Chi-Chih Hung

Echocardiographic parameters are independently associated with rate of renal function decline and progression to dialysis in patients with chronic kidney disease.

BACKGROUND AND OBJECTIVES Cardiac abnormalities were frequently noted in patients with chronic kidney disease (CKD). This study is designed to assess whether echocardiographic parameters are associated with rate of renal function decline and progression to dialysis in CKD stage 3 to 5 patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This longitudinal study enrolled 415 patients. The renal end point was defined as commencement of dialysis. The change in renal function was measured by estimated GFR (eGFR) slope. RESULTS Progression to dialysis was predicted by wide pulse pressure, low albumin, low hemoglobin, high calcium-phosphorous product, proteinuria, diuretics use, and concentric left ventricular hypertrophy (LVH) (hazard ratio, 2.03; 95% confidence interval [CI], 1.00 to 4.10; P = 0.05). The eGFR slope was negatively associated with total cholesterol, uric acid, proteinuria, diuretics use, and left atrial (LA) diameter (change in slope, -0.50; 95% CI, -0.89 to -0.11; P = 0.01) and positively associated with albumin and left ventricular ejection fraction (LVEF) (change in slope, 0.06; 95% CI, 0.03 to 0.08; P < 0.001). CONCLUSIONS Our study in patients of CKD stage 3 to 5 demonstrated that concentric LVH was associated with progression to dialysis, and that increased LA diameter and decreased LVEF were associated with faster renal function decline. Echocardiography may help identify high-risk groups with progressive decline in renal function to dialysis and rapid progression of renal dysfunction in CKD stage 3 to 5 patients.

Association of Symptoms of Depression With Progression of CKD

BACKGROUND Depression is related to morbidity and mortality in patients with kidney failure treated by dialysis, but its influence on patients with earlier stages of chronic kidney disease (CKD) is uncertain. This study investigates the association of depressive symptoms with clinical outcomes in patients with CKD not requiring dialysis. STUDY DESIGN Prospective observational cohort study. SETTING & PARTICIPANTS 568 participants with CKD not requiring maintenance dialysis were recruited consecutively at a tertiary hospital in Southern Taiwan and followed up for 4 years. PREDICTORS Baseline status of depressive symptoms. OUTCOMES The primary outcome is a composite of progression to end-stage renal disease (ESRD), defined as requiring maintenance dialysis treatment, or all-cause mortality; and secondary outcome was first hospitalization. MEASUREMENTS Depressive symptoms were assessed by Beck Depression Inventory. Estimated glomerular filtration rate (eGFR) was computed using the 4-variable MDRD (Modification of Diet in Renal Disease) Study equation. RESULTS 428 participants completed the questionnaires and 160 (37%) had depressive symptoms. During a mean follow-up of 25.2 ± 11.9 months, 136 participants (32%) reached the primary outcome (119 reached ESRD and 17 died) and 110 participants (26%) were hospitalized. High depressive symptoms increased the risk of progression to ESRD or death (HR, 1.66; 95% CI, 1.14-2.44) and first hospitalization (HR, 1.59; 95% CI, 1.03-2.47). Participants with high depressive symptoms had more rapid GFR decrease (eGFR slopes of -2.3 [25th-75th percentile, -5.3 to -0.4] vs -1.2 [25th-75th percentile, -3.5 to 0.3] mL/min/1.73 m(2) per year; P = 0.001) and initial dialysis treatment at a higher eGFR (OR for initiation of dialysis at eGFR >5 mL/min/1.73 m(2), 4.45; 95% CI, 1.44-13.78). LIMITATIONS A single-center study of Taiwanese, Beck Depression Inventory evaluates only depressive symptom burden. CONCLUSIONS Depressive symptoms in CKD are independent predictors of adverse clinical outcomes, including faster eGFR decrease, dialysis therapy initiation, death, or hospitalization. Depression should be evaluated early and treated in patients with CKD.

Association of Fluid Overload with Cardiovascular Morbidity and All-Cause Mortality in Stages 4 and 5 CKD

