Jia-Sin Liu

Renoprotective Effect of Renin-Angiotensin-Aldosterone System Blockade in Patients With Predialysis Advanced Chronic Kidney Disease, Hypertension, and Anemia

IMPORTANCE The benefit of using a renin-angiotensin-aldosterone system blocker such as an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) for patients with advanced chronic kidney disease (CKD) remains undetermined. OBJECTIVE To assess the effectiveness and safety of ACEI/ARB use for advanced predialysis CKD in patients with hypertension and anemia. DESIGN Prospective cohort study. SETTING Taiwan. PARTICIPANTS From January 1, 2000, through June 30, 2009, we selected 28 497 hypertensive adult patients with CKD. Serum creatinine levels were greater than 6 mg/dL, hematocrit levels were less than 28%, and patients were treated with erythropoiesis-stimulating agents. INTERVENTIONS Users (n = 14,117) and nonusers (n = 14,380) of ACEIs/ARBs. MAIN OUTCOMES AND MEASURES We used Cox proportional hazards regression models to estimate hazard ratios (HRs) for commencement of long-term dialysis and all-cause mortality for ACRI/ARB users vs nonusers. RESULTS In a median follow-up of 7 months, 20,152 patients (70.7%) required long-term dialysis and 5696 (20.0%) died before progression to end-stage renal disease requiring dialysis. Use of ACEIs/ARBs was associated with a lower risk for long-term dialysis (HR, 0.94 [95% CI, 0.91-0.97]) and the composite outcome of long-term dialysis or death (0.94 [0.92-0.97]). The renal benefit of ACEI/ARB use was consistent across most patient subgroups, as was that of ACEI or ARB monotherapy. Compared with nonusers, the ACEI/ARB users had a higher hyperkalemia-associated hospitalization rate, but the risk of predialysis mortality caused by hyperkalemia was not significantly increased (HR, 1.03 [95% CI, 0.92-1.16]; P = .30). CONCLUSIONS AND RELEVANCE Patients with stable hypertension and advanced CKD who receive therapy with ACEIs/ARBs exhibit an association with lower risk for long-term dialysis or death by 6%. This benefit does not increase the risk of all-cause mortality.

Metformin use and mortality in patients with advanced chronic kidney disease: national, retrospective, observational, cohort study

BACKGROUND Metformin is recommended as a first-line treatment for patients with type 2 diabetes. However, use of this drug has been contraindicated in individuals with impaired kidney function because of the perceived risk of lactic acidosis. Evidence now supports cautious use of metformin in people with mild-to-moderate chronic kidney disease. However, studies examining the use of metformin in patients with advanced chronic kidney disease are lacking. We aimed to assess the safety of metformin in patients with type 2 diabetes and advanced (approximately stage 5) chronic kidney disease. METHODS We did a retrospective, observational, cohort study of patients with type 2 diabetes who were enrolled prospectively in Taiwans national health insurance research database between Jan 1, 2000, and June 30, 2009, and had follow-up data until Dec 31, 2009. We included individuals with a serum creatinine concentration greater than 530 μmol/L, which is approximately equivalent to stage 5 chronic kidney disease. From a consecutive sample of 12 350 patients with type 2 diabetes and chronic kidney disease, 1005 used metformin and 11 345 were non-users. We matched users and non-users of metformin by propensity score in a 1:3 ratio. Our primary outcome was all-cause mortality. FINDINGS 813 metformin users were matched by propensity score to 2439 non-users. The two groups of patients did not differ significantly by 30 baseline clinical and socioeconomic variables. Median follow-up in the matched cohort was 2·1 years (range 0·3-9·8). All-cause mortality was reported in 434 (53%) of 813 metformin users and in 1012 (41%) of 2439 non-users. After multivariate adjustment, metformin use was an independent risk factor for mortality (adjusted hazard ratio 1·35, 95% CI 1·20-1·51; p<0·0001). The increased mortality risk was dose-dependent and was consistent across all subgroup analyses. However, metformin use compared with no use was associated with a higher but non-significant risk of metabolic acidosis (1·6 vs 1·3 events per 100 patient-years; adjusted hazard ratio 1·30, 95% CI 0·88-1·93; p=0·19). INTERPRETATION Use of metformin in people with type 2 diabetes and a serum creatinine concentration greater than 530 μmol/L is associated with a significantly increased risk of all-cause mortality compared with non-users. Metformin use should not be encouraged in this patient group. FUNDING Taipei Tzu Chi Hospital, Taipei Veterans General Hospital, Foundation for Poison Control, National Health Research Institutes, Ministry of Science and Technology of Taiwan.

