Chih-Kang Chiang

Indoxyl sulfate, a representative uremic toxin, suppresses erythropoietin production in a HIF-dependent manner

Advanced chronic kidney disease (CKD) patients encounter anemia through insufficient erythropoietin (EPO) production by peritubular fibroblasts. Recent studies showed an increase in EPO production by pharmacological activation of hypoxia-inducible transcription factors (HIFs) in dialysis patients, suggesting that desensitization of the oxygen-sensing mechanism is responsible for the development of renal anemia. Our recent work demonstrated that indoxyl sulfate (IS), a uremic toxin, dysregulates oxygen metabolism in tubular cells. Here we provide evidence of an additional property that IS impairs oxygen sensing in EPO-producing cells. HepG2 cells were stimulated with cobalt chloride (CoCl2) or hypoxia under varying concentrations of IS. EPO mRNA was evaluated by quantitative PCR. Nuclear accumulation of HIF-α was evaluated by western blotting. Transcriptional activity of HIF was checked by hypoxia-responsive element (HRE)-luciferase reporter assay. The impact of IS was further evaluated in vivo by administering rats with indole, a metabolic precursor of IS, and subjecting them to CoCl2 stimulation, in which renal EPO mRNA as well as plasma EPO levels were measured by quantitative PCR and enzyme-linked immunosorbent assay, respectively. Although IS induced cellular toxicity at relatively high concentrations (⩾2.5 mM), EPO mRNA expression was significantly suppressed by IS at concentrations below cytotoxic ranges. In HepG2 cells, IS treatment decreased nuclear accumulation of HIF-α proteins and suppressed HRE-luciferase activity following hypoxia. Furthermore, administration of rats with indole suppressed renal EPO mRNA expression and plasma EPO levels, corroborating in vitro findings. Results of the present study provide a possible connection between a uremic toxin and the desensitization of the oxygen-sensing mechanism in EPO-producing cells, which may partly explain inadequate EPO production in hypoxic kidneys of CKD patients.

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.

Metabolic Syndrome and Insulin Resistance as Risk Factors for Development of Chronic Kidney Disease and Rapid Decline in Renal Function in Elderly

CONTEXT Studies addressing the association of metabolic syndrome and insulin resistance with the risks of incident chronic kidney disease (CKD) and the progression of renal function were either lacking or inconclusive. OBJECTIVE The aim of this study was to define the effect of metabolic syndrome and insulin resistance on the development of new CKD and the decline in renal function. DESIGN AND SETTING A prospective cohort study was conducted at a tertiary university-based hospital in Taiwan. PATIENTS AND OTHER PARTICIPANTS We studied a total of 1456 Asians 65 or older who were followed for an average of 3.15 yr. Within the cohort, we measured insulin resistance using the homeostasis model assessment formula in 652 nondiabetic participants. INTERVENTIONS There were no interventions. MAIN OUTCOME MEASURES We measured the prevalence and incidence of CKD and the annual decline of the estimated glomerular filtration rate. RESULTS We found that the adjusted odds ratio for prevalent CKD in association with metabolic syndrome was 1.778 (95% confidence interval, 1.188 to 2.465), the hazard ratio for rapid decline in renal function was 1.042 (0.802-1.355), and the hazard ratio for incident CKD was 1.931 (1.175-3.174). With each one-unit increment of insulin resistance, the odds ratio of prevalent CKD and proteinuria were raised 1.312-fold (1.114 to 1.545) and 1.278-fold (1.098 to 1.488), respectively. Insulin resistance was not associated with incident CKD. Increment of insulin resistance per unit was associated with 1.16-fold (1.06 to 1.26) elevation in the hazard ratios of the decline in renal function. CONCLUSIONS Metabolic syndrome predicts the risks of prevalent and incident CKD, whereas insulin resistance is associated with prevalent CKD and rapid decline in renal function in elderly individuals.

Endoplasmic reticulum stress implicated in the development of renal fibrosis.

Endoplasmic reticulum (ER) stress-associated apoptosis plays a role in organ remodeling after insult. The effect of ER stress on renal tubular damage and fibrosis remains controversial. This study aims to investigate whether ER stress is involved in tubular destruction and interstitial fibrosis in vivo. Renal cell apoptosis was proven by terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) stain and poly-ADP ribose polymerase expression in the unilateral ureteral obstruction (UUO) kidney. ER stress was evoked and confirmed by the upregulation of glucose-regulated protein 78 (GRP78) and the common Lys-Asp-Glu-Leu (KDEL) motif of ER retention proteins after UUO. ER stress-associated proapoptotic signals, including B-cell chronic lymphocytic leukemia (CLL)/lymphoma 2-associated × protein (BAX) expression, caspase-12 and c-Jun N-terminal kinase (JNK) phosphorylation, were activated in the UUO kidney. Prolonged ER stress attenuated both unsplicing and splicing X-box binding protein 1 (XBP-1) protein expression, but continued to activate inositol-requiring 1α (IRE1α)-JNK phosphorylation, protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2α subunit (eIF2α), activating transcription factor (ATF)-4, CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) and cleavage activating transcription factor 6 (cATF6)-CHOP signals, which induce ER stress-related apoptosis but attenuate adaptive unfolded protein responses in UUO kidneys. However, renal apoptosis and fibrosis were attenuated in candesartan-treated UUO kidney. Candesartan was associated with maintenance of XBP-1 expression and attenuated ATF4, cATF6 and CHOP protein expression. Taken together, results show that overwhelming ER stress leads to renal cell apoptosis and subsequent fibrosis; and candesartan, at least in part, restores renal integrity by blocking ER stress-related apoptosis. Reducing ER stress may present a way to attenuate renal fibrosis.

