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Immunologic Risks of Combined Kidney–Pancreas Transplantation
Immunologic Risks of Combined Kidney–Pancreas Transplantation J.S. Odorico, S.C. Rayhill, D.M. Heisey, S.J. Knechtle, A.M. D’Alessandro, J.D. Pirsch, and H.W. Sollinger
W
HETHER young diabetics with end-stage renal disease should be referred for a living related donor (LRD) transplant, a cadaver kidney transplant (CAD), or a simultaneous pancreas– kidney transplant (SPK) is frequently debated. To address this question, it is important to ascertain the level of additional risk a pancreas transplant confers on the simultaneously transplanted kidney. Surgical and post-surgical infectious risks are considered greater for SPK recipients; it is controversial whether this group suffers more immunologic risk as a result of a second organ transplant from the same donor. Several studies have suggested that there is a greater risk of rejection in diabetic recipients of SPK transplants than those who undergo kidney transplantation alone.1 Douzdjian et al.2 compared rates of rejection and renal allograft outcome in SPK versus kidney-alone transplants in diabetic patients. Although acute rejection was more frequent in the SPK group than the kidney-alone group (41% versus 16%), renal graft survival (when censored for death) was no different between the two groups. Interestingly, although graft survival was lower in those kidney-alone diabetic recipients who experienced a combination of acute rejection and delayed graft function, this was not the case in SPK recipients. Interpretation of the results of this study, however, is confounded by the fact that a mixed group of kidney transplants (LRD and CAD) were included in the kidneyalone group, and results were not stratified for immunologic and nonimmunologic causes of graft loss. To determine whether performance of a concomitant pancreas transplant in a CAD recipient confers additional immunologic risk, we compared patient and kidney graft survival (overall, censored for death, immunologic and nonimmunologic) between SPK recipients and diabetic recipients of a cadaver renal allograft at a single institution. METHODS Between 1986 and 1995, 375 consecutive SPK transplants and 259 primary CAD transplants were performed in diabetic recipients. Induction immunosuppression was similar in both groups consisting of a 10 to 14 day course of OKT3, ALG or ATG, delayed initiation of cyclosporine (CsA), azathioprine (AZA), and prednisone. The only exception is that a small subset of CAD recipients received MMF instead of AZA. Renal allograft rejection by biopsy confirmed in 95% of cases, and graft failure assigned upon return to dialysis. Because SPK recipients are generally younger than © 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 30, 249–250 (1998)
diabetic CAD recipients, an age-matched analysis was performed. In addition, SPK transplants were compared to a more closely age-matched group of 69 diabetic one-haplotype-match LRD (hLRD) transplants and 39 diabetic HLA-identical LRD (iLRD) transplants from the same time period. The hLRD recipients received antibody induction immunotherapy, while iLRD recipients did not and subsequently were withdrawn from steroids. Renal allograft survival was determined for each group as follows: overall; overall with censoring for death; based on immunologic causes of graft loss (acute, chronic, and accelerated rejection); and based on nonimmunologic causes (infection, malignancy, vascular, patient death, etc). Discharge creatinine and the incidence and timing of first rejection episode between the groups was compared as well. Kaplan–Meier product limit method was used to compare survivals and times to first rejection. No attempt was made to HLA match recipient to donor for SPK transplants.
