Effect of Low-Sodium versus Conventional Sodium Dialysate on Left Ventricular Mass in Home and Self-Care Satellite Facility Hemodialysis Patients: A Randomized Clinical Trial.

BACKGROUND: Fluid overload in patients undergoing hemodialysis contributes to cardiovascular morbidity and mortality. There is a global trend to lower dialysate sodium with the goal of reducing fluid overload. METHODS: To investigate whether lower dialysate sodium during hemodialysis reduces left ventricular mass, we conducted a randomized trial in which patients received either low-sodium dialysate (135 mM) or conventional dialysate (140 mM) for 12 months. We included participants who were aged >18 years old, had a predialysis serum sodium ≥135 mM, and were receiving hemodialysis at home or a self-care satellite facility. Exclusion criteria included hemodialysis frequency >3.5 times per week and use of sodium profiling or hemodiafiltration. The main outcome was left ventricular mass index by cardiac magnetic resonance imaging. RESULTS: The 99 participants had a median age of 51 years old; 67 were men, 31 had diabetes mellitus, and 59 had left ventricular hypertrophy. Over 12 months of follow-up, relative to control, a dialysate sodium concentration of 135 mmol/L did not change the left ventricular mass index, despite significant reductions at 6 and 12 months in interdialytic weight gain, in extracellular fluid volume, and in plasma B-type natriuretic peptide concentration (ratio of intervention to control). The intervention increased intradialytic hypotension (odds ratio [OR], 7.5; 95% confidence interval [95% CI], 1.1 to 49.8 at 6 months and OR, 3.6; 95% CI, 0.5 to 28.8 at 12 months). Five participants in the intervention arm could not complete the trial because of hypotension. We found no effect on health-related quality of life measures, perceived thirst or xerostomia, or dietary sodium intake. CONCLUSIONS: Dialysate sodium of 135 mmol/L did not reduce left ventricular mass relative to control, despite improving fluid status. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: The Australian New Zealand Clinical Trials Registry, ACTRN12611000975998.

Interventions for preventing bone disease in kidney transplant recipients.

BACKGROUND: People who have chronic kidney disease (CKD) have important changes to bone structure, strength, and metabolism. Children experience bone deformity, pain, and delayed or impaired growth. Adults experience limb and vertebral fractures, avascular necrosis, and pain. The fracture risk after kidney transplantation is four times that of the general population and is related to Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) occurring with end-stage kidney failure, steroid-induced bone loss, and persistent hyperparathyroidism after transplantation. Fractures may reduce quality of life and lead to being unable to work or contribute to community roles and responsibilities. Earlier versions of this review have found low certainty evidence for effects of treatment. This is an update of a review first published in 2005 and updated in 2007. OBJECTIVES: This review update evaluates the benefits and harms of interventions for preventing bone disease following kidney transplantation. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 16 May 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: RCTs and quasi-RCTs evaluating treatments for bone disease among kidney transplant recipients of any age were eligible. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial risks of bias and extracted data. Statistical analyses were performed using random effects meta-analysis. The risk estimates were expressed as a risk ratio (RR) for dichotomous variables and mean difference (MD) for continuous outcomes together with the corresponding 95% confidence interval (CI). The primary efficacy outcome was bone fracture. The primary safety outcome was acute graft rejection. Secondary outcomes included death (all cause and cardiovascular), myocardial infarction, stroke, musculoskeletal disorders (e.g. skeletal deformity, bone pain), graft loss, nausea, hyper- or hypocalcaemia, kidney function, serum parathyroid hormone (PTH), and bone mineral density (BMD). MAIN RESULTS: In this 2019 update, 65 studies (involving 3598 participants) were eligible; 45 studies contributed data to our meta-analyses (2698 participants). Treatments included bisphosphonates, vitamin D compounds, teriparatide, denosumab, cinacalcet, parathyroidectomy, and calcitonin. Median duration of follow-up was 12 months. Forty-three studies evaluated bone density or bone-related biomarkers, with more recent studies evaluating proteinuria and hyperparathyroidism. Bisphosphonate therapy was usually commenced in the perioperative transplantation period (within 3 weeks) and regardless of BMD. Risks of bias were generally high or unclear leading to lower certainty in the results. A single study reported outcomes among 60 children and adolescents. Studies were not designed to measure treatment effects on fracture, death or cardiovascular outcomes, or graft loss.Compared to placebo, bisphosphonate therapy administered over 12 months in transplant recipients may prevent fracture (RR 0.62, 95% CI 0.38 to 1.01; low certainty evidence) although the 95% CI included the possibility that bisphosphonate therapy might make little or no difference. Fracture events were principally vertebral fractures identified during routine radiographic surveillance. It was uncertain whether any other drug class decreased fracture (low or very low certainty evidence). It was uncertain whether interventions for bone disease in kidney transplantation reduce all-cause or cardiovascular death, myocardial infarction or stroke, or graft loss in very low certainty evidence. Bisphosphonate therapy may decrease acute graft rejection (RR 0.70, 95% CI 0.55 to 0.89; low certainty evidence), while it is uncertain whether any other treatment impacts graft rejection (very low certainty evidence). Bisphosphonate therapy may reduce bone pain (RR 0.20, 95% CI 0.04 to 0.93; very low certainty evidence), while it was very uncertain whether bisphosphonates prevent spinal deformity or avascular bone necrosis (very low certainty evidence). Bisphosphonates may increase to risk of hypocalcaemia (RR 5.59, 95% CI 1.00 to 31.06; low certainty evidence). It was uncertain whether vitamin D compounds had any effect on skeletal, cardiovascular, death, or transplant function outcomes (very low certainty or absence of evidence). Evidence for the benefits and harms of all other treatments was of very low certainty. Evidence for children and young adolescents was sparse. AUTHORS' CONCLUSIONS: Bisphosphonate therapy may reduce fracture and bone pain after kidney transplantation, however low certainty in the evidence indicates it is possible that treatment may make little or no difference. It is uncertain whether bisphosphonate therapy or other bone treatments prevent other skeletal complications after kidney transplantation, including spinal deformity or avascular bone necrosis. The effects of bone treatment for children and adolescents after kidney transplantation are very uncertain.

