- Email: [email protected]
New-Onset Diabetes After Transplantation: Comparison Between a Cyclosporine-Based and a Tacrolimus-Based Immunosuppressive Regimen
New-Onset Diabetes After Transplantation: Comparison Between a Cyclosporine-Based and a Tacrolimus-Based Immunosuppressive Regimen A. Zolota*, G. Miserlis, F. Solonaki, A. Tranda, N. Antoniadis, G. Imvrios, and I. Fouzas Surgery Clinic of Transplantation, Aristotle University of Thessaloniki, Ippokrateio General Hospital, Thessaloniki, Greece
ABSTRACT Introduction. New-onset diabetes after transplantation (NODAT) is a complication of renal transplantation (RT) with an adverse effect on graft survival. Objectives. The purpose of the present study was to compare modifiable or non-modifiable clinical and laboratory parameters as well as the course of patients and transplants between 2 groups of RT recipients with NODAT in relation to the use of either a cyclosporine-based (group A) or a tacrolimus-based immunosuppressive regimen (group B). Materials and Methods. Retrospectively comparing 66 renal transplant recipients with NODAT, multiple clinical, and laboratory parameters were investigated. For statistical analysis, the c2 test, the Student t test, and the patient and graft survival or the KaplanMeier analysis from the statistical software SPSS 22.0 for Windows were used. Results. There was no statistically significant difference in association with the majority of the investigated parameters. In group B (tacrolimus [Tac]), more patients had HbA1c >7.2% at 3 years after RT. The mean value of systolic blood pressure was higher in group A (cyclosporine [CsA]) at 6 months and at 1 year after RT. More patients in group A (CsA) experienced at least one acute rejection episode. Finally, greater levels of cold ischemia time were recorded in group B (Tac) and statistically significant difference was found in connection with the patient and graft survival in the fourth year after RT. Conclusions. NODAT in patients on tacrolimus requires the adjustment of modifiable clinical and metabolic parameters and possible change of the immunosuppressive regimen to a cyclosporine-based one.
O
NE serious complication which occurs after transplantation and can not easily be avoided is diabetes mellitus. Although it has been associated with all solid organ transplantations, the development of diabetes is more common after renal transplantation (RT). Nowadays, the term “post-transplant diabetes mellitus” has been replaced by the term “new-onset diabetes after transplantation” (NODAT). The term NODAT is widely used so as to include all new cases of diabetes mellitus that are attributed to immunosuppression. The definition of NODAT includes the need for insulin therapy after transplantation in patients without a known history of diabetes. The exclusion of all the cases of preexisting diabetes is difficult because glucose tolerance tests have not been established yet as a common practice before transplantation [1,2].
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For the past 20 years, graft survival rates have generally increased and as a result, patients who get diagnosed with diabetes after transplantation have to cope with their health problem for a longer period, making complications more likely. Consequently, it is of high importance to keep serum glucose at normal level in order to reduce implications, usually leading to death [1]. The incidence of NODAT depends on many factors such as the patient, the immunosuppressive agent, and the definition given to the term diabetes and has not been precisely *Address correspondence to Apostolia Zolota, Surgery Clinic of Transplantation, Aristotle University of Thessaloniki, Ippokrateio General Hospital, Deligiorgi 9, Thessaloniki, 54642, Thessaloniki, Greece. E-mail: [email protected] ª 2018 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 3386e3391 (2018)
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Table 1. Risk Factors for the Development of NODAT [1,3,6] Risk factors
Origin (Africans-Caribbean Americans-Hispanics) Advanced age (>45 years old) Glucose intolerance (prior to transplantation) Diabetes family history Excessive BMI (>25 kg/m2) Cadaveric donor HLA alleles Hepatitis C infection Immunosuppressive agents Calcineurin inhibitors (cyclosporine, tacrolimus) Corticosteroids Decreased corticosteroids Dyslipidemia (HDL >35 mg/dL and triglycerides >250 mg/dL) High arterial blood pressure (blood pressure >140/190 mmHg Tobacco use Acute rejection syndrome Abbreviations: BMI, body mass index; HDL, high-density lipoprotein; NODAT, new-onset diabetes after transplantation.
