Fish oil for kidney transplant recipients.

BACKGROUND: Calcineurin inhibitors used in kidney transplantation for immunosuppression have adverse effects that may contribute to nephrotoxicity and increased cardiovascular risk profile. Fish oils are rich in very long chain omega-3 fatty acids, which may reduce nephrotoxicity by improving endothelial function and reduce rejection rates through their immuno-modulatory effects. They may also modify the cardiovascular risk profile. Hence, fish oils may potentially prolong graft survival and reduce cardiovascular mortality. OBJECTIVES: This review aimed to look at the benefits and harms of fish oil treatment in ameliorating the kidney and cardiovascular adverse effects of CNI-based immunosuppressive therapy in kidney transplant recipients. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register (up to 17 March 2016) through contact with the Information Specialist using search terms relevant to this review. SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-RCTs of fish oils in kidney transplant recipients on a calcineurin inhibitor-based immunosuppressive regimen. RCTs of fish oil versus statins were included. DATA COLLECTION AND ANALYSIS: Data was extracted and the quality of studies assessed by two authors, with differences resolved by discussion with a third independent author. Dichotomous outcomes were reported as risk ratio (RR) and continuous outcome measures were reported as the mean difference (MD) with 95% confidence intervals using the random effects model. Heterogeneity was assessed using a Chi(2) test on n-1 degrees of freedom and the I(2) statistic. Data not suitable for pooling were tabulated and described. MAIN RESULTS: Fifteen studies (733 patients) were suitable for analysis. All studies were small and had variable methodology. Fish oil did not significantly affect patient or graft survival, acute rejection rates, or calcineurin inhibitor toxicity when compared to placebo. Overall SCr was significantly lower in the fish oil group compared to placebo (5 studies, 237 participants: MD -30.63 µmol/L, 95% CI -59.74 to -1.53; I(2) = 88%). In the subgroup analysis, this was only significant in the long-course (six months or more) group (4 studies, 157 participants: MD -37.41 µmol/L, 95% CI -69.89 to -4.94; I(2) = 82%). Fish oil treatment was associated with a lower diastolic blood pressure (4 studies, 200 participants: MD -4.53 mm Hg, 95% CI -7.60 to -1.45) compared to placebo. Patients receiving fish oil for more than six months had a modest increase in HDL (5 studies, 178 participants: MD 0.12 mmol/L, 95% CI 0.03 to 0.21; I(2) = 47%) compared to placebo. Fish oil effects on lipids were not significantly different from low-dose statins. There was insufficient data to analyse cardiovascular outcomes. Fishy aftertaste and gastrointestinal upset were common but did not result in significant patient drop-out. AUTHORS' CONCLUSIONS: There is insufficient evidence from currently available RCTs to recommend fish oil therapy to improve kidney function, rejection rates, patient survival or graft survival. The improvements in HDL cholesterol and diastolic blood pressure were too modest to recommend routine use. To determine a benefit in clinical outcomes, future RCTs will need to be adequately powered with these outcomes in mind.

Effect of timing of dialysis commencement on clinical outcomes of patients with planned initiation of peritoneal dialysis in the IDEAL trial.

BACKGROUND: Since the mid-1990s, early dialysis initiation has dramatically increased in many countries. The Initiating Dialysis Early and Late (IDEAL) study demonstrated that, compared with late initiation, planned early initiation of dialysis was associated with comparable clinical outcomes and increased health care costs. Because residual renal function is a key determinant of outcome and is better preserved with peritoneal dialysis (PD), the present pre-specified subgroup analysis of the IDEAL trial examined the effects of early-compared with late-start dialysis on clinical outcomes in patients whose planned therapy at the time of randomization was PD. METHODS: Adults with an estimated glomerular filtration rate (eGFR) of 10 - 15 mL/min/1.73 m(2) who planned to be treated with PD were randomly allocated to commence dialysis at an eGFR of 10 - 14 mL/min/1.73 m(2) (early start) or 5 - 7 mL/min/1.73 m(2) (late start). The primary outcome was all-cause mortality. RESULTS: Of the 828 IDEAL trial participants, 466 (56%) planned to commence PD and were randomized to early start (n = 233) or late start (n = 233). The median times from randomization to dialysis initiation were, respectively, 2.03 months [interquartile range (IQR):1.67 - 2.30 months] and 7.83 months (IQR: 5.83 - 8.83 months). Death occurred in 102 early-start patients and 96 late-start patients [hazard ratio: 1.04; 95% confidence interval (CI): 0.79 - 1.37]. No differences in composite cardiovascular events, composite infectious deaths, or dialysis-associated complications were observed between the groups. Peritonitis rates were 0.73 episodes (95% CI: 0.65 - 0.82 episodes) per patient-year in the early-start group and 0.69 episodes (95% CI: 0.61 - 0.78 episodes) per patient-year in the late-start group (incidence rate ratio: 1.19; 95% CI: 0.86 - 1.65; p = 0.29). The proportion of patients planning to commence PD who actually initiated dialysis with PD was higher in the early-start group (80% vs 70%, p = 0.01). CONCLUSION: Early initiation of dialysis in patients with stage 5 chronic kidney disease who planned to be treated with PD was associated with clinical outcomes comparable to those seen with late dialysis initiation. Compared with early-start patients, late-start patients who had chosen PD as their planned dialysis modality were less likely to commence on PD.

