- Email: [email protected]
Eligibility of diabetic patients receiving dialysis for islet after kidney transplantation
Eligibility of Diabetic Patients Receiving Dialysis for Islet After Kidney Transplantation M.C. Vantyghem, F. Pattou, C. Girardot, B. Soudan, M. Hazzan, and C. Noel
ABSTRACT Introduction. The aim of this study was to assess the selection of candidates among 38 dialyzed diabetic patients referred between January 1, 1998 and December 31 2002 for kidney followed by islet transplantation (IAK). The main criteria of eligibility for possible IAK were as follows: (1) plasma C-peptide negative; (2) need for a kidney graft; (3) kidney plus whole pancreas transplantation not desired by the patient; and (4) acceptable results of postkidney graft preislet transplantation evaluation. Results. Seventeen of 38 patients with positive C-p diabetes received a kidney graft alone. Among the 21 C-p–negative diabetic patients, 3 were not eligible for kidney transplantation mainly for psychological reasons and 4 were eligible for kidney plus pancreas transplantation. The remaining 14 C-p–negative patients underwent kidney transplantation or had previously undergone kidney transplantation. Among them, 1 had moved away, 1 refused IAK, one had slightly positive stimulation tests, 1 was overweight, 1 had breast cancer, and 1 had postkidney graft complications. Among the remaining 8 of 14 C-p–negative, kidney-engrafted patients listed for IAK, 5 have undergone transplantation, 3 with a pre-Edmonton and 2 with the Edmonton protocol. Conclusion. In conclusion among this series of 38 diabetic patients undergoing dialysis, more than 90% were kidney-grafted. Approximately 50% were ineligible for pancreas transplantation or IAK because of a positive C-p, and 20% were enlisted for IAK. These results highlight the importance of C-p determinations in diabetic dialysis patients to identify eligible patients for pancreas transplantation or IAK.
A
FTER 3 decades of controversy, pancreas transplantation has become accepted as the preferred treatment for patients with insulin-dependent diabetes mellitus.1–3 The current 1-year actuarial patient, kidney, and pancreas graft survival rates are 95%, 92%, and 84%, respectively.4,5 Nevertheless, the procedure is still associated with significant morbidity in terms of surgical risk and cost. Since the Edmonton protocol, islet transplantation offers the prospect of accurate glycemic control with no major surgical risk.6 –9 Although this protocol was tested as isolated islet transplants in type 1 diabetics without kidney failure, its application in type 1 diabetic patients with immunosuppressive treatment already required for kidney transplantation seems especially justified.10 The aim of this study was to assess the selection of dialysis patients eligible for kidney followed by islet transplantation.
PATIENTS Between January 1998 and December 2002, the 38 dialyzed diabetic patients referred for evaluation included 18 women and 20 men of age range 20 to 67 years and weight range 43 to 127 kg. The
From the Endocrinology and Metabolism Department (M.C.V., C.G.), Department of Endocrine Surgery (F.P.), Laboratory of Endocrinology (B.S.), , Nephrology Department (M.H., C.N.), and INSERM ERIT 0106 (M.C.V., F.P.), Lille University Hospital, Lille, France. This article was supported by a grant from the Hospital Project for Clinical Research (PHRC). Address reprint requests to M.C. Vantyghem, Endocrinology and Metabolism Department, 6, rue du Professeur Laguesse, Centre Hospitalo-Universitaire, 59037 Lille Cedex, France. Email: [email protected]
© 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.04.030
Transplantation Proceedings, 36, 1103–1105 (2004)
1103
1104
VANTYGHEM, PATTOU, GIRARDOT ET AL
Fig 1.
Flowchart of the results. Abbreviation: TX, transplantation.
main criteria of eligibility for possible islet transplantation were as follows: (1) Absence of plasma C-peptide (C-p); (2) need for a kidney graft; (3) patient refusal of kidney plus whole pancreas transplantation, knowing that this surgical procedure required transfer to a distant center with a long waiting list; and (4) acceptable results of post– kidney graft preislet transplantation evaluation, including clinical and especially vascular reassessment and C-p stimulation tests.
METHODS C-p Measurement Fasting serum C-p concentrations were measured with a commercial radioimmunoassay kit and expressed in ng/mL (RIA-coat C-peptide, Mallinckrodt, France). The detection threshold was 0.2 ng/mL.
