The purpose of this project is to test the efficacy and safety of the new immune suppressive agent FK506 as baseline immune suppression in adult and pediatric cadaver renal transplants to attempt to improve the results in kidney transplantation over results currently obtained with conventional Cyclosporine based immune suppression. This will be accomplished by a randomized, open labeled, controlled clinical trial comparing standard Cyclosporine with FK506 based immune suppression. Both groups will receive steroid with an identical regimen. Rejection will be treated in a similar fashion in both groups with bolus steroids and OKT3. Primary outcome variables will be graft and patient survival one and two years after transplantation. Patients will be followed out to five years to determine long term safety. Detection and diagnosis of rejection will be facilitated by fine needle aspiration, core biopsy, and measurement of peripheral and intragraft cytokines. Studies will be carried out to attempt to refine the diagnostic accuracy of fine needle aspiration by use of DNA applification of individual lymphocytes to detect intragraft immune activation. Pharmacokinetic studies of FK506 will enable precise therapeutic dose ranges to be developed. Important secondary outcome variables will be compared. These include drug nephrotoxicity, hypertension, incidence of opportunistic infections, hyperlipidemia, diabetogenesis, growth in children, and compliance. Standard measurements of renal function will be augmented by NMR examination of kidneys prior to implantation, fine needle aspiration to quantitate degrees of tubular damage, and isotope scans to more precisely quantitate kidney function. After one year post transplant a steroid withdrawal protocol will be instituted in a group of patients with stable renal function to determine if FK506 is potentially more steroid sparing than Cyclosporine. Patients will be closely monitored for evidence of acute rejection prior to institution. In vitro measurements of immune functioning will be carried out simultaneously to attempt to predict which patients can prospectively be safely steroid withdrawn. If the results of the randomized trial show a superiority of FK506, then further refinements of its use will be developed, or it will be tested against newer drugs. Depending on the degree of improvement living related recipients will be included in such trials in the fourth and fifth years. If there is not a significant improvement with FK506, then newer drugs which are currently in animal development in our laboratories will be tested against Cyclosporine.
| Colvin, R B; Cohen, A H; Saiontz, C et al. (1997) Evaluation of pathologic criteria for acute renal allograft rejection: reproducibility, sensitivity, and clinical correlation. J Am Soc Nephrol 8:1930-41 |
