Franco Citterio

Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus.

DIRECT (Diabetes Incidence after Renal Transplantation: Neoral C2 Monitoring Versus Tacrolimus) was a 6‐month, open‐label, randomized, multicenter study which used American Diabetes Association/World Health Organization criteria to define glucose abnormalities. De novo renal transplant patients were randomized to cyclosporine microemulsion (CsA‐ME, using C2 monitoring) or tacrolimus, with mycophenolic acid, steroids and basiliximab. The intent‐to‐treat population comprised 682 patients (336 CsA‐ME, 346 tacrolimus): 567 were nondiabetic at baseline. Demographics, diabetes risk factors and steroid doses were similar between treatment groups. The primary safety endpoint, new‐onset diabetes after transplant (NODAT) or impaired fasting glucose (IFG) at 6 months, occurred in 73 CsA‐ME patients (26.0%) and 96 tacrolimus patients (33.6%, p = 0.046). The primary efficacy endpoint, biopsy‐proven acute rejection, graft loss or death at 6 months, occurred in 43 CsA‐ME patients (12.8%) and 34 tacrolimus patients (9.8%, p = 0.211). Mean glomerular filtration rate (Cockcroft–Gault) was 63.6 ± 20.7 mL/min/1.73 m2 in the CsA‐ME cohort and 65.9 ± 23.1 mL/min/1.73 m2 with tacrolimus (p = 0.285); mean serum creatinine was 139 ± 58 and 133 ± 57 μmol/L, respectively (p = 0.005). Blood pressure was similar between treatment groups at month 6, but total cholesterol, LDL‐cholesterol and triglyceride levels were significantly higher with CsA than with tacrolimus (total cholesterol:HDL remained unchanged). The profile and incidence of adverse events were similar between treatments. The incidence of NODAT or IFG at 6 months post‐transplant is significantly lower with CsA‐ME than with tacrolimus without a significant difference in short‐term outcome.

Risk of myocardial infarction and angina in patients with severe peripheral vascular disease: predictive role of C-reactive protein.

Background—Patients undergoing revascularization procedures for peripheral vascular disease (PVD) have a greatly increased risk for coronary artery disease (CAD) that is predicted only partly by clinical data and cardiovascular risk factors. We investigated whether the prognostic assessment in PVD patients could be improved by preoperative measurements of C-reactive protein (CRP). Methods and Results—We assessed clinical and risk factors profiles, Eagle clinical scores, and preoperative CRP serum levels in 51 patients with PVD at Fontaine-Leriche stages II to IV without severe rest ventricular dysfunction or ischemia. During 24 months of follow-up, 17 patients (34%) had fatal (11) or nonfatal (6) myocardial infarction (MI). With univariate logistic regression analysis, only previous history of CAD, Eagle score, and CRP were independently related to MI. At multivariate logistic regression analysis, only CRP values in the upper tertile (<9 mg/L) were significantly associated with MI (P <0.05) and identified 65% of cases. Conclusions—The high incidence of MI in patients with PVD severe enough to require revascularization is strongly predicted by preprocedural measurements of serum CRP, independent of previous CAD, Eagle score index, and traditional cardiovascular risk factors. These patients may benefit from therapy modulating the inflammatory response.

Cyclosporine microemulsion (Neoral®) absorption profiling and sparse-sample predictors during the first 3 months after renal transplantation

Recent data suggest that optimal cyclosporine (CsA) exposure early post‐transplant significantly reduces the risk of acute graft rejection. They indicate that trough level monitoring is inadequate for precise concentration‐controlled therapy, and suggest that absorption profiling may offer a superior approach for guiding clinical immunosuppression with Neoral.

