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The first world pandemic of obesity is driving secondary epidemics of type 2 diabetes, dysmetabolic syndrome, and hypertension. This results in increasing numbers of patients with renal disease and coronary atherosclerosis. Chronic kidney disease (CKD) accelerates the course of coronary artery disease, independent of conventional cardiac risk factors. In addition, CKD has been shown to confer inferior clinical outcomes following successful coronary revascularisation, which may be offset by arterial grafting. This article reviews the evidence for accelerated cardiovascular disease in the presence of renal disease with reference to new diagnostic and therapeutic targets.
Tens of millions of persons worldwide have combined cardiovascular disease (CVD) and CKD.1 In the USA alone, over 300 000 individuals are on renal replacement therapy (RRT),2 which confers a five- to 40-fold increased risk of fatal cardiovascular events.3 w1 w2 CKD is commonly defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, or the presence of a raised urinary albumin to creatinine ratio > 30 mg/g on a spot urine sample. Although conventional risk factors such as hypertension, diabetes mellitus, and dyslipidaemia are commonly associated with CKD and its attendant long term CVD morbidity, these risk factors alone do not fully explain the prevalence of CVD in this population.4 Figure 11 depicts the independent and dominant effect of renal disease on coronary heart disease death rates among diabetics. Novel risk factors such as homocysteinaemia (Hcy), raised lipoprotein Lp(a), oxidative stress, endothelial dysfunction, diminished transforming growth factor β1 (TGF-β1), chronic inflammation, and vascular calcification are increasingly linked to accelerated rates of atherogenesis in the setting of CKD. Furthermore, patients with CKD have inferior clinical outcomes following percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) independent of procedural success.
Few data are available regarding the independent contribution of diet and lifestyle factors on the acceleration of CVD in patients with CKD. However, given the clustering of risk factors associated with obesity and type 2 diabetes, one would expect that a sedentary lifestyle and/or poor dietary habits, including an excessive intake of sugars, simple carbohydrates, and saturated fats, would be common among patients with, at a minimum, early diabetic CKD. Weight reduction has been shown to notably improve blood glucose control and, in some cases, result in the apparent resolution of diabetes as it is currently defined. Moreover, exercise training programmes can improve the conventional cardiac risk profile of renal transplant recipients.w3–5 Although there have been no prospective, comparative studies of diet and lifestyle changes on CVD outcomes in patients with CKD, normalisation of body weight and fat stores, reduction in sodium intake, and regular aerobic exercise would be expected to have a salutary impact on this escalating patient population (table 11).). Given the expected higher rates of novel risk factors including endothelial dysfunction, oxidative stress, and inflammation, intensive lifestyle modification, including dietary changes and regular aerobic exercise, may reduce the incidence of CVD in this population.
The renin–angiotensin system (RAS) and sympathetic nervous system are aberrantly activated, resulting in increased afterload, left ventricular enlargement, greater myocardial oxygen consumption, and augmented sheer stress at the endothelial level in patients with CKD. Opportunities for modulation of the RAS within the vascular tree occur at several points (fig 22).). Additionally, many CKD patients with hypertension develop left ventricular hypertrophy, resulting in an increased myocardial mass to endothelial surface area, and an unfavourable myocardial oxygen supply and demand relation. Hyperactivation of the RAS leads to expression of oxidised low density lipoprotein receptors and acceleration of atherosclerosis (fig 33).). As eGFR declines, systemic blood pressure rises causing greater sheer stress, increased risk of plaque rupture, and episodic coronary occlusion. Consequently, blood pressure control to a target systolic blood pressure < 130 mm Hg (ideally < 120 mm Hg) is currently recommended (table 11).
