Chien-Te Lee

Asymmetric dimethylarginine is associated with developmental programming of adult kidney disease and hypertension in offspring of streptozotocin-treated mothers.

Diabetes mellitus complicates pregnancies, leading to diseases in adult life in the offspring. Asymmetric dimethylarginine (ADMA) is increased in diabetes mellitus, kidney disease, and hypertension. We tested whether maternal diabetes causes increased ADMA in rats, resulting in kidney disease and hypertension in the adult offspring, and whether these can be prevented by maternal citrulline supplementation. Newborn female and pregnant Sprague-Dawley rats were injected with streptozotocin (STZ), which made up the nSTZ and STZ models, respectively. For the STZ model, 4 groups of male offspring were killed at age 3 months: the control, STZ, and Cit and STZ+Cit (control and STZ rats treated with 0.25% l-citrulline solution, respectively) groups. The nSTZ rats had lower nephron numbers. The renal level of ADMA was higher in the nSTZ rats than in controls. The STZ group developed kidney injury, renal hypertrophy, and elevated blood pressure at the age of 12 weeks. These conditions were found to be associated with increased ADMA levels, decreased nitric oxide (NO) production, and decreased dimethylarginine dimethylaminohydrolase (DDAH) activity in the kidney. In addition, ADMA caused a nephron deficit in cultured rat metanephroi. Maternal citrulline supplementation prevented hypertension and kidney injury, increased the renal DDAH-2 protein level, and restored the levels of ADMA and NO in the STZ+Cit group. Reduced nephron number and increased ADMA contribute to adult kidney disease and hypertension in offspring of mothers with STZ-induced diabetes. Manipulation of the ADMA-NO pathway by citrulline supplementation may be a potential approach to prevent these conditions.

Risk of Herpes Zoster in Patients Treated With Long-term Hemodialysis: A Matched Cohort Study

BACKGROUND The risk of herpes zoster in the dialysis population relative to the general population is not known. The aim of this study was to perform a population-based cohort study to investigate the risk of herpes zoster after the initiation of hemodialysis therapy in patients with end-stage renal disease (ESRD) in Taiwan, a country with the highest incidence of ESRD in the world. STUDY DESIGN Matched cohort study. SETTING & PARTICIPANTS Data were obtained from the Taiwan National Health Insurance Research Database. 843 patients who were beginning hemodialysis therapy in 1999-2003 were included as the study cohort and 3,372 patients without ESRD matched for age and sex were included as a comparison cohort. A multivariate frailty Cox proportional hazard regression model was used to adjust for confounding and compare the 6-year herpes zoster-free survival rate between these 2 cohorts. PREDICTORS Hemodialysis. OUTCOMES Herpes zoster. RESULTS Mean years of follow-up were 4.73 and 5.49 for the hemodialysis and comparison cohorts, respectively. 868 patients developed herpes zoster throughout the study period, 294 from the hemodialysis cohort and 574 from the comparison cohort. The incidence rate of herpes zoster (73.34 events/1,000 person-year) was significantly higher in the hemodialysis cohort than in the control cohort (31.03 events/1,000 person-years). After adjusting for potential confounders, the adjusted HR of herpes zoster was 1.98 (95% CI, 1.72-2.27). LIMITATIONS We expect that some patients with mild zoster chose not to seek medical help. CONCLUSIONS We conclude that patients treated with long-term hemodialysis are at an increased risk of herpes zoster compared with the general population.

