Fung, JJ

Mazariegos, GV

Ramos, H

Shapiro, R

Starzl, TE

Zeevi, A

English

PubMed

Name not available

Weaning of immunosuppression in long-term recipients of living related renal transplants: A preliminary study

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, , I ! Weaning of Immunosuppression in Long-Term Recipients of Living Related Renal Transplants: A Preliminary Study G.V. Mazariego5, H. Ramos, R. Shapiro, A. Zeevi, J.J. Fung, and T.E. Starzl A LTHOUGH renal transplantation continues to be associated with increasingly good short- and long-term graft survival, there remains a need for continued chronic immunosuppression and this can lead to significant complications. I - 3 This has prompted the evaluation of withdrawal or modification of immunosuppression by sev-eral investigators with varying results.4•5 Emerging data proposing dendritic cell migration and repopulation with chimerism following solid organ transplantation as the basis for graft acceptance have further encouraged evaluation of titrated withdrawal of immunosuppression in select groups of patients.6 - 8 The finding that donor-specific nonreactivity and chimerism occur simultaneously in long-term living related kidney recipients9 led us to evaluate withdrawal of immunosuppression in these patients. MATERIALS AND METHODS Eight long-term recipients of continuously functioning living re-lated renal allografts were weaned from immunosuppression. Three patients were noncompliant and had self-weaned their medications many years previously. Patient demographic data are listed in Table 1. An additional five patients were deliberately weaned from their immunosuppression according to the following criteria: the patients were recipients of living related kidneys, more than 5 years posttransplant, with at least 2 years of stable graft function. Baseline renal biopsy without evidence of rejection was required, as was a compliant medical history and complications related to immunosuppression. Immunologic reactivity was assessed when available by in vitro mixed lymphocyte reaction (MLR) and cell-mediated Iymphotox-ICily (CML). Unidirectional human MLR cultures used 5 x 104 responder and 5 x 104 irradiated stimulator (donor and third party) cells in tissue culture media supplemented with human serum. The degree of labeled thymidine incorporation during the final 20 hours of incubation determined proliferation. CML was assessed between recipient lymphocytes and donor and third-party targets by using effector lymphocytes incubated with Cr-Iabeled target cells at various effector:target ratios. Weaning proceeded in the following manner. Mter a baseline renal biopsy was obtained. prednisone was weaned to less than 5 mg/d. The ACfH stimulation test was used to assess for intact adrenocortical function. as these patients had been on steroids for many years. IO•11 Patients with an appropriate incremental increase in cortisol levels following stimulation with ACfH were weaned off prednisone completely. 12 The remaining immunosuppressant (aza-thioprine in all cases except case no. 8) was sequentially reduced by 50% at monthly intervals. Patient weight, urine output, blood urea nitrogen, and serum creatinine were followed on a monthly basis. RESULTS Baseline immunosuppression, donor relationship, serum creatinine before and after withdrawal of immunosuppres-sion, episodes of rejection, and time off immunosuppression are listed in Table 2. Renal biopsies obtained on patients 4 to 8 had minimal background infiltrate with no evidence of rejection. One patient developed mild acute cellular rejection diagnosed on biopsy at 5 months postweaning and was treated with pulse steroids and a return to baseline therapy. His creati-nine immediately returned to normal. One patient is still in the process of being weaned; to date, her immunosuppres-sion has been decreased by 75% without any untoward effect. Current time off immunosuppression for the remain-ing six patients ranges from 3 months to 29 years (mean = 12.4 years). One patient is on maintenance steroids (5 mgld prednisone) because of adrenal insufficiency. Donor-specific reactivity by MLR in patients 3, 4, and 5 was unresponsive when initially evaluated for weaning of From the Pittsburgh Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania. Address correspondence to George V. Mazariegos, MD, Falk Clinic, 4th Floor, 3601 Fifth Ave, Pittsburgh, PA 15213. © 1995 by Appleton & Lange 0041-1345/95/$3.001 +0 Table 1. Patient Demographic Data Patient No. Age Sex Ox 1. KP 52 M Chronic glomerulonephritis (GN) 2.5M 45 F Chronic GN 3. IN 62 M Chronic GN 4.JW 49 M Chronic GN 5. OS 45 F Pyelonephritis 6. LN 52 M Chronic GN 7.55 37 F Pyelonephritis 8 .