Supplementation with Folic Acid and Cardiovascular Outcomes in End-Stage Kidney Disease: A Multi-Institution Cohort Study.

BACKGROUND: Folate is a water-soluble vitamin and is essential for maintaining cell functions. Dialysis removes folate, and folate deficiency is reported in patients with end-stage kidney disease (ESKD). However, there is no consensus as to the appropriate dosage of folate supplements and their advantages and disadvantages for patients with ESKD. METHODS: This study was based on the electronic medical records of the Chang Gung Research Database (CGRD) of the Chang Gung Medical Foundation. We included patients who were diagnosed with ESKD, initiated hemodialysis, and were given folic acid supplements at any point from 1 January 2001 to 31 December 2019. The patients were divided into weekly and daily folic acid supplementation groups. We reduced the effects of confounding through the inverse probability of treatment weighting based on the propensity score. RESULTS: We identified 2081 and 954 newly diagnosed patients with ESKD, who received daily and weekly folic acid supplements. The mean follow-up time was 5.8 years, and the event rates of arteriovenous access thrombosis were 17.0% and 23.6% in the daily and weekly folic acid supplementation groups (sub-distribution hazard ratio = 0.69, 95% confidence interval = 0.61 to 0.77), respectively. Neither group significantly differed in the occurrence of other clinical events, such as major cardiovascular cardiac events (e.g., myocardial infarction and ischemic stroke), all-cause mortality, cardiovascular death, infection death, malignancy, and adverse effects. CONCLUSION: a daily 5 mg folic acid supplementation might result in a lower event rate of arteriovenous access thrombosis in patients with ESKD than weekly folic acid supplementation. Further prospective studies are warranted to explore the preventive effect of folate on thrombosis.

Ketoanalogues Supplemental Low Protein Diet Safely Decreases Short-Term Risk of Dialysis among CKD Stage 4 Patients.

Background: Rigid dietary controls and pill burden make a very-low protein (0.3−0.4 g/kg body weight per day), vegetarian diet supplemented with ketoanalogues of amino acids (sVLPD) hard to follow in the long-term. This study aimed to evaluate whether a ketoanalogue supplemental low-protein diet (sLPD) (0.6 g/kg body weight per day) could also reduce the risks of dialysis among CKD stage 4 patients. Methods: Patients aged >20 years with a diagnosis of stage 4 CKD who subsequently received ketosteril treatment, which is the most commonly used ketoanalogue of essential amino acids, between 2003 and 2018 were identified from the Chang Gung Research Database (CGRD). Then, these individuals were divided into two groups according to the continuation of ketosteril for more than three months or not. The primary outcome was ESKD requiring maintenance dialysis. Results: With one-year follow-up, the continuation group (n = 303) exhibited a significantly lower incidence of new-onset end-stage kidney disease (ESKD) requiring maintenance dialysis (6.8% vs. 10.4%, hazard ratio [HR]: 0.62, 95% confidence interval [CI]: 0.41−0.94) in comparison to the discontinuation group (n = 238). Conclusions: This study demonstrated that initiating sLPDs since CKD stage 4 may additionally reduce the short-term risks of commencing dialysis without increasing CV events, infections, or mortality.

Ketoanalogue supplements reduce mortality in patients with pre-dialysis advanced diabetic kidney disease: A nationwide population-based study.

BACKGROUND & AIMS: Metabolism dysregulation and protein energy wasting occur in patients with chronic kidney disease (CKD) and are associated with poor survival, especially in patients prior to starting dialysis. Accumulating evidence indicates that dietary supplementation with ketoanalogues (KAs, a mixture of branched-chain amino acids) exerts a variety of beneficial effects for patients with CKD. However, the role of KAs in diabetic kidney disease (DKD), one of the major causes of CKD, is still controversial. The aim of this study was to explore the impact of KA supplements on survival in patients with stage 5 DKD who have not yet started dialysis (DKD-5-ND). METHODS: We analyzed a nationwide cohort retrieved from the National Health Insurance Research Database in Taiwan to study the long-term impact of KA supplements in patients with DKD-5-ND. We enrolled 15,782 incident pre-dialysis DKD patients between January 1, 2004 and December 31, 2007. Landmark analysis was used to eliminate immortal bias, and overlap weighting was used to balance differences between the KA users and nonusers in the beginning. The primary study endpoint was all-cause mortality, and the occurrence of permanent dialysis (presenting the end-stage renal disease, ESRD) and major adverse cardiovascular events (MACEs) was also evaluated. All patients were followed for five years or until death. RESULTS: The prevalence of KA usage in the DKD-5-ND patients was 6.3%. The 5-year all-cause mortality rate in the KA users was lower than that in the nonusers (34.7% vs 42.7%). After adjusting for known covariates, the KA users still had a lower risk of mortality (adjusted hazard ratio [aHR]: 0.73, 95% confidence interval [CI]: 0.66-0.82). In addition, the incidence of ESRD was also slightly lower among the KA users (90.9% for users vs 91.2% for nonusers, adjusted cause-specific hazard ratio [aCSHR]: 0.65, 95% CI: 0.61-0.69), and the occurrence of MACEs was lower (adjusted incidence rate ratios [aIRR]: 0.76, 95% CI: 0.67-0.86). Although the all-cause mortality was higher among patientsolder than 70 years (60.5% for KA users vs 46.5% for nonusers) the risk reduction seemed prominent among older patients (aHR: 0.65, 95% CI: 0.56-0.76 for patients aged ≥70 years; aHR: 0.82, 95% CI: 0.71-0.96 for patients aged < 70 years). The reduction in risks of mortality was consistent in subgroup analysis and sensitivity tests. CONCLUSIONS: The use of KA supplements seemed to be beneficial for patients with DKD-5-ND; further in-depth analysis of using KA for these patients is warranted.

