Impact of Bioelectrical Impedance-Guided Fluid Management and Vitamin D Supplementation on Left Ventricular Mass in Patients Receiving Peritoneal Dialysis: A Randomized Controlled Trial.

RATIONALE & OBJECTIVE: Hypervolemia and vitamin D deficiency occur frequently in patients receiving peritoneal dialysis and may contribute to left ventricular (LV) hypertrophy. The effect of bioelectrical impedance analysis (BIA)-guided volume management or vitamin D supplementation on LV mass among those receiving peritoneal dialysis is uncertain. STUDY DESIGN: Two-by-two factorial randomized controlled trial. SETTING & PARTICIPANTS: Sixty-five patients receiving maintenance peritoneal dialysis. INTERVENTION: BIA-guided volume management versus usual care and oral cholecalciferol 50,000 U weekly for 8 weeks followed by 10,000 U weekly for 44 weeks or matching placebo. OUTCOME: Change in LV mass at 1 year measured by cardiac magnetic resonance imaging. RESULTS: Total body water decreased by 0.9 + 2.4 (SD) L in the BIA group compared with a 1.5 ± 3.4 L increase in the usual care group (adjusted between-group difference: -2.4 [95% CI, -4.1 to -0.68] L, P = 0.01). LV mass increased by 1.3 ± 14.3 g in the BIA group and decreased by 2.4 ± 37.7 g in the usual care group (between-group difference: +2.2 [95% CI, -13.9 to 18.3] g, P = 0.8). Serum 25-hydroxyvitamin D concentration increased by a mean of 17.2 ± 30.8 nmol/L in the cholecalciferol group and declined by 8.2 ± 24.3 nmol/L in the placebo group (between-group difference: 28.3 [95% CI, 17.2-39.4] nmol/L, P < 0.001). LV mass decreased by 3.0 ± 28.1 g in the cholecalciferol group and increased by 2.0 ± 31.2 g in the placebo group (between-group difference: -4.5 [95% CI, -20.4 to 11.5] g, P = 0.6). LIMITATIONS: Relatively small sample size with larger than expected variation in change in LV mass. CONCLUSIONS: BIA-guided volume management had a modest impact on volume status with no effect on the change in LV mass. Vitamin D supplementation increased serum vitamin D concentration but had no effect on LV mass. FUNDING: Unrestricted Baxter International extramural grant and the Kidney Foundation of Canada. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01045980.

Effect of Bicarbonate-Buffered Dialysate on Ventricular Arrhythmias in Hemodialysis Patients.

BACKGROUND: The etiology of sudden cardiac death in patients with end-stage renal disease (ESRD) on hemodialysis (HD) is largely unknown, though there is evidence to suggest that metabolic alkalosis induced by HD with a high-bicarbonate dialysate/prescription may play a role. METHODS: We investigated the effects of metabolic alkalosis induced by HD with an acetate-containing bicarbonate-buffered dialysate on frequency of ventricular arrhythmia in 47 patients with ESRD on chronic HD using 48-h Holter monitoring in 3 phases: intra-HD, post-HD day 1, and post-HD day 2. Serum levels of bicarbonate, calcium, and potassium along with hemodynamics were measured pre-HD, post-HD, 20-h post-HD, and 44-h post-HD. Correlations were performed to verify the association between bicarbonate prescription and change in serum bicarbonate levels post-HD and to determine if the HD-induced change in serum bicarbonate level (metabolic alkalosis) had any direct association with ambient ventricular arrhythmia (premature ventricular contractions per hour) or indirect associations with ambient ventricular arrhythmia by affecting electrolytes or hemodynamics that are known to increase the risk of ventricular arrhythmia. RESULTS: Mean pre-HD serum bicarbonate level was 21.3 mEq/L. Dialysate bicarbonate prescription (mean of 36.4 mEq/L) correlated with changes in serum bicarbonate levels immediately post-HD 26.7 mEq/L (r = 0.46, p < 0.01), 20-h post-HD 25.2 mEq/L (r = 0.38), and 44-h post-HD 23.2 mEq/L (r = 0.35, p = 0.01). No statistically significant correlations were found between the post-HD change in serum bicarbonate levels (metabolic alkalosis) with ambient ventricular arrhythmia, changes in serum calcium, potassium, or hemodynamics in any phase. CONCLUSIONS: High-bicarbonate dialysate prescription is associated with metabolic alkalosis following the HD procedure. A mild metabolic alkalosis induced by HD with an acetate-containing bicarbonate-buffered dialysate solution had no direct association with ambient ventricular arrhythmia on Holter monitoring and was not associated with changes in hemodynamics or changes in serum total calcium or potassium levels. This study helps to provide guidance for the safe use of high bicarbonate dialysate/prescription in patients with ESRD on HD.

