Kuan-Yu Hung

Comparative effectiveness of renin-angiotensin system blockers and other antihypertensive drugs in patients with diabetes: systematic review and bayesian network meta-analysis

Objective To assess the effects of different classes of antihypertensive treatments, including monotherapy and combination therapy, on survival and major renal outcomes in patients with diabetes. Design Systematic review and bayesian network meta-analysis of randomised clinical trials. Data sources Electronic literature search of PubMed, Medline, Scopus, and the Cochrane Library for studies published up to December 2011. Study selection Randomised clinical trials of antihypertensive therapy (angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), α blockers, β blockers, calcium channel blockers, diuretics, and their combinations) in patients with diabetes with a follow-up of at least 12 months, reporting all cause mortality, requirement for dialysis, or doubling of serum creatinine levels. Data extraction Bayesian network meta-analysis combined direct and indirect evidence to estimate the relative effects between treatments as well as the probabilities of ranking for treatments based on their protective effects. Results 63 trials with 36 917 participants were identified, including 2400 deaths, 766 patients who required dialysis, and 1099 patients whose serum creatinine level had doubled. Compared with placebo, only ACE inhibitors significantly reduced the doubling of serum creatinine levels (odds ratio 0.58, 95% credible interval 0.32 to 0.90), and only β blockers showed a significant difference in mortality (odds ratio 7.13, 95% credible interval 1.37 to 41.39). Comparisons among all treatments showed no statistical significance in the outcome of dialysis. Although the beneficial effects of ACE inhibitors compared with ARBs did not reach statistical significance, ACE inhibitors consistently showed higher probabilities of being in the superior ranking positions among all three outcomes. Although the protective effect of an ACE inhibitor plus calcium channel blocker compared with placebo was not statistically significant, the treatment ranking identified this combination therapy to have the greatest probability (73.9%) for being the best treatment on reducing mortality, followed by ACE inhibitor plus diuretic (12.5%), ACE inhibitors (2.0%), calcium channel blockers (1.2%), and ARBs (0.4%). Conclusions Our analyses show the renoprotective effects and superiority of using ACE inhibitors in patients with diabetes, and available evidence is not able to show a better effect for ARBs compared with ACE inhibitors. Considering the cost of drugs, our findings support the use of ACE inhibitors as the first line antihypertensive agent in patients with diabetes. Calcium channel blockers might be the preferred treatment in combination with ACE inhibitors if adequate blood pressure control cannot be achieved by ACE inhibitors alone.

Rate of decline of residual renal function is associated with all-cause mortality and technique failure in patients on long-term peritoneal dialysis

BACKGROUND Residual renal function (RRF) at the initiation of peritoneal dialysis (PD) therapy can predict patient outcome. However, RRF declines with time at variable rates in different patients. This study was performed to compare the impact of baseline RRF and the rate of RRF decline on patient survival and on death-censored technique survival after initiation of long-term PD. METHODS We enrolled 270 patients with sufficient urine amount (daily urine volume >100 mL) from a medical centre in North Taiwan who began PD between January 1996 and December 2005 and followed them until December 2007. The study population was stratified by the decline rate of RRF into a fast, intermediate and slow decline group. The Kaplan-Meier survival analysis was used to determine patient survival and technique survival. The Cox regression model was used to identify factors associated with patient outcome. The proportional odds polychotomous logistic regression model was used to identify variables associated with rapid decline of RRF. RESULTS During an average follow-up period of 45 months, 50 (18.5%) deaths, 67 (24.8%) death-censored technique failures (transfer to haemodialysis) and 43 (15.9%) renal transplantations occurred. The median rate of RRF decline was 0.885 mL/min/1.73 m(2) per year. Survival analysis showed that patients with fast RRF decline had worse survival and increased risk of technique failure. The multivariate Cox regression model confirmed that the rate of RRF decline was an independent factor associated with patient and technique survival and was a more powerful prognostic factor than basal RRF. Variables associated with a rapid decline of RRF were larger body mass index, presence of diabetes, prior history of congestive heart failure, use of diuretics, peritonitis episodes and hypotensive events. CONCLUSIONS Our data indicate that the rate of decline of RRF is a more powerful prognostic factor than baseline RRF associated with all-cause mortality and technique failure in patients on long-term PD. To prevent accelerated loss of RRF, it is imperative that every effort be made to avoid overdiuresis, peritonitis and hypotensive episodes, especially in those with diabetes, obesity and congestive heart failure.

