dose‐dependently inhibited by antisense RAGE oligodeoxynucleotide (ODN) and captopril. AGE‐induced type I collagen production and JAK2‐STAT1/STAT3 activation were decreased by AG‐490 (a specific JAK2 inhibitor), antisense RAGE ODN and captopril. Meanwhile, STAT1 and STAT3 decoy ODNs also suppressed the induction of collagen by AGE. We concluded that RAGE and the JAK2‐STAT1/STAT3 pathway were involved in AGE‐induced collagen production in NRK‐49F cells. Furthermore, captopril was found to reverse AGE‐induced collagen production, probably by attenuating RAGE expression and JAK2‐STAT1/STAT3 activities. J. Cell. Biochem. 81:102–113, 2001.

Epidemiology, impact and preventive care of chronic kidney disease in Taiwan

Chronic kidney disease (CKD) has emerged as a global public health burden. Taiwan has the highest incidence and prevalence rates of end‐stage renal disease (ESRD) in the world. In this review, the following key issues of CKD in Taiwan are addressed: epidemiological data, underlying diseases patterns, risk factors, public health concerns and a preventive project. Prevalence of CKD are reported to be 6.9% for CKD stage 3–5, 9.83% for clinically recognized CKD and 11.9% for CKD stage 1–5. However, overall awareness of CKD is low, 9.7% for CKD stage 1–3 and 3.5% for stage 1–5. Diabetes mellitus (43.2%), chronic glomerulonephritis (25.1%), hypertension (8.3%) and chronic interstitial nephritis (2.8%) are four major underlying renal diseases of ESRD. Older age, diabetes, hypertension, smoking, obesity, regular use of herbal medicine, family members (both relatives and spouses), chronic lead exposure and hepatitis C are associated with higher risk for CKD. Impact of CKD increases risk of all‐cause mortality and cardiovascular diseases, especially in those with overt proteinuria and advanced CKD stages. These impacts lead to increased medical costs. The nationwide CKD Preventive Project with multidisciplinary care program has proved its effectiveness in decreasing dialysis incidence, mortality and medical costs. It is crucially significant from Taiwan experience on CKD survey and preliminary outcome of the preventive project. Provision of a more comprehensive public health strategy and better care plan for CKD should be achieved by future international collaborative efforts and research.

Impact of the clinical conditions at dialysis initiation on mortality in incident haemodialysis patients: a national cohort study in Taiwan

BACKGROUND Glomerular filtration rate (GFR) and co-morbidity at dialysis initiation in relation to mortality in end-stage renal disease is still controversial. We studied factors potentially related to the mortality in incident haemodialysis (HD) patients. METHODS A national database included 23 551 incident HD patients from July 2001 to December 2004. Kaplan-Meier and Cox regression analyses were performed to assess the association between GFR estimated by the four-variable Modified Diet in Renal Disease equation and all-cause mortality. Analyses were performed from Day 91 after the start of dialysis. Patients were classified into five groups (quintiles) based on estimated glomerular filtration rate (eGFR) at the start of dialysis. RESULTS The median eGFR at dialysis initiation was low (4.7 mL/min/1.73 m(2)), as was the mortality in the first year of dialysis [13.2/100 patient-year, 95% confidence interval (95% CI) = 12.8-13.7]. There was an inverse association between lower eGFR and higher survival rate. The Cox regression model revealed an increase in mortality risk in Q5 (hazard ratio [HR] = 2.44, 95% CI = 2.11-2.81), Q4 (HR = 1.66, 95% CI = 1.43-1.93), Q3 (HR = 1.21, 95% CI = 1.04-1.41) and Q2 (HR = 1.18, 95% CI = 1.01-1.37) compared with the reference group of Q1 after adjusting for year of application, primary diseases (chronic glomerulonephritis, diabetic nephropathy, hypertension, chronic tubulointerstitial nephritis and others), demographics (age, sex), presence of co-morbidity (diabetes mellitus, hypertension, congestive heart failure, ischaemic heart diseases, cerebrovascular diseases, malignancies, liver cirrhosis, tuberculosis, other diseases and free of reported of co-morbidities) and haematocrit. Propensity score analysis also showed a higher eGFR to be associated with increased mortality risks. Adjustment for all covariates explained a high percentage of excess risk of mortality in the groups with low eGFR, but less risk in the groups with higher eGFR. CONCLUSIONS Lower eGFR at dialysis initiation is associated with lower mortality. Conditions at dialysis initiation explained excess 1-year mortality risk differently in patients who began dialysis at different levels of eGFR. Other factors likely contribute to the mortality of patients initiating dialysis at higher eGFR levels, and further study is needed.

