Chih-Jen Wu

Meta-Analysis of the Associations of p-Cresyl Sulfate (PCS) and Indoxyl Sulfate (IS) with Cardiovascular Events and All-Cause Mortality in Patients with Chronic Renal Failure

Background Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are protein-bound uremic toxins that increase in the sera of patients with chronic kidney disease (CKD), and are not effectively removed by dialysis. The purpose of this meta-analysis was to investigate the relationships of PCS and IS with cardiovascular events and all-cause mortality in patients with CKD stage 3 and above. Methodology/Principle Findings Medline, Cochrane, and EMBASE databases were searched until January 1, 2014 with combinations of the following keywords: chronic renal failure, end-stage kidney disease, uremic toxin, uremic retention, indoxyl sulfate, p-cresyl sulfate. Inclusion criteria were: 1) Patients with stage 1 to 5 CKD; 2) Prospective study; 3) Randomized controlled trial; 4) English language publication. The associations between serum levels of PCS and IS and the risks of all-cause mortality and cardiovascular events were the primary outcome measures. Of 155 articles initially identified, 10 prospective and one cross-sectional study with a total 1,572 patients were included. Free PCS was significantly associated with all-cause mortality among patients with chronic renal failure (pooled OR = 1.16, 95% CI = 1.03 to 1.30, P = 0.013). An elevated free IS level was also significantly associated with increased risk of all-cause mortality (pooled OR = 1.10, 95% CI = 1.03 to 1.17, P = 0.003). An elevated free PCS level was significantly associated with an increased risk of cardiovascular events among patients with chronic renal failure (pooled OR = 1.28, 95% CI = 1.10 to 1.50, P = 0.002), while free IS was not significantly associated with risk of cardiovascular events (pooled OR = 1.05, 95% CI = 0.98 to 1.13, P = 0.196). Conclusions/Significance Elevated levels of PCS and IS are associated with increased mortality in patients with CKD, while PCS, but not IS, is associated with an increased risk of cardiovascular events.

Long-Term Risk of Upper Gastrointestinal Hemorrhage after Advanced AKI

BACKGROUND AND OBJECTIVESnThere are few reports on temporary dialysis-requiring AKI as a risk factor for future upper gastrointestinal bleeding (UGIB). This study sought to explore the long-term association between dialysis-requiring AKI and UGIB.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnThis nationwide cohort study used data from the Taiwan National Health Insurance Research Database. Patients who recovered from dialysis-requiring AKI and matched controls were selected from hospitalized patients age ≥18 years between 1998 and 2006. The cumulative incidences of long-term de novo UGIB were calculated, and the risk factors of UGIB and mortality were identified using time-varying Cox proportional hazard models adjusted for subsequent CKD and ESRD after AKI.nnnRESULTSnA total of 4565 AKI-recovery patients and the same number of matched patients without AKI were analyzed. After a median follow-up time of 2.33 years (interquartile range, 0.97-4.81 years), the incidence rates of UGIB were 50 (by stringent criterion) and 69 (by lenient criterion) per 1000 patient-years in the AKI-recovery group and 31 (by stringent criterion) and 48 (by lenient criterion) per 1000 patient-years in the non-AKI group (both P<0.001). When compared with patients in the non-AKI group, the multivariate hazard ratio (HR) for UGIB was 1.30 (95% confidence interval [95% CI], 1.14 to 1.48) for dialysis-requiring AKI, 1.83 (95% CI, 1.53 to 2.20) for time-varying CKD, and 2.31 (95% CI, 1.92 to 2.79) for time-varying ESRD (all P<0.001). Finally, the risk for long-term mortality increased after UGIB (HR, 1.24; 95% CI, 1.12 to 1.38) and dialysis-requiring AKI (HR, 1.66; 95% CI, 1.54 to 1.78).nnnCONCLUSIONSnRecovery from dialysis-requiring AKI was associated with future UGIB and mortality.

Pentoxifylline Decreases Dialysis Risk in Patients With Advanced Chronic Kidney Disease

Few studies evaluated the effects of pentoxifylline on hard endpoints in patients with predialysis stage 5 chronic kidney disease (CKD). Thus, we tried to explore the effects of pentoxifylline and its interaction with renin‐angiotensin‐aldosterone system (RAAS) blockade on the development of endstage renal disease (ESRD) and mortality. This nationwide cohort study retrospectively included patients who had a serum creatinine level of >6 mg/dL and received erythropoiesis‐stimulating agents (ESAs) between 2000 and 2010. We analyzed 7,366 pentoxifylline users and 7,366 propensity score‐matched nonusers. Using Cox proportional hazard models, pentoxifylline reduced the risks of ESRD and the composite renal outcome but not that of mortality. In terms of the risks of developing ESRD, pentoxifylline alone exerted a comparable beneficial effect to combined therapy with an RAAS inhibitor and greater renoprotection than RAAS inhibitor monotherapy. This study suggests pentoxifylline is efficacious in slowing progression to ESRD in patients with predialysis stage 5 CKD.

