The challenge of preserving renal function after liver transplantation.

Thanks to new surgical techniques and the use of calcineurin inhibitors for the prevention of allograft rejection, the long-term outcome of liver transplantation has recently improved. In case of liver transplantation, the occurrence of renal failure can impair the outcome. Renal function preservation is, therefore, necessary to improve transplantation outcome.

Absence of CD4CD25 regulatory T cell expansion in renal transplanted patients treated in vivo with Belatacept mediated CD28-CD80/86 blockade.

AIMS: Belatacept is a new recombinant molecule (CTLA4-Ig) that interferes with the second activation signal of T lymphocytes. CTLA4-Ig induced T cell allograft tolerance in rodents but not in primates. We examined the changes in peripheral lymphocyte subsets, including regulatory T cells, in renal transplant patients treated with Belatacept. METHODS: A cross-sectional immunological study was carried out 6 months after transplantation in 28 patients enrolled in the Belatacept phase II study. Eighteen patients received Belatacept, mycophenolate mofetil and steroids (Belatacept group), while the control group of 10 patients received cyclosporine, mycophenolate mofetil and steroids (CsA group). Lymphocyte subsets were examined by flow cytometry. Foxp3 mRNA expression was measured by quantitative PCR. RESULTS: The number of T lymphocytes and the percentage of CD3+ T cells were similar in both groups. However, the percentage of CD3+ CD4+ T cells was lower in the Belatacept group than in the control CsA group (B=42.5%+/-13.7 vs CsA=52.9%+/-9, p<0.005), and the percentage of CD3+ CD8+ cells was higher in the Belatacept group than in the control (B=32.9%+/-6.7 vs CsA=19.5%+/-8.2, p<0.0002). The percentage of CD19+ cells was similar in both groups. Among CD56+cells, only the percentage of CD16+ cells was significantly higher in the Belatacept group than in the control (B=82%+/-12 vs CsA=59.7%+/-25, p=0.01). Among CD4 and CD8 T cells the percentage of activated lymphocytes expressing CTLA4, HLA-DR or CD40L was similar in both groups. The percentage of CD4+CD25+ T cells was higher in the CsA group. The percentage of regulatory CD4+CD25+ cells with bright CD25 staining was similar in both groups (B=3.6+/-2.3% vs CsA=4.7+/-1.9%, ns) as was the expression of FoxP3. CONCLUSION: Our results indicated that Belatacept did not induce regulatory T cell expansion in vivo. We suggest that Belatacept treatment should be maintained after transplantation to allow graft acceptance.

Long-term results (10 years) of a prospective trial comparing Lo-tact-1 monoclonal antibody and anti-thymocyte globulin induction therapy in kidney transplantation.

To evaluate long-term patient and graft survival, and the incidence of acute and chronic rejection, infectious diseases and malignancies following induction therapy with a rat monoclonal interleukin 2 receptor antibody, Lo-Tact-1, or anti-thymocyte globulin (ATG). Forty first-time kidney transplant patients were prospectively randomized to two groups between May 1990 and June 1991. Twenty recipients were treated with Lo-Tact-1 (group 1) and the other 20, with ATG (group 2) during the first 14 days of the transplantation protocol. All patients were treated with azathioprine, steroids and cyclosporin A. Data were collected over 10 years. Median age was 42.1 years in group 1 and 39.3 years in group 2. Six recipients died during the 10 years of follow-up. All had functioning grafts. Death-censored graft survival was 35% in group 1 and 45% in group 2 after 10 years (P = NS). The number of acute rejection was similar in the two groups. Chronic allograft rejection was significantly more frequent in group 2 (n = 9) than in group 1 (n = 3), P < 0.05. Viral and bacterial infections were more frequent in group 2 than in group 1 (respectively 8 vs. 2 and 16 vs. 10, P < 0.05). Three patients had cancer. Although both Lo-tact-1 and ATG effectively prevented acute renal rejection, fewer bacterial and viral infections and cases of chronic allograft rejection were observed in Lo-tact-1-treated patients after 10 years of follow-up, demonstrating the potential value of this treatment for kidney transplantation.

Single-center experience with cyclosporine therapy for kidney transplantation: analysis of a twenty-year period in 1200 patients.

Since the introduction of cyclosporine (CyA) in our center in February 1983, 1267 kidney transplant patients have received an immunosuppressive regimen based on CyA, usually in association with azathioprine and steroids and following an induction therapy in three quarters of patients. The aim of this study was to retrospectively analyze our 20-year experience with CyA and examine the evolution of therapy during this period. Induction treatment has been less commonly used during the past 5 years. Even in the early years of our experience, CyA doses were low (under 6 mg/kg per day at 3 months after transplantation). Acute tubular necrosis was observed in 39.4% of patients. The incidence of acute rejection episodes has dramatically decreased since 1984, but the frequency of steroid-resistant rejection has remained constant (around 20%). The first year of transplantation, 32.7% of patients had arterial hypertension. De novo diabetes mellitus occurred in 2.5% of patients. An incidence of 11.8% of malignancies was observed. Skin cancer and lymphomas accounted for 50% and 12% of neoplasms. Five-year graft and patient survivals were 70% and 87%, respectively. Renal function remained remarkably constant during the first 10 years of follow-up with a mean creatinine of 150 micromol/L. Chronic allograft nephropathy resulted in 43% graft losses. In conclusion, CyA has been well tolerated in our patients. However, the occurrence of chronic allograft nephropathy was a major concern in our cohort.