The endothelium modulates vascular homeostasis owing to a variety of vasoconstrictors and vasodilators. Endothelial dysfunction (ED), characterized by impaired vasodilation, inflammation, and thrombosis, triggers future cardiovascular (CV) diseases. Chronic kidney disease, a state of chronic inflammation caused by oxidative stress, metabolic abnormalities, infection, and uremic toxins damages the endothelium. ED is also associated with a decline in estimated glomerular filtration rate. After kidney transplantation, endothelial functions undergo immediate but partial restoration, promising graft longevity and enhanced CV health. However, the anticipated CV outcomes do not happen due to various transplant-related and unrelated risk factors for ED, culminating in poor CV health and graft survival. ED in kidney transplant recipients is an under-recognized and poorly studied entity. CV diseases are the leading cause of death among kidney transplant candidates with functioning grafts. ED contributes to the pathogenesis of many of the CV diseases. Various biomarkers and vasoreactivity tests are available to study endothelial functions. With an increasing number of transplants happening every year, and improved graft rejection rates due to the availability of effective immunosuppressants, the focus has now shifted to endothelial protection for the prevention, early recognition, and treatment of CV diseases.

Calcineurin inhibitors have been the choice for maintenance immunosuppression (IS) in kidney transplant recipients (KTR), but they are associated with nephrotoxicity and metabolic side effects. We aim to compare the long-term outcomes of KTR on belatacept (bela) versus tacrolimus (tac) IS, in all KTRs and various subgroups. Using the UNOS-STAR files, we identified adult first-KTR from 2010 to 2022. Patients were categorized based on maintenance-IS at index transplant admission by creating a propensity score matched cohort at 1:5 rate using several clinical characteristics. Primary outcomes included patient death, graft failure (GF), and death-censored graft failure (DCGF). Secondary outcomes included delayed graft function (DGF), acute-rejections (AR) within a year, and serum creatinine (Cr) at 1-year. The propensity-matched cohort included KTRs on bela (N = 2612) and tac (N = 12760). There was no significant difference in the hazard ratio of death (1.03 [0.92, 1.14]), GF (1.07 [0.97, 1.17]), or DCGF (1.11 [0.98, 1.25]). A sensitivity analysis comparing a propensity-matched cohort of bela + tac (n = 2033) versus tac (n = 9004); demonstrated significantly reduced risks of death (0.87 [0.76-1.00], p = 0.043) and GF (0.73 [0.64-0.83] p < 0.001) compared to those on Tac alone. In conclusion, bela + tac seems to be a nephron-sparing and rejection-lowering IS regimen with overall improved graft and patient outcomes when compared to the current standard of tacrolimus. Larger Randomized Controlled studies are needed.

Calcineurin inhibitors (CNIs) have been a cornerstone in solid organ transplantation for many years; however, their prolonged use is linked to significant adverse effects, most notably nephrotoxicity. Belatacept, a modified version of cytotoxic T lymphocyte antigen-4 immunoglobulin with increased binding affinity for its ligand, has emerged as a viable alternative to traditional CNIs due to its lower toxicity profile. Despite these benefits, belatacept is associated with a higher rate of acute rejection, which presents a challenge for long-term graft survival. This review reevaluates the limitations of belatacept in achieving long-term acceptance of transplants and highlights the importance of regulatory T (Treg) cells in maintaining immune tolerance and preventing graft rejection. Additionally, it discusses the potential benefits of combining therapies that boost Treg cells with belatacept to increase the effectiveness of immunosuppression and improve graft outcomes.

Tacrolimus and mycophenolate are important immunosuppressive agents used to prevent organ rejection in post-transplant patients. While highly effective, their use is associated with significant toxicity, requiring careful management. Tacrolimus, a calcineurin inhibitor, is linked to nephrotoxicity, neurotoxicity, metabolic disturbances such as diabetes mellitus and dyslipidemia, and cardiovascular complications such as hypertension and arrhythmias. Mycophenolate, a reversible inhibitor of inosine monophosphate dehydrogenase, frequently causes gastrointestinal disturbances, including diarrhea and colitis, as well as hematologic side effects like anemia and leukopenia, which increase infection risk. Therapeutic drug monitoring (TDM) and pharmacogenomics have emerged as essential strategies for mitigating these toxicities. TDM ensures tacrolimus trough levels are maintained within a therapeutic range, minimizing the risks of nephrotoxicity and rejection. Pharmacogenomic insights, such as CYP3A5 polymorphisms, allow for personalized tacrolimus dosing based on individual metabolic profiles. For mycophenolate, monitoring inosine monophosphate dehydrogenase activity provides a pharmacodynamic approach to dose optimization, reducing gastrointestinal and hematologic toxicities. Emerging tools, including dried blood spot sampling and pharmacokinetic modeling, offer innovative methods to simplify monitoring and enhance precision in outpatient settings. Despite their utility, the toxicity profiles of these drugs, including those of early immunosuppressants such as cyclosporine and azathioprine, necessitate further consideration of alternative immunosuppressants like sirolimus, everolimus, and belatacept. Although promising, these newer agents require careful patient selection and further research. Future directions in immunosuppressive therapy include integrating individual pharmacogenetic data to refine dosing, minimize side effects, and improve long-term graft outcomes. This narrative review underscores the importance of personalized medicine and advanced monitoring in optimizing post-transplant care.