BACKGROUND AND OBJECTIVES Fluid overload is a common characteristic associated with renal progression in CKD. Additionally, fluid overload is an independent predictor of all-cause or cardiovascular mortality in patients on dialysis, but its influence on patients not on dialysis is uncertain. The aim of the study was to assess the relationship between the severity of fluid status and clinical outcomes in an advanced CKD cohort. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In total, 478 predialysis patients with stages 4 and 5 CKD in the integrated CKD care program were enrolled from January of 2011 to December of 2011 and followed-up until August of 2013. The clinical outcomes included cardiovascular morbidity and all-cause mortality. The relative hydration status (overhydration/extracellular water) was used as the presentation of the severity of fluid status and measured using a body composition monitor. Overhydration/extracellular water >7% was defined as fluid overload. RESULTS Over a median follow-up period of 23.2 (12.6-26.4) months, 66 (13.8%) patients reached all-cause mortality or cardiovascular morbidity. The adjusted hazard ratio of the combined outcome of all-cause mortality or cardiovascular morbidity for every 1% higher overhydration/extracellular water was 1.08 (95% confidence interval, 1.04 to 1.12; P<0.001). The adjusted overhydration/extracellular water for the combined outcome of all-cause mortality or cardiovascular morbidity in participants with overhydration/extracellular water ≥7% compared with those with overhydration/extracellular water <7% was 1.93 (95% confidence interval, 1.01 to 3.69; P=0.04). In subgroup analysis, higher overhydration/extracellular water was consistently associated with increased risk for the combined outcome independent of diabetes, cardiovascular disease, and serum albumin. There was no significant interaction between all subgroups. CONCLUSIONS These findings suggest that fluid overload is an independent risk factor of the combined outcome of all-cause mortality or cardiovascular morbidity in patients with advanced CKD.

Hepatitis C Virus Infection Increases Risk of Developing End-Stage Renal Disease Using Competing Risk Analysis

Background Chronic kidney disease (CKD) and hepatitis C virus (HCV) infection are closely linked and both increase patient mortality. The association of HCV and risk of developing end-stage renal disease (ESRD) has not been analyzed with competing risk model. Method We enrolled a prospective cohort of 4,185 patients (mean age, 62 years; 41% female) registered in the CKD integrated care program at two affiliated hospitals of Kaohsiung Medical University in Taiwan between November 11, 2002 and May 31, 2009. With competing risk model, we analyzed the association of HCV infection, defined by seropositive of anti-HCV antibody, and hepatitis B virus (HBV) infection, defined by seropositive of HBV surface antigen, with the risk of entering ESRD. Results The prevalence of HCV infection was 7.6% and it increased with the CKD stages (trend test, P<0.001), while the prevalence of HBV infection was 7.4% and no specific trend among CKD stages (tend test, P = 0.1). During the 9,101 person-year follow-up period, there were 446 death and 1,205 patients entering ESRD. After adjusting death as the competing risk, the estimated 5-year cumulative incidence rate of ESRD among patients with and without HCV infection were 52.6% and 38.4%, respectively (modified log-rank, P<0.001). Multivariable analysis showed that HCV infection, but not HBV infection, had higher risk of developing ESRD compared with cases without infection (HCV, HR: 1.32, 95% CI: 1.07–1.62; HBV, HR: 1.10, 95% CI: 0.89–1.35). Subgroup analyses showed consistent results. Conclusions With death-adjusted competing risk analysis, HCV infection is associated with an increased risk of developing ESRD in CKD cohort.

Association of fluid overload with kidney disease progression in advanced CKD: a prospective cohort study.

BACKGROUND Fluid overload is a common phenomenon in patients in a late stage of chronic kidney disease (CKD). However, little is known about whether fluid overload is related to kidney disease progression in patients with CKD. Accordingly, the aim of the study was to assess the association of the severity of fluid status and kidney disease progression in an advanced CKD cohort. STUDY DESIGN Prospective observational cohort study. SETTING & PARTICIPANTS This cohort study enrolled 472 non-dialysis-dependent patients with CKD stages 4-5 who were in an integrated CKD care program from January 2011 to December 2011 and followed up until December 2012 or initiation of renal replacement therapy (RRT). PREDICTORS Tertile of fluid overload, with cutoff values at 0.6 and 1.6 L. OUTCOMES RRT, rapid estimated glomerular filtration rate (eGFR) decline (faster than 3 mL/min/1.73 m(2) per year), and change in eGFR. MEASUREMENTS The severity of fluid overload was measured by a bioimpedance spectroscopy method. eGFR was computed using the 4-variable MDRD (Modification of Diet in Renal Disease) Study equation. RESULTS During a median 17.3-month follow-up, 71 (15.0%) patients initiated RRT and 187 (39.6%) experienced rapid eGFR decline. The severity of fluid overload was associated with increased risk of RRT (tertile 3 vs tertile 1: adjusted HR, 3.16 [95% CI, 1.33-7.50]). Fluid overload value was associated with increased risk of rapid eGFR decline (tertile 3 vs tertile 1: adjusted OR, 4.68 [95% CI, 2.30-9.52]). Furthermore, the linear mixed-effects model showed that the reduction in eGFR over time was faster in tertile 3 than in tertile 1 (P=0.02). LIMITATIONS The effect of fluid volume variation over time must be considered. CONCLUSIONS Fluid overload is an independent risk factor associated with initiation of RRT and rapid eGFR decline in patients with advanced CKD.

