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Posttransplant diabetes mellitus after kidney transplantation with different immunosuppressive agents
TOXICITY
Posttransplant Diabetes Mellitus After Kidney Transplantation With Different Immunosuppressive Agents J. Romagnoli, F. Citterio, P. Violi, G. Nanni, and M. Castagneto ABSTRACT Posttransplant diabetes mellitus (PTDM) is a disturbing side effect of immunosuppression. The aim of this study was to evaluate the effect of different immunosuppressive agents on the development of PTDM in renal transplant recipients (KTx). The incidence of PTDM was evaluated in 538 consecutive KTx. Baseline immunosuppression was azathioprine (AZA), cyclosporine (CSA), or tacrolimus (TAC), or sirolimus in combination with calcineurin inhibitors (SIR). All patients received steroids for both induction and maintenance therapy during the first 6 months posttransplantation. Mean follow-up after KTx was 73 ⫾ 53.5 months (range 6 months to 16 years). PTDM was defined as two consecutive blood glucose determinations above 126 mg/dL. Thirty-six of 538 (6.7%) recipients experienced PTDM, 31 of whom required insulin treatment and five oral antidiabetic medications. PTDM occurred at 25.3 ⫾ 38 months posttransplantation in 4.8% of KTx treated with AZA, 4.8% of CSA, 6.5% of KTx treated with TAC and 12.5% of KTx treated with SIR. The time of onset of PTDM was significantly shorter (P ⫽ .003) among TAC (2.1 ⫾ 1.7 months posttransplantation) versus CSA (27.8 ⫾ 34 months). PTDM disappeared in 6 of 36 patients. We conclude that with current levels of immunosuppression, there is no difference in the incidence of PTDM between TAC- and CSA-treated KTx.
P
OSTTRANSPLANT DIABETES MELLITUS (PTDM) is a metabolic complication of immunosuppression after renal transplantation. The incidence of PTDM varies according to the definition adopted, the type of immunosuppression, and risk factors such as recipient age and race.1 Particularly, immunosuppression is considered the major pathogenetic factor in the development of PTDM,2,3 although insulin resistance and relative insulin deficiency are also involved in the pathogenesis.3 The aim of our study was to evaluate the effect of various immuno0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.03.012 690
suppressive agents on the development of PTDM in renal transplant recipients (KTx). PATIENTS AND METHODS Five hundred and thirty-eight patients receiving a kidney allograft between January 1981 and June 2002 who had been followed up for From the Clinica Chirurgica, Catholic University, Rome, Italy. Address reprint requests to Jacopo Romagnoli, MD, Clinica Chirurgica, Universita´ Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy. E-mail: [email protected] © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36, 690 – 691 (2004)
POSTTRANSPLANT DIABETES MELLITUS
691
at least 6 months after transplantation were included in the study. Mean follow-up after KTx was 73 ⫾ 53.5 months (range 6 months to 16 years). There were four KTx groups based on the main immunosuppressant: azathioprine (AZA); cyclosporine (CSA); tacrolimus (TAC); sirolimus ⫹ a calcineurin inhibitor (SIR). All KTx received steroids for both induction and maintenance therapy during the first 6 months posttransplantation. The patient’s charts were retrospectively reviewed to collect data on the incidence of PTDM and immunosuppressive regimen at the time of its occurrence. Data were entered into an Excel (Microsoft) database to obtain median or mean values ⫾ SD. Groups of patients treated with different immunosuppressive agents were compared for age at transplant, body mass index (BMI), incidence, time of occurrence, and duration of PTDM, which was defined according to the American Diabetes Association and World Health Organization experts4 as fasting blood glucose levels of 126 mg/dL or greater confirmed by repeat testing on a different day.
CONCLUSIONS
RESULTS
REFERENCES
Thirty-six of 538 (6.7%) recipients experienced PTDM, 31 of whom required insulin treatment and five of whom required oral antidiabetic medications to normalize blood glucose. There were no statistically significant differences among the four groups in terms of age, BMI, and incidence of PTDM, which occurred 25.3 ⫾ 38 months posttransplantation in 4.8% of KTx treated with AZA, 4.8% of KTx treated with CSA, 6.5% of KTx treated with TAC, and 12.5% KTx treated with of SIR. Time of onset of PTDM was significantly shorter (P ⫽ .003) among the TAC (2.1 ⫾ 1.7 months posttransplantation) versus CSA group (27.8 ⫾ 34 months). Mean immunosuppressant dosages before the development of PTDM were 0.12 mg/kg TAC; 4.7 mg/kg CSA; and 0.04 mg/kg SIR. In 6 of 36 patients (16.1%) PTDM disappeared at 11 ⫾ 21 months after onset (range 8.1 to 32.4 months).