Protocol of C-p Stimulation Tests Fasting and postprandial C-p. C-p levels were measured after 12 hours of fasting and 2 hours after breakfast. Standardized meal stimulation test. The standardized meal included carbohydrates (50 g), proteins (22 g), and lipids (9 g) in a highly energetic drink. Samples were drawn at 0 and 90 minutes. Arginine stimulation test. Five grams of arginine (Arginine, Veyron Laboratories, France) were infused intravenously. Samples were drawn at 0, 3, and 5 minutes.
undergone transplantation with secondary pancreatic failure but a functional kidney, and 2 are still on the waiting list. The remaining 14 (37%) underwent kidney transplantation, among whom 8 (21%) were eligible for islet after kidney transplantation (IAK) and 6 (16%) were ineligible. The reasons for their ineligibility were: 1 patient had moved away; 1 refused islet transplantation; 1 had negative basal C-p but slightly positive stimulation tests; 1 was overweight (102 kg); breast cancer was discovered in 1 patient 6 months after kidney transplantation despite negative pre– kidney graft screening; and 1 had post– kidney graft complications with an elevated creatinine level ⬎20 mg/L (N ⬍ 10). Among the remaining 8 of 14 C-p–negative kidney engrafted patients listed for islet transplantation 3 were transplanted with a pre-Edmonton immunosuppressive regimen and secondary islet failure and 5 were listed for an Edmonton-like protocol. Two of these patients have completed 2 or 3 islet transplantations and have subsequently discontinued insulin. During the survey period and among the 14 kidney transplant patients, 2 patients died of sudden stroke, 1 of whom died 3 years after islet transplantation that had been functional for only 3 months, and the other 1 2 years after kidney transplantation that had been removed because of breast cancer. DISCUSSION
RESULTS
The results were as follows (Fig 1): 17 of 38 (46%) with positive C-p diabetes received a kidney graft alone. Among the remaining 21 C-p–negative diabetic patients (54%), 3 (8%) were ineligible for kidney graft mainly for psychological reasons and 18 (47%) were eligible for kidney transplantation. Among these 18 patients, 4 (10%) were listed for kidney plus pancreas transplantation, 2 of whom had
Epidemiological studies have shown a dramatic incidence of diabetes among dialysis patients.11 Distinguishing type 1 from type 2 diabetes mellitus in this population is not so simple. Indeed, an increasing number of type 2 diabetics require insulin because of relative insulinopenia. Moreover nowadays, type 2 diabetes has an earlier onset because of the increasing prevalence of obesity. Also, approximately 20% of type 1 diabetes are of late-onset. In the Edmonton
DIABETIC PATIENTS AND IAK
protocol, one of the main criteria of eligibility was undetectable levels of C-p, to assess the efficiency of islet transplantation by measuring C-p, as an indication of islet function, as well as a decreased insulin need. Although nephrologists consider that C-p is a poor marker of the type 2 diabetes phenotype,12 a previous study has shown that C-p levels in end-stage renal disease significantly correlated with age at the time of diagnosis of diabetes, maximal body mass index, and delay between diagnosis and consistent insulin use. According to this same study, the prediction was better when performed by a diabetologist than by a nephrologist.13 Therefore, C-p measurements have been validated to select patients eligible for islet or pancreas transplantation rather than clinical or therapeutic criteria, such as a need for insulin, because it is a quantitative, easy-to-use parameter. Nevertheless, stimulation tests with either glucose or arginine are still justified on account of the difficulty to detect borderline values of plasma C-p and/or the lack of sensitivity of the assay in the low range. Once C-p–negative patients have been identified, the next step is to choose between kidney plus islet versus pancreas transplantation, or kidney grafting alone with optimized insulin therapy. Recent studies have shown that outcomes of islet transplantation can compare with pancreas transplantation in terms of improvement of diabetic complications.9 Therefore, the pending question is which transplantation for which C-p– negative patient? The answer probably depends on several factors: the type of complication, namely severe macroangiopathy pointing preferentially to islet transplantation, the local organization versus the necessity to be transplanted in a distant center often being a burden to these sometimes severely disabled patients, the local availability of a pancreas and/or an islet isolation team, the long-term results of islet transplantation by comparison with pancreas transplantation, and the optimized insulin therapy, especially with an ambulatory pump. In conclusion, among this series of 38 diabetic dialysis patients more than 90% were eligible for a kidney graft. Nearly 50% were ineligible for a pancreas or an islet transplantation because of a positive C-p. Approximately 20% were eligible for islet transplantation. These results suggest the importance of C-p determinations in diabetic
1105