estimated so far. When therapeutic regimens where based on the use of steroids and azathioprine, the incidence of NODAT appeared to be approximately 7%-15%. After the initiation of new immunosuppressive agents in combination with decreased dosages of steroids, the rates of newly diagnosed cases of diabetes has not changed and in some cases they tended to increase despite the improvement in graft survival rates. NODAT occurs in 2%-53% of kidney transplant recipients with clinical manifestations ranging from asymptomatic hyperglycemia to ketoacidosis with the risk being greater in the first year after RT [3,4,6]. The risk factors which have been related to NODAT are presented in Table 1 [1,3,6]. Kasiske et al, taking advantage of data from the United States Renal Data System database, estimate the incidence of NODAT after RT to be 9.1% at 3 months, 16% at 1 year, and finally, 24% at 3 years [7]. It is supported that the main pathogenic mechanism which leads to the development of NODAT is low insulin levels due to decreased secretion. It appears that NODAT occurs in the context of preexisting abnormalities in glucose metabolism in
addition with the contribution of immunosuppressive agents. The onset of NODAT takes place soon after transplantation. Especially in patients with susceptibility, NODAT is expected approximately 3 months after RT. Hyperglycemia is not always a sign of NODAT, as it often induced by corticosteroids but resolves soon after transplantation [1]. In case hyperglycemia gets persistent, the diagnosis of NODAT in needed at an early stage because of the possible complications which may occur concerning the cardiovascular system, the eye, and the kidneys. Early diagnosis can be achieved taking under consideration the fact that transplanted patients get controlled at least twice a week for the first month and once a week for the first 3 months. Diabetes also constitutes a common threat among those people who undergo transplantation because of its contribution in transplant rejection and mortality [1,5,8]. The objective of the present study was to compare modifiable or non-modifiable clinical and laboratory parameters, as well as the course of patients and transplants between 2 groups of RT recipients with NODAT in relation to the use of either a cyclosporine-based (group A) or a tacrolimus-based immunosuppressive regimen (group B). This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. MATERIALS AND METHODS Patients The present study is an observational retrospective (cross-sectional) study comparing modifiable or non-modifiable clinical and laboratory parameters, as well as the course of patients and transplants between 2 groups of patients with NODAT after RT in relation to the use of either a cyclosporine-based (CsA, group A) or a tacrolimus-based immunosuppressive regimen (Tac, group B). The sample size was n ¼ 66, and each group consisted of 33 patients (group A: patients, age (mean SD): 49.91 10.25 years vs group B: 33 patients, age (mean SD): 53.27 9.74 years, P ¼ NS).
Statistical Analysis For statistical analysis, the c2 test, the Student t test, and the patient and graft survival or the Kaplan-Meier analysis from the statistical
Table 2. Characteristics of the Sample and Differences Between Group A and Group B Characteristics
Group A (CsA)
Group B (Tac)
Patients (n) Sex (male/female) Age (recipients), mean SD (range) Age (donors), mean SD (range) Type (heart-beating/cadaveric) HLA mm (0/1/2/3/4/5) CMV infection (viremia or infection) HCV infection Body weight (kg), mean SD Before/after Cold ischemia time (min) Delayed graft function Acute rejection episodes
33 22/11 49.91 10.25 (23e66) 47.61 19.19 (12e73) 10/21 2/1/5/17/6/2 8 pts/33 4 73.09 15.30/74.52 17.37
33 20/13 53.27 9.74 (23e66) 47.27 18.38 (2e82) 4/29 0/0/10/9/13/1 10 pts/33 1 72.88 11.70/72.76 10.60
661.97 486.8 6 pts/21 13 pts/33
908.79 411.38 8 pts/29 8 pts/33
Abbreviations: CMV, cytomegalovirus; CsA, cyclosporine; HCV, hepatitis C virus; pts, patients; Tac, tacrolimus.
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Table 3. Primary Disease and Its Distribution Between Groups A and B Primary disease
Group A (CsA)
Group B (Tac)
Chronic glomerulonephritis Acute interstitial nephritis Cystic-urethral retrogression Polycystic kidney disease Hypertensive kidney disease Focal segmental glomerulosclerosis IgA nephropathy Systemic lupus erythematosous Wegener granulomatosis Unknown Alport syndrome
7 3 4 3 2 1 1 1 1 10 -
6 5 2 4 7 2 2 4 1
Abbreviations: CsA, cyclosporine; Tac, tacrolimus.
software SPSS 22.0 for Windows (IBM, Armonk, NY, United States) were used.
RESULTS
In Table 2, demographic characteristics of both groups are presented, while it is noted that no significant difference was found between the 2 groups. In Table 3, a reference is made to the types of primary disease that led to RT. The 2 groups were also compared in relation to the type of transplantation (heart-beating or cadaveric donor), distribution of HLA incompatibility and the hepatitis C virus or cytomegalovirus infection, and no significant difference was found between the 2 groups. Moreover, no significant difference was detected between groups A and B in connection with body weight and delayed graft function during the course of the study. In conclusion, groups A and B were considered totally comparable. More patients in group A (CsA) than in group B (Tac) experienced at least one acute rejection episode without the difference being statistically significant (10/33 vs 8/33, P ¼ NS). Moreover, they were recorded greater levels of cold ischemia time (M SD, min) in group B (Tac) vs group A (CsA) (908.79 411.38 vs 661.97 486.8, P < .05). No statistically significant difference was found in the mean values (SD) of serum creatinine, UP24h, serum glucose, as well as HbA1c between the 2 study groups. However, in group B (Tac), more patients had
HbA1c>7.2% at 3 years after RT (group A: 2/33 vs group B: 9/33, P < .05). Results in connection with the above parameters, derived from the statistical analysis, are presented in Figures 1e3 and in Table 4. The mean value (SD) of systolic blood pressure was higher in group A (CsA) compared to group B (Tac) at 6 months and at 1 year after RT (SD SD mmHg) group A: 134.85 14.92 and 135.61 13.33 vs group B: 126.67 13.32 and 129.55 14.16, P < .05, whereas no significant difference was observed in the rest of the study period. The patient’s diastolic blood pressure was similar at all study intervals. The detailed findings of the statistical analysis are presented in Figure 4. Finally, the immunosuppressive regimen was changed from tacrolimus to cyclosporine in 2 patients during the study period. Table 5 shows the patient and graft survival rates for both groups in the first, third, and fourth year after RT. Cardiovascular disease is considered a basic cause of death among renal transplant recipients. The frequency of such disorders is shown in Table 6. DISCUSSION
In literature, it is supported that both tacrolimus and cyclosporine can lead to the development of diabetes after transplantation although the tacrolimus is associated with greater risk [9e11]. More specifically, incidence of NODAT appears to be higher when using tacrolimus (16.6%) rather than in case of cyclosporine use (9.2%) after transplantation of solid organs. After RT, the value of the above percentages is 15.4% for tacrolimus and 9.2% for cyclosporine, respectively [2]. Cho et al state that screening for diabetes is imperative on a regular basis in renal transplant recipients over 40 years old undergoing a tacrolimus-based regimen [12]. In another study, it was found that after the use of cyclosporine, tacrolimus, or sirolimus in combination with mycophenolate and corticosteroids, NODAT was diagnosed in 7.4% of renal transplant recipients, with no difference between the 3 groups and only a small increase in tacrolimus group [13]. In the present study, no statistically significant difference was found in connection with serum creatinine levels between the 2 groups. Nevertheless, it is thought that the risk
Fig 1. Serum creatinine levels at 1, 3, and 5 years after renal transplant.