RESULTS
SPK recipients demonstrated improved patient and overall kidney graft survival when compared to their age-matched CAD counterparts (88% versus 72%, P 5 .01 and 78% versus 65%, P 5 .08, respectively) (Table 1). When immunologic causes of graft loss were separated from other causes of graft loss (ie, death with a functioning graft [DWFG] and non-immunologic causes), there was no difference in immunologic graft survival between CAD and SPK recipients. In fact, only when comparing nonimmunologic causes of graft loss was there a difference in kidney graft survival, indicating that DWFG contributed significantly to the poorer long-term kidney graft survival in the CAD group. Thus, the majority of the kidney graft and patient survival benefit seen in our age-matched cohort of SPK recipients was probably due to their overall better health. Only iLRD transplants, but not hLRD transplants, demonstrated better immunologic and overall five-year renal graft survival than SPK transplants, but this was not statistically significant (Table 2). Compared with CAD recipients, SPK recipients exhibited a significantly increased incidence of rejection episodes within the first year postFrom the University of Wisconsin Hospitals and Clinics, Madison, Wisconsin, USA. Address reprint requests to Jon S. Odorico, MD, Assistant Professor of Surgery, University of Wisconsin Hospital & Clinics, G4/701 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792. 0041-1345/98/$19.00 PII S0041-1345(97)01246-3 249
250
ODORICO, RAYHILL, HEISEY ET AL Table 1. Comparison of Results of Primary SPK and CAD Transplants in Diabetic Recipients From 1986 to 1995: Age-Matched by Decade Paired Analysis 5-Year Kidney Graft Survival Group
n
Overall
Overall DWFG
SPK CAD Log Rank Test, P
375 259
78% 65% 0.08
84% 82% NS
Immunologic
86% 85% NS
Nonimmunologic
5-Year Patient Survival
Incidence of Kidney Rejection at 1 Year
Discharge Creatinine (mg/dL)
90% 76% 0.06
88% 72% 0.01
77% 48% 0.001
1.7 6 .7 1.6 6 .5 NS
Abbreviations: CAD, cadaver kidney transplant; DWFG, death with a functioning graft; SPK, simultaneous kidney–pancreas transplant.
DISCUSSION
transplant. However, an increased risk of rejection did not predict an increased risk of immunologic graft loss. This may be because in contrast to CAD recipients who had occasional late rejection episodes (.1 year), late rejection episodes in SPK recipients were relatively rare. Discharge creatinine was no different between the two groups. The causes of 41 deaths in the SPK group (11% of patients) were cardiac (10), infection (8), cerebrovascular accident (CVA) (3), pulmonary embolism (PE) (2), malignancy (5), withdrawal from dialysis (3), and other (10), whereas the causes of 75 deaths in the CAD group (29% of patients) were cardiac (29), infection (12), CVA (7), PE (1), malignancy (2), withdrawal from dialysis (2), and other (20).
Table 2. Comparison of Results of Primary HLA-Identical LRD, Haplotype-Matched LRD and SPK Transplants in Diabetic Recipients From 1986 to 1995 5-Year Kidney Graft Survival Group
n
Overall (%)
Immunologic (%)
SPK hLRD iLRD
375 69 39
78 75 86
86 83 92
Abbreviations: hLRD, one-haplotype match LRD; iLRD, HLA-identical LRD; LRD, living-related donor; SPK, simultaneous pancreas– kidney transplant.
