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Incidence of Post-transplantation Diabetes Mellitus Within 1 Year After Kidney Transplantation and Related Factors in Korean Cohort Study
Incidence of Post-transplantation Diabetes Mellitus Within 1 Year After Kidney Transplantation and Related Factors in Korean Cohort Study Jin Hyuk Paeka,b, Seong Sik Kanga,b, Woo Yeong Parka,b, Kyubok Jina,b, Sung Bae Parka,b, Seungyeup Hana,b,*, Chan-Duck Kimc, Han Rod, Sik Leee, Cheol Woong Jungf, Jae Berm Parkg, Kyu Ha Huhh, Jaeseok Yangi, and Curie Ahni,j, the KNOW-KT Study Group a Department of Internal Medicine, Keimyung University School of Medicine Daegu, Korea; bKeimyung University Kidney Institute, Daegu, Korea; cDepartment of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Korea; dDepartment of Internal Medicine, Gachon University, Gil Hospital, Incheon, Korea; eDepartment of Internal Medicine, Chonbuk National University Hospital, Jeonju, Korea; fDepartment of Surgery, Korea University College of Medicine, Seoul, Korea; gDepartment of Surgery, Sungkyunkwan University, Seoul Samsung Medical Center, Seoul, Korea; hDepartment of Surgery, Yonsei University College of Medicine, Seoul, Korea; iTransplantation Center, Seoul National University Hospital, Seoul, Korea; and j Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
ABSTRACT Background. Post-transplantation diabetes mellitus (PTDM) is associated with a higher risk of mortality and graft loss. The reported incidence of PTDM after kidney transplantation (KT) varies from 10% to 74% and varies by country and ethnicity. There are few reports of nationwide cohort studies on PTDM incidence and related factors in Korea. The purpose of this study was to evaluate incidence of PTDM and related factors within 1 year after KT in Korea. Methods. The KoreaN cohort study for Outcome in patients With Kidney Transplantation (KNOW-KT) enrolled 1080 recipients from July 2012 to August 2016. This study included 723 recipients, excluding 273 patients with pretransplant DM and 84 patients who were lost from follow-up within 1 year after KT. Results. Among 723 recipients, 85 (11.8%) recipients were diagnosed and treated with PTDM. Recipient age, HLA mismatches, hemoglobin A1c (HbA1c), waist-hip ratio (WHR), and use of prednisolone were significantly higher in PTDM group than the nondiabetic group. In the multivariable logistic regression analysis, independent risk factors for PTDM were older recipient age, higher WHR, and HbA1c before KT. Conclusion. The incidence of PTDM was 11.8% in a nationwide Korean cohort study. The factors related to the development of PTDM within 1 year after KT were older recipient age and higher WHR, and HbA1c levels before KT. In recipients with high WHR, it is important to control pretransplant abdominal obesity to prevent PTDM after KT.
T
HE SURVIVAL time of kidney transplantation (KT) recipients and graft have been improving, and the importance of long-term metabolic complications is emerging. Post-transplantation diabetes mellitus (PTDM) is a common metabolic complication after KT and is associated with a higher risk of cardiovascular disease, infection, and overall graft loss [1,2]. The reported incidence of PTDM after KT varies from 10% to 74%, depending on
ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, XX, 1e4 (2019)
This work was supported by the Research Program funded by the Korea Centers for Disease Control and Prevention (2012E3301100, 2013E3301600, 2013E3301601, 2013E3301602, 2016E3300200, 2016E3300201). *Address correspondence to Seungyeup Han, MD, PhD, Department of Internal Medicine, Keimyung University School of Medicine, Keimyung University Kidney Institute, 56 Dalseong-ro, Jung-gu, Daegu 41931, Korea. Tel.: þ82-53-250-7399, Fax: þ82-53-253-7976. E-mail: [email protected] 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.02.054
1
2
country, ethnicity, and diagnostic criteria [3]. Previous studies have identified risk factors for the development of PTDM such as older age, obesity, genetic background, use of immunosuppressants, and hepatitis C virus infection [3,4]. However, there are few reports of nationwide cohort studies on PTDM incidence and related factors in Korea. Therefore, we conducted this study to investigate the incidence of PTDM and related factors within 1 year after KT in the Korean population. PATIENTS AND METHODS Study Design The KoreaN cohort study for Outcome in patients With Kidney Transplantation (KNOW-KT) is a multicenter, observational, 9-year longitudinal cohort study in the Republic of Korea [5]. From July 2012 to August 2016, a total of 1080 KT recipients were enrolled in the study. Patients were excluded if they had diabetes mellitus at the time of transplantation (n ¼ 273) and if they were lost to follow-up (n ¼ 84). This study included 723 KT recipients. The institutional review board of each participating center approved this study, and informed consent was taken from all study participants.
