Gordon, RD

Hakala, TR

Landreneau, MD

Makowka, L

Rosenthal, TJ

Starzl, TE

Taylor, RJ

Tzakis, AG

English

PubMed

D-Scholarship@Pitt

Cyclosporine Immunosuppression and Delayed Graft Function in 455 Cadaveric Renal Transplants R.J. Taylor, M.D. Landreneau, L. Makowka, T.J. Rosenthal. R.D. Gordon, A.G. Tzakis, T.E. Starzl, and T.R. Hakala SINCE the nephrotoxic properties of cyclo-sporine A (CyA) were first described, there has been concern expressed over the use of CyA in non functioning allograft kidneys.] Several investigators have reported an increased risk of developing delayed graft function for CyA-treated kidneys when com-pared with conventionally treated kidneys.2.3 At the University of Pittsburgh, we have always given CyA preoperatively and have continued the regular dosing protocol postop-eratively regardless of graft function. 4,5 The purpose of this study was to review our recent results in terms of delayed graft function and the relationship of CyA to eventual graft outcome. METHODS AND MATERIALS A retrospective analysis was performed on 455 consec-utive cadaveric renal transplants done at our institution between January 1983 and August 1985. All organs were harvested from heart-beating cadavers and stored in ice slush until transplanted. Local organ procurement, renal transplantions, and postoperative immunosuppressive management were performed under our standard guide-lines,6 Four hundred and thirty-one kidneys were obtained locally; 24 were procured for us by other trans-plant teams as part of our sharing program, and 190 were obtained from multiple organ donors (Tables I and 2). Delayed graft function (DG F) was defmed as the need for dialysis within the first week postoperatively regard-From the Department of Surgery, University of Pitts-burgh Health Center, PA, and the Department of Sur-gery, Louisiana State University Medical Center, Shreveport, Supported by research grants from the Veterans Administration and Project Grant AM-29961 from the National Institutes of Health. Bethesda. MD. Address reprint requests to Dr TE. Starzl, Depart-ment of Surgery. 3601 Fifth Ave, Room 218, Falk Clinic, Pittsburgh, PA 15213. © 1987 by Grune & Stratton,lnc. 0041-1345/87/1901-0792$03.00/0 less of urinary volume. Permanent nonfunction (PNF) was defined as the failure of the kidney to ever regain enough function to negate the need for continued dialy-sis. Other than the type of immunosuppression and graft results, donor factors evaluated included cold storage time, the fate of paired organs, and whether multiple organ recovery was involved. Recipient factors evaluated included age, cause of renal failure, PRA status prior to and at the time of transplant, and primary or retransplant status (Table 2). Immunosuppression was given preoperatively to all patients and consisted of oral, intravenous (IV), or com-bined CyA and steroids as previously described,6 No changes in the standard postoperative CyA dosing were made solely on the basis of DGF. High-performance liquid chromatography (HPLC) whole blood levels were used to aid in dosage adjustment, as was the patients' clinical course. Statistical analysis of demographic variables was per-formed using chi square tests. Allograft and patient survival rate were calculated using Kaplan-Meier sur-vival curves. RESULTS The incidence of DG F for the study popula-tion was 22% (Table 3), which represented 99 kidneys, nine of which were lost early to technical complications. Sixty-two (63%) of the kidneys with DGF eventually regained function adequate to replace maintenance dialysis, Thirty-seven kidneys (8%), however, never regained adequate function and were counted as permanent nonfunctioning losses, The characteristics of the study popUlation were stratified according to the presence or absence of DGF, As shown in Table 2, the Table 1. Study Population: Cadaveric Renal Transplants January 1983 Through August 1985 Total transplants (renal) Locally procured kidneys Shared kidneys Ice Storage preservation 455 431 24 455 (100%) 2100 Transplantation Proceedings, Vol XIX, No 1 (February), 1987: pp 2100-2103 CYCLOSPORINE IMMUNOSUPPRESSION 2101 Table 2. Recipient Demographics (or) Recipient Population Data Base Immediate Function Diabetic 89/356 (25%) Mean age 