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Renal-transplant recipients have shortened life expectancy primarily because of premature cardiovascular disease. Traditional and nontraditional risk factors for cardiovascular disease are prevalent in renal patients. In renal-transplant recipients, immunosuppressive therapy can be nephrotoxic and aggravate cardiovascular disease risk factors. Renal dysfunction has been established as a risk factor for cardiovascular disease and mortality in different populations. We evaluated the effects of baseline renal-transplant function on mortality and cardiovascular and renal endpoints in 1,052 placebo-treated patients of the Assessment of Lescol in Renal Transplantation trial.All renal-transplant recipients were on cyclosporine-based immunosuppressive therapy. Follow-up was 5 to 6 years, and endpoints included cardiac death, noncardiovascular death, all-cause mortality, major adverse cardiac event (MACE), stroke, nonfatal myocardial infarction, and graft loss.Baseline serum creatinine was strongly and independently associated with increased cardiac, noncardiovascular, and all-cause mortality, as well as MACE and graft loss. Serum creatinine was not a risk factor for stroke or nonfatal myocardial infarction.Elevated baseline serum creatinine in renal-transplant recipients is a strong and independent risk factor for all-cause, noncardiovascular and cardiac mortality, MACE, and graft loss.

Background. MO2ART (monitoring of 2-hr absorption in renal transplantation) is the first prospective, multicenter trial of cyclosporine (CsA) blood level 2 hr postdose (C 2 ) monitoring in de novo kidney recipients receiving CsA microemulsion (ME) (Neoral; Novartis, Basel, Switzerland). Efficacy and safety results from the first 3 months are presented here. Methods. MO2ART is a 12-month, open-label, randomized study involving 296 patients. In all patients, the dose of CsA-ME was adjusted to achieve protocol-defined C 2 targets of 1.6 to 2.0 μg/mL for the first month, with subsequent tapering. Randomization into two target groups occurred at 3 months. All patients received steroids and mycophenolate mofetil (89%) or azathioprine. For patients with delayed graft function, the protocol permitted reduced C 2 targets and prophylactic administration of antibodies. Results. At 3 months, overall incidence of biopsy-proven acute rejection was 11.5%. Median serum creatinine was 132 μmol/L. Patient and graft survival were 96.6% and 91.2%, respectively. C 2 levels greater than 1.6 μg/mL were achieved within 5 days by 60.6% of patients with immediate graft function and 19.5% of patients with delayed graft function. Prophylactic antibodies were used in 15% of the total population. Twenty-four patients (8.1%) experienced serious adverse events with a suspected relation to CsA, and 26 patients (8.8%) discontinued the study because of adverse events (n=15) or after a switch in immunosuppression after rejection episodes (n=11). Conclusions. Patient management by C 2 monitoring resulted in a low incidence of biopsy-proven acute rejection in standard risk de novo kidney recipients, 85% of whom did not receive prophylactic antibodies. CsA-ME with C 2 monitoring provides excellent short-term efficacy and safety among de novo renal transplant patients.

BACKGROUND Cyclosporine monitoring using the 2-hr postdose sample, C2, has been shown to have advantages in monitoring de novo renal transplant recipients. The purpose of this study was to assess cyclosporine exposure, using C2, in stable renal transplant patients previously monitored by C0 to determine the effect of dose reduction on patients with C2 more than 10% above target and the course of those with C2 at and more than 10% below target, whose dose was not modified. METHODS One hundred and seventy-five patients, three or more months after transplantation, had C2 assessed. The relationship of C2 to C0 and of both to renal function was analyzed by linear regression. Blood pressure, serum creatinine level, and lipids were followed for a mean of 15+/-2.6 months. RESULTS Eighty-five patients had values more than 10% above target, 42 were within 10% of target, and 48 were more than 10% below target. Cyclosporine dose was reduced in all patients above target. In this group, serum creatinine level was stable overall, but fell significantly in 46 (54%) of 85 from 153+/-55 to 132+/-49 microM. Blood pressure also fell in that group from 135/82 to 131/77. Serum creatinine level was stable in the remaining two groups of patients. CONCLUSIONS These data suggest that dose reduction in many overexposed patients leads to improvements in renal function and blood pressure. Further study is required to confirm the long-term benefits of this strategy.

