Temporal Changes on the Risks and Complications of Posttransplantion Diabetes Mellitus Following Cardiac Transplantation

Iannino, Nadia; Nasri, Amine; Räkel, Agnès; Ducharme, Anique; Lachance, Kim; Racine, Normand; de Denus, Simon; Tremblay-Gravel, Maxime; Fortier, Annik; White, Michel

doi:https://doi.org/10.1155/2018/9205083

Journal of Transplantation

On this page

Abstract Introduction Methods Results Discussion Conclusions Abbreviations Data Availability Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2018 | Article ID 9205083 | https://doi.org/10.1155/2018/9205083

Temporal Changes on the Risks and Complications of Posttransplantion Diabetes Mellitus Following Cardiac Transplantation

Nadia Iannino,¹Amine Nasri,¹Agnès Räkel,²Anique Ducharme,¹Kim Lachance,³Normand Racine,¹Simon de Denus,^1,4Maxime Tremblay-Gravel,¹Annik Fortier,⁵and Michel White¹

Academic Editor: Gian Luigi Adani

Received31 May 2018

Revised27 Sept 2018

Accepted21 Oct 2018

Published08 Nov 2018

Abstract

Background. Recent changes in the demographic of cardiac donors and recipients have modulated the rate and risk, associated with posttransplant diabetes mellitus (PTDM). We investigated the secular trends of the risk of PTDM at 1 year and 3 years after transplantation over 30 years and explored its effect on major outcomes. Methods. Three hundred and three nondiabetic patients were followed for a minimum of 36 months, after a first cardiac transplantation performed between 1983 and 2011. Based on the year of their transplantation, the patients were divided into 3 eras: (1983-1992 [era 1], 1993-2002 [era 2], and 2003-2011 [era 3]). Results. In eras 1, 2, and 3, the proportions of patients with PTDM at 1 versus 3 years were 23% versus 39%, 21% versus 26%, and 33% versus 38%, respectively. Independent risk factors predicting PTDM at one year were recipient’s age, duration of cold ischemic time, treatment with furosemide, and tacrolimus. There was a trend for overall survival being worse for patients with PTDM in comparison to patients without PTDM (p = 0.08). Patients with PTDM exhibited a significantly higher rate of renal failure over a median follow-up of 10 years (p = 0.03). Conclusion. The development of PTDM following cardiac transplantation approaches 40% at 3 years and has not significantly changed over thirty years. The presence of PTDM is weakly associated with an increased mortality and is significantly associated with a worsening in renal function long-term following cardiac transplantation.

1. Introduction

Posttransplantation diabetes mellitus (PTDM), formerly called new-onset diabetes after transplant (NODAT), refers to the development of diabetes in previously nondiabetic patients, excluding transient hyperglycemia [1, 2]. Historically, the incidence of PTDM following solid organ transplantation has been difficult to determine because of the use of different diagnostic criteria. In 2002, Montori et al. [3] systematically reviewed the incidence of new-onset diabetes after heart, liver, and kidney transplantation in adults and reported 12-month cumulative incidence within the range of 2% to 53%. Similarly, Heisel et al. [4], in a systematic review, reported that the incidence of PTDM ranged from 7% to 26% in cardiac transplant (CTx) recipients, showing the large variability of incidence between the earlier studies.

International Consensus Guidelines proposed that the American Diabetes Association (ADA) criteria, published the same year for the diagnosis of diabetes mellitus in the general population, should also be applied to the organ transplant recipients [2, 5]. Nevertheless, the incidence of PTDM has remained quite variable in the previous reports, most likely because of different immunosuppressive regiments from one study to another, the evolution of immunosuppression protocols, and changes in donor and recipient characteristics over time [6]. Following kidney transplantation, the risk factors for PTDM are well established and include both general factors such as an increase in recipient age, the presence of obesity, African and Hispanic ethnicity, family history of diabetes, prediabetes prior to transplantation, as well as some transplant-specific factors such as immunosuppressive regimens including glucocorticoids, and the use of calcineurin inhibitors and/or mammalian target of rapamycin inhibitors [7–10]. In these patients, PTDM impaired long-term graft function and survival, reduced long-term overall survival, and increased the risk of mortality and morbidity associated with cardiovascular disease [11, 12]. Despite these observations in the renal transplant population, the clinical parameters associated with PTDM have been incompletely investigated following CTx [11–14]. The temporal changes assessed over a very long follow-up period have been restricted to data from the International Society of Heart and Lung Transplantation registry [15]. However, these data are limited by the lack of information regarding the donor-recipient characteristics and the specific parameters related to morbidity and mortality in the subgroup of patients who developed PTDM.

The primary objective of this study was to assess the incidence and secular trends for the development of PTDM in a large cohort of patients transplanted in one single center over 30 years. The secondary objectives were to investigate the recipient and donor characteristics over that period to determine the predictors of PTDM and its role in overall mortality and the development of renal failure post-CTx.