Outcomes of patients with planned initiation of hemodialysis in the IDEAL trial.

BACKGROUND: In clinical practice there is considerable variation in the timing of initiation of dialysis. The IDEAL trial (Initiating Dialysis Early and Late study) showed that planned early initiation of dialysis in patients with stage 5 chronic kidney disease (CKD) was not associated with an improvement in clinical outcome, but was associated with increased costs. The predominant dialysis modality worldwide is hemodialysis (HD). This subanalysis of the IDEAL trial examined whether the timing of the initiation of dialysis in those who had chosen HD influenced survival and the occurrence of complications. METHODS: Patients on the IDEAL trial were older than 18 years and had progressive advanced CKD. They were randomly assigned to commence dialysis at an estimated glomerular filtration rate (eGFR) of 10-14 ml/min (early start) or when the eGFR was 5-7 ml/min (late start). The primary outcome was death from any cause. RESULTS: Between 2000 and 2008, 362 of the 828 patients (43.7%) randomized in the trial planned to commence HD. 322 (88.9%) of these subsequently commenced HD and 17 (4.7%) commenced peritoneal dialysis, with a median time to the initiation of dialysis of 1.63 months in the early-start group and 6.93 months in the late- start group. During a median follow-up time of 3.81 years, 50 of 171 patients in the early-start group (29.2%) and 59 in the late-start group (30.1%) died (hazard ratio with early initiation=0.97: 95% CI: 0.66-1.41; p=0.86). There was no significant difference in the frequency of cardiovascular events, infections, or access-related events, but there was a significantly higher frequency of fluid and electrolyte events in the late-start group (p=0.02). CONCLUSION: In this subanalysis of the IDEAL trial, patients commencing dialysis early with stage 5 CKD for whom the planned dialysis modality was HD did not have an improvement in survival or any reduction in most clinical outcomes apart from fluid and electrolyte events.

Cost-effectiveness of initiating dialysis early: a randomized controlled trial.

BACKGROUND: Planned early initiation of dialysis therapy based on estimated kidney function does not influence mortality and major comorbid conditions, but amelioration of symptoms may improve quality of life and decrease costs. STUDY DESIGN: Patients with progressive chronic kidney disease and a Cockcroft-Gault estimated glomerular filtration rate of 10-15 mL/min/1.73 m(2) were randomly assigned to start dialysis therapy at a glomerular filtration rate of either 10-14 (early start) or 5-7 mL/min/1.73 m(2) (late start). SETTING & POPULATION: Of the original 828 patients in the IDEAL (Initiation of Dialysis Early or Late) Trial in renal units in Australia and New Zealand, 642 agreed to participate in this cost-effectiveness study. STUDY PERSPECTIVE & TIMEFRAME: A societal perspective was taken for costs. Patients were enrolled between July 1, 2000, and November 14, 2008, and followed up until November 14, 2009. INTERVENTION: Planned earlier start of maintenance dialysis therapy. OUTCOMES: Difference in quality of life and costs. RESULTS: Median follow-up of patients (307 early start, 335 late start) was 4.15 years, with a 6-month difference in median duration of dialysis therapy. Mean direct dialysis costs were significantly higher in the early-start group ($10,777; 95% CI, $313 to $22,801). Total costs, including costs for resources used to manage adverse events, were higher in the early-start group ($18,715; 95% CI, -$3,162 to $43,021), although not statistically different. Adjusted for differences in baseline quality of life, the difference in quality-adjusted survival between groups over the time horizon of the trial was not statistically different (0.02 full health equivalent years; 95% CI, -0.09 to 0.14). LIMITATIONS: Missing quality-of-life questionnaires and skewed cost data, although similar in each group, decrease the precision of results. CONCLUSION: Planned early initiation of dialysis therapy in patients with progressive chronic kidney disease has higher dialysis costs and is not associated with improved quality of life.