Immunosuppression with Belatacept‐Based, Corticosteroid‐Avoiding Regimens in De Novo Kidney Transplant Recipients

Current immunosuppressive regimens in renal transplantation typically include calcineurin inhibitors (CNIs) and corticosteroids, both of which have toxicities that can impair recipient and allograft health. This 1‐year, randomized, controlled, open‐label, exploratory study assessed two belatacept‐based regimens compared to a tacrolimus (TAC)‐based, steroid‐avoiding regimen. Recipients of living and deceased donor renal allografts were randomized 1:1:1 to receive belatacept‐mycophenolate mofetil (MMF), belatacept‐sirolimus (SRL), or TAC‐MMF. All patients received induction with 4 doses of Thymoglobulin (6 mg/kg maximum) and an associated short course of corticosteroids. Eighty‐nine patients were randomized and transplanted. Acute rejection occurred in 4, 1 and 1 patient in the belatacept‐MMF, belatacept‐SRL and TAC‐MMF groups, respectively, by Month 6; most acute rejection occurred in the first 3 months. More than two‐thirds of patients in the belatacept groups remained on CNI‐ and steroid‐free regimens at 12 months and the calculated glomerular filtration rate was 8–10 mL/min higher with either belatacept regimen than with TAC‐MMF. Overall safety was comparable between groups. In conclusion, primary immunosuppression with belatacept may enable the simultaneous avoidance of both CNIs and corticosteroids in recipients of living and deceased standard criteria donor kidneys, with acceptable rates of acute rejection and improved renal function relative to a TAC‐based regimen.

Polyomavirus BK replication in de novo kidney transplant patients receiving tacrolimus or cyclosporine: a prospective, randomized, multicenter study.

Polyomavirus BK (BKV)‐associated nephropathy causes premature kidney transplant (KT) failure. BKV viruria and viremia are biomarkers of disease progression, but associated risk factors are controversial. A total of 682 KT patients receiving basiliximab, mycophenolic acid (MPA), corticosteroids were randomized 1:1 to cyclosporine (CsA) or tacrolimus (Tac). Risk factors were analyzed in 629 (92.2%) patients having at least 2 BKV measurements until month 12 posttransplant. Univariate analysis associated CsA‐MPA with lower rates of viremia than Tac‐MPA at month 6 (10.6% vs. 16.3%, p = 0.048) and 12 (4.8% vs. 12.1%, p = 0.004) and lower plasma BKV loads at month 12 (3.9 vs. 5.1 log10 copies/mL; p = 0.028). In multivariate models, CsA‐MPA remained associated with less viremia than Tac‐MPA at month 6 (OR 0.60; 95% CI 0.36–0.99) and month 12 (OR 0.33; 95% CI 0.16–0.68). Viremia at month 6 was also independently associated with higher steroid exposure until month 3 (OR 1.19 per 1 g), and with male gender (OR 2.49) and recipient age (OR 1.14 per 10 years) at month 12. The data suggest a dynamic risk factor evolution of BKV viremia consisting of higher corticosteroids until month 3, Tac‐MPA compared to CsA‐MPA at month 6 and Tac‐MPA, older age, male gender at month 12 posttransplant.

Pharmacokinetics for once- versus twice-daily tacrolimus formulations in de novo kidney transplantation: a randomized, open-label trial.

Tacrolimus, a cornerstone immunosuppressant, is widely available as a twice‐daily formulation (Tacrolimus BID). A once‐daily prolonged‐release formulation (Tacrolimus QD) has been developed that may improve adherence and impart long‐lasting graft protection. This study compared the pharmacokinetics (PK) of tacrolimus in de novo kidney transplant patients treated with Tacrolimus QD or Tacrolimus BID. A 6‐week, open‐label, randomized comparative study was conducted in centers in Europe and Australia. Eligible patients received Tacrolimus QD or Tacrolimus BID. PK profiles were obtained following the first tacrolimus dose (day 1), and twice under steady‐state conditions. As secondary objectives, efficacy and safety parameters were also evaluated. Sixty‐six patients completed all PK profiles (34 Tacrolimus QD, 32 Tacrolimus BID). Mean AUC0–24 of tacrolimus on day 1 was approximately 30% lower for Tacrolimus QD than Tacrolimus BID (232 and 361 ng.h/mL, respectively), but was comparable by day 4. There was a good correlation and a similar relationship between AUC0–24 and Cmin for both formulations. Efficacy and safety data were also comparable over the 6‐week period. Tacrolimus QD can be administered once daily in the morning on the basis of the same systemic exposure and therapeutic drug monitoring concept as Tacrolimus BID.