2. Methods

2.1. Study Design

The design of this investigation was a retrospective observational investigation and the study was approved by the Montreal Heart Institute Scientific and Ethics Committees. Data includes all patients who received a heart transplant at the Montreal Heart Institute between January 1983 and December 2010. The last follow-up date was July 31, 2013. The patients were divided into three cohorts according to the date of transplant (1983-1992 = era 1, 1993-2002 = era 2, and 2003-2011 = era 3). These eras were selected in order to subdivide this 30-year follow-up in ten-year periods. All patients who received a first transplantation and who survived hospital discharge following procedure were included in the analysis. The absence or presence of diabetes, documented at the time of surgery, was assessed by medical history and fasting blood glucose to differentiate diabetes pretransplantation from the nondiabetic patients. Patients with diabetes before transplantation were excluded from the posttransplant analyses reported in this study. The diagnosis of posttransplant diabetes was based on the initiation of hypoglycemic drugs including insulin, a fasting blood glucose ≥7 mmol/L, and/or HBA1C ≥6.5% at least once within 12 and 36 months following discharge from CTx (respectively, for PTDM 1 year and PTDM 3 years). We also assessed the rate of PTDM up to 10 year postdischarge for the whole cohort regardless of the year of transplantation. Clinical and paraclinical parameters were collected before heart transplant, at the time of hospital discharge and at each outpatient visit in the transplant clinic for at least 3 years. Outpatient visits were performed at least 1, 2, and 3 months following the intervention, every 3 months thereafter within the first year, and at least twice a year subsequently for up to 30 years. The last follow-up date was July 30, 2013. The rate of PTDM was determined at 1 and 3 years. The first occurrence of any major outcomes including all-cause death and worsening renal function defined by a decline in glomerular filtration rate below 30 ml/min/1.73m² was censored during the follow-up period.

2.2. Statistical Analyses

Continuous variables are presented as mean ± standard deviation or median [lower and upper quartile] and group comparisons were done using Student’s t-test, one-way ANOVA, Mann-Whitney-Wilcoxon test, or Kruskal-Wallis test according to the distribution of the selected variable. Categorical variables are presented as frequency (percentage) and group comparisons were performed using Chi-square test. Statistical significance was set at p < 0.05.

Survival to onset of PTDM was illustrated using Kaplan-Meier curves and the log-rank test was used to compare survival between eras. Univariate and multivariate Cox proportional hazard models were used to seek potential predictors for the development of PTDM in the first year after discharge. The candidate variables considered were pre-, peri-, and postoperative information collected until discharge. Variables showing a p < 0.20 in univariate Cox analysis were introduced in a multivariable Cox model and a stepwise selection process was used to select the final independent predictors. Cox analyses were also performed to assess the role of PTDM as a time-dependent variable in the occurrence of death or renal failure during the follow-up.

Statistical analyses were performed using SAS 9.4 (Cary, NC, USA), and statistical significance was set to p < 0.05.

3. Results

3.1. Study Population

Three hundred seventy-nine adult patients with end-stage heart failure underwent CTx at our institution between 1983 and 2011. Among these patients, forty-two patients (11%) were diabetic before transplantation and thirty-two patients died in-hospital, while two were transferred early to another hospital for their long-term care and were lost in follow-up. Consequently, our study population consisted of 303 nondiabetic patients prior to transplantation discharged alive after surgery (Figure 1). The cohort of transplanted patients was subdivided in 3 eras: era 1 (1983 to 1992) included 104 patients (34%), era 2 (1993 to 2002) included 117 patients (39%), and era 3 (2003 to 2011) included 82 patients (27%). The median duration of follow-up was 10.6 (5.3-16.4) years. The characteristics of the study population are presented in Table 1. Mean recipient age at the time of transplantation was 47±12 years. Recipient age was different between the 6 groups (3 eras, diabetic versus nondiabetics). Patients transplanted more recently (era 3) were mostly men (68%), had nonischemic heart failure etiology, and were most likely to receive inotropic support before CTx (12.5% in era 1 versus 24% in era 3; p = 0.07). The proportion of patients with dyslipidemia at the time of pretransplant evaluation increased with time (27% in era 1 versus 48% in era 3) while mean cholesterol and triglyceride levels decreased in era 3 (3.8 and 1.1 mmol/L) compared with era 1 (5 and 1.4 mmol/L). There were no changes in cold ischemic time between the 3 eras. The rate of cyclosporine use decreased from 100% to 30%, while tacrolimus utilization increased from 0% to 67% from 1983 to 2011. There was a significant increase in donor age and donor weight in the most recent transplant recipients. In fact, donor age increased from 27±9 years (era 1) to 37±15 years (era 3) (p < 0.0001) while donor weight increased from 67±13 kg to 76±17 kg in era 1 and 3, respectively (p = 0.0005). Similarly, donor to recipient weight ratio increased significantly in era 3 compared with era 1 (1.10±0.25 [era 3] versus 0.96±0.2 [era 1]; ). There was no difference in recipient BMI or recipient gender over the three eras. Glomerular filtration rate was also similar over the three eras (62±18 [era 1] versus 66±23 ml/kg/1.73 m² [era 3]; p = NS). More than 95% of patients were chronically treated with prednisone. The mean daily dose of prednisone was 9.79±5.06 mg per day at 6 months and 8.51±5.46 mg per day at one year. Ninety-seven percent of patients with PTDM were chronically treated with steroids compared with 100% of patients without PTDM at 1 year (p = 0.01).

