Abstract
The long-term effects of different immunosuppressive drugs and regimens on renal allograft histology are virtually unknown. Therefore, in order to investigate the long-term effects of triple drug treatment versus different combinations of two immunosuppressive drugs on allograft histology, a prospective, randomized trial was performed. One group received triple therapy consisting of low-dose cyclosporin (CyA), azathioprine (Aza), and methylprednisolone (MP), and three groups received combinations of two drugs, i.e., Aza plus CyA, Aza plus MP, and CyA plus MP. At 2 years, there were no significant differences with regard to graft (80%) or patient (87%) survival, or to graft function between the four groups. After 2 years, a protocol core biopsy was taken of all 102 patients having a functioning graft. Of these patients, 61 (60%) were still following the original, randomized treatment protocol; in the remaining cases, changes had occurred in the original protocol and so these cases were considered drop-outs in this study. Histological specimens were examined blindly by two independent observers. Most of the 34 histological variables examined showed no changes. Diffuse fibrosis was most frequent in the CyA plus MP group (70%) and significantly more severe than in the triple therapy group. Mesangial matrix increase in glomeruli was significantly less common in the triple therapy group (8%) than in any one of the double drug combination groups (47%). Two other changes in glomeruli — Bowman capsular thickening and global glomerular sclerosis — were also less frequent in the triple therapy group. Vascular changes other than intimal proliferation (39%) and arteriosclerosis (24%) were uncommon in all groups and least frequent in the triple therapy group. Isometric vacuolation in proximal tubules was found in every group using CyA. It was least prominent in the triple therapy group and most prominent in the CyA plus MP group; it was not seen in the Aza plus MP group. Other specific findings for the groups treated with Cya could not be identified. To summarize, the changes shown were mild and rather similarly distributed in the four treatment groups. Histopathological alterations comparable with chronic rejection, i.e., persistent interstitial inflammation with pyroninophilic cells, vascular intimal proliferation, and arteriosclerosis, were seen in all groups, but these changes were least prominent in the group receiving triple therapy.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Antonovych TT, Sabnis SG, Austin HA, Palestine AG, Balow JE, Nussenblatt RB, Helfrich GB, Foegh ML, Alijani MR (1988) Cyclosporine A induced arteriolopathy. Transplant Proc 20 [Suppl 3]:951–958
Banfi G, Tarantino A, Fogazzi GB, Mihatsch MJ, Ponticelli C (1985) Significance of vascular lesions in cyclosporine treated renal transplants. Kidney Int 28:392
Cecka MJ, Terasaki PI (1989) Early rejection episodes. In Terasaki PI (ed) Clinical transplants. UCLA Tissue Typing Laboratory, Los Angeles, pp 425–434
Demetris AJ, Zerbe T, Banner B (1989) Morphology of solid organ allograft arteriopathy: identification of proliferating intimal cell populations. Transplant Proc 21:3667–3669
Farnsworth A, Horvath JS, Hall BM, Sheil AG, Ng ABP, Tiller DJ, Duggin GG (1984) Renal biopsy morphology in renal transplantation. A comparative study of the light-microscopic appearances of biopsies from patients treated with cyclosporin A or azathioprine prednisone and antilymphocyte globulin. Am J Surg Pathol 8:243–252
Foegh ML (1990) Chronic rejection — graft arteriosclerosis. Transplant Proc 22:119–122
Isoniemi H (1991) Renal allograft immunosuppression III. Triple therapy versus three different combinations of double drug treatment: two-year results in kidney transplant patients. Transplant Int 4:31–37
Isoniemi H, Ahonen J, Eklund B, Höckerstedt K, Salmela K, Willebrand E von, Häyry P (1990) Renal allograft immunosuppression. II. A randomized trial of withdrawal of one drug in triple drug immunosuppression. Transplant Int 3:121–127
Klintmalm G, Bohman SO, Sundelin B, Wilczek H (1984) Interstitial fibrosis in renal allografts after 12 to 46 months of cyclosporin treatment: beneficial effect of low doses in early post-transplantation period. Lancet II:950–954
Lindgren PG, Frödin L, Larsson E, Tufveson G, Wahlberg J (1986) A new needle device for renal transplant biopsy. Transplant Proc 18:98–99
Mihatsch MJ, Thiel G, Basler V, Ryffel B, Landman J, Overbeck J von, Zollinger HU (1985) Morphological pattern in cyclosporine treated renal transplant recipients. Transplant Proc 17 [Suppl 1]:101–116
Morris PJ, Chapman JR, Allen RD, Ting A, Thompson JF, Dunnill MS, Wood RFM (1987) Cyclosporin conversion versus conventional immunosuppression: long-term follow-up and histological evaluation. Lancet I:586–591
Myers BD, Ross J, Newton L, Luetscher J, Perlroth M (1984) Cyclosporine associated chronic nephropathy. N Engl J Med 311:699–705
Myers BD, Sibley R, Newton L, Tomlanovich SJ, Boshkos C, Stinson E, Luetscher JA, Whitney DJ, Krasny D, Coplon NS, Perlroth MG (1988) Long-term course of cyclosporine associated chronic nephropathy. Kidney Int 33:590–600
Palestine AG, Austin HA III, Balow JE, Antonovych TT, Sabnis SG, Preuss HG, Nussenblatt RB (1986) Renal histopathologic alterations in patients treated with cyclosporine for uveitis. N Engl J Med 314:1293–1298
Salomon D, Brunson M, Van Sickler J, Pfaff W, Howard R, Peterson J, Curry T, Thompson R, Squiers E (1991) Retrospective analysis of late renal graft dysfunction: a correlation with mean cyclosporine levels and lack of evidence for chronic cyclosporine toxicity. Transplant Proc 23:1018–1019
Sanfilippo F (1990) Renal transplantation. In: Sale GE (ed) The pathology of organ transplantation. Butterworth, Stoneham, pp 51–101
Sibley RK, Rynasiewicz J, Ferguson RM, Fryd D, Sutherland DER, Simmons RL, Najarian JS (1983) Morphology of cyclosporine nephrotoxicity and acute rejection in patients immunosuppressed with cyclosporine and prednisone. Surgery 94:225–233
Taube DH, Neild GH, Williams DG, Cameron JS, Hartley B, Ogg CS, Rudge CJ, Welsh KI (1985) Differentiation between allograft rejection and cyclosporin nephrotoxicity in renal transplant recipients. Lancet II:171–174
Terasaki PI, Mickey MR, Cecka M, Cicciarelli J, Cook D, Iwaki Y, Toyotome A, Wang L (1987) Overview. In: Terasaki PI (ed) Clinical transplants. UCLA Tissue Typing Laboratory, Los Angeles, pp 467–498
Thiru S, Maher ER, Hamilton DV, Evans DB, Calne RY (1983) Tubular changes in renal transplantation recipients on cyclosporin. Transplant Proc 15:2846–2851
Versluis DJ, Kate FJW ten, Wenting GJ, Jeekel J, Weimar W (1988) Histological lesions associated with cyclosporin: incidence and reversibility in one year old kidney transplant. J Clin Pathol 41:498–503
Author information
Authors and Affiliations
About this article
Cite this article
Isoniemi, H., Krogerus, L., von Willebrand, E. et al. Renal allograft immunosuppression. Transplant Int 4, 151–156 (1991). https://doi.org/10.1007/BF00335336
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00335336