Cardiovascular Risk after Renal Transplantation

Renal transplantation provides superior survival rates and quality of life for patients with ESKD. However, its long-term success is often limited by patient death with a functioning graft, which remains a major cause of graft loss. Cardiovascular complications are among the leading causes of both mortality and morbidity in renal transplant recipients (RTRs), although their incidence has evolved over recent decades. Data from US registries consistently identify cardiovascular disease (CVD) as the leading cause of death among RTRs, both within the first year and up to 10 years post-transplantation.1 However, the incidence of CVD-related mortality has significantly declined since the late 20th century. Similar trends have been reported in other registries, such as the Australian and New Zealand registry, which has also observed a steady decrease in cardiovascular deaths alongside an increase in deaths due to infections and malignancies.2 Notably, these improvements have occurred despite a shift toward older transplant recipients with more pretransplant comorbidities. Importantly, although elderly RTRs may experience an increased risk of early post-transplant mortality compared with remaining on dialysis, they ultimately benefit from significantly improved long-term survival.3 In this evolving landscape, renal transplant physicians recognize that accurately estimating an individual's CVD risk is crucial for implementing clinical strategies that improve patient outcomes. For many years, efforts have been made to develop reliable methods for assessing CVD risk in RTRs. Although the Framingham Risk Score has proven useful in the general population, it has been shown to underestimate risk in RTRs—particularly among diabetic patients.4 More recent evidence suggests that although current risk scores offer only modest predictive power, they can still effectively identify patients at highest risk of cardiovascular events (CVEs).5 To address these limitations, various attempts have been made over the past decades to develop more accurate risk prediction models by incorporating donor and recipient baseline characteristics at the time of transplant, as well as post-transplant variables. One of the most robust studies in this field—the Patient Outcomes in Renal Transplantation (PORT) study—included over 23,000 patients from several Western countries to identify the best predictors of coronary heart disease both in the early and late post-transplant periods.6 The PORT study validated risk prediction models tailored to three clinically relevant time points: at the time of transplant, 7 days post-transplant, and at any visit during the first 1–5 years post-transplant. The discriminatory power of these models was assessed using a time-dependent C-statistic, with values ranging from 0.73 to 0.85, indicating good predictive performance. Key variables such as delayed graft function and renal function were included in the models. Similarly, data from the Assessment of Lescol in Renal Transplantation study were used to predict major adverse cardiac events using a seven-variable model. This model included age, prior coronary heart disease, diabetes, LDL levels, serum creatinine, number of transplants, and smoking status. The model demonstrated good discriminatory capacity, with an area under the receiver operating characteristic curve of approximately 0.74 in both the assessment and validation cohorts.7Table 1 summarizes key studies conducted in Western countries, showing that models predicting overall and cardiovascular mortality tend to have only moderate predictive performance, with C-statistics ranging from 0.70 to 0.80. In this issue, Amornkanjanawat et al. contribute new insights by analyzing a cohort of 553 Asian RTRs from Thailand receiving tacrolimus-based immunosuppression—reflective of current clinical practices. The authors emphasize the effect of rejection, including both T-cell–mediated rejection (TCMR) and antibody-mediated rejection (ABMR), on post-transplant CVD.8 This association has been noted previously. For instance, the PORT study identified prior acute rejection as a predictor of coronary heart disease within 3 years of a follow-up visit, occurring 1–5 years post-transplant.6 Rejection contributed significantly to the overall risk score both in the PORT and the Thailand study (see Table 1). In the Thailand study, consistent with previous findings, important risk factors for post-transplant CVD included recipient age, preexisting diabetes mellitus, new-onset post-transplant diabetes, and renal function (measured through 24-hour urinary creatinine clearance). The authors used a robust statistical approach—competing risk regression—to minimize overestimation of event probabilities and to provide accurate cumulative incidence estimates. From the multivariable model, a simplified risk score was derived. This model demonstrated excellent discrimination, with a C-statistic of 0.88 (95% confidence interval, 0.83 to 0.93), and calibration plots showed strong agreement between observed and expected risks. Importantly, the study identified kidney allograft rejection as an independent risk factor for CVEs, regardless of graft function. Despite the cohort's low immunologic risk profile (mean age 44 years, median panel reactive antibodies 0%, median HLA mismatch 