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Digoxin is commonly prescribed for heart failure and atrial fibrillation, but there is limited data on its safety in patients with chronic kidney disease (CKD). We conducted a population-based cohort study using the pre-end stage renal disease (ESRD) care program registry and the National Health Insurance Research Database in Taiwan. Of advanced CKD patient cohort (N = 31,933), we identified the digoxin user group (N = 400) matched with age and sex non-user group (N = 2,220). Multivariable Cox proportional hazards and sub-distribution hazards models were used to evaluate the association between digoxin use and the risk of death, cardiovascular events (acute coronary syndrome, ischemic stroke, or hemorrhagic stroke) and renal outcomes (ESRD, rapid decline in estimated glomerular filtration rate-eGFR, or acute kidney injury). Results showed that all-cause mortality was higher in the digoxin user group than in the non-user group, after adjusting for covariates (adjusted hazard ratio, aHR 1.63; 95% CI 1.23-2.17). The risk for acute coronary syndrome (sub-distribution hazard ratio, sHR 1.18; 95% CI 0.75-1.86), ischemic stroke (sHR 1.42; 95% CI 0.85-2.37), and rapid eGFR decline (sHR 1.00 95% CI 0.78-1.27) was not significantly different between two groups. In conclusion, our study demonstrated that digoxin use was associated with increased mortality, but not cardiovascular events or renal function decline in advanced CKD patients. This finding warns the safety of prescribing digoxin in this population. Future prospective studies are needed to overcome the limitations of cohort study design.

BackgroundDepression is common in dialysis patients, but the clinical impact of this condition is poorly defined.MethodsOut of 57,703 patients starting dialysis during 2000-2007 recorded in the National Health Insurance Research Database of Taiwan, we identified 2,475 patients with a clinical diagnosis of depression, and compared them with 1:5 age- and sex-matched patients without a depression diagnosis (n = 12,375). Patients were followed up for hospitalisation due to severe infections, major adverse cardiovascular events (MACE) and death. Multivariable Cox regression and competing risk analyses (accounting for death when appropriate) were used to estimate risk associations.ResultsPatients with depression had a higher frequency of comorbidities. During a mean follow-up of 3.2 years, 1,140 severe infections, 806 MACE, and 1,121 deaths were recorded. Compared to controls, patients with depression were at increased risk of death (adjusted hazard ratio 1.24; 95%CI 1.16-1.33). Patients with depression were also at higher risk of severe (1.14; 1.06-1.22) and fatal infections (death within 30 days, 1.22; 1.09-1.35), attributed mainly to sepsis (1.19; 1.08-1.31), septic shock (1.36; 1.13-1.62) and pneumonia (1.19; 1.07-1.33). Conversely, no association was observed between depression and the MACE risk (1.04; 0.94-1.15).ConclusionDialysis patients with depression are associated with increased risk of infections and death.

INTRODUCTION:Fluid overload is one of the major characteristics and complications in patients with chronic kidney disease (CKD). N-terminal pro-brain natriuretic peptide (NT-proBNP) is related to fluid status and fluid distribution. The aim of this study is to investigate the interaction between NT-proBNP and fluid status in adverse clinical outcomes of late stages of CKD. METHODS:We enrolled 239 patients with CKD stages 4-5 from January 2011 to December 2011 and followed up until June 2017. Fluid status was presented as hydration status (HS) value measured by body composition monitor, while HS>7% was defined as fluid overload. Clinical outcomes included renal outcomes (commencing dialysis and estimated glomerular filtration rate decline>3 ml/min/1.73 m2/year), all-cause mortality and major adverse cardiovascular events (MACEs). RESULTS:During a mean follow-up of 3.3±2.0 years, 129(54.7%) patients commenced dialysis, 88(37.3%) patients presented rapid renal function decline, and 48(20.3%) had MACEs or died. All patients were stratified by HS of 7% and the median of plasma NT-proBNP. The adjusted risks for commencing dialysis was significantly higher in patients with high plasma NT-proBNP and HS>7% compared to those with low plasma NT-proBNP and HS≦7%. There was a significant interaction between plasma NT-proBNP and HS in commencing dialysis (P-interaction = 0.047). Besides, patients with high plasma NT-proBNP and HS>7% had greater risks for MACEs or all-cause mortality than others with either high plasma NT-proBNP or HS>7%. CONCLUSION:NT-proBNP and fluid overload might have a synergistic association of adverse clinical outcomes in patients with late stages of CKD.