Despite the need to expand the donor pool, it is unclear what parameters should be used. The value of donor renal pathology and calculated creatinine clearance (CrCl) in determining recipient outcome was assessed in 57 kidney transplants from 34 donors in whom pretransplant renal biopsies were performed because of ageor =60, hypertension, and/or vascular disease. We retrospectively compared clinical outcomes in these recipients and 57 control recipients selected to have the same baseline demographics but receiving transplants from low risk donors who were significantly younger (32+/-13.9 vs. 61+/-7.3 years) and lighter weight (71+/-18.1 vs. 84+/-20.2 kg) than the high-risk donors (P.001 for both).Recipients of high-risk kidneys had a higher incidence of delayed graft function, defined by a10% fall in serum creatinine (Cr) in the first 24 hr, (56% vs. 30%, P.01), a higher incidence of rejection (60% vs. 37%, P = .02) and a higher Cr level (197+/-64 vs. 144+/-54 micromol/L at 18 months, P.005). Graft and patient survival were similar; 12% and 5% vs. 91% and 9% in high-risk vs. control groups, respectively (P = NS). Donor renal pathology was scored 0-3 (none to severe disease) in four areas: glomerulosclerosis, interstitial fibrosis, tubular atrophy, and vascular disease. A donor vessel score of 3/3 was associated with a 100% incidence of delayed graft function and a mean 1-year Cr level of 275+106 micromol/L (compared with 43% and 192+54 micromol/L in those with lower vessel scores, P.05). Calculated donor CrCl100 ml/min was associated with higher recipient Cr levels at 1 year, 240+/-95 micromol/L vs. 180+/-54 micromol/L in recipients of kidneys from donors with CrCl levels100 ml/min (P.05). The mean 1-year Cr level was 320+/-102 micromol/L in recipients with both a vascular score of 3/3 and a donor CrCl100 ml/min and 184+/-63 micromol/L in those with neither factor (P = .001).Calculated donor CrCl and donor vascular pathology predict recipient graft function and may be helpful in selecting high-risk donors for single kidney transplantation.

Background. The safety, tolerability, and pharmacokinetics of conventional cyclosporine (ConCsA) and cyclosporine microemulsion (MeCsA) were compared under conditions of normal clinical practice in a prospective, randomized, concentration-controlled, pharmacoepidemiologic study. Methods. Between September 1994 and March 1995, 1097 stable renal transplant recipients in 14 Canadian centers were randomized 2:1 to treatment with MeCsA or ConCsA Patients were commenced on each study drug at a dose equal to their previous therapy with ConCsA, and the dose was adjusted to maintain predose whole blood cyclosporine concentrations within the therapeutic range established for each center. Prednisone and azathioprine were continued unless dose adjustment was required for clinical reasons. Results. The mean cyclosporine concentration was comparable in both treatment groups at all time points throughout the 6 months of follow-up. The mean dose of cyclosporine was 3.6 mg/kg/day in both treatment groups at entry to the study, and declined by 0.3% and by 2.8% in patients receiving ConCsA and MeCsA, respectively. The nature and severity of adverse events were similar in both treatment groups, but there was a transient increase in neurological and gastrointestinal complications in the group receiving MeCsA within the first month after conversion (P

The incidence of stroke and risk factors for different subtypes of cerebrovascular (CBV) events in renal transplant recipients have not been examined in any large prospective controlled trial.The Assessment of Lescol in Renal Transplantation was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin (40-80 mg) daily on cardiovascular, and renal outcomes in renal transplant recipients. Patients initially randomized to fluvastatin or placebo in the 5 to 6 year trial was offered open-label fluvastatin in a 2-year extension to the original study. We investigated the incidence of stroke and risk factors for ischemic and hemorrhagic CBV events in 2102 renal graft recipients participating in the Assessment of Lescol in Renal Transplantation core and extension trial with a mean follow-up of 6.7 years.The incidence and type of CBV events did not differ between the lipid lowering arm and the placebo arm. A total of 184 (8.8%, 95% confidence interval 4.6-12.9) of 2102 patients experienced a CBV event during follow-up, corresponding to an incidence of 1.3% CBV event per year. The mortality for patients experiencing a hemorrhagic stroke was 48% (13 of 27), whereas the mortality for ischemic strokes was 6.0% (8 of 133). Diabetes mellitus, previous CBV event, age, and serum creatinine were independent risk factors for cerebral ischemic events. The risk of a hemorrhagic cerebral event was increased by diabetes mellitus, polycystic kidney disease, left ventricular hypertrophy, and systolic blood pressure.Risk factors for CBV events in renal transplant recipients differ according to subtype.