MEASUREMENTS AND DEFINITIONS
Demographic characteristics and clinical history were reviewed. We investigated donor and recipient age at KT, sex, comorbidity, number of HLA mismatches, presence of donor specific antibody, immunosuppressants, proportion of acute rejection, delayed graft function, body mass index (BMI), waist-hip ratio (WHR), hemoglobin A1c (HbA1c), fasting glucose, ferritin, and transferrin saturation. We defined PTDM according to the American Diabetes Association criteria [6] and a need for anti-diabetic drugs at 1 year after KT. BMI was calculated using the following formula: BMI ¼ body weight (kg)/height (m)2 and abdominal obesity was defined as WHR above 0.90 for men and above 0.85 for women according to World Health Organization recommendation [7]. Acute rejection was diagnosed by percutaneous allograft biopsy results. Statistical Analyses
Continuous variables were expressed as mean standard deviation, and categorical variables were presented as frequencies and percentages. The Student t test was used for continuous variables and c2 test was used for analyzing categorical variables. Logistic regression analyses were used to identify the independent risk factors for PTDM. We consider a value of P < .05 to be statistically significant. All data analyses were performed using SPSS version 20 (SPSS Inc., Chicago, IL, USA). RESULTS
A total of 723 KT recipients were enrolled in the study. The mean age was 43.8 11.7 years, and 427 (59.1%) were male. Among 723 recipients, 85 (11.8%) recipients were diagnosed and treated with PTDM. Baseline characteristics
PAEK, KANG, PARK ET AL Table 1. Comparison of Baseline Characteristics Between PostTransplantation Diabetes Mellitus Group and Nondiabetic Group Variables
PTDM Group (n ¼ 85)
Recipient Age (years) 50.3 10.0 Male, n (%) 56 (65.9) Smoking, n (%) 48 (57.1) Comorbidity, n (%) Hypertension 75 (88.2) Dyslipidemia 28 (32.9) Hepatitis C virus 0 (0) infection Donor Age (years) 44.7 10.5 Deceased donor, n (%) 19 (22.4) Comorbidity, n (%) Diabetes mellitus 1 (1.2) Hypertension 11 (13.1) HLA mismatches 3.8 1.4 Presence of DSA, n (%) 8 (9.9) Body mass index (kg/m2) 23.4 3.1 Waist-hip ratio 0.92 0.1 Hemoglobin A1c (%) 5.5 0.5 Fasting glucose (mg/dL) 104.8 27.8 Ferritin (ng/mL) 193.9 155.9 Transferrin saturation 29.4 16.3
Nondiabetic Group (n ¼ 638)
P
42.9 11.6 371 (58.2) 273 (43.0)
< .001 .173 .014
569 (89.2) 168 (26.3) 7 (1.1)
.792 .198 > .999
44.6 11.8 120 (18.8) 23 (3.6) 85 (13.3) 3.2 1.7 73 (13.0) 22.2 3.3 0.88 0.1 5.2 0.5 101.1 26.6 200.4 240.8 34.9 19.2
.937 .464 .344 .950 .002 .430 .002 < .001 < .001 .223 .814 .015
Values are expressed as means standard deviations, n (%). Abbreviation: DSA, donor specific antibody; HLA, human leukocyte antigen.
of patients in this study are shown in Table 1. PTDM group had significantly higher recipient age (P < .001), proportion of smoker (P ¼ .014), number of HLA mismatches (P ¼ .002), BMI (P ¼ .002), WHR (P < .001), and HbA1c level (P < .001) than the nondiabetic group. Transferrin saturation was significantly lower in the PTDM group than the nondiabetic group (P ¼ .015). Clinical parameters and laboratory findings at 1 year after KT are shown in Table 2. The episode of acute rejection (P ¼ .012), WHR (P < .001), HbA1c (P < .001), and fasting Table 2. Comparison of Clinical Parameters and Laboratory Findings at 1 Year After Kidney Transplantation Between PostTransplantation Diabetes Mellitus Group and Nondiabetic Group
Variables
Graft loss, n (%) Delayed graft function, n (%) Acute rejection, n (%) Body mass index (kg/m2) Waist-hip ratio Hemoglobin A1c (%) Fasting glucose (mg/dL) Ferritin (ng/mL) Transferrin saturation
PTDM Group (n ¼ 85)
Nondiabetic Group (n ¼ 638)
P
0 (0) 0 (0)
9 (1.4) 1 (0.2)
.609 > .999
14 (16.5) 22.7 2.9
52 (8.2) 22.2 3.1
0.91 0.1 6.3 0.8 111.1 22.1
0.87 0.1 5.6 0.6 100.1 20.6
120.3 130.5 28.9 13.5
144.4 204.8 29.9 15.1
Values are expressed as means standard deviations, n (%).