Use of Nonsteroidal Anti-Inflammatory Drugs and Risk of Chronic Kidney Disease in Subjects With Hypertension Nationwide Longitudinal Cohort Study

Limited studies have examined the effects of nonsteroidal anti-inflammatory drug (NSAID) use on the risk of chronic kidney disease (CKD), especially in subjects with hypertension. Using National Health Insurance claims data in Taiwan, we conducted a propensity score–matched cohort study to investigate the relationship between NSAID use and CKD in subjects with hypertension. A total of 31976 subjects were included in this study: subjects not taking any NSAIDs in 2007 (n=10782); subjects taking NSAIDs for 1 to 89 days in 2007 (n=10605); and subjects taking NSAIDs for ≥90 days in 2007 (n=10589). We performed multivariable proportional hazard models to determine the relationship between NSAID use and CKD. The results showed that NSAID use was associated with a 1.18-fold increased risk of CKD in subjects taking NSAIDs for 1 to 89 days; and a 1.32-fold increased risk of CKD in hypertension subjects taking NSAIDs for ≥90 days, compared with subjects not taking any NSAIDs, after controlling for the confounding factors. In subgroup analyses, subjects taking NSAIDs for ≥90 days, >1 defined daily dose per day or taking NSAIDs >15 cumulative defined daily doses had a greater risk of CKD than subjects not taking any NSAID, but not for congestive heart failure, stroke, cancer, osteoarthritis, or rheumatoid arthritis. These results provide supportive evidence that NSAID use is associated with increased risk of CKD in subjects with hypertension. It is important to closely monitor the effects of NSAID use, particularly in patients with hypertension, a susceptible population for CKD.

Add-on Protective Effect of Pentoxifylline in Advanced Chronic Kidney Disease Treated with Renin-Angiotensin-Aldosterone System Blockade - A Nationwide Database Analysis

A combination therapy of pentoxifylline with an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) decreased proteinuria or glomerular filtration rate decline in early chronic kidney disease (CKD). Whether adding pentoxifylline to ACEI/ARB provides additional benefits on outcome is unclear in CKD stage 5 patients who have not yet received dialysis (CKD 5 ND). A prospective cohort study was conducted based on the Taiwan National Health Insurance Research Database. From January 1, 2000 to June 30, 2009, we enrolled 14,117 CKD 5 ND with serum creatinine levels >6 mg/dL and hematocrit levels <28% and who have been treated with ACEI/ARB. All patients were divided into pentoxifylline users and nonusers. Patient follow-up took place until dialysis, death before initiation of dialysis or December 31, 2009. Finally, 9,867 patients (69.9%) required long-term dialysis and 2,805 (19.9%) died before dialysis. After propensity score-matching, use of pentoxifylline was associated with a lower risk for long-term dialysis or death in ACEI/ARB users (HR, 0.94; 95% CI, 0.90–0.99) or ARB users (HR, 0.91; 95% CI, 0.85–0.97). In conclusion, pentoxifylline exhibited a protective effect in reducing the risk for the composite outcome of long-term dialysis or death in ACEI/ARB treated CKD 5 ND.