Effective post-transplant immunosuppression is essential to induce tolerance to allogeneic tissues and promote long-term graft survival. However, suppression of the immune system significantly increases the risk of opportunistic infections. In addition to the ongoing challenge of balancing graft survival and preventing infections, previous gold-standard calcineurin inhibitor-based immunosuppression also posed an increased risk of nephrotoxicity, cardiac disease, and diabetes. Belatacept is approved as an alternative to calcineurin inhibitor-based regimens. Although belatacept has improved cardiovascular and metabolic adverse events in renal transplant patients' but it carries a notably higher risk of long-term graft survival and renal toxicity, similar to calcineurin inhibitor-based regimens. However, there may be an increased risk of infections with its mechanism of action. We present a case of a 62-year-old female who developed disseminated histoplasmosis 18 months after being on belatacept-based immunosuppression after a deceased donor renal transplant for end-stage renal disease secondary to focal segmental glomerulosclerosis. Grocott Methenamine Stain (GMS) of peripheral blood smear showed intracellular yeast in neutrophils, consistent with histoplasmosis. Disseminated histoplasmosis was confirmed with positive bronchoalveolar lavage (BAL) and urine culture. The patient later developed hemophagocytic lymphohistiocytosis (HLH) secondary to immunosuppression and disseminated histoplasmosis. The patient succumbed to the disease despite maximal medical therapy. To our knowledge, there is one other published report of disseminated histoplasmosis in a patient with belatacept-based immunosuppression. The unique feature of this case is the development of HLH secondary to disseminated histoplasmosis while on belatacept. Further research is needed to evaluate the need for antifungal prophylaxis in patients on belatacept therapy.

Efficacy and safety of belatacept have not been specifically reported for kidney transplantations from donors after circulatory death.

In this retrospective multicenter paired kidney study, we compared the outcome of kidney transplantations with a belatacept-based to a calcineurin inhibitor (CNI)-based immunosuppression. We included all kidney transplant recipients from donors after uncontrolled or controlled circulatory death performed in our center between February 2015 and October 2020 and treated with belatacept (n = 31). The control group included the recipients of the contralateral kidney that were treated with CNI in 8 other centers (tacrolimus n = 29, cyclosporine n = 2).

There was no difference in the rate of delayed graft function. A higher incidence of biopsy-proven rejections was noted in the belatacept group (24 versus 6 episodes). Estimated glomerular filtration rate (eGFR) was significantly higher in the belatacept group at 3-, 12-, and 36-mo posttransplant, but the slope of eGFR was similar in the 2 groups. During a mean follow-up of 4.1 y, 12 patients discontinued belatacept and 2 patients were switched from CNI to belatacept. For patients who remained on belatacept, eGFR mean value and slope were significantly higher during the whole follow-up. At 5 y, eGFR was 80.7 ± 18.5 with belatacept versus 56.3 ± 22.0 mL/min/1.73 m2 with CNI (P = 0.003). No significant difference in graft and patient survival was observed.

The use of belatacept for kidney transplants from either uncontrolled or controlled donors after circulatory death resulted in a better medium-term renal function for patients remaining on belatacept despite similar rates of delayed graft function and higher rates of cellular rejection.

Memory T cells that are specific for alloantigen can arise from a variety of stimuli, ranging from direct allogeneic sensitization from prior transplantation, blood transfusion, or pregnancy to the elicitation of pathogen-specific T cells that are cross-reactive with alloantigen. Regardless of the mechanism by which they arise, alloreactive memory T cells possess key metabolic, phenotypic, and functional properties that render them distinct from naive T cells. These properties affect the immune response to transplantation in 2 important ways: first, they can alter the speed, location, and effector mechanisms with which alloreactive T cells mediate allograft rejection, and second, they can alter T-cell susceptibility to immunosuppression. In this review, we discuss recent developments in understanding these properties of memory T cells and their implications for transplantation.

Lipid disorder is a prevalent complication in kidney transplant recipients (KTRs) resulting in cardiovascular disease (CVD), which influences on patient outcomes. Immunosuppressive therapy demonstrated the major detrimental effects on metabolic disturbances. This review will focus on the effect of immunosuppressive drugs, lipid-lowering agents with current management, and future perspectives for lipid management in KTRs.

The main pathogenesis of hyperlipidemia indicates an increase in lipoprotein synthesis whilst the clearance of lipid pathways declines. Optimization of immunosuppression is a reasonable therapeutic strategy for lipid management regarding immunologic risk. Additionally, statin is the first-line lipid-lowering drug, followed by a combination with ezetimibe to achieve the low-density lipoprotein cholesterol (LDL-C) goal. However, drug interaction between statins and immunosuppressive medications should be considered because both are mainly metabolized through cytochrome P450 3A4. The prevalence of statin toxicity was significantly higher when concomitantly prescribed with cyclosporin, than with tacrolimus.