.012 .147 < .001 < .001 < .001 .313 .570
POST-TRANSPLANTATION DIABETES MELLITUS
3
P ¼ .002) were independent risk factors for PTDM after KT after adjusting for the selected variables in the univariable analysis (Table 4).
Table 3. Comparison of Induction Therapy and Immunosuppressants at 1 Year After Kidney Transplantation Between Post-Transplantation Diabetes Mellitus Group and Nondiabetic Group
Variables
PTDM Group (n ¼ 85)
Nondiabetic Group (n ¼ 638)
Induction therapy, n (%) Basiliximab 81 (95.3) 571 (89.5) Thymoglobulin 4 (4.7) 71 (11.1) Immunosuppressants at 1 year after KT, n (%) Tacrolimus 81 (95.3) 598 (93.7) Cyclosporine 3 (3.5) 33 (5.2) MMF 63 (74.1) 501 (78.5) Sirolimus 8 (9.4) 48 (7.5) Everolimus 1 (1.2) 15 (2.4) Prednisolone 85 (100) 582 (91.2) Immunosuppressant concentrations at 1 year after KT Tacrolimus concentration (C0) 6.2 2.3 6.0 2.3 Cyclosporine concentration (C0) 117.2 44.3 98.7 57.7
DISCUSSION P
.092 .068
.571 .798 .357 .541 .709 .004
.384 .593
Values are expressed as means standard deviations, n (%). Abbreviations: KT, kidney transplantation; MMF, mycophenolate mofetil.
glucose level (P < .001) were significantly higher in the PTDM group than the nondiabetic group. However, there were no statistical differences in graft loss, delayed graft function, BMI, and transferrin saturation between the PTDM group and nondiabetic group. In PTDM group, proportion of prednisolone prescription was significantly higher than the nondiabetic group at 1 year after KT (P ¼ .004). However, there were no significant differences in induction therapy, use of immunosuppressants except prednisolone at 1 year after KT, and trough level of immunosuppressants at 1 year after KT between the PTDM group and nondiabetic group (Table 3). In multivariable analysis, recipient age (odds ratio [OR], 1.043; 95% confidence interval [CI], 1.015e1.071; P ¼ .002), WHR (OR, 1.043; 95% CI, 1.015e1.071; P ¼ .002), and HbA1c before KT (OR, 1.043; 95% CI, 1.015e1.071;
This was the multicenter observational study to evaluate the incidence and risk factors for PTDM in Korea. In the present study, we observed that the incidence of PTDM was 11.8% in our cohort. We found that older recipient age and higher WHR and HbA1c level before KT were independent risk factors for PTDM within 1 year after KT. The prevalence of PTDM after KT varies from 10% to 74%, based on country, ethnicity, and diagnostic criteria [3]. In the Korean population, the incidence of PTDM at 1 year after KT was reported between 20.4% and 39% in previous studies [8,9]. In our group, the incidence of PTDM was 11.8%, and this result was lower than previous studies. The variation may be due to the differences in diagnostic criteria. Since we defined PTDM group as who diagnosed PTDM and were prescribed anti-diabetic medicines at 1 year after KT, patients who were diagnosed with PTDM in the early stage of transplantation and recovered may have been excluded in the analysis. Older recipient age is a well-established risk factor for PTDM in many reports [3,4,8,10]. It is associated with physiological changes that the function of pancreatic beta cell decreases as age increases. Hyperglycemia before transplantation is also an important risk factor for PTDM in previous studies [8,10]. These results were consistent with our results. Obesity is a major cause of type 2 diabetes in the general population as well as in the transplant patients by increasing peripheral insulin resistance [11]. In our study, BMI and WHR were significantly higher in the PTDM group than the nondiabetic group, and higher WHR was identified as an independent risk factor for PTDM. It has been suggested that the distribution of body fat had an important role for insulin resistance and WHR is a surrogate marker of abdominal obesity [10]. Moreover, recent study revealed causal relationship between abdominal obesity and type 2 diabetes by Mendelian randomization analyses [12]. Our study supported these results in KT recipients.
