Impact of Type 2 Diabetes on the Outcomes of Solid Organ Transplantations in the U.S.: Data From a National Registry

Type 2 diabetes (T2D) is commonly observed in patients with advanced chronic diseases, including chronic liver disease, cardiovascular disease, chronic lung disease, and chronic renal disease. In this setting, the presence of T2D may further contribute to organ dysfunction, speed up the progression of the underlying disease, and eventually contribute to organ failure and death (1–7). Although transplantation can restore the function of underlying organs, T2D can still negatively affect outcomes by increasing the risk of infections, impairing wound healing, exacerbating the adverse effects of immunosuppressive therapy, and increasing the risk of cardiovascular events (1–3).

The association of T2D with posttransplantation outcomes has been studied previously. In heart transplant recipients, single-center reports were inconclusive (8,9) but a few recent larger studies found that patients with pretransplantation T2D did have more adverse post–heart transplantation outcomes, including increased all-cause mortality (9–12). Reports of a similarly negative association have been published for T2D in lung transplant recipients (12–14). The impact of T2D in liver transplantation outcomes has been better studied, and the association has been shown in both large-scale and single-center studies (15–17). Finally, kidney transplant recipients with T2D have been consistently shown to have increased risks of posttransplantation infections, cardiovascular events, and all-cause and cause-specific mortality (8,18–23).

Although expected and largely consistent, most of these studies addressed one particular type of organ transplantation. In this context, it may be useful to assess the impact of T2D on multiple solid organ transplantations and compare the outcomes of transplant recipients who are at the highest risk. This has become even more of an urgent issue, given the rapid rise in global prevalence of T2D leading to an increased number of transplant recipients with T2D (4–7).

In this study, we used recent the Scientific Registry of Transplant Recipients (SRTR) with long-term follow-up data to assess the potential association of pretransplantation T2D with posttransplantation outcomes, including all-cause and cause-specific mortality, in solid organ transplant recipients.

In this study, we used data from the SRTR. The SRTR data system includes data on all donors, wait-listed candidates, and transplant recipients in the U.S., submitted by the members of the Organ Procurement and Transplantation Network. The Health Resources and Services Administration, U.S. Department of Health and Human Services, provides oversight of the activities of the Organ Procurement and Transplantation Network and SRTR contractors.

For this study, we included all lung, heart, liver, and kidney single-organ transplant recipients of at least 18 years of age who underwent transplantation from 2006 through 2021. For lung, heart, or liver transplant recipients, history of pretransplantation T2D was collected from candidates’ medical history. In addition, for kidney transplant recipients, pretransplantation T2D was defined as a comorbid diagnosis recorded in the medical history similar to above or as a transplantation listing diagnosis. In all groups, patients without known T2D status were excluded from the study.

For all included transplant recipients, the studied outcomes were time to posttransplantation mortality (determined by matching with the Social Security Death Master File provided by SRTR) and graft loss (defined by either a documented retransplantation or a cause of death that indicated graft failure). Patients undergoing retransplantation were included in the mortality analysis only with their most recent transplantations. Patients with no documented date of death were presumed alive as of 2 March 2022.

All collected clinical and demographic parameters of included transplant recipients were summarized as mean ± SD or count with percentage and were compared between patients with and without T2D using the χ² or Mann-Whitney U test. The independent association of T2D with time to posttransplantation mortality was assessed by Cox proportional hazards models adjusted for confounders (age, sex, race, education, insurance, functional status score, BMI, history of cancer, prior transplantation, other elements of medical history relevant for each organ, being in intensive care unit (ICU) or on life support before transplantation, donor age and heart beating status, and type of transplantation procedure). The applicability of the proportional hazards assumption was assessed using Schoenfeld residuals. Given the large size of the study sample, two-sided P values of ≤0.01 were considered significant.

All analyses were run in SAS 9.4 (SAS Institute, Cary, NC). The study was granted nonhuman subject research status by the Inova Institutional Review Board.

In this study, we included 462,692 solid organ transplant recipients: 31,503 lung, 38,004 heart, 106,639 liver, and 286,506 kidney transplantations performed in the U.S. from 2006 to 2021.

