Edward Cole

Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial

BACKGROUNDnRenal transplant recipients are at increased risk of premature cardiovascular disease. Although statins reduce cardiovascular risk in the general population, their efficacy and safety in renal transplant recipients have not been established. We investigated the effects of fluvastatin on cardiac and renal endpoints in this population.nnnMETHODSnWe did a multicentre, randomised, double-blind, placebo-controlled trial in 2102 renal transplant recipients with total cholesterol 4.0-9.0 mmol/L. We randomly assigned patients fluvastatin (n=1050) or placebo (n=1052) and follow up was for 5-6 years. The primary endpoint was the occurrence of a major adverse cardiac event, defined as cardiac death, non-fatal myocardial infarction (MI), or coronary intervention procedure. Secondary endpoints were individual cardiac events, combined cardiac death or non-fatal MI, cerebrovascular events, non-cardiovascular death, all-cause mortality, and graft loss or doubling of serum creatinine. Analysis was by intention to treat.nnnFINDINGSnAfter a mean follow-up of 5.1 years, fluvastatin lowered LDL cholesterol concentrations by 32%. Risk reduction with fluvastatin for the primary endpoint (risk ratio 0.83 [95% CI 0.64-1.06], p=0.139) was not significant, although there were fewer cardiac deaths or non-fatal MI (70 vs 104, 0.65 [0.48-0.88] p=0.005) in the fluvastatin group than in the placebo group. Coronary intervention procedures and other secondary endpoints did not differ significantly between groups.nnnINTERPRETATIONnAlthough cardiac deaths and non-fatal MI seemed to be reduced, fluvastatin did not generally reduce rates of coronary intervention procedures or mortality. Overall effects of fluvastatin were similar to those of statins in other populations.

Fluvastatin prevents cardiac death and myocardial infarction in renal transplant recipients: post-hoc subgroup analyses of the ALERT Study

Renal transplant recipients have a greatly increased risk of premature cardiovascular disease. The ALERT study was a multicenter, randomized, double‐blind, placebo‐controlled trial of fluvastatin (40–80 mg/day) in 2102 renal transplant recipients followed for 5–6 years. The main study used a composite cardiac end‐point including myocardial infarction, cardiac death and cardiac interventions. Although reduced by fluvastatin, this primary end‐point failed to achieve statistical significance thus precluding analysis of predefined subgroups. Therefore, in the present survival analysis, we used an alternative primary end‐point of cardiac death or definite nonfatal myocardial infarction (as used in other cardiac outcome trials) which was significantly reduced by Fluvastatin therapy and permits subgroup analysis. Fluvastatin reduced LDL‐cholesterol by 1 mmol/L compared with placebo, and the incidence of cardiac death or definite myocardial infarction was reduced from 104 to 70 events (RR 0.65; 95% CI 0.48, 0.88; p = 0.005). Fluvastatin use was associated with reduction in cardiac death or nonfatal myocardial infarction, which achieved statistical significance in many subgroups. The subgroups included patients at lower cardiovascular risk, who were younger, nondiabetic, nonsmokers and without pre‐existing CVD. These data support the early introduction of statins following renal transplantation.

Renal dysfunction is a strong and independent risk factor for mortality and cardiovascular complications in renal transplantation

Renal transplant recipients (RTR) have shortened life expectancy, primarily due to premature cardiovascular disease (CVD). Traditional CVD risk factors are highly prevalent. In addition, several non‐traditional risk factors may contribute to the high risk. The aim of the study was to evaluate the effects of renal dysfunction on mortality and cardiovascular complications in 1052 placebo‐treated patients of the Assessment of LEscol in Renal Transplantation (ALERT) trial. Follow‐up was 5–6 years and endpoints included cardiac death, non‐cardiovascular death, all‐cause mortality, major adverse cardiac event (MACE), non‐fatal myocardial infarction (MI) and stroke. The effects of serum creatinine at baseline on these endpoints were evaluated. Elevated serum creatinine in RTR was a strong and independent risk factor for MACE, cardiac, non‐cardiovascular, and all‐cause mortality, but not for stroke or non‐fatal MI alone. Serum creatinine was associated with increased mortality and MACE, independent of established CVD risk factors. Graft loss resulted in increased incidences of non‐cardiovascular death, all‐cause mortality, MACE and non‐fatal MI. In conclusion, elevated serum creatinine is a strong risk factor for all‐cause, non‐cardiovascular and cardiac mortality, and MACE, independent of traditional risk factors, but not for stroke or non‐fatal MI alone.

