The incidence and risk factors of post-transplant diabetes mellitus in living donor kidney transplantation patients: a retrospective study

Abstract

Background

Post-transplant diabetes mellitus (PTDM) is a well-known complication of kidney transplantation that significantly impacts recipient morbidity and mortality. Over the recent years, the incidence of PTDM has increased considerably worldwide. Therefore, the primary purpose of this study was to evaluate the incidence and risk factors for PTDM in living donor kidney transplantation patients in Riyadh, Saudi Arabia.

Methods

A retrospective cohort study was conducted at a tertiary transplant center in Riyadh, Saudi Arabia, and data were extracted between February 2016 and March 2022. Patients aged ≥ 18 years who underwent renal transplant with at least one year of post-transplant follow-up were included in the analysis, and their medical records were comprehensively reviewed. Patients < 18 years of age, history of diabetes mellitus, other organ transplants, or those who underwent transplantation outside the Kingdom of Saudi Arabia were excluded from the study.

Results

The study included 247 living donor kidney transplant patients, with a mean age of 39.5 ± 14.6 years. 17.0% of the patients were diagnosed with PTDM. Patient age and fasting glucose levels at 6-months and 12-months after transplantation were found to be significant risk factors for the development of PTDM.

Conclusion

An increased occurrence of PTDM emphasizes the importance of identifying high-risk patients prior to transplantation and implementing early interventions to prevent potential complications that could affect graft and patient survival.

Introduction

The curative treatment for patients with end-stage kidney disease (ESKD) is kidney transplantation [1, 2]. One well-recognized complication of kidney transplantation is post-transplant diabetes mellitus (PTDM). PTDM can raise the possibility of serious complications, such as infections and cardiovascular diseases, further increasing morbidity and mortality [2].

After transplantation, blood glucose levels may rise due to factors such as stress, infections, or pain [3]. While these elevations can be temporary and may resolve on their own, persistent high blood glucose levels require confirmation of post-transplant diabetes mellitus (PTDM) [4]. The gold standard for diagnosing PTDM is an oral glucose tolerance test (OGTT) [4]. HbA1c is impacted by intraoperative and postoperative complications such as blood loss and iron deficiency; therefore, it should be waited for a minimum period of 3 months post-transplant to be used for diagnosing PTDM [3, 4].

The incidence of PTDM among individuals who have received a kidney transplant from either living or deceased donors ranges between 15 and 30%, making it a major concern that has gained global attention and been extensively studied in recent years [5]. Globally conducted studies showed that risk factors such as advanced age, high BMI, use of steroids, and the use of cetrain immunosuppressive medications have been associated with an increased likelihood of developing PTDM [6,7,8]. In Saudi Arabia, the incidence of PTDM is between 6.2% and 28.2% among kidney transplant recipients [9, 10]. Despite the benefits of immunosuppressive medications in improving both short-term and long-term outcomes, specifically graft survival, these medications might affect patient survival by increasing glucose levels in the blood [10, 11].

However, few local studies have investigated the incidence and risk factors for PTDM in living-donor kidney transplantation patients [9,10,11]. Therefore, community-based data might be useful to understand the incidence of this complication and its risk factors, which may help guide the design of standardized measures to identify patients at high risk of developing PTDM. Thus, the primary purpose of this study was to evaluate the incidence and risk factors for PTDM in living-donor kidney transplantation patients.

Materials and methods

Study design and patients

This was an observational retrospective cohort study conducted at a single tertiary transplant center to identify incidence of PTDM in living donor kidney transplants between February 2016 and March 2022 in Riyadh, Kingdom of Saudi Arabia. The study was ethically approved from King Abdullah International Medical Research Centre (IRB approval number: 0653/23).

A total of 247 living donor kidney transplantation patients were identified after a detailed review of our hospital’s electronic database (Best-Care system). Patients aged ≥ 18 years with a minimum duration of follow-up of one-year post-transplant were included. Patients aged < 18 years, with a history of diabetes mellitus, history of other organ transplantation were excluded due to the potential effect of immunosuppressive medications on glucose parameters. In addition, patients who had previous transplants outside the Kingdom of Saudi Arabia were excluded due to insufficient registered data in our electronic system.

Data collection

Patient demographic data such as age, sex, weight, and blood group were collected. Pre-transplant clinical data included height, weight, family history of diabetes mellitus, comorbidities, underlying cause of ESKD, and the modality and duration of renal replacement therapy. Post-transplant clinical data included height, weight, immunosuppressive regimen and duration, complications, episodes of graft rejection, pre- and post-transplantation laboratory test results including serum creatinine, fasting glucose, or random glucose levels (if fasting levels were unavailable).