Benefits and limitations of plasmapheresis in renal diseases: an evidence-based approach.

In use for over 50 years, the rationale for plasmapheresis remains based largely on case series and retrospective studies. Recently, results from several randomized controlled trials, meta-analyses, and prospective studies have shown plasmapheresis may be of benefit in various renal diseases, and have provided insights into more rational use of this therapy. A multicenter trial by the European Vasculitis Study Group has shown it is the preferred additional form of therapy for patients with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis and severe renal failure. A recent study conducted at Mayo Clinic also found it effective at reversing renal failure from myeloma-related cast nephropathy if serum free light chain levels were reduced by at least 50%. In addition, a Cochrane review has analyzed the available evidence for its use in thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. The objective of this article is to review recent and past evidence and, thereby, the current indications for treatment in renal disease.

A randomized, controlled trial of early versus late initiation of dialysis.

BACKGROUND: In clinical practice, there is considerable variation in the timing of the initiation of maintenance dialysis for patients with stage V chronic kidney disease, with a worldwide trend toward early initiation. In this study, conducted at 32 centers in Australia and New Zealand, we examined whether the timing of the initiation of maintenance dialysis influenced survival among patients with chronic kidney disease. METHODS: We randomly assigned patients 18 years of age or older with progressive chronic kidney disease and an estimated glomerular filtration rate (GFR) between 10.0 and 15.0 ml per minute per 1.73 m2 of body-surface area (calculated with the use of the Cockcroft-Gault equation) to planned initiation of dialysis when the estimated GFR was 10.0 to 14.0 ml per minute (early start) or when the estimated GFR was 5.0 to 7.0 ml per minute (late start). The primary outcome was death from any cause. RESULTS: Between July 2000 and November 2008, a total of 828 adults (mean age, 60.4 years; 542 men and 286 women; 355 with diabetes) underwent randomization, with a median time to the initiation of dialysis of 1.80 months (95% confidence interval [CI], 1.60 to 2.23) in the early-start group and 7.40 months (95% CI, 6.23 to 8.27) in the late-start group. A total of 75.9% of the patients in the late-start group initiated dialysis when the estimated GFR was above the target of 7.0 ml per minute, owing to the development of symptoms. During a median follow-up period of 3.59 years, 152 of 404 patients in the early-start group (37.6%) and 155 of 424 in the late-start group (36.6%) died (hazard ratio with early initiation, 1.04; 95% CI, 0.83 to 1.30; P=0.75). There was no significant difference between the groups in the frequency of adverse events (cardiovascular events, infections, or complications of dialysis). CONCLUSIONS: In this study, planned early initiation of dialysis in patients with stage V chronic kidney disease was not associated with an improvement in survival or clinical outcomes. (Funded by the National Health and Medical Research Council of Australia and others; Australian New Zealand Clinical Trials Registry number, 12609000266268.)

Campylobacter insulaenigrae causing septicaemia and enteritis.

Campylobacter insulaenigrae is a novel species that has been recently only isolated from marine mammals. This is the first report of C. insulaenigrae causing enteritis and septicaemia in a patient with end-stage hepatic and renal disease.

Probiotic treatment of vancomycin-resistant enterococci: a randomised controlled trial.

OBJECTIVE: To determine whether eating Lactobacillus rhamnosus GG (LGG) in the form of commercially available yoghurt improves clearance of vancomycin-resistant enterococci (VRE). DESIGN: Double-blind, randomised, placebo-controlled trial. SETTING: Renal ward of Austin Health, a tertiary hospital, Feb-Oct 2005. PARTICIPANTS: 27 VRE-positive patients, 14 receiving active treatment and 13 controls. INTERVENTIONS: Subjects were randomly assigned to either a treatment group (receiving 100 g daily of yoghurt containing LGG for 4 weeks) or a control group (receiving standard pasteurised yoghurt). Faecal samples were obtained three times at about weekly intervals. Treated patients were tested for VRE again at 8 weeks. Patients in the control group who had failed to clear VRE after 4 weeks were then given LGG-containing yoghurt for 4 weeks, as an open continuation. MAIN OUTCOME MEASURE: Number of faecal specimens clear of VRE. RESULTS: Of the 27 patients enrolled, 23 completed the study. Two patients were lost to follow-up, one died and one withdrew. All 11 patients in the treatment group who completed the study cleared VRE. Three subjects reverted to VRE positivity after using antibiotics to which LGG is sensitive, while all others remained negative for at least 4 weeks after trial completion. Twelve control subjects completed the study, of whom one cleared VRE and 11 remained VRE-positive. Eight of these 11 patients were subsequently crossed over to receive LGG yoghurt, and all cleared VRE within 4 weeks. CONCLUSION: To our knowledge, this is the first description of a probiotic therapy to successfully treat gastrointestinal carriage of VRE in renal patients. Further investigation of the use of LGG in VRE-positive patients is warranted.