Kinetic Analysis of a Unique Direct Prothrombinase, fgl2, and Identification of a Serine Residue Critical for the Prothrombinase Activity

fgl2 prothrombinase, by its ability to generate thrombin, has been shown to be pivotal to the pathogenesis of viral-induced hepatitis, cytokine-induced fetal loss syndrome, and xeno- and allograft rejection. In this study, the molecular basis of fgl2 prothrombinase activity was examined in detail. Purified fgl2 protein generated in a baculovirus expression system had no measurable prothrombinase activity, whereas the activity was restored when the purified protein was reconstituted into phosphatidyl-l-serine-containing vesicles. Reconstituted fgl2 catalyzed the cleavage of human prothrombin to thrombin with kinetics consistent with a first order reaction, with an apparent Vmax value of 6 mol/min/mol fgl2 and an apparent Km value for prothrombin of 8.3 μM. The catalytic activity was totally dependent on calcium, and factor Va (500 nM) enhanced the catalytic efficiency of fgl2 by increasing the apparent Vmax value to 3670 mol/min/mol fgl2 and decreasing the apparent Km value for prothrombin to 7.2 μM. By a combination of site-directed mutagenesis and production of truncated proteins, it was clearly shown that residue Ser89 was critical for the prothrombinase activity of fgl2. Furthermore, fgl2 prothrombinase activity was not inhibited by antithrombin III, soybean trypsin inhibitor, 4-aminobenzamidine, aprotinin, or phenylmethylsulfonyl fluoride, whereas diisopropylfluorophosphate completely abrogated the activity. In this work we provide direct evidence that fgl2 cleaves prothrombin to thrombin consistent with serine protease activity and requires calcium, phospholipids, and factor Va for its full activity.

Renal transplant outcome in high-cardiovascular risk recipients

Abstract:u2002 Background: Cardiovascular (CV) disease is the foremost cause of mortality and an important cause of morbidity in renal transplant recipients. The disease burden is likely to increase as older patients are accepted for transplantation. The outcome of these high‐CV risk patients after renal transplantation, especially with known pre‐transplant coronary artery disease (CAD), has not been studied. Hence, we looked at the CV outcome in patients with known pre‐transplant CAD. Methods: All renal transplants performed between 1998 and 2002 at our center, followed up to 2005, were divided into high‐ and low‐risk groups, based on the presence of one or more of the following: pre‐transplant angina, myocardial infarction, and positive coronary angiogram. The two groups were compared for post‐transplant cardiac events and patient and graft survival. The factors predictive of post‐transplant cardiac events were also determined by Cox‐regression multivariate analysis. Results: Forty‐five patients (10.5%), out of 429, had post‐transplant cardiac events; 31.3% in the high risk, and 6.5% in the low‐risk group (pu2003=u20030.001). Five‐yr patient survival was lower in the high‐risk group (82.8% vs. 93.1%, pu2003=u20030.004), while five‐yr overall graft survival and death censored graft survival were statistically not different (74.8% vs. 84.1%, pu2003=u20030.08 and 87.3% vs. 90%, pu2003=u20030.25). Forty‐one percent of patients who were treated with angioplasty plus stenting or bypass graft prior to transplantation had post‐transplant cardiac events, as compared with 28% of those without intervention in the high‐risk group and 6.5% of patients in the low‐risk group (pu2003=u20030.001). Age, pre‐transplant cardiac disease, arrhythmias, and low‐ejection fraction (≤40%) were significant independent predictors of post‐transplant cardiac events. Conclusion: Post‐transplant survival of high‐CV risk patients (with known CAD) is lower than that of low‐risk recipients but remains acceptable. Cardiac interventions may reduce perioperative risk but do not reduce the probability of post‐transplant cardiac events to that of low‐risk group.

Deceased Organ Donation in Canada : An Opportunity to Heal a Fractured System

There has been no significant increase in the number of deceased organ donors in Canada over the past decade. Canadas donation and transplant system will be restructured with the formation of a new national organization to oversee activity in provincially governed donation and transplantation services. We review the current status of deceased organ donation, highlight issues contributing to the current stagnation in donation and identify changes that will enable success in a new Canadian system. Determining Canadas organ donation performance is difficult because the data required to calculate meaningful metrics of donation performance are not available. Canadians wait longer for transplantation than Americans, and Canada is falling further behind the United States primarily because of fewer donations after cardiac death. The ongoing divide between intergovernmental jurisdictional domains limits national initiatives to improve Canadas donation system. The success of a new national system will be enabled by uniform provincial legislation to ensure that all patients are offered the option to donate, commitment of resources to support organ donation by provincial governments, transparent reporting of comparable metrics of donation performance, establishment of processes to introduce and implement new initiatives and alterations to reimbursement models for organ donation and recovery.