Treatment of prolonged tacrolimus toxicity using phenytoin in a haemodialysis patient.

WHAT IS KNOWN AND OBJECTIVE: Treatment of tacrolimus toxicity includes holding tacrolimus and supportive care. The objective is to describe considerations for pharmacologic induction of tacrolimus metabolism. CASE DESCRIPTION: A 52-year-old male with a failed renal transplant on chronic haemodialysis developed tacrolimus toxicity due to a drug-drug interaction with darunavir/ritonavir. Tacrolimus concentrations were >60 ng/mL for 10 days despite holding tacrolimus and darunavir/ritonavir. Development of encephalopathy prompted initiation of phenytoin to induce tacrolimus metabolism. Tacrolimus concentration was <2 ng/mL within 4 days and mental status normalized. WHAT IS NEW AND CONCLUSION: Phenytoin metabolic induction is a therapeutic option for prolonged tacrolimus toxicity.

Changes in Serum Bicarbonate Levels Caused by Acetate-Containing Bicarbonate-Buffered Hemodialysis Solution: An Observational Prospective Cohort Study.

Fresenius Medical Care's NaturaLyte dialysate has been associated with increased risk of sudden cardiac death by causing metabolic alkalosis from its acetate content based on retrospective data using pre-dialysis bicarbonate levels only. The study objective was to measure inter/intra-dialytic changes in serum bicarbonate and degree of alkalosis conferred by varying concentrations of NaturaLyte bicarbonate dialysate. Thirty-nine hemodialysis patients were divided into four groups based on prescribed bicarbonate dialysate concentrations; Group 1 (N = 9): 30-32 mEq/L, Group 2 (N = 5): 33-34 mEq/L, Group 3 (N = 10): 35-36 mEq/L, Group 4 (N = 15): 37-40 mEq/L. Serial (pre-dialysis, immediate post-dialysis, 2 h post-dialysis, and 68 h post-dialysis) bicarbonate levels were measured. Mean pre-dialysis serum bicarbonate levels (representing 44 h post-dialysis levels) in all four groups were not statistically different. Pre-dialysis and 68 h post-dialysis bicarbonate levels in each group were also not significantly different. However, immediate post-dialysis and 2 h post-dialysis bicarbonate levels were significantly increased in all four groups proportional to dialysate dose. There was statistically significant inter-group bicarbonate level difference (P < 0.05) except between the first and second (P = 0.43) and second and third (P = 0.07) groups in the immediate post-dialysis period. Similar results were obtained for the 2 h post-dialysis period. High bicarbonate dialysate causes large and rapid fluctuations in serum bicarbonate levels during the intra/inter-dialytic period, which returns to baseline within 44 to 68 h after dialysis. This refutes the necessity to correct pre-dialysis acidosis with high bicarbonate dialysate since rapid equilibration is likely to occur and unnecessarily exposes patients to large shifts in their acid base balance.

Exercise as an alternative to oral estrogen for amelioration of endothelial dysfunction in postmenopausal women.

BACKGROUND: Both exercise and postmenopausal estrogen therapy augment endothelial function. We hypothesized that their interaction would be additive. The study objectives were to determine in postmenopausal women (1) the effects of an acute bout of exercise on brachial artery endothelium-dependent flow-mediated vasodilation (FMD), (2) whether these responses to exercise are augmented by concurrent estrogen treatment, and (3) whether these 2 interventions, independently or together, achieve FMD values observed in premenopausal women. METHODS: In postmenopausal women (n = 13; age 54 +/- 2 [mean +/- SE] years), FMD was quantified during supine rest and again 60 minutes after treadmill exercise for 45 minutes at 60% V* O2max. Subjects were studied twice: before and after 4 weeks of oral estradiol. To obtain reference normal values, FMD was determined concurrently in 14 premenopausal (28 +/- 1 years) women under identical basal conditions. RESULTS: Flow-mediated vasodilation in postmenopausal women, markedly impaired when compared with premenopausal women (5.3% +/- 0.5% vs 12.1% +/- 1.5%, P < .01), was significantly increased by exercise (to 9.9% +/- 0.6%, P < .01). In contrast, after estrogen, FMD was augmented at rest (P < .01) but was not further enhanced after exercise (11.5% +/- 0.6% vs 9.9% +/- 0.5%, P = .3). Both interventions increased, independently, FMD to values in premenopausal women (P > .05). CONCLUSIONS: In postmenopausal women, both acute exercise and estrogen therapy normalize FMD. However, their effects are not additive, possibly because of redundancy of nitric oxide signaling pathways activated by these 2 interventions. When considered in the context of recent trials with adverse cardiovascular outcomes, these results reinforce the therapeutic potential of exercise as an alternative nonpharmacological intervention to estrogen in postmenopausal women with endothelial dysfunction.