Risk of Myocardial Infarction and Angina in Patients With Severe Peripheral Vascular Disease

Background— Patients undergoing revascularization procedures for peripheral vascular disease (PVD) have a greatly increased risk for coronary artery disease (CAD) that is predicted only partly by clinical data and cardiovascular risk factors. We investigated whether the prognostic assessment in PVD patients could be improved by preoperative measurements of C-reactive protein (CRP). Methods and Results— We assessed clinical and risk factors profiles, Eagle clinical scores, and preoperative CRP serum levels in 51 patients with PVD at Fontaine-Leriche stages II to IV without severe rest ventricular dysfunction or ischemia. During 24 months of follow-up, 17 patients (34%) had fatal (11) or nonfatal (6) myocardial infarction (MI). With univariate logistic regression analysis, only previous history of CAD, Eagle score, and CRP were independently related to MI. At multivariate logistic regression analysis, only CRP values in the upper tertile (<9 mg/L) were significantly associated with MI (P<0.05) and identifie...

Wound healing complications and the use of mammalian target of rapamycin inhibitors in kidney transplantation: a critical review of the literature.

&NA; Surgical complications, including events such as lymphocele and urological complications that affect wound healing, are reported with an incidence of 15% to 32% after kidney transplantation. The experience of the surgeon and comorbidities play an important role in determining the risk of such complications occurring. Since the introduction of the inosine 5′-monophosphate dehydrogenase inhibitors (mycophenolate mofetil) to the immunosuppressive armamentarium, replacing the antimetabolite prodrug azathioprine, reports have associated certain forms of wound healing complications (wound dehiscence, impaired healing, lymphocele, and incisional hernia) with the use of these agents. When mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus) became available, these findings were observed increasingly, particularly in direct comparisons with inosine 5′-monophosphate dehydrogenase inhibitors. The purpose of this article was to review the reported incidence of wound healing complications from randomized clinical trials that investigated the use of sirolimus- and everolimus-based treatment regimens in de novo kidney transplantation and the information available from the U.S. Food and Drug Administration database. The clinical trials included were primarily identified using biomedical literature database searches, with additional studies added at the authors’ discretion. This review summarizes these studies to consider whether modern mTOR inhibitor–based immunosuppressive regimens exert and affect wound healing after kidney transplantation.

Everolimus with very low-exposure cyclosporine a in de novo kidney transplantation: a multicenter, randomized, controlled trial.

Background. In combination with everolimus (EVL), cyclosporine A (CsA) may be used at low exposure, so reducing the risk of renal dysfunction in renal transplant recipients (RTR). We evaluated whether higher exposure of EVL could allow a further reduction of CsA. Methods. De novo RTR were randomized to standard exposure EVL (C0 3–8 ng/mL) with low-concentration CsA (C2 maintenance levels 350–500 ng/mL, group A) or higher EVL exposure (C0 8–12 ng/mL) with very low-concentration CsA (C2 maintenance levels 150–300 ng/mL, group B). The primary endpoints were 6-month creatinine clearance (CrCl) and biopsy-proven acute rejection (BPAR) rate. After 6 months, patients were followed up (observational extension) to 12 months. Results. Two hundred eighty-five RTR (97% from deceased donors) were enrolled. Two patients per group died (1.4%). The 6-month death-censored graft survival was 90.2% in group A and 97.9% in group B and was unchanged at 12 months (P=0.007). There was no significant difference between groups at 6 months in CrCl (59.9 vs. 57.8 mL/min) and BPAR rates (14.7% vs. 11.9%) and also at 12 months (CrCl 62.5±20.7 vs. 61.3±22.0 mL/min, BPAR 14.7% vs. 14.1%). No significant differences were seen in treated acute rejections, steroid-resistant acute rejections, treatment failures, or delayed graft function, although there was a trend to better results in group B. Conclusions. EVL given at higher exposure for 6 months plus very low CsA concentration may obtain low acute rejection rate and good graft survival in De novo renal transplantation. However, there was no difference between groups in CrCl.

Randomized, international study of cyclosporine microemulsion absorption profiling in renal transplantation with basiliximab immunoprophylaxis

Increasing information suggests that absorption profiling may be superior to trough level monitoring for optimal concentration control of cyclosporine microemulsion (NeoralTM) therapy, and that CsA exposure early post‐transplant may correlate significantly with reduced risk of acute graft rejection.