Anders Hartmann

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

BACKGROUND Renal 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. METHODS We 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. FINDINGS After 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. INTERPRETATION Although 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.

Long-term risks for kidney donors

Previous studies have suggested that living kidney donors maintain long-term renal function and experience no increase in cardiovascular or all-cause mortality. However, most analyses have included control groups less healthy than the living donor population and have had relatively short follow-up periods. Here we compared long-term renal function and cardiovascular and all-cause mortality in living kidney donors compared with a control group of individuals who would have been eligible for donation. All-cause mortality, cardiovascular mortality, and end-stage renal disease (ESRD) was identified in 1901 individuals who donated a kidney during 1963 through 2007 with a median follow-up of 15.1 years. A control group of 32,621 potentially eligible kidney donors was selected, with a median follow-up of 24.9 years. Hazard ratio for all-cause death was significantly increased to 1.30 (95% confidence interval 1.11-1.52) for donors compared with controls. There was a significant corresponding increase in cardiovascular death to 1.40 (1.03-1.91), while the risk of ESRD was greatly and significantly increased to 11.38 (4.37-29.6). The overall incidence of ESRD among donors was 302 cases per million and might have been influenced by hereditary factors. Immunological renal disease was the cause of ESRD in the donors. Thus, kidney donors are at increased long-term risk for ESRD, cardiovascular, and all-cause mortality compared with a control group of non-donors who would have been eligible for donation.

Oral Valganciclovir Is Noninferior to Intravenous Ganciclovir for the Treatment of Cytomegalovirus Disease in Solid Organ Transplant Recipients

Intravenous ganciclovir is the standard treatment for cytomegalovirus disease in solid organ transplant recipients. Oral valganciclovir is a more convenient alternative. In a randomized, international trial, recipients with cytomegalovirus disease were treated with either 900 mg oral valganciclovir or 5 mg/kg i.v. ganciclovir twice daily for 21 days, followed by 900 mg daily valganciclovir for 28 days. A total of 321 patients were evaluated (valganciclovir [n = 164]; i.v. ganciclovir [n = 157]). The success rate of viremia eradication at Day 21 was 45.1% for valganciclovir and 48.4% for ganciclovir (95% CI –14.0% to +8.0%), and at Day 49; 67.1% and 70.1%, respectively (p = NS). Treatment success, as assessed by investigators, was 77.4% versus 80.3% at Day 21 and 85.4% versus 84.1% at Day 49 (p = NS). Baseline viral loads were not different between groups and decreased exponentially with similar half‐lives and median time to eradication (21 vs. 19 days, p = 0.076). Side‐effects and discontinuations of assigned treatment (18 of 321 patients) were comparable.

Glucose intolerance after renal transplantation depends upon prednisolone dose and recipient age

BACKGROUND Retrospective studies on the prevalence of posttransplant diabetes mellitus (PTDM) in patients on triple-drug immunosuppressive therapy have shown great dispersity, while the incidence of posttransplant impaired glucose tolerance (IGT) is unknown. The aim of our study was to prospectively examine the incidence of posttransplant glucose intolerance and to assess potential risk factors. METHODS Glucose intolerance was prospectively examined in 173 consecutive kidney transplant recipients by oral glucose tolerance tests (n=167) or the diagnosis of manifest diabetes mellitus (n=6) at 10 weeks after transplant. RESULTS We found a high incidence of PTDM (18%) and IGT (31%). Univariate analysis revealed that age, family history of diabetes, HLA-B27 phenotype, DR mismatch, rejection, actual prednisolone dose, total methylprednisolone dose, total steroid dose, cytomegalovirus (CMV) infection, and the use of furosemide were associated with PTDM. Age, prednisolone dose, CMV infection, and the use of beta-blockers were associated with IGT. Gender, body mass index, donor source, and cyclosporine level did not influence glucose tolerance. Prednisolone dose, age, family history of diabetes, CMV infection, and HLA-B27 phenotype were independent predictors of PTDM with the use of multiple stepwise logistic regression analysis. Age, prednisolone dose, and the use of a beta-blocker were associated with IGT in the multivariate model. Both univariate and multivariate linear regression analysis revealed a significant relationship between the 2-hr serum glucose and prednisolone dose. The risk of developing PTDM was 5% per 0.01 mg/kg/day of increase in prednisolone dose. CONCLUSIONS Increased prednisolone dose and older age are strongly associated with the development of posttransplant glucose intolerance.