Hemodynamic after-effects of acute dynamic exercise in sedentary normotensive postmenopausal women.

OBJECTIVES: To determine, in sedentary normotensive postmenopausal women, the after-effects of exercise on systemic and regional hemodynamics, and whether changes in total peripheral conductance after exercise relate to changes in brachial artery flow-mediated vasodilation (FMD). METHODS: In 13 sedentary postmenopausal women, the blood pressure (BP), cardiac output, total peripheral resistance and total peripheral conductance, calf vascular resistance and FMD were measured during baseline rest, and again commencing 45 min after treadmill exercise. Fourteen premenopausal women completed the identical protocol to obtain reference values for the after-effects of exercise in healthy females. RESULTS: In postmenopausal women, exercise was followed by falls in systolic BP (P < 0.01) and diastolic BP (P < 0.001). BP did not fall after exercise in premenopausal women. In both groups the cardiac output (P < 0.01) increased and the calf vascular resistance (P < 0.01) and total peripheral resistance (P < 0.05) decreased after exercise, but resistance fell more (P < 0.05) in postmenopausal women. Baseline FMD was greater in premenopausal women (12.1 +/- 1.5 versus 5.3 +/- 1.3%, P < 0.01), and similar before and after exercise, whereas prior exercise nearly doubled the FMD of postmenopausal women (to 9.9 +/- 1.4%, P < 0.01). These increases in FMD correlated with baseline values (r = -0.75, P < 0.01) and with relative changes in total peripheral conductance (r = 0.72, P < 0.02). The latter relationship was absent in premenopausal women (r = -0.29). CONCLUSIONS: In postmenopausal women, acute dynamic exercise elicits sustained increases in FMD that could facilitate post-exercise hypotension in this population. These observations reinforce the concept of exercise as an important non-pharmacological intervention to modify cardiovascular risk in postmenopausal women.

Management of hypophosphatemia in nocturnal hemodialysis with phosphate-containing enema: a technical study.

Hypophosphatemia is observed in patients undergoing nocturnal hemodialysis. Phosphate is commonly added to the dialysate acid bath, but systematic evaluation of the safety and reliability of this strategy is lacking. The objectives of this study were 4-fold. First, we determined whether predictable final dialysate phosphate concentrations could be achieved by adding varying amounts of Fleet® enema. Second, we assessed the stability of calcium (Ca) and phosphate dialysate levels under simulated nocturnal hemodialysis conditions. Third, we assessed for Ca-phosphate precipitate. Finally, we evaluated whether dialysate containing Fleet® enema met the current sterility standards. We added serial aliquots of enema to 4.5 L of dialysate acid concentrate and proportioned the solution on Gambro and Althin/Baxter dialysis machines for up to 8 hours. We measured dialysate phosphate, Ca, pH, and bicarbonate concentrations at baseline, and after simulated dialysis at 4 and 8 hours. We evaluated for precipitation visually and by assessing optical density at 620 nm. We used inoculation of agar to detect bacteria and Pyrotell reaction for endotoxin. For every 30 mL of Fleet® (1.38 mmol/mL of phosphate) enema added, the dialysate phosphate concentration increased by 0.2 mmol/L. There were no significant changes in dialysate phosphate, Ca, pH, and bicarbonate concentrations over 8 hours. No precipitate was observed in the dialysate by optical density measures at 620 nm for additions of up to 90 mL of enema. Bacterial and endotoxin testing met sterility standards. The addition of Fleet® enema to dialysate increases phosphate concentration in a predictable manner, and no safety problems were observed in our in vitro studies.

The fluid study protocol: a randomized controlled study on the effects of bioimpedance analysis and vitamin D on left ventricular mass in peritoneal dialysis patients.