3.2. Prevalence of PTDM at One and Three Years

The rates of PTDM for the whole cohort and for the 3 specific eras are presented in Table 1 and Figures 2 and 3. Seventy-six patients (25%) developed PTDM within the first year of follow-up and from those, 12 died or were lost in follow-up. Consequently, 215 CTx recipients were diabetes-free at 1 year. Cumulative survival free of diabetes was 58% at 5 years and only 48% at 10 years (Figure 2). Figure 3 presents the Kaplan-Meier curves for the survival free of PTDM up to three 3 years after transplantation according to the era of surgery. Despite an overall borderline significance when the three eras where analyzed using log-rank test, (p = 0.067 and p = 0.056, respectively, at 1 and 3 years), subsequent intergroup analyses yielded a significantly higher rate of diabetes at 1 and 3 years in era 2 when compared with the most recently transplanted patient (era 3) (both p < 0.05).

3.3. Risk Factors and Outcome Analyses

The relationship between the risk of developing PTDM and some selected clinical and paraclinical parameters is presented in Table 2. Using univariate Cox analyses, donor and recipient age, a higher body mass index (BMI), increased blood glucose level before transplantation, a longer cold ischemic time, and the use of tacrolimus were significantly associated with an increased risk of developing PTDM at 1 year. Using multivariate Cox analyses older recipient age, longer cold ischemic time, and the use of furosemide and tacrolimus immunoprophylaxis were independently associated with an increased risk of developing PTDM at 1 year. The use of tacrolimus was the strongest predictor of PTDM with a hazard ratio close to 4-fold compared with cyclosporine immunoprophylaxis. There was a significant interaction between triglycerides level and the use of tacrolimus for the risk of developing PTDM (p = 0.03). Patients who developed PTDM between 1 and 3 years exhibited similar rate of use and prednisone daily dose compared with those who did not develop PTDM (not shown).

We further explored the association between PTDM, all-cause death, and the development of renal failure in our study population using the Cox proportional hazards model (Table 3). The development of PTDM yielded a p value = 0.08 on survival using univariate analysis and this variable was forced in the model while other parameters including age at transplantation, year of transplantation, donor gender, hypertension, use of inotrope, MPA, use of furosemide or of any other diuretics, and use of inotrope were included in a stepwise fashion in the multivariate model. Age at the time of surgery and the nonutilization of MPA were significantly associated with death, while having a female donor was protective for all-cause death. The presence of PTDM was associated with the highest risk for developing renal failure during the follow-up period (Table 3).

4. Discussion

In this study, we report a rate of PTDM at 1 and 3 years of 25% and 34%, respectively, in a large cohort of cardiac transplant recipients. Despite an overall statistical trend, the rate of PTDM was higher in era 3, compared to era 2, at 1 and 3 years. The development of PTDM was associated with a significant decrease in renal function over time.

The incidence and the rate of diabetes reported here are in agreement with those reported in the heart transplantation literature. Nieuwenhuis [16], Martinez [13], and Depczynski [12] reported a rate of PTDM of 19.6%, 20.3%, and 15.7%, respectively, for patients followed for about 3 years after CTx, while Mogollon [14] reported a prevalence of PTDM of nearly 40% over 5 years. However, the comparison with previous reports is difficult to assess as previous available studies reported observations for a specific follow-up time as opposed to the incidence at 1 year and the prevalence at 3 years. To our knowledge these temporal changes on the rate of PTDM, as well as the description of clinical and para-clinical parameters for those with and without PTDM, have not been reported before in a large cohort of CTx recipients studied over 30 years. Interestingly, data in renal transplant recipients have shown controversial results suggesting that the incidence of PTDM may have increased in the more recent era (before versus after 1995) [17]. In contrast, another study has reported a decrease in the rate of PTDM in the most recent era [18].

The evolution of donor and recipient characteristics from 1983 to 2011 at our institution are in agreement with data reported from the ISHLT registry [15]. As outlined in the registry, we also report an increasing proportion of female recipients, little change in donor gender (approximately 70% males), an increase in donor age, a larger proportion of nonischemic cardiomyopathy, and an increase in the use of mechanical support before CTx. In contrast, we observed a slight increase in recipient age (45±11 in era 1 versus 47±13 in era 3), while the ISHLT registry reported steadily older (median 54 years) recipients since 1992. In contrast with the registry, we reported an increased use of inotropes prior to transplantation. These findings may be related to the small number of VAD used in our cohort. Nevertheless, the increased utilization of inotropes is in agreement with the transplantation of sicker patients in the most recent era.

