Interventions for lowering plasma homocysteine levels in dialysis patients.

BACKGROUND: People with end-stage kidney disease (ESKD) have high rates of cardiovascular events. Randomised controlled trials (RCTs) of homocysteine-lowering therapies have not shown reductions in cardiovascular event rates in the general population. However, people with kidney disease have higher levels of homocysteine and may have different mechanisms of cardiovascular disease. We performed a systematic review of the effect of homocysteine-lowering therapies in people with ESKD. OBJECTIVES: To evaluate the benefits and harms of established homocysteine lowering therapy (folic acid, vitamin B6, vitamin B12) on all-cause mortality and cardiovascular event rates in patients with ESKD. SEARCH METHODS: We searched Cochrane Kidney and Transplant's Specialised Register to 25 January 2016 through contact with the Information Specialist using search terms relevant to this review. SELECTION CRITERIA: Studies conducted in people with ESKD that reported at least 100 patient-years of follow-up and assessed the effect of therapies that are known to have homocysteine-lowering properties were included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data using a standardised form. The primary outcome was cardiovascular mortality. Secondary outcomes included all-cause mortality, incident cardiovascular disease (fatal and nonfatal myocardial infarction and coronary revascularisation), cerebrovascular disease (stroke and cerebrovascular revascularisation), peripheral vascular disease (lower limb amputation), venous thromboembolic disease (deep vein thrombosis and pulmonary embolism), thrombosis of dialysis access, and adverse events. The effects of homocysteine-lowering therapies on outcomes were assessed with meta-analyses using random-effects models. Prespecified subgroup and sensitivity analyses were conducted. MAIN RESULTS: We included six studies that reported data on 2452 participants with ESKD. Interventions investigated were folic acid with or without other vitamins (vitamin B6, vitamin B12). Participants' mean age was 48 to 65 years, and proportions of male participants ranged from 50% to 98%.Homocysteine-lowering therapy probably leads to little or no effect on cardiovascular mortality (4 studies, 1186 participants: RR 0.93, 95% CI 0.70 to 1.22). There was no evidence of heterogeneity among the included studies (I² = 0%). Homocysteine-lowering therapy had little or no effect on all-cause mortality or any other of this review's secondary outcomes. All prespecified subgroup and sensitivity analyses demonstrated little or no difference. Reported adverse events were mild and there was no increase in the incidence of adverse events from homocysteine-lowering therapies (3 studies, 1248 participants: RR 1.12, 95% CI 0.51 to 2.47; I(2) = 0%). Overall, studies were assessed as being at low risk of bias and there was no evidence of publication bias. AUTHORS' CONCLUSIONS: Homocysteine-lowering therapies were not found to reduce mortality (cardiovascular and all-cause) or cardiovascular events among people with ESKD.

Interventions for lowering plasma homocysteine levels in kidney transplant recipients.

BACKGROUND: Elevated homocysteine levels have been shown to be an independent risk factor for cardiovascular disease. However studies of homocysteine lowering in general and end-stage kidney disease (ESKD) populations have not demonstrated a reduction in cardiovascular event rates. Kidney transplant recipients have high homocysteine levels, high cardiovascular event rates and, unlike the ESKD population, may achieve normalisation of homocysteine levels with homocysteine lowering therapies. Thus may benefit from homocysteine lowering therapy. OBJECTIVES: To evaluate the effects of established homocysteine lowering therapy on cardiovascular mortality in patients with functioning kidney transplants. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 16 March 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: Randomised controlled trials of any therapy that has been shown to significantly lower homocysteine levels conducted in people with functioning kidney transplants. Studies were to be included if they compared homocysteine lowering therapy with placebo or usual care, or compare higher versus lower doses of homocysteine lowering therapy. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Results were to be expressed as the risk ratio (RR) for dichotomous outcomes or mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). Data was to be pooled using the random effects model. MAIN RESULTS: The literature search yielded 359 reports of which only one study was identified that met our inclusion criteria and reported relevant clinical endpoints. This study randomised 4110 adult participants with a functioning kidney transplant and elevated homocysteine levels to folic acid plus high dose B multivitamins or low dose multivitamins who were followed for a mean 4.0 years. Despite effectively lowering homocysteine levels) in homocysteine levels at follow-up (MD -4.40 µmol/L, 95% CI -5.98 to -2.82) there was no evidence the intervention impacted on any of the outcomes reported including cardiovascular mortality (RR 0.91, 95% CI 0.69 to 1.20), all-cause mortality (RR 1.04, 95% CI 0.88 to 1.22), myocardial infarction (RR 1.02, 95% CI 0.77 to 1.35), stroke (RR 1.08, 95% CI 0.69 to 1.71), commencement of renal replacement therapy (RR 1.12, 95% CI 0.91 to 1.37) or all reported adverse events (RR 1.02, 95% CI 0.87 to 1.20). There was no evidence the intervention impacted on the primary endpoint of the study, a cardiovascular event composite (RR 0.99, 95% CI 0.85 to 1.15). The study was of high quality. AUTHORS' CONCLUSIONS: There is no current evidence to support the use of homocysteine lowering therapy for cardiovascular disease prevention in kidney transplant recipients.

