EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: New-onset diabetes after transplant is a well-recognized complication of solid-organ trans-plant. The true incidence of this complication in Sudan is not known. The aim of this study was to define the prevalence of new-onset diabetes after transplant in a Sudanese renal transplant population and to identify the contributing risk factors.

Materials and Methods: Fifty-nine patients who underwent living-donor related kidney transplant and who were followed for 2 years were included in this pilot study. Only patients who were not diabetic before transplant were included. Patients who developed new-onset diabetes after transplant were compared with those who did not develop type 2 diabetes mellitus. The variables analyzed were age, sex, body mass index, family history of type 2 diabetes mellitus, and interval between time of transplant and onset of diabetes.

Results: Five patients (5/58) developed diabetes after transplant (8.62%). There was no association between new-onset diabetes after transplant and age, sex, and body mass index. However, there was a strong association between family history of diabetes and new-onset diabetes after transplant. The mean duration for developing new-onset diabetes after transplant was 10 months posttransplant. Patients in the new-onset diabetes after transplant group had no graft loss or deterioration in graft function compared with those who did not develop diabetes.

Conclusions: The prevalence of new-onset diabetes after transplant in our studied Sudanese population was found to be < 10%. There was no association between new-onset diabetes after transplant and age, sex, and body mass index. However, there was a significant association with family history of diabetes mellitus.

Key words : End-stage renal disease, Immunosuppressive medications, Kidney transplant, Type 2 diabetes mellitus

Renal transplant has long been an established treatment for end-stage renal disease. The first transplant in Sudan was performed in the early 1970s. However, established renal transplant programs have only been running for the past 10 years.

New-onset diabetes after transplant (NODAT) is a well-known and common complication of renal transplant, as recognized by the 2003 NODAT inter-national consensus guidelines.¹ New-onset diabetes after transplant affects a patient’s quality of life and increases cardiovascular and renal risks, which can ultimately lead to graft loss and death. The main underlying cause of NODAT is immuno-suppressive medications. Glucocorticoids increase the risk of diabetes mellitus (DM) by causing impairment in the β-cell function of the pancreas.² Calcineurin inhibitors induce β-cell toxicity, which leads to increased insulin resistance and decreased insulin production.³

There are multiple predisposing risk factors for NODAT, which have been classified into modifiable and nonmodifiable risk factors.⁴ Nonmodifiable risk factors include age, ethnic origin, a positive family history for DM, and history of glucose intolerance. For ethnic origin, it is reported that African Americans have a higher risk of developing NODAT than white individuals.⁴ However, there are no reports about the incidence or risk factors for NODAT in Sub-Saharan African populations, as all reports about Africans come from North Africa.

The aim of this study was to identify the prevalence and risk factors for NODAT in a Sudanese transplant population.

Materials and Methods

Patients
Ethical approval was granted before the com-mencement of the study. This is a descriptive cross-sectional study conducted at the Renal Transplant Unit, Sharg El-Neel Hospital, Khartoum, Sudan. All patients who underwent living-donor related renal transplant at our center between July 2012 and July 2013 and who fulfilled the set inclusion and exclusion criteria were included in this study. Inclusion criteria included those who were not diabetic before transplant. Exclusion criteria included those with diagnosed diabetic nephropathy as the cause of renal failure and those with diabetes before transplant.

New-onset diabetes after transplant was defined according to the 2003 NODAT Consensus Guidelines adopted from definitions of DM by the American Diabetes Association and the World Health Organization. A patient is considered to have NODAT if he/she has random plasma glucose level of ≥ 11.1 mmol/L or 8-hour fasting plasma glucose level of ≥ 7.0 mmol/L.1 The 2010 American Diabetes Association amendment in the definition of NODAT was not adopted in our center because the financial constraints would not allow the use of the oral glucose tolerance test (oGTT) for routine monitoring. Patients who developed transient steroid-induced dysglycemia and needing insulin treatment during the initial postoperative period and then reverted to normal glycemic levels after steroid dose reduction were not censored as having NODAT.

The variables included in this study were age at time of transplant, sex, body mass index (BMI), family history of diabetes, and, for those who developed NODAT, the time interval between transplant and diagnosis of diabetes.