The ISHLT transplant registry reported no data on the changes in donor weights or in the donor/recipient ratio. However, despite an increase in the rate of obesity in the North American population [19], we reported an increasing weight of donors but no significant changes in recipients BMI over a 30-year follow-up, most likely reflecting strict selection criteria excluding obese patients from the transplant process in our center. The increasing weight ratio found in our study may also be explained by the raising awareness of avoiding undersized donors because this condition has been associated with poorer survival [20].

In this study, we reported novel findings on the long-term changes in other risk factors following CTx such as dyslipidemia. Interestingly, the increase in the rate of dyslipidemia over decades, despite a decreased in mean cholesterol and triglyceride levels, appears counterintuitive. However, these observations may be related to an increase in awareness in the transplant community, as well as changes in the guidelines for the diagnostic and treatment of dyslipidemia published in recent years [21]. Also, a decrease in lipid levels overtime is likely related to the increased use of more powerful statins and other better tolerate drugs such as ezetimibe [22].

In this investigation, we report four independent factors associated with the development of PTDM. Those include tacrolimus immunoprophylaxis, recipient age, duration of cold ischemic time, and use of furosemide. As such, our study adds important and novel observations to the large ISHLT registry that have reported no specific risk factors for PTDM following CTx. Tacrolimus is known to reduce insulin synthesis and secretion within the first months following transplantation [23]. Despite some controversial observations, tacrolimus use has been associated with an increased rate of PTDM after renal transplantation [24, 25]. Nevertheless, this issue has been a matter of controversy following CTx due to the failure of many clinical studies to report a significant impact of tacrolimus on glucose level, HBA1C, and prevalence of diabetes, short-term and long-term, following CTx [26–29]. Our findings suggest that use of tacrolimus immune-prophylaxis may increase the rate of PTDM compared to cyclosporine utilization in an unselected cohort of patients investigated over 30 years following CTx.

The recipients’ age, ethnicity, and family history of diabetes are nonmodifiable risk factors for PTDM that have been previously reported in the literature [17, 30]. The majority (98%) of the population studied here was of Caucasian ethnicity, precluding us to screen for an effect of ethnicity. Also, the family history of diabetes was not collected in our database. Although obesity is a well-known risk factor for diabetes, we only computed a trend between recipient body mass index (BMI) and PTDM at 1 year. This may be related to the fact that the proportion of obese patients in our study population was below 10% (7%) for those with a BMI over 30 kg/m² at the time of CTx. Another explanation is that intra-abdominal fat, not assessed here, may be a more significant risk factor than total body weight or BMI [31].

In this study, we also report a significant relationship between the risk of diabetes and cold ischemic time. Although a significant relationship between cold ischemic time and survival has been reported for ischemic times longer than 3 hours [32], no studies have reported the relationship between this specific parameter and the rate of PTDM. The reasons for this are largely unknown. Czer et al. [33] reported an association between longer cold ischemic preservation time and higher rejection score and consequently more advanced graft vascular disease in a rat heterotopic cardiac transplantation model. No human studies have been reported on these findings. Consequently, we speculate that the patients with longer ischemic time may have also presented higher rejection burden leading to an increase in steroid use, which are well known to increase the risk of diabetes. However, we observed no significant differences in the rate of use and or the dose of steroids between patients who developed PTDM compared with those who did not. Other unknown mechanisms are likely involved and require further investigation. Diuretics, specially the thiazide diuretics, are known for their diabetogenic effects. The use and dosage of furosemide have been associated with an increased rate of diabetes following myocardial infarction [34] and in established heart failure, [35] two conditions that often precede CTX. Also the use of furosemide has been associated with beta cell dysfunction [10] and PTDM following renal transplantation [36]. Accordingly, our observations on the association between furosemide use and PTDM following CTX are in agreement with the previous but limited observations reported in the renal transplant population.

Here we reported a significant beneficial impact of MPA on all-cause mortality. The use of MPA has been associated with a decreased rejection rate and better survival rate compared with azathioprine-based therapy following CTx [37, 38]. MPA also impacts microvascular oxygenation and inflammation in an experimental model [39]. In the multivariate model, recipient age was positively associated with mortality, while female donor gender was protective. Previous studies reported that sex mismatch and female donor gender have been associated with adverse outcomes following CTx [40, 41]. However, Kush et al. [42] reported that female recipients of female allografts yielded a 10% decrease in overall mortality. Indeed, in this study female recipients of female allograft exhibited the lowest mortality rate (12 [32%]) compared with the other groups. Nevertheless, the sample size for this specific subgroup was small (n=38) and further investigations are needed to better understand this issue.

Previous papers have reported the detrimental effects of PTDM on outcome following renal transplantation [11, 43, 44]. These studies showed that, beyond prognosis, the presence of PTDM decreases graft survival impairs graft function and increases cardiovascular disease and treatment cost. Our observations are in agreement with the data from Mogollon et al. [14] who reported a significant impact of PTDM on renal function long-term following CTX. Our observations are also in agreement with our previous work published by Lachance et al. [6] who reported a significant relationship between some clinical parameters including diabetes and a worsening in renal function post-CTX. There have been some limited observations on the impact of PTDM on outcomes following CTX. These studies have reported an increase in the rate of acute rejection and cardiovascular diseases, but no differences on the short or long-term mortality rate [45–47]. Here we reported that the development of PTDM may increase all-cause mortality. Such differences may be related to the much longer follow-up reported in the present study.

