0022-534 7/89/1423-0694$02.00/0 Vol. 142, September
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1989 by AMERICAN UROLOGICAL ASSOCIATION, INC.
RECENT RESULTS OF CADAVER KIDNEY RETRANSPLANTATION CHARLES L. JACKSON, ANDREW C. NOVICK,* STEVAN B. STREEM, DONALD STEINMULLER, ROBERT CUNNINGHAM, ERNEST HODGE AND KAVITA BADHWAR From the Departments of Urology, Hypertension and Nephrology, Cleveland Clinic Foundation, Cleveland, Ohio
ABSTRACT
The results of secondary cadaver renal transplantation in 42 patients treated from 1980 to 1986 have been reviewed. The initial graft was from a cadaver donor in all cases. All patients were managed with a maintenance immunosuppressive regimen, including either antilymphoblast globulin and/or cyclosporine. The over-all 1 and 2-year patient survival rates were 97 and 94 per cent, respectively. The over-all 1 and 2-year graft survival rates were 69 and 63 per cent, respectively. Graft success was not influenced by patient age greater than 50 years, diabetes, initial graft removal, interval between initial graft removal and retransplantation, duration of initial graft function, level ofpresensitization or HLA-Dr antigen matching. Currently, cadaver renal retransplantation can be performed safely and with an improved opportunity for graft success. Patients who return to dialysis after losing an allograft should be encouraged to consider another transplant for the same reasons that prompted initial transplantation. (J. Ural., 142: 694-696, 1989) With conventional azathioprine-prednisone maintenance immunosuppression, the results of secondary cadaver renal transplantation have been less successful than for primary cadaver transplants, particularly with a short duration of initial graft function. 1-6 Recent reports, however, have indicated improved secondary graft survival with the use of cyclosporine.7-10 We reviewed our results with cadaver retransplantation to re-evaluate patient and allograft outcome with modern immunosuppressive therapy, over-all and in relation to specific prognostic factors.
were managed with prednisone and cyclosporine from the time of transplantation. 12 A total of 18 patients received azathioprine, prednisone and antilymphocyte globulin immediately after transplantation; when adequate graft function was assured antilymphocyte globulin was discontinued and cyclosporine therapy was initiated (sequential therapy). 13 Episodes of rejection were treated with either intravenous 500 mg. methylprednisolone daily for 3 days or a 10-day course of antilymphocyte globulin. Complete post-transplant followup has been obtained in all patients. Followup ranged from 14 to 75 months (mean 23.6 months). Graft failure was considered to occur at the time of return to dialysis, transplant nephrectomy or patient death. Graft survival rates were determined by actuarial calculation with the Kaplan-Meier method. Univariate comparisons among survival curves were done with a generalized Wilcoxon test.
MATERIALS AND METHODS
From January 1980 to November 1986, 586 renal transplants were performed at our clinic. Of these procedures 44 were second transplants with a cadaver donor kidney. Two of these patients were lost to followup (with a functioning graft) early postoperatively and they are excluded from this study. The remaining 42 second cadaver transplant recipients form the basis of this report. The series included 26 male and 16 female patients between 8 and 62 years old (mean age 31.9 years). The initial grafts were from cadaver donors in all cases. Ten patients were diabetic and all patients had returned to dialysis before retransplantation. The duration of initial cadaver transplant function was less than 12 and 12 or more months in 33 and 9 patients, respectively. The cause of initial graft loss was rejection in all patients. The failed initial graft was removed in 26 patients and was left in situ in 16. The interval between loss of the initial graft and retransplantation was less than 6 months in 14 patients and 6 or more months in 28. Of the patients 40 had received at least 2 third-party blood transfusions before retransplantation. The current preformed antibody level at retransplantation was less than 10 per cent in 20 patients, 10 to 50 per cent in 16 and greater than 50 per cent in 6. HLA-Dr antigen matching information was available for 34 donor-recipient pairs. Three distinct maintenance immunosuppressive regimens were used after retransplantation, each of which has been described in detail in previous reports from our center. Of the patients 18 were managed with azathioprine, prednisone and adjunctive Minnesota antilymphoblast globulin. 11 Six patients Accepted for publication March 1, 1989. *Requests for reprints: Department of Urology, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, Ohio 44106.
