- Email: [email protected]
Incidence and Risk Factors of New-Onset Diabetes Mellitus After Renal Transplantation
Incidence and Risk Factors of New-Onset Diabetes Mellitus After Renal Transplantation Y.-S. Chien, Y.-T. Chen, C.-H. Chuang, Y.-T. Cheng, F.-R. Chuang, and H. Hsieh ABSTRACT Purpose. New-onset diabetes mellitus (PTDM), a major metabolic complication after renal transplantation, examined for incidence and risk factors. Methods. The records of 358 renal transplant recipients with functioning grafts, from 1986 to 2006, were categorized into two groups according to the usage of tacrolimus (FK): FK-based (n ⫽ 120 patients) and non–FK-based (n ⫽ 238). Using Kaplan-Meier survival analysis and a Cox regression model, this study analyzed the cumulative incidence of PTDM and risk factors, including gender, age, and presence of hepatitis. Results. Cumulative incidences of PTDM after 1, 3, and 5 years posttransplantation in the FK-based group were 11%, 18%, and 22%, respectively. In the non–FK-based group, the cumulative incidences were 5%, 9%, and 12% (P ⫽ .01). Taking into account the risk factors, the cumulative incidence of PTDM was significant among patients 51 years or older (odds ratio, 3.965; P ⫽ .005), but not with regard to gender or presence of hepatitis B and/or C. Overall cumulative incidence of PTDM in our series was 15% (54/358), including 44% (24/54) of cases that occurred within 1 year after renal transplantation. Conclusion. FK is more diabetogenic than cyclosporine or sirolimus. Older age (⭌51 years) is a significant risk factor, in contrast to hepatitis and gender. About half of these cases of PTDM occurred within 1 year after transplantation. These results suggest that aggressive monitoring of blood sugar is necessary for early detection of PTDM.
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EW-ONSET diabetes mellitus (PTDM) is a major metabolic post transplant complication that predisposes patients to graft dysfunction, infection, and cardiovascular disease,1,2 adversely affecting patient and graft survivals.3 PTDM is associated with the use of immunosuppressants as well as patient gender, age, and presence of hepatitis B and/or C. The rate of PTDM varies in different renal transplant programs because there has been no uniform definition for its diagnosis.4,5 The aim of this study was to determine the incidence and risk factors for PTDM.
PATIENTS AND METHODS We retrospectively reviewed the medical records of 358 renal transplant recipients with functioning grafts who were transplanted between August 1986 and July 2006. We selected recipients with no known diabetes mellitus before transplantation. The characteristics of patients were recorded as mean values ⫾ standard deviation (SD), as summarized in Table 1. Patients were categorized into subgroups according to their most recent immunosuppressive regimen as summarized in Table 2.
PTDM was defined as the presence of classic symptoms with casual glucoses ⱖ200 mg/dL and/or fasting glucose ⱖ126 mg/dL, with a duration of ⬎1 month. Kaplan-Meier survival analysis and Cox regression models were used to analyze the incidence and risk factors for PTDM, including gender, age, and hepatitis B and/or C. The date of the first PTDM event posttransplantation was the basis for calculating PTDM-free survival by both Kaplan-Meier and Cox survival plots.