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Fig 2. 24-hour albuminuria at 6 months and at 1e5 years after renal transplant.
of doubling serum creatinine after diagnosis of NODAT is 2 times higher, while in recipients with pre-existing diabetes this risk is increased by 6 times [14]. In connection with cardiovascular problems, we concluded that cyclosporine is associated with higher systolic blood pressure at 6 months and at 1 year after RT. Blood pressure and serum cholesterol level were also higher in patients on cyclosporine in the study of Alghhamdi et al [15]. Relevant results were exported by Krämer et al who supported that more patients on cyclosporine received
medication for dislipidaemia and finally developed cardiovascular problems [16]. It is not yet clear whether NODAT can be directly associated with the development of cardiovascular disease. Generally, the metabolic syndrome (insulin resistance, dislipidaemia, and hypertension is considered a phenotype which can predispose for the occurrence of atherosclerosis and features of that syndrome have been identified in patients after RT [17]. Consequently, we recommend that the above classical triangle is included in future studies.
Fig 3. Serum glucose levels at 3 months, at 6 months, and at 1e5 years after renal transplant.
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Table 4. Number of Patients With HbA1c levels >7.2 3 Years After RT Patients with HbA1c >7.2 3 years after RT
Group A
Group B Tac
2 pts/33
9 pts/33
Abbreviations: pts, patients; RT, renal transplantation; Tac, tacrolimus.
There are many studies in favor of tacrolimus use after RT as it is connected with lower percentages of acute rejection during the first months after transplantation and better graft function [10,11,18e20]. In the present study, more patients in group A (CsA) than in group B (Tac) experienced at least one acute rejection episode without the difference being statistically significant. Respectively, Knoll and Bell support that a cyclosporine-based regimen is more likely to cause an acute rejection episode compared with a tacrolimus-based one [21]. Moreover, both groups appear to have high graft survival rates until the third year after transplantation without the difference being statistically significant between them. In contrast, statistically significant difference between group A
and B was detected in the fourth year after RT with the relevant percentages being 97% for cyclosporine and 90% for tacrolimus. According to Kasiske et al, there is an association between NODAT and graft rejection, as well as between NODAT and tacrolimus, but tacrolimus-based regimens seem to have an overall beneficial effect on graft survival [5]. Furthermore, Alghamdi et al concluded that there was no difference in patient and graft survival between patients on cyclosporine in comparison with those on tacrolimus 1 and 2 years after RT [15]. In their 7-year observational study, Krämer et al conclude that patients on tacrolimus had higher survival rates accompanied by lower rates of acute rejection episodes [16]. The question is whether the immunosuppressive effects of both tacrolimus and cyclosporine can compensate for the higher risk of transplant rejection caused by NODAT. Despite the high incidence of NODAT among patients undergoing tacrolimus-based regimens, no statistically significant difference has been found in transplant rejection rates. Generally, it is supported that tacrolimus-based and cyclosporine-based regimes can both prove beneficial for
Fig 4. Systolic and diastolic blood pressure at 3 months and at 1e5 years after renal transplant.
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Table 5. Patient and Graft Survival Rates in the First, Third, and Fourth Year After RT
Pts survival % (CsA/Tac) Graft survival % (CsA/Tac)
1y
3y
4y
P
100/100 100/100
100/100 100/97
97/90 97/90
<.05 <.05
Abbreviations: CsA, cyclosporine; Pts, patients; RT, renal transplantation; Tac, tacrolimus.
