EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Kidney transplant is the best renal replacement therapy for pediatric patients with end-stage renal disease; however, this procedure is not without complications. A major complication is the development of new-onset diabetes mellitus, which affects the outcomes of transplant in terms of kidney and patient survival. In this study, our objective was to calculate the percentage of pediatric patients who developed new-onset diabetes mellitus or transient hyperglycemia after kidney transplant, compare our data with international data, and discuss the related factors that predispose to diabetes.

Materials and Methods: A retrospective study was conducted by reviewing the medical records of pediatric patients who had transplant procedures or were followed at the Royal Medical Services (Amman, Jordan) from 2007 to 2017.

Results: Our study cohort included 104 patients. The average follow-up time was 4 years and 7 months, with a maximum follow-up of 9 years. Ten patients developed posttransplant hyperglycemia, with 8 developing early hyperglycemia (during the first 3 months posttransplant). In 40% of patients, this complication was transient, and patients stopped insulin after immunosuppressant medications were decreased. However, 60% of patients continued to have diabetes, with 20% having late-onset diabetes and treatment with oral hypoglycemic agent.

Conclusions: Pretransplant awareness of risk factors of new-onset diabetes mellitus after transplant and close monitoring of hyperglycemia during the posttransplant period are mandatory. Transient hyperglycemia after kidney transplant is common, and kidney transplant does not alleviate the high risk of diabetes in patients with chronic kidney disease.

Key words : Graft survival, New-onset diabetes mellitus, Renal transplantation

Kidney transplant is the best renal replacement therapy for pediatric patients who have end-stage renal disease, as it has a positive impact on linear and developmental growth and quality of life for patients and their families due to improvements in economic and psychosocial aspects. However, kidney transplant is not without complications, which are related to surgical and medical causes and can occur early or late after transplant. An important complication is the development of new-onset diabetes mellitus after transplant (NODAT), which affects transplant outcomes in terms of kidney and patient survival and increased risk of cardiovascular morbidity. Kidney transplant can increase the risk of diabetes in patients with normal glycemic levels pretransplant and is related to immunosuppressant drugs used after transplantation.¹

Diabetes has an incidence of occurrence of approximately 6% per year among adult dialysis patients; in the first year after transplant, it has an incidence of almost 18% and 30% among adult patients receiving cyclosporine and tacrolimus. There are no data describing the incidence of diabetes in pediatric patients with end-stage renal failure who have been listed for transplant.² Although one report stated that the incidence ranges from 4% to 25% in adult patients after kidney transplant,³ the incidence of NODAT in pediatric patients has not been well established, with a range from 3% to 13% in different studies.^4,5

The definition of posttransplant diabetes varies, with the most accepted definition being the need for insulin use within 30 days after kidney transplant.

In 2013, there was an agreement as to terminology from the American Diabetes Association, which stated that normal fasting blood glucose (FBG) is less than 100 mg/dL, impaired FBG ranges from 100 to 126 mg/dL, and diabetic FBG is more than 126 mg/dL. With glucose tolerance test at 2 hours posttest, normal is defined as a reading below 140 mg/dL, impaired is defined as a reading ranging from 140 to 199 mg/dL, and diabetic is defined as reading greater than or equal to 200 mg/dL.⁶ Hemoglobin A1c testing has limitations, especially in diseases that increase red blood cell turnover as occurs with chronic kidney diseases⁷; therefore, it is not used to screen for diabetes in posttransplant patients.