Altering expression of α3β1 integrin on podocytes of human and rats with diabetes

Abstract The adhesion molecule integrin α3β1 is the major receptor of podocyte to the glomerular capillary basement membrane (GBM). Since progressive alteration of the glomerular extracellular matrix (ECM) compartment leading to GBM thickening is common in diabetic nephropathy, we investigated the cellular distribution of α3β1 integrin in podocytes of patients with diabetic nephropathy and streptozotocin-induced diabetic rats, and we evaluated the effects of high glucose on the cultured rat podocytes. Both human and rat kidneys were stained using the immunoelectron microscopy and immunoperoxidase technique with mouse monoclonal antibodies to human integrin α3 subunit. The results showed that both the number of immunogold particles and the staining of integrin α3 subunit on podocytes were weaker in patients with diabetic nephropathy than those of control kidneys. The staining of α3 on podocytes in the poorly-controlled diabetic rats was also weaker after one and three months of hyperglycemia. However, the staining was identical to controls in rats with only one week of hyperglycemia. High glucose (25 mM) but not streptozotocin in vitro suppressed the α3 expression of cultured rat podocytes. Our results demonstrated that the expression of integrin α3β1 on podocytes was suppressed in both human and rats with diabetes, possibly due to the effects of hyperglycemia, and the suppression became more severe with the duration of diabetes.

Impact of type 2 diabetes on manifestations and treatment outcome of pulmonary tuberculosis.

Diabetes mellitus (DM) is a known risk factor for pulmonary tuberculosis (PTB). This study aimed to determine if type 2 DM alters manifestations and treatment outcome of PTB. Records of 217 consecutive culture-proven PTB patients were analysed retrospectively. The manifestations and treatment outcomes of 74 patients with type 2 DM (PTB-DM group) were compared to 143 patients without DM (PTB group). PTB-DM patients showed higher frequencies of fever, haemoptysis, positive acid-fast bacilli sputum smears, and consolidation, cavity, and lower lung field lesions on chest radiographs, and higher mortality rate. Furthermore, type 2 DM, age 65 years, and extensive radiographic disease were factors independently associated with an unfavorable outcome. This study confirmed that clinical manifestations and chest radiographs of PTB patients associated with type 2 DM significantly depart from the typical presentation. Type 2 DM seems to have a negative effect on treatment outcome of PTB.

Association of Hyperuricemia with Renal Outcomes, Cardiovascular Disease, and Mortality

BACKGROUND AND OBJECTIVES Hyperuricemia is an independent risk factor for mortality, cardiovascular disease, and renal disease in general population. However, the relationship between hyperuricemia with clinical outcomes in CKD remains controversial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The study investigated the association between uric acid with all-cause mortality, cardiovascular events, renal replacement therapy, and rapid renal progression (the slope of estimated GFR was less than -6 ml/min per 1.73 m(2)/y) in 3303 stages 3-5 CKD patients that were in the integrated CKD care system in one medical center and one regional hospital in southern Taiwan. RESULTS In all subjects, the mean uric acid level was 7.9 ± 2.0 mg/dl. During a median 2.8-year follow-up, there were 471 (14.3%) deaths, 545 (16.5%) cardiovascular events, 1080 (32.3%) participants commencing renal replacement therapy, and 841 (25.5%) participants with rapid renal progression. Hyperuricemia increased risks for all-cause mortality and cardiovascular events (the adjusted hazard ratios for quartile four versus quartile one of uric acid [95% confidence interval] were 1.85 [1.40-2.44] and 1.42 [1.08-1.86], respectively) but not risks for renal replacement therapy (0.96 [0.79-1.16]) and rapid renal progression (1.30 [0.98-1.73]). CONCLUSIONS In stages 3-5 CKD, hyperuricemia is a risk factor for all-cause mortality and cardiovascular events but not renal replacement therapy and rapid renal progression.

Brachial-Ankle Pulse Wave Velocity and Rate of Renal Function Decline and Mortality in Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Increased arterial stiffness was reported to be associated with decreased estimated GFR (eGFR). Previous studies suggested that arterial stiffness might play a role in renal function progression in patients with chronic kidney disease (CKD). The aim of this study was to investigate whether there was an independent association between brachial-ankle pulse wave velocity (baPWV), a marker of arterial stiffness, and renal function progression in CKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This longitudinal study enrolled 145 patients with CKD stages 3 to 5. The baPWV was measured by using an ABI-form device. The change in renal function was estimated by eGFR slope. The study endpoints were defined as commencement of dialysis or death. RESULTS After a stepwise multivariate analysis, the eGFR slope was positively associated with baseline eGFR and negatively associated with hypertension and baPWV (β=-0.165, P=0.033). Seventeen patients entering dialysis, and eight deaths were recorded. Multivariate forward Cox regression analysis identified that higher baPWV (hazard ratio, 1.001; P=0.001), lower baseline eGFR, and higher serum phosphate level were independently associated with progression to commencement of dialysis or death. CONCLUSIONS Our results show an independent association between baPWV and renal function decline and progression to commencement of dialysis or death in patients with CKD. Screening CKD patients by means of baPWV may help identify a high-risk group of rapid renal function decline and progression to commencing dialysis or death.