Over 40% of end stage renal disease (ESRD) is secondary to diabetic nephrosclerosis,w6 and 48–57% of patients with diabetes mellitus (DM) have overt diabetic nephropathy.1 Patients with diabetes have significantly raised concentrations of serum insulin, a potent growth factor for atherosclerosis, in addition to a dyslipidaemic state. The epidemic of diabetes so measurably impacts CVD that the most recent National Cholesterol Education Program adult treatment panel guidelines listed DM as a CVD equivalent, and recommend treating afflicted patients accordingly.w7 In those with excess adiposity and type 2 diabetes, weight reduction is the intervention of choice to improve or resolve the diabetic condition. Optimal glycaemic control (glycohaemoglobin < 7%) has been shown to reduce microvascular events (retinopathy) and, along with blood pressure lowering, decrease the incidence of macrovascular events (myocardial infarction, stroke, and CVD death) in patients with type 1 or type 2 diabetes.
Dyslipidaemias occur in up to 67% of CKD patients.w8 This patient population often demonstrates diminished concentrations of cardioprotective high density lipoprotein cholesterol (HDL-C), and atherogenic increases in triglycerides and low density lipoprotein cholesterol (LDL-C). In particular, CKD patients have heightened concentrations of apolipoproteins AIV and B48. Furthermore, uraemic stress results in increased concentrations of oxidised LDL-C, a highly reactive and atherogenic species. Thus, it appears that hyperactivation of the RAS, raised insulin concentrations, and the dyslipidaemia of CKD work in concert to advance atherosclerosis at faster rates than in those with preserved renal function. Current guidelines support the lipid targets given in table 11.
ACE: angiotensin converting enzyme
CABG: coronary artery bypass grafting
CKD: chronic kidney disease
Cr: serum creatinine
CRP: C reactive protein
CVD: cardiovascular disease
DM: diabetes mellitus
eGFR: estimated glomerular filtration rate
ESRD: end stage renal disease
HDL-C: high density lipoprotein cholesterol
LDL-C: low density lipoprotein cholesterol
PCI: percutaneous coronary intervention
RAS: renin–angiotensin system
RRT: renal replacement therapy
TGF-β1: transforming growth factor beta 1
Homocysteine (Hcy), a product of methionine metabolism, is increased two- to fourfold in patients with CKD,w9 as renal tubular excretion normally accounts for 70% of Hcy clearance. When the eGFR drops below 60 ml/min/1.73 m2, Hcy is predictably raised. Furthermore, mean Hcy concentrations are increased 14–20% in ESRD patients with CVD compared to those without.5,6 Patients with raised Hcy concentrations have a three- to fourfold increased CVD event rate5 w10 and a 10.9-fold increased cerebrovascular event rate.w11 Hcy values inversely correlate with red blood cell folate concentrations. Accordingly, supratherapeutic doses of folic acid (5–20 mg daily) and vitamin B12, both components of Hcy metabolism, may decrease Hcy concentrations by 20–55% in ESRD patients.w12 w13 One trial showed that N-acetylcysteine, a potent antioxidant, may acutely lower plasma Hcy concentrations in this patient population.w14
Lipoprotein Lp(a) concentrations are increased 43% in patients on RRT as compared with the general population.7 In addition, CKD patients have higher concentrations of the low molecular weight isoforms, which have even more pronounced atherogenic characteristics.w15 Lp(a) is raised in 64% of RRT patients with CVD in contrast to 3.8% of those without.8 The putative atherogenic mechanism of Lp(a) includes macrophage foam cell production, inhibition of fibrinolysis, and adverse effects on endothelial dependent vascular reactivity.7 Preliminary studies demonstrate that Lp(a) concentrations may be reduced with niceritrol (a niacin prodrug), plasma apheresis, and renal transplantation.w16 w17
Patients with CKD and ESRD experience significant oxidative stress manifested by abundant glycosylation products and oxidised proteins such as LDL-C. Oxidative stress has profound atherogenic effects as reactive oxygen species combine with nitric oxide resulting in endothelial dysfunction. Preliminary studies in ESRD patients have demonstrated that N-acetylcysteine decreases the concentrations of oxidised LDL-C by 76%, and the composite end points of non-fatal myocardial infarction, cardiovascular death, revascularisation, and ischaemic stroke by 40%. While antioxidants have not reduced CVD events in the general population, two clinical trials of antioxidant use in ESRD patients reported reductions in morbidity and mortality.9,10 Additional clinical trials in this population are warranted.