Table 4. Clinical Predictors for PTDM Within 1 Year After Kidney Transplantation in Logistic Regression Analysis Univariable
Multivariable
Variables
OR
95% CI
P Value
OR
95% CI
P Value
Sex (male) Use of tacrolimus Acute rejection Body mass index HLA mismatches Transferrin saturation Recipient age (years) Waist-hip ratio > 0.9 (men), > 0.85 (women) HbA1c before KT
1.390 0.738 2.222 1.109 1.251 0.982 1.046 3.946 2.921
0.864e2.235 0.257e2.118 1.172e4.212 1.038e1.185 1.086e1.441 0.968e0.997 1.019e1.074 2.209e7.049 1.767e4.831
.175 .572 .014 .002 .002 .016 .001 < .001 < .001
2.373 1.038 1.163 0.986 1.043 3.674 3.003
0.973e5.788 0.949e1.135 0.984e1.373 0.969e1.003 1.015e1.071 1.949-6.924 1.671e5.396
.058 .413 .076 .099 .002 < .001 < .001
Abbreviations: CI, confidence interval; HbA1c, hemoglobin A1c; HLA, human leukocyte antigen; OR, odds ratio.
4
Calcineurin inhibitors are associated with insulin resistance and suppression of insulin secretion [13]. The hyperglycemic effect of calcineurin inhibitors has been reported in previous studies [3,8,10]. However, diabetogenic potency between tacrolimus and cyclosporine is controversial. Although the more diabetogenic potency of tacrolimus compared to cyclosporine has been revealed in a previous study [14], our group showed that the use of tacrolimus was not associated with the development of PTDM. In recent years, the target trough level of tacrolimus was lower than in the past. This may affect the results, and these results were in concordance with recent studies [1,8]. In the general population, low transferrin saturation is associated with an increased risk of impaired fasting glucose and insulin resistance [15]. In our study, transferrin saturation was significantly lower in the PTDM group compared to the nondiabetic group. However, lower transferrin saturation was not an independent risk factor for PTDM in multivariable analysis. This may be due to the differences in study population. We did not exclude menopausal women in the study enrollment, and this may contribute to the differences in serum iron indices. The present study had some limitations. First, we cannot exclude selection bias. Second, we investigated the incidence of PTDM at 1 year after KT and could not compare PTDM according to the time of onset. Third, each center had a different immunosuppressant protocol, and these variations in immunosuppression regimen may have affected the incidence of PTDM. CONCLUSION
The incidence of PTDM was 11.8% in a nationwide Korean cohort study. The current study demonstrated that risk factors related to the development of PTDM within 1 year after KT were older recipient age and higher WHR and HbA1c levels before KT. In recipients with high WHR, it is important to control pretransplant abdominal obesity to prevent PTDM after KT. REFERENCES [1] Siraj ES, Abacan C, Chinnappa P, Wojtowicz J, Braun W. Risk factors and outcomes associated with posttransplant diabetes
PAEK, KANG, PARK ET AL mellitus in kidney transplant recipients. Transplant Proc 2010;42: 1685e9. [2] Eide IA, Halden TAS, Hartmann A, Dahle DO, Asberg A, Jenssen T. Associations between posttransplantation diabetes mellitus and renal graft survival. Transplantation 2017;101: 1282e9. [3] Shivaswamy V, Boerner B, Larsen J. Post-transplant diabetes mellitus: causes, treatment, and impact on outcomes. Endocr Rev 2016;37:37e61. [4] Han E, Kim MS, Kim YS, Kang ES. Risk assessment and management of post-transplant diabetes mellitus. Metabolism 2016;65:1559e69. [5] Yang J, Lee J, Huh KH, et al. KNOW-KT (Korean cohort study for outcome in patients with kidney transplantation: a 9-year longitudinal cohort study): study rationale and methodology. BMC Nephrol 2014;15:77. [6] Sharif A, Hecking M, de Vries AP, et al. Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: recommendations and future directions. Am J Transplant 2014;14:1992e2000. [7] World Health Organization. Waist circumference and waisthip ratio: report of a WHO expert consultation, Geneva. Geneva, Switzerland: World Health Organization; 2011. p. 8e11. December 2008. [8] Yu H, Kim H, Baek CH, et al. Risk factors for new-onset diabetes mellitus after living donor kidney transplantation in Koreada retrospective single center study. BMC Nephrol 2016;17: 106. [9] Hur KY, Kim MS, Kim YS, et al. Risk factors associated with the onset and progression of posttransplantation diabetes in renal allograft recipients. Diabetes Care 2007;30: 609e15. [10] Pham PT, Pham PM, Pham SV, Pham PA, Pham PC. New onset diabetes after transplantation (NODAT): an overview. Diabetes Metab Syndr Obes 2011;4:175e86. [11] Parikh CR, Klem P, Wong C, Yalavarthy R, Chan L. Obesity as an independent predictor of posttransplant diabetes mellitus. Transplant Proc 2003;35:2922e6. [12] Emdin CA, Khera AV, Natarajan P, et al. Genetic association of waist-to-hip ratio with cardiometabolic traits, type 2 diabetes, and coronary heart disease. JAMA 2017;317:626e34. [13] Ozbay LA, Smidt K, Mortensen DM, Carstens J, Jorgensen KA, Rungby J. Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in inse1e beta-cells. Br J Pharmacol 2011;162:136e46. [14] Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and meta-analysis. Am J Transplant 2004;4: 583e95. [15] Park RJ, Moon JD. Low transferrin saturation is associated with impaired fasting glucose and insulin resistance in the south Korean adults: the 2010 Korean national health and nutrition examination survey. Diabet Med 2015;32:673e8.