Despite a greater risk of early rejection following SPK transplantation, age-matched SPK recipients enjoy better patient and overall graft survival than their CAD counterparts. This is due primarily to the poorer general health of CAD diabetic recipients. When compared to a healthier and younger age-matched group of hLRD recipients, SPK transplants fared equally well, suggesting the combined procedure affords very little increase in immunologic risk over the kidney transplant alone. This study does not directly address the possibility that SPK kidneys fare better long-term than CAD kidneys because of generally shorter cold ischemic times and younger donors. If these were major factors in improved long-term graft survival seen in SPK recipients, then one would expect to see worse discharge creatinines in CAD recipients. This was not the case in our study population. Only iLRD transplants had better overall and immunologic graft survival than SPK transplants. In summary, simultaneous transplantation of a cadaver pancreas, in addition to a cadaver kidney in diabetics does not appear to add to the risk of immunologic renal graft loss after transplantation. Thus, SPK transplantation should be considered in all young uremic diabetic patients. REFERENCES 1. Cantarovich D, Giral M, Josien R, et al: Transplant Proc 27:1319, 1995 2. Douzdjian V, Rice JC, Gugliuzza KK, et al: Am J Kidney Dis 27:106, 1996
W
HETHER young diabetics with end-stage renal disease should be referred for a living related donor (LRD) transplant, a cadaver kidney transplant (CAD), or a simultaneous pancreas– kidney transplant (SPK) is frequently debated. To address this question, it is important to ascertain the level of additional risk a pancreas transplant confers on the simultaneously transplanted kidney. Surgical and post-surgical infectious risks are considered greater for SPK recipients; it is controversial whether this group suffers more immunologic risk as a result of a second organ transplant from the same donor. Several studies have suggested that there is a greater risk of rejection in diabetic recipients of SPK transplants than those who undergo kidney transplantation alone.1 Douzdjian et al.2 compared rates of rejection and renal allograft outcome in SPK versus kidney-alone transplants in diabetic patients. Although acute rejection was more frequent in the SPK group than the kidney-alone group (41% versus 16%), renal graft survival (when censored for death) was no different between the two groups. Interestingly, although graft survival was lower in those kidney-alone diabetic recipients who experienced a combination of acute rejection and delayed graft function, this was not the case in SPK recipients. Interpretation of the results of this study, however, is confounded by the fact that a mixed group of kidney transplants (LRD and CAD) were included in the kidneyalone group, and results were not stratified for immunologic and nonimmunologic causes of graft loss. To determine whether performance of a concomitant pancreas transplant in a CAD recipient confers additional immunologic risk, we compared patient and kidney graft survival (overall, censored for death, immunologic and nonimmunologic) between SPK recipients and diabetic recipients of a cadaver renal allograft at a single institution. METHODS Between 1986 and 1995, 375 consecutive SPK transplants and 259 primary CAD transplants were performed in diabetic recipients. Induction immunosuppression was similar in both groups consisting of a 10 to 14 day course of OKT3, ALG or ATG, delayed initiation of cyclosporine (CsA), azathioprine (AZA), and prednisone. The only exception is that a small subset of CAD recipients received MMF instead of AZA. Renal allograft rejection by biopsy confirmed in 95% of cases, and graft failure assigned upon return to dialysis. Because SPK recipients are generally younger than © 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 30, 249–250 (1998)
diabetic CAD recipients, an age-matched analysis was performed. In addition, SPK transplants were compared to a more closely age-matched group of 69 diabetic one-haplotype-match LRD (hLRD) transplants and 39 diabetic HLA-identical LRD (iLRD) transplants from the same time period. The hLRD recipients received antibody induction immunotherapy, while iLRD recipients did not and subsequently were withdrawn from steroids. Renal allograft survival was determined for each group as follows: overall; overall with censoring for death; based on immunologic causes of graft loss (acute, chronic, and accelerated rejection); and based on nonimmunologic causes (infection, malignancy, vascular, patient death, etc). Discharge creatinine and the incidence and timing of first rejection episode between the groups was compared as well. Kaplan–Meier product limit method was used to compare survivals and times to first rejection. No attempt was made to HLA match recipient to donor for SPK transplants.