OBJECTIVES: We will evaluate the effects of bioimpedance analysis-guided fluid management to reduce volume expansion, of vitamin D(3) supplementation, and of the combination of those techniques on decrease of left ventricular mass in peritoneal dialysis (PD) patients. DESIGN: This multicenter randomized controlled trial, with a 2 × 2 factorial design, will be conducted at PD clinics affiliated with 3 Canadian teaching hospitals. Consenting PD patients 18 years of age or older will be included. Patients will be excluded if they have contraindications to bioimpedance or magnetic resonance imaging, life or technique expectancy of less than 1 year, peritonitis within the preceding 3 months, or serum calcium above 2.55 mmol/L. INTERVENTION: The study will randomize 70 patients to bio-impedance-guided volume management or to usual care and to vitamin D(3) 50,000 U weekly for 8 doses, and then 10,000 U weekly or to matching placebo. MAIN OUTCOME MEASURES: The primary outcome will be change in left ventricular mass at 1 year as determined by cardiac magnetic resonance imaging. The secondary outcome will be a composite endpoint of death, nonfatal cardiovascular event, and transfer to hemodialysis for dialysis inadequacy or ultrafiltration failure. Other outcome measures will include blood pressure, quality of life, 6-minute walk test, inflammatory and fibrotic markers and their association with peritoneal membrane transport properties, and residual renal function. Patients will be followed for clinical outcomes for up to 3 years. CONCLUSIONS: This study will assess whether bioimpedance-directed volume management and vitamin D(3) supplementation can improve left ventricular mass in PD patients.

Waist-to-Hip Ratio, Cardiovascular Outcomes, and Death in Peritoneal Dialysis Patients.

Objectives. The primary objective of this study was to determine the relationship between waist-to-hip ratio (WHR), cardiovascular (CV) events, and mortality in peritoneal dialysis (PD) patients. A secondary objective was to investigate the association between abdominal obesity and systemic inflammatory markers. Methods. This is a prospective study of 22 prevalent PD patients. WHR was measured at baseline. C-reactive protein (CRP), tumour necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were measured. Main outcomes were first CV event and death from all causes. Survival analysis was used to examine the relationship between anthropomorphic measures and clinical outcomes. Results. Mean follow-up period was 3.1 years. In Kaplan-Meier analysis, survival was lower in those with higher WHR (P = .002). In Cox regression, WHR independently predicted mortality and first CV event after adjustment for known ischemic heart disease (hazard ratio [HR] 1.17, confidence interval [CI] 1.05-1.30 for death; HR 1.13, CI 1.01-1.26 for CV event). WHR correlated with serum TNF-α (r = 0.45; P = .05). Conclusion. The results of this study suggest WHR may be a risk factor for increased CV events and mortality in PD patients. Abdominal obesity is also associated with inflammatory markers. Larger studies are warranted to confirm these findings.

Chloroquine prevention of murine MHC-disparate acute graft-versus-host disease correlates with inhibition of splenic response to CpG oligodeoxynucleotides and alterations in T-cell cytokine production.

The 4-aminoquinolines, chloroquine and hydroxychloroquine, are established, with a 52% response rate, as therapy for human steroid-refractory GVHD after BMT. Chloroquine affects numerous mechanisms that play a role in GVHD, including inhibition of major histocompatibility complex (MHC) class II antigen presentation, cytokine production, and antigen-presenting cell activation by bacterially derived CpG oligodeoxynucleotides (ODNs). Using an MHC-disparate murine model, we evaluated the effect of chloroquine treatment on the development of acute GVHD. We assessed the effect of chloroquine on the immunostimulatory responses induced by CpG ODNs after BMT. We also evaluated the impact of chloroquine on cytokine-producing populations known to affect GVHD, including CD4+ and CD8+ T-cell and CD3(+)/NK1.1(+) natural killer T-cell (NKT cell) populations. Twelve (86%) of 14 mice receiving phosphate-buffered saline solution (PBS) developed lethal GVHD; only 4 (29%) of 14 mice receiving chloroquine 20 mg/kg 3 times per week developed lethal GVHD (P < .01). Chloroquine significantly suppressed CpG ODN-induced splenic proliferation and interleukin 6 (IL-6) production associated with GVHD. Chloroquine suppressed CD8+ T-cell production of IL-2 and IL-4 associated with GVHD in this model and maintained an early expansion (day 7) of splenic NKT cells. These results indicate that the 4-aminoquinolines are effective in therapy for or prevention of acute GVHD secondary to MHC disparities. Chloroquine actions may include inhibition of CpG ODN augmentation of GVHD. Other mechanisms involved may include suppression of CD8+ T-cell production of IL-2 and IL-4 and an increase in NKT cells associated with GVHD inhibition by chloroquine.