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Background We explored the long-term safety and efficacy of ferric citrate in hemodialysis patients in Taiwan, and further evaluated the iron repletion effect and change of iron parameters by different baseline groups. Methods This was a 12-month, Phase IV, multicenter, open-label study. The initial dose of ferric citrate was administered by patients’ clinical condition and further adjusted to maintain serum phosphorus at 3.5–5.5 mg/dL. The primary endpoint was to assess the safety profiles of ferric citrate. The secondary endpoints were to evaluate the efficacy by the time-course changes and the number of subjects who achieved the target range of serum phosphorus. Results A total of 202 patients were enrolled. No apparent or unexpected safety concerns were observed. The most common treatment-emergent adverse events were gastrointestinal-related with discolored feces (41.6%). Serum phosphorus was well controlled, with a mean dose of 3.35±1.49 g/day, ranging from 1.5 to 6.0 g/day. Iron parameters were significantly improved. The change from baseline of ferritin and TSAT were 227.17 ng/mL and 7.53%, respectively (p-trendConclusions Ferric citrate is an effective phosphate binder with favorable safety profile in ESRD patients. The iron-repletion by ferric citrate is effective, and the increase is limited in patients with a higher baseline. In addition to controlling hyperphosphatemia, ferric citrate also shows additional benefits in the treatment of renal anemia. Clinical trial registration ClinicalTrials.gov ID: NCT03256838; 12/04/2017.

[This corrects the article DOI: 10.1371/journal.pone.0184380.].

AIMS:Several studies reported treatment benefits of tolvaptan in patients with congestive heart failure (CHF). However, the optimal dosage remains unclear. We aimed to compare different dosage of tolvaptan to determine the optimal dosage in terms of the efficacy and safety. METHODS:We searched MEDLINE, PubMed, EMBASE, Cochrane CENTRAL and ClinicalTrials.gov through Aug 31, 2016. Randomized controlled trials (RCTs) comparing tolvaptan of different dosages or to placebo in patients with CHF were included. We used network meta-analysis to look for the optimal dosage in terms of effectiveness and safety. Urine output, body weight change and change in serum sodium were the main outcomes of efficacy. Adverse effects were the secondary outcomes. Quality was assessed by Cochrane risk-of-bias tool. RESULTS:Twelve RCTs reporting 14 articles with 5793 patients (mean age, 65.7 ± 11.9 years; 73.7% man) were included. Compared with placebo, the tolvaptan 30 mg had similar effects to tolvaptan 45-90 mg in terms of urine output (mean difference [MD] 2.03 liter; 95% confidence interval [CI] 1.3 to 2.71), body weight change (MD -1.12 kg; 95% CI -1.37 to -0.88) and change in serum sodium (MD 3.06 meq/L; 95% CI 2.43 to 3.68). Compared with placebo, tolvaptan of different dosage showed a non-significant higher risk of adverse effects. CONCLUSIONS:These findings suggest that tolvaptan 30 mg and 45 mg may be the optimum dosage for CHF patients, because of its ability to provide favourable clinical results without greater adverse effects. However, tolvaptan is not beneficial for reducing all-cause mortality in CHF patients.

Traumatic brain injury (TBI) is an important cause of death and disability worldwide. The relationship between TBI and kidney diseases is largely unknown.We aimed to determine whether TBI is associated with long-term adverse renal outcomes. We performed a nationwide, population-based, propensity score-matched cohort study of 32,152 TBI patients and 128,608 propensity score-matched controls. Data were collected by the National Health Insurance Research Database of Taiwan from 2000 to 2012. Our clinical outcomes were chronic kidney disease (CKD), end-stage renal disease (ESRD) and the composite endpoint of ESRD or all-cause mortality.The incidence rate of CKD was higher in the TBI than in the control cohort (8.99 vs. 7.4 per 1000 person-years). The TBI patients also showed higher risks of CKD (adjusted hazard ratio [aHR] 1.14, 95% confidence interval [CI] 1.08-1.20; P < 0.001) and composite endpoints (aHR 1.08, 95% CI 1.01-1.15; P = 0.022) than the control groups, but the ESRD was not significantly different between the groups. In subgroup analyses, the risks of incident CKD and composite endpoints were significantly raised in TBI patients aged < 65 years and/or without comorbidities. However, the risks of both CKD and composite outcome were little affected by the severity of TBI.TBI has a modest but significant effect on incident CKD and composite endpoint, but not on ESRD alone. TBI patients under 65 are at greater risk of CKD and composite outcome than their older counterparts.