Statistical analysis

Data processing and analysis were conducted using RStudio (R version 4.3.1). Descriptive statistics are presented for categorical variables (frequencies and percentages) and numerical variables (means ± standard deviations [SDs]). Inferential tests such as Fisher’s exact test (for categorical variables) or the Wilcoxon rank sum test (for numerical variables) were used to compare patients with and without PTDM.

The assessment of risk factors for PTDM was implemented using univariable logistic regression models, with the PTDM status as dependent variable and patients characteristics as independent variables. Variables that were found to be statistically significant in the univariable models were incorporated into multiple logistic regression models to identify the independent risk factors for PTDM. Results were expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs). Statistical significance was considered at p < 0.05.

Results

The study included 247 living donor kidney transplantation patients from Riyadh, with a median (IQR) age of 36.0 years (27.0–52.0 years). Majority of the reciepent patients were male (61.1%). Blood group O + was the most common among recipient patients (42.5%), followed by A+ (23.5%). Pre-transplantation BMI for majority of the patients (41%) was within 18.5–24.9 kg/m². About 87.4% of the patients had comorbidities, of which, hypertension (HTN) was the most prevalent (89.4%, Table 1).

Table 1 Demographic and clinical characteristics

Fewer than half of the patients had an unknown cause of ESKD at 48.4%, while 23.6% were diagnosed with glomerulonephritis. Among the various types of glomerulonephritis, IgA nephropathy was the most common subtype, accounting for 43.1%. Other causes of ESKD, which comprised 15.9%, included nephrocalcinosis, atrophied kidneys, SLE nephritis, Joubert syndrome, and C-ANCA vasculitis. Additionally, 76.1% of patients received hemodialysis, with a median (IQR) dialysis duration of 12.0 months (ranging from 7.0 to 36.0 months).

The admission/baseline serum creatinine level was 913.9 ± 312.1(µmol/L). Mean fasting glucose level was 5.4 ± 1.4 mmol/L and random glucose level was 5.3 ± 1.2 mmol/L (Table 2).

Table 2 Characteristics of end-stage kidney failure and laboratory findings before transplantation

Within 6–12 months post-transplantation stage, the majority of patients had a BMI range of 25–29.9 kg/m² (35.4%). In general, 50 patients (20.2%) had an increase in BMI from underweight or normal to overweight or obese categories. The immunosuppressive medications included Tacrolimus + Steroid (Prednisolone) + Mycophenolate mofetil (MMF) (90.3%). A significant proportion of patients experienced complications (64.4%, Table 3), with CMV infection (44.7%) and urinary tract infections (27.0%) being the most common. Acute rejection episodes occurred in 3.6% of patients. Notably, fasting glucose was 5.6 ± 1.4 mmol/L at 6 months and 5.7 ± 2.0 mmol/L at 12 months post-transplantation. Other laboratory values are presentedin Table 3.

Table 3 Post-transplantation characteristics

Incidence of post-transplant diabetes mellitus

Only 8.1% of patients in the study had a documented family history of diabetes mellitus (DM). Prevalence of diagnosed pre-diabetes mellitus (pre-DM) before transplantation was low (2.4%). After transplantation, the majority of patients remained without pre-DM (98.4%). Notably, 17.0% of patients were diagnosed with PTDM. The interval between transplantation and PTDM diagnosis varied, with the highest incidence being observed within 24–48 months (28.6%) and 12–24 months (26.2%), Table 4.

Table 4 Characteristics of diabetes mellitus

Risk factors for post-transplant diabetes mellitus

Statistical comparisons between patients with and without PTDM showed several significant associations (Table 5). Patients with PTDM were significantly older than those without PTDM, with a mean age of 46.7 ± 14.9 years compared to 38.1 ± 14.2 years (p < 0.001). Further, significant differences were observed in fasting glucose levels at 6 months (7.1 ± 2.5 mmol/L for PTDM vs. 5.3 ± 0.8 mmol/L for non-PTDM, p < 0.001) and at 12 months (7.8 ± 3.6 mmol/L for PTDM vs. 5.3 ± 0.8 mmol/L for non-PTDM, p < 0.001). No significant associations were found between PTDM and pre-transplantation BMI, random glucose levels, and serum creatinine at the time of discharge or 12 months post-transplantation.

