Terry Ting-Yu Chiou

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.

Comparison of Iodixanol and Iohexol in Patients Undergoing Intravenous Pyelography: A Prospective Controlled Study

Background. Nephropathy associated with contrast medium exposure is a well-known complication of IVP. However, it is uncertain whether iso-osmolar non-iodinated contrast medium (iodixanol) is less nephrotoxic than low-osmolar contrast medium (iohexol). Materials and Methods. In this single-center, double-blind, prospective study, 50 patients undergoing IVP were randomized into two groups receiving different contrast medium: iodixanol and iohexol. Patients in high risk for contrast nephropathy were included, 28 with renal insufficiency and 19 with diabetes mellitus. We compared the nephrotoxic effect (contrast nephropathy), complement and cytokines profile between the iodixanol and iohexol groups. The mean volume of contrast medium in each IVP procedure was 0.8 mL/kg. Results. The incidence of contrast nephropathy was 4 percent among all patients (one iodixanol and one iohexol). We found no significant differences in contrast nephropathy and allergic reactions between the two groups. There was no significant difference in cytokine profiles in both groups (p > 0.05).The incidence of allergic reaction was 16 percent among all patients. Twelve percent (3/25) had late reaction after iohexol exposure compared to four percent (2/25) with iodixanol (p = 1.0). One patient had severe skin rash due to late adverse reaction after iodixanol. No mortality was found. Conclusions. New iodixanol and iohexol contrast medium for routine IVP examination are safe and have low nephrotoxicity profile, especially in elderly or high-risk patients. Iodixanol contrast medium has an increased risk to induce severe late adverse reaction compared to iohexol. Allergic reaction may be the main adverse effect after contrast medium infusion.

Effects of AST-120 on blood concentrations of protein-bound uremic toxins and biomarkers of cardiovascular risk in chronic dialysis patients.

Background: Removal of protein-bound uremic toxins by dialysis therapy is limited. The effect of oral adsorbent AST-120 in chronic dialysis patients has rarely been investigated. Methods: AST-120 was administered 6.0 g/day for 3 months in 69 chronic dialysis patients. The blood concentrations of indoxyl sulfate, p-cresol sulfate and biomarkers of cardiovascular risk were determined before and after AST-120 treatment. Results: AST-120 significantly decreased both the total and free forms of indoxyl sulfate and p-cresol sulfate ranging from 21.9 to 58.3%. There were significant simultaneous changes of the soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK, 24% increase), malondialdehyde (14% decrease) and interleukin-6 (19% decrease). A significant association between the decrease of indoxyl sulfate and changes of sTWEAK and interleukin-6 was noted. Conclusions: AST-120 effectively decreased indoxyl sulfate and p-cresol sulfate levels in both total and free forms. AST-120 also improved the profile of cardiovascular biomarkers.

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.

Calcification of the Aortic Arch Predicts Cardiovascular and All-Cause Mortality in Chronic Hemodialysis Patients

Background: Cardiovascular calcification represents a marker of cardiovascular risk in chronic dialysis patients. In the general population, aortic arch calcification (AAC) can predict cardiovascular mortality. We conducted a prospective study to investigate factors associated with AAC in hemodialysis patients and examined its prognostic value in long-term outcome. Methods: A total of 712 hemodialysis patients were enrolled. AAC was identified on postero-anterior chest X-ray films and classified as grade (Gr.) 0, 1, 2 or 3. Demographic data including age, gender, dialysis vintage, co-morbidity and biochemical data were reviewed and recorded. The patients were followed for 10 years. Results: AAC was present in 164 patients (23%) as Gr. 1, in 116 patients (16.3%) as Gr. 2 and in 126 patients (17.7%) as Gr. 3. An increase in the severity of calcification was associated with older patients who had lower albumin, higher calcium and glucose levels. During the follow-up period of 10 years, we found that the grade of AAC was directly related to cardiovascular mortality (Gr. 0: 5.3%; Gr. 1: 12.7%; Gr. 2: 18.9%, and Gr. 3: 24.4%; p < 0.05) and all-cause mortality (Gr. 0: 19.9%; Gr. 1: 31.1%; Gr. 2: 44.8%, and Gr. 3: 53.2%; p < 0.001). Multivariate Cox proportional hazards analysis revealed that high-grade calcification was associated with cardiovascular and all-cause mortality. Patients with AAC were associated with a worse outcome in survival analysis. The severity of AAC also influenced their survival. Conclusion: Calcification of the aortic arch detected in plain chest radiography was an important determinant of cardiovascular as well as all-cause mortality in chronic hemodialysis patients. The presence and severity of AAC predicted long-term survival.

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.

Renin angiotensin system blockade ameliorates lead nephropathy.

Lead intoxication is usually insidious and may cause a variety of complications such as kidney damage and hypertension. The role of intrarenal renin-angiotensin system (RAS) in lead-induced nephropathy has not been investigated. Adult male Sprague-Dawley rats were fed with water containing 250ppm of lead acetate (lead group) and deionized water (control group) for 4weeks. Another two groups started to receive intraperitoneal captopril (50mg/kg/d) or losartan (10mg/kg/d) after 2weeks of lead feeding and continued for another 2weeks. Immunoblotting was used to analyze the protein amount of intrarenal RAS components and transforming growth factor-beta (TGF-β). Compared with control group, lead exposure resulted in increased proteinuria after 2-week treatment (4.2±0.9mg/100g vs. 1.8±0.8mg/100g, p<0.05) and 4-week (5.2±1.7mg/100g, p<0.05). Serum creatinine level was increased (0.40±0.2 vs. 0.3 ±.04mg/dL, p<0.05) and calculated glomerular filtration rate (GFR) was decreased (2.68±1.03 vs. 3.37±0.11mL/min, p<0.05). Intrarenal angiotensin converting enzyme (ACE), angiotensin II (ANG II), angiotensin II type 1 receptor (AT1R) and transforming growth factor-beta (TGF-β) were upregulated in lead group. Captopril and losartan administration reduced proteinuria significantly (3.0±0.50mg/100g of captopril and 2.7±0.4mg/100g of losartan group) and lowered systolic blood pressure when compared with lead group. Furthermore, serum creatinine levels and GFR were improved by RAS blockade. Captopril treatment significantly reduced protein abundance of ACE, ANG II, AT1R and TGF-β. Losartan treatment also decreased ANG II and TGF-β. We concluded that lead exposure elicited intrarenal RAS activation with associated proteinuria and impaired renal function. RAS blockade was effective in alleviating lead-associated kidney injury and lowering blood pressure.

A Quality and Cost-Benefit Analysis of Dialyzer Reuse in Hemodialysis Patients

Background. To evaluate the benefits of dialyzer reuse for hemodialysis (HD) patients, including the cost of HD treatment and patients survival, a comparison was made regarding the standard practice of single-use dialysis. Methods. From January 1, 2005, to December 31, 2005, a total of 128,232 successive HD treatments in 822 patients in Chang Gung Memorial Hospital-Kaohsiung Medical Center were included in this study. Results. Approximately 54.25% (446/822) of patients reused dialyzers. The average times of dialyzer reuse was 2.54. The annual hollow fiber cost is reduced by

Leukoencephalopathy Associated with Dialysis Disequilibrium Syndrome

241,054.08 U.S. dollars (NT

Gelsolin and Progression of Aortic Arch Calcification in Chronic Hemodialysis Patients

7,834,257.60). The annual cost of hollow fiber was reduced by