Variability of plasma and urine betaine in diabetes mellitus and its relationship to methionine load test responses: an observational study.

BACKGROUND: Since betaine is an osmolyte and methyl donor, and abnormal betaine loss is common in diabetes mellitus (>20% patients), we investigated the relationship between betaine and the post-methionine load rise in homocysteine, in diabetes and control subjects. The post-methionine load test is reported to be both an independent vascular risk factor and a measure of betaine sufficiency. METHODS: Patients with type 2 diabetes (n = 34) and control subjects (n = 17) were recruited. We measured baseline fasting plasma and 4-hour post-methionine load (L-methionine, 0.1 mg/kg body weight) concentrations of homocysteine, betaine, and the betaine metabolite N,N-dimethylglycine. Baseline urine excretions of betaine, dimethylglycine and glucose were measured on morning urine samples as the ratio to urine creatinine. Statistical determinants of the post-methionine load increase in homocysteine were identified in multiple linear regression models. RESULTS: Plasma betaine concentrations and urinary betaine excretions were significantly (p < 0.001) more variable in the subjects with diabetes compared with the controls. Dimethylglycine excretion (p = 0.00014) and plasma dimethylglycine concentrations (p = 0.039) were also more variable. In diabetes, plasma betaine was a significant negative determinant (p < 0.001) of the post-methionine load increase in homocysteine. However, it was not conclusive that this was different from the relationship in the controls. In the patients with diabetes, a strong relationship was found between urinary betaine excretion and urinary glucose excretion (but not with plasma glucose). CONCLUSIONS: Both high and low plasma betaine concentrations, and high and low urinary betaine excretions, are more prevalent in diabetes. The availability of betaine affects the response in the methionine load test. The benefits of increasing betaine intake should be investigated.

Vitamin D compounds for people with chronic kidney disease requiring dialysis.