2.8) and the low incidence rates for TCMR and ABMR (28.90 and 20.65 per 1000 patient-years, respectively), rejection episodes were associated with a more than three-fold increase in 10-year cumulative CVD incidence—slightly higher for ABMR than for TCMR. Although external validation is lacking, the findings suggest that in RTRs receiving standard tacrolimus-based immunosuppression, rejection independently contributes to cardiovascular risk. The underlying mechanisms were not explored in this study, but possible explanations include systemic inflammation triggered by the immune response, treatment with high-dose steroids, and intensified immunosuppression—all potentially accelerating diffuse vascular injury. It remains unproven whether rejection itself initiates systemic inflammation that propagates endothelial dysfunction in distant vascular beds. Importantly, in a large cohort of RTR (n=744) analyzed by a multidisciplinary-based approach, it has been shown that circulating HLA donor-specific antibodies (DSAs) are a strong determinant of major CVEs, independent of traditional cardiovascular risk factors.9 Data from this French study suggest that the severe arteriosclerosis observed in the allograft may be only a part of a more general vascular process operating in patients with circulating DSA. They hypothesized that circulating DSA may trigger allograft endothelial activation and injury, complement cascade activation, and the release of cytokines and inflammatory mediators that extend to a more general vascular injury process. This process can lead to plaque progression and destabilization. In the absence of direct access to patient arteries outside the allograft, their study cannot make conclusions, but it seems prudent to identify patients with circulating anti-HLA antibodies to screen them for CVDs and aggressively treat traditional risk factors. Unfortunately, in the Thailand study, monitoring of DSA during follow-up was not available. Table 1 - Scores to predict cardiovascular outcomes after renal transplantation Reference/Country/Transplant Era No. of Patients/Mean Follow Up/Validation Framingham Variables Pretransplant Variables Transplant-Related Variables Acute Rejection Outcome Performance (C-Statistic) Israni et al. 6 Am J Transplant 2009International (PORT study)1990–2004 N=19,578FU: 4.5 yrBootstrapping Age, sex, ethnicity, DM Malignancy, CVD comorbidity, dialysis vintage DGF, PRA, PTDM, PTLD, post-transplant CVD, renal function Yes (five points out of 64) Coronary heart disease beyond the first year 0.73–0.80 Soveri et al. 7 Transplantation 2012Europe and Canada (ALERT study)1996–1997 N=2012FU.: 6.7 yrModeling and testing (66%/33%) Age, smoking, diabetes, LDL-CL Coronary heart disease, re-transplantation Renal function No MACE 0.74 (0.70–0.77) Amornkanjanawat et al. 8 Kidney360 2025Thailand2010–2022 N=553FU.: 6.15 yrBootstrapping Age >40 yr, DM PTDM, 24-h creatinine clearance <60 ml/min; HbA1c >7%, serum calcium <8.5 mg/dl TCMR/ABMR (one/two points out of 11) CVE 0.88 (0.83–0.93) It is shown the type of variables included into each model: variables included into the Framingham score; baseline variables at the time of transplantation and variables associated with the transplant procedure. It is specifically shown whether acute rejection was included or not into the model as well as its contribution to the final score. The defined outcome is also shown as well as the performance of the model (C-statistic). ABMR, antibody-mediated rejection; ALERT, Assessment of Lescol in Renal Transplantation; CL, cholesterol; CVD, cardiovascular disease; CVE, cardiovascular events (myocardial infarction, heart failure, stroke, peripheral arterial disease, and cardiovascular death); DGF, delayed graft function; DM, diabetes mellitus; FU, follow up; HbA1c, hemoglobin A1c; MACE, major cardiac events (cardiac death, nonfatal myocardial infarction, or coronary revascularization); PORT, Patient Outcomes in Renal Transplantation; PRA, plasma renin activity; PTDM, post-transplant diabetes; PTLD, post-transplant lymphoproliferative disease; SBP, systolic BP; TCMR, T-cell–mediated rejection. Alternatively, the increased CVD risk may be driven by aggressive immunosuppressive therapy. However, steroid doses were not reported, preventing an assessment of their specific impact. Finally, calcineurin inhibitors, commonly used in these patients, are known to exacerbate hypertension, glucose dysregulation, and dyslipidemia. Interestingly, in the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial study, patients receiving belatacept had a higher incidence of rejection compared with those on cyclosporine, but they demonstrated better long-term renal function, lower de novo DSA formation, and a significantly reduced overall mortality at 7 years,10 suggesting that circulating DSA and renal function are strongly associated with cardiovascular risk. In summary, the study highlights the significant effect of allograft rejection on the progression of CVD in the current era of immunosuppression, even among recipients with low immunologic risk and relatively low rejection rates. Further research is needed to clarify the complex interactions between rejection, renal function, circulating DSA, and immunosuppressive therapy in shaping cardiovascular risk among RTRs.

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