From the Renal Transplant Program, Departments of Nephrology (Y.-S.C., C.-H.C., F.R.C.) and Urology (Y.-T.Chen, Y.-T.Cheng), Chang Gung Memorial Hospital -Kaohsiung Medical Center, Chang Gung University College of Medicine and in Private Practice (H.H.), Kaohsiung, Taiwan. Address reprint requests to Yu-Shu Chien, MD, Department of Nephrology, Chang Gung Memorial Hospital -Kaohsiung Medical Center, No.123, Ta Pei Road, Niao Sung Hsiang, Kaohsiung Hsien, Taiwan. E-mail: [email protected]
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.06.034
Transplantation Proceedings, 40, 2409 –2411 (2008)
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CHIEN, CHEN, CHUANG ET AL Table 1. Patient Characteristics
Male:female ratio Months of PTDM diagnosis posttransplantation, range, (mean ⫾ SD) Age, range, (mean ⫾ SD) Age (y) ⬉30 31–40 41–50 51–60 ⱖ61 Hepatitis None B C B⫹C
200:158 1–231 (70 ⫾ 55) 16–75 (41 ⫾ 11) 72 93 116 65 12 245 44 54 15
RESULTS
Overall cumulative incidence of PTDM in our series was 15% (54/358), regardless of FK usage. The distribution of onset time after renal transplantation is shown in Figure 1. The onset time was 44% (24/54) within 1 year; only 16% (9/54) occurred ⬎5 years after renal transplantation. Among the FK-based group, the cumulative incidence of Table 2. Subgroups of Immunosuppressive Medication Group
FK-based 1. FK ⫹ MPA ⫹ P 2. FK ⫹ P Non–FK-based 1. CsA ⫹ MPA ⫹ P 2. CsA ⫹ P 3. SRL ⫹ MPA ⫹ P or AZA ⫹ P Total
n
47 73 41 169 28 358
Abbreviations: FK, tacrolimus; MPA, mycophenolate acid; P, prednisolone; CsA, cyclosporine; SRL, sirolimus; AZA, azathioprine.
Fig 1. Distribution of onset time of PTDM after renal transplantation.
Fig 2. PTDM-free survival for patients treated without and with tacrolimus (FK)-based immunosuppressive regimens.
PTDM after 1, 3, or 5 years posttransplantation was 11%, 18%, or 22%, respectively. In the non–FK-based group, cumulative incidences were 5%, 9%, and 12% (P ⫽ .01 by log-rank test; Fig 2). Taking into account the risk factors the cumulative incidence of PTDM was significant for patients ⭌51 years old (odds ratio, 3.965; P ⫽ .005), but not with regard to gender or presence of hepatitis B and/or C (Fig 3; Table 3). DISCUSSION
PTDM is a common complication of immunosuppressive medications after kidney transplantation. Our results revealed that tacrolimus was more diabetogenic than cyclosporine or sirolimus. Hepatitis B and/or C, as well as gender, were not significant risk factors in our study. Past research had demonstrated that hepatitis C is associated with PTDM, particularly among patients on FK-based
Fig 3.
PTDM-free survival for all patients by age group.
NEW-ONSET DIABETES AFTER RENAL TRANSPLANTATION Table 3. Risk Factors Correlated With PTDM Characteristic
Age (y) ⱕ30 31–40 41–50 ⱖ51 Gender Female Male Hepatitis None B C B⫹C
Odds Ratio for PTDM
P-Value
1.00 (reference) 2.405 (0.954–6.604) 1.977 (0.746–5.242) 3.965 (1.522–10.330)
— .063 .171 .005
1.00 (reference) 1.25 (0.7–2.22)
— .44
1.00 (reference) 1.18 (0.51–2.74) 1.20 (0.56–2.55) 1.32 (0.39–4.44)
— .685 .627 .649
Abbreviation: PTDM, new-onset diabetes mellitus.
