Our study is the first systematic review and meta-analysis assessing the impact of PTDM on patient outcomes. In a pooled analysis of 14 retrospective studies, we found that the development of PTDM significantly increases the risk of all-cause mortality and graft failure as compared to non-diabetic kidney transplant patients.
Over the last few decades, the role of kidney transplantation for managing ESRD has increased significantly and it can be attributed to the cost-effective nature of the treatment with lowered impact on patients’ quality of life as compared to dialysis [33]. While mortality rates of transplant patients are lower than those on maintenance dialysis, overall patient survival is still worse as compared to the general population [34]. In this context, efforts have been directed to improve patients’ survival as well as graft survival in kidney transplantation patients. An important factor impacting mortality and graft survival, which has been much discussed but never systematically reviewed, is PTDM. With conflicting results from several studies, the exact impact of PTDM on patient outcomes has never been quantified to date. In this context, the results of our meta-analysis assume clinical significance by providing true estimates of the effect of PTDM on patient outcomes. In our analysis, we noted a statistically significant 67% increased risk of all-cause mortality, ranging from 43 to 94%, in patients with PTDM as compared to non-diabetic controls. On close examination of the meta-analysis plot, it can be noted that seven of the 11 studies in the meta-analysis demonstrated a significant increase in mortality while no such difference was noted in four studies [27, 28, 31, 32]. The contrasting results of three [27, 28, 31]of these four studies may be partly explained by their small sample size. On the other hand, the lack of significant results in the study of Kuo et al. [32] may be somewhat explained by their non-standard criteria for diagnosing PTDM and shorter follow-up.
In 2003, the ADA and World Health Organization (WHO) published the first international consensus guidelines for PTDM which included the standard criteria for diagnosis of this disease. PTDM or NODAT, as per the then nomenclature, was defined as fasting glucose ≥ 126 mg/dL (7 mmol/L) on more than one occasion, random glucose ≥ 200 mg/dL (11.1 mmol/L) with symptoms, or a 2-h glucose level after a 75-g oral glucose tolerance test (OGTT) of ≥ 200 mg/dL (11.1 mmol/L) [35]. Later in the year 2014, these criteria were revised to include hemoglobin A1c as well [36]. It is quite pertinent to note that varying criteria for diagnosis can influence the outcome of PTDM. While most of the included studies used the ADA definition of PTDM some did not. However, on sub-group analysis, we still noted an increased risk of all-cause mortality with PTDM irrespective of the diagnostic criteria. Another important factor is the timing of diagnosis. Transient hyperglycemia is very common in the early period after transplantation and therefore it is recommended to delay diagnosis by at least 10 weeks [6]. While the impact of transient hyperglycemia on patient and graft survival is unclear, evidence suggests that it certainly increases the risk of PTDM in the future [37]. Few studies have reported that impaired fasting glucose without overt PTDM also increases the risk of all-cause mortality as compared to non-diabetic controls [15, 30]. This may be one of the reasons that we found a statistically significant increased risk of mortality even in studies not using the ADA definition of PTDM.
The increased risk of mortality in PTDM can be due to several reasons. Specific analysis on cause-related mortality could not be conducted in our review due to limited data. However, a few studies have analyzed cause-specific mortality in PTDM patients. Yeh et al. [17] in their study have noted a significantly increased risk of cardiovascular, infectious as well as cancer-related mortality in PTDM as compared to controls. On the other hand, Valderhaug et al. [30] have noted that PTDM increases the risk of only cardiovascular mortality but not of infection or cancer-related mortality. Because of the limited evidence, there is a need for more studies examining cause-specific mortality in PTDM patients.
Compared to all-cause mortality, the evidence on the impact of PTDM on graft failure is further unclear [9]. In our analysis, we noted that PTDM leads to a statistically significant 35% increased risk of graft failure as compared to non-diabetic controls. However, the results should be interpreted with caution as only seven studies reported data for this analysis which represent only half of the total studies in this review. On a positive note, this is the only pooled analysis of the multivariable-adjusted risk of graft failure after kidney transplantation conducted to date. On examination of the forest plot, almost all studies noted an increased risk or a tendency for increased risk of graft failure, except for Tsai et al [31]. This may be partly attributed to the small sample size of this study and more importantly to the difference in the confounding variables adjusted. It is well recognized that acute rejection and opportunistic infections especially in the first year after transplantation are important risk factors for graft failure [38]. In the study of Tsai et al [31] none of these factors were adjusted. Four of the studies in this meta-analysis included acute rejection as an adjusted factor [16, 17, 23, 29], while two studies excluded patients with acute rejection from their analysis [18, 32]. The importance of this factor is emphasized with the fact that management of acute rejection involves aggressive use of immunosuppressive drugs which in turn can lead to PTDM [16]. Cole et al. [18] in the study have separately analyzed the impact of acute rejection and PTDM on graft failure. The authors reported that while both acute rejection and PTDM reduce all-cause graft survival, the mechanisms are different, with acute rejection significantly associated with death-censored graft loss while PTDM leading to significantly increased risk of death with functioning graft and was not associated with death-censored graft loss. Similar results have been reported by other included studies in our review as well [16, 17, 24, 32]. Valderhaug et al. [29] in their study have reported no association between fasting plasma glucose or any level of hyperglycemia and graft failure. The results of these studies indicate that the negative association between PTDM and graft failure may be related to the increased mortality due to PTDM and the elevated glucose levels in PTDM may not result in irreversible kidney damage [29].
Our review has some limitations. Firstly, we understand that our analysis is not an exhaustive data analysis of available literature as a large number of studies not reporting adjusted outcomes were excluded. However, this was deemed important owing to the several confounding variables which can influence outcomes of PTDM. Secondly, an important limitation of our analysis is that the factors adjusted in included studies were not the same. The exclusion of known or unknown confounders may have influenced the study results. Thirdly, the sample size of many of the included studies was not high. The outcomes were not universally reported by all included studies and only seven studies were available for the analysis on graft failure. Fourthly, all included studies were retrospective in nature which have inherent selection bias. Studies from administrative databases or insurance records are prone to data entry errors which could skew the study outcomes. Fifthly, most of the studies were conducted on kidney transplantations done before 2010. The impact of recent immunosuppressive therapies and advances in the care and management of PTDM may have not been reflected in our results. The included studies also had variations in the definition of PTDM and the duration of follow-up. Furthermore, it is plausible to assume that the immunosuppressive protocol, the time of diagnosis, and management of PTDM would have been variable in the included studies and these factors could also have influenced outcomes. Lastly, majorities studies were from North America and this would limit the generalizability of our results.
Nevertheless, our study has some strengths. Data of 9872 patients with PTDM was analyzed in our review. The overall quality of studies on the NOS scale was high and the results were stable on sensitivity analysis which lends credibility to our results. By pooling only multivariable-adjusted data, we have hereby presented the best available evidence in the literature on the impact of PTDM on patient outcomes.
To conclude, our results indicate that kidney transplant patients developing PTDM have a 67% increased risk of mortality and a 35% increased risk of graft failure. Further studies are needed to determine the exact cause of increased mortality and the mechanism involved in graft failure.