Table 6. Cardiovascular Disorders in Group A and B After RT Cardiovascular disorders
Diastolic function Ischemic disease Arrhythmias MV dysfunction MV stenosis AV regurgitation
Group A (CsA)
Group B (Tac)
7 pts 2 pts 3 pts 4 pts 1 pt -
6 pts 3 pts 1 pt 2 pts 3 pts
Abbreviations: AV, atrial valve; CsA, cyclosporine; MV, mitral valve; pt, patient; RT, renal transplantation; Tac, tacrolimus.
the prevention of acute rejection episodes, thus increasing the survival of the transplant [2]. The fact that pre-existing diabetes may be an aggravating factor for graft survival [22] in combination with the detection of statistically significant difference between the 2 regimens in the fourth year after RT makes it imperative to carry out more systematic and prospective studies focusing on pre-transplant evaluation and longterm graft survival. Moreover, in literature, there are controversial findings in relation to mortality. Although there are studies according to which mortality rates are lower after the use of tacrolimus [19] in the present study patient survival appear to be higher in the case of cyclosporine use. CONCLUSION
New-onset diabetes after transplantation in kidney transplant recipients undergoing tacrolimus-based immunosuppressive treatment, although slowly evolving, requires the timely adjustment of modifiable clinical and metabolic parameters, such as body weight, arterial blood pressure, serum glucose levels, and HbA1c of the transplanted patients, and possible change of the immunosuppressive regimen from a tacrolimus-based to a cyclosporine-based one. Systemic and prospective studies about NODAT complications and their impact on long-term survival of the renal graft are needed. REFERENCES [1] Salifu MO, Tedla F, Murty PV, Aytug S, McFarlane SI. Challenges in the diagnosis and management of new-onset diabetes after transplantation. Curr Diab Rep 2005;5:194e9. [2] Pavlakis M. New-onset diabetes after transplantation. Curr Diab Rep 2005;5:300e4.
[3] Mazali FC, Lalli CA, Alves Filho G, Mazzali M. Posttransplant diabetes mellitus: incidence and risk factors. Transplant Proc 2006;38:764e6. [4] Luan FL, Zhang H, Schauben DE, Miles CD, Cibrik D, Norman S, et al. Comparative risk of impaired glucose metabolism associated with cyclosporine versus tacrolimus in the late posttransplant period. Am J Transplant 2008;8:1871e7. [5] Therasse A, Wallia A, Molitch ME. Management of posttransplant diabetes. Curr Diab Rep 2012;13:121e9. [6] Palepu S, Prasad GV. New-onset diabetes mellitus after kidney transplantation: current status and future directions. World J Diabetes 2015;6:445e55. [7] Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003;3:178e85. [8] Peev V, Reiser J, Alachkar N. Diabetes mellitus in the transplanted kidney. Front Endocrinol 2014;5:141. [9] Cosio FG, Ferguson RM. Post-transplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent years. Kidney Int Suppl 2001;59:732e7. [10] Webster AC, Taylor RRS, Chapman JR, Craig JC. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev 2005;4: CD003961. [11] Martins L, Ventura A, Branco A, Carvalhoa MJ, Henriques AC, Dias L, et al. Cyclosporine versus tacrolimus in kidney transplantation: are there differences in nephrotoxicity? Transplant Proc 2004;36:877e9. [12] Cho YM, Park KS, Jung HS, Jeon HJ, Ahn C, Ha J, et al. High incidence of tacrolimus-associated posttransplantation diabetes in the Korean renal allograft recipients according to American Diabetes Association Criteria. Diabetes Care 2003;26:1123e8. [13] Araki M, Flechner SM, Ismail HR, Flechner LM, Zhou L, Derweesh IH, et al. Posttransplant diabetes mellitus in kidney transplant recipients receiving calcineurin or mTOR inhibitor drugs. Transplantation 2006;81:335e41. [14] Tsai JP, Lian JD, Wu SW. Long-term impact of pretransplant and posttransplant diabetes mellitus on kidney transplant outcomes. World J Surg 2011;35:2818e25. [15] Alghamdi S, Nabi Z, Skolnik E, Alkorbi L, Albaqumi M. Cyclosporine versus tacrolimus maintenance therapy in renal transplant. Exp Clin Transplant 2011;9:170e4. [16] Krämer BK, Montagnino G, Krüger B, Margreiter R, Olbricht CJ, Marcen R, et al. Efficacy and safety of tacrolimus compared with ciclosporin-A in renal transplantation: 7-year observational results. Transpl Int 2006;29. [17] Ravindran V, Baboolal K, Moore R. Post transplant diabetes mellitus after renal transplantation: the emerging clinical challenge. Yonsei Med J 2004;45:1059e64. [18] Rath T. Tacrolimus in transplant rejection. Expert Opin Pharmacother 2013;14:115e22. [19] Krämer BK, Montagnino G, Del Castillo D, Margreiter R, Sperschneider H, Olbricht CJ, et al. Efficacy and safety of tacrolimus compared with cyclosporin A microemulsion in renal transplantation: 2 year follow-up results. Nephrol Dial Transplant 2005;20:968e73. [20] Raeisil D, Omrani1 H, Najafi F, Mahruei1 A, Shavisizadeh F, Zare ME, et al. A comparative study of tacrolimus versus cyclosporine as immunosuppression for kidney transplant recipients. J Paramed Sci 2013;4:11e4. [21] Knoll GA, Bell RC. Tacrolimus versus cyclosporin for immunosuppression in renal transplantation: meta-analysis of randomised trials. BMJ 1999;318:1104e7. [22] Woodward RS, Flore MC, Machnicki G, Brennan DC. The long-term outcomes and costs of diabetes mellitus among renal transplant recipients: tacrolimus versus cyclosporine. Value Health 2011;14:443e9.
