Hakala, Thomas B

Iwatsuki, Shunzaburo

Rosenthal, J Thomas

Shaw, Byers W

Starzl, Thomas E

English

PubMed

D-Scholarship@Pitt

K~ Volume 2. Number I February. 1983 Diabcztic nczphropath\] ·:~KI -.; .. -. '. II~:I!I-~~D:"D~D~1::_:"~"" :.': ,' .... <,: <>:"": D~"K< :':" "_;.-::'r. ';' D-~D-D" '"" ... _' .. " .. :.': ,-,'" Of • ,-, Cadaveric Renal Transplantation in Diabetics in the 1980's: with Special Reference to Cyclosporine Thomas E. Starzl, MD, PhD, Thomas B. Hakala, MD, J. Thomas Rosenthal, MD, Shunzaburo Iwatsuki, MD, and Byers W. Shaw, Jr., MD Department of Surgery, University of Pittsburgh Health Center, University of Pittsburgh, Pittsburgh, Pennsylvania. When renal transplantation became a practical means of therapy Jlmost two decades ago, I diabetes melIirus was considered a high r:sk factor, which precluded candidacy, except when related donors were available. Najarian et aI. 2 popularized renal"transplantation in diabetics, provided evidence that patient survival was superior to that with chronic dialysis, and emphasized the necessity for an inter~isciplinary health care team before and after transplantation. In an exhaustive report covering a lO-year period, Najarian et al. 2 provided a follow-up for 109 diabetic patients who underwent primary cadaveric renal transplantation under treatment with azathioprine, prednisone, and antilymphocyte globulin (ALG). ;!.e one-year cadaveric graft survival of 60% was a high water mark, marred only by the patient mortality which was 30% in the flfst post-operative year. Discussions of Najarian's paper by several transplantation surgeons made it clear that others were not achieving even this level of success.! The unsatisfactory results with cadaveric transplantation in diabetic, (or for that matter non~abeticFI patients has been a nagging indictment of the deficiencies of the techniques of immunosuppression, which have changed little since the mid-1960's. Treatment in most centers has been with the double drug combination of azathioprine-prednisone,"3 and in almost all of the rest, triple drug therapy with azathioprine, prednisone, and anti-lymphocyte globulin (ALG) has been used. l " With either approach, high~ose chronic therapy with steroids has been an unusually adverse factor for diabetics, with a predictable increase in insulin needs, and with a high incidence of infections and vascular complications. Minor variations from basic double and triple drug therapy have been reviewed. l These did not have a major impact. Other attempts to improve the outlook have been with tissue typing,6.1 and with systematic preoperative blood transfusion of the recipient.' With the introduction by Caine et aI. 9,10 of the new drug, cyclosporine, as a single immunosuppressive agent, or with the use of cyclosporine plus a limited quantity of steroids as we have recOlrunended,ll.12 there has been the prospect of better graft sur-vival with less morbidity. To see if this objective has been realized, we report here the fate of diabetic patients during our early expe-rience with cyclosporine-steroid therapy. For comparison. a small group of patients given azathioprine and steroids during the same time will be included. METHODS The cases were divided into three groups. There were three type I diabetics treated during pilot trials with cyclosporine and steroids in 1980 (Group 1); follow-ups are available of 21h to 3 years (Table 1). In 1981, seven type I diabetics were given cyclosporine and steroids (Group 2), most during participation in a randomized trial which included seven other patients (Group 3) treated with azathio-prine and steroids (Table 1), All of the patients treated with azathioprine and prednisone (Group 3) were undergoing transplantation for the first time. whereas one of the 10 treated with cyclosporine (Groups 1 and 2) had rejected a primary kidney under conventional therapy, and was undergoing retransplantation (Table 1). The features of the three groups are summarized in Table I. The patients were reasonably matched for age, lack of good typing at the A and B loci, and transfusion history, but with a slight advantage for the azathioprine-steroid group (Table 1), Matching at the DR locus was random, The Table I. Type I Diabetics Receiving Cadaveric Kidneys 1980 -1981 (Data, Mean ± SO) No. of No. pJimary Matches 2:3 Preop Patient Followup Group Patients Grafts Age Transplantation A, B Loci Transfusions (Months) 1 Cyclosporine-Steroids 3 3 44 ± 2 3/3 0.33 ± 0.57 0/3 33.3 ± 2.9 (Pilot) 2 Cyclosporine-Steroids 7 S" 40.6 ± 10.S 617 1.57 ± 1.39 3/7 15.7 ± 2.9 (Randomized) 3 Azathioprine-Steroids 7 S" 36.9 ± 6,2 717 2.00 ± 1.52 5/7 19.7 ± 2.9 (Randomized) • One of the kidneys in each group was transplanted in 1982 after loss of a graft transplanted in 1981. -K~C=;M=-;;;:;;D-;;;h~*MeTd"tii#r""~· ~gii>l t- ~ I (. w z -v -@ ~ ~ ~ -...J -~ UJ jE --....J 0.. 