BACKGROUND:Fluid overload is not only the characteristic but also an important complication in chronic kidney disease (CKD) patients. Angiopoietin-2 (Angpt2) disturbs endothelium and vessel permeability, which may induce fluid overload. The aim of this study is to examine the interaction between fluid status and Angpt2 in adverse renal outcomes of CKD. METHODS:This cohort study enrolled 290 patients with CKD stages 3-5 from January 2011 to December 2011 and followed up until December 2015. Fluid status was presented as overhydration (OH) value measured by body composition monitor, while OH>1.1L was defined as fluid overload. Renal outcomes were defined as commencing dialysis and rapid renal function decline (the slope of estimated glomerular filtration rate < -5 ml/min/1.73 m2/y). RESULTS:During a mean follow-up of 38.6±18.3 months, 125 (43.1%) patients progressed to commencing dialysis and 99(34.7%) patients presented rapid renal function decline. All patients were stratified by OH of 1.1L and the median of circulating Angpt2. These patients with both OH>1.1L and high circulating Angpt2 were more likely to reach commencing dialysis compared to other groups. The risks for commencing dialysis and rapid renal function decline were significantly higher in patients with OH>1.1L and high circulating Angpt2 level compared to those with OH≦1.1L and low circulating Angpt2 (2.14, 1.21-3.78, P = 0.009; 4.96, 1.45-16.97, P = 0.01). There was a significant interaction between OH level and circulating Angpt2 in entering dialysis (P-interaction = 0.02). CONCLUSIONS:Fluid overload and Angpt2 might have a synergistic effect on adverse renal outcomes in CKD patients.

Chronic kidney disease (CKD) patients have higher prevalence of major adverse cardiovascular events (MACE) and all-cause mortality. Endothelial damage and dysfunction have been regarded as early portents of MACE in CKD patients. Angiopoietin-2 (Ang-2) impairs endothelial function and promotes aberrant neovascularization. The aim of the study was to assess the relationship between circulating Ang-2 and MACE or all-cause mortality in a CKD cohort.A total of 621 pre-dialysis stage 3-5 CKD patients were enrolled from January 2006 to December 2011 and were followed up till October 2014. Plasma Ang-2 was measured in duplicate using commercial enzyme-linked immunosorbent assays (ELISA). Clinical outcomes included MACE or all-cause mortality.Of all patients, 122 (19.8%) reached MACE or all-cause mortality. Seventy-two had MACE, 79 died, and 29 had both MACE and all-cause mortality during the follow-up period of 41.5±28.3 months. Ang-2 quintile was divided at 1405.0, 1730.0, 2160.9, and 2829.9 pg/ml. The adjusted HR of MACE or all-cause mortality for every single higher log Ang-2 was 5.69 (95% CI: 2.00-16.20, P = 0.001). The adjusted HR of MACE or all-cause mortality was 2.48 (95% CI: 1.25-4.90) for patients of quintile 5 compared with those of quintile 1. A longitudinal association between MACE or all-cause mortality and stepwise increases in Ang-2 levels was found (P-trend = 0.008).Ang-2 is an independent predictor of MACE or all-cause mortality in CKD patients. Additional study is necessary in order to explore the mechanism of the association of Ang-2 with adverse outcomes in patients with CKD.