ABSTRACT Introduction. New-onset diabetes after transplantation (NODAT) is a complication of renal transplantation (RT) with an adverse effect on graft survival. Objectives. The purpose of the present study was to compare modifiable or non-modifiable clinical and laboratory parameters as well as the course of patients and transplants between 2 groups of RT recipients with NODAT in relation to the use of either a cyclosporine-based (group A) or a tacrolimus-based immunosuppressive regimen (group B). Materials and Methods. Retrospectively comparing 66 renal transplant recipients with NODAT, multiple clinical, and laboratory parameters were investigated. For statistical analysis, the c2 test, the Student t test, and the patient and graft survival or the KaplanMeier analysis from the statistical software SPSS 22.0 for Windows were used. Results. There was no statistically significant difference in association with the majority of the investigated parameters. In group B (tacrolimus [Tac]), more patients had HbA1c >7.2% at 3 years after RT. The mean value of systolic blood pressure was higher in group A (cyclosporine [CsA]) at 6 months and at 1 year after RT. More patients in group A (CsA) experienced at least one acute rejection episode. Finally, greater levels of cold ischemia time were recorded in group B (Tac) and statistically significant difference was found in connection with the patient and graft survival in the fourth year after RT. Conclusions. NODAT in patients on tacrolimus requires the adjustment of modifiable clinical and metabolic parameters and possible change of the immunosuppressive regimen to a cyclosporine-based one.
O
NE serious complication which occurs after transplantation and can not easily be avoided is diabetes mellitus. Although it has been associated with all solid organ transplantations, the development of diabetes is more common after renal transplantation (RT). Nowadays, the term “post-transplant diabetes mellitus” has been replaced by the term “new-onset diabetes after transplantation” (NODAT). The term NODAT is widely used so as to include all new cases of diabetes mellitus that are attributed to immunosuppression. The definition of NODAT includes the need for insulin therapy after transplantation in patients without a known history of diabetes. The exclusion of all the cases of preexisting diabetes is difficult because glucose tolerance tests have not been established yet as a common practice before transplantation [1,2].
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For the past 20 years, graft survival rates have generally increased and as a result, patients who get diagnosed with diabetes after transplantation have to cope with their health problem for a longer period, making complications more likely. Consequently, it is of high importance to keep serum glucose at normal level in order to reduce implications, usually leading to death [1]. The incidence of NODAT depends on many factors such as the patient, the immunosuppressive agent, and the definition given to the term diabetes and has not been precisely *Address correspondence to Apostolia Zolota, Surgery Clinic of Transplantation, Aristotle University of Thessaloniki, Ippokrateio General Hospital, Deligiorgi 9, Thessaloniki, 54642, Thessaloniki, Greece. E-mail: [email protected] ª 2018 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 3386e3391 (2018)
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Table 1. Risk Factors for the Development of NODAT [1,3,6] Risk factors
Origin (Africans-Caribbean Americans-Hispanics) Advanced age (>45 years old) Glucose intolerance (prior to transplantation) Diabetes family history Excessive BMI (>25 kg/m2) Cadaveric donor HLA alleles Hepatitis C infection Immunosuppressive agents Calcineurin inhibitors (cyclosporine, tacrolimus) Corticosteroids Decreased corticosteroids Dyslipidemia (HDL >35 mg/dL and triglycerides >250 mg/dL) High arterial blood pressure (blood pressure >140/190 mmHg Tobacco use Acute rejection syndrome Abbreviations: BMI, body mass index; HDL, high-density lipoprotein; NODAT, new-onset diabetes after transplantation.
estimated so far. When therapeutic regimens where based on the use of steroids and azathioprine, the incidence of NODAT appeared to be approximately 7%-15%. After the initiation of new immunosuppressive agents in combination with decreased dosages of steroids, the rates of newly diagnosed cases of diabetes has not changed and in some cases they tended to increase despite the improvement in graft survival rates. NODAT occurs in 2%-53% of kidney transplant recipients with clinical manifestations ranging from asymptomatic hyperglycemia to ketoacidosis with the risk being greater in the first year after RT [3,4,6]. The risk factors which have been related to NODAT are presented in Table 1 [1,3,6]. Kasiske et al, taking advantage of data from the United States Renal Data System database, estimate the incidence of NODAT after RT to be 9.1% at 3 months, 16% at 1 year, and finally, 24% at 3 years [7]. It is supported that the main pathogenic mechanism which leads to the development of NODAT is low insulin levels due to decreased secretion. It appears that NODAT occurs in the context of preexisting abnormalities in glucose metabolism in
addition with the contribution of immunosuppressive agents. The onset of NODAT takes place soon after transplantation. Especially in patients with susceptibility, NODAT is expected approximately 3 months after RT. Hyperglycemia is not always a sign of NODAT, as it often induced by corticosteroids but resolves soon after transplantation [1]. In case hyperglycemia gets persistent, the diagnosis of NODAT in needed at an early stage because of the possible complications which may occur concerning the cardiovascular system, the eye, and the kidneys. Early diagnosis can be achieved taking under consideration the fact that transplanted patients get controlled at least twice a week for the first month and once a week for the first 3 months. Diabetes also constitutes a common threat among those people who undergo transplantation because of its contribution in transplant rejection and mortality [1,5,8]. The objective of the present study was to compare modifiable or non-modifiable clinical and laboratory parameters, as well as the course of patients and transplants between 2 groups of RT recipients with NODAT in relation to the use of either a cyclosporine-based (group A) or a tacrolimus-based immunosuppressive regimen (group B). This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. MATERIALS AND METHODS Patients The present study is an observational retrospective (cross-sectional) study comparing modifiable or non-modifiable clinical and laboratory parameters, as well as the course of patients and transplants between 2 groups of patients with NODAT after RT in relation to the use of either a cyclosporine-based (CsA, group A) or a tacrolimus-based immunosuppressive regimen (Tac, group B). The sample size was n ¼ 66, and each group consisted of 33 patients (group A: patients, age (mean SD): 49.91 10.25 years vs group B: 33 patients, age (mean SD): 53.27 9.74 years, P ¼ NS).
