Chien-Chun Kuo

FACTORS ASSOCIATED WITH BLOOD CONCENTRATIONS OF INDOXYL SULFATE AND p-CRESOL IN PATIENTS UNDERGOING PERITONEAL DIALYSIS

♦ Background: Accumulating evidence supports the important role of protein-bound uremic toxins such as indoxyl sulfate and p-cresol in uremic syndrome. They exert direct deleterious effects on a variety of cells and could link to clinical outcome. Factors relevant to indoxyl sulfate and p-cresol levels in peritoneal dialysis (PD) patients have rarely been investigated. We conducted a cross-sectional study to analyze the factors that correlate with both total and free indoxyl sulfate and p-cresol. ♦ Methods: 182 stable PD patients with mean PD therapy duration 38.5 ± 33.3 months were enrolled. Their mean age was 48.9 ± 13.5 years; 62.6% (114/182) were female patients. Demographic data, including age, gender, and PD therapy duration, were reviewed and recorded. PD-associated features such as residual kidney function (RKF), peritoneal transport property, and dialysis modality were also recorded. Hemoglobin, blood urea nitrogen (BUN), serum creatinine, C-reactive protein, interleukin (IL)-6, and IL-10 were measured. Levels of total and free indoxyl sulfate and p-cresol were determined. ♦ Results: Patients without RKF had lower Kt/V and weekly creatinine clearance and higher serum creatinine and IL-6 levels. These patients also had higher total and free indoxyl sulfate levels. There was no difference in indoxyl sulfate or p-cresol levels compared to patients with different peritoneal transport properties or with different treatment modalities. Multivariate regression analysis revealed that weekly creatinine clearance and serum creatinine were independent associates of total indoxyl sulfate level; IL-6, total indoxyl sulfate, and free p-cresol were associated with free indoxyl sulfate level. Weekly creatinine clearance and free p-cresol level independently correlated with total p-cresol; while gender, total p-cresol, and free indoxyl sulfate were associated with free p-cresol level. ♦ Conclusion: The free forms of indoxyl sulfate and p-cresol constituted a small portion of their total forms. The presence of RKF affected levels of free and total indoxyl sulfate. IL-6 level was significantly associated with free indoxyl sulfate level. There was a close relationship between indoxyl sulfate and p-cresol levels in their free forms in PD patients.

The risk of upper gastrointestinal bleeding in patients treated with hemodialysis: a population-based cohort study

BackgroundThere are no prior studies that have estimated the risk of upper gastrointestinal bleeding (UGIB) among the dialysis population relative to the general population. The aim of this study was to examine the risk of UGIB among end-stage renal disease (ESRD) patients during a 6-year period following their initiation of hemodialysis (HD) therapy in Taiwan- a country with the highest incidence of ESRD in the world, using general population as an external comparison group.MethodsData were obtained from the Taiwan National health Insurance Research Database. In total, 796 patients who were beginning HD between 1999 and 2003 were recruited as the study cohort and 3,184 patients matched for age and sex were included as comparison cohort. Multivariate Cox proportional hazard regression models were used to adjust for confounding and to compare the 6-year UGIB-free survival rate between these two cohorts.ResultsThe incidence rate of UGIB (42.01 per 1000 person-year) was significantly higher in the HD cohort than in the control cohort (27.39 per 1000 person-years). After adjusting for potential confounders, the adjusted hazard ratios for UGIB during the 6-year follow-up periods for HD patients was 1.27 (95% CI=1.03-1.57) compared to patients in the comparison cohort.ConclusionsWe conclude that HD patients were at an increased risk for UGIB compared with the general population.

Biomarkers associated with vascular and valvular calcification in chronic hemodialysis patients

Background: Cardiovascular calcification, including arterial intimal and medial calcification (AIC and AMC) and valvular calcification (VC) are important predictors of outcome in chronic dialysis patients. We aimed to compare their prevalence and analyze respective risk factors in hemodialysis (HD) patients. Methods: A total of 81 HD patients were enrolled. Vascular calcification was assessed by plain film radiography of the pelvis and VC was diagnosed by echocardiography. Demographic data was reviewed and serum levels of calcification-relevant biomarkers were determined. Patients with and without calcification were then compared. Results: The prevalence study indicated that 36 patients had AIC (44.4%), 17 had AMC (21%) and 60 (74.1%) had VC. Patients with vascular calcification were older, and had a higher prevalence of diabetes. Their IL-6, osteoprotegerin, and uric acid levels were higher. Serum fetuin-A was lower in patients with VC. Logistic regression analysis revealed age, uric acid and diabetes to be independently associated with AIC; uric acid, diabetes and osteoprotegerin with AMC. Fetuin-A was the sole associate of VC. Conclusions: It is concluded that the prevalence of cardiovascular calcification in chronic HD patients was high with cardiac valve involvement more frequent. Factors associated with different type of calcification were not identical. Changes in biomarkers may represent clinical clues for assessment of cardiovascular calcification in HD patients.

