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Incidence of Posttransplantation Diabetes Mellitus in Kidney Transplantation: A Single-Center Experience
Incidence of Posttransplantation Diabetes Mellitus in Kidney Transplantation: A Single-Center Experience J. Roozbeh, A.R. Mehdizadeh, A. Razmkon, and S.A. Malek-Hosseini ABSTRACT Posttransplantation diabetes mellitus (PTDM) is a well-recognized complication of renal transplantation. PTDM is reported to contribute to major infections and cardiovascular complications and leads to increased posttransplantation morbidity. The present study was conducted to evaluate the frequency of PTDM in our center, to identify the role of immunosuppressive therapy and other risk factors in the genesis of PTDM, and to assess the impact of PTDM on graft and patient survival. From December 1998 to December 2003 we followed-up 1200 renal transplant recipients, including 121 recipients with pretransplantation diabetes mellitus and 1079 recipients without diabetes. PTDM occurred in 203 patients (mean age, 35.4 ⫾ 5.9 years); 131 (64.5%) were male. Graft loss and mortality were significantly higher in patients with PTDM versus those without. The overall reported incidence of PTDM worldwide varies from 3.4% to 46%. The incidence in our center is 18.8%. We also found a significantly higher incidence of PTDM among patients receiving grafts from living-related donors. This may be related to the higher cumulative doses of immunosuppressive drugs administered (in part, due to the greater number of acute rejections) in these patients.
K
IDNEY transplantation is considered the best treatment for patients with end-stage renal disease (ESRD). Posttransplantation diabetes mellitus (PTDM), a well-recognized complication of transplantation,1 contributes to major infections and cardiovascular complications leading to increased morbidity.2,3 The present study was performed to evaluate the frequency of PTDM and its impact on graft and patient outcome in different donor groups of renal transplant recipients. MATERIAL AND METHODS This retrospective study included all 1200 kidney transplant recipients operated on between December 1988 and December 2003 (Table 1). The immunosuppressive protocol (including azathioprine or mycophenolate mofetil, prednisolone, and cyclosporine) and general procedures used in our transplantation unit are nearly the same for all patients as described previously.4 All patients were followed up on a regular basis for an indefinite time. PTDM was defined according to World Health Organization (WHO) criteria.5 All recipients with transient hyperglycemia after steroid pulse treatment were excluded. Information on age, gender, family history of diabetes, donor type, body mass index (BMI) at the time of transplantation, weight gain after transplantation, serum creatinine levels, duration of onset of PTDM from the date of transplantation, complications, rejections, and mortality were collected by retrospective review of patient files and added to the Persian Network for Organ
Transplant (PNOT) database. The chi-square test was used to calculate categorical variables, t test was used to compare values, and Kaplan-Meier analysis was used to calculate survival rates.