Statistical Analysis For statistical analysis, the c2 test, the Student t test, and the patient and graft survival or the Kaplan-Meier analysis from the statistical
Table 2. Characteristics of the Sample and Differences Between Group A and Group B Characteristics
Group A (CsA)
Group B (Tac)
Patients (n) Sex (male/female) Age (recipients), mean SD (range) Age (donors), mean SD (range) Type (heart-beating/cadaveric) HLA mm (0/1/2/3/4/5) CMV infection (viremia or infection) HCV infection Body weight (kg), mean SD Before/after Cold ischemia time (min) Delayed graft function Acute rejection episodes
33 22/11 49.91 10.25 (23e66) 47.61 19.19 (12e73) 10/21 2/1/5/17/6/2 8 pts/33 4 73.09 15.30/74.52 17.37
33 20/13 53.27 9.74 (23e66) 47.27 18.38 (2e82) 4/29 0/0/10/9/13/1 10 pts/33 1 72.88 11.70/72.76 10.60
661.97 486.8 6 pts/21 13 pts/33
908.79 411.38 8 pts/29 8 pts/33
Abbreviations: CMV, cytomegalovirus; CsA, cyclosporine; HCV, hepatitis C virus; pts, patients; Tac, tacrolimus.
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Table 3. Primary Disease and Its Distribution Between Groups A and B Primary disease
Group A (CsA)
Group B (Tac)
Chronic glomerulonephritis Acute interstitial nephritis Cystic-urethral retrogression Polycystic kidney disease Hypertensive kidney disease Focal segmental glomerulosclerosis IgA nephropathy Systemic lupus erythematosous Wegener granulomatosis Unknown Alport syndrome
7 3 4 3 2 1 1 1 1 10 -
6 5 2 4 7 2 2 4 1
Abbreviations: CsA, cyclosporine; Tac, tacrolimus.
software SPSS 22.0 for Windows (IBM, Armonk, NY, United States) were used.
RESULTS
In Table 2, demographic characteristics of both groups are presented, while it is noted that no significant difference was found between the 2 groups. In Table 3, a reference is made to the types of primary disease that led to RT. The 2 groups were also compared in relation to the type of transplantation (heart-beating or cadaveric donor), distribution of HLA incompatibility and the hepatitis C virus or cytomegalovirus infection, and no significant difference was found between the 2 groups. Moreover, no significant difference was detected between groups A and B in connection with body weight and delayed graft function during the course of the study. In conclusion, groups A and B were considered totally comparable. More patients in group A (CsA) than in group B (Tac) experienced at least one acute rejection episode without the difference being statistically significant (10/33 vs 8/33, P ¼ NS). Moreover, they were recorded greater levels of cold ischemia time (M SD, min) in group B (Tac) vs group A (CsA) (908.79 411.38 vs 661.97 486.8, P < .05). No statistically significant difference was found in the mean values (SD) of serum creatinine, UP24h, serum glucose, as well as HbA1c between the 2 study groups. However, in group B (Tac), more patients had
HbA1c>7.2% at 3 years after RT (group A: 2/33 vs group B: 9/33, P < .05). Results in connection with the above parameters, derived from the statistical analysis, are presented in Figures 1e3 and in Table 4. The mean value (SD) of systolic blood pressure was higher in group A (CsA) compared to group B (Tac) at 6 months and at 1 year after RT (SD SD mmHg) group A: 134.85 14.92 and 135.61 13.33 vs group B: 126.67 13.32 and 129.55 14.16, P < .05, whereas no significant difference was observed in the rest of the study period. The patient’s diastolic blood pressure was similar at all study intervals. The detailed findings of the statistical analysis are presented in Figure 4. Finally, the immunosuppressive regimen was changed from tacrolimus to cyclosporine in 2 patients during the study period. Table 5 shows the patient and graft survival rates for both groups in the first, third, and fourth year after RT. Cardiovascular disease is considered a basic cause of death among renal transplant recipients. The frequency of such disorders is shown in Table 6. DISCUSSION
In literature, it is supported that both tacrolimus and cyclosporine can lead to the development of diabetes after transplantation although the tacrolimus is associated with greater risk [9e11]. More specifically, incidence of NODAT appears to be higher when using tacrolimus (16.6%) rather than in case of cyclosporine use (9.2%) after transplantation of solid organs. After RT, the value of the above percentages is 15.4% for tacrolimus and 9.2% for cyclosporine, respectively [2]. Cho et al state that screening for diabetes is imperative on a regular basis in renal transplant recipients over 40 years old undergoing a tacrolimus-based regimen [12]. In another study, it was found that after the use of cyclosporine, tacrolimus, or sirolimus in combination with mycophenolate and corticosteroids, NODAT was diagnosed in 7.4% of renal transplant recipients, with no difference between the 3 groups and only a small increase in tacrolimus group [13]. In the present study, no statistically significant difference was found in connection with serum creatinine levels between the 2 groups. Nevertheless, it is thought that the risk
Fig 1. Serum creatinine levels at 1, 3, and 5 years after renal transplant.