Dual renin angiotensin system (RAS) blockade using angiotensin-receptor blockers (ARBs) in combination with angiotensin converting enzyme inhibitors (ACEIs) is reported to improve proteinuria in both diabetic and non-diabetic patients. However, its renoprotective effect and safety remain uncertain in patients with advanced chronic kidney disease (CKD). From January 1, 2000 through June 30, 2009, we enrolled 14,117 pre-dialytic stage 5 CKD patients with serum creatinine >6mg/dL and hematocrit

There is little information about the association between stroke and kidney diseases. We aimed to investigate the impact of stroke on long-term renal outcomes.In this large population-based retrospective cohort study, we identified 100,353 subjects registered in the National Health Insurance Research Database of Taiwan from January 1, 2000, through December 31, 2012, including 33,451 stroke patients and 66,902 age-, sex- and Charlson's comorbidity index score-matched controls.The incidence rate of chronic kidney disease (CKD) was higher in the stroke than in the control cohort (17.5 vs. 9.06 per 1000 person-years). After multivariate adjustment, the risk of developing CKD was significantly higher in patients with stroke (adjusted hazard ratio [aHR] 1.43, 95% confidence interval [CI] 1.36-1.50, P

To assess the effect of pioglitazone on renal outcome, including urinary albumin excretion and estimated glomerular filtration rate (eGFR), in diabetic patients.A prospective, randomized, open-labeled, controlled study.Taipei Veterans General Hospital.Sixty type 2 diabetic patients treated with sulfonylureas and metformin, whose glycated hemoglobin (HbA1c) levels were between 7% and 10% and eGFR was between 45 and 125 mL/min/1.73 m2.The patients were randomized to receive acarbose or pioglitazone and followed up for 6 months. Thirty patients were randomly assigned to receive acarbose, and 30 patients were assigned to receive pioglitazone.The primary study endpoint was the changes in the urinary albumin-to-creatinine ratio (UACR). The secondary endpoint was the changes in eGFR and other parameters.After 6 months of treatment, the mean changes in UACR were -18 ± 104 and 12 ± 85 (p = 0.25, between groups) for the acarbose and pioglitazone groups, respectively. The mean changes in eGFR were 0 ± 14 and -7 ± 16 mL/min/1.73 m2 (p = 0.09, between groups) for the acarbose and pioglitazone groups, respectively. The reductions in HbA1c were similar in both groups. Fasting blood glucose was lower in the pioglitazone group than in the acarbose group. Significant body weight gain was observed in the pioglitazone group as compared with the acarbose group (1.3 ± 2.8 vs. -0.6 ± 1.5 kg, p = 0.002).In type 2 diabetic patients who were treated with sulfonylureas and metformin and possessed HbA1c levels between 7% and 10%, additional acarbose or pioglitazone for 6 months provided similar glycemic control and eGFR and UACR changes. In the pioglitazone group, the patients exhibited significant body weight gain.ClinicalTrials.gov NCT01175486.

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.

