Demetris, AJ

Ellis, D

Fung, JJ

Gilboa, N

Gritsch, HA

Hakala, TR

Irish, W

Jordan, ML

Lombardozzi-Lane, S

McCauley, J

Randhawa, P

Scantlebury, VP

Shapiro, R

Simmons, RL

Starzl, TE

Vivas, C

English

PubMed

Name not available

Tacrolimus in renal transplantation

D-Scholarship@Pitt

Tacrolimus in Renal Transplantation R. Shapiro, M.L. Jordan, V.P. Scantlebury, C. Vivas, HA Gritsch, J. McCauley, D. Ellis, N. Gilboa, S. Lombardozzi-Lane, P. Randhawa, AJ. Demetris, W. Irish, T.R. Hakala, R.L. Simmons, J.J. Fung, and T.E. Starzl TACROLIMUS (Prograf-FK506) has been used since 1989 as a primary immunosuppressive agent in adult and pediatric renal transplant recipients at our institu-tion.1.2 This report will summarize our experience with it over the past six years and will demonstrate its overall efficacy and superiority. Adults The early studies with tacrolimus. from 1989 through 1991, included a pilot series, a small randomized trial, and a larger nonrandomized group. I.3.4 When the outcome of these patients was compared with that in a roughly concur-rent (although somewhat less challenging) group of cyclo-sporine (CyA)-treated patients, equivalent patient and graft survival rates were seen. However, improved secondary outcomes were noted in the tacrolimus-treated patients, including lower steroid and antihypertensive medication requirements, and lower serum cholesterollevels.4 This led to a second prospective, randomized trial, between August, 1991 and December, 1993, comparing two tacrolimus-based regimens, with and without azathioprine.5- 8 Earlier analy-ses of this trial (by intention to treat, without patient censoring) demonstrated excellent outcomes with tacroli-mus overall, but with unclear benefit for azathioprine. The most recent analysis, with a mean follow-up of 33 :!: 10 months, showed a one- and three-year actuarial patient survival of 95% and 92%, with no significant difference between the two groups (Table 1). Overall one- and three-year actuarial graft survival was 89% and 80%, with worse results in the tacrolimus/azathioprine/prednisone group than in the tacrolimus/prednisone group. Overall one- and three-year actuarial graft survival in first cadaver recipients was 91 % and 82%, without a statistically significant differ-Table 1. Tacrolimus in Renal Transplantation Adults n = 397 Tacro/Pred Tacrol AzaiPred Overall Actuarial Patient Survival 1 year 97% 94% 95% 3 year 94% 90% 92% Actuarial Graft Survival 1 year 90% 88% 89% 3 year' 84% 76% 80% 'p = .031 S. Creatinine (mgldL) 1.9:!: 1.0 1.9:!: 1.8 1.9:!: 1.5 Off Steroids 70% 68% 69% Off Anti-Hypertensive 39% 36% 38% Medications Table 2. Tacrolimus in Renal Transplantation Pediatrics n = 43 Actuarial Survival Patient Graft S. Creatinine Off Steroids Off Anti-Hypertensive Medications 1 year 100% 98% 1.2 :!: 0.6 mg/dL 62% 62% 3 year 100% 85% ence between the two groups. The projected half-life of first cadaver kidneys was 11.9 :!: 2.5 years. Sixty-nine percent of successfully transplanted patients have been taken off steroids, and 38% are off antihyperten-sive medications. The mean serum creatinine is 1.9 :!: 1.5 mgldL. There are no differences between the double and triple drug groups in these parameters. The incidence of rejection was 50%, and steroid-resistant rejection was seen in 11 % of cases. There was a slightly lower. but not statistically different, incidence of rejection in the azathio-prine group (45% vs 55% overall, and 8% vs 14% steroid resistance). There was also a substantial crossover between the two groups, more from triple to double therapy than vice versa. Subsequent to completion of the second randomized trial, a third randomized trial was begun in December, 1993, evaluating the role of one week of low-dose cyclophospha-mide in tacrolimus-treated recipients. Analysis of this trial is currently in progress, and a fourth randomized trial, comparing tacrolimus/prednisone and tacrolimus/pred-nisone/mycophenolate mofetil, has just begun. Pediatrics Between December, 1989 and December, 1993,43 pediatric patients received kidneys under tacrolimus-based immuno-suppression (concomitant or previous liver recipients were excluded from this analysis).2 With a mean follow-up of 25 :!: 14 months, overall one- and three-year actuarial patient survival was 100% (Table 2). Overall one- and three-year actuarial graft survival was 98% and 85%. Sixty-two percent of the successfully transplanted children have From the Pittsburgh Transplantation Institute (R.S., V.S., J.M., W.I., J.F., T.S.), Urologic Surgery (M.J., C.V., H.G., T.H.), Renal Electrolyte (D.E., N.G., S.L.L.), Transplant Pathology (P.R., A.D.), Surgery (R.S.), and the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. © 1996 by Appleton & Lange 0041-1345/96/$3.00/ + 0 Transplantation Proceedings, Vol 28, No 4 (August), 1996: pp 2117-2118 2117 2118 heen weaned o1l steroids. and 62<;, arc not taking anti-hypertensive medications. The mean serum creatinine i, 1.2 ::':: 0.6 mg/dL. The incidence of rejection was SW,. and the incidence of steroid resistant rejection was Y;. An additional 26 children were transplanted hetween January. 1994 and July. 1995. with IOO'!, patient and graft survival. The overall experience with tacrolimus in Ollr renal transplant patients has heen gratifying. Better short-term graft survival. longer projected half-lives. and a remarkahle ability to wean from steroids in a majority of patients have heen the most notahle observations. Based on these find-ings. we believe that taerolimus is a superior immunosup-pressive agent in renal transplant recipients and is. at present. the drug of choice. The prolongation of cadaver kidney half-life in patients treated with tacrolimus is similar to that reported by Gjertson. Cecka. and Terasaki in a collection of cases compiled in the United Network for Organ Sharing (UN OS) Scientific Registry from 24 Amer-ican renal transplant centers." Ongoing work is continuing to evaluate the role of new third agents and other modali-ties (eg bone marrow augmentation) 10.11 in an effort to improve further the outcomes after transplantation. SHAPIRO. JORDAN. SCANTLEBURY ET AL REFERENCES I. Starzl TE. Fung JJ. Jordan M. ct al: lAMA 264:63. 19911 2. Shapiro R. Scantlchury VP. Jordan ML. ct al: Pediatric Ncrhrologv 9:S4:1. 1995 3. Shapiro R. Jordan M. Fung l. ct al: Trans Proc 23:920. 1991 4. Shapiro R. Jordan ML. Scantlchury V. ct .Ii: Trans Proc 23:3065.1991 5. Shapiro R. Jordan M. Scantlehury V. ct al: Trans Proe 25:669. 1993 6. Shapiro R. Jordan M. Scantlebury V. ct al: Clin Trans S:5llS. 1994 7. Shapiro R. Jordan ML. Scantlebury VP. et al: Transplantation 59:485. 1995 R. Shapiro R. Jordan ML. Scantlchury VP. et al: Trans Proc 27( I ):814. 1995 9. Gjertson DW. Cecka JM. Terasaki PI: Transplantation 60: 13R4. 1995 10. Shapiro R, Rao AS. Fontes P, et al: Transplantation 59(2): 306. 1995 11. Shapiro R. Rao AS, Fontes P. ct al: Transplantation 60:1421. 1995 

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Tacrolimus in renal transplantation

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