Association of Dyslipidemia with Renal Outcomes in Chronic Kidney Disease

Dyslipidemia is highly prevalent in patients with chronic kidney disease (CKD) and the relationship between dyslipidemia with renal outcomes in patients with moderate to advanced CKD remains controversial. Hence, our objective is to determine whether dyslipidemia is independently associated with rapid renal progression and progression to renal replacement therapy (RRT) in CKD patients. The study analyzed the association between lipid profile, RRT, and rapid renal progression (estimated glomerular filtration rate [eGFR] slope <−6 ml/min/1.73 m2/yr) in 3303 patients with stages 3 to 5 CKD. During a median 2.8-year follow-up, 1080 (32.3%) participants commenced RRT and 841 (25.5%) had rapid renal progression. In the adjusted models, the lowest quintile (hazard ratios [HR], 1.23; 95% confidence interval [CI], 1.01 to 1.49) and the highest two quintiles of total cholesterol (HR, 1.25; 95% CI, 1.02 to 1.52 and HR, 1.35; 95% CI, 1.11 to 1.65 respectively) increased risks for RRT (vs. quintile 2). Besides, the highest quintile of total cholesterol was independently associated with rapid renal progression (odds ratio, 1.36; 95% CI, 1.01 to 1.83). Our study demonstrated that certain levels of dyslipidemia were independently associated with RRT and rapid renal progression in CKD stage 3–5. Assessment of lipid profile may help identify high risk groups with adverse renal outcomes.

Urinary neutrophil gelatinase-associated lipocalin levels predict cisplatin-induced acute kidney injury better than albuminuria or urinary cystatin C levels

Cisplatin‐induced acute kidney injury (AKI) is a major concern among clinicians in prescribing cisplatin‐based chemotherapy. This study evaluated and compared the ability of urinary biomarkers, including urinary neutrophil gelatinase‐associated lipocalin (NGAL), cystatin C, and the urinary albumin to creatinine ratio (ACR) to predict cisplatin‐induced AKI. Thirty‐three cancer patients receiving cisplatin‐based chemotherapy were prospectively studied, including 10 (30%) who developed AKI (the study group). Changes of urinary biomarkers were compared at 4 hours, 8 hours, and 12 hours, and 1 day, 2 days, 3 days, and 4 days after cisplatin intravenous infusions (75 mg/m2) versus the baseline. There was a significant increase in urinary NGAL levels from 12 hours to 4 days (p < 0.05) compared to baseline after cisplatin infusion in the AKI group. The magnitude of these changes over time differed significantly by group (p < 0.001). The area under the receiver operating curve describing the relationship between urinary NGAL levels and AKI within 12 hours was 0.865 (95% confidence interval = 0.691–1.000). Urinary NGAL levels independently predicted AKI 12 hours after cisplatin (p = 0.045) after adjustments for age, gender, body mass index, baseline serum creatinine, and urinary total protein. Urinary NGAL levels may be an early biomarker of AKI in patients receiving cisplatin‐based treatment.

Effects of the mTOR inhibitor Rapamycin on Monocyte-Secreted Chemokines

BackgroundMammalian target of rapamycin (mTOR) inhibitors, such as sirolimus and its derivative, everolimus, are potent immunosuppressive and antiproliferative drugs. Inflammatory diseases are characterized by immunological dysfunction, and monocyte recruitment underlies the mechanism of cell damage. Chemokines attract inflammatory cells to sites of inflammation. Interleukin-8 (IL-8/CXCL8); the monocyte chemoattractant protein-1 (MCP-1/CCL2); the regulated on activation, normal T cell expressed, presumably secreted protein (RANTES/CCL5); the macrophage inflammatory protein (MIP)-1α (CCL3); and MIP-1β (CCL4) are involved in the pathogenesis of inflammation. However, whether mTOR inhibitors moderate the production of chemokines in monocytes remains unclear.MethodsA human monocyte cell line, THP-1, and primary monocytes obtained from human volunteers, were stimulated using lipopolysaccharide (LPS), and then treated with sirolimus. The expression of the MCP-1, RANTES, IL-8, MIP-1α, MIP-1β, and TNF-α proteins was measured using enzyme-linked immunosorbent assays, and intracellular signalling was examined using western blotting.ResultsSirolimus significantly suppressed the LPS-induced expression of MCP-1, IL-8, RANTES, MIP-1α, and MIP-1β in the THP-1 cells and human primary monocytes. The mitogen-activated protein kinase (MAPK) inhibitors that were examined suppressed the LPS-induced expression of MCP-1, IL-8, RANTES, MIP-1α, and MIP-1β. In addition, sirolimus suppressed the LPS-induced phosphorylation of p38 and p65 in the THP-1 and human primary monocytes.ConclusionSirolimus downregulates the expression of chemokines in monocytes, including MCP-1, RANTES, IL-8, MIP-1α, and MIP-1β, by inhibiting the NF-κB-p65 and MAPK-p38 signalling pathways.