The pathophysiological mechanisms of renal function progression in chronic kidney disease (CKD) have still not been completely explored. In addition to well-known traditional risk factors, non-traditional risk factors, such as endothelial dysfunction, have gradually attracted physicians' attention. Angiopoietin-2 (Ang-2) impairs endothelial function through preventing angiopoietin-1 from binding to Tie2 receptor. Whether Ang-2 is associated with renal function progression in CKD is unknown.This study enrolled 621 patients with stages 3-5 CKD to assess the association of circulating Ang-2 with commencing dialysis, doubling creatinine and rapid decline in renal function (the slope of estimated glomerular filtration rate (eGFR) greater than 5 ml/min per 1.73 m2/y) over follow-up of more than 3 years.Of all patients, 224 patients (36.1%) progressed to commencing dialysis and 165 (26.6%) reached doubling creatinine. 85 subjects (13.9%) had rapid decline in renal function. Ang-2 quartile was divided at 1494.1, 1948.8, and 2593.1 pg/ml. The adjusted HR of composite outcomes, either commencing dialysis or doubling creatinine was 1.53 (95% CI: 1.06-2.23) for subjects of quartile 4 compared with those of quartile 1. The adjusted OR for rapid decline in renal function was 2.96 (95% CI: 1.13-7.76) for subjects of quartile 4 compared with those of quartile 1. The linear mixed-effects model shows a more rapid decrease in eGFR over time in patients with quartile 3 or more of Ang-2 than those with the lowest quartile of Ang-2.Ang-2 is an independent predictor of adverse renal outcome in CKD. Further study is needed to identify the pathogenic role of Ang-2 in CKD progression.

Fluid overload is one of the characteristics in chronic kidney disease (CKD). Changes in extracellular fluid volume are associated with progression of diabetic nephropathy. Not only diabetes but also fluid overload is associated with cardiovascular risk factors The aim of the study was to assess the interaction between fluid overload, diabetes, and cardiovascular risk factors, including arterial stiffness and left ventricular function in 480 patients with stages 4-5 CKD. Fluid status was determined by bioimpedance spectroscopy method, Body Composition Monitor. Brachial-ankle pulse wave velocity (baPWV), as a good parameter of arterial stiffness, and brachial pre-ejection period (bPEP)/brachial ejection time (bET), correlated with impaired left ventricular function were measured by ankle-brachial index (ABI)-form device. Of all patients, 207 (43.9%) were diabetic and 240 (50%) had fluid overload. For non-diabetic CKD, fluid overload was associated with being female (β = -2.87, P = 0.003), heart disease (β = 2.69, P = 0.04), high baPWV (β = 0.27, P = 0.04), low hemoglobin (β = -1.10, P < 0.001), and low serum albumin (β = -5.21, P < 0.001) in multivariate analysis. For diabetic CKD, fluid overload was associated with diuretics use (β = 3.69, P = 0.003), high mean arterial pressure (β = 0.14, P = 0.01), low bPEP/ET (β = -0.19, P = 0.03), low hemoglobin (β = -1.55, P = 0.001), and low serum albumin (β = -9.46, P < 0.001). In conclusion, baPWV is associated with fluid overload in non-diabetic CKD and bPEP/bET is associated with fluid overload in diabetic CKD. Early and accurate assessment of these associated cardiovascular risk factors may improve the effects of entire care in late CKD.

Fluid overload is one of the major presentations in patients with late stage chronic kidney disease (CKD). Diabetes is the leading cause of renal failure, and progression of diabetic nephropathy has been associated with changes in extracellular fluid volume. The aim of the study was to assess the association of fluid overload and diabetes in commencing dialysis and rapid renal function decline (the slope of estimated glomerular filtration rate (eGFR) less than -3 ml/min per 1.73 m(2)/y) in 472 patients with stages 4-5 CKD. Fluid status was determined by bioimpedance spectroscopy method, Body Composition Monitor. The study population was further classified into four groups according to the median of relative hydration status (△HS =fluid overload/extracellular water) and the presence or absence of diabetes. The median level of relative hydration status was 7%. Among all patients, 207(43.9 %) were diabetic. 71 (15.0%) subjects had commencing dialysis, and 187 (39.6%) subjects presented rapid renal function decline during a median 17.3-month follow-up. Patients with fluid overload had a significantly increased risk for commencing dialysis and renal function decline independent of the presence or absence of diabetes. No significantly increased risk for renal progression was found between diabetes and non-diabetes in late CKD without fluid overload. In conclusion, fluid overload has a higher predictive value of an elevated risk for renal progression than diabetes in late CKD.

Inflammation is a pathogenic factor in renal injury, but whether inflammation is related to renal outcome in chronic kidney disease (CKD) patients is little known. We thus assess the association of inflammation and renal outcome in an advanced CKD cohort. This study analyzed the association between inflammatory markers, such as C-reactive protein (hsCRP), white blood cell (WBC) count and ferritin, renal replacement therapy (RRT) and rapid renal progression (estimated GFR slope