Chronic opioid analgesic usage post-kidney transplantation and clinical outcomes.

Chronic opioid usage (COU) is common among patients with end-stage renal disease (ESRD) qualified for kidney transplantation and associated with inferior post-transplant outcomes. The magnitude of COU after kidney transplantation and its impact on transplant outcomes remain unknown. We performed a single-center retrospective study aimed to describe the prevalence of COU during the first year, to identify the predictors of COU and to determine the impact of COU on post-transplant outcomes including the rates of hospitalization and acute rejection during the first year, as well as long-term patient and graft survival. Among 1045 kidney transplant patients, 119 (11.4%) had required continued outpatient prescription of opioid analgesics during the first year after kidney transplantation, mostly for non-surgery-related pain (85%). A positive history of COU prior to transplantation was the strongest predictor of COU in the first year post-transplantation (adjusted odds ratio [AOR] 4.31, p < 0.001). Patients with COU had more often hospital admission during the first year (AOR 2.48, p = 0.001, for 1 or 2 admissions, and AOR 6.03, p < 0.001 for ≥3 admissions), but similar rate of acute rejection (19.3% vs. 15.7%, p = 0.31). During long-term follow-up, however, the patient and/or death-censored kidney survival was not different. COU early post-kidney transplantation, when clinically indicated and properly supervised, does not appear to affect the risk of death and death-censored graft failure.

Metabolic syndrome, vitamin D deficiency and hypoadiponectinemia among nondiabetic patients early after kidney transplantation.

BACKGROUND AND AIMS: Metabolic syndrome (MetS) is common among kidney transplant patients. We studied the relationship between MetS, vitamin D deficiency/insufficiency and hypoadiponectinemia early posttransplantation and their impact on clinical outcomes. METHODS: Seventy-four previously nondiabetic kidney transplant patients were enrolled in a prospective cohort study between February and November 2008. Participants underwent a 2-hour oral glucose tolerance test and had their plasma levels of 25-hydroxyvitamin D (25[OH]D), adiponectin, insulin, intact parathyroid hormone and lipids measured at 11 weeks posttransplantation. Clinical events including cardiovascular events, new-onset diabetes after transplantation, acute rejection, graft loss and death were recorded during the follow-up to December 2012. RESULTS: Thirty-four study patients (45.9%) had MetS. Patients with MetS had lower plasma concentrations of 25[OH]D (20.5 ± 7.2 vs. 24.8 ± 11.1 ng/ml, p = 0.049) and adiponectin (8.2 ± 4.5 vs. 14.6 ± 8.0 µg/ml, p < 0.0001) early on, and higher composite clinical event rate (61.8 vs. 27.5%, p = 0.003) during the follow-up. Multivariate analysis showed that the presence of MetS early after transplantation was independently associated with 25[OH]D deficiency/insufficiency (OR: 14.0, 95% CI: 1.8, 107.5; p = 0.011), depressed plasma adiponectin levels (ß -6.39, r(2) 0.195, p < 0.0001) and increased risk for clinical events (OR: 5.6, 95% CI: 1.9, 16.5; p = 0.002). CONCLUSION: Kidney transplant patients with MetS early after transplantation had lower levels of 25[OH]D and adiponectin, and unfavorable clinical outcomes.

Y-box binding protein 1 and RNase UK114 mediate monocyte chemoattractant protein 1 mRNA stability in vascular smooth muscle cells.

Monocyte chemoattractant protein 1 (MCP-1) plays a pivotal role in many inflammatory processes, including the progression of atherosclerosis and the response of the arterial wall to injury. We previously demonstrated that dexamethasone (Dex) inhibits MCP-1 mRNA accumulation in smooth muscle cells by decreasing its half-life. The effect of Dex was dependent upon the glucocorticoid receptor (GR) and independent of new transcription. Using RNA affinity and column chromatography, we have identified two proteins involved in regulating MCP-1 mRNA stability: Y-box binding protein 1 (YB-1), a multifunctional DNA/RNA-binding protein, and endoribonuclease UK114 (UK). By immunoprecipitation, YB and GR formed a complex present in equal amounts in extracts from untreated and Dex-treated cells. YB-1, UK, and GR small interfering RNA (siRNA) substantially inhibited the effect of Dex on MCP-1 mRNA accumulation. In addition, YB-1 antibody blocked the degradation of MCP-1 mRNA by cytoplasmic extracts from the Dex-treated cells. The degradative activity of extracts immunoprecipitated with antibodies to either YB-1 or GR was blocked with UK antibody. UK did not degrade MCP-1 mRNA; however, upon addition to nondegrading control extracts, it rapidly degraded MCP-1 mRNA. These studies define new roles for GR, YB-1, and UK in the formation of a molecular complex that degrades MCP-1 mRNA.