BACKGROUND: Currently, the contribution of kidney function decline in renal and patient outcomes is unclear. There are few data on the associations of different etiologies of estimated glomerular filtration rate (eGFR) decline with outcomes in multidisciplinary care. The purpose of this investigation was to establish whether eGFR decline in patients with disease is an important risk factor for developing end-stage renal disease (ESRD) and death. METHODS: From December 1, 2001 to December 31, 2011, 5097 adults with chronic kidney disease (CKD) received biochemical tests, physical examinations, a pathological examination, and a comprehensive questionnaire. We used linear regression models and multivariate Cox proportional hazards model to examine the outcome of eGFR decline in renal diseases with different etiologies. RESULTS: Mean age was 68.1±16.1 (standard deviation, SD) years, and 63.3% patients were male. In the studied cohort, 58.2% of the patients had systemic disease-related nephropathy (SDRN), 29.4% had primary renal diseases (PRDs), and 12.4% had other etiologies. The eGFR decline in SDRN had a significant association with dialysis in the Cox proportional hazards model [crude hazard ratio (HR) = 1.07, 95% confidence interval (CI), 1.04 to 1.10; adjusted HR 1.05, 95% CI, 1.02 to 1.08]. Diabetic nephropathy (DN) had the most severe eGFR decline in CKD stages 3, 4, and 5, and all contributed to the initiation of dialysis and death regardless of whether DN with or without eGFR decline was considered to be the cause. Although hypertensive nephropathy (HN) was related to significant acceleration of eGFR decline, it did not lead to poor outcome. There were still discrepancies between eGFR decline and outcomes in PRDs, hypertensive nephropathy, and lupus nephritis. CONCLUSIONS: eGFR decline and CKD staging provide an informative guide for physicians to make proper clinical judgments in the treatment of CKD, especially SDRN. Poor control of the underlying systemic disease will thus lead to more rapid progression of SDRN.

Endotoxemia is exaggerated and contributes to systemic inflammation and atherosclerosis in patients requiring continuous ambulatory peritoneal dialysis (CAPD). The risk of mortality is substantially increased in patients requiring CAPD for >2 years. However, little is known about the effects of long-term CAPD on circulating endotoxin and cytokine levels. Therefore, the present study evaluated the associations between plasma endotoxin levels, cytokine levels, and clinical parameters with the effects of a short-dwell exchange on endotoxemia and cytokine levels in patients on long-term CAPD.A total of 26 patients were enrolled and divided into two groups (short-term or long-term CAPD) according to the 2-year duration of CAPD. Plasma endotoxin and cytokine levels were measured before and after a short-dwell exchange (4-h dwell) during a peritoneal equilibration test (a standardized method to evaluate the solute transport function of peritoneal membrane). These data were analyzed to determine the relationship of circulating endotoxemia, cytokines and clinical characteristics between the two groups.Plasma endotoxin and monocyte chemotactic protein-1 (MCP-1) levels were significantly elevated in the long-term group. PD duration was significantly correlated with plasma endotoxin (r = 0.479, P = 0.016) and MCP-1 (r = 0.486, P = 0.012). PD duration was also independently associated with plasma MCP-1 levels in multivariate regression. Plasma MCP-1 levels tended to decrease (13.3% reduction, P = 0.077) though endotoxin levels did not decrease in the long-term PD group after the 4-h short-dwell exchange.Long-term PD may result in exaggerated endotoxemia and elevated plasma MCP-1 levels. The duration of PD was significantly correlated with circulating endotoxin and MCP-1 levels, and was an independent predictor of plasma MCP-1 levels. Short-dwell exchange seemed to have favorable effects on circulating MCP-1 levels in patients on long-term PD.