Inhibition of NADPH oxidase-related oxidative stress-triggered signaling by honokiol suppresses high glucose-induced human endothelial cell apoptosis.

Angiopathy is a major complication of diabetes. Abnormally high blood glucose is a crucial risk factor for endothelial cell damage. Nuclear factor-kappaB (NF-kappaB) has been demonstrated as a mediated signaling in hyperglycemia or oxidative stress-triggered apoptosis of endothelial cells. Here we explored the efficacy of honokiol, a small molecular weight natural product, on NADPH oxidase-related oxidative stress-mediated NF-kappaB-regulated signaling and apoptosis in human umbilical vein endothelial cells (HUVECs) under hyperglycemic conditions. The methods of morphological Hoechst staining and annexin V/propidium iodide staining were used to detect apoptosis. Submicromolar concentrations of honokiol suppressed the increases of NADPH oxidase activity, Rac-1 phosphorylation, p22(phox) protein expression, and reactive oxygen species production in high glucose (HG)-stimulated HUVECs. The degradation of IkappaBalpha and increase of NF-kappaB activity were inhibited by honokiol in HG-treated HUVECs. Moreover, honokiol (0.125-1 microM) also suppressed HG-induced cyclooxygenase (COX)-2 upregulation and prostaglandin E(2) production in HUVECs. Honokiol could reduce increased caspase-3 activity and the subsequent apoptosis and cell death triggered by HG. These results imply that inhibition of NADPH oxidase-related oxidative stress by honokiol suppresses the HG-induced NF-kappaB-regulated COX-2 upregulation, apoptosis, and cell death in HUVECs, which has the potential to be developed as a therapeutic agent to prevent hyperglycemia-induced endothelial damage.

Cognitive-Behavioral Therapy for Sleep Disturbance in Patients Undergoing Peritoneal Dialysis: A Pilot Randomized Controlled Trial

BACKGROUND Greater than 50% of dialysis patients experience sleep disturbances. Cognitive-behavioral therapy (CBT) is effective for treating chronic insomnia, but its effectiveness has never been reported in peritoneal dialysis (PD) patients and its association with cytokines is unknown. We investigated the effectiveness of CBT in PD patients by assessing changes in sleep quality and inflammatory cytokines. STUDY DESIGN Randomized control study with parallel-group design. SETTING & PARTICIPANTS 24 PD patients with insomnia in a tertiary medical center without active medical and psychiatric illness were enrolled. INTERVENTION The intervention group (N = 13) received CBT from a psychiatrist for 4 weeks and sleep hygiene education, whereas the control group (N = 11) received only sleep hygiene education. OUTCOMES & MEASUREMENTS Primary outcomes were changes in the Pittsburgh Sleep Quality Index and Fatigue Severity Scale scores, and secondary outcomes were changes in serum interleukin 6 (IL-6), IL-1beta, IL-18, and tumor necrosis factor alpha levels during the 4-week trial. RESULTS Median percentages of change in global Pittsburgh Sleep Quality Index scores were -14.3 (interquartile range, -35.7 to - 6.3) and -1.7 (interquartile range, -7.6 to 7.8) in the intervention and control groups, respectively (P = 0.3). Median percentages of change in global Fatigue Severity Scale scores were -12.1 (interquartile range, -59.8 to -1.5) and -10.5 (interquartile range, -14.3 to 30.4) in the intervention and control groups, respectively (P = 0.04). Serum IL-1beta level decreased in the intervention group, but increased in the control group (P = 0.04). There were no significant differences in changes in other cytokines. LIMITATIONS This study had a small number of participants and short observation period, and some participants concurrently used hypnotics. CONCLUSIONS CBT may be effective for improving the quality of sleep and decreasing fatigue and inflammatory cytokine levels. CBT can be an effective nonpharmacological therapy for PD patients with sleep disturbances.

