Jenq-Wen Huang

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.

Preoperative Proteinuria Predicts Adverse Renal Outcomes after Coronary Artery Bypass Grafting

Whether preoperative proteinuria associates with adverse renal outcomes after cardiac surgery is unknown. Here, we performed a secondary analysis of a prospectively enrolled cohort of adult patients undergoing coronary artery bypass grafting (CABG) at a medical center and its two affiliate hospitals between 2003 and 2007. We excluded patients with stage 5 CKD or those who received dialysis previously. We defined proteinuria, measured with a dipstick, as mild (trace to 1+) or heavy (2+ to 4+). Among a total of 1052 patients, cardiac surgery-associated acute kidney injury (CSA-AKI) developed in 183 (17.4%) patients and required renal replacement therapy (RRT) in 50 (4.8%) patients. In a multiple logistic regression model, mild and heavy proteinuria each associated with an increased odds of CSA-AKI, independent of CKD stage and the presence of diabetes mellitus (mild: OR 1.66, 95% CI 1.09 to 2.52; heavy: OR 2.30, 95% CI 1.35 to 3.90). Heavy proteinuria also associated with increased odds of postoperative RRT (OR 7.29, 95% CI 3.00 to 17.73). In summary, these data suggest that preoperative proteinuria is a predictor of CSA-AKI among patients undergoing CABG.

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.

Impact of timing of renal replacement therapy initiation on outcome of septic acute kidney injury

IntroductionSepsis is the leading cause of acute kidney injury (AKI) in critical patients. The optimal timing of initiating renal replacement therapy (RRT) in septic AKI patients remains controversial. The objective of this study is to determine the impact of early or late initiation of RRT, as defined using the simplified RIFLE (risk, injury, failure, loss of kidney function, and end-stage renal failure) classification (sRIFLE), on hospital mortality among septic AKI patients.MethodsPatient with sepsis and AKI requiring RRT in surgical intensive care units were enrolled between January 2002 and October 2009. The patients were divided into early (sRIFLE-0 or -Risk) or late (sRIFLE-Injury or -Failure) initiation of RRT by sRIFLE criteria. Cox proportional hazard ratios for in hospital mortality were determined to assess the impact of timing of RRT.ResultsAmong the 370 patients, 192 (51.9%) underwent early RRT and 259 (70.0%) died during hospitalization. The mortality rate in early and late RRT groups were 70.8% and 69.7% respectively (P > 0.05). Early dialysis did not relate to hospital mortality by Cox proportional hazard model (P > 0.05). Patients with heart failure, male gender, higher admission creatinine, and operation were more likely to be in the late RRT group. Cox proportional hazard model, after adjustment with propensity score including all patients based on the probability of late RRT, showed early dialysis was not related to hospital mortality. Further model matched patients by 1:1 fashion according to each patients propensity to late RRT showed no differences in hospital mortality according to head-to-head comparison of demographic data (P > 0.05).ConclusionsUse of sRIFLE classification as a marker poorly predicted the benefits of early or late RRT in the context of septic AKI. In the future, more physiologically meaningful markers with which to determine the optimal timing of RRT initiation should be identified.

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.

Left Ventricular Systolic Strain in Chronic Kidney Disease and Hemodialysis Patients

Background: The impact of chronic kidney disease (CKD) and hemodialysis on heart function is not fully understood. We aimed to investigate the influence of different stages of CKD and maintenance hemodialysis on heart function. Methods: One hundred fifty-three patients were categorized into 3 subgroups [56 without CKD as controls; 37 with moderate-advanced CKD, stages 3, 4 or 5, and 60 with end-stage renal disease (ESRD) undergoing maintenance hemodialysis]. Left ventricular (LV) function was assessed by conventional echocardiography and 2-dimensional speckle-tracking echocardiography with strain analysis (2D strain analysis). Results: There was no significant difference of gender, age and LV ejection fraction among groups. Compared with controls, global peak systolic longitudinal strain (GSl), circumferential strain and strain rate were decreased in the CKD group. Along with the decline of renal function, GSl deteriorated. Moreover, compared with moderate-advanced CKD patients, GSl, circumferential strain and strain rate were better in ESRD group receiving maintenance hemodialysis. Conclusions: Worsening renal function was associated with a reduction of systolic function, and could be quantified by 2D strain analysis. The hemodialysis patients have better LV systolic function than the moderate-advanced CKD patients.