Meglitinides increase the risk of hypoglycemia in diabetic patients with advanced chronic kidney disease: a nationwide, population-based study

The safety of short-acting meglitinides in diabetic patients with advanced chronic kidney disease (CKD) has not been widely reported. Diabetic patients with advanced CKD who had a serum creatinine level of > 6 mg/dL a hematocrit level of ≦ 28% and received erythropoiesis-stimulating agent treatment between 2000 and 2010, were included in this nationwide study in Taiwan. The outcomes of interest were defined as hypoglycemia and long-term mortality. The risks of hypoglycemia and death were analyzed using Cox proportional hazards models, with end-stage renal disease and anti-diabetic drugs as time-dependent variables. Fresh users and matched non-users of meglitinides (both n = 2,793) were analyzed. The use of meglitinides increased the risk of hypoglycemia (HR, 1.94, p<0.001), as did other anti-diabetic agents. Concomitant use of meglitinide and insuilin will incresase the hypoglycemic risk. (HR, 1.69, p=0.018) Moreover, it was not the use of meglitinides, but the presence of hypoglycemia that predicted mortality. The function curve showed an insignificant trend towards increased hypoglycemic risk in patients aged > 62 and ≤ 33 years from the generalized additive model. This study suggests that the use of short-acting meglitinides could be associated with increased risk of hypoglycemia in diabetic patients with advanced CKD, especially in patients aged > 62 and ≤ 33 years. Meglitinide combined with insulin will increase hypoglycemia in patients with advanced CKD.The safety of short-acting meglitinides in diabetic patients with advanced chronic kidney disease (CKD) has not been widely reported.Diabetic patients with advanced CKD who had a serum creatinine level of > 6 mg/dL a hematocrit level of ≦ 28% and received erythropoiesis-stimulating agent treatment between 2000 and 2010, were included in this nationwide study in Taiwan.The outcomes of interest were defined as hypoglycemia and long-term mortality. The risks of hypoglycemia and death were analyzed using Cox proportional hazards models, with end-stage renal disease and anti-diabetic drugs as time-dependent variables.Fresh users and matched non-users of meglitinides (both n = 2,793) were analyzed. The use of meglitinides increased the risk of hypoglycemia (HR, 1.93; 95% CI, 1.56-2.39), as did sulfonylurea and insulin use. The hypoglycemic effect of meglitinides was consistent among patient subgroups stratified by the status of concomitant use of other oral anti-diabetic agents. Concomitant use of meglitinide and insuilin will incresase the hypoglycemic risk. Moreover, it was not the use of meglitinides, but the presence of hypoglycemia that predicted mortality. The function curve showed an insignificant trend towards increased hypoglycemic risk in patients aged > 62 and ≤ 33 years from the generalized additive model.This study suggests that the use of short-acting meglitinides could be associated with increased risk of hypoglycemia in diabetic patients with advanced CKD, especially in patients aged > 62 and ≤ 33 years. Meglitinide combined with insulin will increase hypoglycemia in patients with advanced CKD.

The role of indoxyl sulfate in renal anemia in patients with chronic kidney disease

Renal anemia is a common complication in patients with advanced chronic kidney disease. In vitro studies have shown that indoxyl sulfate decreases erythropoietin production. Whether this effect is seen in vivo remains unclear. Our goal was to explore the role of indoxyl sulfate in renal anemia. We found serum indoxyl sulfate levels are significantly and negatively associated with erythropoietin levels in human. A multiple stepwise linear regression analyses after adjustment for other independent parameters revealed that free indoxyl sulfate, and total indoxyl sulfate were significantly associated with erythropoietin levels. In animal studies, erythropoietin gene and protein expression were markedly inhibited in rats with chronic kidney disease; however, this effect was significantly reversed by lowering serum indoxyl sulfate with AST-120. Indoxyl sulfate may also inhibit erythropoietin expression in animal models with chronic kidney disease. These findings further support the role of indoxyl sulfate in the development of renal anemia.

The Case | Metabolic disarray after fire extinguisher powder ingestion

Cheng-Jui Lin, Han-Hsiang Chen, Kuo-Song Chang, Cheng-Yi Hsu, Yi-Chou Chen and Chih-Jen Wu Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan; Department of Emergency Medicine, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Medicine, Nursing and Management College, Taipei, Taiwan and Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan

The prevalence and association of chronic kidney disease and diabetes in liver cirrhosis using different estimated glomerular filtration rate equation