patients during hemodialysis to identify patients eligible for pancreas or islet transplantation. REFERENCES 1. Bohman SO, Tyden G, Wilczek H, et al: Prevention of kidney graft diabetic nephropathy by pancreas transplantation in man. Diabetes 34:306, 1985 2. Fioretto P, Steffes MW, Sutherland D, Goetz FC, Mauer M, et al: Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 339:69, 1998 3. Jukema JW, Smets YFC, Van der Piji JW, et al: Impact of simultaneous pancreas and kidney transplantation on progression of coronary atherosclerosis in patients with end-stage renal failure due to type 1 diabetes. Diabetes Care 25:906, 2002 4. Gruessner AC, Sutherland DE: Analysis of United States and non-US pancreas transplantation reported to the United Network for Organ Sharing at the international pancreas transplant registry as of October 2001. Clin Transpl :41, 2001 5. Bunnapradist S, Cho YW, Cecka JM, et al: Kidney allograft and patient survival in type 1 diabetic recipients of cadaveric kidney alone and simultaneous pancreas/kidney transplants: a multivariate analysis of the UNOS database. J Am Soc Nephrol 14:208, 2003 6. Shapiro AM, Lakey JRT, Ryan EA, et al: Islet transplantation in seven patients with type 1 diabetes. N Engl J Med 34:230, 2000 7. Ryan EA, Lakey JR, Paty BW, et al: Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes 51:2148, 2002 8. Pattou F, Vantyghem MC, Noel C, et al: Sequential intraportal islet allografts in immunosuppressed type 1 diabetic patients: preliminary results. Transplant Proc 32:391, 2000 9. Fioretto P, Folli F, Maffi P, et al: Islet transplantation improves vascular diabetic complications in patients with diabetes who underwent kidney transplantation: a comparison between kidney-pancreas and kidney-alone transplantation. Transplantation 75:1296, 2003 10. Lehmann R, Weber M, Zullig R, et al: Islet graft and kidney function in combined islet-kidney transplantation under a glucocorticoid free immunosuppressive regimen. 22nd Workshop of the AIDSPIT Study Group Igls, Austria, January 24, 2003 11. Halimi S, Zmirou D, Benhamou PY, et al: Huge progression of diabetes prevalence and incidence among dialysed patients in mainland France and overseas French territories. A second national survey six years apart (Uremidiab 2 study). Diab Metab 2:507, 1999 12. Covic AM, Schelling JR, Constantiner M, et al: Serum C-peptide concentrations poorly phenotype type 2 diabetic endstage renal disease patients. Kidney Int 58:1742, 2000 13. Benhamou PY, Marwah T, Balducci F, et al: Classification of diabetes in patients with end-stage renal disease. Validation of clinical criteria according to fasting plasma C-peptide. Clin Neprol 38:239, 1992
ABSTRACT Introduction. The aim of this study was to assess the selection of candidates among 38 dialyzed diabetic patients referred between January 1, 1998 and December 31 2002 for kidney followed by islet transplantation (IAK). The main criteria of eligibility for possible IAK were as follows: (1) plasma C-peptide negative; (2) need for a kidney graft; (3) kidney plus whole pancreas transplantation not desired by the patient; and (4) acceptable results of postkidney graft preislet transplantation evaluation. Results. Seventeen of 38 patients with positive C-p diabetes received a kidney graft alone. Among the 21 C-p–negative diabetic patients, 3 were not eligible for kidney transplantation mainly for psychological reasons and 4 were eligible for kidney plus pancreas transplantation. The remaining 14 C-p–negative patients underwent kidney transplantation or had previously undergone kidney transplantation. Among them, 1 had moved away, 1 refused IAK, one had slightly positive stimulation tests, 1 was overweight, 1 had breast cancer, and 1 had postkidney graft complications. Among the remaining 8 of 14 C-p–negative, kidney-engrafted patients listed for IAK, 5 have undergone transplantation, 3 with a pre-Edmonton and 2 with the Edmonton protocol. Conclusion. In conclusion among this series of 38 diabetic patients undergoing dialysis, more than 90% were kidney-grafted. Approximately 50% were ineligible for pancreas transplantation or IAK because of a positive C-p, and 20% were enlisted for IAK. These results highlight the importance of C-p determinations in diabetic dialysis patients to identify eligible patients for pancreas transplantation or IAK.
A
FTER 3 decades of controversy, pancreas transplantation has become accepted as the preferred treatment for patients with insulin-dependent diabetes mellitus.1–3 The current 1-year actuarial patient, kidney, and pancreas graft survival rates are 95%, 92%, and 84%, respectively.4,5 Nevertheless, the procedure is still associated with significant morbidity in terms of surgical risk and cost. Since the Edmonton protocol, islet transplantation offers the prospect of accurate glycemic control with no major surgical risk.6 –9 Although this protocol was tested as isolated islet transplants in type 1 diabetics without kidney failure, its application in type 1 diabetic patients with immunosuppressive treatment already required for kidney transplantation seems especially justified.10 The aim of this study was to assess the selection of dialysis patients eligible for kidney followed by islet transplantation.