Activation of Intrarenal Renin-Angiotensin System during Metabolic Acidosis

Background: Chronic metabolic acidosis is a common metabolic disturbance and its clinical impact can be severe and extensive. The role and the change of the intrarenal renin-angiotensin system (RAS) during metabolic acidosis are uncertain, and whether acidosis can evoke inflammation remains unclear. Methods: Male Sprague-Dawley rats were fed with water containing 0.14 M NH4Cl to induce metabolic acidosis for 1 and 8 weeks, respectively. They were compared with animals fed with deionized water (control) and equimolar sodium chloride water (NaCl). Gene expression analysis of RAS components included renin, renin/prorenin receptor, angiotensinogen, angiotensin-converting enzyme (ACE), and angiotensin II type 1 and 2 receptors (AT1R and AT2R). Histological examination was also performed to detect morphological change. Results: Acidosis was found in 1-week NH4Cl-treated rats but not in the 8-week group. More than twofold proteinuria and a significant decline of glomerular filtration rate (GFR) were observed in acid-loaded rats. Compared to the control and NaCl groups, angiotensinogen, ACE, AT1R and AT2R were significantly increased in the 1-week acidosis group (all p < 0.05). Sustained increase of AT1R expression was found as NH4Cl was continued for 8 weeks. There was no significant change in transforming growth factor-β and nuclear factor-ĸB. The architecture of tubular epithelial cells was affected during our experiment. Conclusion: Metabolic acidosis induced proteinuria and decline of GFR in association with activation of intrarenal RAS.

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.

Melatonin prevents increased asymmetric dimethylarginine in young rats with bile duct ligation

Abstract:  Identifying and treating kidney injury in cirrhosis is important. Bile duct ligation (BDL) is a commonly used cholestatic liver disease model. We hypothesized that asymmetric dimethylarginine (ADMA) is involved in BDL‐induced oxidative stress and kidney injury, which can be prevented by melatonin. We also intended to elucidate whether increased ADMA is due to increased protein arginine methyltransferase‐1 (PRMT1, ADMA‐synthesizing enzyme) and/or decreased dimethylarginine dimethylaminohydrolase (DDAH, ADMA‐metabolizing enzyme). Three groups of young rats were studied, sham (N = 7), untreated BDL rats (N = 9), and melatonin‐treated BDL rats (N = 6, BDL + M). Melatonin‐treated BDL rats received daily melatonin 1 mg/kg/day via intraperitoneal injection. One‐third of the young BDL rats died compared with none in the BDL + M group. All surviving rats were killed 14 days after surgery. BDL rats had higher plasma aspartate aminotransferase, alanine aminotransferase, direct and total bilirubin, and ammonia levels than shams. They also had kidney injury characterized by increased tubulointerstitial injury scores and plasma creatinine and symmetric dimethylarginine levels, which melatonin prevented. Plasma ADMA levels were elevated in BDL rats, combined with increased hepatic PRMT1 and decreased renal DDAH activity. In addition, melatonin increased hepatic DDAH2 expression, increased DDAH activity and concomitantly decreased ADMA contents in both the liver and kidney. In conclusion, melatonin therapy decreased mortality and prevented kidney injury induced by BDL via reduction of ADMA (by increasing DDAH activity) and oxidative stress.

Mitochondrial DNA copy number correlates with oxidative stress and predicts mortality in nondiabetic hemodialysis patients

BACKGROUND Oxidative stress is highly prevalent in hemodialysis patients and may contribute to atherosclerosis and mortality. The copy number of mitochondrial DNA (mtDNA) is affected by oxidative stress in blood circulation. This study aimed to test whether mtDNA copy number correlates with oxidative stress and predicts all-cause mortality in nondiabetic hemodialysis patients. METHODS Ninety-five nondiabetic hemodialysis patients and 95 healthy subjects were enrolled. Plasma thiobarbituric acid-reactive substances (TBARS) and plasma free thiol were used as indicators of oxidative stress and antioxidant defense, respectively. Mitochondrial DNA copy number in peripheral blood leukocytes was measured by determining relative amounts of mtDNA to nuclear DNA by quantitative real-time PCR. All-cause mortality of hemodialysis patient was recorded during a follow-up of 3 years. RESULTS Nondiabetic hemodialysis patients showed higher TBARS levels, lower free thiol levels and higher mtDNA copy numbers compared with normal control subjects. The plasma TBARS level was a significant factor correlating positively to the mtDNA copy number (p=0.024). Patients with a mtDNA copy number higher than the median had a higher all-cause mortality than patients with a lower mtDNA copy number (17.0% vs. 4.2%; log-rank test: p=0.038). A 1-log increase in mtDNA copy number was independently related to an increase in the risk for mortality (hazard ratio 21.360; 95% confidence interval, 1.298-351.572). CONCLUSIONS Nondiabetic hemodialysis patients had higher oxidative stress and mtDNA copy numbers than healthy subjects. The mtDNA copy number correlates with oxidative stress and predicts mortality in nondiabetic hemodialysis patients.