Traditional Chinese medicine use is associated with lower end-stage renal disease and mortality rates among patients with diabetic nephropathy: a population-based cohort study.

BACKGROUND: Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM) that imposes an enormous burden on the healthcare system. Although some studies show that traditional Chinese medicine (TCM) treatments confer a protective effect on DN, the long-term impact remains unclear. This study aims to examine end-stage renal disease (ESRD) and mortality rates among TCM users with DN. METHODS: A total of 125,490 patients with incident DN patients from 2004 to 2006 were identified from the National Health Insurance Research Database in Taiwan and followed until 2012. The landmark method was applied to avoid immortal time bias, and propensity score matching was used to select 1:1 baseline characteristics-matched cohort. The Kaplan-Meier method and competing-risk analysis were used to assess mortality and ESRD rates separately. RESULTS: Among all eligible subjects, about 60% of patients were classified as TCM users (65,812 TCM users and 41,482 nonusers). After 1:1 matching, the outcomes of 68,882 patients were analyzed. For the ESRD rate, the 8-year cumulative incidence was 14.5% for TCM users [95% confidence interval (CI): 13.9-15.0] and 16.6% for nonusers (95% CI: 16.0-17.2). For the mortality rate, the 8-year cumulative incidence was 33.8% for TCM users (95% CI: 33.1-34.6) and 49.2% for nonusers (95% CI: 48.5-49.9). After adjusting for confounding covariates, the cause-specific hazard ratio of ESRD was 0.81 (95% CI: 0.78-0.84), and the hazard ratio of mortality for TCM users was 0.48 (95% CI: 0.47-0.50). The cumulative incidence of mortality increased rapidly among TCM users with ESRD (56.8, 95% CI: 54.6-59.1) when compared with TCM users without ESRD (30.1, 95% CI: 29.4-30.9). In addition, TCM users who used TCM longer or initiated TCM treatments after being diagnosed with DN were associated with a lower risk of mortality. These results were consistent across sensitivity tests with different definitions of TCM users and inverse probability weighting of subjects. CONCLUSIONS: The lower ESRD and mortality rates among patients with incident DN correlates with the use of TCM treatments. Further studies about specific TCM modalities or medications for DN are still needed.

The anti-tumor activity of Antrodia salmonea in human promyelocytic leukemia (HL-60) cells is mediated via the induction of G1 cell-cycle arrest and apoptosis in vitro or in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: The medicinal mushroom Antrodia salmonea has been used as a traditional Chinese medicine and has demonstrated antioxidant and anti-inflammatory effects. MATERIALS AND METHODS: In the present study, we examined the anti-tumor activity of the fermented culture broth of Antrodia salmonea (AS) in vitro and in vivo and revealed its underlying molecular mechanism of action. RESULTS: Treatment of human promyelocytic leukemia (HL-60) cells with AS (50-150 µg/mL) significantly reduced cell viability and caused G1 arrest via the inhibition of cell-cycle regulatory proteins, including cyclin D1, CDK4, cyclin E, cyclin A, and phosphorylated retinoblastoma protein (p-Rb). Furthermore, AS treatment induced apoptosis, which was associated with DNA fragmentation, followed by a sequence of events, including intracellular ROS generation; mitochondrial dysfunction; Fas ligand activation; cytochrome c release; caspase-3, -8, -9, and PARP activation; and Bcl-2/Bax dysregulation. The results of the in vitro study suggested that AS-induced apoptosis in HL-60 cells was mediated by both the mitochondrial and death receptor pathways. Furthermore, we found that AS treatment was effective in delaying tumor incidence in HL-60 xenografted nude mice and reducing tumor burden. CONCLUSIONS: To the best of our knowledge, this is the first report confirming the anti-tumor activity of this potentially beneficial mushroom against human promyelocytic leukemia.

Angiotensin II receptor antagonists supplementation is associated with arterial stiffness: insight from a retrospective study in 116 peritoneal dialysis patients.

BACKGROUND: Brachial-ankle pulse wave velocity (baPWV), a non-invasive waveform analysis, is a useful tool for the vascular evaluation of arterial stiffness. Increased baPWV values have been found increased in patients with arterial stiffness. The aim of this study was to investigate retrospectively the association between arterial stiffness and the common medications used in peritoneal dialysis patients. METHODS: In all, 116 peritoneal dialysis patients (35 males and 81 females) received peritoneal dialysis for more than four months. Patients who had dialysis-related peritonitis or other infection within six months prior to this study, inflammation disease, fasting serum sugar >or=126 mg/dL, and/or use of oral hypoglycemic agents or insulin injections were excluded. The medications that were enrolled in our study were calcium-containing phosphate binders, vitamin-B complex, folic acid, and antihypertensive medications. baPWV was determined using an automated, non-invasive, waveform analysis device. RESULTS: In a step-wise multiple linear regression analysis, baPWV correlated independently with systolic blood pressure (t = 8.4, p < 0.001) and age (t = 5.5, p < 0.001), and inversely correlated with body mass index (t = -3.19, p = 0.002) and the use of angiotensin II receptor antagonists (t = -2.35, p = 0.021). CONCLUSION: In this retrospective study of peritoneal dialysis patients, we found that angiotensin II receptor antagonists (ARBs) in peritoneal dialysis patients may be an independent factor for arterial stiffness. Hence, we suggest that compared with other antihypertensive drugs, ARBs may be a good choice for lowering arterial stiffness in PD patients. However, further studies on the optimal treatment of arterial stiffness in peritoneal dialysis patients are warranted.