Editorial

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Distribution of plasma folate forms in hemodialysis patients receiving high daily doses of l-folinic or folic acid

Distribution of plasma folate forms in hemodialysis patients receiving high daily doses of l-folinic or folic acid.BackgroundWe have previously reported that a daily oral high dose of l-folinic acid for the treatment of hyperhomocysteinemia in hemodialysis patients does not provide significantly greater reduction in fasting total homocysteine (tHcy) levels than an equimolar dose of folic acid. The present study uses the affinity/HPLC method to analyze the distribution of plasma folate forms in patients who received l-folinic acid versus those who received folic acid. This was done to investigate claims that renal insufficiency is associated with impaired folate interconversion, a stance that is supportive of the premise that tHcy lowering in these patients is more efficacious with folinic acid and other reduced folates, than folic acid.MethodsForty-eight chronic and stable hemodialysis patients were block-randomized, based on their screening predialysis tHcy levels, sex, and dialysis center, into two groups treated for 12 weeks with oral folic acid at 15 mg/day or an equimolar amount (20 mg/day) of oral l-folinic acid. All 48 subjects also received 50 mg/day of oral vitamin B6 and 1 mg/day of oral vitamin B12. Folate distribution was determined in plasma of 46 participants (Folinic acid group, N = 22; Folic acid group, N = 24) by using the affinity/HPLC method, with electrochemical (coulometric) detection.ResultsBoth groups had similar baseline geometric means of plasma total folate and similar folate forms distribution. Following treatment, both groups demonstrated similar marked elevation in plasma total folate (geometric mean of the increase: Folinic acid group, +337 ng/mL; Folic acid group, +312 ng/mL; P = 0.796). In the folinic acid-treated group, practically all of the increase in total folate was due to 5-methyltetrahydrofolate. In the folic acid-treated group 5-methyltetrahydrofolate accounted for 35% of the increase in total folate and the remainder was unmethylated folic acid.ConclusionsData from the present findings suggest that defects in folate absorption or impairment in folate interconversion are not the cause of the persistent hyperhomocysteinemia in hemodialysis patients

Ecdysone Elicits Chronic Renal Impairment via Mineralocorticoid-Like Pathogenic Activities

Background/Aims: Ecdysteroids are steroidal insect molting hormones that also exist in herbs. Ecdysteroid-containing adaptogens have been popularly used to improve well-being and by bodybuilders for muscle growth. However, the use of ecdysone in mammals is also associated with kidney growth and enlargement, indications of disturbed kidney homeostasis. The underlying pathogenic mechanism remains to be clarified. Methods: Virtual screening tools were employed to identify compounds that are homologous to ecdysone and to predict putative ecdysone-interacting proteins. The kidney effect of ecdysone was examined in vitro and in vivo and compared with that of aldosterone. Cellular apoptosis was estimated by terminal deoxynucleotidyl transferase dUTP nick end labeling. Cell motility was assessed by scratch-wound cell migration assay. Blood urea nitrogen was measured to evaluate renal function. Western immunblot analysis was employed to determine the expression profile of interested proteins. Results: Computational molecular structure analysis revealed that ecdysone is highly homologous to aldosterone. Moreover, virtual screening based on compound-protein interaction profiles identified the Mineralocorticoid Receptor (MR) to potentially interact with ecdysone. Accordingly, to assess potential biological functions of ecdysone in mammals, ecdysone was applied to mineralocorticoid-sensitive inner medullar collecting duct cells. Ecdysone induced mesenchymal accumulation of extracellular matrix and epithelial dedifferentiation characterized by de novo expression of α-smooth muscle actin. In addition, ecdysone elicited cellular apoptosis and retarded cell motility, akin to the effect of aldosterone. In vivo, daily treatment of mice with ecdysone increased cell apoptosis in the kidney, impaired renal function and elicited early signs of renal fibrogenesis, marked by deposition of collagen and fibronectin in tubulointerstitium, reminiscent of the action of aldosterone. The MR signaling pathway is likely responsible for the cellular and pathobiological effects of ecdysone, as evidenced by strong ecdysone-induced MR nuclear translocation in renal tubular cells both in vitro and in vivo, while blockade of MR by concomitant spironolactone treatment largely abolished the detrimental effects of ecdysone. Conclusion: Our findings suggest that ecdysone induces mineralocorticoid-dependent activities that impair renal function and elicit renal injury

Prediction of cardiovascular outcomes with machine learning techniques: application to the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study.