There were 31,503 lung transplantations included. The prevalence of T2D was 14.7%, averaged across the study period, but that rate increased from 11.9% in 2006 to the highest rate, 16.7%, in 2012 and had been in the range of 14% to 16% since then (Table 1 and Supplementary Fig. 1). In comparison with those without T2D, lung transplant recipients with T2D were of similar age, more commonly Black or Hispanic, were significantly more commonly male, and had higher rates of overweight and obesity (P < 0.0001) (Table 1). Patients with T2D more commonly were undergoing retransplantation, were receiving chronic steroid regimens before transplantation, and had a lower functional status score (0–100); those patients also more commonly had cystic fibrosis or pulmonary fibrosis but less commonly chronic obstructive pulmonary disease or emphysema as a listing diagnosis and were more commonly on life support or in ICU before transplantation (P < 0.0001) (Table 1).

Posttransplantation survival was significantly lower in patients with T2D starting at 2 years after transplantation (P < 0.01) (Table 2 and Fig. 1A). There was no difference in cause of death, with the most common causes being pulmonary disease and graft failure (all P > 0.01) (Table 2). In multivariate analysis adjusted for confounders, the independent association of T2D with higher posttransplantation mortality in lung transplant recipients was significant (adjusted hazard ratio [aHR] 1.08 [95% CI 1.03–1.13]; P = 0.003) (Fig. 1A and Supplementary Table 1). Other predictors of higher mortality included earlier calendar year, older age, having publicly sponsored insurance and not having a college degree, being obese, having lower functional status and a history of cancer, undergoing retransplantation, being in ICU, and receiving a transplant from an older donor after a longer ischemic time (all aHR >1.0; P < 0.01) (Supplementary Table 1). Independent predictors of a higher risk of graft loss included earlier calendar year, younger age, being obese, lower functional status score, undergoing retransplantation, being in ICU before transplantation, and receiving a single lung transplant or a graft from an older donor (P < 0.01). In the multivariate model adjusted for confounders, having T2D was not associated with a risk of graft loss (P > 0.01) (Supplementary Table 2).

There were 38,044 heart transplantations included. The prevalence of T2D was 26.1%; over time, the rate increased from 22.2% in 2006 to 27.9% in 2021 (Table 3 and Supplementary Fig. 1). In comparison with those without T2D, heart transplant recipients with T2D more commonly were older, non-White, and male and had a higher prevalence of obesity (P < 0.0001) (Table 3). Patients with T2D were also less commonly undergoing retransplantation (P = 0.0001) but had similar pretransplantation functional status (P > 0.01) (Table 3). The patients with T2D also more commonly had ischemic cardiomyopathy or coronary artery disease but less commonly had other kinds of cardiomyopathy or congenital heart defects as a listing diagnosis and more commonly were on life support or had a left ventricular assist device before transplantation (P < 0.0001) (Table 3).

Posttransplantation survival was significantly lower in heart transplant recipients with T2D throughout the follow-up duration (all P < 0.01) (Table 2 and Fig. 1B). Death resulting from infections was more common in patients with T2D (Table 2). In multivariate analysis adjusted for confounders, the independent association of T2D with higher posttransplantation mortality in heart transplant recipients was significant (aHR 1.26 [95% CI1.20–1.32]; P < 0.0001) (Fig. 1B and Supplementary Table 1). Other predictors of higher mortality included earlier calendar year, older age, Black race, having publicly sponsored insurance and not having a college degree, being obese, having lower functional status and a history of cancer, undergoing retransplantation, having a left ventricular assist device, and receiving a transplant from an older donor after a longer ischemic time (all aHR >1.0; P < 0.01) (Supplementary Table 1). Independent predictors of a higher risk of graft loss included earlier calendar year, younger age, Black race, not having a college degree, being covered by public insurance, obesity, a lower functional status score, undergoing retransplantation, and receiving a graft from an older donor (P < 0.01). In the multivariate model adjusted for confounders, having T2D was not associated with a risk of heart graft loss (P > 0.01) (Supplementary Table 2).