Patients with CKD have increased concentrations of asymmetric dimethyl arginine, a nitric oxide synthase inhibitor, and correspondingly diminished concentrations of nitric oxide, a potent coronary vasodilator and an important local factor in endothelial function.w18 Other aberrancies of CKD include raised endothelin production and reduced thrombomodulin expression.w18 The end result is impairment of coronary flow reserve and the myocardial microcirculation. Hyperactivation of the RAS further negates the actions of nitric oxide, inhibiting endothelium dependent vasodilation, and hastening the inexorable progression of coronary disease (fig 44).
Transforming growth factor beta 1 (TGF-β1) is implicated in the pathogenesis of diabetic nephropathy. TGF-β1 is an anti-inflammatory cytokine that may show some repair or protective effects in atherosclerosis. In ESRD patients, serum concentrations of TGF-β1 are reduced as compared with the general population, and may result in accelerated atherosclerosis. TGF-β1 values are reduced in CKD patients with CVD or peripheral arterial disease. Furthermore, patients with triple vessel coronary artery disease have even greater reductions of serum TGF-β1. For every 1 ng/ml decrease in TGF-β1 there is a corresponding increase (~9%) in the CVD event rate.11
Trauma, infection, and inflammation may result in increased serum concentrations of positive acute phase reactants such as C reactive protein (CRP), fibrinogen, ferritin, interleukin-6 (IL-6) and Lp(a). In addition, there is a corresponding decrease in negative acute phase reactants such as albumin, prealbumin, cholesterol, and apolipoprotein A1 and B. IL-6 potently induces hepatic synthesis of CRP, which binds to the Fc-receptor of the immunoglobulin protein, and subsequently activates the complement cascade. Chronic inflammation commonly occurs in ESRD as a result of intercurrent illnesses such as glomerulonephritis and infection, as well as RRT specific factors, including exposure to water born endotoxins and bioincompatible dialysis membranes.w19 A raised serum CRP value is the most powerful predictor of mortality in patients on RRT and portends a 4.6-fold increased risk of CVD death.w20 In addition to abnormal CRP concentrations, ESRD patients are 16.6-fold more likely to have raised fibrinogen concentrations as part of the acute phase response,w20 which may result in increased plasma viscosity, endothelial injury, and thrombosis. Plasma apheresis has been shown to effectively reduce the acute phase reactant fibrinogen in ESRD patients. While inflammatory factors may be slightly raised in those with normal renal function, they are disproportionately high in CKD and should be treated with aspirin and statins.
Patients on RRT have coronary calcification scores far exceeding those of the general population, including those found in younger patients. Coronary calcification as measured by computed tomography is present in 88% of ESRD patients between the ages of 20–30 years in contrast to 5% of age matched controls.12 In addition, serum calcium and phosphate concentrations as well as the calcium–phosphate product significantly impact vascular calcification. ESRD patients on non-calcium based phosphate binders are less likely to have vascular calcification within the coronary arteries (0 v 37%, p = 0.03) and thoracic aorta (0 v 75%, p = 0.01) after a 52 week follow up period as compared with ESRD patients on calcium based phosphate binders.13 While vascular calcification cannot be reversed with current treatments, it appears that LDL-C reduction with sevelamer and statins attenuates progression in humans. Although a controversial topic, future randomised trials of phosphate lowering and lipid manipulation with measurement of vascular calcification are clearly needed.
