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Subjects:
Cardiac & Cardiovascular Systems
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Transplantation
Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with chronic kidney disease (CKD), especially in end-stage renal disease (ESRD) patients and during the first year after transplantation. Besides the traditional cardiovascular risk factors (hypertension, hypercholesterolemia, diabetes, tobacco use, family history), in CKD patients non-traditional risk factors play an important role in CAD pathophysiology.
- kidney transplant
- coronary artery disease
- end-stage renal disease
1. Introduction
Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with chronic kidney disease (CKD), especially in end-stage renal disease (ESRD) [1]. Furthermore, the risk of cardiovascular adverse events continues to be relevant during the first year after the transplantation, necessitating a regular cardiological follow-up [2,3]. On the other hand, the prevalence of CKD in the general population is increasing [4], especially in some subgroups of patients like diabetics, in which kidney microvascular disease often leads to the need for dialysis or renal transplantation [5]. Moreover, the prevalence of type 2 diabetes mellitus (T2DM) has reached pandemic proportions, representing it as a relevant health problem [6].
For these reasons, and due to the shortage of organs available for transplant, it is of outmost importance to identify patients with a good life expectancy after transplant and minimize the transplant peri-operative risk. Severe pulmonary diseases, previous myocardial infarction, stroke/transient ischemic attack (TIA) within the last 6 months or severe aorto-iliac atherosclerosis are some of the conditions to rule out before listing a patient for kidney transplant [7].
Whether a systematic coronary artery disease (CAD) treatment before kidney transplant may improve short- and long-term cardiovascular outcomes is still under debate, not to mention that a nontailored screening could lead to unnecessary invasive procedures and delay or exclude some patients from transplantation unjustifiably [8].
2. CAD Presentation and Its Pathophysiology
ESRD patients have cardiovascular mortality twenty times higher than the general population [14]. At least 35% of these patients complain of effort angina or had a previous myocardial infarction (MI) at the time of first medical contact with the nephrologist. However, stable CAD seems to be more common than acute coronary syndromes (ACS) [15].Among ACS, non-ST-elevation MI is more frequent than ST-elevation MI [16]. Heart failure (HF), arrhythmias, and sudden cardiac death (SCD) are other possible clinical manifestations [17]. Sometimes these patients may complain of “atypical” symptoms or angina equivalents like dyspnea or fatigue [18].
Besides the classic cardiovascular risk factors (CVRF), like hypertension, hypercholesterolemia, diabetes, tobacco use, and family history, it is supposed that in patients with ESRD additional CKD-related factors might play a role in CAD pathophysiology. Furthermore, whilst the correction of CVRF in the general population results in a well-established cardiovascular event reduction [19], among patients with ESRD, this benefit is so far lower [20]. Nontraditional risk factors can be distinguished into CKD/ESRD-related and hemodialysis-related risk factors. They are summarized in Table 1.
Table 1. Traditional and nontraditional risk factors involved in CV risk of ESRD patients. ROS = reactive oxygen species. A-V = artero-venous.
| Traditional Risk Factors | CKD-Related Risk Factors | Haemodialysis-Related Risk Factors |
|---|---|---|
| Age | Inflammation and oxidative stress (ROS) | A-V fistula |
| Sex | Anemia | Biomaterials contact |
| Family history | Uremic toxins | Hemodynamic stress |
| Hypertension | Hypervolemia | Hemoglobin decompartmentalization |
| Diabetes mellitus | Secondary hyperparathyroidism | |
| Dyslipidemia | Prothrombotic state and platelet dysfunction | |
| Tobacco use | ||
| Physical inactivity |
2.1. Classic CV Risk Factors
Traditional CVRF are highly prevalent in CKD patients. They contribute not only to the progression of the atherosclerotic process but also to kidney damage, generating a vicious cycle known as cardiorenal syndrome type 4 [21].
Among all CVRF, hypertension (HTN) and diabetes mellitus (DM) play a pivotal role in CKD development and progression. The relationship between HTN and CKD is complex: HTN is, in fact, both the cause and effect of CKD. Moreover, the prevalence of HTN is roughly 84% among CKD patients, and it becomes more common if diabetic nephropathy coexists [22]. Finally, with the decline of eGFR, HTN incidence, prevalence, and severity significantly increase [23].
DM is the most common cause of CKD worldwide. Approximately 20% of all adults with DM have an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 [24]. DM is now globally the leading cause of ESRD, accounting for roughly 33% of all patients on renal replacement therapy (RRT) [25].
Both HTN and DM are responsible for macro and microvascular damage, such as, kidney artery stenosis, nephrosclerosis and glomerular dysfunction, and accelerated coronary and peripheral artery disease. In particular, the term “nephrosclerosis” refers to the process of interstitial inflammatory fibrosis that affects the glomerular capillaries and largely contributes to renal function decline [26,27].