0.. :J (J) ---DR matches were obtained after the transplamations had been completed. and were uniformly poor. Azathioprine and prednisone were used together in the standard way, I beginning high dose steroid therapy at 200 mg on the day of operation. with subsequent gradual weaning. In Groups I and 2, cyclosporine was begun at I7 mg/Kg/day, and prednisone was begun at 200 mg, with daily decrements of 40 mg until a main-tenance dose of 20 mg/day was reached in adults after 5 days. Further adjustments in cyclosporine or steroid doses were as previously described. 11·1) RESULTS Patient Survival All 17 patients are alive with follow-ups of one to three years. Graft Survival Group One All three of the cadaveric grafts in this pilot trial are still functioning after 21h to 3 years. Tho of the three patients have normal renal function. The third had nearly normal graft function for 21h years, but developed an elevation of creatinine to 3.6 mg% when maintenance steroid therapy was reduced from 10 to O/mg/ day. The deterioration was reversed after return to low dose steroid therapy . Group Two Six of the seven recipients achieved chronic survival of their grafts (Table m. Through a blood typing error, the seventh patient who was of 0 blood type was given an A kidney, which underwent--Table II. Graft Survival, Blindness and Amputations Patients Survival Survival of Patients Legally 1980-1981 Subsequent Dialysis Blind Post-Op Group Grafts Grafts Free Preop Amputations 1 3/3 3/3 1/3 3/3 2 6/7 1 "/1 7/7 2/7 1/7 3 5/7 1 "/1 6/7 117 3/7 Total 14/17 212 16/17 4117 7/17 ·Subsequent grafts were placed in 1982 under cyclosporine-steroid therapy with present follow-ups of 9 (the patient in Group 2) and 4 (the patient in Group 3) months. hyperacute rejection and renal vein thrombosis. Nine months later. this patient underwent cadaveric retransplantation, again ... lth cyclosporine-steroid therapy, with a good result for the ~ months of follow-up. Thus all seven patients are dialysis-free. Five of the six original grafts function well enough to kccp the serum creatinine concentration less than 2.5 mg%. The pl~th patient has had chronic rejection with a creatinine of 6 mg % (Tat-Ie ITI). Group Three Tho of the seven kidneys were rejected after three and nine months. Four of the five other original transplants are maintaining serum creatinine values of less than 2.5 mg% (Table llI). One of the two patients whose primary allograft was rej~ed under azathioprine-steroid therapy underwent retransplantatton 9 months later with cyc1osporine-steroid therapy, and has good func-tion three months later. Thus, six of the seven patients in the group are dialysis-free. Steroid and Insulin Requirements Comparison was made between Groups 2 and 3. In all patients of both groups the daily insulin requirements increased after trans-plantation (fable ITI), and in a number of recipients the upward adjustments were striking. The greatest increases were in the patients treated with conventional immunosuppression. With almost identical average periods of follow-up, the maintenan<Ce doses of prednisone are almost twice as high in the azathiopriIk!-steroid group as in the cyclosporine-steroid group (Table llI). Diabetic Complications All of the patients bearing kidneys have had a major improve-ment in well-being. Four of the 17 patients were legally blind before operation (Table IT). None of the others have become blind since transplantation, but several have required ophthalmologic care, including laser treatment for detached retinae. A striking statistic was the frequent necessity for amputation (Table m. During follow-ups of 21h to 3 years, all 3 of the cyclosporine-steroid-treated patients in Group 1 have undergone unilateral below knee amputation, and one of the patients of Group 2 has had a finger amputation. Three of the patients in the azathioprine-steroid series (Group .3 J have had amputations (Table m, one each at the great toe, trans-metatarsal, and below knee level. DISCUSSION The value of this experience is limited by the small number of patients. Nevertheless, the absence of mortality, the 90% one-year Table III. Graft Function, Steroids, and Insulin Requirements in Randomized Patients Still Bearing Grafts (Mean ± SD) Group 2 3 No. 7' 6" • Creatinine Mg% 2.45 ± 1.68 1.6 ± 0.64 CR Range Mg% 1.0 to 6.1 0.9 to 2.8 Daily Prednisone Mg% 12.5 ± 3.2 16.7 ± 2.6 Daily Daily Insunn Insunn Preop Now Units Units 32.2 ± 21.6 44.7 ± 38.5 51.6 ± 31.1 79.3 ± 30.8 "One of these patients had retransplantation 9 months ago, again under cyclosporine-steroids. " • One of these patients had retransplantatioA 4 months ago under cyclosporine-steroids and is receiving 20 mglday prednisone. DIABETIC TRANSPLANTATION 1980'S: CYCLOSPORINE graft survival using cyclosporine-steroid therapy, the lower • chronic maintenance doses of prednisone, and the lower eventual insulin requirements are worth noting in comparison