4.1. Limitations of the Study

As for any retrospective investigation, some limitations need to be outlined. Laboratory test cut-offs, which we chose to diagnose PTDM, are those recommended by the ADA for the diagnosis of diabetes [48]. Elevated blood glucose levels and the need for hypoglycemic medication are frequent in the early postoperative period [49]. Timing for food intake was not collected in the database. To avoid potential significant bias, patients were classified with PTDM based on the selected parameters screened at the time of discharge and during the outpatient follow-up. Nevertheless, the incidence of PTDM reported here may have been somewhat miss-diagnosed. In fact, oral glucose tolerance tests (OGTT), the gold standard for diagnosing PTDM [50, 51], were not performed routinely in our patients before and after CTx. As such, the rate of PTDM may have been overestimated by missing high-risk patients prior to CTx. On the other hand, HbA1C may be underestimated during the few months following solid organ transplantation, and it is recommended to do an OGTT when HbA1C values are between 5.7 and 6.4% [52]. By choosing a cut-off value of 6.5% from the time of discharge to outpatient follow-up, we may have underestimated the rate of diabetes within the first few months following CTx. However, these patients were likely diagnosed later in the year, when both glucose and HgbA1c had stabilized. Because of these issues we realize that the difference in the rate of PTDM reported here may be difficult to compare with previous studies. More than 95% of our study population were chronically treated by prednisone. As such, the impact of prednisone on PTDM could not be assessed with accuracy using Cox proportional hazard model. Finally, because of the retrospective design of this study, changes in the immunosuppressive medication, the rate of PTDM treated by diet alone, and how many of our patients exhibited transient hyperglycemia remain unknown.

5. Conclusions

The rate of PTDM approaches nearly 40% at three years following CTx. This prevalence has not significantly changed over 30 years, despite higher risk for both donors and recipients through the analyzed eras. The development of PTDM is associated with an increase in all-cause mortality and a worsening in renal function over time. Such a high rate of newly diagnosed diabetes justifies aggressive preventive measures very early following CTx in order to minimize long-term complications such as renal dysfunction. Prospective studies using larger sample size are needed to confirm our results and address the proper diagnostic and therapeutic strategies in this high-risk population.

Abbreviations

ADA:	American Diabetes Association
BMI:	Body mass index
CTx:	Cardiac transplant
CVD:	Cardiovascular disease
eGFR:	excreted glomerular filtration rate
HBA1C:	Glycated hemoglobin
ISHLT:	International Society of Heart and Lung Transplant
MPA:	Mycophenolate acid
NODAT:	New-onset diabetes after transplantation
OGTT:	Oral glucose tolerance test
PTDM:	Posttransplant diabetes mellitus.

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest

The authors of this manuscript have no conflicts of interest to disclose.

Authors’ Contributions

Nadia Iannino participated in research design, participated in the writing of the paper, participated in the performance of the research, and participated in data analysis. Amine Nasri participated in the writing of the paper, participated in the performance of the research, and participated in data analysis. Agnès Räkel participated in data analysis. Anique Ducharme participated in the writing of the paper and participated in the performance of the research. Kim Lachance participated in research design, participated in the writing of the paper, and participated in the performance of the research. Normand Racine participated in the writing of the paper, participated in the performance of the research, and participated in data analysis. Simon de Denus participated in research design, participated in the writing of the paper, and participated in data analysis. Maxime Tremblay-Gravel participated in data analysis. Annik Fortier participated in the writing of the paper and participated in data analysis. Michel White participated in research design, participated in the writing of the paper, participated in the performance of the research, and participated in data analysis.

Acknowledgments

This study was funded by the Carolyn and Richard Renaud Research Chair in Heart Failure of the Montreal Heart Institute.