ABSTRACT Background. Post-transplantation diabetes mellitus (PTDM) is associated with a higher risk of mortality and graft loss. The reported incidence of PTDM after kidney transplantation (KT) varies from 10% to 74% and varies by country and ethnicity. There are few reports of nationwide cohort studies on PTDM incidence and related factors in Korea. The purpose of this study was to evaluate incidence of PTDM and related factors within 1 year after KT in Korea. Methods. The KoreaN cohort study for Outcome in patients With Kidney Transplantation (KNOW-KT) enrolled 1080 recipients from July 2012 to August 2016. This study included 723 recipients, excluding 273 patients with pretransplant DM and 84 patients who were lost from follow-up within 1 year after KT. Results. Among 723 recipients, 85 (11.8%) recipients were diagnosed and treated with PTDM. Recipient age, HLA mismatches, hemoglobin A1c (HbA1c), waist-hip ratio (WHR), and use of prednisolone were significantly higher in PTDM group than the nondiabetic group. In the multivariable logistic regression analysis, independent risk factors for PTDM were older recipient age, higher WHR, and HbA1c before KT. Conclusion. The incidence of PTDM was 11.8% in a nationwide Korean cohort study. The factors related to the development of PTDM within 1 year after KT were older recipient age and higher WHR, and HbA1c levels before KT. In recipients with high WHR, it is important to control pretransplant abdominal obesity to prevent PTDM after KT.
T
HE SURVIVAL time of kidney transplantation (KT) recipients and graft have been improving, and the importance of long-term metabolic complications is emerging. Post-transplantation diabetes mellitus (PTDM) is a common metabolic complication after KT and is associated with a higher risk of cardiovascular disease, infection, and overall graft loss [1,2]. The reported incidence of PTDM after KT varies from 10% to 74%, depending on
ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, XX, 1e4 (2019)
This work was supported by the Research Program funded by the Korea Centers for Disease Control and Prevention (2012E3301100, 2013E3301600, 2013E3301601, 2013E3301602, 2016E3300200, 2016E3300201). *Address correspondence to Seungyeup Han, MD, PhD, Department of Internal Medicine, Keimyung University School of Medicine, Keimyung University Kidney Institute, 56 Dalseong-ro, Jung-gu, Daegu 41931, Korea. Tel.: þ82-53-250-7399, Fax: þ82-53-253-7976. E-mail: [email protected] 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.02.054
1
2
country, ethnicity, and diagnostic criteria [3]. Previous studies have identified risk factors for the development of PTDM such as older age, obesity, genetic background, use of immunosuppressants, and hepatitis C virus infection [3,4]. However, there are few reports of nationwide cohort studies on PTDM incidence and related factors in Korea. Therefore, we conducted this study to investigate the incidence of PTDM and related factors within 1 year after KT in the Korean population. PATIENTS AND METHODS Study Design The KoreaN cohort study for Outcome in patients With Kidney Transplantation (KNOW-KT) is a multicenter, observational, 9-year longitudinal cohort study in the Republic of Korea [5]. From July 2012 to August 2016, a total of 1080 KT recipients were enrolled in the study. Patients were excluded if they had diabetes mellitus at the time of transplantation (n ¼ 273) and if they were lost to follow-up (n ¼ 84). This study included 723 KT recipients. The institutional review board of each participating center approved this study, and informed consent was taken from all study participants.