Association of Kidney Function With Residual Hypertension After Treatment of Aldosterone-Producing Adenoma

BACKGROUND Autonomous secretion of aldosterone in patients with primary aldosteronism increases glomerular filtration rate and causes kidney damage. The influence of a mild decrease in kidney function on residual hypertension after adrenalectomy is unexplored. STUDY DESIGN Nonconcurrent prospective study. SETTING & PARTICIPANTS The study was based on the Taiwan Primary Aldosteronism Investigation (TAIPAI) database. 150 patients (61 men; overall mean age, 47.2 +/- 11.6 years) with a diagnosis of aldosterone-producing adenoma had undergone unilateral adrenalectomy at National Taiwan University Hospital from July 1999 to January 2007. PREDICTOR Presurgery estimated glomerular filtration rate (eGFR). OUTCOMES & MEASUREMENTS Residual hypertension after adrenalectomy, defined either as less than 75% of recorded blood pressure measurements with systolic blood pressure less than 140 mm Hg and diastolic blood pressure less than 90 mm Hg or requiring antihypertensive medications during the first year after surgery. RESULTS Before surgery, 27 (18%), 72 (48%), and 51 (34%) patients had moderately to severely decreased (<60 mL/min/1.73 m(2)), mildly decreased (60 <or= eGFR < 90 mL/min/1.73 m(2)), or nondecreased eGFR (>or=90 mL/min/1.73 m(2)), respectively. After surgery, 16 (59.3%), 29 (40.3%), and 10 (19.3%) patients in each category had postsurgery residual hypertension. Compared with patients without decreased eGFR before surgery, adjusted odds ratios for postsurgery residual hypertension were 2.7 (95% confidence interval, 1.03 to 7.0; P = 0.04) and 2.8 (95% confidence interval, 1.05 to 9.3) for mildly and moderately to severely decreased eGFR, respectively. LIMITATIONS Arbitrary definition for residual hypertension. CONCLUSIONS Two-thirds of patients with aldosterone-producing adenoma were cured of hypertension by means of unilateral adrenalectomy. Kidney function impairment, even mild, appears to be associated with a high incidence of postsurgery residual hypertension.

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.

Cancer-Specific Mortality in Chronic Kidney Disease: Longitudinal Follow-Up of a Large Cohort

BACKGROUND AND OBJECTIVES Chronic kidney disease (CKD) is known to be associated with increased all-cause and cardiovascular mortality, but no large studies examined the cancer-specific mortality in non-dialysis-dependent CKD patients. Such outcome data are needed for proper allocation of resources and would help to develop better preventive services. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Between 1998 and 1999, 123,717 adults were recruited from four health screening centers in Taiwan. The estimated glomerular filtration rate was calculated using the four-variable Modification of Diet in Renal Disease Study equation for the Chinese. Mortality was ascertained by computer linkage to the national death registry after a median follow-up of 7.06 years. Cox proportional hazards regression models were used to estimate the impact of CKD on cancer-specific mortality. RESULTS A higher risk for overall cancer mortality was found in CKD patients compared with non-CKD patients (adjusted hazard ratio, 1.2). CKD was associated with increased mortality from liver cancer, kidney cancer, and urinary tract cancer, with an adjusted hazard ratio of 1.74, 3.3, and 7.3, respectively. A graded relationship between the severity of renal impairment and cancer mortality was also found. CONCLUSIONS Patients with CKD had a higher mortality risk of liver cancer, kidney cancer, and urinary tract cancer. This is the first large study that showed an inverse association between renal function and liver cancer mortality. The increased mortality could be caused by higher cancer incidence or worse response to cancer treatment. Future research is warranted to clarify the mechanism.

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.

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.

Health-Related Quality of Life of Hemodialysis Patients in Taiwan: A Multicenter Study

Background/Aims: Health-related quality of life (HRQOL) is an important determinant of treatment effectiveness in dialysis patients. To our knowledge, there are no reports evaluating HRQOL of hemodialysis (HD) in Chinese patients. The purpose of this study is to present our results about HRQOL using the 36-Item Short-Form (SF-36) questionnaire on Taiwanese hemodialysis patients. Methods: HRQOL was measured by using the SF-36 questionnaire in 497 HD patients in five hospitals. Results: The following attributes, male gender, age <50 years old, higher education level (HEL), marriage status, employment status (EPS), less comorbid medical condition (CMC), and non-diabetic patients (NDP) were all predicted on a better Physical Component Scale (PCS). Age <50 years old, body mass index >18.5, HEL, EPS and NDP were all predicted on a higher Mental Component Scale (MCS). Scales contributing to a summary measure of physical health, the PCS score was significantly lower in women (35.0 ± 12.3) than in men (37.9 ± 12.3). However, there was no difference in the MCS score between women and men. In multivariate analysis, age, CMC, diabetes, serum creatinine (SCr), and erythropoietin responsiveness were significant independent predictors of PCS. Diabetes, educational level, SCr, and erythropoietin responsiveness were significant independent predictors of MCS. All of the individual scales were lower in Taiwanese HD patients than in both the general Taiwanese and US population. Each of the individual scales and MCS scores were substantially lower in the Taiwan HD group than in the US HD cohort. However, the bodily pain of PCS was significantly higher in the Taiwan HD group, although the mean PCS scores for the Taiwan HD group and the US HD study participants were nearly equal at 36.3 and 36.1, respectively. Conclusion: The physical and mental aspects of quality of life are substantially lower for Taiwanese HD patients, except for higher bodily pain tolerance. A number of demographic and clinical characteristics have a significant impact on HRQOL in Taiwanese HD patients.