37.8 PRA > 30 at transplant 49/356 (13.7%) Multiple organ 145/356 (41 %) Retransplant 48/356 (13.5%) Age >55 yr 34/356 (9.5%) incidence of regrafted patients in the DGf group was 28% v 13.5% in the early function group (P < 0.05). The other significant differ-ence was in the number of patients older than 55 in the DG F group. The influence of DGF on graft and patient survival for primary and regrafted recipients is shown in Table 4. The DG F rate for primary transplant recipients was 19%, including eight technical losses, compared with 37% of patients undergoing retransplants (P < 0.01). Furthermore, DGF had a signifi-cant effect on the long-term graft survival within each group, the effect being most dele-Table 3. Incidence of Delayed Graft Function on Postoperative Renal Allograft Function ----Number Percentage Immediate function 356 78 Delayed graft function' 99 22 Permanent nonfunctiont 37 89 'Patients that required hemodialysis within 1 week of transplant. tNine permanent nonfuctions were due to technical error. Delayed Graft Function 16/99 (16%) 38.5 18/99 (18%) 45/99 (45%) 28/99 (28%) 18/99 (18%) PValue NS NS NS <0.05 <0.05 terious in retransplant patients where the combination resulted in a I-year actuarial graft survival of only 32% compared with 62(!t. for primary transplants with DG F. The DG F rate, however, did not have any impact on patient survival which was 96% and 98.6% for retransplants and primary transplants, re-spectively. The permanent non function rate (Table 5) for the entire group was 8%; how-ever, it was 23.6% for retransplant recipients v only 5% for primary transplants (P < 0.01). To determine whether the detrimental efl'ect of DGF was related to the length of preserva-tion, we looked at the cold storage for each group was examined. As shown in Table 6, there were no significant differences between any of the groups for either the mean cold storage time or in the percentage of kidneys that were stored for greater than 24 hours. The fate of paired kidneys was examined to see if donor factors seemed to be more respon-sible than recipient factors for DG F. There were 69 pairs of kidneys that could be fully evaluated where either one or both kidneys Table 4. Influence of Delayed Graft Function on Patient Survival Actuarial Survival Grafts (%1 Patient Grafts Percentage 1 ma 1 yr (1 yr; %1 Primary transplants Immediate function 308 81 93.5 80 99 Delayed graft function 71 19 72 62 96 Total 379 100 89 77 98.6 Retransplants Immediate function 48 63 81 62.5 98 Delayed graft function 28 37 39 32 93 Total 76 100 66 51 96 --------- ~ _ ... --~~-~~ 2102 Table 5. Permanent Nonfunction Rate Primary transplant Retransplant Number of Kidneys 19/379 (5%) 18/76 (23.6%) Technical Loss 8 had DGF (Table 7). In only 27.5% did both kidneys experience DGF while in 50 pairs, or 72.5%, only one kidney had DGF. In this latter group, there were no significant differ-ences between the ages of the recipients or the storage times for those kidneys that func-tioned early and those that experienced DGF. DISCUSSION The nephrotoxic properties of CyA were first reported in clinical studies by Caine et aV who recommended that the drug be with-held until it was determined that the graft was functioning to avoid the potentially additive effect of a nephrotoxic agent to an already compromised renal unit. Some investigators2,3 have described a significant increase in DG F to 40% or 50% (Table 8) in patients pre-treated with CyA compared with 20% to 30% for patients transplanted with conventional immunosuppression. They have ascribed this difference to CyA nephrotoxicity. However, other reports7 12 have failed to document any difference in the rate of DGF patients treated pre- or postoperatively with CyA and those treated with conventional immunosuppression including antilymphocyte globulin (ALG). Our overall DGF rate of 22% compares favor-ably with this latter experience and with our own historical patients treated with conven-TAYLOR ET AL tional immunosuppression, \3 thus supporting the argument that CyA does not increase the rate of DGF. Furthermore, studies by ourselves6 and oth-ers l4 have failed to show any difference in the incidence of DGF whether CyA is given oral-ly, IV, or in combination