Fish oil treatment for kidney transplant recipients: a meta-analysis of randomized controlled trials.

BACKGROUND: Calcineurin inhibitors have adverse effects that contribute to nephrotoxicity and cardiovascular risk profile, and these may be reduced by administration of fish oil. The aim of this review was to assess the benefits and harms of fish oil supplementation in kidney transplant recipients on a calcineurin inhibitor-based immunosuppressive regimen. METHODS: The Cochrane Controlled Trials Registry, MEDLINE, and EMBASE were searched for randomized controlled trials of fish oil treatment in kidney transplant recipients on a calcineurin inhibitor-based immunosuppressive regimen. Trials comparing fish oil to both placebo and statins were included. Data were extracted for patient and graft survival, acute rejection, calcineurin inhibitor toxicity, cardiovascular events, adverse effects, compliance, renal function, blood pressure, and lipid profile. Dichotomous outcomes were reported as relative risk and continuous outcome measures as weighted mean differences (WMD), with 95% confidence intervals. RESULTS: Sixteen suitable trials were analyzed. Fish oil treatment was associated with a lower diastolic blood pressure (WMD 4.5 mmHg, P=0.004) and higher high-density lipoprotein (HDL) cholesterol (WMD 0.12 mmol/L, P=0.01) but did not affect the other outcomes. Fishy aftertaste and gastrointestinal upset were common but did not result in significant dropout. Fish oil effects on lipids were not significantly different than low-dose statins. CONCLUSION: There is insufficient evidence from currently available randomized controlled trials to recommend fish oil therapy to improve renal function, rejection rates, and patient or graft survival. Improvements in HDL cholesterol and diastolic blood pressure were too modest to recommend routine use.

Cardiac troponin levels in asymptomatic patients on the renal transplant waiting list.

AIMS: Cardiac troponin levels predict mortality and cardiovascular events in asymptomatic patients receiving dialysis and may be a useful clinical tool to stratify high-risk asymptomatic individuals. METHODS: The present study examined levels of troponins I (cTnI) and T (cTnT) in patients with chronic renal impairment, patients receiving dialysis and renal transplant recipients. Patients receiving dialysis on the renal transplant waiting list were compared with those excluded from the list based on medical criteria. Median levels were compared using the Kruskal-Wallis test and proportions compared by chi-squared. RESULTS: Median troponin levels were higher in patients on dialysis than transplant recipients. Comparing patients receiving dialysis not listed compared with those listed for renal transplant, median cTnI levels were significantly higher (0.03 versus 0.02 microg/L, P < 0.01) whereas median cTnT levels were not. Patients listed for transplantation were younger, had less clinical cardiovascular disease and lower C-reactive protein than those awaiting renal transplantation. The proportion of patients with elevated cTnT was not substantially different between patients awaiting renal transplantation (38%) and those excluded (52%). Levels of cTnI and cTnT were inversely related to renal function in predialysis and transplant patients, but were not related to time on dialysis for those receiving dialysis therapy. CONCLUSION: As patients awaiting renal transplantation are clinically screened for cardiovascular disease but have frequently elevated cardiac troponin levels, troponin may be a useful clinical tool to identify high-risk asymptomatic patients on dialysis prior to renal transplantation. The influence of renal function on the interpretation of cardiac troponin and risk prediction requires further evaluation.

Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure: a multicenter, randomized, controlled trial.