RESULTS
The over-all 1 and 2-year patient survival rates in this series were 97 and 94 per cent, respectively. The over-all 1 and 2-year graft survival rates were 69 and 63.3 per cent, respectively (fig. 1). Graft survival was not significantly different in patients managed with azathioprine, prednisone and antilymphocyte globulin (66 per cent at 2 years) compared to those managed with cyclosporine as sequential therapy (61.1 per cent at 2 years, p = 0.18, fig. 2). The number of patients receiving cyclosporine from the time of transplantation is too small for meaningful interpretation. Cadaver retransplant success was not significantly different in patients whose initial graft had functioned for less than 12, or 12 or more months (p = 0.63). The 1 and 2-year graft survival rates were 64.6 and 61.8 per cent, respectively, in the former, and 77.8 and 55.6 per cent, respectively, in the latter patients. Among patients with less than 12 months of initial graft function cadaver retransplant survival was not significantly different in those managed with sequential therapy compared to those managed with azathioprine, prednisone and antilymphocyte globulin (68 versus 60 per cent at 2 years, respectively). Several other variables were evaluated as possible determinants of graft outcome, including patient age of greater than or less than 50 years, diabetes, performance of initial graft nephrectomy, interval between initial graft loss and retransplantation, current preformed antibody level and HLA-Dr antigen matching (see table). None of these variables demon-
694
695
RECENT RESULTS OF CitDAVER. K.fl))\fEY RETRA.l\fS?L1\l\J'I'/{!1IOl..J
Influence of various factors on graft survival following cadaver retransplantation No, Grafts
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40
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4
6
8
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12
14
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FIG. 1. Over-all patient and graft survival after cadaver renal retransplantation in 42 patients.
100 90 80 70
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Age (yrs.): <50 is:50 Diabetic Nondiabetic Primary transplant nephrectomy: Yes No Mos. between transplants: <6 is:6 Mos. of initial graft function: <12 is:]2 Current preformed antibody ( %) : <10 10-50 >50 HLA-Dr match: 0
2
4
6
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8
12
14
16
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FIG. 2. Graft survival following cadaver renal retransplantation according to maintenance immunosuppression with azathioprine (AZA), prednisone (PRED) and antilymphocyte globulin (ALG) in 18 patients, cyclosporine (CYA) and prednisone in 6 or antiiymphocyte globulin, azathioprine, prednisone and cyclosporine in 18.
strated a significant effect on graft survival in our series. HLADr antigen "'"A"""",,,., ,.vas not available for all ~-·"·-···"~ and the number of 2-antigen matched grafts admittedly is small, DISCUSSION
the recent progress in results of renal transplantation, many patients continue to return to dialysis after loss of an initially successful allograft. The number of ,.m,ocv,'""u in this category is increasing, which simply reflects an expanding over-all population of transplant recipients, Such patients may elect either to remain on dialysis indefinitely or to be evaluated for retransplantation. The risk of mortality on dialysis after allograft failure is the same as for patients who have never undergone t:ransplantation.H However, in the past the results of retransplantation were much less successful than for primary transplants. Gifford and associates reported a 2year second graft survival rate of 33 per cent and a patient survival rate of 67 per cent for those with early loss of the initial graft. 1 They suggested that these patients should remain on dialysis until "more effective methods of immunosuppression are available". Several recent studies, including ours, indicate that such methods currently are available. With conventional azathioprine-prednisone immunosuppression, over-all 1-year second graft survival rates ranged from 30 to 50 per cent. 1 " There presently are several reports of greatly improved second graft
% Graft Survival
P Value
l YL
2 Yrs,
64.7 100 80.0 65.3
58.2 100 70,0 61.:l
16
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75.0 66.7 25.0
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26
0.10 0.52
survival using immunosuppressive regimens that incorporate cyclosporine. 7 10 We evaluated the outcome of 42 patients who had each received 2 cadaver renal transplants during the last decade. After retransplantation all of these patients received antilymphocyte globulin and/or cyclosporine. The over-all 1 and 2-year graft survival rates in this series were 69 and 63 per cent, respectively. While these rates are satisfactory, they are approximately 10 per cent less than those obtained for primary cadaver transplants in our program during the same period. 