PATIENTS Between January 1998 and December 2002, the 38 dialyzed diabetic patients referred for evaluation included 18 women and 20 men of age range 20 to 67 years and weight range 43 to 127 kg. The
From the Endocrinology and Metabolism Department (M.C.V., C.G.), Department of Endocrine Surgery (F.P.), Laboratory of Endocrinology (B.S.), , Nephrology Department (M.H., C.N.), and INSERM ERIT 0106 (M.C.V., F.P.), Lille University Hospital, Lille, France. This article was supported by a grant from the Hospital Project for Clinical Research (PHRC). Address reprint requests to M.C. Vantyghem, Endocrinology and Metabolism Department, 6, rue du Professeur Laguesse, Centre Hospitalo-Universitaire, 59037 Lille Cedex, France. Email: [email protected]
© 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.04.030
Transplantation Proceedings, 36, 1103–1105 (2004)
1103
1104
VANTYGHEM, PATTOU, GIRARDOT ET AL
Fig 1.
Flowchart of the results. Abbreviation: TX, transplantation.
main criteria of eligibility for possible islet transplantation were as follows: (1) Absence of plasma C-peptide (C-p); (2) need for a kidney graft; (3) patient refusal of kidney plus whole pancreas transplantation, knowing that this surgical procedure required transfer to a distant center with a long waiting list; and (4) acceptable results of post– kidney graft preislet transplantation evaluation, including clinical and especially vascular reassessment and C-p stimulation tests.
METHODS C-p Measurement Fasting serum C-p concentrations were measured with a commercial radioimmunoassay kit and expressed in ng/mL (RIA-coat C-peptide, Mallinckrodt, France). The detection threshold was 0.2 ng/mL.
Protocol of C-p Stimulation Tests Fasting and postprandial C-p. C-p levels were measured after 12 hours of fasting and 2 hours after breakfast. Standardized meal stimulation test. The standardized meal included carbohydrates (50 g), proteins (22 g), and lipids (9 g) in a highly energetic drink. Samples were drawn at 0 and 90 minutes. Arginine stimulation test. Five grams of arginine (Arginine, Veyron Laboratories, France) were infused intravenously. Samples were drawn at 0, 3, and 5 minutes.
undergone transplantation with secondary pancreatic failure but a functional kidney, and 2 are still on the waiting list. The remaining 14 (37%) underwent kidney transplantation, among whom 8 (21%) were eligible for islet after kidney transplantation (IAK) and 6 (16%) were ineligible. The reasons for their ineligibility were: 1 patient had moved away; 1 refused islet transplantation; 1 had negative basal C-p but slightly positive stimulation tests; 1 was overweight (102 kg); breast cancer was discovered in 1 patient 6 months after kidney transplantation despite negative pre– kidney graft screening; and 1 had post– kidney graft complications with an elevated creatinine level ⬎20 mg/L (N ⬍ 10). Among the remaining 8 of 14 C-p–negative kidney engrafted patients listed for islet transplantation 3 were transplanted with a pre-Edmonton immunosuppressive regimen and secondary islet failure and 5 were listed for an Edmonton-like protocol. Two of these patients have completed 2 or 3 islet transplantations and have subsequently discontinued insulin. During the survey period and among the 14 kidney transplant patients, 2 patients died of sudden stroke, 1 of whom died 3 years after islet transplantation that had been functional for only 3 months, and the other 1 2 years after kidney transplantation that had been removed because of breast cancer. DISCUSSION
RESULTS
The results were as follows (Fig 1): 17 of 38 (46%) with positive C-p diabetes received a kidney graft alone. Among the remaining 21 C-p–negative diabetic patients (54%), 3 (8%) were ineligible for kidney graft mainly for psychological reasons and 18 (47%) were eligible for kidney transplantation. Among these 18 patients, 4 (10%) were listed for kidney plus pancreas transplantation, 2 of whom had
Epidemiological studies have shown a dramatic incidence of diabetes among dialysis patients.11 Distinguishing type 1 from type 2 diabetes mellitus in this population is not so simple. Indeed, an increasing number of type 2 diabetics require insulin because of relative insulinopenia. Moreover nowadays, type 2 diabetes has an earlier onset because of the increasing prevalence of obesity. Also, approximately 20% of type 1 diabetes are of late-onset. In the Edmonton
DIABETIC PATIENTS AND IAK