to those in the azathioprine-steroid group. The results in the latter series were acceptable, however, in that six of the seven patients are dialysis-free. No matter what the immunosuppression, there were reminders of the difficulty of treating patients with diabetes meUitus. Even with relatively low maintenance doses of steroids, the insulin requirements invariably rose, and not uncommonly doubled or tripled. Ophthalmalogic problems contmued, with several patients requiring cataract removal or laser treatments. TIle fact that vascu-lar disease had not been stabilized was reflected by amputation in 7 of 17 cases. It seems unlikely that the patient or graft survival curves in diabetics will be able to match those of non-diabetic recipients as the years go by, unless there is perfect glucose control, an objective that cannot be achieved under ordinary clinical circumstances. Long term parity of results in diabetic and ndn-diabetic transplant recipients undoutedly will depend upon widespread application of insulin pump technology, or upon advances in pancreatic trans-plantation. SUMMARY The courses were reviewed of seventeen type I diabetic patients who were treated with cadaveric renal transplantation in 1980 and 1981, including IO who were treated with cyc!osporine-steroid immunosuppression, and seven who had azathioprine-steroid therapy. With follow-ups of I to 3 years, all I7 patients are alive, and 16 are dialysis-free. The results were better under cyclos-porine-steroid therapy, but they were also acceptable under con-ventional inununosuppression. Whatever the treatment protocol, there was a high incidence of continuing diabetic complications, including ophthalmalogic. disease and a striking need for limb or digit amputation. ACKNOWLEDGEMENTS Supported by research grants from the Veterans Administration; by project grant AM-29961 from the National Institutes of Health and by grant RR'{)()84 from the General Clinical Research Center Program of the Division of Research Resources, National Institutes of Health. 11 REFERENCES I. Starzl, TE: Experience in Renal Trarupianrarion. W B. Saunders Company, Philadelphia, 1964, 383 pp. 2. Najarian. JS, Sutherland, DER, Simmons. RL. Howard. RJ. KjeU-strand, CM, Ramsay, RC, Goest, FC, Fryd. OS. Sommer. BG: Ten-year experience with renal transplantation in juvenile onset diabetics. Ann Surg 1<xl:487-500, 1979. 3. StarzI. TE, Marchioro, TL. Waddell. WR: The reversal of rejection in human renal homografts with subsequent development of homograft tolerance. Surg GynecolObsrer 117:385-395. 1963. 4. Stanl, TE, Marchioro, TL. Poner. KA, Iwasaki. Y, Cerilli. GJ: The use of heterologous antilymphoid agents in canine renal and liver homotransplantation and in human renal transplantation. Surg Gyne-colObstet 124:301-318, 1967. 5. StarzI, TE. Rosenthal. IT, Hakala. TR. Iwatsuki, S. Shaw, BW. Ir .. Klinnna1m. GBG: Steps in immunosuppression for renal transplanta-tion. Kidney Inter (in press). 6. Opelz, G, Mickey, MR, Teraski, PI: HLA matching and cadaver transplant survival in North America. Transplantation 23:490-497,1977. 7. McDonald, IC, Vaughn, W. Filo, RS, Picon. GM, Niblack, G, Spees. EK, Williams, GM: Cadaver donor renal transplantation by centers of the Southeastern Organ Procurement Foundation. Ann Surg 193: 1-8. 1981. 8. Opelz, G, Sengar. DPS, Mickey, MR, Terasaki. PI: Effect of blood transfusions on subsequent kidney transplants. Transpianr Proc 5:253-259, 1973. 9. Caine, RY, White. DJG,Thiru, S, Evans. DB, McMaster. P, Dunn_ DC, Craddock, GN. Pend ow , BD, RoUes. K: Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancer 2:1323-1327. 1978. 10. Caine, RY, RoUes, K. White, DJG, Thiru. S. Evans. DB, McMaster. p. Dunn, DC. Craddock. GN. Henderson. RG. Aziz. S. Lewis. P: Cyc1osporin A initially as the Only immunosuppressant in 34 recipi-ents of cadaveric organs; 32 kidneys.·2 pancreases. and 2 livers. Lancer 2: 1022-1036, 1979. 11. Stanl, TE. Weil. R, m, Iwatsuki, S, Klintmalm, GBG. Schroter. GPI, Koep, U., Iwasaki, Y, Terasaki. PI, Porter. KA: The use of cyclosporin A and prednisone in cadaver kidney transplantation. Surg GynecolObsrer 151:17-26,1980. 12. Stanl. TE, Klintma1m, GBG. Weil. R. ill, Porter. KA. Iwatsuki, S. Schroter, Gp, Fernandez-Bueno. C, MacHugh. N: Cyclosporin-A and steroid therapy in 66 cadaver kidney recipients. Surg Gynecol Obsrt'r 153:486-494,1981. 13. Starzl, TE. Hakala, TR, Rosenthal, IT, Iwatsuki, S, Shaw, BW. Jr.: Variable convalescence and therapy after cadaveric renal transplanta-.tions under cyclosporin A and steroids. Surg Gynecol Obsrer 154:819-825, 1982. 

Cadaveric Renal Transplantation in Diabetics in the 1980's: with Special Reference to Cyclosporine.

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Cadaveric Renal Transplantation in Diabetics in the 1980's: with Special Reference to Cyclosporine.

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