Among traditional CVRF, tobacco use should be mentioned as well. A relationship between tobacco use and its adverse effects on kidney function has been highlighted in several observational studies [28,29,30]. A cross-sectional study by Hallan et al. showed an increased risk of CKD incidence and progression in smokers with a high cumulative lifetime cigarette exposure (RR 1.42 for 25–49 pack years, RR 2.05 for > 50 pack years). However, only a few studies were specifically focused on the CKD population [31]. Among these, a prospective study conducted by Wesson et al. deserves mention. The authors enrolled 216 CKD-stage 2 (eGFR 60–89 mL/min/1.73 m2 and spot urine albumin-to-creatinine ratio > 200 mg/g), hypertensive, nondiabetic patients to test if smoking cessation could increase the beneficial effects of ACE inhibition (in particular enalapril) and mitigate kidney damage progression [32]. At 5 years, the smokers had lower eGFR compared with quitters and nonsmokers. Moreover, smoking cessation attenuated eGFR decline compared with smokers (−1.7 ± 1.5 vs. −3.4 ± 1.8 mL/ min/1.73 m2/year), while eGFR did not significantly change in nonsmokers (–1.3 ± 1.5 mL/min/1.73 m2/year). Different pathogenic mechanisms have been supposed to explain the relationship between cigarette smoking and CKD. Endothelial damage and oxidative stress play a primary role. Furthermore, tobacco use can induce a hyperoxidative stress state in synergy with DM and HTN [33], increasing tissue angiotensin II (AII) level, which exacerbates kidney oxidative stress further [34].
For all these reasons, adequate blood pressure and glycemic control and smoking cessation are strictly recommended, both leading to a reduction in the combined outcome of major adverse cardiac and cerebrovascular events (MACCEs) [35,36].
2.2. Anemia
Anemia is a common complication of CKD. It is associated with a reduced quality of life, worse renal survival, and a higher rate of adverse cardiovascular events [37]. Its prevalence and severity are higher as the glomerular filtration declines (ranging between 8.4% at stage I and 53.4% at ESRD). In most cases, CKD-related anemia is due to several complex pathogenic mechanisms, like (1) erythropoietin (EPO) deficiency; (2) iron deficiency due to blood loss or increased hepcidin levels; (3) reduced red cell life span; (4) inflammation and comorbidities; (5) reduced marrow response to EPO; (6) B12 and/or folic acid deficiencies.
Among these factors, EPO deficiency is the most important. It is possible to find low EPO levels at the early stages of CKD, but the deficiency becomes clinically relevant when eGFR is <30 mL/min/1.73 m2. Chronic low oxygen arterial content due to anemia induces a cardiovascular compensatory response with increased cardiac output and consequent left ventricular hypertrophy (LVH) [38].
2.3. Volume Overload, Fluid Retention, and LVH
Sodium loading related to reduced glomerular filtration velocity causes significant fluid retention and consequent volume overload. The main effect of volume overload is the left ventricular mass increase [39].
LVH is present in about one-third of all patients with CKD, and it is an independent predictor of survival in patients with CKD [40]. Furthermore, LVH is one of the most important causes of myocardial ischemia due to the oxygen supply−demand mismatch [41]. LVH in CKD is caused by cardiac preload increase and cardiac afterload boost secondary to a systemic arterial resistance increase. This condition causes cardiac maladaptive changes and cardiomyocyte death, which in turn result in left ventricular concentric remodeling; over time, left ventricle dilatation and systolic dysfunction occur. Moreover, many nonhemodynamic factors also contribute to the development of LVH and cardiomyopathy in CKD patients. Among these, inappropriate activation of the renin–angiotensin system (RAAS), oxidative stress, inflammation, and stimulation of profibrogenic factors (cardiotrophin-1, galectin-3, transforming growth factor-b, fibroblast growth factor-23) deserve mention [42].
2.4. Secondary Hyperparathyroidism
CKD is associated with the development of secondary hyperparathyroidism. This condition compromises calcium, phosphate, and vitamin D homeostasis, finally leading to vascular and valvular calcifications. These findings are the result of vascular smooth muscle cell transformation into osteoblast-like cells by the uptake of phosphorus. Phosphate levels and vascular calcification have been associated with increased CAD and cardiovascular events [43].
2.5. Endothelial Dysfunction, Oxidative Stress, and Inflammation
CKD causes a chronic pro-inflammatory and pro-oxidative state with immune cell dysregulation, reactive oxygen species (ROS) production, and reduced nitric oxide (NO) availability that, in turn, lead to endothelial dysfunction, vascular remodeling, accelerated atherosclerosis, and myocardial damage [44,45,46].