Proinflammatory Cytokines, Hepatocyte Growth Factor and Adipokines in Peritoneal Dialysis Patients

Chronic inflammation is a well-recognized complication in dialysis patients and a potential role of the adipose tissue as an important tissue of origin contributing to inflammation has been proposed. Stable peritoneal dialysis (PD) patients were enrolled to investigate the relationship between serum levels of proinflammatory cytokines and adipokines. Our results revealed that there was a strong association between high sensitivity C-reactive protein and interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-alpha) but not with IL-10 and IL-18. IL-6 correlated with TNF-alpha, IL-10, and IL-18. No association was found between IL-10 and IL-18. Adiponectin was positively correlated with all proinflammatory cytokines, except IL-10. No significant association was found between resistin and proinflammatory cytokines. Hepatocyte growth factor (HGF) was directly related to proinflammatory cytokines but not with adipokines. The presence of residual kidney function (RKF) affected IL-6, TNF-alpha, and HGF levels. The peritoneal transport property did not influence inflammatory cytokine and adipokine levels. In conclusion, there was a close relationship between proinflammatory cytokines and adipokines. HGF correlated with proinflammatory cytokines but not with adipokines. The PD-related factors such as RKF, peritoneal property and dialysis glucose load affected levels of proinflammatory cytokines. Body mass index was an important determinant of leptin and adiponectin in PD patients.

Inflammatory Marker but Not Adipokine Predicts Mortality among Long-Term Hemodialysis Patients

Aims: chronic inflammation contributes significantly to the morbidity and mortality of chronic hemodialysis patients. A recent research has shown that adipokines were associated with inflammation in these patients. We aim to investigate whether biomarkers of inflammation, adipokines, and clinical features can predict the outcome of hemodialysis patients. Materials and methods: we enrolled 181 hemodialysis patients (men: 97, mean age: 56.3±13.6) and analyzed predictors of long-term outcomes. Results: during the 3-year followup period, 41 patients died; the main causes of death were infection and cardiovascular disease. Elevated serum levels of hsCRP and albumin and advanced age were highly associated with death (all P<.001). Leptin and adiponectin levels were not significantly different between deceased patients and survivors. Cox-regression analysis indicated that age, diabetes, albumin level, and hsCRP were independent factors predicting mortality. Conclusion: the presence of underlying disease, advanced age, and markers of chronic inflammation is strongly related to survival rate in long-term hemodialysis patients.

Relationship between Kt/V urea-based dialysis adequacy and nutritional status and their effect on the components of the quality of life in incident peritoneal dialysis patients

BackgroundIt is well known that the quality of life of patients with chronic kidney disease can be improved by dialysis. While previous studies have used retrospective designs and adhered to a standard target prescribed by clinical guidelines, our study prospectively investigates the association between the adequacy of peritoneal dialysis (PD) and measures of nutritional status on quality-of-life domains in a cohort of incident PD patients.MethodsIt was a prospective 6-month observational study. Eighty incident PD participants who were treated in a hospital-based PD center were enrolled. The period of enrollment was January 2009–June 2010; follow-up continued until December 2010. PD adequacy indices, including Kt/V urea, weekly Ccr (WCcr), measures of nutritional status (albumin, BMI), and nPCR were measured at 1 month and 6 months after PD initiation. SF-36 health survey questionnaires were used to measure the quality of life. The outcomes were used to measure the changes in the domains of the SF-36 after 6 months of PD therapy.ResultsSeventy-seven incident patients who underwent PD for 6 months were included in the study. The mean age was 47.3 years, and the male-to-female ratio was 38:39. A peritoneal Kt/V urea value of 1.2, which was also the baseline cutoff value, was found to have the highest influence on SF-36 domains. Patients with baseline peritoneal Kt/V urea value of <1.2 showed improvement in the physical functioning and role limitation of physical functioning components after 6 months of PD. In contrast, patients with baseline peritoneal Kt/V urea values of ≥1.2 showed remarkable improvement in the general health, physical functioning, role limitation caused by physical problems, and bodily pain components. However, the trend of improvement decreased in patients with baseline nPCR of <1.2. Baseline renal WCcr did not influence the improvement in the SF-36 domains.LimitationsA small cohort and a short observation period.ConclusionsThe baseline level of peritoneal Kt/V urea affected the components of the quality of life after PD initiation. In contrast, a lower baseline nPCR level was associated with deterioration in the quality of life after PD therapy.

Lack of modulatory effect of simvastatin on indoxyl sulfate-induced activation of cultured endothelial cells

AIMS Endothelial dysfunction is a common manifestation of chronic kidney disease (CKD). The protein-bound uremic toxins have emerged as important factors associated with cardiovascular disease and the outcome of CKD. The effect of indoxyl sulfate (IS) on endothelial cells remains unclear. MAIN METHODS Human umbilical endothelial cells (HUVEC) were incubated using IS at two concentrations: 100 μM and 1000 μM over two periods of time: 16 and 48 h. HUVEC were also pre-treated with simvastatin to examine its effect. RT-PCR was used to assess changes in the gene expression of intracellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), Monocyte chemotactic protein-1 (MCP-1), E-selectin, and angiotensin receptor type 1 (AT1R). Protein abundance of the investigated molecules was assessed by immunoblotting. KEY FINDINGS Treatment with 100 μM IS for 16 h induced a 2-fold increase in the expression of ICAM-1, VCAM-1, and MCP-1. At a concentration of 1000 μM, there was a 2-3-fold increase. An extended treatment period at low concentrations was associated with a 2-3 fold increase and the increase of ICAM-1 and VCAM-1 was more prominent under high concentration. Results of immunoblotting confirmed an increase in the abundance of ICAM-1, VCAM-1 and MCP-1. No significant change was noted in E-selectin and AT1R according to concentration or treatment duration. Pre-treatment with simvastatin did not alter IS-induced changes. SIGNIFICANCE IS increased the expression of adhesion molecules of endothelial cells exhibiting a concentration and duration dependent pattern. Simvastatin did not demonstrate any effect on IS-associated endothelial activation.