11 • 1 '1 Notwithstanding the latter, patient survival after retransplantation is excellent (94 per cent at 2 years) and identical to that after primary transplantation. We evaluated the role of several factors as possible determinants of second cadaver transplant success, including patient age greater than 50 years, diabetes, initial graft removal, interval between initial graft removal and retransplantation, duration of initial graft function, preformed antibody level and HLA-Dr antigen matching. None of these factors demonstrated a statistically significant impact on graft survival. A particularly important observation is the finding of unimpaired repeat graft outcome among patients who had lost the initial graft to rejection within less than 12 months, Of our patients 33 (78 per cent) were in this nrPv1011.~1v high risk category. There was no detrimental effect of a high nn°tnrm level on graft outcome that may be due to of potent immunosuppression; the number (6) of highly than 50 per cent) presensitized patients in our study is small and caution is advised in interpreting this observation. Our data also do not allow the effect of HLA-Dr antigen matching on graft outcome to be evaluated due to the small number (4) of 2-antigen matched grafts in this series. Our retransplant success rate, over-all and in specific patient subgroups, is improved over corresponding previously reported rates with azathioprine-prednisone immunosuppression. We believe that these improved results are due to more effective immunosuppression with antilymphocyte globulin and/or cyclosporine. During the study period the 2 predominant maintenance immunosuppressive regimens used were an earlier one involving adjunctive prophylactic antilymphocyte globulin, and a recent one involving the sequential administration of antilymphocyte globulin and cyclosporine. Both are potent immunosuppressive regimens and the absence of a significant difference in graft survival mirrors our experience in primary cadaver transplantation. 11 • 11 The sequential antilymphocyte globulincyclosporine regimen remains our current preference on the
696
JACKSON AND ASSOCIATES
basis of an over-all diminished frequency and severity of rejection episodes. 1 " In summary, our results support the emerging view that cadaver retransplantation currently may be performed safely and with an improved likelihood of graft success. While second graft survival probably is not as good as that for an initial graft, the over-all results are satisfactory and the previously observed detrimental effect of certain risk factors no longer is evident. The safety of this approach is attested by the finding of excellent patient survival, which is identical to that obtained after primary transplantation. Patients who return to dialysis after renal allograft failure may be encouraged to consider another transplant for the same reasons that prompted initial transplantation. REFERENCES 1. Gifford, R. R. M., Sr., Sutherland, D. E. R., Fryd, D. S., Simmons, R. L. and Najarian, J. S.: Duration of first renal allograft survival as indicator of second allograft outcome. Surgery, 88: 611, 1980. 2. Opelz, G. and Terasaki, P. I.: Second kidney transplants and presensitization. Transplant. Proc., 4: 743, 1972. 3. Waltzer, W. C., Zincke, H., Sterioff, S., Offord, K. P. and Frohnert, P. P.: Renal transplantation after failure of a first graft. Surg., Gynec. & Obst., 152: 476, 1981. 4. Ascher, N. L., Ahrenholz, D. H., Simmons, R. L. and Najarian, J. S.: 100 second renal allografts from a single transplantation institution. Transplantation, 27: 30, 1979. 5. Howard, R. J., Scornik, J., Fennel, R. and Pfaff, W.W.: Results of kidney retransplantation. Arch. Surg., 119: 796, 1984. 6. Casali, R., Simmons, R. L., Ferguson, R. M., Mauer, S. M., Kjellstrand, C. M., Buselmeier, T. J. and Najarian, J. S.: Factors
7.
8.
9. 10.
11.
12.
13.
14.
related to success or failure of second renal transplants. Ann. Surg., 184: 145, 1976. Bonser, R. S., Crowson, M. C., McGonigle, R., Adu, D., Michael, J., Barnes, A. D. and McMaster, P.: Cadaveric renal retransplantation-the use of cyclosporine and low-dose prednisolone. Transplant. Proc., 17: 2673, 1985. Rosenthal, J. T., Hakala, T. R., Starzl, T., Iwatsuki, S. and Shaw, B. W.: Second cadaver kidney transplants: improved graft survival in secondary kidney transplants using cyclosporine A. J. Urol., 131: 17, 1983. Stratta, R. J., Oh, C.-S., Sollinger, H. W., Pirsch, J. D., Kalayoglu, M. and Belzer, F. 0.: Kidney retransplantation in the cyclosporine era. Transplantation, 45: 40, 1988. Anderson, P.A. M., Belitsky, P., Bitter-Suermann, H., Cohen, A. D. and MacDonald, A. S.: Repeat cadaver kidney transplantation using cyclosporine A immunosuppression. J. Urol., 138: 1376, 1987. Novick, A. C., Khauli, R. B., Braun, W. E., Steinmuller, D., Cunningham, R., Buszta, C. and Goormastic, M.: Improved results of cadaver renal transplantation with azathioprine, prednisone and antilymphoblast globulin. J. Urol., 131: 636, 1984. Novick, A. C., Hwei, H. H., Steinmuller, D., Streem, S. B., Cunningham, R. J., Steinhilber, D., Goormastic, M. and Buszta, C.: Detrimental effects of cyclosporine on initial function of cadaver renal allografts following extended preservation: results of a randomized prospective study. Transplantation, 42: 154, 1986. Lewis, R., Hodge, E., Novick, A., Steinmuller, D., Streem, S., Cunningham, R., Swift, C., Goormastic, M. and Badhwar, K.: Effect of initial versus delayed cyclosporine therapy in cadaveric renal transplant patients. Transplant. Proc., 19: 2088, 1987. Curtis, J. J., Diethelm, A.G., Whelchel, J. D., Jones, P. and Luke, R. G.: Survival of patients returning to chronic dialysis after a failed renal transplant. Transplantation, 32: 451, 1981.