RESULTS
One thousand thirty-two patients (86.0%) received organs from living donors, of which 480 (40.0%) were related and 552 (46.0%) were unrelated; 168 patients (14.0%) received organs from deceased donors. One hundred twenty-one patients (10.1%) with pretransplantation diabetes mellitus were excluded from the analysis. There were 1079 patients without diabetes before transplantation, among whom 203 (18.8%) developed PTDM following transplantation. Patients developed PTDM at a mean age of 35.4 ⫾ 5.9 years; 131 (64.5%) were male and 72 (35.5%) were female; the male-to-female ratio was 1:8. Patients with PTDM tended to be significantly older compared with those without PTDM (29.6 ⫾ 11.0; P ⫽ .03). Family history of diabetes was positive in 24 patients with PTDM (11.8%) compared From the Organ Transplant Center, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran. Address reprint requests to Jamshid Roozbeh, PO Box 71455-166, Shiraz, Iran. E-mail: [email protected]
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.08.039
Transplantation Proceedings, 37, 3095–3097 (2005)
3095
3096
ROOZBEH, RAZMKON, MEHDIZADEH ET AL
Table 1. Demographic Data of Patients in 2 Groups Based on Development of PTDM With PTDM
Without PTDM
Age ⬍18 y 10 (5.7%) 164 (94.3%) 18–34 y 82 (18.3%) 366 (81.7%) 34–50 y 87 (24.1%) 274 (75.9%) ⬎50 y 24 (25%) 72 (75%) Total Gender Male 131 (18.5%) 575 (81.5%) Female 72 (19.3%) 301 (79.7%) Total Organ source Living unrelated 107 (21.9%) 381 (78.1%) Living related 65 (15.2%) 361 (84.8%) Cadaver 31 (18.8%) 134 (81.2%) Total Weight gain (⬎10 kg) 47 (23.1%) 215 (24.5%) Positive family history 24 (11.8%) 79 (9.0%) for DM Body mass index (⬎25) 47 (23.1%) 172 (19.6%) Serum creatinine 2 wk 2.1 ⫾ 0.5 mg/dL 1.8 ⫾ 0.4 mg/dL postoperative Patient survival 1y 91% 95% 3y 87% 90% Graft survival 1y 85% 89% 3y 80% 85% Total no. in each group 203 876
Total
174 448 361 96 1079 706 373 1079 488 426 165 1079 262 103 219
1079
with 90 patients without PTDM (9.0%), which was not significant (P ⫽ .4). Mean duration of onset of PTDM after transplantation was 96 days (range, 34 –345 days). Mean serum creatinine level at the time of diagnosis of PTDM was 2.1 ⫾ 0.5 mg/dL. PTDM occurred more frequently in recipients of kidneys from live unrelated donors compared with those who received kidneys from live related donors (19.8% vs 15.2%). Thirty-one patients with PTDM (18.8%) underwent deceased donor renal transplantation. There was no significant relationship between BMI at the time of transplantation in the 2 groups (P ⫽ .63), and
patients with PTDM had smaller increases in weight than did patients without PTDM (P ⫽ .3). The incidence of nonsurgical complications was similar in both groups, except that cardiovascular and infectious complications occurred more frequently in patients with PTDM (P ⫽ .01). Acute and chronic rejection occurred more frequently in recipients with PTDM (P ⫽ .02). Death also occurred more frequently in recipients with PTDM compared with those without PTDM (P ⫽ .005); the most common cause of death was cardiovascular-related in both groups. Patient survival rates at 1 and 3 years in patients with PTDM were 91% and 87%, respectively, and they were 95% and 90% in patients without PTDM, respectively. Graft survival rates at 1 and 3 years in patients with PTDM were 85% and 80%, respectively, and they were 89% and 85% in patients without PTDM, respectively (Table 2).
DISCUSSION
The overall reported incidence of PTDM worldwide varies from 3.4% to 46%.2–7 The incidence in our center is 18.8%. Higher age was associated with greater risk of acquiring PTDM in our center, which is in agreement with other Middle Eastern reports.1,8,9 Family history was not found to be significantly correlated in patients with PTDM; this may be because of the higher age of patients with PTDM, where they may not recall exactly the occurrence of the disease in their deceased family members (recall bias). We also found a significantly higher incidence of PTDM primarily in recipients of kidneys from living unrelated donors, followed by those who had received deceased donor transplants, which may be related to the higher cumulative doses of immunosuppressive drugs (in part due to the greater number of acute rejections) given to these patients. Unexpectedly, a higher BMI at the time of transplantation and greater weight gain after transplantation were not associated with a higher risk of acquiring PTDM in this study (unpublished data), nor were these parameters associated with higher serum glucose levels. The role of hepatitis C virus status of patients as an important factor in the genesis of PTDM9 could not be