Table 5 Statistical comparisons between patients with and without PTDM

Multiple regression analysis indicated that patient age was a significant risk factor for PTDM (OR = 1.04; 95% CI: 1.01 to 1.06; p = 0.002). Table 6 presents the results of the multivariable logistic regression analysis, comparing various etiologies of end-stage kidney disease (ESKD) to hypertension (HTN) as the reference point. It shows that causes other than hypertension, such as glomerulonephritis, graft failure, polycystic kidney disease, and unknown etiology, were associated with a lower likelihood of developing PTDM (OR = 0.19; 95% CI: 0.03 to 0.92; p = 0.045). The regression analysis did not identify any other significant risk factors.

Table 6 Risk factors for post-transplant diabetes mellitus

Discussion

PTDM can be associated with several factors such as age, family history, race, obesity, hepatitis C virus (HCV) infection, and genetic predisposition (factors commonly associated with type 2 DM). In addition, the use of immunosuppressants, cytomegalovirus (CMV) infection, and episodes of rejection have also been identified as risk factors for PTDM [3].

The observed incidence rate of PTDM in our study was 17%, falling within the global incidence of 15–30% [5] and consistent with with findings from previous studies conducted in Saudi Arabia [9, 10]. This alignment may indicate specific characteristics within our study population, as genetic factors [12]. In our analysis, the peak time to diagnosis was within 24–48 months, which is in contrast to previous studies in which most patients were diagnosed within 3–6 months after transplantation [13]. This finding is contrary to the expectation that the dosage of immunosuppressants decreases over time and influences the incidence of PTDM [7]. In our study, the mean duration of using immunosuppressants was 3.9+/- 1.8 years. Steroids were tapered off from 6th day as per the triple regimen: starting at 20 mg for 5 days, then 15 mg for 5 days, followed by 10 mg for 5 days, and finally 5 mg daily for 3 months, leaving patients on only MMF and tacrolimus for the remaining duration. This implies that immunosuppressive drug use alone may not be the only factor influencing PTDM in our study population.

Our study showed that patient age was a significant factor for PTDM, which is consistent with previous regional studies [10, 11]. Abdulrahman et al. [10] and Alshamsi et al. [11] reported a significant age difference between those with and without PTDM. PTDM risk is generally increased in older patients. For example, Cosio et al. [13] found that transplant recipients who were older than 45 years of age were 2.2 times more likely than their younger counterparts to acquire PTDM. Although other causes such as nephrocalcinosis, atrophied kidney, neurogenic bladder, SLE nephritis, Joubert syndrome, and C-ANCA vasculitis demonstrate a reduced likelihood of PTDM compared to hypertension, it is crucial to carefully interpret these results. Consideration of the underlying causes of graft failure and their influence on the heightened risk of PTDM is crucial. These factors can act as indirect contributors; for instance, the administration of aggressive immunosuppressive regimens in managing acute rejection may contribute to the pathogenesis of PTDM [14].

Our results did not show any significant correlations between pre- or post-transplant BMI and PTDM. Notably, the mean pre-transplant BMI for our patients was classified as overweight, and only 50 (20.2%) patients experienced an increase in post-transplant BMI. By contrast, a study from Spain showed no obvious association between BMI and the development of PTDM [15]. Another study from Saudi Arabia showed that BMI although higher in patients with PTDM the difference was not statistically significant [16]. On the other hand, a number of studies have reported a significant association between BMI and the development of PTDM [17,18,19], and BMI has been shown to be an independent risk factor for PTDM [18].

Limitations of the study are as follows. This was a single center study, and patients who underwent more than one organ transplantation were excluded from the study which prevented estimation of PTDM incidence in this patient group. Additionally, 99.6% of patients in our study received immunosuppressant within the first year after kidney transplantation. Therefore, the association between the use of tacrolimus and the development of PTDM could not be analyzed. In our study, although significant associations were observed between fasting blood glucose and the development of PTDM at 6 months and 12 months, it is important to acknowledge that 12.6% of patients had missing data, which could have introduced potential bias.

Conclusion

In conclusion, the incidence of PTDM underscores the importance of identifying high-risk patients before transplantation. Older individuals need early interventions, such as monitoring fasting glucose levels in routine follow-up labs as it is crucial for the early identification of PTDM, allowing for timely intervention and treatment to help prevent potential complications. Our study findings emphasize the need for prospective studies with long-term follow-ups to assess graft outcome in patients with PTDM.