References

A. Sharif, M. Hecking, A. P. J. De Vries et al., “Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: recommendations and future directions,” American Journal of Transplantation, vol. 14, no. 9, pp. 1992–2000, 2014.
View at: Publisher Site | Google Scholar
V. Shivaswamy, B. Boerner, and J. Larsen, “Post-transplant diabetes mellitus: Causes, Treatment, and Impact on Outcomes,” Endocrine Reviews, vol. 37, no. 1, pp. 37–61, 2016.
View at: Publisher Site | Google Scholar
V. M. Montori, A. Basu, P. J. Erwin, J. A. Velosa, S. E. Gabriel, and Y. C. Kudva, “Posttransplantation diabetes: a systematic review of the literature,” Diabetes Care, vol. 25, no. 3, pp. 583–592, 2002.
View at: Publisher Site | Google Scholar
O. Heisel, R. Heisel, R. Balshaw, and P. Keown, “New Onset Diabetes Mellitus in Patients Receiving Calcineurin Inhibitors: A Systematic Review and Meta-Analysis,” American Journal of Transplantation, vol. 4, no. 4, pp. 583–595, 2004.
View at: Publisher Site | Google Scholar
J. Davidson, A. Wilkinson, J. Dantal et al., “New-onset diabetes after transplantation: 2003 International Consensus Guidelines - Proceedings of an International Expert Panel Meeting Barcelona, Spain 19 February 2003,” Transplantation, vol. 75, no. 10, pp. SS1–SS24, 2003.
View at: Publisher Site | Google Scholar
K. Lachance, M. White, and S. D. Denus, “Risk factors for chronic renal insufficiency following cardiac transplantation,” Annals of Transplantation, vol. 20, pp. 576–587, 2015.
View at: Publisher Site | Google Scholar
G. Sarno, G. Muscogiuri, and P. De Rosa, “New-onset diabetes after kidney transplantation: Prevalence, risk factors, and management,” Transplantation, vol. 93, no. 12, pp. 1189–1195, 2012.
View at: Publisher Site | Google Scholar
M. Hecking, J. Werzowa, M. Haidinger et al., “Novel views on new-onset diabetes after transplantation: Development, prevention and treatment,” Nephrology Dialysis Transplantation , vol. 28, no. 3, pp. 550–566, 2013.
View at: Publisher Site | Google Scholar
F. G. Cosio, T. E. Pesavento, S. Kim, K. Osei, M. Henry, and R. M. Ferguson, “Patient survival after renal transplantation: IV. Impact of post-transplant diabetes,” Kidney International, vol. 62, no. 4, pp. 1440–1446, 2002.
View at: Publisher Site | Google Scholar
J. Hjelmesaeth, T. Jenssen, M. Hagen, T. Egeland, and A. Hartmann, “Determinants of insulin secretion after renal transplantation,” Metabolism - Clinical and Experimental, vol. 52, no. 5, pp. 573–578, 2003.
View at: Publisher Site | Google Scholar
D. Ducloux, A. Kazory, and J.-M. Chalopin, “Posttransplant diabetes mellitus and atherosclerotic events in renal transplant recipients: A prospective study,” Transplantation, vol. 79, no. 4, pp. 438–443, 2005.
View at: Publisher Site | Google Scholar
B. Depczynski, B. Daly, L. V. Campbell, D. J. Chisholm, and A. Keogh, “Predicting the occurrence of diabetes mellitus in recipients of heart transplants,” Diabetic Medicine, vol. 17, no. 1, pp. 15–19, 2000.
View at: Publisher Site | Google Scholar
L. Martinez-Dolz, L. Almenar, L. Martinez-Ortiz et al., “Predictive factors for development of diabetes mellitus post-heart transplant,” Transplantation Proceedings, vol. 37, no. 9, pp. 4064–4066, 2005.
View at: Publisher Site | Google Scholar
M. V. Mogollón, E. Lage Gallé, R. Hinojosa Pérez et al., “Prognosis After Heart Transplant in Patients With Pulmonary Hypertension Secondary to Cardiopathy,” Transplantation Proceedings, vol. 40, no. 9, pp. 3031–3033, 2008.
View at: Publisher Site | Google Scholar
L. H. Lund, L. B. Edwards, A. Y. Kucheryavaya et al., “The Registry of the International Society for Heart and Lung Transplantation: Thirty-second Official Adult Heart Transplantation Report - 2015; Focus Theme: Early Graft Failure,” The Journal of Heart and Lung Transplantation, vol. 34, no. 10, pp. 1244–1254, 2015.
View at: Publisher Site | Google Scholar
M. G. Nieuwenhuis and J. H. Kirkels, “Predictability and other aspects of post-transplant diabetes mellitus in heart transplant recipients,” The Journal of Heart and Lung Transplantation, vol. 20, no. 7, pp. 703–708, 2001.
View at: Publisher Site | Google Scholar
F. G. Cosio, T. E. Pesavento, K. Osei, M. L. Henry, and R. M. Ferguson, “Post-transplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent years,” Kidney International, vol. 59, no. 2, pp. 732–737, 2001.
View at: Publisher Site | Google Scholar
A. J. Matas, J. M. Smith, M. A. Skeans et al., “OPTN/SRTR 2013 Annual Data Report: Kidney,” American Journal of Transplantation, vol. 15, pp. 1–34, 2015.
View at: Publisher Site | Google Scholar
P. T. Katzmarzyk, “The Canadian obesity epidemic, 1985-1998,” Canadian Medical Association Journal, vol. 166, no. 8, pp. 1039-1040, 2002.
View at: Google Scholar