Background. There are few data directly comparing the effects of two-hour postingestion monitored cyclosporine (C2-CsA) vs. trough-monitored tacrolimus (C0-Tac) on renal function and cardiovascular risk factors. Methods. We studied 378 (202 C2-CsA vs. 176 CO-Tac) incident kidney transplant recipients in Toronto, Canada, from August 1,2000 and December 31,2003. Outcomes included changes in estimated glomerular filtration rate (eGFR at 1 and 6 months by modification of diet in renal disease four-variable equation), mean arterial pressure (MAP), total cholesterol (TC), and new-onset diabetes mellitus (NODM) at six months posttransplant. The independent effect of treatment/monitoring strategies on continuous outcomes and time-to-NODM was modeled using linear and Cox regression, respectively. Results. Mean eGFR was 59.5 vs. 62.9 ml/min at one month and 50.6 vs. 61.2 ml/min at six months for C2-CsA vs. CO-Tac, respectively. Multiple linear regression revealed the slope of eGFR to be 0.93 ml/min/month lower in C2-CsA patients. This was equivalent to an adjusted average eGFR difference of 4.64 ml/min between months one and six posttransplant. There was no significant difference in average MAP and TC. In a stepwise multivariable Cox model and a propensity score analysis, there was no significant association between the type of treatment/monitoring strategy and time-to-NODM. Conclusions. There was a greater decline in eGFR for patients on C2-CsA (vs. CO-Tac) between one and six months posttransplant. However, MAP, TC, and the risk of NODM were comparable in both treatment/monitoring groups. The long-term impact of short-term reductions in eGFR as a function of the type of treatment/monitoring strategy requires further study.

Background. The clinical benefits of C 2 monitoring of cyclosporine microemulsion have been demonstrated, but C 2 targets in renal transplant recipients during the first year require validation. Methods. MO2ART was a prospective, multicenter study of renal transplant recipients managed by C 2 monitoring of cyclosporine microemulsion with steroids and mycophenolate mofetil or azathioprine. Patients were randomized on day 3 to two groups, which were managed from month 3 with higher or lower C 2 target ranges (months 4-6, 1,0001,200 ng/mL vs. 800-1,000 ng/mL; months 7-12, 800-1,000 ng/mL vs. 600-800 ng/mL, respectively). The primary endpoint was the glomerular filtration rate (GFR) at month 12. Results. A total of 296 patients were recruited, of whom 250 remained in the study at 3 months (higher-C 2 , n=131; lower-C 2 , n=119). GFR at 12 months did not differ between the higher- and lower-C 2 groups (65±17 mL/min vs. 66±14 mL/min). When patients were regrouped according to C 2 achieved by months 8 to 12, those with the lowest C 2 (

The aim of the study was to identity risk factors for long-term renal transplant function and development of chronic allograft nephropathy (CAN) in renal transplant recipients included in the Assessment of Lescol in Renal Transplantation (ALERT) trial.The ALERT trial was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin, 40 and 80 mg/day, in renal transplant recipients who were randomized to receive fluvastatin (Lescol) (n = 1,050) or placebo (n = 1,052) over 5 to 6 years of follow-up. Renal endpoints including graft loss or doubling of serum creatinine or death were analyzed by univariate and multivariate regression analysis in the placebo group.There were 137 graft losses (13.5%) in the placebo group, mainly caused by CAN (82%). Univariate risk factors for graft loss or doubling of serum creatinine were as follows: serum creatinine, proteinuria, hypertension, pulse pressure, time since transplantation, donor age, human leukocyte antigen-DR mismatches, treatment for rejection, low high-density lipoprotein cholesterol, and smoking. Multivariate analysis revealed independent risk factors for graft loss as follows: serum creatinine (relative risk [RR], 3.12 per 100-microM increase), proteinuria (RR, 1.64 per 1-g/24 hr increase), and pulse pressure (RR, 1.12 per 10 mm Hg), whereas age was a protective factor. With patient death in the composite endpoint, diabetes mellitus, smoking, age, and number of transplantations were also risk factors.Independent risk factors for graft loss or doubling of serum creatinine or patient death are mainly related to renal transplant function, proteinuria, and blood pressure, which emphasizes the importance of renoprotective treatment regimens in this population.