Clinical impact
PTDM is associated with various short-term and long-term complications. In our study, the development of PTDM had an adverse effect upon kidney function, graft survival and bacterial infection.
Death-censored graft failure
The literature is unclear about the effects of PTDM on graft failure. A large, retrospective study suggested that PTDM was associated with an increased risk for both overall allograft failure and death-censored allograft failure. However, this study did not control for acute rejection in the multivariate analysis[4]. An analysis of the data from OPTN/UNOS database 10 found that acute rejection was associated with death-censored graft failure, but PTDM was not associated with any of the outcomes investigated[5]. Whether PTDM affects allograft survival remains unknown. In our study, one-year allograft survival was 90 and 99.97 % in those with and without PTDM, respectively. Additionally, we performed multivariate analysis to suggest that PTDM was an independent risk factor for overall allograft failure. In addition, we excluded those who lost grafts or died during the perioperative period, which might have influenced our results.
Infections
PTDM has been associated with an increased risk for infection because hyperglycaemia may alter the immune response. Urinary tract infection, pneumonia, CMV and opportunistic infection have also been reported to occur at increased rates with diabetes [6]. The risk of infection in transplant recipients will be closely related to the extent of immunosuppression in a given individual, in addition to many other confounding variables, such as age, acute rejection and medications. Our research showed that PTDM was an independent risk factor for bacterial infection, with delayed graft function, acute rejection and obesity.
Prevalence
In this study, which included 310 non-diabetic patients who underwent renal transplantation, 16.4% of patients developed PTDM during 1 year of follow-up after transplantation. A meta-analysis, published in 2004, which included 35 publications, reported the prevalence rate of new-onset diabetes mellitus after kidney transplantation ranging from 6 to 47 percent[7]. The reported incidence of PTDM is variable and must be interpreted in the context of definition used, time from transplant, study population, and immunosuppressive agents used for individual studies. In particular, in this meta-analysis, PTDM was defined as insulin-dependent diabetes mellitus, which might underestimate the incidence of PTDM. In recent years, several studies have reported the incidence of PTDM, which was defined by the 2009 KDIGO criteria. In the USA[8], the incidence of PTDM was reported as 11%, and in Japan[9] and Korea[10], it was 11.3% and 20.4%, respectively. The prevalence rate in our study, including patients who all came from China, was similar to that in other countries, especially the east Asian countries. The results showed that 74% of patients developed PTDM within 3 months, so we recommended screening diabetes mellitus weekly within 3 months after transplantation instead of weekly within the first month and monthly between the second month and the third month, which was suggested by KDIGO guidelines.
Risk factors
Many prior studies have studied the risk factors of PTDM. These factors can be divided into transplant-related and non-transplant-related factors. The former includes increased age, obesity, African American race, Hispanic ethnicity and family history of diabetes. The latter includes medications, infection and posttransplant hyperglycaemia. According to our results, independent risk factors of PTDM included preoperative FPG greater than or equal to 5.6 mmol/L, age greater than or equal to 46 and tacrolimus use after transplantation. Polycystic kidney disease and post-transplant hyperlipidaemia might be independent risk factors for PTDM.
CNI
Both cyclosporine and tacrolimus increase the risk of PTDM. A meta-analysis published by Penninga et al. in the Cochran library in 2013 showed that tacrolimus was more likely to cause new diabetes after renal transplantation than cyclosporine[11] (RR = 4.24, 95% CI: 1.58–11.4). The conclusion of our study was that the use of tacrolimus as maintenance therapy with prednisone and MMF was an independent risk factor for PTDM, a conclusion similar to that of other investigators. Since CNI-like immunosuppressive agents can regulate the growth and function of islet B cells by activating the T cell nuclear factor pathway[12], the use of CNI inhibitors may lead to elevated blood glucose through this pathway, while tacrolimus The pathogenic effect is clearly stronger than cyclosporine.
Fasting plasma glucose levels before transplantation
Impaired glucose tolerance and impaired fasting glucose have been proven to be risk factors for PTDM[13]. By plotting the ROC curve, the point with the largest Youden index was set as the segmentation point. The obtained segmentation point is approximately 5.6 mmol/L. The results of this study suggest that we should also pay more attention to those whose fasting plasma glucose level is greater than or equal to 5.6 mmol/L because they are at high risk of PTDM.
Age
Older age increases the risk of developing diabetes mellitus. Many studies consider age over 50 years to be a risk factor [14,15], and some studies suggest that age over 45 years is a risk factor [16]. In our study, according to ROC curve and logistics regression, when the age is greater than or equal to 48 years old, patients are more likely to suffer PTDM. This result is similar to those of other research, and this slight difference may be due to sample size, region and race. The mechanism of new-onset kidney transplantation in elderly patients with renal transplantation may be related to the gradual decline of islet B cell function with age[17].
Polycystic kidney disease
A retrospective study of 429 people in 2007 has shown that patients with autosomal dominant polycystic kidney disease (ADPKD) have a 2.4-fold increased risk of developing new-onset diabetes after renal transplantation[18,19]. In 2016, Wisit et al. published a meta-analysis showing that the probability of new-onset diabetes after ADPKD is 1.92 times that of other kidney diseases[20]. However, the statistical method of this article has been questioned by Zhang C et al. [21]. In the two existing large sample studies, whether ADPKD is an independent risk factor is quite different. A 5000 study by Antoine et al. showed that ADPKD was a risk factor (RR = 1.33, CI: 1.01–1.75)[22]. However, a study of 2,000 people by Cecile et al. showed that ADPKD was not a risk factor (RR = 0.96, CI: 0.6–1.54)[23]. Therefore, according to current research, whether the ADPKD kidney is an independent risk factor for new-onset diabetes after renal transplantation remains to be discussed. In this study, a total of 14 patients developed polycystic kidney disease, 6 of whom developed PTDM, and according to binary logistic regression results, PKD is an independent risk factor for new-onset diabetes after renal transplantation. At present, the mechanism of polycystic kidney disease leading to PTDM is still unclear. Some scholars suggest that polycystic kidney disease may induce diabetes onset after renal transplantation, as insulin resistance genes combined with PKD1 gene transcription and PKD2 gene mutations may interfere with insulin secretion and liver gluconeogenesis.
Limitations
Our study had some limitations. This study was a single centre study, and the observation time was too short to observe further prognosis of transplantation. In addition, the sample size was not large enough, and 36 patients were lost to follow-up. Therefore, the reliability of some results still requires a large sample study to confirm that PTDM will increase the risk of death-censored graft loss in Chinese patients. We did not perform the OGTT and HbA1c, potentially leading to an underestimation of the incidence of PTDM and a misestimation of the onset timing. Additionally, those who were diagnosed with PKD did not accept gene sequencing, so we had no idea whether these individuals were ADPKD or not. Therefore, we cannot determine whether ADPKD is a risk factor for PTDM.