Iron supplementation associates with low mortality in pre-dialyzed advanced chronic kidney disease patients receiving erythropoiesis-stimulating agents: a nationwide database analysis

BACKGROUND A risk/benefit analysis of iron supplementation in pre-dialysis advanced chronic kidney disease (CKD) patients has not been conducted. We aim to assess the effectiveness and the safety of iron supplementation in patients with CKD Stage 5 who have not yet received dialysis (CKD 5 ND). METHODS A prospective cohort study was conducted based on the Taiwan National Health Insurance Research Database. From 1 January 2000 to 30 June 2009, we enrolled 31 971 adult patients who had a serum creatinine >6 mg/dL and a haematocrit <28% and who were treated with erythropoiesis-stimulating agents (ESAs). All patients were further divided into two groups with or without iron supplementation within 90 days after starting ESA therapy. Patient follow-up took place until dialysis, death before initiation of dialysis or 31 December 2009. The primary outcomes were death before initiating dialysis, hospitalization before death or long-term dialysis. RESULTS After propensity score matching, the patients who received iron supplementation were associated with a lower risk of all-cause death [hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.80-0.90] compared with non-users. The survival benefit of iron use was consistent across the majority of dosage groups, except for those who were treated with monthly IV iron >200 mg. Moreover, compared with the non-users, the iron users were associated with a lower risk of hospitalizations (HR, 0.97; 95% CI, 0.94-0.99) but with a higher risk of faster progression to end-stage renal disease (HR, 1.05; 95% CI, 1.01-1.08). CONCLUSIONS Iron supplementation is associated with 15% risk reduction in death among CKD 5 ND patients who received ESA treatment. Randomized studies are needed to validate this association.

High Uric Acid Ameliorates Indoxyl Sulfate-Induced Endothelial Dysfunction and Is Associated with Lower Mortality among Hemodialysis Patients

High uric acid (UA) can act as a pro-oxidant in normal physiological conditions; however, emerging evidence is still debatable with regard to the association between high UA and poor outcomes among chronic hemodialysis (HD) patients. In the present study, 27,229 stable prevalent HD patients were enrolled and divided into four groups according to the quartiles of baseline UA concentration, and 5737 died during a median follow-up of 38 months. Multivariate Cox regression analysis showed that a UA level of <6.1 mg/dL was associated with a higher risk of all-cause mortality compared with a UA level of >8.1 mg/dL [HR, 1.20, 95% CI (1.10–1.31)] adjusting for baseline demographic and biochemical parameters. Moreover, a UA level of <6.1 mg/dL was associated with greater risks of cardiovascular mortality [HR, 1.26, 95% CI (1.13–1.41)] and stroke-related mortality [HR, 1.59, 95% CI (1.12–2.25)], respectively. In vitro experiments further showed an increase in oxidative stress and an inhibition nitric oxide synthesis by indoxyl sulfate (IS) in human aortic endothelial cells, which were significantly attenuated by UA in a dose-dependent manner. We concluded that higher UA in serum was associated with lower risk of all-cause and cardiovascular mortality among HD patients probably through its antioxidant property in ameliorating the IS-related vascular toxicity.

Thiazolidinediones and Risk of Long-Term Dialysis in Diabetic Patients with Advanced Chronic Kidney Disease: A Nationwide Cohort Study

Thiazolidinediones (TZDs) reduce urinary albumin excretion and proteinuria in diabetic nephropathy. The effect of TZDs on hard renal outcome in diabetic patients with chronic kidney disease (CKD) is unknown. We investigate the association of TZDs and risk of long-term dialysis or death in diabetic patients with advanced CKD. The nationwide population-based cohort study was conducted using Taiwan’s National Health Insurance Research Database. From January 2000 to June 2009, 12350 diabetic patients with advanced CKD (serum creatinine levels greater than 6 mg/dL but not yet receiving renal replacement therapy) were selected for the study. We used multivariable Cox regression models and a propensity score-based matching technique to estimate hazard ratios (HRs) for development of long-term dialysis and the composite outcome of long-term dialysis or death for TZD users (n=1224) as compared to nonusers (n=11126). During a median follow-up of 6 months, 8270 (67.0%) patients required long-term dialysis and 2593 (21.0%) patients died before starting long-term dialysis. Using propensity score matched analysis, we found TZD users were associated with a lower risk for long-term dialysis (HR, 0.80; 95% confidence interval [CI], 0.74-0.86) and the composite outcome of long-term dialysis or death (HR, 0.85; 95% CI, 0.80-0.91). The results were consistent across most patient subgroups. Use of TZDs among diabetic patients with advanced CKD was associated with lower risk for progression to end-stage renal disease necessitating long-term dialysis or death. Further randomized controlled studies are required to validate this association.