Comparison between Calcitriol and Calcitriol Plus Low-Dose Cinacalcet for the Treatment of Moderate to Severe Secondary Hyperparathyroidism in Chronic Dialysis Patients

Aim: Uremic hyperparathyroidism (UHPT) has been shown to contribute to the development and progression of chronic kidney disease—mineral bone disorder. UHPT is frequently observed in chronic dialysis patients, and patients with UHPT are associated with increased risk of all-cause and cardiovascular mortality. Cinacalcet is a novel agent that increases sensitivity to the calcium-sensing receptor and is approved for control of UHPT. Nevertheless, cinacalcet is costly and information regarding efficacy of low-dose cinacalcet on UHPT is limited. Methods: We conducted a retrospective study to evaluate treatment with either low-dose calcitriol combined with low-dose cinacalcet (25 mg) (d-Cinacalcet) or calcitriol alone (VitD) in dialysis patients with moderate to severe UHPT. A total of 81 dialysis patients were enrolled (40 subjects in d-Cinacalcet group and 41 subjects in VitD group). Demographic data including age, gender, duration on dialysis and biochemical data were reviewed and recorded. Results: At the end of the study, the intact parathyroid hormone (iPTH) levels of the d-Cinacalcet group declined significantly (from 1166.0 ± 469.3 pg/mL to 679.8 ± 421.6 pg/mL, p < 0.0001), while there was no significant change in the VitD group. Significant decrease of serum calcium (Ca: 9.9 ± 0.6 mg/dL vs. 9.6 ± 0.8 mg/dL, p = 0.002), phosphorus (P: 5.9 ± 1.3 mg/dL vs. 4.9 ± 0.9 mg/dL, p < 0.0001) and calcium phosphate product (Ca × P: 58.7 ± 15.0 mg2/dL2 vs. 46.9 ± 8.9 mg2/dL2, p < 0.0001) were observed in the d-Cinacalcet group. In addition, the subjects in the d-Cinacalcet group had a greater proportion to achieve Kidney Disease Outcomes Quality Initiative (KDOQI)-recommended biochemical targets than the subjects in the VitD group (Ca: 48% vs. 24%; P: 78% vs. 32%; Ca × P: 85% vs. 37%; iPTH: 15% vs. 0%). Conclusions: We conclude that combination therapy of low-dose cinacalcet and calcitriol is more effective than calcitriol alone as a treatment for moderate and severe UHPT in chronic dialysis patients. Furthermore, this therapy is associated with improvement in hyperphosphatemia and hypercalcemia.

Free p-cresol sulfate is associated with survival and function of vascular access in chronic hemodialysis patients.

Background: Protein-bound uremic toxins indoxyl sulfate (IS) and p-cresol sulfate (p-CS) have been implicated as an important factor in uremic syndrome. Recent evidence indicates that both IS and p-CS are predictors of cardiovascular as well as all-cause mortality among chronic dialysis patients. We conducted a study to analyze the relationship between IS and p-CS and vascular access (VA) outcome in chronic hemodialysis (HD) patients. Methods: A total of 91 chronic stable HD patients were divided into groups according to survival of VA and frequency of VA dysfunction. Demographic and biochemical data were reviewed and recorded. Serum levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1, and the total and free forms of IS and p-CS were determined. Results: Patients with a history of frequent VA failure and dysfunction had lower albumin and higher levels of ICAM-1, free IS, free and total p-CS. Diabetes was associated with higher IS and p-CS. Logistic regression revealed that diabetes and free p-CS were independent factors associated with poor outcome of VA. Conclusion: Endothelial dysfunction and uremic toxins were associated with survival and function of VA. Diabetes and free p-CS were significantly related to the outcome of VA among chronic HD patients.

Leukoencephalopathy Associated with Dialysis Disequilibrium Syndrome

Dialysis disequilibrium syndrome (DDS) is usually seen in severely uremic patients who are dialyzed aggressively. DDS mostly appeared within 24 hours after hemodialysis (HD) and may last for a few hours. This diagnosis is made by the exclusion of other causes including metabolic and intracranial events and has been recognized for more than 40 years. Few reports described the cerebral radiographic features associated with DDS. We present an 83-year-old uremic patient experiencing DDS at initial HD. DDS-related cerebral radiographic manifestations reported in the literature are reviewed, along with a discussion of the role of neuroimaging in the diagnosis of DDS.