Non-traditional cardiovascular risk factors after kidney transplantation

Abstract

Kidney transplantation remains the best treatment option for patients with end-stage kidney disease, offering superior outcomes and improved quality of life. However, as in the general population, cardiovascular disease remains the leading cause of mortality among kidney transplant recipients. While traditional cardiovascular risk factors—such as hypertension, diabetes, dyslipidemia, and tobacco use—are prevalent in this population, they are often compounded by transplant-specific and non-traditional risk factors unique to the post-transplant setting. This review aims to explore these non-traditional and transplant-related cardiovascular risk factors, including allograft dysfunction and acute rejection episodes. Moreover, we will provide an overview of the cardiovascular implications of immunosuppressive therapy, including its association with opportunistic infections such as cytomegalovirus. Finally, we will touch upon considerations for special populations of kidney transplant recipients based on our current understanding of these non-traditional cardiovascular risks with the currently available data.

Key Words: Kidney transplantation; Non-traditional cardiovascular risk factors; Immunosuppression; Acute rejection; Cytomegalovirus

Core Tip: Kidney transplantation offers improved quality of life and survival advantages in addition to a reduced cardiovascular disease risk overall compared to remaining on long-term dialysis. However, kidney transplant recipients continue to experience a higher risk of adverse cardiovascular disease outcomes compared to the general population, with many of these risk factors worsened by and specific to their transplant.

INTRODUCTION

Despite advancements in kidney transplantation surgery and follow-up, cardiovascular death continues to be the most common cause of post-transplant mortality with a functioning graft among kidney transplant recipients (KTRs)[1]. A retrospective analysis of 210327 first-time KTRs between 1996 and 2014 found a mortality rate of 3.2% at 1-year post-transplant, with cardiovascular deaths being responsible for 24.7% of these deaths[2]. This is consistent with other patients with chronic kidney disease (CKD) being of an elevated risk for cardiovascular disease[3]. While there is a mortality benefit of kidney transplant over recipients remaining on dialysis, kidney transplant recipients continue to have increased overall mortality when compared to the general population[4]. KTRs continue to experience up to 10 times the rate of cardiac death and 50 times the rate of fatal or non-fatal cardiovascular events to that of the general population as these recipients’ renal function, on average, remains lower than that of the general population[5]. This is at least in part due to the challenges controlling traditional risk factors (e.g., hypertension, diabetes, dyslipidemias) in KTRs[6].

TRADITIONAL CARDIOVASCULAR RISK FACTORS

Established traditional cardiovascular risk factors are certainly present in the subset of the population with kidney transplants, with some risk factors being of high prevalence. For example, hypertension is present in up to 90% of KTRs based on a retrospective cohort study of 1666 patients followed for 5 years post-transplant with hypertension found to be closely associated with increased adjusted risk for graft failure and death[7]. The prevalence of dyslipidemias among KTRs is also high compared to the general population, particularly with elevated total cholesterol and low-density lipoprotein (LDL) levels, though triglycerides are also often times increased on fasting lipid panels[8]. Given that diabetes continues to be the leading cause of end-stage kidney disease, it too is highly prevalent in KTRs and is associated with an increased risk of cardiovascular events post-transplant, particularly when uncontrolled[4,9]. Transplant-specific risk factors that exacerbate traditional risk factors such as hypertension for KTRs include factors related to their immunosuppression, donor factors, and if they have experienced episodes of rejection (particularly vascular rejection episodes associated with angiotensinogen 1 receptor antibodies), and transplant renal artery stenosis[10]. These KTRs may also be at risk of poorly controlled hypertension in the perioperative period due to volume overload, particularly in the setting of slow or delayed graft function[9].