BACKGROUND: Clinical guidelines recommend vitamin D compounds to suppress serum parathyroid hormone (PTH) in chronic kidney disease (CKD), however treatment may be associated with increased serum phosphorus and calcium, which are associated with increased mortality in observational studies. Observational data also indicate vitamin D therapy may be independently associated with reduced mortality in CKD. OBJECTIVES: We assessed the effects of vitamin D compounds on clinical, biochemical, and bone outcomes in people with CKD and receiving dialysis. SEARCH STRATEGY: We searched The Cochrane Renal Group's specialised register, Cochrane's Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and reference lists of retrieved articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) in subjects with CKD and requiring dialysis that assessed treatment with vitamin D compounds. DATA COLLECTION AND ANALYSIS: Data was extracted by two authors. Results are summarised as risk ratios (RR) for dichotomous outcomes or mean differences (MD) for continuous outcomes, with 95% confidence intervals (CI). MAIN RESULTS: Sixty studies (2773 patients) were included. No formulation, route, or schedule of administration was associated with altered risks of death, bone pain, or parathyroidectomy. Marked heterogeneity in reporting of outcomes resulted in few data available for formal meta-analysis. Compared with placebo, vitamin D compounds lowered serum PTH at the expense of increasing serum phosphorus. Trends toward increased hypercalcaemia and serum calcium did not reach statistical significance but may be clinically relevant. Newer vitamin D compounds (paricalcitol, maxacalcitol, doxercalciferol) lowered PTH compared with placebo, with increased risks of hypercalcaemia, although inadequate data were available for serum phosphorus. Intravenous vitamin D may lower PTH compared with oral treatment, and be associated with lower serum phosphorus and calcium levels, although limitations in the available studies precludes a conclusive statement of treatment efficacy. Few studies were available for intermittent versus daily and intraperitoneal versus oral administration or directly comparative studies of newer versus established vitamin D compounds. AUTHORS' CONCLUSIONS: We confirm that vitamin D compounds suppress PTH in people with CKD and requiring dialysis although treatment is associated with clinical elevations in serum phosphorus and calcium. All studies were inadequately powered to assess the effect of vitamin D on clinical outcomes and until such studies are conducted the relative importance of changes in serum PTH, phosphorus and calcium resulting from vitamin D therapy remain unknown. Observational data showing vitamin D compounds may be associated with improved survival in CKD need to be confirmed or refuted in specifically designed RCTs.

Vitamin D compounds for people with chronic kidney disease not requiring dialysis.

BACKGROUND: Vitamin D compounds are used to suppress elevated serum parathyroid hormone (PTH) in people with chronic kidney disease (CKD). OBJECTIVES: To assess the efficacy of vitamin D therapy on biochemical, bone, cardiovascular, and mortality outcomes in people with CKD and not requiring dialysis. SEARCH STRATEGY: We searched The Cochrane Renal Group's specialised register, Cochrane's Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and reference lists of retrieved articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing different forms, schedules, or routes of administration of vitamin D compounds for people with CKD not requiring dialysis were included. Vitamin D compounds were defined as established (calcitriol, alfacalcidol, 24,25(OH)(2)vitamin D(3)) or newer (doxercalciferol, maxacalcitol, paricalcitol, falecalcitriol) vitamin D compounds. DATA COLLECTION AND ANALYSIS: Data were extracted by two authors. Statistical analyses were performed using the random effects model. Results were summarized as risk ratio (RR) for dichotomous outcomes or mean differences (MD) for continuous outcomes with 95% confidence intervals (CI). MAIN RESULTS: Sixteen studies (894 patients) were included. No formulation, route, or schedule of vitamin D compound was found to alter the mortality risk or need for dialysis. Vitamin D compounds significantly lowered serum PTH (4 studies, 153 patients: MD -49.34 pg/mL, 95% CI -85.70 to -12.97 (-5.6 pmol/L, 95% CI -9.77 to -1.48)) and were more likely to reduce serum PTH > 30% from baseline value (264 patients: RR 7.87, 95% CI 4.87 to 12.73). Vitamin D treatment was associated with increased end of treatment serum phosphorus (3 studies, 140 patients: MD 0.37 mg/dL, 95% CI 0.09, 0.66 (0.12 mmol/L, 95% CI 0.03, 0.21)) and serum calcium (5 studies, 184 patients: MD 0.20 mg/dL, 95% CI 0.17 to 0.23 (0.05 mmol/L, 95% CI 0.04 to 0.06)). Few data were available comparing intermittent with daily vitamin D administration, or other schedules of dosing. AUTHORS' CONCLUSIONS: There are not sufficient data to determine the effect of vitamin D compounds on mortality and cardiovascular outcomes in people with CKD not requiring dialysis. While vitamin D compounds reduce serum PTH (49.3 pg/mL (5.6 pmol/L)) compared with placebo, the relative clinical benefits of PTH lowering versus treatment-related increases in serum phosphorus and calcium remain to be understood.

Meta-analysis: vitamin D compounds in chronic kidney disease.