Efficacy and Safety of Pegylated Interferon Alfa-2b and Ribavirin Combination Therapy Versus Pegylated Interferon Monotherapy in Hemodialysis Patients: A Comparison of 2 Sequentially Treated Cohorts

BACKGROUND Pegylated interferon (peginterferon; interferon with an attached polyethylene glycol molecule) monotherapy is the recommended treatment for chronic hepatitis C virus (HCV) infection in hemodialysis patients. Limited data concerning peginterferon alfa-2b and ribavirin treatment in this population are available. STUDY DESIGN 2 prospective observational cohort studies. SETTING & PARTICIPANTS From 2007-2009, a total of 26 patients received peginterferon alfa-2b monotherapy. From 2009-2012, an additional 26 patients were treated with peginterferon alfa-2b and ribavirin. PREDICTORS Peginterferon alfa-2b monotherapy, 1.0 μg/kg/wk, versus peginterferon alfa-2b, 1.0 μg/kg/wk, and ribavirin, 200 mg, 3 times per week. Treatment durations were 24 and 48 weeks for HCV genotypes non-1 and 1, respectively. OUTCOMES & MEASUREMENTS End-of-treatment virologic response and sustained virologic response (SVR) were undetectable HCV RNA at the end of treatment and 24 weeks after treatment ended, respectively. SVR and treatment-related withdrawal rate were evaluated by intention-to-treat (ITT) and per-protocol (PP) analyses. Severe anemia was defined as nadir hemoglobin level <8 g/dL. RESULTS Patients who received combination therapy had a higher end-of-treatment virologic response than patients who received monotherapy (85% vs 62% in ITT [P = 0.03] and 100% vs 80% in PP [P = 0.03]). The SVR rate was higher in the combination-treatment cohort than in the monotherapy cohort (62% vs 27% in ITT [P = 0.01] and 73% vs 35% in PP [P = 0.01]). Patients who received combination therapy had a significantly higher rate of severe anemia than those who received monotherapy (58% vs 27%; P = 0.03). However, treatment withdrawal rates were similar between the combination (15%) and monotherapy (23%) groups. LIMITATIONS Comparison of 2 sequential cohorts rather than a randomized control study. CONCLUSIONS Peginterferon alfa-2b and ribavirin combination therapy provided a higher SVR rate than peginterferon alfa-2b monotherapy for treatment-naive dialysis patients with chronic HCV infection through careful monitoring of hematologic parameters and ribavirin dose modification. Severe anemia was significantly higher in patients receiving combination therapy than patients treated with monotherapy.

Aliskiren in early postnatal life prevents hypertension and reduces asymmetric dimethylarginine in offspring exposed to maternal caloric restriction

Introduction: Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is involved in hypertension. We tested whether aliskiren treatment in early postnatal life can reduce ADMA and regulate the renin-angiotensin system to prevent hypertension in rat offspring exposed to maternal caloric restriction (CR). Materials and methods: Four groups of 12-week-old male offspring were sacrificed: control, CR, CR+aliskiren, and CR+losartan group. The CR group included offspring from 50% food-restricted maternal rats. The CR+aliskiren and CR+losartan groups were produced by treating CR offspring with oral aliskiren 10 mg/kg/day or losartan 20 mg/kg/day between 2–4 weeks of age, respectively. Results: Blood pressure increased in CR rats, which was prevented by aliskiren or losartan. CR increased plasma ADMA levels, which aliskiren prevented. Renal renin and prorenin receptor (PRR) expression increased in CR rats treated with aliskiren, whereas both were reduced by losartan. Both aliskiren and losartan decreased renal mRNA expression of angiotensinogen, angiotensin II type 2 receptor, and Mas in CR rats. However, aliskiren increased angiotensin II type 2 receptor and Mas protein levels in CR kidneys. Conclusions: Early aliskiren therapy prevents CR-induced hypertension via ADMA reduction, decreases angiotensinogen expression, and increases renal angiotensin II type 2 receptor and Mas protein.

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.