Potential of emerging immunosuppressive strategies to improve the posttransplant cardiovascular risk profile.

Currently used immunosuppressants exacerbate cardiovascular risk. However, attempts to limit the use of these agents increase the risk of allograft rejection. Immunosuppressants targeting signal 2 and signal 3 lymphocyte activation pathways are under clinical development. Clinical data from trials of the Janus family protein tyrosine kinase-3 inhibitor tasocitinib and the costimulation blocker belatacept are presented. Additional pipeline agents are described. Results from two phase III clinical trials of belatacept revealed efficacy that is not inferior to that provided by cyclosporine (CsA). In the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial enrolling recipients of standard criteria living or deceased donor organs, the risk of rejection was higher among patients treated with a more intensive treatment regimen. Increased risk of posttransplant lymphoproliferative disorder, particularly among Epstein-Barr virus-patients, was a notable adverse event. Data from a phase II trial of tasocitinib suggested good prophylaxis of rejection. Safety signals included increased risk of infection and potential myelosuppression, leading to anemia, neutropenia, and leukopenia. Both belatacept and tasocitinib were associated with a low cardiovascular risk profile and improved renal function compared with CsA. New immunosuppressive regimens should maintain the effectiveness provided by current agents while preserving renal function and cardiovascular health. Surveillance for new adverse events must be an integral part of the long-term management strategy.

The metabolic syndrome following kidney transplantation.

The metabolic syndrome is a constellation of defined cardiovascular risk factors occurring simultaneously in a single individual. The result of dysregulated glucose and vascular metabolism, the syndrome has been identified as a significant risk factor for cardiovascular morbidity in the general population. More recently, a relatively high prevalence of the metabolic syndrome has been recognized among kidney transplant recipients. The prevalence, risk factors, pathophysiology, and potential consequences of the metabolic syndrome in the general population and in kidney transplant recipients are reviewed. The definitions and clinical utility of the metabolic syndrome as a medical condition continue to be debated. Nevertheless, the burden of risk increases with the presence of multiple components, including insulin resistance, abdominal obesity, and dysregulated lipid metabolism. Risk factors specific to transplant recipients include the duration of pretransplant dialysis and posttransplant immunosuppression and weight gain. The metabolic syndrome is emerging as a significant surveillance target following kidney transplantation. Control of body mass index, blood glucose and lipid levels, as well as blood pressure, is required to prevent the consequences of the metabolic syndrome, including cardiovascular events and cardiovascular death. Immunosuppressive regimens should be designed to limit exacerbation of components of the metabolic syndrome.

Delayed onset CMV disease in solid organ transplant recipients.

It is estimated that three-quarters of all patients undergoing solid organ transplantation experience new infection or reactivation of latent cytomegalovirus (CMV). The adoption of universal antiviral prophylactic strategies among high risk patients has significantly reduced the incidence of CMV infection and disease over the first three months. However, depending on the type of transplant and the pretransplant donor-recipient CMV serostatus, up to 30% of patients may develop disease after three months (late disease), or at any time later than 1-2 years following transplantation (very late disease). The occurrence of late and very late CMV, referred to here as delayed onset CMV, places patients at risk for malignancy, graft loss and mortality. Clinical management of delayed onset CMV disease may be complicated by the presentation of nonspecific or atypical symptoms. The potential for missed diagnoses may be compounded by the long term management of patients by healthcare professionals who do not practice transplantation as a primary specialty. The current clinical goal is to ensure excellent long term outcomes among transplant recipients. Therefore, the present review will discuss the natural history and risk factors, as well as the therapeutic strategies relevant to the occurrence and management of late and very late CMV disease following solid organ transplantation in adults.

Argatroban anticoagulation for heparin-induced thrombocytopenia in elderly patients.

BACKGROUND: Argatroban, a direct thrombin inhibitor that has reduced clearance in elderly versus younger volunteers, is used for thromboprophylaxis or treatment in heparin-induced thrombocytopenia (HIT). OBJECTIVE: To evaluate the effect of aging on argatroban therapy, including dosage, anticoagulant responses, clinical outcomes and factors influencing those responses, in elderly patients with HIT or a history of HIT. METHODS: This was a retrospective multicentre database analysis of 118 inpatients treated with argatroban at six medical centres between August 2001 and January 2005. Sixty-two adults aged >/=65 years were administered argatroban for clinically diagnosed HIT (n = 54) or a history of HIT (n = 8). Argatroban infusion was adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline. All study measures and analyses were prospectively defined. Argatroban dosage patterns, aPTTs and platelet count responses, and 37-day outcomes (death, amputation, new thrombosis, major bleeding) were summarised for patients stratified by age (65-74 years [n = 31]; 75-84 years [n = 26]; >/=85 years [n = 5]) to identify possible age-related trends. Regression analyses explored relationships between dose and patient age, liver function and renal function. Cox proportional hazards models evaluated the effect of age, dose, gender, aPTT and platelet count on the risk of new thrombosis. RESULTS: In each age group, the median argatroban dosage was initially 1.0 microg/kg/min and was generally maintained at or near that dose during therapy (median, 5-7 days). Therapeutic aPTTs occurred within 11.5 hours; the median aPTT during therapy was 54.7 seconds, without obvious trend by age. By regression analysis, the initial and mean argatroban dosages decreased 0.08-0.09 microg/kg/min with each 0.2 mg/dL increase in serum creatinine, but no association was detected between dose and patient age, serum total bilirubin, calculated creatinine clearance or blood urea nitrogen. Platelet counts recovered within 6-7 days of initiating therapy, without apparent trend by age. No patient experienced amputation or major bleeding, and no patient in the oldest group died or had new thrombosis. Overall, 13 (21%) patients died (9 in the 65-74 years group; 1 receiving argatroban) and 5 (8%) had new thrombosis (4 in the 65-74 years group; 2 receiving argatroban), comparing favourably with previously reported rates, irrespective of patient age. By univariate (but not multivariate) analysis, the risk of new thrombosis decreased with increasing argatroban dose (hazard ratio 0.020; 95% CI 0.001, 0.757; p = 0.035). No effect of age or the other covariates considered on thrombotic risk was detected. CONCLUSION: Argatroban at a median initial dosage of 1.0 microg/kg/min, adjusted to achieve median aPTTs of 54.7 seconds during therapy, generally provided safe, adequate anticoagulation across a wide age range in elderly patients with HIT or a history of HIT. In these elderly patients, age was not a significant determinant of argatroban dosage or thrombotic risk. Prospective evaluation of this initial dose of argatroban in the elderly is warranted.