In ESRD patients, exposure to heparin, bioincompatible dialysis membranes, and arteriovenous shunts may result in increased platelet aggregation.14 w21 Similar effects on platelet aggregation have been shown in chronic ambulatory peritoneal dialysis patients and CKD patients with hypertriglyceridaemia.w22 Nonetheless, many CKD patients at risk for CVD do not receive antiplatelet treatment because of concerns over platelet dysfunction and the potential for bleeding complications. The combination of excess thrombin generation and decreased platelet aggregability make the patient with CKD at risk, simultaneously, for thrombotic events and haemorrhage. In general, low dose daily aspirin is recommended for those with CKD, since it is considered a CVD risk equivalent state.
Studies have consistently shown that CKD patients presenting with acute myocardial infarction are less likely to receive standard treatments. For example, ESRD patients are less likely to receive cardioprotective medications such as aspirin, heparin, β blockers, and angiotensin converting enzyme (ACE) inhibitors, and are 51% less likely to receive reperfusion therapy for acute myocardial infarction as compared with patients with normal renal function.10,15–17 In general, patients with CKD have a greater relative risk reduction with aspirin, β blockers, ACE inhibitors, glycoprotein IIb/IIIa inhibitors, and lipid lowering treatment as compared with the general population after an acute coronary event. Efforts should be made to improve the quality of medical care to coronary patients with CKD, and future randomised trials of contemporary treatments should target this at-risk population.
CKD significantly impacts clinical outcomes following coronary revascularisation procedures. Even in patients with angiographically successful PCI, adverse clinical events have been shown to increase exponentially with graded declines in eGFR.18–20 w23 The Mayo Clinic reported the following one year mortality rates stratified according to renal function: 1.5% (eGFR 70 ml/min), 3.6% (eGFR 50–69 ml/min), 7.8% (eGFR 30–49 ml/min), and 18.3% (eGFR < 30 ml/min).18 With saphenous vein graft intervention, inferior clinical outcomes in CKD patients are reported, with one year mortality rates of 7.1% (eGFR 70 ml/min), 8.0% (eGRF 50–69 ml/min), 19.0% (eGFR 30–49 ml/min), and 36.7% (eGFR < 30 ml/min).19 Clinical outcomes in CKD patients following CABG are poorer as well with an in-hospital mortality of 1.6% (serum creatinine (Cr) < 88.4 mmol/l), 5.9% (Cr 132.6 mmol/l), and 11% (maintenance haemodialysis).w24 Actuarial 10 year survival remains dismal in CKD following surgical revascularisation with survival rates of 87% (Cr < 88.4 mmol/l), 32% (Cr 132.6 mmol/l), and 29% (maintenance haemodialysis).w24 However, bilateral internal thoracic artery grafting has been associated with notable improvement in survival for CKD patients (100%, n = 23).w24 Thus, CKD confers an exponential increase in major adverse cardiac events following PCI and CABG, which may be offset by arterial graft revascularisation.
Patients with renal disease have a high prevalence of CVD and its associated sequelae, which may be partially explained by conventional CVD risk factors such as hypertension, diabetes mellitus, and dyslipidaemia. Thus, aggressive treatment of these risk factors with diet, exercise, weight reduction, and drug treatment should reduce the CVD burden in CKD patients to some extent. Nevertheless, conventional risk factors per se cannot fully explain the prevalence of CVD in this patient population (fig 55).). Novel CVD risk factors such as homocysteinaemia, raised Lp(a), oxidative stress, endothelial dysfunction, decreased concentrations of TGF-β1, chronic inflammation, and vascular calcification appear to play an escalating role in the accelerated rates of atherogenesis in these patients. Understanding the mechanisms behind novel CVD risk factors and how to modify them favourably may allow us to attenuate the high incidence of non-fatal and fatal cardiovascular events in patients with CKD. In addition, CKD confers inferior clinical outcomes following successful PCI and CABG. Aggressive risk factor modification, preventive treatments, and arterial graft revascularisation may result in improved outcomes.