OBJECTIVES: The Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) aimed to establish whether high-dose folic acid would slow the progression of atherosclerosis and reduce cardiovascular events in patients with chronic renal failure (CRF). BACKGROUND: Hyperhomocysteinemia is a potential contributor to the high rates of cardiovascular morbidity and mortality in patients with CRF. METHODS: A total of 315 subjects with CRF, mean age 57 years (range 24 to 79 years) were randomized to 15 mg folic acid daily or placebo and followed for a median of 3.6 years. The primary intima-media thickness (IMT) and clinical end points were: rate of progression of mean maximum carotid IMT and a composite of myocardial infarction (MI), stroke, and cardiovascular death. Secondary end points included all cardiovascular events and change in pulse wave velocity, systemic arterial compliance and augmentation index. Data were analyzed by intention-to-treat. RESULTS: Plasma total homocysteine was reduced by 19% in the folic acid group. There was no significant difference between the treatment groups in rate of change of IMT or any measure of artery function. Seventy-seven events occurred in the folic acid group (14.9 per 100 patient-years) as compared with 86 in the placebo group (16.3 per 100 patient-years). The rates of the primary and secondary clinical end points at five years were not significantly different after adjustment for baseline differences between the groups (adjusted hazard ratio for MI, stroke, and cardiovascular death: 0.98 [95% confidence interval: 0.66 to 1.47]; p = 0.94; for all cardiovascular events: 0.95 [95% confidence interval: 0.69 to 1.30]; p = 0.75). CONCLUSIONS: High-dose folic acid does not slow atheroma progression or improve cardiovascular morbidity or mortality in patients with CRF.

Atherosclerosis and folic acid supplementation trial in chronic renal failure: baseline results.

BACKGROUND: Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) is a randomized placebo controlled trial assessing whether high-dose folic acid can reduce cardiovascular events and atherosclerosis progression in patients with chronic renal failure (CRF). Here we report the baseline results and compare indices of arterial structure (carotid intima-medial thickness (IMT)) and function (systemic arterial compliance (SAC)), pressure augmentation index (AI(x)) and pulse wave velocity (PWV a-f and PWV f-d)) to age- and sex-matched controls. METHODS: Three hundred and fifteen subjects with CRF (serum creatinine > or = 0.40 mmol/L) aged 24-79 years (mean +/- SD: 56.6 +/- 13.6 years) and 213 healthy controls (58.2 +/- 10.2 years) were studied. Fasting blood samples were assayed for lipids (both groups), total homocysteine (tHcy), red cell folate, cobalamin and fibrinogen (CRF group). Ultrasound B mode measurements were used to determine mean carotid IMT and applanation tonometry techniques to determine SAC, AI(x), PWV (a-f), PWV (f-d) and central pressures. RESULTS: Ninety-six per cent of the CRF group had at least one of: hypertension, hypercholesterolaemia, diabetes or smoking; 35% had established cardiovascular disease. The mean IMT was greater in CRF patients than in controls (0.86 +/- 0.19 vs 0.68 +/- 0.11 mm, P < 0.001). The SAC was significantly lower, and PWV (a-f) and AI(x) significantly higher. The tHcy was increased in 97% of the CRF group (27.3 +/- 2.9 micromol/L (normal < 13)). Total homocysteine did not correlate with IMT or any other measure of arterial function. However, those in the upper quantile of tHcy (> or =25 micromol/L) did have higher PWV (a-f) and lower SAC than those in the lower quantile. CONCLUSIONS: Compared to normals, patients with CRF exhibited a 10-15-year shift to the right in age-related increases in carotid IMT and PWV (a-f), and significantly increased central pressure augmentation. This 5-year study is examining the impact of high-dose folic acid therapy on cardiovascular end-points, IMT progression and arterial function in CRF.

The Initiating Dialysis Early and Late (IDEAL) study: study rationale and design.

OBJECTIVES: The primary objective of the IDEAL study is to determine whether the timing of dialysis initiation has an effect on survival in subjects with end-stage renal disease (ESRD). The secondary objectives are to determine the impact of "early start" versus "late start" dialysis on nutritional and cardiac morbidity, quality of life, and economic cost. DESIGN: Prospective multicenter randomized controlled trial. Patients are randomized to commence dialysis at a glomerular filtration rate (by Cockcroft-Gault) of either 10-14 mL/minute/1.73 m2 ("early start") or 5-7 mL/min/1.73 m2 ("late start"), with stratification for dialysis modality (hemodialysis vs peritoneal dialysis), study center, and the presence or not of diabetes mellitus. SETTING: Dialysis units throughout Australia and New Zealand. PATIENTS: Patients with ESRD commencing chronic dialysis therapy. OUTCOME MEASURES: Three years from randomization, all-cause mortality, morbidity, and economic impact; structural and functional cardiac status, nutritional state, and quality of life will be assessed. RESULTS: To date, 388 patients of a minimum 800 patients have been entered and randomized into the study. Current recruitment rates suggest sufficient patients will be enrolled by December 2004 and follow-up completed by December 2007. CONCLUSIONS: The IDEAL study will provide evidence for the optimal time to commence dialysis.