Patients with CKD may have a dysfunction of different immune cells, which is responsible for negative effects on the kidney and cardiovascular system [47]. For example, it has been shown that monocytes have increased expression of macrophage scavenger receptors (CD36) and consequent enhanced vascular uptake of oxidized, low-density lipoproteins (LDL), contributing to the atherosclerotic process [48]. Moreover, monocyte cells showed an aberrant expression of integrin and toll-like receptors (TLRs) with high expressions of genes encoding pro-inflammatory cytokines (like IL-6, IL-1β and TNFα) [49,50]. Pro-inflammatory cytokines are responsible for dendritic cell activation, which in turn promotes T-cell proliferation. T-CD8+ cells can infiltrate the myocardium and produce potent cytokines, including IL-17, IFN-γ, and TNFα [51]. A variety of immune cells can also induce TGFβ production, which is responsible for fibroblast activation and consequent peri-arteriolar and myocardial fibrosis [52].
The endothelial dysfunction not only facilitates coronary atherosclerotic plaque formation, progression, and destabilization but also involves the coronary microcirculatory system [53]. Different studies have demonstrated the relationship between the degree of glomerular filtration impairment and the reduction of coronary flow reserve (CFR) [54]. High ROS levels are associated with both eGFR decline and CFR impairment. Among ROS, asymmetric dimethylarginine (ADMA) has been shown to compromise coronary endothelial function. In fact, ADMA is an endogenous competitive inhibitor of NO synthase (NOS). In turn, decreased endothelial NO production impairs microcirculation both in the kidneys and heart [55]. Moreover, high ADMA levels have also been associated with higher intima−media thickness and cardiovascular (CV) events in ESRD [56].
2.6. Platelet Abnormalities
Acquired platelet abnormalities, such as a reduced serotonin content and an altered thrombin-induced release of adenosine triphosphate (ATP), have been identified in CKD patients. These conditions may promote both a prothrombotic and hemorrhagic state [57].
2.7. Uremic Toxins
With the decline of renal function, a large group of uremic solutes, normally cleared by the kidneys, accumulate with a detrimental effect on the cardiovascular system [58]. Over 100 uremic toxins have been identified and classified by The European Uremic Toxin Work Group (EUTox). Among these, an important group is represented by the protein-bound uremic toxins, accounting for approximately 25% of all currently identified uremic toxins, like indoxyl sulfate, hippuric acid, and p-cresyl sulfate. Uremic toxins lead to endothelial dysfunction and ROS production, with negative effects on myocardial and endothelial cells [59,60]. Trimethylamine N-oxide (TMAO), a gut-derived, free water-soluble, low-molecular-weight uremic toxin, deserves mention. TMAO has been recently associated with the atherosclerotic process by NLRP3 inflammasome activation and inflammatory interleukins production, like IL-1β and IL-18. NLRP3 increases endothelial permeability, enhancing macrophage and monocyte infiltration into vascular atherosclerotic lesions [61]. Although hemodialysis prolongs the survival of ESRD patients, it does not completely relieve the uremic state, leaving patients with the so-called “residual syndrome” [62].
2.8. Hemodialysis-Related Factors
Although hemodialysis (HD) should improve cardiovascular function by fluid overload correction and uremic toxin removal, cardiovascular mortality in ESRD patients continues to be high [63]. Different HD-related risk factors must be mentioned. Artero-venous (A-V) fistula used for HD creates a reduced vascular resistance state leading to a compensatory hyperactivation of RAAS and the sympathetic system, finally resulting in cardiac output increase. Furthermore, HD itself determines hemodynamic stress: dialysis pulls fluid from the intravascular compartment, which in turn draws fluid from the interstitial. Any mismatch in plasma removal and refill rates can lead to rapid volume contraction and consequent hypotension, which is predictive of increased mortality [64]. Moreover, the interdialytic period is associated with fluid retention and overload increase that adds further stress on the cardiovascular system [65]. Despite the fact that HD removes different toxins that may impair platelet function and hemostasis, current hydrophobic dialyzer membranes promote protein deposition (IgG, C3, fibrinogen, etc.) and consequent abnormal activation of complement, coagulation, and inflammation [66]. Finally, HD contributes to endothelial dysfunction by a NO bioactivity reduction and ROS generation [67].
Despite the lack of clear evidence, a systematic pre-operative clinical evaluation of transplant candidates should identify and correct classical and nontraditional CV risk factors.
This entry is adapted from the peer-reviewed paper 10.3390/diagnostics13162709
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