Long‐term Cardiac Outcomes in Renal Transplant Recipients Receiving Fluvastatin: The ALERT Extension Study

Renal transplant recipients (RTR) have an increased risk of premature cardiovascular disease. The ALERT study is the first trial to evaluate the effect of statin therapy on cardiac outcomes following renal transplantation. Patients initially randomized to fluvastatin or placebo in the 5–6 year ALERT study were offered open‐label fluvastatin XL 80 mg/day in a 2‐year extension to the original study. The primary endpoint was time to first major adverse cardiac event (MACE). Of 1787 patients who completed ALERT, 1652 (92%) were followed in the extension. Mean total follow‐up was 6.7 years. Mean LDL‐cholesterol was 98 mg/dL (2.5 mmol/L) at last follow‐up compared to a pre‐study level of 159 mg/dL (4.1 mmol/L). Patients randomized to fluvastatin had a reduced risk of MACE (hazards ratio [HR] 0.79, 95% CI 0.63–0.99, p = 0.036), and a 29% reduction in cardiac death or definite non‐fatal MI (HR 0.71, 95% CI 0.55–0.93, p = 0.014). Total mortality and graft loss did not differ significantly between groups. Fluvastatin produces a safe and effective reduction in LDL‐cholesterol associated with reduced risk of MACE in RTR. The lipid‐lowering and cardiovascular benefits of fluvastatin are comparable to those of statins in other patient groups, and support use of fluvastatin in RTR.

Early cyclosporine withdrawal from a sirolimus‐based regimen results in better renal allograft survival and renal function at 48 months after transplantation

We report the 48‐month results of a trial testing whether withdrawal of cyclosporine (CsA) from a sirolimus (SRL)‐CsA‐steroid (ST) regimen would impact renal allograft survival. Eligible patients receiving SRL‐CsA‐ST from transplantation were randomly assigned at 3 months to remain on triple therapy (SRL‐CsA‐ST, n = 215) or to have CsA withdrawn and SRL trough concentrations increased (SRL‐ST, n = 215). SRL‐ST therapy resulted in significantly better graft survival, either when including death with a functioning graft as an event (84.2% vs. 91.5%, P = 0.024) or when censoring it (90.6% vs. 96.1%, P = 0.026). Calculated glomerular filtration rate (43.8 vs. 58.3 ml/min, P < 0.001) and mean arterial blood pressure (101.3 vs. 97.1 mmHg, P = 0.047) were also improved with SRL‐ST. Differences in the incidences of biopsy‐proven acute rejection after randomization (6.5% vs. 10.2%, SRL‐CsA‐ST versus SRL‐ST, respectively) and mortality (7.9% vs. 4.7%) were not significant. SRL‐CsA‐ST‐treated patients had significantly higher incidences of adverse events generally associated with CsA, whereas those in the SRL‐ST group experienced greater frequencies of events commonly related to higher trough levels of SRL. In conclusion, early withdrawal of CsA from a SRL‐CsA‐ST regimen rapidly improves renal function and ultimately results in better graft survival.

The Impact of Cytomegalovirus Infection and Disease on Rejection Episodes in Renal Allograft Recipients

Cytomegalovirus (CMV) infection and disease are potential risk factors for acute allograft rejection in renal transplant recipients. The present study specifically addresses this issue. From October 1994 to July 1997, 477 consecutive renal allograft recipients (397 first transplants and 80 retransplants) were included in the study. CMV infection (cytomegalovirus pp65 antigen in leukocytes) and disease (infection and clinical symptoms or signs of disease) were examined prospectively for 3 months. No CMV prophylaxis was given, and CMV disease was treated with intravenous (i.v.) ganciclovir. The retransplantation of four patients transplanted twice during the study and 22 patients receiving kidneys from human leucocyte antigen (HLA)‐identical siblings were excluded from statistical analysis. Rejections were evaluated clinically [277(61%)] and 173 (38%) also had a biopsy verified rejection. CMV infection occurred in 64% of the patients and 24% experienced CMV disease. In a multiple time‐dependent Cox analysis, CMV infection and CMV disease were independent significant predictors for clinical acute rejections, RR = 1.6 (1.1–2.5, p = 0.02) and RR = 2.5 (1.2–5.1, p = 0.01), respectively. Among 173 patients with biopsy verified rejection, 72% of the patients had tubulointerstitial rejection whereas 28% had a vascular rejection. CMV disease, but not CMV infection was a predictor of tubulointerstitial rejection, RR = 3.1 (1.1–9.3, p = 0.04). CMV infection and disease are independent risk factors for clinical acute rejection in kidney allograft recipients. CMV disease is an independent risk factor for biopsy verified acute tubulointerstitial rejection in kidney allograft recipients.