BACKGROUND: Vitamin D compounds are widely used to prevent and treat secondary hyperparathyroidism. PURPOSE: To determine whether vitamin D therapy improves biochemical markers of mineral metabolism and cardiovascular and mortality outcomes in chronic kidney disease. DATA SOURCES: MEDLINE (January 1966 to July 2007), EMBASE (January 1980 to July 2007), and Cochrane databases were searched without language restriction. STUDY SELECTION: Randomized, controlled trials of vitamin D compounds in chronic kidney disease were identified. DATA EXTRACTION: Two authors independently extracted data. DATA SYNTHESIS: Seventy-six trials were identified for inclusion; 3667 participants were enrolled. Vitamin D compounds did not reduce the risk for death, bone pain, vascular calcification, or parathyroidectomy. Compared with placebo, established vitamin D sterols were associated with an increased risk for hypercalcemia (relative risk, 2.37 [95% CI, 1.16 to 4.85]) and hyperphosphatemia (relative risk, 1.77 [CI, 1.15 to 2.74]) but did not show a consistent reduction in parathyroid hormone (PTH) levels. Compared with placebo, more recently developed vitamin D analogues were associated with hypercalcemia (relative risk, 5.15 [CI, 1.06 to 24.97]) but not hyperphosphatemia, and levels of PTH were reduced (weighted mean difference, -10.77 pmol/L [CI, -20.51 to -1.03 pmol/L]). For suppression of PTH, intravenous administration was superior to oral vitamin D, but higher intravenous doses were used. LIMITATIONS: Few studies reported patient-level outcomes, including mortality (8 of 76 trials), and only 5 trials directly compared the effects of treatment with newer vitamin D compounds versus established ones. Heterogeneity in some comparisons remained unexplained by metaregression analyses. CONCLUSION: Vitamin D compounds do not consistently reduce PTH levels, and beneficial effects on patient-level outcomes are unproven. The value of vitamin D treatment for people with chronic kidney disease remains uncertain.

Interventions for preventing bone disease in kidney transplant recipients: a systematic review of randomized controlled trials.

BACKGROUND: Before renal transplantation complex abnormalities of bone metabolism exist and lead to increased risk for fracture after transplantation. This study was conducted to assess the evidence available to guide targeted treatment to reduce bone disease in transplant recipients. METHODS: The Cochrane CENTRAL Registry, MEDLINE, and EMBASE were searched for randomized trials of interventions for bone disease after renal transplantation. Data were extracted on fracture, bone mineral density (BMD) by means of dual-energy X-ray absorptiometry, acute graft rejection, and adverse events. Analysis was performed with a random-effects model, and all results are expressed as relative risk with 95% confidence intervals (CIs). RESULTS: Twenty-three eligible trials (1,209 patients) were identified. No trial found a reduction in risk for fracture. Bisphosphonates (7 trials; 268 patients; weighted mean difference [WMD], 7.66; 95% CI, 4.82 to 10.50), vitamin D analogues (2 trials; 51 patients; WMD, 6.13; 95% CI, 4.97 to 7.29), and calcitonin (1 trial; 31 patients; WMD, 5.00; 95% CI, 0.88 to 9.12) favorably affected the percentage of change in BMD at the lumbar spine compared with no treatment. Bisphosphonates (4 trials; 149 patients; WMD, 7.18; 95% CI, 6.22 to 8.13) and vitamin D analogues (2 trials; 51 patients; WMD, 3.73; 95% CI, 2.71 to 4.75), but not calcitonin (1 trial; 31 patients; WMD, -0.30; 95% CI, -5.00 to 4.40), had a favorable effect on BMD measured at the femoral neck compared with no treatment. The incidence of reported toxicity was low. CONCLUSION: The trials were inadequately powered to show a reduction in risk for fracture. Bisphosphonates and vitamin D have a beneficial effect on BMD at the lumbar spine and femoral neck. With increasing survival after renal transplantation, this study stresses the importance of randomized controlled trial evidence of interventions of bone disease after renal transplantation.

Dimethylglycine supplementation does not affect plasma homocysteine concentrations in pre-dialysis chronic renal failure patients.

OBJECTIVE: To determine whether daily dimethylglycine supplementation affects plasma homocysteine concentrations. DESIGN AND METHODS: A randomized, blinded, crossover design was used. Seven pre-dialysis chronic renal failure patients consumed 400 mg of dimethylglycine or placebo daily for 28 days. Fasting blood samples and 12-h urine samples were collected at baseline and at the end of each treatment period for analysis. RESULTS: No significant differences were observed in plasma homocysteine (P = 0.624), glycine betaine (P = 0.452) and methionine (P = 0.457) concentrations between dimethylglycine and placebo treatments. CONCLUSION: Daily supplementation with dimethylglycine does not affect plasma homocysteine.

Effects of long and short hemodialysis on endothelial function: a short-term study.