The triple therapy immunosuppressive protocol is administered in our center. This protocol consists of steroids, calcineurin inhibitors (tacrolimus), and antiproliferative agents (azathioprine). Steroids are initially started intraoperatively with an intravenous dose of 500 mg of methylprednisolone before removal of clamps. Two further doses of intravenous methylprednisolone are given during the first 2 postoperative days (500 mg on the first day and 250 mg on the second postoperative day). Patients are then converted to oral prednisolone at a dose of 20 mg/day, taken as a single dose. Gradual tapering of prednisolone is started 6 weeks postoperatively to reach the minimum dose of 5 mg/day, which is the maintenance dose, by month 3 posttransplant. Tacrolimus is started 48 hours before transplant at a dose of 0.15 mg/kg body weight, keeping the serum tacrolimus level at 10 to 15 ng/mL for the first 6 weeks. The dose is reduced to reach a target serum tacrolimus level of 7 to 10 ng/mL by month 3 posttransplant and then reduced further at that point in time to reach a target level of 5 to 7 ng/mL, which is the long-term maintenance level. Azathioprine is started on the first postoperative day at a dose of 5 mg/kg/day and then reduced at month 3 to 3 mg/kg/day. Induction therapy was not used in this study group as it was not part of the protocol, again due to financial constraints. However, induction with basiliximab is now used selectively at our center.

Kidney function was monitored by regular measurement of the serum creatinine level and calculating the creatinine clearance using the Cock-Croft Gault formula as well as checking urine for proteinuria. Laboratory tests were done daily during the initial postoperative period until discharge, usually within 5 to 7 days.

Blood sugar was measured every 12 hours during the first 3 days posttransplant and then every 24 hours until discharge from the hospital. For nondiabetic patients who developed dysglycemia during the initial postoperative period, blood sugar was measured every 6 hours until blood sugar levels were controlled and then every 12 hours thereafter. These patients were treated with subcutaneous soluble insulin, according to the hospital’s insulin sliding scale protocol, with insulin dose adjusted according to the blood sugar level, which was checked every 6 hours. Insulin administration was stopped when blood sugar levels reached and remained at a level of ≤ 8.3 mmol/L.

After discharge from hospital, patients were seen for clinical and laboratory assessments twice weekly for the first 2 to 3 weeks, then once weekly until postoperative week 6, and then monthly until postoperative month 6. For long-term follow-up, patients were seen every 2 months.

Statistical analyses
Numeric data are expressed as means ± standard deviation. Chi-square and Fisher exact tests were used to analyze quantitative data. Unpaired t tests were used to analyze the means of 2 continuous variables. P < .05 was considered as statistically significant. Data were analyzed using Statistical Package for Social Sciences software (version 10, SPSS Inc., Chicago, IL, USA).

Sixty-two patients underwent living-donor related kidney transplant during the study period. The du-ration of follow-up was 1 to 26 months (18.9 ± 9.4 mo). No grafts or patients were lost during this period. Three patients were excluded because the cause of renal failure was diabetic nephropathy, leaving 59 patients suitable for analyses. The characteristics of the studied patients are shown in Table 1.

Of the 59 patients, 47 were males (79.7%) and 12 were females (20.3%). The ages of the study groups ranged from 18 to 56 years (mean of 34.6 years).

Five patients (8.5%) developed NODAT during the study period. The mean interval between transplant and diagnosis of NODAT was 3.6 months (range, 1-10 mo). However, 27 patients (46%) developed dysglycemia, needing insulin treatment, in the immediate postoperative period. Of these, 26 patients reverted back to normal glycemic state within 4 to 7 days. One patient continued to be dysglycemic and continued on insulin treatment until his last follow-up. This patient was censored as having NODAT.

Of the 5 patients who developed NODAT, 3 were men and 2 were women (mean age of 38.6 y). There was no statistically significant association between age and NODAT (P = .27).

Most of the study group (58 patients) had a BMI of < 25 kg/m2. One patient had a BMI of 27 kg/m2. All patients who developed NODAT had a BMI of < 25 kg/m2. Hence, there was no statistically significant association between BMI and NODAT (P = 1.0).

Four of the 5 patients who developed NODAT had a strong family history of diabetes mellitus that affected at least one first-degree relative. There was a statistically significant correlation between family history of DM and NODAT (P ≤ .05).

