Discussion
In this study, we report contemporary national US estimates of survival in first-time single kidney transplant recipients by diabetes status, with several important findings. First, in crude models, we show that survival probabilities at 1, 5, 10 and 15 years post-transplant are consistently highest among people with no diabetes and lowest among people with T2D. Second, in fully adjusted models, we show that people with T1D and T2D have a 95% and 65% increased risk of mortality, respectively, as compared with those with no diabetes. This excess risk is not explained by differences in age, graft failure, comorbidities or donor characteristics. Third, we show that age-standardized mortality among transplant recipients has declined since 2000 but remains approximately twofold to sevenfold higher compared with the general population with highest rates among T1D.
Our results of T2D are consistent with other published data. In an Australian/New Zealand study between 1994 and 2012, transplant recipients with T2D had a twofold increased risk of 10-year mortality as compared with those without diabetes, and 5-year survival probabilities of 79% vs 92%, respectively.19 In a regional US study from the Mayo Clinic (Minnesota, 1998–2006), patients with diabetes (majority assumed to be T2D) had reduced survival compared with patients without diabetes (5 years, 70% vs 93%, p<0.0001).7 This was, in part, explained by the population with diabetes being older, heavier, and having a higher prevalence of pre-transplant cardiovascular disease (CVD) (48% vs 16%, p<0.0001) relative to the population without diabetes, consistent with findings in the current study as well as other studies comparing baseline characteristics of transplant recipients with and without diabetes.12 Reduced survival in patients with versus without diabetes in the Mayo Clinic study was shown to be largely driven by a higher risk of CVD and infection-related mortality.7 Other recent studies have similarly shown that infection-related mortality, even more so than CVD-related mortality, is driving the higher mortality rate in transplant patients with versus without diabetes and should be a focus of future outcome studies among transplant recipients with diabetes.10 11 In particular, examining infection-related mortality in transplant recipients with T1D versus T2D may help identify specific subgroups for _targeted interventions. Unfortunately, the current study was unable to examine cause-specific mortality due to a high proportion of missing cause of death data. However, in keeping with the growing evidence base, future studies that focus on types and dosage of lowering of immunosuppressive therapies may play a role in elucidating causes for excess mortality in transplant recipients with diabetes.10 11
Our results are consistent with several other studies insofar as we also demonstrate that male (vs female) sex, older (vs younger) age, non-Hispanic white (vs non-Hispanic black and Hispanic) race, longer (vs shorter) ESKD duration, Medicare/Medicaid (vs private) insurance, comorbidities (vs none), and high (vs low) DD risk are associated with increased risks of mortality in kidney transplant recipients.19–22 These risk factors are also associated with graft failure, excluding race, whereby non-Hispanic black people have a greater increased risk of graft failure, also consistent with other findings.23 These risk factors, while independently associated with mortality and graft failure, do not attenuate the association between diabetes status and mortality and graft failure risk in multivariate models. Nonetheless, it is perhaps surprising that non-Hispanic white people have a higher risk of mortality compared with other race and ethnic groups. However, this so-called survival paradox has been observed in several other studies24–26 with the most commonly cited reasons to explain this including: (1) a survival bias among black patients with ESKD who make it to renal replacement therapy; and (2) a lower transplant rate in black patients that artificially inflates the survival advantage as they are a highly select population.
Few studies have compared survival among the transplant population by diabetes status (both T1D and T2D). In Europe, data from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA), encompassing registry data from 10 European countries, showed that crude 1-year and 5-year patient survival after a first transplant was, respectively, 94% and 79% for T1D, 86% and 61% for patients with T2D, and 96% and 87% for patients without diabetes.20 The lower survival probabilities relative to the current study are likely explained by the differences in study period, 1991–2000 in ERA-EDTA vs 2000–2017 in the current study. ERA-EDTA also reported that mortality risk, adjusted for age, gender, donor type, and country, was higher in patients with T1D (HR: 2.21 (1.98 to 2.47)) and T2D (2.02 (1.68 to 2.43)), as compared with those with no diabetes.20 The higher HR estimates in ERA-EDTA relative to the current USRDS study are likely explained by the limited variables adjusted for in ERA-EDTA. In addition, in the current study we stratified by donor status (LD vs DD) and found that while patterns were similar insofar as T1D and T2D had higher risks of mortality and graft failure relative to non-diabetes, excess risk estimates were greater in LD versus DD groups. Reasons for this are speculative but may include a lower mortality risk overall in LD versus DD groups,27 owing in part to the younger patient population, such that the relative impact of diabetes is greater.
Only one other study that we are aware of has compared mortality rates over time in the transplant population with diabetes relative to the general population. Comparisons with the general population allow us to ascertain whether the improvement in survival seen in transplant patients is greater than or equal to the enhanced survival in the general population. In Finland, among 1100 kidney transplant recipients with T1D, SMRs declined 58% between 1964–1990 and 2006–2016 despite an apparent plateau in SMRs from 2000 onwards.28 In our study, SMRs in the population with T1D declined at a relatively consistent rate (APC: −2.2, p<0.05) between 2000 and 2017. For people without diabetes, we showed a significant decline in SMR between 2000 and 2008 (APC: −5.7, p<0.05), which continued between 2008 and 2017 but at a slower rate (APC: −1.8, p<0.05). For T2D, SMRs declined between 2000 and 2013 (APC: −3.4, p<0.05) but appeared to plateau thereafter (APC: −0.1, p>0.05) which warrants further investigation.