Table 2. Analysis of Different Variables in 2 Groups Based on Development of PTDM
Age (mean ⫾ SD) Gender (male/female ratio) Living unrelated source (% in each group) BMI (⬎25) Weight gain (10 kg) Positive family history Chronic and acute rejection Cardiovascular complication Infection Other nonsurgical complication Mortality rate in first 3 years
With vs Without PTDM
P
Correlation
29.6 ⫾ 11.0 vs 35.4 ⫾ 5.9 1.8 vs 1.9 52.7% vs 43.5% 23.1% vs 19.6% 23.1% vs 24.5% 11.8% vs 9.0% 23.6% vs 16.9% 21.1% vs 16.2% 17.2% vs 13.8% 17.0% vs 15.8% 13.2% vs 10.3%
.03 .07 .03 .63 .3 .4 .02 .01 .01 .09 .005
Significant No Significant No No No Significant Significant Significant No Significant
PTDM IN KIDNEY TRANSPLANTATION
determined owing to the low number of patients with hepatitis C virus in our study population. Nonsurgical complications, rejections, graft loss, and mortality were significantly higher in patients with PTDM as compared with those without PTDM. A high incidence of infections and cardiovascular diseases has been reported in patients with PTDM.2,3 In conclusion, PTDM is a significant complication after renal transplantation. Efforts to reduce the incidence of PTDM should be part of an overall strategy toward reducing cardiovascular-related and infection-related morbidity in renal transplant recipients.
REFERENCES 1. Sakhuja V, Sharma UK, Jha V, et al: High incidence of posttransplant diabetes mellitus in renal transplant recipients on triple-drug immunosuppression. Transplant Proc 27:2728, 1995
3097 2. Rao M, Jacob CK, Shastry JCM: Post-renal transplant diabetes mellitus–a retrospective study. Nephrol Dial Transplant 7:1039, 1992. 3. Paul LC, Sutherland F, Klassen J, et al: Cardiovascular risk impact of cyclosporine immunosuppression in renal transplant recipients. Transplant Proc 24:2740, 1992 4. Ahmad E, Malek-Hosseini SA, Salahi H, et al: Experience with 300 renal transplants in Shiraz, Iran. Transplant Proc 27:2767, 1995 5. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183, 1997 6. Ahn KJ, Kim YS, Lee HC, et al: Clinical characteristics and possible risk factors in postrenal transplant diabetes mellitus. Transplant Proc 24:1581, 1992 7. Basri N, Aman H, Adiku W, et al: Diabetes mellitus after renal transplantation. Transplant Proc 24:1780, 1992 8. Johny KV, Nampoory MRN, Costandi JN, et al: High incidence of post-transplant diabetes mellitus in Kuwait. Diabetes Res Clin Pract 55:123, 2002 9. Vesco L, Busson M, Bedrossian J, et al: Diabetes mellitus after renal transplantation: characteristics, outcome, and risk factors. Transplantation 61:1475, 1996
K
IDNEY transplantation is considered the best treatment for patients with end-stage renal disease (ESRD). Posttransplantation diabetes mellitus (PTDM), a well-recognized complication of transplantation,1 contributes to major infections and cardiovascular complications leading to increased morbidity.2,3 The present study was performed to evaluate the frequency of PTDM and its impact on graft and patient outcome in different donor groups of renal transplant recipients. MATERIAL AND METHODS This retrospective study included all 1200 kidney transplant recipients operated on between December 1988 and December 2003 (Table 1). The immunosuppressive protocol (including azathioprine or mycophenolate mofetil, prednisolone, and cyclosporine) and general procedures used in our transplantation unit are nearly the same for all patients as described previously.4 All patients were followed up on a regular basis for an indefinite time. PTDM was defined according to World Health Organization (WHO) criteria.5 All recipients with transient hyperglycemia after steroid pulse treatment were excluded. Information on age, gender, family history of diabetes, donor type, body mass index (BMI) at the time of transplantation, weight gain after transplantation, serum creatinine levels, duration of onset of PTDM from the date of transplantation, complications, rejections, and mortality were collected by retrospective review of patient files and added to the Persian Network for Organ
Transplant (PNOT) database. The chi-square test was used to calculate categorical variables, t test was used to compare values, and Kaplan-Meier analysis was used to calculate survival rates.