There were 106,639 liver transplantations included. The crude prevalence of T2D was 25.2%, and over time, it increased from 19.7% in 2006 to the highest prevalence, 28.2%, in 2019 (Supplementary Table 3 and Supplementary Fig. 1). In comparison with those without T2D, liver transplant recipients with T2D were older, more commonly Hispanic, and more commonly male and had a significantly higher prevalence of obesity and any cancer (P < 0.0001) (Supplementary Table 3). Liver transplant recipients with T2D also more commonly had nonalcoholic steatohepatitis, cryptogenic cirrhosis, or hepatocellular carcinoma (with or without cirrhosis) but less commonly had hepatitis C, alcoholic liver disease, or autoimmune liver disease as a listing diagnosis, had lower Model for End-Stage Liver Disease scores, and were less commonly on life support or in ICU before transplantation (P < 0.0001) (Supplementary Table 3).

Posttransplantation survival was significantly lower in patients with T2D throughout the entire follow-up duration (all P < 0.01) (Table 2 and Fig. 1C). A higher proportion of deaths resulting from cardiovascular causes occurred in patients with T2D (P < 0.0001) (Table 2). In multivariate analysis adjusted for confounders, the independent association of T2D with higher posttransplantation mortality in liver transplant recipients was significant (aHR 1.26 [95% CI 1.22–1.30]; P < 0.0001) (Fig. 1C and Supplementary Table 1). Other predictors of higher mortality included an earlier calendar year, older age, male sex, Black race, having publicly sponsored insurance and not having a college degree, having lower functional status and a history of cancer, undergoing retransplantation, being on life support or in ICU before transplantation, and receiving a transplant from an older or non–heart beating donor (all aHR >1.0; P < 0.01) (Supplementary Table 1). However, unlike in other studied solid organs, there was no association of obesity with higher post–liver transplantation mortality (aHR 0.93 [95% CI 0.90–0.96]) (Supplementary Table 1). Independent predictors of a higher risk of graft loss included earlier calendar year, younger age, Black race, undergoing retransplantation, and receiving a graft from an older or non–heart beating donor (P < 0.01). In the multivariate model adjusted for confounders, having T2D was not associated with a risk of liver graft loss (P > 0.01) (Supplementary Table 2).

There were 286,506 kidney transplantations included. The prevalence of T2D was 30.2%, of which 75% of patients had T2D as an etiology of their end-stage kidney disease (Supplementary Table 4). Over time, the rate increased from 25.7% in 2006 to the highest rate, 33.9%, in 2020 (Supplementary Table 4 and Supplementary Fig. 1). In comparison with those without T2D, kidney transplant recipients with T2D were significantly older, more commonly non-White and male, and had higher rates of overweight and obesity (P < 0.0001) (Supplementary Table 4). Patients with T2D were substantially less commonly undergoing retransplantation but had lower pretransplantation functional status and significantly less commonly received a transplant from a living donor (P < 0.0001) (Supplementary Table 4).

Posttransplantation mortality was substantially higher in patients with T2D throughout the follow-up duration (all P < 0.01) (Table 2 and Fig. 1D). On the other hand, the rate of graft failure was lower in that group (P < 0.01) (Table 2). The primary causes of death were infections and cardiovascular events, both substantially more prevalent in those with T2D (P < 0.0001) (Table 2). In multivariate analysis adjusted for confounders, the independent association of T2D with higher posttransplantation mortality in kidney transplant recipients was highly significant (aHR 1.65 [95% CI 1.62–1.68]; P < 0.0001) (Fig. 1D and Supplementary Table 1). Other predictors of higher mortality included earlier calendar year, older age, male sex, White race, having publicly sponsored insurance and not having a college degree, having lower functional status and a history of cancer, undergoing retransplantation, and receiving a transplant from an older or deceased donor (all aHR >1.0; P < 0.01) (Supplementary Table 1). In a subgroup of kidney transplant patients with a listing diagnosis other than T2D, the association of comorbid T2D with increased mortality remained significant (aHR 1.45 [95% CI 1.41–1.49]; P < 0.0001). Independent predictors of a higher risk of graft loss included earlier calendar year, younger age, Black race, being covered by private insurance, being overweight or obese, and receiving a graft from an older or cadaver donor (P < 0.01). In the multivariate model adjusted for confounders, there was no association of having T2D with a higher risk of kidney graft loss (aHR 0.93 [95% CI 0.87–0.99]; P = 0.03) (Supplementary Table 2).