Effect of spironolactone on the risks of mortality and hospitalization for heart failure in pre-dialysis advanced chronic kidney disease: A nationwide population-based study

BACKGROUND Spironolactone has been shown to reduce cardiovascular death in patients with mild-to-moderate chronic kidney disease (CKD), but its risks and benefits in advanced CKD remain unsettled. We aimed to assess whether spironolactone reduces cardiovascular mortality and morbidity in pre-dialysis stage 5 CKD patients. METHODS Using Taiwans National Health Insurance Research Database from January 2000 to June 2009, we enrolled 27,213 pre-dialysis stage 5 CKD adult patients, in whom 1363 patients were treated with spironolactone (user) and 25,850 were not (nonuser). Outcomes were all-cause mortality, hospitalization for heart failure (HHF) and major adverse cardiac event (MACE, the composite of acute myocardial infarction and ischemic stroke). Patients were followed up till December 31, 2009. RESULTS Over 85,758 person-years of follow-up, spironolactone users had higher incidence for all-cause mortality (24.7/100 person-years vs. 10.6/100 person-years), infection-related death (4.4/100 person-years vs. 1.7/100 person-years) and HHF (4.0/100 person-years vs. 1.4/100 person-years). Multivariable Cox hazards model showed that spironolactone users were associated with higher risks of all-cause mortality (adjusted hazard ratio [aHR] 1.35, 95% confidence interval [CI] 1.24-1.46), infection-related death (aHR 1.42, CI 1.16-1.73) and HHF (aHR 1.35, CI 1.08-1.67) as compared to nonusers. The risks for cardiovascular mortality, MACE and hyperkalemia-associated hospitalization were similar between two groups. After matching users and nonusers (1:3 ratio) by propensity scores, the results were consistent in matched cohort and across subgroups. CONCLUSIONS Spironolactone may be associated with higher risks for all-cause and infection-related mortality and HHF in pre-dialysis stage 5 CKD patients. Spironolactone should be used with caution in advanced CKD patients.

Use of non-steroidal anti-inflammatory drugs and risk of chronic kidney disease in people with Type 2 diabetes mellitus, a nationwide longitudinal cohort study

To investigate the temporal relationship between non‐steroidal anti‐inflammatory drug use and the development of chronic kidney disease in people with Type 2 diabetes mellitus.

Severe Decline of Estimated Glomerular Filtration Rate Associates with Progressive Cognitive Deterioration in the Elderly: A Community-Based Cohort Study

Cognitive dysfunction is closely related to aging and chronic kidney disease (CKD). However, the association between renal function changes and the risk of developing cognitive impairment has not been elucidated. This longitudinal cohort study was to determine the influence of annual percentage change in estimated glomerular filtration rate (eGFR) on subsequent cognitive deterioration or death of the elderly within the community. A total of 33,654 elders with eGFR measurements were extracted from the Taipei City Elderly Health Examination Database. The Short Portable Mental Status Questionnaire was used to assess their cognitive progression at least twice during follow-up visits. Multivariable Cox regression models were used to estimate the hazard ratio (HR) for cognitive deterioration or all-cause mortality with the percentage change in eGFR. During a median follow-up of 5.4 years, the participants with severe decline in eGFR (>20% per year) had an increased risk of cognitive deterioration (HR, 1.33; 95% confidence interval [CI], 1.08–1.72) and the composite outcome (HR, 1.17; 95% CI, 1.03–1.35) when compared with those who had stable eGFR. Severe eGFR decline could be a possible predictor for cognitive deterioration or death among the elderly. Early detection of severe eGFR decline is a critical issue and needs clinical attentions.