RESULTS
One thousand thirty-two patients (86.0%) received organs from living donors, of which 480 (40.0%) were related and 552 (46.0%) were unrelated; 168 patients (14.0%) received organs from deceased donors. One hundred twenty-one patients (10.1%) with pretransplantation diabetes mellitus were excluded from the analysis. There were 1079 patients without diabetes before transplantation, among whom 203 (18.8%) developed PTDM following transplantation. Patients developed PTDM at a mean age of 35.4 ⫾ 5.9 years; 131 (64.5%) were male and 72 (35.5%) were female; the male-to-female ratio was 1:8. Patients with PTDM tended to be significantly older compared with those without PTDM (29.6 ⫾ 11.0; P ⫽ .03). Family history of diabetes was positive in 24 patients with PTDM (11.8%) compared From the Organ Transplant Center, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran. Address reprint requests to Jamshid Roozbeh, PO Box 71455-166, Shiraz, Iran. E-mail: [email protected]
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.08.039
Transplantation Proceedings, 37, 3095–3097 (2005)
3095
3096
ROOZBEH, RAZMKON, MEHDIZADEH ET AL
Table 1. Demographic Data of Patients in 2 Groups Based on Development of PTDM With PTDM
Without PTDM
Age ⬍18 y 10 (5.7%) 164 (94.3%) 18–34 y 82 (18.3%) 366 (81.7%) 34–50 y 87 (24.1%) 274 (75.9%) ⬎50 y 24 (25%) 72 (75%) Total Gender Male 131 (18.5%) 575 (81.5%) Female 72 (19.3%) 301 (79.7%) Total Organ source Living unrelated 107 (21.9%) 381 (78.1%) Living related 65 (15.2%) 361 (84.8%) Cadaver 31 (18.8%) 134 (81.2%) Total Weight gain (⬎10 kg) 47 (23.1%) 215 (24.5%) Positive family history 24 (11.8%) 79 (9.0%) for DM Body mass index (⬎25) 47 (23.1%) 172 (19.6%) Serum creatinine 2 wk 2.1 ⫾ 0.5 mg/dL 1.8 ⫾ 0.4 mg/dL postoperative Patient survival 1y 91% 95% 3y 87% 90% Graft survival 1y 85% 89% 3y 80% 85% Total no. in each group 203 876
Total
174 448 361 96 1079 706 373 1079 488 426 165 1079 262 103 219
1079
with 90 patients without PTDM (9.0%), which was not significant (P ⫽ .4). Mean duration of onset of PTDM after transplantation was 96 days (range, 34 –345 days). Mean serum creatinine level at the time of diagnosis of PTDM was 2.1 ⫾ 0.5 mg/dL. PTDM occurred more frequently in recipients of kidneys from live unrelated donors compared with those who received kidneys from live related donors (19.8% vs 15.2%). Thirty-one patients with PTDM (18.8%) underwent deceased donor renal transplantation. There was no significant relationship between BMI at the time of transplantation in the 2 groups (P ⫽ .63), and
patients with PTDM had smaller increases in weight than did patients without PTDM (P ⫽ .3). The incidence of nonsurgical complications was similar in both groups, except that cardiovascular and infectious complications occurred more frequently in patients with PTDM (P ⫽ .01). Acute and chronic rejection occurred more frequently in recipients with PTDM (P ⫽ .02). Death also occurred more frequently in recipients with PTDM compared with those without PTDM (P ⫽ .005); the most common cause of death was cardiovascular-related in both groups. Patient survival rates at 1 and 3 years in patients with PTDM were 91% and 87%, respectively, and they were 95% and 90% in patients without PTDM, respectively. Graft survival rates at 1 and 3 years in patients with PTDM were 85% and 80%, respectively, and they were 89% and 85% in patients without PTDM, respectively (Table 2).