Clinical characteristics of patients with segmental renal infarction

Background:  Renal infarction is usually an underestimated disease due to its rare and non‐specific presentations; the renal survival of these patients is not well studied. The aim of the present analysis is to study the clinical features and outcome in patients who had documented renal infarction.

Identification of a novel FN1–FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour

Phosphaturic mesenchymal tumours (PMTs) are uncommon soft tissue and bone tumours that typically cause hypophosphataemia and tumour‐induced osteomalacia (TIO) through secretion of phosphatonins including fibroblast growth factor 23 (FGF23). PMT has recently been accepted by the World Health Organization as a formal tumour entity. The genetic basis and oncogenic pathways underlying its tumourigenesis remain obscure. In this study, we identified a novel FN1–FGFR1 fusion gene in three out of four PMTs by next‐generation RNA sequencing. The fusion transcripts and proteins were subsequently confirmed with RT‐PCR and western blotting. Fluorescence in situ hybridization analysis showed six cases with FN1–FGFR1 fusion out of an additional 11 PMTs. Overall, nine out of 15 PMTs (60%) harboured this fusion. The FN1 gene possibly provides its constitutively active promoter and the encoded proteins oligomerization domains to overexpress and facilitate the activation of the FGFR1 kinase domain. Interestingly, unlike the prototypical leukaemia‐inducing FGFR1 fusion genes, which are ligand‐independent, the FN1–FGFR1 chimeric protein was predicted to preserve its ligand‐binding domains, suggesting an advantage of the presence of its ligands (such as FGF23 secreted at high levels by the tumour) in the activation of the chimeric receptor tyrosine kinase, thus effecting an autocrine or a paracrine mechanism of tumourigenesis. Copyright

Chronic Fatigue in Long-Term Peritoneal Dialysis Patients

Objective: Fatigue is a common symptom in long-term dialysis patients. This study investigated possible clinical factors which may cause the development of fatigue in patients receiving peritoneal dialysis (PD). We also investigated the relationship between total solute clearance (TSC) and fatigue symptoms in PD patients. Design: A cross-sectional study design was used to compare the clinical characteristics among groups of PD patients classified by different degrees of fatigue. The relationship among dialysis adequacy (including Kt/Vurea and weekly creatinine clearance; Ccr), clinical characteristics and fatigue symptoms were also assessed. Setting: The PD unit of a major university teaching hospital in Taipei, Taiwan. Patients: Consecutive patients who had received PD for a minimum duration of 4 months were recruited for participation in the study. Patients were excluded if they had a history of ischemic heart disease, severe heart failure (NYHA function III or IV), malignant neoplasm, active infection, major psychiatric problems, chronic obstructive pulmonary disease, or disturbed consciousness. Finally, a total of 64 patients, 31 of whom were receiving continuous ambulatory peritoneal dialysis and 33 who were receiving continuous cycling-assisted peritoneal dialysis, were enrolled in the study. Methods: Fatigue was evaluated using a specially designed questionnaire that includes fourteen items. Patients were divided into three groups according to their fatigue scores (FS): mild (FS, 0–3), moderate (FS, 4–8), and severe (FS, 9–14) fatigue. The demographic data, dialysis variables, and clinical parameters of patients were compared among these groups. The relationship between fatigue and TSC was also examined. Results: The FS were correlated with serum intact parathyroid hormone (iPTH) level and total cholesterol concentration (p < 0.05). A linear correlation was also noted between serum iPTH level and total cholesterol level. When the patients were divided into an adequate- and an inadequate-dialysis group according to values of TSC, Kt/Vurea as well as weekly creatinine clearance, a significant correlation was found between weekly Ccr and FS. Conclusion: This study has demonstrated that dialysis adequacy plays a key role in the development chronic fatigue. In addition, weekly Ccr was better correlated with fatigue than Kt/Vurea.