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Fig 2. 24-hour albuminuria at 6 months and at 1e5 years after renal transplant.
of doubling serum creatinine after diagnosis of NODAT is 2 times higher, while in recipients with pre-existing diabetes this risk is increased by 6 times [14]. In connection with cardiovascular problems, we concluded that cyclosporine is associated with higher systolic blood pressure at 6 months and at 1 year after RT. Blood pressure and serum cholesterol level were also higher in patients on cyclosporine in the study of Alghhamdi et al [15]. Relevant results were exported by Krämer et al who supported that more patients on cyclosporine received
medication for dislipidaemia and finally developed cardiovascular problems [16]. It is not yet clear whether NODAT can be directly associated with the development of cardiovascular disease. Generally, the metabolic syndrome (insulin resistance, dislipidaemia, and hypertension is considered a phenotype which can predispose for the occurrence of atherosclerosis and features of that syndrome have been identified in patients after RT [17]. Consequently, we recommend that the above classical triangle is included in future studies.
Fig 3. Serum glucose levels at 3 months, at 6 months, and at 1e5 years after renal transplant.
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Table 4. Number of Patients With HbA1c levels >7.2 3 Years After RT Patients with HbA1c >7.2 3 years after RT
Group A
Group B Tac
2 pts/33
9 pts/33
Abbreviations: pts, patients; RT, renal transplantation; Tac, tacrolimus.
There are many studies in favor of tacrolimus use after RT as it is connected with lower percentages of acute rejection during the first months after transplantation and better graft function [10,11,18e20]. In the present study, more patients in group A (CsA) than in group B (Tac) experienced at least one acute rejection episode without the difference being statistically significant. Respectively, Knoll and Bell support that a cyclosporine-based regimen is more likely to cause an acute rejection episode compared with a tacrolimus-based one [21]. Moreover, both groups appear to have high graft survival rates until the third year after transplantation without the difference being statistically significant between them. In contrast, statistically significant difference between group A
and B was detected in the fourth year after RT with the relevant percentages being 97% for cyclosporine and 90% for tacrolimus. According to Kasiske et al, there is an association between NODAT and graft rejection, as well as between NODAT and tacrolimus, but tacrolimus-based regimens seem to have an overall beneficial effect on graft survival [5]. Furthermore, Alghamdi et al concluded that there was no difference in patient and graft survival between patients on cyclosporine in comparison with those on tacrolimus 1 and 2 years after RT [15]. In their 7-year observational study, Krämer et al conclude that patients on tacrolimus had higher survival rates accompanied by lower rates of acute rejection episodes [16]. The question is whether the immunosuppressive effects of both tacrolimus and cyclosporine can compensate for the higher risk of transplant rejection caused by NODAT. Despite the high incidence of NODAT among patients undergoing tacrolimus-based regimens, no statistically significant difference has been found in transplant rejection rates. Generally, it is supported that tacrolimus-based and cyclosporine-based regimes can both prove beneficial for
Fig 4. Systolic and diastolic blood pressure at 3 months and at 1e5 years after renal transplant.
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Table 5. Patient and Graft Survival Rates in the First, Third, and Fourth Year After RT
Pts survival % (CsA/Tac) Graft survival % (CsA/Tac)
1y
3y
4y
P
100/100 100/100
100/100 100/97
97/90 97/90
<.05 <.05
Abbreviations: CsA, cyclosporine; Pts, patients; RT, renal transplantation; Tac, tacrolimus.