To improve cardiovascular outcomes, LDL-C should be controlled at the target level. Initiation statin at a low dose and meticulous titration is crucial in KTRs. Novel therapy with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which is highly effective in reducing LDL-C and cardiovascular complications, and might prove to be promising therapy for KTRs with statin resistance or intolerance.

Posttransplant diabetes (PTD) is a common medical complication after solid organ transplantation. Because of adverse outcomes associated with its development and detrimental impact on long-term survival, strategies to prevent or manage PTD are critically important but remain underresearched. Treatment hierarchies of antidiabetic therapies in the general population are currently being revolutionized based on cardiovascular outcome trials, providing evidence-based rationale for optimization of medical management. However, opportunities for improving medical management of PTD are challenged by 2 important considerations: (1) translating clinical evidence data from the general population to underresearched solid organ transplant cohorts and (2) targeting treatment based on primary underlying PTD pathophysiology. In this article, the aim is to provide an overview of PTD treatment options from a new angle. Rationalized by a consideration of underlying PTD pathophysiological defects, which are heterogeneous among diverse transplant patient cohorts, a critical appraisal of the published literature and summary of current research in progress will be reviewed. The aim is to update transplant professionals regarding medical management of PTD from a new perspective tailored therapeutic intervention based on individualized characteristics. As the gap in clinical evidence between management of PTD versus type 2 diabetes widens, it is imperative for the transplant community to bridge this gap with targeted clinical trials to ensure we optimize outcomes for solid organ transplant recipients who are at risk or develop PTD. This necessary clinical research should help efforts to improve long-term outcomes for solid transplant patients from both a patient and graft survival perspective.

Belatacept was developed to replace calcineurin inhibitors in kidney transplantation. Its use is associated with better kidney transplant function, a lower incidence of anti-donor antibodies and higher graft survival. However, it is also associated with a higher risk of cellular rejection. We studied the activation and proliferation mechanisms of belatacept-resistant T lymphocytes (TLs), to identify new pathways for control. We performed a transcriptomic analysis on CD4⁺ CD57⁺ PD1^- memory TLs, which are responsible for a higher incidence of graft rejection, after allogeneic stimulation with activated dendritic cells (aDCs) in the presence or absence of belatacept. After six hours of contact with aDCs, the (CD4⁺ CD57⁺ PD1^- ) (CD4⁺ CD57⁺ PD1⁺ ) and (CD4⁺ CD57^- ) lymphocytes had different transcriptional profiles with or without belatacept. In the CD4⁺ CD57⁺ PD1^- population, the IFNα-dependent activation pathway was positively overrepresented, and IRF7 transcript levels were high. IRF7 was associated with IFNα/β and IL-6 regulation. The inhibition of both these cytokines in a context of belatacept treatment inhibited the proliferation of CD4⁺ CD57⁺ PD1^- T cells. Our results show that IRF7 is rapidly upregulated in belatacept-resistant CD4⁺ CD57⁺ PD1^- TLs. The inhibition of type I IFN or IL-6 in association with belatacept treatment reduces the proliferation of belatacept-resistant TLs, paving the way for new treatments for use in organ transplantation.

To quantify the wider impacts of increased graft survival on the size of the kidney transplant waitlist and health and economic outcomes.

The analysis employed known steady-state solutions to a double-queueing system as well as simulations of this system. Baseline input parameters were sourced from the Organ Procurement and Transplant Network and the United States Renal Data System. Three increased graft survival scenarios were modeled: decreases in repeat transplant candidates joining the waitlist of 25%, 50%, and 100%.

Under the three scenarios, we estimated that the US waitlist size would decrease from 91,822 to 85,461 (6.9% decrease), 80,073 (12.8% decrease), and 69,340 (24.4% decrease), respectively. Patient outcomes improved, with lifetime quality-adjusted life years (QALYs) for a 1-year cohort of transplant recipients increasing by 10,010, 16,888, and 43,345 over the three scenarios. Discounted lifetime costs for the cohort in the new steady state were lower by $1.6 billion, $2.3 billion, and $9.0 billion for each scenario, respectively. Spillover impacts (i.e. benefits that accrued beyond the patients who directly experienced increased graft survival) accounted for 41-48% of the QALY gains and ranged from cost increases of 3.3% to decreases of 5.5%.

The model is a simplification of reality and does not account for the full degree of patient heterogeneity occurring in the real world. Health economic outcomes are extrapolated based on the assumption that the median patient is representative of the overall population.

Increasing graft survival reduces demand from repeat transplants candidates, allowing additional candidates to receive transplants. These spillover impacts decrease waitlist size and shorten wait times, leading to improvements in graft and patient survival as well as quality-of-life. Cost-effectiveness analyses of treatments that increase kidney graft survival should incorporate spillover benefits that accrue beyond the direct recipient of an intervention.