Hypokalemia, Its Contributing Factors and Renal Outcomes in Patients with Chronic Kidney Disease

Background In the chronic kidney disease (CKD) population, the impact of serum potassium (sK) on renal outcomes has been controversial. Moreover, the reasons for the potential prognostic value of hypokalemia have not been elucidated. Design, Participants & Measurements 2500 participants with CKD stage 1–4 in the Integrated CKD care program Kaohsiung for delaying Dialysis (ICKD) prospective observational study were analyzed and followed up for 2.7 years. Generalized additive model was fitted to determine the cutpoints and the U-shape association between sK and end-stage renal disease (ESRD). sK was classified into five groups with the cutpoints of 3.5, 4, 4.5 and 5 mEq/L. Cox proportional hazard regression models predicting the outcomes were used. Results The mean age was 62.4 years, mean sK level was 4.2±0.5 mEq/L and average eGFR was 40.6 ml/min per 1.73 m2. Female vs male, diuretic use vs. non-use, hypertension, higher eGFR, bicarbonate, CRP and hemoglobin levels significantly correlated with hypokalemia. In patients with lower sK, nephrotic range proteinuria, and hypoalbuminemia were more prevalent but the use of RAS (renin-angiotensin system) inhibitors was less frequent. Hypokalemia was significantly associated with ESRD with hazard ratios (HRs) of 1.82 (95% CI, 1.03–3.22) in sK <3.5mEq/L and 1.67 (95% CI,1.19–2.35) in sK = 3.5–4 mEq/L, respectively, compared with sK = 4.5–5 mEq/L. Hyperkalemia defined as sK >5 mEq/L conferred 1.6-fold (95% CI,1.09–2.34) increased risk of ESRD compared with sK = 4.5–5 mEq/L. Hypokalemia was also associated with rapid decline of renal function defined as eGFR slope below 20% of the distribution range. Conclusion In conclusion, both hypokalemia and hyperkalemia are associated with increased risk of ESRD in CKD population. Hypokalemia is related to increased use of diuretics, decreased use of RAS blockade and malnutrition, all of which may impose additive deleterious effects on renal outcomes.

Body mass index, mortality, and gender difference in advanced chronic kidney disease.

Background and Aim A higher body mass index (BMI) appears to be reversely associated with mortality in dialysis patients. Moreover, although women have better survival in chronic kidney disease (CKD), this survival advantage is cancelled in dialysis. The association between BMI and mortality and the gender difference remain controversial in advanced CKD. Methods This study enrolled 3,320 patients (1,938 men and 1,382 women) from southern Taiwan who had CKD stages 3–5 with a BMI of 15.0–35.0 kg/m2. Results During a median 2.9-year follow-up, there were 328 (16.9%) all-cause mortality and 319 (16.5%) cardiovascular (CV) events and death in male patients, 213 (15.4%) all-cause mortality and 224 (16.2%) CV events and death in female patients. Compared with the reference BMI of 27.6–30.0 kg/m2 in an adjusted Cox model, lower-BMI groups in men, BMI 15.0–20.0 kg/m2 and 20.1–22.5 kg/m2, were associated with higher risks of all-cause mortality: hazard ratios (HRs) 3.19 (95% confidence interval [CI], 1.97–5.18) and 2.01 (95% CI, 1.29–3.14), respectively. Higher-BMI group in men, BMI 30.1–35.0 kg/m2, was associated with a higher risk of all-cause mortality: HR 1.72 (95% CI, 1.02–2.96). Likewise, lower- and higher-BMI groups in men were associated with a higher risk of CV events and death. In women, these associations between BMI and poor outcomes were not observed. Conclusions In advanced CKD, there was a reverse J-shaped association between BMI and all-cause mortality, and a U-shaped association between BMI and CV outcomes in men. Neutral associations between BMI and poor outcomes were detected in women. Gender could modify the effect of BMI on mortality in patients with CKD.