Hypercalcemia in renal transplant patients: prevalence and management in Canadian transplant practice

Hypercalcemia, occurring in up to 25% of patients within 12 months following renal transplantation, and persistent hyperparathyroidism were evaluated following renal transplantation, by retrospective chart review of 1000 adult patients transplanted between January 1, 2003 and January 31, 2008 with at least six months follow‐up. Serum calcium, parathyroid hormone, and phosphate levels were recorded at 12, 24, 36, and 48 months. Average follow‐up was 766 (535) d (mean (SD); median 668 d). Majority were first transplants (85%); deceased donor 57%. Point prevalence of hypercalcemia (serum Ca2+ > 2.6 mM) was 16.6% at month 12, 13.6% at month 24, 9.5% at month 36, and 10.1% at month 48. Point prevalence of serum parathyroid hormone (PTH) > 10 pM was 47.6% at month 12, 51.1% at month 24, 43.4% at month 36, and 39.3% at month 48. Estimated glomerular filtration rate (GFR) was maintained throughout and was not different between patients with or without hypercalcemia or elevated PTH. Cinacalcet was prescribed in 12% of patients with hypercalcemia and persistent hyperparathyroidism; parathyroidectomy was performed in 112/1000 patients, 15 post‐transplant. Persistent hyperparathyroidism, often accompanied by hypercalcemia, is common following successful renal transplantation, but the lack of clear management suggests the need for further study and development of evidence‐based guidelines.

The dual kidney transplant registry.

There has been a steady increase in the utilization of aged donor kidneys for dual transplantation during the past several years. As the follow-up of these dual kidney recipients accrues, it is clear that the long-term graft survival rate approaches that seen in recipients of single kidneys transplanted from younger donors. Because the kidneys used for dual kidney transplants would have otherwise been discarded, it is imperative to recognize that kidneys from cadaver donors that fall outside the normal acceptance criteria are a valuable resource and can provide excellent long-term function when properly placed. Reducing cold storage time may be the single most important aspect to insuring long-term graft survival in recipients of aged dual kidney transplants.

A pilot study of reduced dose cyclosporine and corticosteroids to reduce new onset diabetes mellitus and acute rejection in kidney transplant recipients

BackgroundNew onset diabetes mellitus (NODM) and acute rejection (AR) are important causes of morbidity and risk factors for allograft failure after kidney transplantation.MethodsIn this multi-center, open label, single-arm pilot study, 49 adult (≥18 years of age), low immunologic risk, non-diabetic recipients of a first deceased or living donor kidney transplant received early steroid reduction to 5 mg/day combined with Thymoglobulin® (Genzyme Transplant, Cambridge, MA, USA) induction, low dose cyclosporine (2-hour post-dose (C2) target of 600 to 800 ng/ml) and mycophenolic acid (MPA) therapy.ResultsSix months after transplantation, two patients (4%) developed NODM and one patient (2%) developed AR. Four patients had impaired fasting glucose tolerance based on 75-g oral glucose tolerance testing (OGTT). There was one patient death. There were no episodes of cytomegalovirus (CMV) infection or BK virus nephritis. In contrast, in a historical cohort of n = 27 patients treated with Thymoglobulin induction, and conventional doses of cyclosporine and corticosteroids, the incidence of NODM and AR was 18% and 15%.ConclusionsThe pilot study results suggest that Thymoglobulin induction combined with early steroid reduction, reduced cyclosporine exposure and MPA, may reduce the incidence of both NODM and AR in low immunological risk patients. A future controlled study enriched for patients at high risk for NODM is under consideration.Trial registrationClinicalTrials.gov: NCT00706680

The Evolution of Immunosuppressant Therapy in Renal Transplantation

For patients with end-stage renal disease (ESRD), kidney transplantation offers the greatest chance for survival and improved quality of life. However, with the limited supply of kidneys available for transplantation, and a growing number of patients with ESRD, the importance of optimizing each transplant has never been greater. Recent studies have shown significant reductions in the incidence of acute rejection following transplantation, probably related to the availability of newer immunosuppressive therapies. However, these short-term gains have not been translated into a significant increase in long-term graft survival. Indeed, the rate of graft loss after the first year has not really changed. Since the greatest reasons for graft loss after 1 year are patient death and progressive allograft fibrosis (chronic allograft nephropathy/interstitial fibrosis/tubular atrophy not otherwise specified), many approaches have focused on potential strategies for reducing these complications.