Table 6. Cardiovascular Disorders in Group A and B After RT Cardiovascular disorders
Diastolic function Ischemic disease Arrhythmias MV dysfunction MV stenosis AV regurgitation
Group A (CsA)
Group B (Tac)
7 pts 2 pts 3 pts 4 pts 1 pt -
6 pts 3 pts 1 pt 2 pts 3 pts
Abbreviations: AV, atrial valve; CsA, cyclosporine; MV, mitral valve; pt, patient; RT, renal transplantation; Tac, tacrolimus.
the prevention of acute rejection episodes, thus increasing the survival of the transplant [2]. The fact that pre-existing diabetes may be an aggravating factor for graft survival [22] in combination with the detection of statistically significant difference between the 2 regimens in the fourth year after RT makes it imperative to carry out more systematic and prospective studies focusing on pre-transplant evaluation and longterm graft survival. Moreover, in literature, there are controversial findings in relation to mortality. Although there are studies according to which mortality rates are lower after the use of tacrolimus [19] in the present study patient survival appear to be higher in the case of cyclosporine use. CONCLUSION
New-onset diabetes after transplantation in kidney transplant recipients undergoing tacrolimus-based immunosuppressive treatment, although slowly evolving, requires the timely adjustment of modifiable clinical and metabolic parameters, such as body weight, arterial blood pressure, serum glucose levels, and HbA1c of the transplanted patients, and possible change of the immunosuppressive regimen from a tacrolimus-based to a cyclosporine-based one. Systemic and prospective studies about NODAT complications and their impact on long-term survival of the renal graft are needed. REFERENCES [1] Salifu MO, Tedla F, Murty PV, Aytug S, McFarlane SI. Challenges in the diagnosis and management of new-onset diabetes after transplantation. Curr Diab Rep 2005;5:194e9. [2] Pavlakis M. New-onset diabetes after transplantation. Curr Diab Rep 2005;5:300e4.
[3] Mazali FC, Lalli CA, Alves Filho G, Mazzali M. Posttransplant diabetes mellitus: incidence and risk factors. Transplant Proc 2006;38:764e6. [4] Luan FL, Zhang H, Schauben DE, Miles CD, Cibrik D, Norman S, et al. Comparative risk of impaired glucose metabolism associated with cyclosporine versus tacrolimus in the late posttransplant period. Am J Transplant 2008;8:1871e7. [5] Therasse A, Wallia A, Molitch ME. Management of posttransplant diabetes. Curr Diab Rep 2012;13:121e9. [6] Palepu S, Prasad GV. New-onset diabetes mellitus after kidney transplantation: current status and future directions. World J Diabetes 2015;6:445e55. [7] Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003;3:178e85. [8] Peev V, Reiser J, Alachkar N. Diabetes mellitus in the transplanted kidney. Front Endocrinol 2014;5:141. [9] Cosio FG, Ferguson RM. Post-transplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent years. Kidney Int Suppl 2001;59:732e7. [10] Webster AC, Taylor RRS, Chapman JR, Craig JC. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev 2005;4: CD003961. [11] Martins L, Ventura A, Branco A, Carvalhoa MJ, Henriques AC, Dias L, et al. Cyclosporine versus tacrolimus in kidney transplantation: are there differences in nephrotoxicity? Transplant Proc 2004;36:877e9. [12] Cho YM, Park KS, Jung HS, Jeon HJ, Ahn C, Ha J, et al. High incidence of tacrolimus-associated posttransplantation diabetes in the Korean renal allograft recipients according to American Diabetes Association Criteria. Diabetes Care 2003;26:1123e8. [13] Araki M, Flechner SM, Ismail HR, Flechner LM, Zhou L, Derweesh IH, et al. Posttransplant diabetes mellitus in kidney transplant recipients receiving calcineurin or mTOR inhibitor drugs. Transplantation 2006;81:335e41. [14] Tsai JP, Lian JD, Wu SW. Long-term impact of pretransplant and posttransplant diabetes mellitus on kidney transplant outcomes. World J Surg 2011;35:2818e25. [15] Alghamdi S, Nabi Z, Skolnik E, Alkorbi L, Albaqumi M. Cyclosporine versus tacrolimus maintenance therapy in renal transplant. Exp Clin Transplant 2011;9:170e4. [16] Krämer BK, Montagnino G, Krüger B, Margreiter R, Olbricht CJ, Marcen R, et al. Efficacy and safety of tacrolimus compared with ciclosporin-A in renal transplantation: 7-year observational results. Transpl Int 2006;29. [17] Ravindran V, Baboolal K, Moore R. Post transplant diabetes mellitus after renal transplantation: the emerging clinical challenge. Yonsei Med J 2004;45:1059e64. [18] Rath T. Tacrolimus in transplant rejection. Expert Opin Pharmacother 2013;14:115e22. [19] Krämer BK, Montagnino G, Del Castillo D, Margreiter R, Sperschneider H, Olbricht CJ, et al. Efficacy and safety of tacrolimus compared with cyclosporin A microemulsion in renal transplantation: 2 year follow-up results. Nephrol Dial Transplant 2005;20:968e73. [20] Raeisil D, Omrani1 H, Najafi F, Mahruei1 A, Shavisizadeh F, Zare ME, et al. A comparative study of tacrolimus versus cyclosporine as immunosuppression for kidney transplant recipients. J Paramed Sci 2013;4:11e4. [21] Knoll GA, Bell RC. Tacrolimus versus cyclosporin for immunosuppression in renal transplantation: meta-analysis of randomised trials. BMJ 1999;318:1104e7. [22] Woodward RS, Flore MC, Machnicki G, Brennan DC. The long-term outcomes and costs of diabetes mellitus among renal transplant recipients: tacrolimus versus cyclosporine. Value Health 2011;14:443e9.