protocol, one of the main criteria of eligibility was undetectable levels of C-p, to assess the efficiency of islet transplantation by measuring C-p, as an indication of islet function, as well as a decreased insulin need. Although nephrologists consider that C-p is a poor marker of the type 2 diabetes phenotype,12 a previous study has shown that C-p levels in end-stage renal disease significantly correlated with age at the time of diagnosis of diabetes, maximal body mass index, and delay between diagnosis and consistent insulin use. According to this same study, the prediction was better when performed by a diabetologist than by a nephrologist.13 Therefore, C-p measurements have been validated to select patients eligible for islet or pancreas transplantation rather than clinical or therapeutic criteria, such as a need for insulin, because it is a quantitative, easy-to-use parameter. Nevertheless, stimulation tests with either glucose or arginine are still justified on account of the difficulty to detect borderline values of plasma C-p and/or the lack of sensitivity of the assay in the low range. Once C-p–negative patients have been identified, the next step is to choose between kidney plus islet versus pancreas transplantation, or kidney grafting alone with optimized insulin therapy. Recent studies have shown that outcomes of islet transplantation can compare with pancreas transplantation in terms of improvement of diabetic complications.9 Therefore, the pending question is which transplantation for which C-p– negative patient? The answer probably depends on several factors: the type of complication, namely severe macroangiopathy pointing preferentially to islet transplantation, the local organization versus the necessity to be transplanted in a distant center often being a burden to these sometimes severely disabled patients, the local availability of a pancreas and/or an islet isolation team, the long-term results of islet transplantation by comparison with pancreas transplantation, and the optimized insulin therapy, especially with an ambulatory pump. In conclusion, among this series of 38 diabetic dialysis patients more than 90% were eligible for a kidney graft. Nearly 50% were ineligible for a pancreas or an islet transplantation because of a positive C-p. Approximately 20% were eligible for islet transplantation. These results suggest the importance of C-p determinations in diabetic
1105
patients during hemodialysis to identify patients eligible for pancreas or islet transplantation. REFERENCES 1. Bohman SO, Tyden G, Wilczek H, et al: Prevention of kidney graft diabetic nephropathy by pancreas transplantation in man. Diabetes 34:306, 1985 2. Fioretto P, Steffes MW, Sutherland D, Goetz FC, Mauer M, et al: Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 339:69, 1998 3. Jukema JW, Smets YFC, Van der Piji JW, et al: Impact of simultaneous pancreas and kidney transplantation on progression of coronary atherosclerosis in patients with end-stage renal failure due to type 1 diabetes. Diabetes Care 25:906, 2002 4. Gruessner AC, Sutherland DE: Analysis of United States and non-US pancreas transplantation reported to the United Network for Organ Sharing at the international pancreas transplant registry as of October 2001. Clin Transpl :41, 2001 5. Bunnapradist S, Cho YW, Cecka JM, et al: Kidney allograft and patient survival in type 1 diabetic recipients of cadaveric kidney alone and simultaneous pancreas/kidney transplants: a multivariate analysis of the UNOS database. J Am Soc Nephrol 14:208, 2003 6. Shapiro AM, Lakey JRT, Ryan EA, et al: Islet transplantation in seven patients with type 1 diabetes. N Engl J Med 34:230, 2000 7. Ryan EA, Lakey JR, Paty BW, et al: Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes 51:2148, 2002 8. Pattou F, Vantyghem MC, Noel C, et al: Sequential intraportal islet allografts in immunosuppressed type 1 diabetic patients: preliminary results. Transplant Proc 32:391, 2000 9. Fioretto P, Folli F, Maffi P, et al: Islet transplantation improves vascular diabetic complications in patients with diabetes who underwent kidney transplantation: a comparison between kidney-pancreas and kidney-alone transplantation. Transplantation 75:1296, 2003 10. Lehmann R, Weber M, Zullig R, et al: Islet graft and kidney function in combined islet-kidney transplantation under a glucocorticoid free immunosuppressive regimen. 22nd Workshop of the AIDSPIT Study Group Igls, Austria, January 24, 2003 11. Halimi S, Zmirou D, Benhamou PY, et al: Huge progression of diabetes prevalence and incidence among dialysed patients in mainland France and overseas French territories. A second national survey six years apart (Uremidiab 2 study). Diab Metab 2:507, 1999 12. Covic AM, Schelling JR, Constantiner M, et al: Serum C-peptide concentrations poorly phenotype type 2 diabetic endstage renal disease patients. Kidney Int 58:1742, 2000 13. Benhamou PY, Marwah T, Balducci F, et al: Classification of diabetes in patients with end-stage renal disease. Validation of clinical criteria according to fasting plasma C-peptide. Clin Neprol 38:239, 1992