NON-TRADITIONAL CARDIOVASCULAR RISK FACTORS

Additional non-traditional cardiovascular risk factors in patients with CKD, such as kidney function impairment, CKD-mineral bone disease (CKD-MBD), proteinuria, and anemia are also represented in the KTR population[11]. In a retrospective post hoc analysis of a trial including 3676 renal transplant recipients, it was found that each 5 mL/minute/1.73 m² higher estimated glomerular filtration rate below a threshold of 45 mL/minute/1.73 m² was independently associated with a 15% lower risk of both cardiovascular disease and death[12]. With regards to CKD-MBD, hyperparathyroidism is often persistent post-transplant with associated poorer allograft and patient survival[13]. Anemia is observed in 20%-45% of KTRs and is often multifactorial from suboptimal allograft function to the utilization of immunosuppressants and prophylactic medications[14]. Finally, proteinuria is also noted in upwards of 20% of KTRs, and as in the general population, it is a potent independent risk factor for cardiovascular disease[15,16]. In a study of 532 KTRs, the development of proteinuria greater than 0.5 g/day was found to be associated with significantly lower five- and ten-year survival of 85% and 60% compared to 90% and 83% for patients without significant proteinuria with the presence of post-transplant cardiovascular disease and ischemic heart disease significantly higher in the proteinuria group as well (45.9% and 24% compared to 28% and 13%)[17].

IMMUNOSUPPRESSIVE THERAPY AND CARDIOVASCULAR RISK FACTORS

Regarding transplant-specific risk factors for cardiovascular disease in KTRs, we have touched on both induction and maintenance immunosuppression and their impact on patients’ cardiovascular risk but will expound upon it here as well as in Figure 1. Based on 2023 data, 93% of adult KTRs received induction immunosuppression, with 75% of these being given T-cell-depleting agents and maintenance immunosuppression being a triple therapy regimen of tacrolimus, mycophenolate, and steroids was the most common regimen for initial immunosuppression for 68% of recipients[18].

Figure 1 Non-traditional cardiovascular risk factors post kidney transplant. This figure depicts a schema for several non-traditional cardiovascular risk factors for kidney transplant recipients with particular emphasis on cardiovascular risks posed for commonly utilized maintenance immunosuppressant agents of the current era.

Calcineurin inhibitors (CNIs) such as tacrolimus and cyclosporine have nuanced mechanisms of action as it relates to their hypertensive properties, including activation of the renin-angiotensin system, increased activity of the thiazide-sensitive sodium chloride cotransporters as well as vasoconstrictive effects by way of increased endothelin production in larger preglomerular arteries[19]. There has also been found to be intragroup variability for CNIs in regards to the effect on systemic vascular resistance and sodium-dependent hypertension with clinically relevant outcomes of less hypertension for patients treated with tacrolimus when compared to cyclosporine[20,21]. CNI-associated dyslipidemias have also been observed due to the interference of LDL cholesterol binding to the LDL receptor, thus reducing its clearance[22]. These dyslipidemias too have intraclass variability between tacrolimus and cyclosporine, with tacrolimus-based regimens having less incidence of hyperlipidemias at 6 months post-transplant compared to cyclosporine-based regimens[23]. The use of CNIs also imposes impairment in insulin secretion with pancreatic islet-cell toxicity thus, CNIs are also associated with glucose intolerance and post-transplant diabetes mellitus (PTDM) again with intraclass variability in incidence, though tacrolimus-based regimens portend greater numerical incidence of PTDM compared to cyclosporine-based regimens[22,24]. Beyond these traditional metabolic cardiovascular risk factors exacerbated by the use of CNIs, the use of CNIs has been found to be associated with direct cardiovascular toxicity by such mechanisms and their deleterious effects on endothelial dysfunction and arterial stiffness[25]. Concerning post-transplant proteinuria, CNIs appear to have antiproteinuric effects by way of stabilization of the kidney filtration barrier and inhibition of intracellular signaling of nuclear factor activated T-cells that can result in podocyte damage and increased proteinuria[26,27].

The antimetabolite mycophenolate mofetil or its active metabolite mycophenolic acid has been well studied in its association with the development of dose-dependent anemia in KTRs by way of bone marrow aplasia as well as pure red cell aplasia likely due to their antiproliferative effects[28]. Anemia due to pure red cell aplasia in patients treated with tacrolimus and azathioprine have also rarely been observed[29,30]. Additional triggers for worsening anemia for KTRs include opportunistic viral infections [e.g. Parvovirus B19, Epstein-Barr virus, cytomegalovirus (CMV)], use of mammalian target of rapamycin (mTOR) inhibitors, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and prophylactic medications such as valganciclovir and trimethoprim- sulfamethoxazole[28,31]. Chronic anemia has been associated with the development of congestive heart failure in KTRs, as it may lead to maladaptive left ventricular hypertrophy (LVH) and cavitary enlargement[32]. This LVH is highly associated with increased cardiovascular morbidity and mortality[25].