MEASUREMENTS AND DEFINITIONS
Demographic characteristics and clinical history were reviewed. We investigated donor and recipient age at KT, sex, comorbidity, number of HLA mismatches, presence of donor specific antibody, immunosuppressants, proportion of acute rejection, delayed graft function, body mass index (BMI), waist-hip ratio (WHR), hemoglobin A1c (HbA1c), fasting glucose, ferritin, and transferrin saturation. We defined PTDM according to the American Diabetes Association criteria [6] and a need for anti-diabetic drugs at 1 year after KT. BMI was calculated using the following formula: BMI ¼ body weight (kg)/height (m)2 and abdominal obesity was defined as WHR above 0.90 for men and above 0.85 for women according to World Health Organization recommendation [7]. Acute rejection was diagnosed by percutaneous allograft biopsy results. Statistical Analyses
Continuous variables were expressed as mean standard deviation, and categorical variables were presented as frequencies and percentages. The Student t test was used for continuous variables and c2 test was used for analyzing categorical variables. Logistic regression analyses were used to identify the independent risk factors for PTDM. We consider a value of P < .05 to be statistically significant. All data analyses were performed using SPSS version 20 (SPSS Inc., Chicago, IL, USA). RESULTS
A total of 723 KT recipients were enrolled in the study. The mean age was 43.8 11.7 years, and 427 (59.1%) were male. Among 723 recipients, 85 (11.8%) recipients were diagnosed and treated with PTDM. Baseline characteristics
PAEK, KANG, PARK ET AL Table 1. Comparison of Baseline Characteristics Between PostTransplantation Diabetes Mellitus Group and Nondiabetic Group Variables
PTDM Group (n ¼ 85)
Recipient Age (years) 50.3 10.0 Male, n (%) 56 (65.9) Smoking, n (%) 48 (57.1) Comorbidity, n (%) Hypertension 75 (88.2) Dyslipidemia 28 (32.9) Hepatitis C virus 0 (0) infection Donor Age (years) 44.7 10.5 Deceased donor, n (%) 19 (22.4) Comorbidity, n (%) Diabetes mellitus 1 (1.2) Hypertension 11 (13.1) HLA mismatches 3.8 1.4 Presence of DSA, n (%) 8 (9.9) Body mass index (kg/m2) 23.4 3.1 Waist-hip ratio 0.92 0.1 Hemoglobin A1c (%) 5.5 0.5 Fasting glucose (mg/dL) 104.8 27.8 Ferritin (ng/mL) 193.9 155.9 Transferrin saturation 29.4 16.3
Nondiabetic Group (n ¼ 638)
P
42.9 11.6 371 (58.2) 273 (43.0)
< .001 .173 .014
569 (89.2) 168 (26.3) 7 (1.1)
.792 .198 > .999
44.6 11.8 120 (18.8) 23 (3.6) 85 (13.3) 3.2 1.7 73 (13.0) 22.2 3.3 0.88 0.1 5.2 0.5 101.1 26.6 200.4 240.8 34.9 19.2
.937 .464 .344 .950 .002 .430 .002 < .001 < .001 .223 .814 .015
Values are expressed as means standard deviations, n (%). Abbreviation: DSA, donor specific antibody; HLA, human leukocyte antigen.
of patients in this study are shown in Table 1. PTDM group had significantly higher recipient age (P < .001), proportion of smoker (P ¼ .014), number of HLA mismatches (P ¼ .002), BMI (P ¼ .002), WHR (P < .001), and HbA1c level (P < .001) than the nondiabetic group. Transferrin saturation was significantly lower in the PTDM group than the nondiabetic group (P ¼ .015). Clinical parameters and laboratory findings at 1 year after KT are shown in Table 2. The episode of acute rejection (P ¼ .012), WHR (P < .001), HbA1c (P < .001), and fasting Table 2. Comparison of Clinical Parameters and Laboratory Findings at 1 Year After Kidney Transplantation Between PostTransplantation Diabetes Mellitus Group and Nondiabetic Group
Variables
Graft loss, n (%) Delayed graft function, n (%) Acute rejection, n (%) Body mass index (kg/m2) Waist-hip ratio Hemoglobin A1c (%) Fasting glucose (mg/dL) Ferritin (ng/mL) Transferrin saturation
PTDM Group (n ¼ 85)
Nondiabetic Group (n ¼ 638)
P
0 (0) 0 (0)
9 (1.4) 1 (0.2)
.609 > .999
14 (16.5) 22.7 2.9
52 (8.2) 22.2 3.1
0.91 0.1 6.3 0.8 111.1 22.1
0.87 0.1 5.6 0.6 100.1 20.6
120.3 130.5 28.9 13.5
144.4 204.8 29.9 15.1
Values are expressed as means standard deviations, n (%).
.012 .147 < .001 < .001 < .001 .313 .570
POST-TRANSPLANTATION DIABETES MELLITUS
3
P ¼ .002) were independent risk factors for PTDM after KT after adjusting for the selected variables in the univariable analysis (Table 4).