Association of hepatitis C and B virus infection with CKD in an endemic area in Taiwan: a cross-sectional study.

BACKGROUND Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections may lead to nephropathy. However, the association between different types of viral hepatitis and chronic kidney disease (CKD) is not well established. STUDY DESIGN Cross-sectional study. SETTING & PARTICIPANTS A large-scale community study with 54,966 adults in a Taiwanese county endemic for HBV and HCV infection. PREDICTOR HCV infection alone, HBV infection alone, HBV/HCV coinfection, and neither. OUTCOMES Proteinuria (urine protein, >or=1+), low (<60 mL/min/1.73 m(2)) estimated glomerular filtration rate (eGFR), and CKD (proteinuria or eGFR <60 mL/min/1.73 m(2)). MEASUREMENTS HBV and HCV infection were defined as a seropositive test result for hepatitis B surface antigen and HCV antibody. Proteinuria was assessed using a repeated dipstick method. eGFR was computed using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation. RESULTS Mean age of the study group was 60.8 years. Prevalences of HCV infection alone, HBV infection alone, HBV/HCV coinfection, and neither were 9.4%, 9.9%, 0.9%, and 79.8%, respectively. 2,994 (5.4%), 7,936 (14.5%), and 9,602 (17.5%) participants had proteinuria, low eGFR, and CKD, respectively. Multivariate logistic regression analyses showed that HCV infection alone (OR, 1.26; 95% CI, 1.17-1.38), but not HBV infection alone (OR, 1.04; 95% CI, 0.96-1.14) or HBV/HCV coinfection (OR, 1.12; 95% CI, 0.87-1.45), was an independent risk factor for CKD. The prevalence of HCV seropositivity was higher in later CKD stages, changing from 8.5% in CKD stage 1 to 14.5% in CKD stages 4-5. Adjusted ORs for HCV infection alone were 1.14 (95% CI, 1.003-1.300) for proteinuria and 1.30 (95% CI, 1.20-1.42) for low eGFR. LIMITATIONS The definition of CKD status requires a 3-month duration of low eGFR or kidney damage; this was presumed, not documented, in this study. CONCLUSIONS HCV infection, but not HBV infection, was associated significantly with prevalence and disease severity of CKD in this HBV and HCV endemic area.

Echocardiographic parameters are independently associated with rate of renal function decline and progression to dialysis in patients with chronic kidney disease.

BACKGROUND AND OBJECTIVES Cardiac abnormalities were frequently noted in patients with chronic kidney disease (CKD). This study is designed to assess whether echocardiographic parameters are associated with rate of renal function decline and progression to dialysis in CKD stage 3 to 5 patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This longitudinal study enrolled 415 patients. The renal end point was defined as commencement of dialysis. The change in renal function was measured by estimated GFR (eGFR) slope. RESULTS Progression to dialysis was predicted by wide pulse pressure, low albumin, low hemoglobin, high calcium-phosphorous product, proteinuria, diuretics use, and concentric left ventricular hypertrophy (LVH) (hazard ratio, 2.03; 95% confidence interval [CI], 1.00 to 4.10; P = 0.05). The eGFR slope was negatively associated with total cholesterol, uric acid, proteinuria, diuretics use, and left atrial (LA) diameter (change in slope, -0.50; 95% CI, -0.89 to -0.11; P = 0.01) and positively associated with albumin and left ventricular ejection fraction (LVEF) (change in slope, 0.06; 95% CI, 0.03 to 0.08; P < 0.001). CONCLUSIONS Our study in patients of CKD stage 3 to 5 demonstrated that concentric LVH was associated with progression to dialysis, and that increased LA diameter and decreased LVEF were associated with faster renal function decline. Echocardiography may help identify high-risk groups with progressive decline in renal function to dialysis and rapid progression of renal dysfunction in CKD stage 3 to 5 patients.

Chronic kidney disease care program improves quality of pre‐end‐stage renal disease care and reduces medical costs

Aim:  Multidisciplinary care of patients with chronic kidney disease (CKD) provides better care outcomes. This study is to evaluate the effectiveness of a CKD care program on pre‐end‐stage renal disease (ESRD) care.