Paolo Rigotti

Everolimus with Optimized Cyclosporine Dosing in Renal Transplant Recipients: 6-Month Safety and Efficacy Results of Two Randomized Studies

Two prospective, randomized studies evaluated everolimus 1.5 vs. 3 mg/day with steroids and low‐exposure cyclosporine (CsA) (C2 monitoring) in de novo renal transplant patients. Everolimus dosing was adjusted to maintain a minimum trough level of 3 ng/mL. Study 1 (A2306; n = 237) had no induction therapy; in Study 2 (A2307; n = 256) basiliximab was administered (Days 0 and 4). The primary endpoint was renal function at 6 months. CsA C2 target levels, initially 1200 ng/mL in Study 1 and 600 ng/mL in Study 2, were tapered over time post‐transplant. Median creatinine levels in Study 1 were 133 and 132 μmol/L at 6 months in the 1.5 and 3 mg/day groups, respectively, and 130 μmol/L in both groups in Study 2. Biopsy‐proven acute rejection (BPAR) occurred in 25.0% and 15.2% of patients in the 1.5 and 3 mg/day groups in Study 1, and 13.7% and 15.1% in Study 2. Incidence of BPAR was significantly higher in patients with an everolimus trough < 3 ng/mL. There were no significant between‐group differences in the composite endpoint of BPAR, graft loss or death, nor any significant between‐group differences in adverse events in either study. Concentration‐controlled everolimus with low‐exposure CsA provided effective protection against rejection with good renal function.

Minimization of Immunosuppressive Therapy After Renal Transplantation: Results of a Randomized Controlled Trial

Modern immunosuppressive regimens reduce the acute rejection rate by combining a cornerstone immunosuppressant like tacrolimus or cyclosporine with adjunctive agents like corticosteroids, mycophenolate mofetil (MMF) or azathioprine, often associated with untoward side effects.

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.

12-month safety and efficacy of everolimus with reduced exposure cyclosporine in de novo renal transplant recipients

The proliferation signal inhibitor everolimus (Certican), has demonstrated efficacy with full‐dose cyclosporine (CsA) (Neoral®). Two multicenter randomized controlled studies were performed to compare 12‐month efficacy and safety of everolimus 1.5 and 3.0 mg/day with reduced‐dose CsA. Study 1 enrolled 237 de novo renal allograft recipients, randomizing 222 nonblack patients to either everolimus 1.5 or 3.0 mg/day, with the Neoral® dose guided by C2 (monitoring of CsA concentration 2 h after dosing). Study 2 had a similar protocol, with basiliximab included, enrolling 256 recipients and randomizing 243 nonblack patients. In Study 1, there was a lower incidence of acute rejection in nonblack patients on 3 mg/day (16.4%) compared with 1.5 mg/day (25.9%), P = 0.08. In Study 2, the inclusion of basiliximab lowered the overall incidence of acute rejection; 14.3% of nonblack patients (3 mg/day) and 13.6% of nonblack patients (1.5 mg/day) had acute rejection by 12 months (P =0.891). Renal function was preserved throughout the study, with no differences observed between groups within studies. Everolimus was well tolerated with no significant differences between doses. Everolimus, in combination with reduced‐dose Neoral®, demonstrated efficacy and was well tolerated. Basiliximab allows for utilization of lower doses of everolimus with reduced dosing of Neoral®.

Alendronate Prevents Further Bone Loss in Renal Transplant Recipients

The aim of this study was to investigate the effects of alendronate, calcitriol, and calcium in bone loss after kidney transplantation. We enrolled 40 patients (27 men and 13 women, aged 44.2 ± 11.6 years) who had received renal allograft at least 6 months before (time since transplant, 61.2 ± 44.6 months). At baseline, parathyroid hormone (PTH) was elevated in 53% of the patients and the Z scores for bone alkaline phosphatase (b‐ALP) and urinary type I collagen cross‐linked N‐telopeptide (u‐NTX) were higher than expected (p < 0.001). T scores for the lumbar spine (−2.4 ± 1.0), total femur (−2.0 ± 0.7), and femoral neck (−2.2 ± 0.6) were reduced (p < 0.001). After the first observation, patients were advised to adhere to a diet containing 980 mg of calcium daily and their clinical, biochemical, and densitometric parameters were reassessed 1 year later. During this period, bone density decreased at the spine (−2.6 ± 5.7%; p < 0.01), total femur (−1.4 ± 4.2%; p < 0.05), and femoral neck (−2.0 ± 3.0%; p < 0.001). Then, the patients were randomized into two groups: (1) group A—10 mg/day of alendronate, 0.50 μg/day of calcitriol, and 500 mg/day of calcium carbonate; and (2) group B—0.50 μg/day of calcitriol and 500 mg/day of calcium carbonate. A further metabolic and densitometric reevaluation was performed after the 12‐month treatment period. At the randomization time, group A and group B patients did not differ as to the main demographic and clinical variables. After treatment, bone turnover markers showed a nonsignificant fall in group B patients, while both b‐ALP and u‐NTX decreased significantly in alendronate‐treated patients. Bone density of the spine (+5.0 ± 4.4%), femoral neck (+4.5 ± 4.9%), and total femur (+3.9 ± 2.8%) increased significantly only in the alendronate‐treated patients. However, no trend toward further bone loss was noticed in calcitriol and calcium only treated subjects. No drug‐related major adverse effect was recorded in the two groups. We conclude that renal transplanted patients continue to loose bone even in the long‐term after the graft. Alendronate normalizes bone turnover and increases bone density. The association of calcitriol to this therapy seems to be advantageous for better controlling the complex abnormalities of skeletal metabolism encountered in these subjects.