Table 3. Comparison of Induction Therapy and Immunosuppressants at 1 Year After Kidney Transplantation Between Post-Transplantation Diabetes Mellitus Group and Nondiabetic Group
Variables
PTDM Group (n ¼ 85)
Nondiabetic Group (n ¼ 638)
Induction therapy, n (%) Basiliximab 81 (95.3) 571 (89.5) Thymoglobulin 4 (4.7) 71 (11.1) Immunosuppressants at 1 year after KT, n (%) Tacrolimus 81 (95.3) 598 (93.7) Cyclosporine 3 (3.5) 33 (5.2) MMF 63 (74.1) 501 (78.5) Sirolimus 8 (9.4) 48 (7.5) Everolimus 1 (1.2) 15 (2.4) Prednisolone 85 (100) 582 (91.2) Immunosuppressant concentrations at 1 year after KT Tacrolimus concentration (C0) 6.2 2.3 6.0 2.3 Cyclosporine concentration (C0) 117.2 44.3 98.7 57.7
DISCUSSION P
.092 .068
.571 .798 .357 .541 .709 .004
.384 .593
Values are expressed as means standard deviations, n (%). Abbreviations: KT, kidney transplantation; MMF, mycophenolate mofetil.
glucose level (P < .001) were significantly higher in the PTDM group than the nondiabetic group. However, there were no statistical differences in graft loss, delayed graft function, BMI, and transferrin saturation between the PTDM group and nondiabetic group. In PTDM group, proportion of prednisolone prescription was significantly higher than the nondiabetic group at 1 year after KT (P ¼ .004). However, there were no significant differences in induction therapy, use of immunosuppressants except prednisolone at 1 year after KT, and trough level of immunosuppressants at 1 year after KT between the PTDM group and nondiabetic group (Table 3). In multivariable analysis, recipient age (odds ratio [OR], 1.043; 95% confidence interval [CI], 1.015e1.071; P ¼ .002), WHR (OR, 1.043; 95% CI, 1.015e1.071; P ¼ .002), and HbA1c before KT (OR, 1.043; 95% CI, 1.015e1.071;
This was the multicenter observational study to evaluate the incidence and risk factors for PTDM in Korea. In the present study, we observed that the incidence of PTDM was 11.8% in our cohort. We found that older recipient age and higher WHR and HbA1c level before KT were independent risk factors for PTDM within 1 year after KT. The prevalence of PTDM after KT varies from 10% to 74%, based on country, ethnicity, and diagnostic criteria [3]. In the Korean population, the incidence of PTDM at 1 year after KT was reported between 20.4% and 39% in previous studies [8,9]. In our group, the incidence of PTDM was 11.8%, and this result was lower than previous studies. The variation may be due to the differences in diagnostic criteria. Since we defined PTDM group as who diagnosed PTDM and were prescribed anti-diabetic medicines at 1 year after KT, patients who were diagnosed with PTDM in the early stage of transplantation and recovered may have been excluded in the analysis. Older recipient age is a well-established risk factor for PTDM in many reports [3,4,8,10]. It is associated with physiological changes that the function of pancreatic beta cell decreases as age increases. Hyperglycemia before transplantation is also an important risk factor for PTDM in previous studies [8,10]. These results were consistent with our results. Obesity is a major cause of type 2 diabetes in the general population as well as in the transplant patients by increasing peripheral insulin resistance [11]. In our study, BMI and WHR were significantly higher in the PTDM group than the nondiabetic group, and higher WHR was identified as an independent risk factor for PTDM. It has been suggested that the distribution of body fat had an important role for insulin resistance and WHR is a surrogate marker of abdominal obesity [10]. Moreover, recent study revealed causal relationship between abdominal obesity and type 2 diabetes by Mendelian randomization analyses [12]. Our study supported these results in KT recipients.
Table 4. Clinical Predictors for PTDM Within 1 Year After Kidney Transplantation in Logistic Regression Analysis Univariable
Multivariable
Variables
OR
95% CI
P Value
OR
95% CI
P Value
Sex (male) Use of tacrolimus Acute rejection Body mass index HLA mismatches Transferrin saturation Recipient age (years) Waist-hip ratio > 0.9 (men), > 0.85 (women) HbA1c before KT
1.390 0.738 2.222 1.109 1.251 0.982 1.046 3.946 2.921
0.864e2.235 0.257e2.118 1.172e4.212 1.038e1.185 1.086e1.441 0.968e0.997 1.019e1.074 2.209e7.049 1.767e4.831
.175 .572 .014 .002 .002 .016 .001 < .001 < .001
2.373 1.038 1.163 0.986 1.043 3.674 3.003
0.973e5.788 0.949e1.135 0.984e1.373 0.969e1.003 1.015e1.071 1.949-6.924 1.671e5.396
.058 .413 .076 .099 .002 < .001 < .001
Abbreviations: CI, confidence interval; HbA1c, hemoglobin A1c; HLA, human leukocyte antigen; OR, odds ratio.
