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 C(2) (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).

Spontaneous renal allograft rupture without acute rejection.

Renal allograft rupture (RAR) is a rare but potentially serious complication in the transplanted recipients. The most common cause is acute rejection. We report four cases (0.5%) of RAR occurred in a series of 778 consecutive kidney transplantations due to severe acute tubular necrosis and renal vein thrombosis with no evidence of acute rejection. Transplant nephrectomy was performed in three patients, whereas graft repair was achieved in one patient. These data suggest that RAR may be associated with renal vein thrombosis or severe acute tubular necrosis in absence of acute rejection. Frequently nephrectomy is necessary, but conservative surgical treatment should be attempted to preserve the allograft in selected cases.

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 micromol/L at 6 months in the 1.5 and 3 mg/day groups, respectively, and 130 micromol/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.

Urinary soluble CD14 mediates human proximal tubular epithelial cell injury induced by LPS.

Renal proximal tubular epithelial cells (PTEC) are target for LPS during sepsis and renal infections. In the present study, we evaluated whether stimulation of human PTEC by LPS is modulated through the soluble or the membrane form of the LPS receptor CD14. We found that PTEC lacked expression of the membrane form of CD14 and did not release soluble CD14 (sCD14). sCD14 was detected in the urine of normal subjects and it was increased in patients with renal sepsis or with proteinuria. In the presence of sCD14 and LPS binding protein (LBP), PTEC were 10 to 100-fold more sensitive to LPS activation, resulting in cytokine production (IL-6, IL-8 and TNF-alpha) and NO release. We found that sCD14 purified from urine was biologically active on PTEC. Moreover, the presence of sCD14 and LBP was required for cytotoxicity induced by low concentrations of LPS (1-10 ng/ml) in PTEC. Cell death showed the characteristics of both necrosis and apoptosis, as demonstrated by LDH release and by TUNEL and acridine orange staining and caspase-3 activation. Whereas the LPS alone was sufficient to induce necrosis, sCD14 and LBP were required for apoptosis. Our results suggest that sCD14 excreted in urine may participate with endotoxin in the activation and injury of renal proximal tubules. In particular, sCD14 may contribute to the tubulo-interstitial injury in clinical settings characterised by proteinuria and enhanced susceptibility to infections such as in diabetes.

Long-term results of a randomized study comparing three immunosuppressive schedules with cyclosporine in cadaveric kidney transplantation.

In this randomized controlled trial started in October 1990, 354 cadaveric kidney transplant recipients were assigned to receive either cyclosporine (CsA) monotherapy (115 patients), CsA + steroids (117 patients), or CsA + steroids + azathioprine (122 patients). The median follow-up was 85.1 mo. Thirty-one deaths occurred (infection, 12; cardiovascular disease, 11; neoplasia, 4; and others, 4), and 65 grafts were lost, mostly due to acute (15) or chronic rejection (50). The cumulative graft half-life was 18.1 yr. According to the "intention-to-treat," the 9-yr actuarial patient and graft survival were 94.0% and 73.3%, respectively, in monotherapy, 87.3% and 65.9% in dual therapy, and 87% and 72.2% in triple therapy (P = 0.647). At the last follow-up, the percentage of patients who remained with the original treatment was 51.2% in monotherapy, 81.7% in dual therapy, and 63.3% in triple therapy. At the seventh year, the mean creatinine clearances were 54.9 +/- 17.6 ml/min in monotherapy, 57.9 +/- 23.4 in dual therapy, and 60.6 +/- 20.7 in triple therapy (P = 0.375). Cataracts (P = 0.000), osteoporosis (P = 0.000), and cardiovascular complications (P = 0.000) were more frequent in dual or triple therapy than in monotherapy. Actuarial graft survival at 9 yr in patients on monotherapy who had to have steroids added was similar to that of the other two groups (62.2% versus 69.3%, P = 0.134). In conclusion, actuarial patient and graft survivals did not differ among the three schemes. The long-term renal function and survival were not affected in the patients on monotherapy who needed the addition of steroids. Monotherapy was associated with a lower incidence of extrarenal complications than the other two regimens.