D. O. Taylor, L. B. Edwards, M. M. Boucek et al., “Registry of the international society for heart and lung transplantation: twenty-fourth official adult heart transplant report—2007,” The Journal of Heart and Lung Transplantation, vol. 26, no. 8, pp. 769–781, 2007.
View at: Publisher Site | Google Scholar
J. Genest, J. Frohlich, G. Fodor, and R. McPherson, “Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: Summary of the 2003 update,” Canadian Medical Association Journal, vol. 169, no. 9, pp. 921–924, 2003.
View at: Google Scholar
V.-V. Le, N. Racine, G. B. Pelletier, M. Carrier, M. Cossette, and M. White, “Impact of ezetimibe on cholesterol subfractions in dyslipidemic cardiac transplant recipients receiving statin therapy,” Clinical Transplantation, vol. 23, no. 2, pp. 249–255, 2009.
View at: Publisher Site | Google Scholar
J. B. Redmon, L. K. Olson, M. B. Armstrong, M. J. Greene, and R. P. Robertson, “Effects of tacrolimus (FK506) on human insulin gene expression, insulin mRNA levels, and insulin secretion in HIT-T15 cells,” The Journal of Clinical Investigation, vol. 98, no. 12, pp. 2786–2793, 1996.
View at: Publisher Site | Google Scholar
F. Vincenti, S. Friman, E. Scheuermann et al., “Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus,” American Journal of Transplantation, vol. 7, no. 6, pp. 1506–1514, 2007.
View at: Publisher Site | Google Scholar
A. C. Webster, R. C. Woodroffe, R. S. Taylor, J. R. Chapman, and J. C. Craig, “Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: Meta-analysis and meta-regression of randomised trial data,” British Medical Journal, vol. 331, no. 7520, pp. 810–814, 2005.
View at: Publisher Site | Google Scholar
J. Groetzner, B. M. Meiser, J. Schirmer et al., “Tacrolimus or cyclosporine for immunosuppression after cardiac transplantation: Which treatment reveals more side effects during long-term follow-up?” Transplantation Proceedings, vol. 33, no. 1-2, pp. 1461–1464, 2001.
View at: Publisher Site | Google Scholar
D. O. Taylor, M. L. Barr, B. Radovancevic et al., “A randomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: Decreased hyperlipidemia and hypertension with tacrolimus,” The Journal of Heart and Lung Transplantation, vol. 18, no. 4, pp. 336–345, 1999.
View at: Publisher Site | Google Scholar
M. White, H. Haddad, M.-H. Leblanc et al., “Conversion from cyclosporine microemulsion to tacrolimus-based immunoprophylaxis improves cholesterol profile in heart transplant recipients with treated but persistent dyslipidemia: the canadian multicentre randomized trial of tacrolimus vs cyclosporine microemulsion,” The Journal of Heart and Lung Transplantation, vol. 24, no. 7, pp. 798–809, 2005.
View at: Publisher Site | Google Scholar
M. White, B. Cantin, H. Haddad et al., “Cardiac signaling molecules and plasma biomarkers after cardiac transplantation: Impact of tacrolimus versus cyclosporine,” The Journal of Heart and Lung Transplantation, vol. 32, no. 12, pp. 1222–1232, 2013.
View at: Publisher Site | Google Scholar
E. Sulanc, J. T. Lane, S. E. Puumala, G. C. Groggel, L. E. Wrenshall, and R. B. Stevens, “New-onset diabetes after kidney transplantation: An application of 2003 International Guidelines,” Transplantation, vol. 80, no. 7, pp. 945–952, 2005.
View at: Publisher Site | Google Scholar
M. E. Von Düring, T. Jenssen, J. Bollerslev et al., “Visceral fat is better related to impaired glucose metabolism than body mass index after kidney transplantation,” Transplant International, vol. 28, no. 10, pp. 1162–1171, 2015.
View at: Publisher Site | Google Scholar
R. A. Sorabella, L. Guglielmetti, A. Kantor et al., “Cardiac Donor Risk Factors Predictive of Short-Term Heart Transplant Recipient Mortality: An Analysis of the United Network for Organ Sharing Database,” Transplantation Proceedings, vol. 47, no. 10, pp. 2944–2951, 2015.
View at: Publisher Site | Google Scholar
L. S. C. Czer, A. V. Wong, H. Soukiasian, S. Gallagher, M. De Robertis, and A. Trento, “Prolonged cold ischemic times and less donor-recipient histocompatibility accelerate graft vascular disease,” Transplantation Proceedings, vol. 43, no. 10, pp. 3863–3868, 2011.
View at: Publisher Site | Google Scholar
C. Andersson, M. L. Norgaard, P. R. Hansen et al., “Heart failure severity, as determined by loop diuretic dosages, predicts the risk of developing diabetes after myocardial infarction: A nationwide cohort study,” European Journal of Heart Failure, vol. 12, no. 12, pp. 1333–1338, 2010.
View at: Publisher Site | Google Scholar
M. N. Demant, G. H. Gislason, L. Køber, A. Vaag, C. Torp-Pedersen, and C. Andersson, “Association of heart failure severity with risk of diabetes: A Danish nationwide cohort study,” Diabetologia, vol. 57, no. 8, pp. 1595–1600, 2014.