In this study, we used a recent national registry of solid organ transplant recipients to assess the association of having pretransplantation T2D with posttransplantation outcomes. This is an updated analysis of outcomes in multiple solid organ transplantations, which, in addition to quantifying clinical end points for each organ group, allows for a better understanding of the comparative burden of multiple end-stage diseases and, therefore, may be relevant to other stakeholders, including basic scientists, payers, policy makers, health economists, and health care managers. Our results demonstrated an independent association of T2D with higher posttransplantation mortality for all studied organ groups; the magnitude of that association, however, varied substantially. In this context, the associated excessive risk was highest in kidney transplant and lowest in lung transplant recipients.

In this study, the risk of posttransplantation mortality was least affected by the presence of T2D in lung transplant recipients. Indeed, after adjustment for confounders, the HR was estimated at 1.08, and the crude mortality rates in patients with versus without T2D differed by <10% throughout the follow-up duration. Although the exact reasons are unclear, this may partially reflect selection criteria for this organ transplantation, according to which suboptimal control of T2D may be a contraindication for the procedure (2,24). Indeed, the prevalence of pretransplantation T2D in lung transplant recipients was lowest among all studied organ groups. On the other hand, in comparison with other studied organs, the overall posttransplantation mortality was highest among lung transplant recipients, with 6-year survival of only ∼50% regardless of the presence of T2D. Given that, it is plausible that the contribution of T2D to patient prognosis was indeed relatively mild in comparison with the overall severity of post–lung transplantation status. As overall survival of lung transplant recipients improves over time while the prevalence of T2D in the general population continues to increase, its impact on the outcomes of this patient group may become more pronounced.

On the other end of spectrum was the association of T2D with increased posttransplantation mortality among kidney transplant recipients, with an aHR of 1.65 and at least a twofold difference in crude mortality rates throughout the follow-up duration. This is not unexpected, given that approximately three of four kidney transplant recipients had pretransplantation T2D as a cause of their end-stage renal disease. Exacerbated by posttransplantation immunosuppression, the condition may cause diabetic nephropathy in the graft while also contributing to the overall inflammatory milieu, increasing the risk of cardiovascular events and infections (25–27). Notably, the association of pretransplantation T2D with increased posttransplantation mortality remained strong, even in patients with non-T2D etiologies of chronic renal disease. This is consistent with prior reports from both small single-center and larger national studies in which T2D was linked to significantly higher risks of posttransplantation cardiovascular events (21,22), infection-related deaths (23), and overall mortality (18) in kidney transplant recipients. On the other hand, we did not find any association of pretransplantation T2D with an increased risk of graft failure; this is again consistent with prior observations that a majority of post–kidney transplantation deaths happen with a functioning graft, regardless of the presence of diabetes (8,28).

There was a significant association of T2D with higher posttransplantation mortality among both heart and liver transplant recipients, which was greater in magnitude than that seen in lung transplant recipients but weaker than that in kidney transplant recipients; the aHR was 1.26 (95% CI 1.20–1.32) and 1.25 (1.21–1.28) in the two organ groups, respectively, although with a differing impact on the primary cause of death. Specifically, the presence of T2D was associated with a greater share of infection-related deaths in heart transplant recipients, but this was not so in liver transplant recipients. In turn, the proportion of cardiovascular deaths was higher in liver transplant recipients with T2D but lower in heart transplant recipients with T2D in comparison with the respective patient groups without T2D. In this context, although not to the extent of kidney transplant recipients, T2D may play a role in causing chronic liver disease (nonalcoholic fatty liver disease) and cardiovascular disease (T2D-related cardiomyopathy and coronary artery disease). The association of pretransplantation T2D with adverse posttransplantation outcomes in those patient groups is consistent with prior reports (9,15). Notably, in all studied organs, diabetes was almost never a primary cause of death, regardless of pretransplantation history. Furthermore, there was no association of T2D with an increased risk of graft failure for any studied organ.