immunosuppression.6 We recognized that there was a potential bias in our study, as compared with other reports. First, our data were retrospectively collected; information on hepatitis C viral load and liver histology data could not be obtained. Second, pretransplant diabetes was precluded but only screened according to patient history, and baseline fasting and postprandial blood sugars. We generally did not perform more sensitive studies, such oral glucose tolerance tests, glycosylated hemoglobin measurements, and C-peptide levels. Third, most of our hepatitis C renal transplants recipients (70%) received a CsA-based immunosuppressive regimen (41/59); only 22% (13/59) re-
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ceived an FK-based regimen, leading to an underestimation of the impact of hepatitis C on the risk of PTDM. Older age (⭌51 years) was a risk factor in our study, as reported in the literature.7 About half of the cases of PTDM developed within 1 year after transplantation. These results suggest that aggressive monitoring of blood sugar is necessary for early detection of PTDM. REFERENCES 1. Hariharan S, Johnson CP, Brshnahan BA, et al: Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Eng J Med 342:605, 2000 2. Cosio FG, Kudva Y, Velde M, et al: New onset hyperglycemia and diabetes are associated with increased cardiovascular risk after kidney transplantation. Kidney Int 67:2415, 2005 3. Kasiske BL, Snyder JJ, Gilbertson D, et al: Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 3:178, 2003 4. Cho YM, Park KS, Jung HS, et al: High incidence of tacrolimus-associated posttransplantation diabetes in the Korean renal allograft recipients according to American Diabetes Association criteria. Diabetes Care 26:1123, 2003 5. Montori VM, Velosa JA, Basu A, et al: Posttransplantation diabetes. A systematic review of the literature. Diabetes Care 25: 583, 2002 6. Bloom RD, Rao V, Weng F, et al: Association of hepatitis C with posttransplant diabetes in renal transplant patients on tacrolimus. J Am Soc Nephrol 13:1374, 2002 7. Numakura K, Satoh S, Tsuchiya N, et al: Clinical and genetic risk factors for posttransplant diabetes mellitus in adult renal transplant recipients treated with tacrolimus. Transplantation 80: 1419, 2005
N
EW-ONSET diabetes mellitus (PTDM) is a major metabolic post transplant complication that predisposes patients to graft dysfunction, infection, and cardiovascular disease,1,2 adversely affecting patient and graft survivals.3 PTDM is associated with the use of immunosuppressants as well as patient gender, age, and presence of hepatitis B and/or C. The rate of PTDM varies in different renal transplant programs because there has been no uniform definition for its diagnosis.4,5 The aim of this study was to determine the incidence and risk factors for PTDM.
PATIENTS AND METHODS We retrospectively reviewed the medical records of 358 renal transplant recipients with functioning grafts who were transplanted between August 1986 and July 2006. We selected recipients with no known diabetes mellitus before transplantation. The characteristics of patients were recorded as mean values ⫾ standard deviation (SD), as summarized in Table 1. Patients were categorized into subgroups according to their most recent immunosuppressive regimen as summarized in Table 2.
PTDM was defined as the presence of classic symptoms with casual glucoses ⱖ200 mg/dL and/or fasting glucose ⱖ126 mg/dL, with a duration of ⬎1 month. Kaplan-Meier survival analysis and Cox regression models were used to analyze the incidence and risk factors for PTDM, including gender, age, and hepatitis B and/or C. The date of the first PTDM event posttransplantation was the basis for calculating PTDM-free survival by both Kaplan-Meier and Cox survival plots.
From the Renal Transplant Program, Departments of Nephrology (Y.-S.C., C.-H.C., F.R.C.) and Urology (Y.-T.Chen, Y.-T.Cheng), Chang Gung Memorial Hospital -Kaohsiung Medical Center, Chang Gung University College of Medicine and in Private Practice (H.H.), Kaohsiung, Taiwan. Address reprint requests to Yu-Shu Chien, MD, Department of Nephrology, Chang Gung Memorial Hospital -Kaohsiung Medical Center, No.123, Ta Pei Road, Niao Sung Hsiang, Kaohsiung Hsien, Taiwan. E-mail: [email protected]
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.06.034
Transplantation Proceedings, 40, 2409 –2411 (2008)
2409
2410
CHIEN, CHEN, CHUANG ET AL Table 1. Patient Characteristics
Male:female ratio Months of PTDM diagnosis posttransplantation, range, (mean ⫾ SD) Age, range, (mean ⫾ SD) Age (y) ⬉30 31–40 41–50 51–60 ⱖ61 Hepatitis None B C B⫹C
200:158 1–231 (70 ⫾ 55) 16–75 (41 ⫾ 11) 72 93 116 65 12 245 44 54 15
RESULTS
Overall cumulative incidence of PTDM in our series was 15% (54/358), regardless of FK usage. The distribution of onset time after renal transplantation is shown in Figure 1. The onset time was 44% (24/54) within 1 year; only 16% (9/54) occurred ⬎5 years after renal transplantation. Among the FK-based group, the cumulative incidence of Table 2. Subgroups of Immunosuppressive Medication Group
FK-based 1. FK ⫹ MPA ⫹ P 2. FK ⫹ P Non–FK-based 1. CsA ⫹ MPA ⫹ P 2. CsA ⫹ P 3. SRL ⫹ MPA ⫹ P or AZA ⫹ P Total
n
47 73 41 169 28 358
Abbreviations: FK, tacrolimus; MPA, mycophenolate acid; P, prednisolone; CsA, cyclosporine; SRL, sirolimus; AZA, azathioprine.