New-onset diabetes after transplant is a well-recognized complication of solid-organ transplant. It is associated with significantly increased risk of cardiovascular events, impairment in the trans-planted renal function, and death. It is generally known that the prevalence rate of diabetes in transplant patients with NODAT is significantly elevated compared with the normal population, with the rate being approximately 20% of transplanted patients.

Multiple risk factors have been associated with NODAT, some modifiable and others not modifiable.⁵ Among those that are not modifiable are age at time of transplant, sex, ethnic origin, family history of diabetes, previously diagnosed glucose intolerance, HLA tissue type, presence of multiple genetic polymorphisms, and underlying kidney disease. Patients above the age of 45 years at time of transplant are at a higher risk of developing NODAT.6 Male sex, black race, a positive family history of DM, history of impaired glucose tolerance, and adult polycystic kidney disease are all associated with increased risk of NODAT.⁷ Some of the modifiable risk factors include BMI, metabolic syndrome, immunosuppressive medications and induction therapy, hepatitis B and C viruses, and Cytomegalovirus.⁴ New-onset diabetes after trans-plant mostly develops during the first 6 months after transplant.

In this pilot study, we followed 58 patients who were within the inclusion and exclusion criteria for a mean of 18.9 months. Follow-up duration was quite adequate to detect new cases of NODAT, as most new events happen during the first year after transplant.⁵ For our patients, we applied the 2003 Consensus Guidelines of the American Diabetes Association and the World Health Organization in defining diabetes.1 The newer guidelines (2010) could not be applied as these guidelines include performing routine oGTT. Performing routine oGTT is not possible at our center due to the financial constraints. The prevalence of NODAT in our study group was 8.5%. This rate is lower than reported in the literature for the prevalence of NODAT, which has been shown to range from 9.1%8 to 20%.⁹ The reported incidence of NODAT in Northern Africa is 18.1%,¹⁰ which is still higher than our reported rate. Our reported rate is also lower than the reported prevalence of DM mellitus in Sudan, which is 19.1%.¹¹ It is also lower than the reported 18% to 75% prevalence of DM in Northern Africa.¹² The explanation for this finding is that most of the patients being operated on in our center and included in this study were younger (mean age of 34.6 y).

Studies have shown that the risk of developing NODAT increases with increasing age,^1,8 with patients above 45 years of age being at an even higher risk of developing NODAT. In this study, no association could be found between age and NODAT. The probable explanation for this finding is because most of the patients were in a younger age group, with few patients above the age of 45 years.

In our study, we could not find any association between NODAT and BMI, although a large BMI is known to increase the risk of developing NODAT. However, it must be noted that almost all of the patients in our study had a BMI of < 25 kg/m². This is almost a true reflection of patients with end-stage renal disease in Sudan. These patients are rarely overweight due to the fact that they are undertreated with dialysis (the standard is 2 dialysis sessions per week) and most have chronic anemia.

We showed a statistically significant association between family history of DM and NODAT. This is in line with the published literature.^1,5-7 It is not possible to speculate whether these patients who developed NODAT were bound to develop DM because of their family history or whether the kidney transplant and the associated immunosuppressive medications have predisposed them to NODAT.

To the best of our knowledge, this is the first study to report the prevalence of NODAT in Sudan. In addition, there are no similar reports from Sub-Saharan Africa. There are some limitations to this study. The main limitation is that the sample size was rather small; for this reason, other variables (including HLA type and cytomegalovirus status) could not be included as a multivariate analysis would not be feasible. However, this paper is the pilot study of an ongoing investigation. Other limitations are that the mean age of the study group was rather young (34.6 years) and the fact that most of the patients included in this study had a BMI < 25 kg/m². These limitations would not allow accurate examination of the true correlation between NODAT and age and BMI. However, the age and BMI data presented in this paper are true reflections of the patients who present for transplant in our center.

In conclusion, the incidence of NODAT observed in a Sudanese renal transplant population was smaller than that reported in the literature. The main risk factor identified for the development of NODAT was a positive family history of DM. Further studies in a larger group of patients are needed to find the exact incidence and risk factors for NODAT in our population.

Volume: 15 Issue: 6 December 2017

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