Comparing Mycophenolate Mofetil Regimens for de Novo Renal Transplant Recipients: The Fixed-Dose Concentration-Controlled Trial

Background. Fixed-dose mycophenolate mofetil (MMF) reduces the incidence of acute rejection after solid organ transplantation. The Fixed-Dose Concentration Controlled trial assessed the feasibility and potential benefit of therapeutic drug monitoring in patients receiving MMF after de novo renal transplant. Methods. Patients were randomized to a concentration-controlled (n=452; target exposure 45 mg hr/L) or a fixed-dose (n=449) MMF-containing regimen. The primary endpoint was treatment failure (a composite of biopsy-proven acute rejection [BPAR], graft loss, death, or MMF discontinuation) by 12 months posttransplantation. Results. Mycophenolic acid (MPA) exposures for both groups were similar at most time points and were below 30 mg hr/L in 37.3% of patients at day 3. There was no difference in the incidence of treatment failure (25.6% vs. 25.7%, P=0.81) or BPAR (14.9% vs. 15.5%, P>0.05) between the concentration-controlled and the fixed-dose groups, respectively. We did find a significant relationship between MPA-area under the concentration–time curve on day 3 and the incidence of BPAR in the first month (P=0.009) or in the first year posttransplantation (P=0.006). For later time points (day 10, month 1) there was no significant relationship between area under the concentration–time curve and BPAR (0.2572 and 0.5588, respectively). Conclusions. There was no difference in the incidence of treatment failure between the concentration-controlled and the fixed-dose groups. The applied protocol of MMF dose adjustments based on target MPA exposure was not successful, partly because physicians seemed reluctant to implement substantial dose changes. Current initial MMF doses underexpose more than 35% of patients early after transplantation, increasing the risk for BPAR.

Asymptomatic cytomegalovirus infection is associated with increased risk of new-onset diabetes mellitus and impaired insulin release after renal transplantation

Aims/hypothesisThe human cytomegalovirus (CMV) may increase the risk of diabetes mellitus, but the literature is scarce. The present study was designed to test the hypothesis that asymptomatic CMV infection is associated with increased risk of new-onset diabetes after renal transplantation, and to assess the impact of asymptomatic CMV infection on OGTT-derived estimates of insulin release and insulin action.MethodsA total of 160 consecutive non-diabetic renal transplant recipients on cyclosporine (Sandimmun Neoral)-based immunosuppression were closely monitored for CMV infection during the first 3 months after transplantation. All patients underwent a 75-g OGTT at 10 weeks. Excluded from the analyses were 36 patients with symptomatic CMV infection (disease).ResultsThe incidence of new-onset diabetes was 6% in a control group of recipients without CMV infection (4/63) and 26% in the group with asymptomatic CMV infection (16/61). Asymptomatic CMV infection was associated with a significantly increased risk of new-onset diabetes (adjusted odds ratio: 4.00; 95% CI: 1.19 to 13.43, p=0.025). The group of patients with CMV infection had a significantly lower median insulin release than controls.Conclusions/interpretationOur findings support the hypothesis that asymptomatic CMV infection is associated with increased risk of new-onset post-transplant diabetes mellitus, and suggest that impaired insulin release may involve one pathogenetic mechanism.

Insulin Resistance after Renal Transplantation: The Effect of Steroid Dose Reduction and Withdrawal

Cardiovascular disease is a prevalent and serious complication after solid organ transplantation. Treatment with glucocorticoids is associated with increased risk for diabetes mellitus, insulin resistance, weight gain, hypercholesterolemia, and hypertension, all shown to be independent risk factors for cardiovascular disease. We sought to test the hypothesis that tapering of prednisolone (TAP) the first year after renal transplantation improves insulin sensitivity (IS), and to assess the effect of complete steroid withdrawal (SW) on IS in patients on a cyclosporine-based immunosuppressive regimen. All patients (n = 57) completed two consecutive hyperinsulinemic euglycemic glucose clamp procedures, a TAP group (n = 34) and a control group (n = 12) at 3 and 12 mo after transplantation, and a SW group (n = 11) before and 5 mo after SW. The IS index (ISI) was calculated as the glucose disposal rate divided by mean serum insulin the last 60 min of the clamp. In the TAP group, the mean (range) daily prednisolone was reduced from 16 (10 to 30) to 9 (5 to 12.5) mg accompanied by an average increased ISI of 24% (P = 0.008). In contrast, no significant change in ISI was observed in the control group (0%, P = 0.988). In the SW group, withdrawal of 5 mg prednisolone did not influence mean ISI significantly (-8%, P = 0.206). Lowering daily prednisolone toward 5 mg/d has beneficial effects on insulin action after renal transplantation, but withdrawal of 5 mg prednisolone may not influence IS significantly.