Kidney impairment in primary aldosteronism

BACKGROUND Kidney impairment is noted in primary aldosteronism (PA), and probably initiated by glomerular hyperfiltration. METHODS A prospectively defined survey was conducted on 602 patients who were suspected of PA in the multiple-center Taiwan Primary Aldosteronism Investigation (TAIPAI) database. Estimated glomerular filtration rate (eGFR) was calculated and followed up at 1 yr after treatment. RESULTS The diagnosis of PA was confirmed in 330 patients. Among them 17% of these patients had kidney impairment (eGFR<60 ml/min/1.73 m²). Patients with PA had a higher prevalence of estimated hyperfiltration than those with essential hypertension (EH) (14.5% vs. 7.0%, p=0.005). The eGFR independently predicted PA (OR, 1.017) in the propensity-adjusted multivariate logistic model. In PA, plasma renin activity and lower serum potassium (p=0.018) was correlated with kidney impairment (p=0.001), while this relationship was not significant in patients with EH. Either unilateral adrenalectomy or treatment of spironolactone for PA patients caused a decrease of eGFR (p<0.001). Pre-operative hypokalemia (p=0.013) and the long latency of hypertension (p=0.016) could enhance the significant decrease of eGFR after adrenalectomy. CONCLUSIONS Patients with aldosteronism had relative estimated hyperfiltration than patients with EH. Calculation of eGFR may increase the specificity in identifying patients with PA. Our findings demonstrate the correlation of serum potassium and renin with estimated hyperfiltration in PA and their relationship to kidney damage. These results provide a high priority for future renal protective strategies and methods for the early diagnosis and prompt treatment of PA.

Investigation of the Associations Between Low-Dose Serum Perfluorinated Chemicals and Liver Enzymes in US Adults

OBJECTIVES:Perfluorinated chemicals (PFCs) have been largely used for years in a variety of products worldwide. However, the toxic effect of PFCs on exposure to the liver in the general population has not yet been determined.METHODS:In this study, 2,216 adults (18 years of age or older) were recruited in a National Health and Nutrition Examination Survey (NHANES) in 1999–2000 and 2003–2004 to determine the relationship between serum level of PFCs and the levels of liver enzymes. The data were adjusted for all other confounding variants.RESULTS:After performing mathematical analysis, we determined when serum log-perfluorooctanoic acid (PFOA) increases in one unit, the serum alanine aminotransferase (ALT) concentration (U/l) increases by 1.86 units (95% confidence interval (CI), 1.24–2.48; P=0.005), and the serum log-γ-glutamyltransferase (GGT) concentration (U/l) is 0.08 unit higher (95% CI, 0.05–0.11; P=0.019). The association between PFOA and liver enzymes was more evident in obese subjects, as well as subjects with insulin resistance and/or metabolic syndromes. When dividing the serum PFOA into quartiles in the fully adjusted models in subjects with a body mass index ≥30 kg/m2, the ALT level trend across the serum PFOA quartiles was significant (P=0.003).CONCLUSIONS:On the basis of these data, we conclude that a higher serum concentration of PFOA may cause liver enzymes to increase abnormally in the general population, particularly in obese individuals. Further studies are warranted to clarify the casual relationship between PFCs and these liver enzymes.

Relationship Between Periodontal Disease and Mortality in Patients Treated With Maintenance Hemodialysis

BACKGROUND The relationship between periodontitis and outcomes in patients treated with long-term hemodialysis is controversial. Our previous work suggests that periodontitis is associated with malnutrition and inflammation. Here, we hypothesize that periodontitis is associated with mortality in hemodialysis patients. STUDY DESIGN Prospective observational study. SETTING & PARTICIPANTS 253 patients undergoing hemodialysis at a single hospital-based dialysis facility. PREDICTOR Severity of periodontal disease (mild, moderate, or severe based on oral examination of 6 teeth). OUTCOMES & MEASUREMENTS All-cause and cardiovascular mortality during a 6-year follow-up after an oral health examination of index teeth. RESULTS During the 6-year follow-up, 102 patients died. Death occurred in 70.6%, 41.8%, and 24.0% of patients with severe, moderate, and mild/no periodontitis, respectively. Using mild/no periodontitis as the reference group and adjustment for demographic characteristics, comorbid conditions, and selected laboratory values, HRs for all-cause mortality were 1.39 (95% CI, 0.83-2.34) and 1.83 (95% CI, 1.04-3.24) for moderate and severe periodontitis, respectively. HRs for cardiovascular mortality were not statistically significant. LIMITATIONS Single assessment of periodontal disease severity. CONCLUSIONS For patients undergoing long-term hemodialysis, periodontitis is associated with increased risk of death. Clinical trials are required to determine whether treatment of periodontitis decreases mortality.

Glomerular diseases: genetic causes and future therapeutics

The glomerulus consists of capillary tufts, a mesangial cell component and the Bowman capsule. The glomerular filtration barrier is composed of glomerular endothelial cells, a basement membrane, and podocytes. Particular components of the slit diaphragm and the glomerular basement membrane strictly orchestrate the integrity of the glomerular filtration barrier. The basement membrane is made of a highly crosslinked macromolecular meshwork of type IV collagen, proteoglycans, and laminin. Genetic forms of glomerular disease are predominantly caused by genetic defects in these molecular structures or in factors that regulate the glomerular filtration barrier. In addition, abnormal IgA1 glycosylation can increase susceptibility to IgA nephropathy. Dysregulation of the complement system or of platelet activation can lead to the development of endocapillary lesions, which manifest as thrombotic microangiopathy. Glomerular dysfunction is also encountered in several genetic metabolic and mitochondrial disorders. Discoveries of mutations in a range of genes have provided new insights into the mechanisms of glomerular disease. In this Review, we summarize recent progress in the genetics and therapeutics of a number of glomerular diseases.