View at: Publisher Site | Google Scholar
J. Hjelmesæth, A. Hartmann, J. Kofstad et al., “Glucose intolerance after renal transplantation depends upon prednisolone dose and recipient age,” Transplantation, vol. 64, no. 7, pp. 979–983, 1997.
View at: Publisher Site | Google Scholar
J. Kobashigawa, L. Miller, D. Renlund et al., “A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Mycophenolate Mofetil Investigators,” Transplantation, vol. 66, no. 4, pp. 507–515, 1998.
View at: Publisher Site | Google Scholar
H. J. Eisen, J. Kobashigawa, A. Keogh et al., “Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients,” The Journal of Heart and Lung Transplantation, vol. 24, no. 5, pp. 517–525, 2005.
View at: Publisher Site | Google Scholar
B. Ergin, M. Heger, A. Kandil, C. Demirci-Tansel, and C. Ince, “Mycophenolate mofetil improves renal haemodynamics, microvascular oxygenation, and inflammation in a rat model of supra-renal aortic clamping-mediated renal ischaemia reperfusion injury,” Clinical and Experimental Pharmacology and Physiology, vol. 44, no. 2, pp. 294–304, 2017.
View at: Publisher Site | Google Scholar
R. A. Sorabella, L. Guglielmetti, A. Kantor et al., “Cardiac Donor Risk Factors Predictive of Short-Term Heart Transplant Recipient Mortality: An Analysis of the United Network for Organ Sharing Database,” Transplantation Proceedings, vol. 47, no. 10, pp. 2944–2951, 2015.
View at: Publisher Site | Google Scholar
H. Bergenfeldt, J. Stehlik, P. Höglund, B. Andersson, and J. Nilsson, “Donor-recipient size matching and mortality in heart transplantation: Influence of body mass index and gender,” The Journal of Heart and Lung Transplantation, vol. 36, no. 9, pp. 940–947, 2017.
View at: Publisher Site | Google Scholar
K. K. Khush, J. T. Kubo, and M. Desai, “Influence of donor and recipient sex mismatch on heart transplant outcomes: analysis of the international society for heart and lung transplantation registry,” The Journal of Heart and Lung Transplantation, vol. 31, no. 5, pp. 459–466, 2012.
View at: Publisher Site | Google Scholar
K. L. Lentine, D. C. Brennan, and M. A. Schnitzler, “Incidence and predictors of myocardial infarction after kidney transplantation,” Journal of the American Society of Nephrology, vol. 16, no. 2, pp. 496–506, 2005.
View at: Publisher Site | Google Scholar
R. S. Woodward, M. A. Schnitzler, J. Baty et al., “Incidence and cost of new onset diabetes mellitus among U.S. wait-listed and transplanted renal allograft recipients,” American Journal of Transplantation, vol. 3, no. 5, pp. 590–598, 2003.
View at: Publisher Site | Google Scholar
H. Bedanova, J. Ondrasek, J. Cerny et al., “Impact of diabetes mellitus on survival rates after heart transplantation,” Biomedical Papers, vol. 153, no. 4, pp. 283–287, 2009.
View at: Publisher Site | Google Scholar
H. Valantine, “Cardiac allograft vasculopathy after heart transplantation: Risk factors and management,” The Journal of Heart and Lung Transplantation, vol. 23, no. 5, pp. S187–S193, 2004.
View at: Publisher Site | Google Scholar
M. S. Cho, H.-I. Choi, I.-O. Kim et al., “The clinical course and outcomes of post-transplantation diabetes mellitus after heart transplantation,” Journal of Korean Medical Science, vol. 27, no. 12, pp. 1460–1467, 2012.
View at: Publisher Site | Google Scholar
J. J. Chamberlain, A. S. Rhinehart, C. F. Shaefer, and A. Neuman, “Diagnosis and management of diabetes: synopsis of the 2016 american diabetes association standards of medical care in diabetes,” Annals of Internal Medicine, vol. 164, no. 8, pp. 542–552, 2016.
View at: Publisher Site | Google Scholar
H. A. Chakkera, E. J. Weil, J. Castro et al., “Hyperglycemia during the immediate period after kidney transplantation,” Clinical Journal of the American Society of Nephrology, vol. 4, no. 4, pp. 853–859, 2009.
View at: Publisher Site | Google Scholar
A. Sharif, R. H. Moore, and K. Baboolal, “The use of oral glucose tolerance tests to risk stratify for new-onset diabetes after transplantation: An underdiagnosed phenomenon,” Transplantation, vol. 82, no. 12, pp. 1667–1672, 2006.
View at: Publisher Site | Google Scholar
T. G. Valderhaug, T. Jenssen, A. Hartmann et al., “Fasting plasma glucose and glycosylated hemoglobin in the screening for diabetes mellitus after renal transplantation,” Transplantation, vol. 88, no. 3, pp. 429–434, 2009.
View at: Publisher Site | Google Scholar
S. Shabir, S. Jham, L. Harper, S. Ball, R. Borrows, and A. Sharif, “Validity of glycated haemoglobin to diagnose new onset diabetes after transplantation,” Transplant International, vol. 26, no. 3, pp. 315–321, 2013.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2018 Nadia Iannino et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

1391

Downloads

1138

Citations