There are many risk factors associated with the development of NODAT. A risk factor that cannot be modified is a positive family history of diabetes in first- or second-degree relatives, which is associated with high risk of NODAT in both adult and pediatric patients.^5,8 Patients who are of African American and white ethnicities have a higher risk of development of NODAT than Hispanic patients.⁴ Diabetes is also more likely to occur in younger recipients than in adult recipients, who have higher risk only after the age of 45 years.⁹

A modifiable risk is obesity, which is associated with higher rates of development of NODAT, especially when body mass index (BMI) is ≥ 25 kg/m².10 Other risk factors include hepatitis C and cytomegalovirus infections^5,11 and the use of certain immunosuppressants, including glucocorticoids,¹² tacrolimus,¹³ and sirolimus,¹⁴ versus risk with cyclosporine use. Certain diseases are also associated with higher incidence of development of diabetes after kidney transplant; these include cystinosis,¹⁵ hemolytic uremic syndrome, and autosomal-recessive polycystic kidney disease.¹⁶ In addition, the presence of hypomagnesemia after transplant has been found to be an independent risk factor for NODAT.¹⁷

In this study, our objective was to estimate the percentage of pediatric patients who developed NODAT after kidney transplant who were seen at the Queen Rania Children’s Hospital (Amman, Jordan), compare our results with international data, and discuss the related factors that predispose to diabetes as well as graft and patient survival rates.

Materials and Methods

This retrospective study was conducted by reviewing the medical records of pediatric patients who received transplant procedures or were followed at our institution from 2007 to 2017. The study was approved by the ethics committee of the Jordanian Royal Medical Service. Patients who developed hyperglycemia after transplant were included in the study, and their medical records were reviewed for timing and period of hyperglycemia and care that they received. The period of follow-up was recorded, and risk factors were reviewed.

Immunosuppressant medications included prednisolone, mycophenolate mofetil, and tacrolimus, with target trough level from 10 to 15 μg/L in the first month, from 8 to 10 μg/L during months 2 and 3, and from 5 to 8 μg/L after month 3.

The diagnosis of diabetes was based on FBG levels equal or above 126 mg/dL in more than one reading.⁶ Fasting blood glucose was measured daily for the first 2 weeks posttransplant, then twice weekly up to month 3, and then once monthly from months 3 to 6 and every 3 months after that. It was also measured if there was suspicion of hyperglycemia based on clinical findings. Hemoglobin A1c testing was not routinely used unless hyperglycemia developed as a baseline and then repeated every 3 months at follow-up visits.

Inclusion criteria included all patients who received living-donor or deceased-donor kidney transplant and who had complete data and/or were followed at our nephrology clinic.

Statistical analyses
Pearson chi-square analyses were used to identify the recipient factors that were associated with development of hyperglycemia and/or NODAT. These included patient characteristics (age, sex, BMI, positive family history of diabetes mellitus), having hypomagnesemia after transplant, development of other complications (including rejection and cytomegalovirus infection), primary causes of renal failure, whether the patient received dialyses before transplant versus received a preemptive transplant, and graft loss.

Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 20.0, IBM Corporation, Armonk, NY, USA). Differences were considered statistically significant at P < .005 (2-sided test).

Of 119 patients who had received transplants or were followed at our nephrology clinic, 104 patients who did not have diabetes before transplant were included in this cohort. Fifteen patients had been excluded from the study or were lost to follow-up for different causes. These reasons included only traveling to Jordan for transplant procedure and then returning to their home country, lost to follow-up after transfer to adult services, and death during the first month after transplant (n = 3 patients).

Table 1 shows the total number of patients who developed hyperglycemia. The primary causes of end-stage renal failure before transplant are shown in Table 2. Our study group included 61 male patients (59%) and 43 female patients (41%) (male-to-female ratio of 1.4:1). The average follow-up time was 4 years and 7 months, with maximum follow-up of 9 years. In our study group, 97% of patients received a kidney from a living donor (only 3 patients received a kidney from a deceased donor) (Table 3).

Ten patients developed posttransplant hyperglycemia (Table 4), with 7 patients developing hyperglycemia early (during the first 3 months posttransplant) and 3 patients developing hyperglycemia later (6 months or more after transplant). Four of the 10 patients (40%) had resolution of hyperglycemia after steroid doses were decreased and after shifting from tacrolimus to cyclosporine or sirolimus. Seven patients were treated with insulin, and 3 patients were treated with oral hypoglycemic agents. Two years after transplant, 2 patients developed type 2 diabetes mellitus because of obesity, which was treated with oral hypoglycemic agents.