BACKGROUND: Elevated aldosterone is associated with increased mortality in the general population. In patients on dialysis, however, the association is reversed. This paradox may be explained by volume overload, which is associated with lower aldosterone and higher mortality. METHODS: We evaluated the relationship between aldosterone and outcomes in a prospective cohort of 328 hemodialysis patients stratified by the presence or absence of volume overload (defined as extracellular water/total body water >48%, as measured with bioimpedance). Baseline plasma aldosterone was measured before dialysis and categorized as low (280 pg/mL). RESULTS: Overall, 36% (n = 119) of the hemodialysis patients had evidence of volume overload. Baseline aldosterone was significantly lower in the presence of volume overload than in its absence. During a median follow-up of 54 months, 83 deaths and 70 cardiovascular events occurred. Cox multivariate analysis showed that by using the low aldosterone as the reference, high aldosterone was inversely associated with decreased hazard ratios for mortality (0.49; 95% confidence interval, 0.25-0.76) and first cardiovascular event (0.70; 95% confidence interval, 0.33-0.78) in the presence of volume overload. In contrast, high aldosterone was associated with an increased risk for mortality (1.97; 95% confidence interval, 1.69-3.75) and first cardiovascular event (2.01; 95% confidence interval, 1.28-4.15) in the absence of volume overload. CONCLUSIONS: The inverse association of aldosterone with adverse outcomes in hemodialysis patients is due to the confounding effect of volume overload. These findings support treatment of hyperaldosteronemia in hemodialysis patients who have achieved strict volume control.

BACKGROUND: Circulating matrix metalloproteinase (MMP)-2, -3 and -9 are well recognized in predicting cardiovascular outcome in coronary artery disease (CAD), but their risks for chronic kidney disease (CKD) are lacking. Therefore, the present study aimed to investigate whether circulating MMP levels could independently predict future kidney disease progression in non-diabetic CAD patients. METHODS: The prospective study enrolled 251 non-diabetic subjects referred for coronary angiography, containing normal coronary artery (n = 30) and CAD with insignificant (n = 95) and significant (n = 126) stenosis. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI formula. eGFR decline rate was calculated and the primary endpoint was a decline in eGFR over 25% from baseline. RESULTS: The eGFR decline rate (ml/min/1.73 m(2) per year) in patients with CAD (1.22 [-1.27, 1.05]) was greater than that in those with normal coronary artery (0.21 [-2.63, 0.47], P20% in eGFR from baseline or final eGFR < 60 mL/min/1.73 m(2). CONCLUSION: Circulating MMP-2, -3 and -9 are independently associated with kidney disease progression in non-diabetic CAD patients and add incremental predictive power to conventional risk factors.

BACKGROUND: The association between intravenous (IV) iron administration and outcomes in hemodialysis (HD) patients is still debated. Therefore, this study was aimed to assess the relationship between the IV administration of ferric chloride hexahydrate (Atofen®) and cardiovascular (CV) outcome and the interaction between iron-induced oxidative stress and endothelial dysfunction in chronic HD patients. METHODOLOGY/PRINCIPAL FINDINGS: A cohort of 1239 chronic HD patients was recruited. In a follow-up of 12 months, Kaplan-Meier survival curves showed that higher doses of IV Atofen associated with higher risks for CV events and deaths in HD patients. In multivariate Cox models, compared to no iron supplementation, IV Atofen administration was an independent predictor for CV events and overall mortality. However, the nature of the observational cohort study possibly bears selection bias. We further found that IV Atofen enhanced the superoxide production of mononuclear cells (MNCs), the levels of circulating soluble adhesion molecules, and the adhesion of MNCs to human aortic endothelial cells (HAECs). In vitro experiments showed that Atofen increased the expression of intracellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 in HAECs and aggravated the endothelial adhesiveness in a dose-dependent manner. These iron-induced changes were significantly attenuated by the co-treatment of HAECs with N-acetylcysteine and inhibitors of NADPH oxidase, nuclear factor κB, and activator protein-1. CONCLUSION: A cumulative dose of IV Atofen >800 mg within 6 months was associated with an adverse CV outcome and a higher mortality among chronic HD patients. The detrimental effects of IV iron supplementation were partly due to the increased oxidative stress and induction of MNC adhesion to endothelial cells, a pivotal index of early atherogenesis.