Although this study was primarily focused on T2D, other interesting observations were made. Specifically, we found that obesity was also associated with a higher risk of posttransplantation mortality in heart and lung transplant recipients, and the magnitude of this association was similar to or greater than that of T2D (aHR 1.13 [95% CI 1.08–1.19]) in lung and 1.20 [1.14–1.27] in heart). This association was also statistically significant in the kidney transplant group, but of a weak magnitude (aHR 1.04 [95% CI 1.02–1.06]), and nonexistent in liver transplant recipients (aHR 0.94 [95% CI 0.91–0.97]). Importantly, the association of obesity with posttransplantation mortality, where present, was independent of the impact of T2D; this indicates that even patients with obesity who do not have diabetes have an increased risk of posttransplantation adverse events. This is also supported by the observed association of obesity with a higher risk of graft loss in all organ groups that was independent of T2D. The observed inconsistency between the studied organ groups is likely due to the inaccuracy of BMI as a surrogate of body fat in patients with advanced liver (ascites) or kidney (fluid retention) disease.

The limitations of this study start with its retrospective observational design. The quality of SRTR data is not centrally controlled and may vary across centers and over time, resulting in some random or systemic error. In addition, while using SRTR, we had to rely on patients’ medical records to rule in and rule out the presence of T2D rather than use universal diagnostic criteria, which may have not been absolutely accurate because of variability in coding practices across transplantation centers. The outcomes were limited to mortality and graft loss only; however, other clinical outcomes, such as limited functioning and impaired quality of life after transplantation, postoperative complications, adverse events with immunosuppressive treatment, and de novo or exacerbated comorbidities, could also significantly affect patients’ well-being in the posttransplantation period. The study was limited to the variables available and consistently recorded in the SRTR database, so we could not control for potentially important confounding factors, such as duration of diabetes, history of other relevant comorbidities, socioeconomic factors that could have influenced posttransplantation survival, and relevant laboratory parameters like HbA_1c.

In conclusion, in this large study that used a national registry of solid organ transplant recipients, we found that pretransplantation T2D was independently associated with increased posttransplantation all-cause mortality in all studied organ groups. However, in lung transplant recipients, its contribution to posttransplantation mortality did not exceed a single-digit percentage because of high baseline levels. In contrast, the risk of post–kidney transplantation mortality increased by 65% in the presence of T2D and by 46% in patients with a non-T2D etiology of end-stage renal disease. Heart and liver transplant recipients with pretransplantation T2D also experienced higher posttransplantation all-cause mortality, although the impact of T2D on the primary cause of death varied by organ. Because the prevalence of T2D continues to increase in the general U.S. population and in most clinical populations, additional research is needed to identify interventions that could improve posttransplantation outcomes in patients with a history of T2D, including management of glycemia, effective immunosuppression, and prevention of infections and cardiovascular events as the primary causes of death.

Funding. The data reported here were supplied by the Hennepin Healthcare Research Institute as the contractor for the SRTR. The study was partially funded by the Global Nonalcoholic Steatohepatitis Council, the Beatty Liver and Obesity Research Fund, and the Center for Outcomes Research in Liver Disease.

The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy of or interpretation by the SRTR or the U.S. government.

Duality of Interest. Z.M.Y. consults for or has received research funds from Bristol-Myers Squibb, Gilead Sciences, Intercept Pharmaceuticals, Novo Nordisk, AstraZeneca, Boehringer Ingelheim, CymaBay Therapeutics, GlaxoSmithKline, Siemens, Madrigal Pharmaceuticals, and Merck. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. M.S. was involved in the conceptualization and design of the study, conducted the data analysis and data interpretation, and prepared the first draft of the manuscript. A.K., P.B., N.G., and K.C. provided critical review and editing of the manuscript. S.A.Q. conceptualized the study, interpreted the results, and assisted in manuscript writing and critical review and editing of the manuscript. Z.M.Y. conceptualized and designed the study, provided project management and oversight, and assisted in manuscript writing and critical review and editing of the manuscript. All authors approved the final version of the manuscript before submission. M.S. and Z.M.Y. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.