DISCUSSION
The overall reported incidence of PTDM worldwide varies from 3.4% to 46%.2–7 The incidence in our center is 18.8%. Higher age was associated with greater risk of acquiring PTDM in our center, which is in agreement with other Middle Eastern reports.1,8,9 Family history was not found to be significantly correlated in patients with PTDM; this may be because of the higher age of patients with PTDM, where they may not recall exactly the occurrence of the disease in their deceased family members (recall bias). We also found a significantly higher incidence of PTDM primarily in recipients of kidneys from living unrelated donors, followed by those who had received deceased donor transplants, which may be related to the higher cumulative doses of immunosuppressive drugs (in part due to the greater number of acute rejections) given to these patients. Unexpectedly, a higher BMI at the time of transplantation and greater weight gain after transplantation were not associated with a higher risk of acquiring PTDM in this study (unpublished data), nor were these parameters associated with higher serum glucose levels. The role of hepatitis C virus status of patients as an important factor in the genesis of PTDM9 could not be
Table 2. Analysis of Different Variables in 2 Groups Based on Development of PTDM
Age (mean ⫾ SD) Gender (male/female ratio) Living unrelated source (% in each group) BMI (⬎25) Weight gain (10 kg) Positive family history Chronic and acute rejection Cardiovascular complication Infection Other nonsurgical complication Mortality rate in first 3 years
With vs Without PTDM
P
Correlation
29.6 ⫾ 11.0 vs 35.4 ⫾ 5.9 1.8 vs 1.9 52.7% vs 43.5% 23.1% vs 19.6% 23.1% vs 24.5% 11.8% vs 9.0% 23.6% vs 16.9% 21.1% vs 16.2% 17.2% vs 13.8% 17.0% vs 15.8% 13.2% vs 10.3%
.03 .07 .03 .63 .3 .4 .02 .01 .01 .09 .005
Significant No Significant No No No Significant Significant Significant No Significant
PTDM IN KIDNEY TRANSPLANTATION
determined owing to the low number of patients with hepatitis C virus in our study population. Nonsurgical complications, rejections, graft loss, and mortality were significantly higher in patients with PTDM as compared with those without PTDM. A high incidence of infections and cardiovascular diseases has been reported in patients with PTDM.2,3 In conclusion, PTDM is a significant complication after renal transplantation. Efforts to reduce the incidence of PTDM should be part of an overall strategy toward reducing cardiovascular-related and infection-related morbidity in renal transplant recipients.
REFERENCES 1. Sakhuja V, Sharma UK, Jha V, et al: High incidence of posttransplant diabetes mellitus in renal transplant recipients on triple-drug immunosuppression. Transplant Proc 27:2728, 1995
3097 2. Rao M, Jacob CK, Shastry JCM: Post-renal transplant diabetes mellitus–a retrospective study. Nephrol Dial Transplant 7:1039, 1992. 3. Paul LC, Sutherland F, Klassen J, et al: Cardiovascular risk impact of cyclosporine immunosuppression in renal transplant recipients. Transplant Proc 24:2740, 1992 4. Ahmad E, Malek-Hosseini SA, Salahi H, et al: Experience with 300 renal transplants in Shiraz, Iran. Transplant Proc 27:2767, 1995 5. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183, 1997 6. Ahn KJ, Kim YS, Lee HC, et al: Clinical characteristics and possible risk factors in postrenal transplant diabetes mellitus. Transplant Proc 24:1581, 1992 7. Basri N, Aman H, Adiku W, et al: Diabetes mellitus after renal transplantation. Transplant Proc 24:1780, 1992 8. Johny KV, Nampoory MRN, Costandi JN, et al: High incidence of post-transplant diabetes mellitus in Kuwait. Diabetes Res Clin Pract 55:123, 2002 9. Vesco L, Busson M, Bedrossian J, et al: Diabetes mellitus after renal transplantation: characteristics, outcome, and risk factors. Transplantation 61:1475, 1996