Background Chronic kidney disease (CKD) in cirrhosis is one of the dreaded complications associated with a steep rise in mortality and morbidity, including diabetes. There are limited data on the prevalence of CKD and the association with diabetes in outpatients with cirrhosis. Methodology This is a cross-sectional study of 7,440 adult liver cirrhosis patients enrolled from August 2001 to April 2010 in a medical center. Case control matching by age and sex with 1,967 pairs, and conditional logistic regression for odds of diabetes was analyzed using adjusted model. Results CKD was present in 46.0%, 45.7% and 45.6% of the study population using the MDRD-6, CKD-EPI and MDRD-4 estimated glomerular filtration rate (eGFR) equations, respectively. Using a conditional logistic regression model after adjusting for other risk factors, odds for diabetes increased significantly compared with non-CKD in CKD stage 3 to 5 (stage 3~5) based on MDRD-6–adjusted model, ORs were: stage 3~5, 2.34 (95% CI, 1.78-3.01); MDRD-4–adjusted model, ORs were: stage 3~5, 8.51 (95% CI, 5.63-11.4); CKD-EPI–adjusted model, ORs were: stage 3~5, 8.61 (95% CI, 5.13-13.9). Conclusion In cirrhosis patients, prevalence of diabetes was higher in patients with advanced stage of CKD. For patients with cirrhosis, patients with CKD stages 3~5 defined by MDRD-4, MDRD-6, and CKD-EPI eGFR equations had increased risk for diabetes. More severe cirrhosis, indicated by the Child-Turcott-Pugh classification was also accompanied by an increased risk for diabetes.

Improvement in Mortality and End-Stage Renal Disease in Patients With Type 2 Diabetes After Acute Kidney Injury Who Are Prescribed Dipeptidyl Peptidase-4 Inhibitors

Objective: To focus on the potential beneficial effects of the pleiotropic effects of dipeptidyl peptidase‐4 inhibitors (DPP4is) on attenuating progression of diabetic kidney disease in reducing the long‐term effect of the acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Patients and Methods: Data from the National Health Insurance Research Database from January 1, 1999, to July 31, 2011, were analyzed, and patients with diabetes weaning from dialysis‐requiring AKI were identified. Cox proportional hazards models and inverse‐weighted estimates of the probability of treatment were used to adjust for treatment selection bias. The outcomes were incident end‐stage renal disease (ESRD) and mortality, major adverse cardiovascular events, and hospitalized heart failure. Results: Of a total of 6165 patients with diabetes weaning from dialysis‐requiring AKI identified, 5635 (91.4%) patients were DPP4i nonusers and 530 (8.6%) patients were DPP4i users. Compared with DPP4i nonusers, DPP4i users had a lower risk of ESRD (hazard ratio, 0.81; 95% CI, 0.70‐0.94; P=.04) and all‐cause mortality (hazard ratio, 0.28; 95% CI, 0.23‐0.34; P<.001) after adjustments for CKD, advanced CKD, and angiotensin‐converting enzyme inhibitor or angiotensin II receptor blocker use. In contrast, the risk of major adverse cardiovascular events and hospitalized heart failure did not differ significantly between groups. Conclusion: Dipeptidyl peptidase‐4 inhibitor users had a lower risk of ESRD and mortality than did nonusers among patients with diabetes after weaning from dialysis‐requiring AKI. Therefore, a prospective study of AKI to CKD transitions after episodes of AKI is needed to optimally target DPP4i interventions.

Intelligent system to predict intradialytic hypotension in chronic hemodialysis

BACKGROUNDnIntradialytic hypotension (IDH) is a serious complication and a major risk factor of increased mortality during hemodialysis (HD). However, predicting the occurrence of intradialytic blood pressure (BP) fluctuations clinically is difficult. This study aimed to develop an intelligent system with capability of predicting IDH.nnnMETHODSnIn developing and training the prediction models in the intelligent system, we used a database of 653 HD outpatients who underwent 55,516 HD treatment sessions, resulting in 285,705 valid BP records. We built models to predict IDH at the next BP check by applying time-dependent logistic regression analyses.nnnRESULTSnOur results showed the sensitivity of 86% and specificity of 81% for both nadir systolic BP (SBP) of <90xa0mmHg and <100xa0mmHg, suggesting good performance of our prediction models. We obtained similar results in validating via test data and data of newly enrolled patients (new-patient data), which is important for simulating prospective situations wherein dialysis staff are unfamiliar with new patients. This compensates for the retrospective nature of the BP records used in our study.nnnCONCLUSIONnThe use of this validated intelligent system can identify patients who are at risk of IDH in advance, which may facilitate well-timed personalized management and intervention.

Norepinephrine Administration Is Associated with Higher Mortality in Dialysis Requiring Acute Kidney Injury Patients with Septic Shock

(1) Background: Norepinephrine (NE) is the first-line vasoactive agent used in septic shock patients; however, the effect of norepinephrine on dialysis-required septic acute kidney injury (AKI-D) patients is uncertain. (2) Methods: To evaluate the impact of NE on 90-day mortality and renal recovery in septic AKI-D patients, we enrolled patients in intensive care units from 30 hospitals in Taiwan. (3) Results: 372 patients were enrolled and were divided into norepinephrine users and non-users. After adjustment by Inverse probability of treatment weighted (IPTW), there was no significant difference of baseline comorbidities between the two groups. NE users had significantly higher 90-day mortality rate and using NE is a strong predictor of 90-day mortality in the multivariate Cox regression (HR = 1.497, p = 0.027) after adjustment. The generalized additive model disclosed norepinephrine alone exerted a dose–dependent effect on 90-day mortality, while other vasoactive agents were not. (4) Conclusion: Using norepinephrine in septic AKI-D patients is associated with higher 90-day mortality and the effect is dose-dependent. Further study to explore the potential mechanism is needed.