BACKGROUND: Endothelial dysfunction is common in end-stage renal disease and may contribute to the development of both hypertension and atherosclerosis. Long-slow hemodialysis (HD) has been associated with superior blood pressure control and fewer cardiovascular complications. We hypothesized that long dialysis times would improve endothelial function compared with shorter dialysis times. METHOD: Eight long-term hemodialysis patients, not on antihypertensive drugs and with no evidence of vascular disease, were studied in a three-way randomized crossover-controlled trial. Each received, for one week and in randomized sequence, four hours of HD (SD), eight hours of HD, and eight hours of HD using a smaller dialyzer and slower blood pump. The same post-dialysis target weights were used with each treatment. On the third day of each treatment endothelium-dependent (flow mediated) and independent glyceryl trinitrate (GTN) induced vasodilation were measured by forearm strain-gauge plethysmography, and von Willebrand (vW) antigen, plasma homocysteine (tHcy) and neurohormones were measured pre- and post-dialysis. RESULTS: Despite achieving target post-dialysis weights with all treatments, pre-dialysis weight tended higher on SD. Endothelial dependent vasodilation increased after all HD treatments but did not differ between them. Adrenomedullin, N-terminal brain natriuretic peptide and vW antigen increased similarly across all HD whereas atrial and C-type natriuretic peptide, and endothelin-1 decreased across dialysis and were higher with SD. Pre-dialysis plasma tHcy concentrations were 13% higher during SD treatment. CONCLUSION: Hemodialysis improved endothelial-dependent vasodilation but the effect was similar with all three HD treatments. Improved endothelial function might result in part from altered local hormone production (endothelin-1 and adrenomedullin). These data suggest that increasing dialysis time is unlikely, in the short-term, to significantly improve endothelial function in patients with end-stage renal disease, but longer term studies are needed.

Hypertension as a determinant of survival for patients treated with home dialysis.

BACKGROUND: Previous studies of the risks of hypertension for dialysis patients have yielded conflicting results. The aim of this study was to investigate, in a home dialysis population with low rates of diabetes and antihypertensive drug use, whether blood pressure (BP) was an independent risk factor for survival. METHODS: The outcome of 168 consecutive patients (94 male, 88% Caucasian), aged 48 years (SD 16), who began home hemodialysis (HD; N = 124) or home continuous ambulatory peritoneal dialysis (CAPD; N = 44) between January 1, 1985 and December 31, 1994 were analyzed retrospectively. Only 4.7% of patients took antihypertensive drugs while on dialysis. The patients were followed to December 31, 1998 with the primary outcome being all-cause mortality. Censoring events were transplantation, transfer to another center and treatment modality change. The Cox proportional hazard model was used with baseline predictors. RESULTS: Seventy-one patients died and the median overall survival was 4.2 years (5.6 on HD, 2.2 on CAPD, P < 0.0001). Mean BP at start of dialysis predicted survival on its own (P = 0.0009) and in the joint Cox model (P = 0.047). Other significant predictors in the joint model were age [10 year increase, relative hazard (RH) = 1.55, P = 0.0008], albumin (10 g/L decrease, RH = 2.05, P = 0.007), diabetes (RH = 3.42, P = 0.015) and peripheral vascular disease (RH = 2.19, P = 0.02) but not dialysis modality (RH = 1.63, P = 0.13). High and low mean blood pressure (BP) values at the start of dialysis were associated with the highest mortality. CONCLUSIONS: Among the home dialysis patients, most of whom did not require antihypertensive drugs, hypertension was a risk factor for survival and patients with mid-range BP values survived the longest.

Betaine supplementation decreases post-methionine hyperhomocysteinemia in chronic renal failure.

BACKGROUND: Fasting and post-methionine load hyperhomocysteinemia are independent risk factors for vascular disease that are common in chronic renal failure. Folate decreases but seldom normalizes fasting total homocysteine (tHcy) concentrations in such patients. Glycine betaine (GB) is known to decrease tHcy in other clinical settings, but whether it is beneficial in chronic renal failure has not been established. METHODS: We conducted a crossover-controlled trial in 36 patients with chronic renal failure to determine if oral GB decreased fasting or post-methionine tHcy concentrations. All subjects received, in randomized sequence, 5-mg folic acid and 50-mg pyridoxine daily, with or without GB 4-g daily, for three months each. Fasting plasma tHcy, GB, folate, B vitamins, serum lipids and creatinine were measured at one and three months, and methionine load tests were performed at the end of each three-month treatment phase. RESULTS: GB and N,N-dimethylglycine (DMG) levels in plasma and urine increased markedly during GB treatment. Fasting tHcy decreased from baseline with both treatments but did not differ between treatments. Post-methionine tHcy decreased with both treatments and was 18% lower on GB than on folate and pyridoxine alone (P < 0.001). There were small increases in lipids during treatment with GB but the ratio of total: HDL cholesterol was unchanged. CONCLUSIONS: GB supplementation had no effect on fasting tHcy in patients with chronic renal failure who were folate and pyridoxine replete, but it significantly decreased tHcy concentrations after methionine loading.