1. Hjelmesaeth J, Hartmann A, Kofstad J, et al: Glucose intolerance after renal transplantation depends upon prednisolone dose and recipient age. Transplantation 64:979, 1997 2. First RM, Gerber DA, Hariharan S, et al: Posttransplant diabetes mellitus in kidney allograft recipients: incidence, risk factors and management. Transplantation 73:379, 2002 3. Jindal RM, Hjelmesaeth J: Impact and management of postransplant diabetes mellitus. Transplantation 70:S85, 2000 4. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 26:S5, 2003 5. Von Kiparski A, Frei D, Uhlschmid G, et al: Post-transplant diabetes mellitus in renal allograft recipients: a matched-pair control study. Nephrol Dial Transplant 5:220, 1990 6. Sumrani NB, Delaney V, Ding ZK, et al: Diabetes mellitus after renal transplantation in the cyclosporine era—an analysis of risk factors. Transplantation 51:343, 1991 7. Andoh TF, Lindsley J, Franceschini N, et al: Synergistic effects of cyclosporine and rapamycin in a chronic nephrotoxicity model. Transplantation 62:311, 1996
The incidence of PTDM was low in our population, although we adopted a sensitive criterion for the definition of diabetes.4 The mean incidence reported in the literature varies between 3.6% and 18%.2,5,6 This study suggests that with current levels of immunosuppression there is no difference in the incidence of PTDM between TAC- and CSA-treated KTx. The relatively higher incidence of PTDM in the SIR group, although not statistically significant, may be related to an intrinsic toxic effect of SIR, which has been described in an experimental model in the rat where SIR, given at a subtherapeutic dose of 0.1 mg/kg in combination with cyclosporine, worsened glucose metabolism and potentiated chronic CSA-induced nephrotoxicity.7
Posttransplant Diabetes Mellitus After Kidney Transplantation With Different Immunosuppressive Agents J. Romagnoli, F. Citterio, P. Violi, G. Nanni, and M. Castagneto ABSTRACT Posttransplant diabetes mellitus (PTDM) is a disturbing side effect of immunosuppression. The aim of this study was to evaluate the effect of different immunosuppressive agents on the development of PTDM in renal transplant recipients (KTx). The incidence of PTDM was evaluated in 538 consecutive KTx. Baseline immunosuppression was azathioprine (AZA), cyclosporine (CSA), or tacrolimus (TAC), or sirolimus in combination with calcineurin inhibitors (SIR). All patients received steroids for both induction and maintenance therapy during the first 6 months posttransplantation. Mean follow-up after KTx was 73 ⫾ 53.5 months (range 6 months to 16 years). PTDM was defined as two consecutive blood glucose determinations above 126 mg/dL. Thirty-six of 538 (6.7%) recipients experienced PTDM, 31 of whom required insulin treatment and five oral antidiabetic medications. PTDM occurred at 25.3 ⫾ 38 months posttransplantation in 4.8% of KTx treated with AZA, 4.8% of CSA, 6.5% of KTx treated with TAC and 12.5% of KTx treated with SIR. The time of onset of PTDM was significantly shorter (P ⫽ .003) among TAC (2.1 ⫾ 1.7 months posttransplantation) versus CSA (27.8 ⫾ 34 months). PTDM disappeared in 6 of 36 patients. We conclude that with current levels of immunosuppression, there is no difference in the incidence of PTDM between TAC- and CSA-treated KTx.