preoperatively. Additionally, Belitsky et al 15 showed that there is no difference in the incidence of DGF when high (15 mg/kg) loading doses are used preoperatively v low (10 mg/kg) loading doses. However, a significant prolongation of DGF has been demonstrated when IV and oral loading were combined,6,14 suggesting that the nephrotoxic effect of CyA is less likely to cause DG F than to prolong it if it occurs. The data from this study also support recent reports on the detrimental effect of delayed graft function on eventual graft sur-vival regardless of whether conventional immunosu ppression 16 or Cy A is used. \0 It fur-ther supports the finding that regrafted patients are more likely to develop DGF with significantly worse results than when primary recipients develop DGF.12 However, Kramer et al reported that the long-term survival of the kidneys that developed DGF and were treated with CyA was superior in all groups when compared with the DGF long-term sur-vival rates of conventionally treated organs. \0 Our results compare favorably with the CyA results reported by Kramer et al for DG F treated kidneys with the exception of regrafted patients who developed DGF. For this group of patients, the results were the Table 6. Donor Factor (Mean Cold Ischemia Time) Mean ± SD Stored Over 24 h (h) Number Percentage Entire group (455) 25 + /- 7 h 218/455 48 Immediate function (356) 26 +/- 7 h 162/356 4R~R DGF (99) 28 +/- 7 h 56/99 56 Retransplant, DGF (28) 27+/-7h 13/28 46 Retransplant. immediate (48) 25+/-7h 26/148 54 Numbers in parentheses denote the number of patients in each group. CYCLOSPORINE IMMUNOSUPPRESSION Table 7. Status of Paired Organs Pairs with DGF and DGF Pairs with DGF and function Total Pairs Grafts Number Percentage With DGF 19 50 69 27.5 72.5 100 38 50 88 same as those reported with conventional immunosuppression. Patient survival in all categories was excellent, once again docu-menting the relative safety of CyA. We conclude that CyA does not increase the risk of developing DG F and indeed the overall CyA-DGF results are superior to con-----"""-"--------"-------2103 Table 8. Rate of Delayed Graft Function With eyA DGF-Institutions DGF-CyA Conventional P Minnesota" 18.7% 11.5% n.s. Oxford" 51% 27% p < 0.05 Birminghamt 34% 40% n.S. Brussels" 45% 19% P < 0.05 "Preoperative CyA. tCyA given after diuresis began. vention-DG F results. Furthermore, we agree with the recommendation of Kramer et al that the probability of DGF should not be a deter-rent to the use of CyA in cadaveric trans-plants.s REFERENCES I. CaIne RY. White DJG. Thiru S, et al: Lancet 2: 1323, 1978 2. Wood RFM, Thompson JF, Ting A, ct al: Trans-plant Proc 17:1164,1985 3. Squiffiet JP, Pirson Y, Jamart J, et al: Transplant Proc 17:1212, 1985 4. Slarzl TE, Hakala TR, et al: Cyclosporine A. Proceedings of an International Conference on Cyclospo-rine A, Cambridge, 32:365 5. Starzl TE, Hakala TR, et al: Surg Gynecol Obstet 154:819,1982 6. Ptachinski RJ, Hakala TR, Schleicher C, ct al: Transplant Proc (in press) 7. Ferguson RM, RynasicwiczJJ.Sutherland DER,et al: Surgery 92:175, 1982 8. McMaster P, Haynes IG, Michael J, et al: Trans-plant Proc 15:307, 1983 (suppl I) 9. Cats S: In Tedisaki P (ed): Kidney Transplants 1985. Los Angeles, UCLA, 1985, P 217 10. Kramer NC, Vaughn WK, Bollinger RR, et al: Transplant Proc (in press) 11. Canafax OM, Torres A, Fryd OS, et al: Trans-plantation: 41: 177, 1986 12. Kramer NC, Vaughn WK, Bollinger RR, et al: Transplant Proc (in press) 13. Rosenthal JT, Denny 0, Hakala TR: J Urol 129:111,1983 14. Sommer BG, Ferguson RM: Transplant Proc 17:1235,1985 15. Belitsky P, Lowen J, MacDonald AS, et a1: J Urol 133:206A, 1985 (abstr 372) 16. San Fillipo F, Vaughn WK, Spees EK, et al: Transplantation 38:643, 1985 17. Ladowski J, Rosenthal JT, Taylor RJ, et al: Trans-plant Proc 17:1218,1985 

Cyclosporine immunosuppression and delayed graft function in 455 cadaveric renal transplants.

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Cyclosporine immunosuppression and delayed graft function in 455 cadaveric renal transplants

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Cyclosporine immunosuppression and delayed graft function in 455 cadaveric renal transplants.

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