RESULTS
SPK recipients demonstrated improved patient and overall kidney graft survival when compared to their age-matched CAD counterparts (88% versus 72%, P 5 .01 and 78% versus 65%, P 5 .08, respectively) (Table 1). When immunologic causes of graft loss were separated from other causes of graft loss (ie, death with a functioning graft [DWFG] and non-immunologic causes), there was no difference in immunologic graft survival between CAD and SPK recipients. In fact, only when comparing nonimmunologic causes of graft loss was there a difference in kidney graft survival, indicating that DWFG contributed significantly to the poorer long-term kidney graft survival in the CAD group. Thus, the majority of the kidney graft and patient survival benefit seen in our age-matched cohort of SPK recipients was probably due to their overall better health. Only iLRD transplants, but not hLRD transplants, demonstrated better immunologic and overall five-year renal graft survival than SPK transplants, but this was not statistically significant (Table 2). Compared with CAD recipients, SPK recipients exhibited a significantly increased incidence of rejection episodes within the first year postFrom the University of Wisconsin Hospitals and Clinics, Madison, Wisconsin, USA. Address reprint requests to Jon S. Odorico, MD, Assistant Professor of Surgery, University of Wisconsin Hospital & Clinics, G4/701 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792. 0041-1345/98/$19.00 PII S0041-1345(97)01246-3 249
250
ODORICO, RAYHILL, HEISEY ET AL Table 1. Comparison of Results of Primary SPK and CAD Transplants in Diabetic Recipients From 1986 to 1995: Age-Matched by Decade Paired Analysis 5-Year Kidney Graft Survival Group
n
Overall
Overall DWFG
SPK CAD Log Rank Test, P
375 259
78% 65% 0.08
84% 82% NS
Immunologic
86% 85% NS
Nonimmunologic
5-Year Patient Survival
Incidence of Kidney Rejection at 1 Year
Discharge Creatinine (mg/dL)
90% 76% 0.06
88% 72% 0.01
77% 48% 0.001
1.7 6 .7 1.6 6 .5 NS
Abbreviations: CAD, cadaver kidney transplant; DWFG, death with a functioning graft; SPK, simultaneous kidney–pancreas transplant.
DISCUSSION
transplant. However, an increased risk of rejection did not predict an increased risk of immunologic graft loss. This may be because in contrast to CAD recipients who had occasional late rejection episodes (.1 year), late rejection episodes in SPK recipients were relatively rare. Discharge creatinine was no different between the two groups. The causes of 41 deaths in the SPK group (11% of patients) were cardiac (10), infection (8), cerebrovascular accident (CVA) (3), pulmonary embolism (PE) (2), malignancy (5), withdrawal from dialysis (3), and other (10), whereas the causes of 75 deaths in the CAD group (29% of patients) were cardiac (29), infection (12), CVA (7), PE (1), malignancy (2), withdrawal from dialysis (2), and other (20).
Table 2. Comparison of Results of Primary HLA-Identical LRD, Haplotype-Matched LRD and SPK Transplants in Diabetic Recipients From 1986 to 1995 5-Year Kidney Graft Survival Group
n
Overall (%)
Immunologic (%)
SPK hLRD iLRD
375 69 39
78 75 86
86 83 92
Abbreviations: hLRD, one-haplotype match LRD; iLRD, HLA-identical LRD; LRD, living-related donor; SPK, simultaneous pancreas– kidney transplant.
Despite a greater risk of early rejection following SPK transplantation, age-matched SPK recipients enjoy better patient and overall graft survival than their CAD counterparts. This is due primarily to the poorer general health of CAD diabetic recipients. When compared to a healthier and younger age-matched group of hLRD recipients, SPK transplants fared equally well, suggesting the combined procedure affords very little increase in immunologic risk over the kidney transplant alone. This study does not directly address the possibility that SPK kidneys fare better long-term than CAD kidneys because of generally shorter cold ischemic times and younger donors. If these were major factors in improved long-term graft survival seen in SPK recipients, then one would expect to see worse discharge creatinines in CAD recipients. This was not the case in our study population. Only iLRD transplants had better overall and immunologic graft survival than SPK transplants. In summary, simultaneous transplantation of a cadaver pancreas, in addition to a cadaver kidney in diabetics does not appear to add to the risk of immunologic renal graft loss after transplantation. Thus, SPK transplantation should be considered in all young uremic diabetic patients. REFERENCES 1. Cantarovich D, Giral M, Josien R, et al: Transplant Proc 27:1319, 1995 2. Douzdjian V, Rice JC, Gugliuzza KK, et al: Am J Kidney Dis 27:106, 1996