Mycophenolate Mofetil versus Azathioprine for Prevention of Chronic Allograft Dysfunction in Renal Transplantation: The MYSS Follow-Up Randomized, Controlled Clinical Trial

The Mycophenolate Steroids Sparing (MYSS) study found that in renal transplant recipients who were on immunosuppressive therapy with the cyclosporine microemulsion Neoral, mycophenolate mofetil (MMF) was not better than azathioprine in preventing acute rejection at 21 mo after transplantation and was 15 times more expensive. The MYSS Follow-up Study, an extension of MYSS, was aimed at comparing long-term outcome of 248 MYSS patients according to their original randomization to MMF (1 g twice daily) or azathioprine (75 to 100 mg/d). Primary outcome was estimated GFR at 5 yr after transplantation. Mean 5-yr GFR difference between azathioprine and mycophenolate was 4.67 ml/min per 1.73 m(2) (95% confidence interval [CI] -0.43 to 9.77 ml/min per 1.73 m(2); P = 0.07). GFR from month 6 (mean +/- SEM: 54.3 +/- 1.6 versus 53.9 +/- 1.5 ml/min per 1.73 m(2); P = 0.83) to month 72 after transplantation (49.5 +/- 2.2 versus 47.3 +/- 2.4 ml/min per 1.73 m(2); P = 0.50); GFR slopes (mean +/- SEM: -1.10 +/- 0.56 versus -1.23 +/- 0.31 ml/min per 1.73 m(2) per year; P = 0.83); and 72-mo patient mortality (4.0 versus 4.0% [P = 0.95]; HR 0.96; 95% CI 0.28 to 3.31; P = 0.95), graft loss (6.8 versus 6.1% [P = 0.82]; HR 0.89; 95% CI 0.32 to 2.46; P = 0.83), incidence of persistent proteinuria (25.0 versus 27.4%; P = 0.72), late (>6 mo after transplantation) rejections (25.3 versus 21.2%; P = 0.53), and adverse events were similar on azathioprine (n = 124) and MMF (n = 124), respectively. Outcomes in the two groups were comparable also among patients with or without steroid therapy, considered separately. In kidney transplantation, the long-term risk/benefit profile of MMF and azathioprine therapy in combination with cyclosporine Neoral is similar. In view of the cost, standard immunosuppression regimens for kidney transplantation should perhaps include azathioprine rather than MMF.

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.

Incidence of cancer after kidney transplant: Results from the north italy transplant program

Background. Patients undergoing kidney transplantation demonstrate a higher risk of developing cancer as the result of immunosuppressive treatment and concurrent infections. Methods. The incidence of cancer in a cohort of patients who underwent kidney transplantation between 1990 and 2000, and who survived the acute phase (10 days), was analyzed as part of the North Italy Transplant program. Results. A total of 3,521 patients underwent transplantation during a 10-year period in 10 of 13 participating centers; the length of follow-up after kidney transplant was 67.7±36.0 months. During the follow-up, 172 patients developed cancer (39 with Kaposi sarcoma, 38 with lymphoproliferative diseases, and 95 with carcinomas [17 kidney, 11 non-basal cell carcinoma of the skin, 10 colorectal, 8 breast, 7 gastric, 7 lung, 6 bladder, and 3 mesothelioma]). The average time to cancer development after transplant was 40.1±33.4 months (range 0–134 months). Twenty-four patients developed cancer within 6 months from the transplant (10 with carcinomas, 7 with Kaposi sarcoma, and 7 with lymphoproliferative diseases). Three patients demonstrated a second primary cancer. The average cancer incidence was 4.9%. The incidence of cancer was 0.01 per year. Independent determinants of cancer development were age, gender, and immunosuppressive protocol including induction. Ten-year mortality was significantly higher in patients with cancer (33.1%) than among patients without cancer (5.3%). The relative risk of death in subjects with cancer was 5.5 (confidence interval 4.1–7.4). Conclusions. These preliminary data underline the importance of long-term surveillance of transplant recipients, choice of immunosuppressive treatment, and careful donor selection.

Sotrastaurin, a Novel Small Molecule Inhibiting Protein Kinase C: First Clinical Results in Renal‐Transplant Recipients

Sotrastaurin, a novel protein‐kinase‐C inhibitor, blocks early T‐cell activation. In this 12‐month, Phase II study, de novo renal‐transplant patients were randomized to sotrastaurin (200 mg b.i.d.) + standard‐exposure tacrolimus (SET) or reduced‐exposure tacrolimus (RET) (SET: n = 76; RET: n = 66), or control (SET + mycophenolic acid [MPA, 720 mg b.i.d.]; n = 74). In both sotrastaurin groups, patients were converted from tacrolimus to MPA after Month 3, achieving calcineurin inhibitor‐free immunosuppression. The primary endpoint was composite efficacy failure (treated biopsy‐proven acute rejection, graft loss, death or loss to follow‐up). The key secondary endpoint was glomerular filtration rate (GFR). Composite efficacy failure rates were: 4.1%, 5.4% and 1.5% at Month 3 (preconversion) and 7.8%, 44.8% and 34.1% at study end in the control, sotrastaurin + SET and sotrastaurin + RET groups, respectively; these results led to premature study discontinuation. Median GFR at Month 6 was: 57.0, 53.0 and 60.0 mL/min/1.73 m2, respectively. Study‐drug discontinuations due to adverse events occurred in 16.2%, 18.4% and 12.1%, respectively. Leukopenia and neutropenia occurred more frequently preconversion in control versus sotrastaurin groups: 13.7%, 5.6%, and 4.6%; and 11.1%, 4.3% and 3.1%, respectively. The initial sotrastaurin + tacrolimus regimen was efficacious and well tolerated but the postconversion sotrastaurin + MPA regimen showed inadequate efficacy. Longer‐term evaluation of sotrastaurin + tacrolimus is warranted.

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.