Background: Data derived from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study were analyzed in an effort to employ machine learning methods to predict the composite endpoint described in the original study. Methods: We identified 573 CORAL subjects with complete baseline data and the presence or absence of a composite endpoint for the study. These data were subjected to several models including a generalized linear (logistic-linear) model, support vector machine, decision tree, feed-forward neural network, and random forest, in an effort to attempt to predict the composite endpoint. The subjects were arbitrarily divided into training and testing subsets according to an 80%:20% distribution with various seeds. Prediction models were optimized within the CARET package of R. Results: The best performance of the different machine learning techniques was that of the random forest method which yielded a receiver operator curve (ROC) area of 68.1%±4.2% (mean ± SD) on the testing subset with ten different seed values used to separate training and testing subsets. The four most important variables in the random forest method were SBP, serum creatinine, glycosylated hemoglobin, and DBP. Each of these variables was also important in at least some of the other methods. The treatment assignment group was not consistently an important determinant in any of the models. Conclusion: Prediction of a composite cardiovascular outcome was difficult in the CORAL population, even when employing machine learning methods. Assignment to either the stenting or best medical therapy group did not serve as an important predictor of composite outcome. Clinical Trial Registration: ClinicalTrials.gov, NCT00081731

Interleukin 10-Mediated Response and Correlated Anemia in a Patient with Advanced Non-Small Cell Lung Carcinoma

Anemia in cancer patients is associated with poor quality of life, reduced response to therapy, and decreased overall survival. We describe a case of a 56-year old woman with advanced metastatic non-small cell lung carcinoma who demonstrated marked response to a novel combinational immunotherapy approach involving a long-acting PEGylated construct of recombinant human Interleukin-10 with Nivolumab, an anti-PD-L1 checkpoint inhibitor. While on treatment, the patient developed severe anemia and hyper-ferritinemia requiring RBC transfusion support. Here we discuss a possible novel immune mechanism of IL10-mediated anemia in correlation with tumor response

Delivering an Optimised Behavioural Intervention (OBI) to people with low back pain with high psychological risk; results and lessons learnt from a feasibility randomised controlled trial of Contextual Cognitive Behavioural Therapy (CCBT) vs. Physiotherapy

Background: Low Back Pain (LBP) remains a common and costly problem. Psychological obstacles to recovery have been identified, but psychological and behavioural interventions have produced only moderate improvements. Reviews of trials have suggested that the interventions lack clear theoretical basis, are often compromised by low dose, lack of fidelity, and delivery by non-experts. In addition, interventions do not directly target known risk mechanisms. We identified a theory driven intervention (Contexual Cognitive Behavioural Therapy, CCBT) that directly targets an evidence-based risk mechanism (avoidance and ensured dose and delivery were optimised. This feasibility study was designed to test the credibility and acceptability of optimised CCBT against physiotherapy for avoidant LBP patients, and to test recruitment, delivery of the intervention and response rates prior to moving to a full definitive trial. Methods: A randomised controlled feasibility trial with patients randomised to receive CCBT or physiotherapy. CCBT was delivered by trained supervised psychologists on a one to one basis and comprised up to 8 one-hour sessions. Physiotherapy comprised back to fitness group exercises with at least 60 % of content exercise-based. Patients were eligible to take part if they had back pain for more than 3 months, and scored above a threshold indicating fear avoidance, catastrophic beliefs and distress. Results: 89 patients were recruited. Uptake rates were above those predicted. Scores for credibility and acceptability of the interventions met the set criteria. Response rates at three and six months fell short of the 75 % target. Problems associated with poor response rates were identified and successfully resolved, rates increased to 77 % at 3 months, and 68 % at 6 months. Independent ratings of treatment sessions indicated that CCBT was delivered to fidelity. Numbers were too small for formal analysis. Although average scores for acceptance were higher in the CCBT group than in the group attending physiotherapy (increase of 7.9 versus 5.1) and change in disability and pain from baseline to 6 months were greater in the CCBT group than in the physiotherapy group, these findings should be interpreted with caution. Conclusions: CCBT is a credible and acceptable intervention for LBP patients who exhibit psychological obstacles to recovery