Statistical analyses using Pearson chi-square tests were used to evaluate the associations between different risk factors and development of diabetes mellitus after kidney transplant. Our analyses showed that the incidence of NODAT was higher in female patients (14%) than in male patients (3.3%) (P = .044).

The incidences of transient hyperglycemia after transplant and NODAT were higher in children who had BMI levels of ≥ 24 kg/m2 (incidence of 27.3%) than in children with BMI levels of < 24 kg/m2 (incidence of 5.4%). Furthermore, rapid weight gain after transplant (defined as more than 1 kg/month in the first 6 months posttransplant) was associated with higher incidence of transient hyperglycemia after transplant and NODAT development (31%; P = .010).

A positive family history of diabetes mellitus as a risk factor was strongly associated with NODAT (100%; P < .001). The development of hypomagnesemia after kidney transplant was also strongly associated with hyperglycemia and NODAT development (30%; P = .005).

Finally, the development of complications after transplant increased the rate of NODAT development by 27% compared with patients who did not develop complications (P = .004). These complications included cell- and antibody-mediated rejection, viral and bacterial infection, hypertension, surgical complications, thrombosis, and suggesting the need to intensify immunosuppressant treatment.

Age at transplant, occurrence of cytomegalovirus infection, cause of end-stage renal failure, preemptive transplant, and graft loss showed no significant association with NODAT development.

To our knowledge, this is the first study describing the incidence of NODAT and posttransplant transient hyperglycemia in a pediatric population in our region. Our study showed a prevalence of hyperglycemia of 10% and a prevalence of persistent hyperglycemia and development NODAT of 6%. In a previous study of 274 pediatric patients, the rate of occurrence of NODAT was 10.5%.¹⁸

Regarding the traditional risk factors for development of diabetes in nontransplanted patients (obesity and positive family history), our results were similar in our pediatric transplant group versus those who are not transplanted. The relative risk of development of NODAT has been shown19 to be 1.4 for transplant patients with a BMI between 25 and 30 kg/m2 and 1.7 to 1.8 for transplant patients with a BMI greater than 30 kg/m². However, these results are for adult transplant recipients, and we found no similar data for pediatric transplant recipients in the literature. In our study, the rate of occurrence of transient hyperglycemia after transplant and NODAT was higher in children with BMI ≥ 24 kg/m² at 27.3% versus a rate of 5.4% in children with BMI less than 24 kg/m². Rapid weight gain after transplant (which we defined as > 1 kg/month increase during the first 3 months posttransplant) is a significant risk factor for development of NODAT. Weight gain after transplant can be explained by the general condition of pediatric patients improving, including increased appetite and increased nutritional intake in patients, as well as the effects of steroids, which can add to weight gain.

The most significant transplant-related risk factor is the use of immunosuppressants, which include corticosteroids and calcineurin inhibiters. The mechanism of development of transient hyperglycemia after transplant and NODAT is beta-cell dysfunction, in which glucocorticoids induce insulin resistance and calcineurin inhibiters decrease insulin secretion and increase a direct toxic effect on beta cells.²⁰

Hyperglycemic patients have been shown to have significantly higher rates of cytomegalovirus infections than patients who are normoglycemic.²¹ Conversely, in our study, we observed no significant correlation between diabetes mellitus and cytomegalovirus infection after kidney transplant, which are findings similar to 2 other studies.^22,23 However, the significant association may not have been shown due to the small size of our cohort. Small cohort size and the retrospective design were the two main limitations of our study.

Transient hyperglycemia after kidney transplant is common, and kidney transplant does not alleviate the high risk of diabetes in patients with chronic kidney disease. Pretransplant awareness of risk factors of NODAT and close monitoring of hyperglycemia during the posttransplant period are mandatory.

In addition, unnecessary high doses of immunosuppressants should be avoided and levels of calcineurin inhibitors should be strictly monitored, with tapering of doses over the first 6 months after transplant. These are important preventive measures that may reduce the rate of development of NODAT and hence improve patient and kidney survival.

Volume: 17 Issue: 2 April 2019

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