In this study, we are unable to definitively discern if increases in survival are due to improved treatment and management of transplant patients, or changes in the pool of transplant candidates. However, additional post-hoc analyses point to the former. For example, we show that the characteristics (at the time of transplant) among transplant patients between 2000–2005 vs 2010–2015 remain largely unchanged in recipients without diabetes, with T1D, and with T2D (online supplemental table 6). These findings are consistent with the characteristics of the broader US ESKD population reported in other studies.29 Therefore, we believe the overall increase in survival is more likely to be attributable to improvements in the treatment and management of transplant patients.30 31
Despite improved overall survival of the transplant population, disparities in mortality among patients without diabetes and those with T1D/T2D remained throughout the study period. Transplant recipients with T1D and T2D had a 95% and 65% increased risk of mortality, respectively, as compared with those with no diabetes. These disparities were not explained by differences in age, insurance status, recipient or donor characteristics, graft failure, or comorbidities. However, a greater excess risk among T1D versus T2D mirrors what we see in the general population with diabetes and may be explained, in part, by a greater diabetes duration in T1D versus T2D. Several studies have now been able to show that as diabetes duration increases, so too does the risk of several health outcomes including mortality.32–34 We were unable to explore the impact of diabetes duration in this study as data on diabetes diagnosis date are not available in USRDS. Future studies incorporating data on diabetes duration in transplant populations are needed to address this. It is also possible that differences in mortality between non-diabetes and T1D/T2D are due to shortcomings in the management of diabetes or hyperglycemia. Additional research is needed to identify effective interventions to further reduce mortality in those with diabetes who receive a kidney transplant, especially those with T1D where age-standardized mortality remains considerably higher than T2D and non-diabetes-related ESKD. In the interim, adequate management of glycemia35 36 in parallel with blood pressure control and anticipation of effects of immunosuppression31 37 as early as possible may be effective in reducing mortality in kidney transplant recipients with T1D and T2D.
There are important public health implications from this study to be considered. The prevalence of T2D remains high despite evidence that incidence may be declining.38 39 This is largely due to declining mortality in the population with diabetes, leading to increased life expectancy and cumulative exposure to the diabetic state.40 In addition, recent US data show that rates of ESKD among people with diabetes have not declined since 2009/2010, and have in fact increased in young adults.41 Taken together, it is likely that we will see a further rise in the incidence of diabetic ESKD with major impacts on public health. Namely, an increase in diabetic ESKD will increase demand for transplants which is already not matched by the availability of donor organs.1 Patients with diabetes who are typically older and have more comorbidities compared with patients without diabetes4 are already less likely to be considered for a transplant. An increase in diabetic ESKD is likely to exacerbate this existing disparity. As we and others6–8 show, diabetes type is an important modifier in the prognosis of transplant recipients. Therefore, routine reporting of diabetes-specific outcomes in annual reports, such as the USRDS annual data report,1 may assist in future healthcare planning and resource allocation.
Although we use a large, national database of individuals with ESKD linked to mortality, some limitations should be considered. First, we use clinician-assigned ‘primary cause’ of ESKD to assign diabetes status and so it is possible we have overestimated or underestimated the proportion of ESKD attributed to diabetes. The use of ICD codes to distinguish between T1D and T2D also lends itself to the possibility of misclassification. Second, we cannot exclude the possibility of misclassification in the USRDS database more generally. For example, we note that there are 820 (0.5%) dual pancreas and kidney transplant recipients without diabetes in this study which seems unlikely. Unfortunately, without additional information pertaining to other conditions (eg, exocrine insufficiency), we are unable to explore the possible reasons for this observation. Nonetheless, exclusion of dual pancreas/kidney transplant recipients (online supplemental table 4) did not materially change the results of the study. Third, there is the possibility for unmeasured confounding. While our analyses accounted for several possible confounders (eg, prior CVD, donor quality, insurance status), adjustment for these factors in multivariate models did not completely attenuate the association between T1D and T2D and mortality. This suggests there are other factors that may explain the excess mortality in T1D and T2D and elucidating the underlying causal mechanisms should be a focus of future research. For example, data on medications, diabetes duration, and lifestyle factors (eg, physical activity, diet) may provide additional insight into the excess mortality seen in T1D versus T2D. Fourth, more than 30% of cause of death data are missing in USRDS and thus we were unable to examine cause-specific mortality in this population. Ensuring complete cause of death data are captured in USRDS should be a high priority to enable future research in both the transplant population and broader population with ESKD. Last, estimating survival among transplant recipients is hampered by selection bias: younger patients with fewer comorbidities are more likely to be referred for a transplant as compared with the general population with ESKD, and we expect differences by diabetes status.4 For example, transplant candidates with T1D are younger and undergo screening for coronary artery disease, angioplasty or coronary bypass prior to transplant, while transplant candidates with T2D are older and more likely to have comorbid disease, and cohorts without diabetes are populated predominantly by hypertensive, genetic or immunologic glomerulopathy causes of ESKD. While we are able to adjust for several possible confounders such as age and comorbidities, we cannot rule out that these underlying pathologies drive both selection for a transplant and future risk of graft failure and mortality.