4
Calcineurin inhibitors are associated with insulin resistance and suppression of insulin secretion [13]. The hyperglycemic effect of calcineurin inhibitors has been reported in previous studies [3,8,10]. However, diabetogenic potency between tacrolimus and cyclosporine is controversial. Although the more diabetogenic potency of tacrolimus compared to cyclosporine has been revealed in a previous study [14], our group showed that the use of tacrolimus was not associated with the development of PTDM. In recent years, the target trough level of tacrolimus was lower than in the past. This may affect the results, and these results were in concordance with recent studies [1,8]. In the general population, low transferrin saturation is associated with an increased risk of impaired fasting glucose and insulin resistance [15]. In our study, transferrin saturation was significantly lower in the PTDM group compared to the nondiabetic group. However, lower transferrin saturation was not an independent risk factor for PTDM in multivariable analysis. This may be due to the differences in study population. We did not exclude menopausal women in the study enrollment, and this may contribute to the differences in serum iron indices. The present study had some limitations. First, we cannot exclude selection bias. Second, we investigated the incidence of PTDM at 1 year after KT and could not compare PTDM according to the time of onset. Third, each center had a different immunosuppressant protocol, and these variations in immunosuppression regimen may have affected the incidence of PTDM. CONCLUSION
The incidence of PTDM was 11.8% in a nationwide Korean cohort study. The current study demonstrated that risk factors related to the development of PTDM within 1 year after KT were older recipient age and higher WHR and HbA1c levels before KT. In recipients with high WHR, it is important to control pretransplant abdominal obesity to prevent PTDM after KT. REFERENCES [1] Siraj ES, Abacan C, Chinnappa P, Wojtowicz J, Braun W. Risk factors and outcomes associated with posttransplant diabetes
PAEK, KANG, PARK ET AL mellitus in kidney transplant recipients. Transplant Proc 2010;42: 1685e9. [2] Eide IA, Halden TAS, Hartmann A, Dahle DO, Asberg A, Jenssen T. Associations between posttransplantation diabetes mellitus and renal graft survival. Transplantation 2017;101: 1282e9. [3] Shivaswamy V, Boerner B, Larsen J. Post-transplant diabetes mellitus: causes, treatment, and impact on outcomes. Endocr Rev 2016;37:37e61. [4] Han E, Kim MS, Kim YS, Kang ES. Risk assessment and management of post-transplant diabetes mellitus. Metabolism 2016;65:1559e69. [5] Yang J, Lee J, Huh KH, et al. KNOW-KT (Korean cohort study for outcome in patients with kidney transplantation: a 9-year longitudinal cohort study): study rationale and methodology. BMC Nephrol 2014;15:77. [6] Sharif A, Hecking M, de Vries AP, et al. Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: recommendations and future directions. Am J Transplant 2014;14:1992e2000. [7] World Health Organization. Waist circumference and waisthip ratio: report of a WHO expert consultation, Geneva. Geneva, Switzerland: World Health Organization; 2011. p. 8e11. December 2008. [8] Yu H, Kim H, Baek CH, et al. Risk factors for new-onset diabetes mellitus after living donor kidney transplantation in Koreada retrospective single center study. BMC Nephrol 2016;17: 106. [9] Hur KY, Kim MS, Kim YS, et al. Risk factors associated with the onset and progression of posttransplantation diabetes in renal allograft recipients. Diabetes Care 2007;30: 609e15. [10] Pham PT, Pham PM, Pham SV, Pham PA, Pham PC. New onset diabetes after transplantation (NODAT): an overview. Diabetes Metab Syndr Obes 2011;4:175e86. [11] Parikh CR, Klem P, Wong C, Yalavarthy R, Chan L. Obesity as an independent predictor of posttransplant diabetes mellitus. Transplant Proc 2003;35:2922e6. [12] Emdin CA, Khera AV, Natarajan P, et al. Genetic association of waist-to-hip ratio with cardiometabolic traits, type 2 diabetes, and coronary heart disease. JAMA 2017;317:626e34. [13] Ozbay LA, Smidt K, Mortensen DM, Carstens J, Jorgensen KA, Rungby J. Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in inse1e beta-cells. Br J Pharmacol 2011;162:136e46. [14] Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and meta-analysis. Am J Transplant 2004;4: 583e95. [15] Park RJ, Moon JD. Low transferrin saturation is associated with impaired fasting glucose and insulin resistance in the south Korean adults: the 2010 Korean national health and nutrition examination survey. Diabet Med 2015;32:673e8.