P.G.P Machado

The purpose of this study was to prospectively analyze the relationship between the post-transplant anti-HLA class I and/or class II panel reactive antibodies and graft failure due to chronic allograft nephropathy (CAN). We studied 512 first kidney recipients transplanted at a single center, with a graft functioning for at least 3 years. A single blood sample was collected from each patient for antibody evaluation. The median posttransplant time after blood collection was 4.4 years and did not differ between patients with (n = 91) or without anti-HLA antibodies (n = 421). Female gender, pregnancies and blood transfusions were associated with the presence of anti-HLA class I antibodies. Graft function deterioration was associated with anti-HLA class II antibodies. Multivariate analysis showed independent association for creatinine levels (RR = 7.5), acute rejection (RR = 2.6), recipient male gender (RR = 3.6) and anti-HLA class II antibodies (RR = 2.9) and CAN-associated graft loss. In conclusion, the presence of anti-HLA class II antibodies conferred a risk for graft loss before a decline in renal function and increased the risk of graft failure in patients who already had a decline in graft function. Thus, anti-HLA class II antibody monitoring is a useful tool for the management of long-term kidney recipients. The purpose of this study was to prospectively analyze the relationship between the post-transplant anti-HLA class I and/or class II panel reactive antibodies and graft failure due to chronic allograft nephropathy (CAN). We studied 512 first kidney recipients transplanted at a single center, with a graft functioning for at least 3 years. A single blood sample was collected from each patient for antibody evaluation. The median posttransplant time after blood collection was 4.4 years and did not differ between patients with (n = 91) or without anti-HLA antibodies (n = 421). Female gender, pregnancies and blood transfusions were associated with the presence of anti-HLA class I antibodies. Graft function deterioration was associated with anti-HLA class II antibodies. Multivariate analysis showed independent association for creatinine levels (RR = 7.5), acute rejection (RR = 2.6), recipient male gender (RR = 3.6) and anti-HLA class II antibodies (RR = 2.9) and CAN-associated graft loss. In conclusion, the presence of anti-HLA class II antibodies conferred a risk for graft loss before a decline in renal function and increased the risk of graft failure in patients who already had a decline in graft function. Thus, anti-HLA class II antibody monitoring is a useful tool for the management of long-term kidney recipients.

PURPOSE: We evaluated the rate of function decline of the renal allograft in patients with augmented bladder. We also evaluated the prevalence of asymptomatic bacteriuria and urinary tract infection in these patients, and to demonstrate if these findings are predictors of allograft function decline, comparing children who underwent bladder augmentation with a control group. MATERIALS AND METHODS: Among 170 children and adolescents undergoing renal transplantation at our institution 23 (14%) had previously undergone bladder augmentation. These patients were retrospectively compared (1:2 ratio) to 42 controls matched for gender, age, race, donor type, weight and immunosuppression protocol. The type of donor (living or cadaver), rate of acute tubular necrosis and cold ischemia time during transplantation were also similar between groups. RESULTS: Mean followup was 18.0 +/- 13.9 months and 25.2 +/- 14.1 months for the augmented and nonaugmented bladder groups, respectively (p >0.05). The incidence of acute rejection within the first 12 months of kidney transplantation was 9% in the bladder augmentation group and 26% in controls (p >0.05). The rate of urinary tract infection or asymptomatic bacteriuria in the first 12 months after kidney transplantation was higher in the bladder augmentation group (19 patients, 83%) compared to controls (7 patients, 17%, p <0.001). Patients with augmented bladder had a higher number of hospital admissions (14 patients, 61%) compared to the control group (12 patients, 29%, p = 0.004). Despite the higher incidence of urinary tract infection in the augmented bladder group, there was no statistically significant difference in graft function between the groups at 6 months (1.1 +/- 0.3 mg/dl vs 1.0 +/- 0.3 mg/dl) or 12 months (1.0 +/- 0.2 mg/dl vs 1.2 +/- 0.7 mg/dl) after transplantation. CONCLUSIONS: Our study demonstrated that patients with transplanted kidney and augmented bladder had more asymptomatic bacteriuria and urinary tract infections than those without bladder augmentation. However, the rate of graft survival was similar between the groups.

FTY720 is a new and effective immunosuppressive agent, which produces peripheral blood lymphopenia through a lymphocyte homing effect. We investigated the relationship between the dose of FTY720 or blood concentration (pharmacokinetics, PK) and peripheral lymphopenia (pharmacodynamics, PD) in 23 kidney transplant recipients randomized to receive FTY720 (0.25-2.5 mg/day) or mofetil mycophenolate (2 mg/day) in combination with cyclosporine and steroids. FTY720 dose, blood concentrations and lymphocyte counts were determined weekly before and 4 to 12 weeks after transplantation. The effect of PD was calculated as the absolute lymphocyte count or its reductions. PK/PD modeling was used to find the best-fit model. Mean FTY720 concentrations were 0.36 +/- 0.05 (0.25 mg), 0.73 +/- 0.12 (0.5 mg), 3.26 +/- 0.51 (1 mg), and 7.15 +/- 1.41 ng/ml (2.5 mg) between 4 and 12 weeks after transplantation. FTY720 PK was linear with dose (r(2) = 0.98) and showed low inter- and intra-individual variability. FTY720 produced a dose-dependent increase in mean percent reduction of peripheral lymphocyte counts (38 vs 42 vs 56 vs 77, P < 0.01, respectively). The simple Emax model [E = (Emax * C)/(C + EC50)] was the best-fit PK/PD modeling for FTY720 dose (Emax = 87.8 +/- 5.3% and ED50 = 0.48 +/- 0.08 mg, r(2) = 0.94) or concentration (Emax = 78.3 +/- 2.9% and EC50 = 0.59 +/- 0.09 ng/ml, r(2) = 0.89) vs effect (% reduction in peripheral lymphocytes). FTY720 PK/PD is dose dependent and follows an Emax model (EC50 = 0.5 mg or 0.6 ng/ml). Using lymphopenia as an FTY720 PD surrogate marker, high % reductions (~80%) in peripheral lymphocytes are required to achieve best efficacy to prevent acute allograft rejection.