• IK 50 M Renal agenesis -SCCalDJD hIP. squamous cell cancer/degenerative joint disease of hip. Transplantation Proceedings. Vol 27, No 1 (February). 1995: pp 207-209 Date of LRRT 219/63 2117/64 1/15164 7/10/64 7/19/62 7/29/66 5/10n8 2/25/87 Complications Related to Immunosuppression SCCalDJD hip Verrucous warts Obesity, hypertension. verrucous warts HypertenSion. verrucous warts Basal celi carcinoma. verrucous warts 207 208 MAZARIEGOS, RAMOS, SHAPIRO ET AL Table 2. E1fect of Weaning Immunosuppression on Renal Function Baseline Immunosuppression Patient No. (mgld) Great. Pre/Post 1 Azathioprine (AZA) 0.7/0.9 2 Pred 15 AZA 25 1.0/1.1 3 AZA 0.8/0.9 4 AZA 125/pred 10 1.6/1. 5 AZA 75 0.8/0.7 6 AZA 100/pred 10 0.9/0.9 7 AZA 75/pred 10 1.411.0 8 AZA5 1.0/3.4-1.2 7.5 pred <CyA 50 "Maintenance steroids 5/d prednisone (pred) for adrenal cortical insufficiency. immunosuppression. Repeat MLR in patients 4 and 5 now show a significant response (Fig 1). These patients have remained off immunosuppression for 1 and 2 years, respec-tively, and have normal serum creatinines. The MLR of patient 3 would be expected to remain unresponsive, as he is a double haplotype match. CML activity remains absent in patients 3, 4, and 5 (Table 3). Skin lesions were a prominent complication in these EFFECT OF WEANING IMMUNOSUPPRESSION ON DONOR·SPECIFIC MLR i 40000 .. PATIENT 4 Cd. On. class II HLA·OR Match <II w <II Z 0 .. <II III Ir 20000 w > ;::: C Ir W u. ::; 0 Ir .. 0 Before After l 50000 PATIENT 5 Cd. One haplotype match <II w II> Z 0 .. II> ~ 25000 III > ;::: C Ir u.o ~ .... 0 a: 0 .. Before After tf~eaoAtAi OF IMMUNOSUPPRESSION Fig 1. Effect of weaning immunosuppression on donor-specific MLR. T. P. = third party cells. Rejection Time Off Drug (y) No 29 No 148 No 28 No 2 No No Still weaning; doses decreased by 75% No 3 months Yes 5 months (then restarted) long-term recipients. One patient had metastatic squamous cell cancer. Four others had disfiguring verrucous warts. Patients 4 to 7 have had dramatic improvement of their verrucous lesions. Patient 4 had successful surgical therapy for his metastatic squamous cell lesion. DISCUSSION Long-term survival following renal transplantation has been previously reported. 13 Multiple drug immunosuppressive therapy based on steroids and azathioprine was found to prevent or treat renal allograft rejection in the early clinical experience. 14.IS The addition of cyclosporine (CyA) to the immunosuppressive regimen significantly improved graft survival. 16 The risks of chronic immunosuppression have been well described,17 and include opportunistic infection and neo-plasia. 18•19 Less life-threatening but equally disabling se-quelae of immunosuppression such as steroid-related weight gain, edema, growth retardation, and osteopenia have also had significant morbidity.10 CyA-related nephro-toxicity and hypertension have also been described exten-sively.17 The benefits of withdrawal of immunosuppression21.22 must be weighed against the dangers of graft rejection and loss. Our data suggest that weaning of immunosuppression can be carried out in a select group of patients. Only one patient has demonstrated rejection during weaning of im-munosuppression. Absolute or relative donor-specific unre-sponsiveness with MLR prior to weaning was shown in three patients available for study who maintained normal renal function after weaning. Patients 4 and 5 have had return of antidonor reactivity on MLR but not CML; clinically, they have had no evidence of rejection. The recovery of MLR in the absence of cytotoxic effector cells is under investigation. The study remains preliminary and