Fig 1. Distribution of onset time of PTDM after renal transplantation.
Fig 2. PTDM-free survival for patients treated without and with tacrolimus (FK)-based immunosuppressive regimens.
PTDM after 1, 3, or 5 years posttransplantation was 11%, 18%, or 22%, respectively. In the non–FK-based group, cumulative incidences were 5%, 9%, and 12% (P ⫽ .01 by log-rank test; Fig 2). Taking into account the risk factors the cumulative incidence of PTDM was significant for patients ⭌51 years old (odds ratio, 3.965; P ⫽ .005), but not with regard to gender or presence of hepatitis B and/or C (Fig 3; Table 3). DISCUSSION
PTDM is a common complication of immunosuppressive medications after kidney transplantation. Our results revealed that tacrolimus was more diabetogenic than cyclosporine or sirolimus. Hepatitis B and/or C, as well as gender, were not significant risk factors in our study. Past research had demonstrated that hepatitis C is associated with PTDM, particularly among patients on FK-based
Fig 3.
PTDM-free survival for all patients by age group.
NEW-ONSET DIABETES AFTER RENAL TRANSPLANTATION Table 3. Risk Factors Correlated With PTDM Characteristic
Age (y) ⱕ30 31–40 41–50 ⱖ51 Gender Female Male Hepatitis None B C B⫹C
Odds Ratio for PTDM
P-Value
1.00 (reference) 2.405 (0.954–6.604) 1.977 (0.746–5.242) 3.965 (1.522–10.330)
— .063 .171 .005
1.00 (reference) 1.25 (0.7–2.22)
— .44
1.00 (reference) 1.18 (0.51–2.74) 1.20 (0.56–2.55) 1.32 (0.39–4.44)
— .685 .627 .649
Abbreviation: PTDM, new-onset diabetes mellitus.
immunosuppression.6 We recognized that there was a potential bias in our study, as compared with other reports. First, our data were retrospectively collected; information on hepatitis C viral load and liver histology data could not be obtained. Second, pretransplant diabetes was precluded but only screened according to patient history, and baseline fasting and postprandial blood sugars. We generally did not perform more sensitive studies, such oral glucose tolerance tests, glycosylated hemoglobin measurements, and C-peptide levels. Third, most of our hepatitis C renal transplants recipients (70%) received a CsA-based immunosuppressive regimen (41/59); only 22% (13/59) re-
2411
ceived an FK-based regimen, leading to an underestimation of the impact of hepatitis C on the risk of PTDM. Older age (⭌51 years) was a risk factor in our study, as reported in the literature.7 About half of the cases of PTDM developed within 1 year after transplantation. These results suggest that aggressive monitoring of blood sugar is necessary for early detection of PTDM. REFERENCES 1. Hariharan S, Johnson CP, Brshnahan BA, et al: Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Eng J Med 342:605, 2000 2. Cosio FG, Kudva Y, Velde M, et al: New onset hyperglycemia and diabetes are associated with increased cardiovascular risk after kidney transplantation. Kidney Int 67:2415, 2005 3. Kasiske BL, Snyder JJ, Gilbertson D, et al: Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 3:178, 2003 4. Cho YM, Park KS, Jung HS, et al: High incidence of tacrolimus-associated posttransplantation diabetes in the Korean renal allograft recipients according to American Diabetes Association criteria. Diabetes Care 26:1123, 2003 5. Montori VM, Velosa JA, Basu A, et al: Posttransplantation diabetes. A systematic review of the literature. Diabetes Care 25: 583, 2002 6. Bloom RD, Rao V, Weng F, et al: Association of hepatitis C with posttransplant diabetes in renal transplant patients on tacrolimus. J Am Soc Nephrol 13:1374, 2002 7. Numakura K, Satoh S, Tsuchiya N, et al: Clinical and genetic risk factors for posttransplant diabetes mellitus in adult renal transplant recipients treated with tacrolimus. Transplantation 80: 1419, 2005