P
OSTTRANSPLANT DIABETES MELLITUS (PTDM) is a metabolic complication of immunosuppression after renal transplantation. The incidence of PTDM varies according to the definition adopted, the type of immunosuppression, and risk factors such as recipient age and race.1 Particularly, immunosuppression is considered the major pathogenetic factor in the development of PTDM,2,3 although insulin resistance and relative insulin deficiency are also involved in the pathogenesis.3 The aim of our study was to evaluate the effect of various immuno0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.03.012 690
suppressive agents on the development of PTDM in renal transplant recipients (KTx). PATIENTS AND METHODS Five hundred and thirty-eight patients receiving a kidney allograft between January 1981 and June 2002 who had been followed up for From the Clinica Chirurgica, Catholic University, Rome, Italy. Address reprint requests to Jacopo Romagnoli, MD, Clinica Chirurgica, Universita´ Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy. E-mail: [email protected] © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36, 690 – 691 (2004)
POSTTRANSPLANT DIABETES MELLITUS
691
at least 6 months after transplantation were included in the study. Mean follow-up after KTx was 73 ⫾ 53.5 months (range 6 months to 16 years). There were four KTx groups based on the main immunosuppressant: azathioprine (AZA); cyclosporine (CSA); tacrolimus (TAC); sirolimus ⫹ a calcineurin inhibitor (SIR). All KTx received steroids for both induction and maintenance therapy during the first 6 months posttransplantation. The patient’s charts were retrospectively reviewed to collect data on the incidence of PTDM and immunosuppressive regimen at the time of its occurrence. Data were entered into an Excel (Microsoft) database to obtain median or mean values ⫾ SD. Groups of patients treated with different immunosuppressive agents were compared for age at transplant, body mass index (BMI), incidence, time of occurrence, and duration of PTDM, which was defined according to the American Diabetes Association and World Health Organization experts4 as fasting blood glucose levels of 126 mg/dL or greater confirmed by repeat testing on a different day.
CONCLUSIONS
RESULTS
REFERENCES
Thirty-six of 538 (6.7%) recipients experienced PTDM, 31 of whom required insulin treatment and five of whom required oral antidiabetic medications to normalize blood glucose. There were no statistically significant differences among the four groups in terms of age, BMI, and incidence of PTDM, which occurred 25.3 ⫾ 38 months posttransplantation in 4.8% of KTx treated with AZA, 4.8% of KTx treated with CSA, 6.5% of KTx treated with TAC, and 12.5% KTx treated with of SIR. Time of onset of PTDM was significantly shorter (P ⫽ .003) among the TAC (2.1 ⫾ 1.7 months posttransplantation) versus CSA group (27.8 ⫾ 34 months). Mean immunosuppressant dosages before the development of PTDM were 0.12 mg/kg TAC; 4.7 mg/kg CSA; and 0.04 mg/kg SIR. In 6 of 36 patients (16.1%) PTDM disappeared at 11 ⫾ 21 months after onset (range 8.1 to 32.4 months).
1. Hjelmesaeth J, Hartmann A, Kofstad J, et al: Glucose intolerance after renal transplantation depends upon prednisolone dose and recipient age. Transplantation 64:979, 1997 2. First RM, Gerber DA, Hariharan S, et al: Posttransplant diabetes mellitus in kidney allograft recipients: incidence, risk factors and management. Transplantation 73:379, 2002 3. Jindal RM, Hjelmesaeth J: Impact and management of postransplant diabetes mellitus. Transplantation 70:S85, 2000 4. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 26:S5, 2003 5. Von Kiparski A, Frei D, Uhlschmid G, et al: Post-transplant diabetes mellitus in renal allograft recipients: a matched-pair control study. Nephrol Dial Transplant 5:220, 1990 6. Sumrani NB, Delaney V, Ding ZK, et al: Diabetes mellitus after renal transplantation in the cyclosporine era—an analysis of risk factors. Transplantation 51:343, 1991 7. Andoh TF, Lindsley J, Franceschini N, et al: Synergistic effects of cyclosporine and rapamycin in a chronic nephrotoxicity model. Transplantation 62:311, 1996
The incidence of PTDM was low in our population, although we adopted a sensitive criterion for the definition of diabetes.4 The mean incidence reported in the literature varies between 3.6% and 18%.2,5,6 This study suggests that with current levels of immunosuppression there is no difference in the incidence of PTDM between TAC- and CSA-treated KTx. The relatively higher incidence of PTDM in the SIR group, although not statistically significant, may be related to an intrinsic toxic effect of SIR, which has been described in an experimental model in the rat where SIR, given at a subtherapeutic dose of 0.1 mg/kg in combination with cyclosporine, worsened glucose metabolism and potentiated chronic CSA-induced nephrotoxicity.7