Corticosteroids have also been strongly associated with metabolic derangements post-kidney transplant, particularly with resultant hyperglycemia and hyperlipidemia[33,34]. Corticosteroid utilization as part of the KTR immunosuppression regimen has also been associated with increased average blood pressure readings that are improved alongside their corresponding lipid profiles and incidence of PTDM with corticosteroid reduction[35].

Turning to the less often but still commonly utilized mTOR inhibitors, this class of immunosuppressants has been well known to have an association with worsening proteinuria, often times with nephrotic syndrome[36]. The hypothesis on the mechanism of worsening proteinuria with mTOR inhibitor initiation in KTR is that it may be due to induction of de novo focal segmental glomerulosclerosis by the mTOR inhibitor causing dose dependent changes on the podocyte cytoskeleton and slit diaphragm due to reduction in CD2 associated protein (CD2ap), nephrin, WT1 protein, and podocin protein expression[37]. The use of mTOR inhibitors has also been implicated in PTDM and dyslipidemia[38,39].

KIDNEY ALLOGRAFT REJECTION AND CARDIOVASCULAR RISK

Kidney allograft rejection is associated with inflammation, and an inflammatory state has been found in clinical studies to lead to atherosclerosis and arteriosclerosis[40,41]. The process of transplantation in itself an inflammatory process beginning with the initial ischemia-reperfusion injury with the initial surgical organ acquisition and allograft perfusion that promotes the release of damage-associated molecular patterns that activate the alloimmune recognition and sensitization processes by the host’s innate and adaptive immune system[42]. The circulation of so called de novo donor-specific antibodies that typify antibody-mediated rejection episodes in KTR has also been pointed to as immune-mediated cause of accelerated arteriosclerosis[43]. A recent retrospective cohort study of 553 KTRs conducted in Bangkok, Thailand, found that the risk of a post-transplant cardiovascular event was increased by a factor of 3 for a history of a T-cell mediated rejection and by a factor of 3.38 for a history of antibody mediated rejection[44]. The role on a non-HLA antibody in acute rejection and hypertension has also been previously elucidated. In a seminal study, Dragun et al[45] demonstrated that KTRs with vascular transplant rejection and accelerated hypertension without anti-HLA antibody had pathogenic antibodies against some angiotensin type 1 receptor epitopes.

CYTOMEGALOVIRUS INFECTION AND CARDIOVASCULAR RISK

CMV is a DNA virus from the Herpesviridae, with strong evidence available that it is a significant risk factor for cardiovascular disease[46]. This assertion is built on prior studies that atherosclerosis is the underlying disorder in multiple aspects of cardiovascular disease[47]. Previous infection with CMV has been associated with an increased risk of coronary thrombotic events after stent placement in immunocompetent individuals as well[48,49]. The use of mTOR inhibitors over other immunosuppressants has been associated with reduced rates of CMV infection following kidney transplantation, as mTOR inhibitors are thought to improve T-cell fitness[50].

CONCLUSION

As can be gleaned through the course of this overview, there are several transplant specific risk factors for cardiovascular disease in KTRs that can be attributed to the ongoing need for immunosuppression. Thus, we are in agreement with the assertion that as much as possible the regimen should be tailored to the specific clinical characteristics of the KTRs[51]. Patients of higher cardiovascular and lower immunological risk may be given consideration for a steroid-free regimen or early steroid discontinuation regimen for maintenance. Given the dangers detailed above of the aforementioned immunosuppressants (e.g., particularly of CNIs), treatment with novel immunosuppressant agent belatacept has been seen as a promising alternative to permit CNI avoidance while minimizing risk for allograft rejection in select patients of lower immunological risk for rejection[52]. Belatacept is a blocker of the second signal in the pathway for T-cell activation by binding to CD80/CD86 and improved graft outcomes with positive effects on the cardiovascular risk profile when compared to CNIs, albeit with increased incidence of early acute rejections[53,54]. On long-term analysis, the use of belatacept was associated with an increased incidence of proteinuria and increased CMV reactivation infections in KTRs when compared to CNI-based regimens[55,56]. In conclusion, further investigation on additional means to stratify cardiovascular risk in KTRs needs to occur to customize therapy plans and optimize the need for immunosuppressants while mitigating potential adverse events.