the enrolled patient number is small. It is known that serum creatinine is not completely accurate as an assessment of renal function. Studies using creatinine clearance or glomerular filtration will be more conclusive. We continue to follow up these WEANING OF IMMUNOSUPPRESSION 209 Table 3. MLR and CML Data Patient No. Donor Haplotype Match MLR CML 1 Fraternal twin Double Not available (N/A) NlA 2 Father Single NlA 3 Sister Double Unresponsive 4 Aunt No haplotype; one class II match Unresponsive -+ responsive N/A Nonresponsive Nonresponsive Nonresponsive N/A 5 Mother Single 6 Brother Single 7 Brother Single 8 Sister Single patients as well as consider additional suitable patients for withdrawal of immunosuppression. CONCLUSION How to safely wean immunosuppression in kidney recipi-ents is still unknown. The kidney is known to be susceptible to rapid rejection from preformed antibodies. whereas the liver. for example. has been said to be tolerogenic.23 We have postulated that the critical difference may be the leukocyte component of the organ, thus explaining why the leukocyte-poor kidney is less likely to be tolerogenic. Thus, weaning is expected to be more dangerous for kidney than for liver recipients and should not be recommended except for disabling or life-threatening indications. Therapies to augment cell migration with infusion of donor bone marrow at the time of solid organ transplantation are a strategy to balance cell traffic in the direction of graft acceptance,24 and these are expected to increase the eventual possibility of achieving a drug-free state. CyA may be safely withdrawn from recipients of HLA identical living related grafts after a year of stable graft function,S yet others report lack of predictive immunologic parameters in this same "good risk" category of patients.2S Our data suggest that some recipients of living related HLA nonidentical grafts may be able to discontinue immunosuppression. The clinical "tol-erance" exhibited here may be explained by the leukocyte microchimerism previously demonstrated. An attempt at complete weaning may be indicated in long-term survivors of living related kidney grafts, especially in those with significant complications, but close monitoring of renal function is required and long-term results are unknown. REFERENCES 1. Starzl TE. Schroler GPJ. Hartmann NJ. et ai: Transplant Proc :!2: 2361. 1990 2. Burke JF Jr. Pirsh JD. Ramos E. et ai: N Engl J Med 331:358. 1994 Unresponsive -+ responsive NlA N/A N/A N/A N/A 3. Suthanthiran M, Strom TB: N Engl J Med 331:365, 1994 4. Kasiske BL, Heim-Duthoy K, Ma JZ: JAMA 269:395,1993 5. Luke RG: N Eng! J Med 331:393, 1994 6. Starzl TE, Demetris AJ, Trucco M, et al: Hepatology 17:1127, 1993 7. Steinman RM. Inaba K, Aosten JM: Hepatology 17:1153, 1993 8. Ramos HC, Reyes J, Abu-Elmagd K, et al: Transplantation (in press) 9. Starzl TE, Demetris AJ, Trucco M, et al: Transplantation 55:1272, 1993 10. Kenlet H, Binder C: Br Med J 2:147, 1973 11. Wood JB, James VHT. Franckland A W, et al: Lancet. 243, 1965 12. Bynny RL: N Engl J Med 295:30, 1976 13. Lee HM. Posner MP. King AL, et al: Transplant Proc 25:1336, 1993 14. Starzl TE. Marchioro TL. Waddell WR: Surg Gynecol Obstet 117:385. 1963 15. Starzl TE: Experience in Renal Transplantation. Philadel-phia: WB Saunders, 1964 16. The Canadian Multi-center Transplant Group: N Eng! J Med 314:1219, 1986 17. Fabrega AJ, Lopez-Boado M, Gonzalez S: Crit Care Clin 6:979,1990 18. Dunn DL: Crit Care Clin 6:955, 1990 19. Sheil AGR, Disney APS. Mathew TH. et al: Transplant Proc 25:1383, 1993 20. Julian BA, Laskow DA, Dubovsky J, et al: N Engl J Med 325:544. 1991 21. Ignulli E, Tejani A, Markell M: Transplantation 55:1029, 1993 22. Ratcliffe PJ. Firth JD, Higgins RM. et al: Transplant Proc 25:590, 1993 23. Starzl TE: Transplant Proc 25:8, 1993 24. Fontes p, Rao AS. Demetris AJ. et al: Lancet 344:151.1994 25. Burke GW. Allouch M. Cirocco R. et al: Transplantation 57:750. 1993 

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Weaning of immunosuppression in long-term recipients of living related renal transplants: A preliminary study

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