Key Points
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The number of patients around the world with chronic kidney disease (CKD) has increased alarmingly.
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Even mild to moderate worsening of kidney function has become an independent risk factor for cardiovascular morbidity and mortality.
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In the future, novel risk markers—such as cystatin C, adiponectin, and possibly new inflammatory markers other than C-reactive protein (CRP) and microalbuminuria—may be used to assess risk for cardiovascular events.
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Management of patients with CKD is important for protection against both progression of kidney disease and progression of cardiovascular disease.
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Close monitoring and follow-up are key in the therapeutic management of patients with CKD.
Chronic kidney disease (CKD), defined as persistent kidney damage reflected by a glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m 2 for 3 months, is a major public health problem worldwide. More than 8 million people in the United States have stage 3 CKD, and the number is rising. This trend in CKD is reflected around the world, not just in the United States.
Patients with stage 3 or higher CKD have higher rates of cardiovascular morbidity, manifested by higher incidences of heart failure, arrhythmias, and myocardial infarctions. Progression of CKD in these patients to end-stage kidney disease—defined as a GFR of less than 10 mL/min/1.73 m 2 —further increases the risk for cardiovascular events; the annual mortality rate has improved since 2000 but remains approximately 19% per year. In earlier stage nephropathy (i.e., GFR >60 and <90 mL/min/1.73 m 2 ), less is known regarding cardiovascular risk. Investigators increasingly appreciate, however, the fact that risk markers such as microalbuminuria that are associated with vascular inflammation are indicative of higher cardiovascular risk ( Table 6-1 ).
| Risk Factors for Cardiovascular Disease | Novel Risk Markers for Cardiovascular Disease |
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Pathophysiology
Various abnormalities are commonly observed in patients with CKD that may enhance their risk for cardiovascular disease (CVD) events. Although the precise mechanism by which CKD increases CVD risk is not fully elucidated, most cases of CKD are clearly associated with increased oxidative stress and magnified inflammatory responses at the level of the vasculature. Endothelial dysfunction is an early event in people with CKD, and microalbuminuria is associated with the presence of endothelial dysfunction. In most patients with advanced CKD, atherosclerosis is accelerated and characterized by more advanced, heavily calcified plaques that extend to both the intima and medial layers of the coronary vessels. Increased expression of several cytokines, as well as of macrophages, plays a role in the evolution of the plaque development.
Several inflammatory markers have been implicated as potential triggers of atherosclerotic complications. High-sensitivity C-reactive protein (hs-CRP) is considered a biomarker of chronic systemic inflammation, as well as a mediator of atherosclerosis. Of patients with end-stage kidney disease, 20% to 50% have been shown to have elevated CRP levels. Hyperhomocysteinemia is also a predictor of future CVD events in patients with established coronary artery disease and in patients with type 2 diabetes, as well as those undergoing dialysis. Adiponectin level also plays an important role in modulating atherosclerosis and is decreased in people with impaired glucose homeostasis or diabetes. In the Mild and Moderate Kidney Disease (MMKD) study group, patients with low adiponectin levels experienced significant cardiovascular events.
The amount of nitric oxide present is reflective of how well the endothelium is functioning. It has a protective role in that it inhibits vascular muscle cell proliferation, platelet aggregability, and the adhesion of monocytes to the endothelium. The enzyme responsible for the genesis of nitric oxide can be inhibited by endogenous methyl arginine production such as asymmetric dimethylarginine (ADMA). Levels of ADMA are postulated to be increased in patients with advanced nephropathy, and such elevation is recognized as a putative biomarker in cardiovascular and kidney disease. Two large clinical trials, the Coronary Artery Risk Determination investigating the Influence of ADMA Concentration (CARDIAC) and the AtheroGene Study, demonstrated that ADMA is an independent risk factor for cardiovascular disease. In these studies, baseline ADMA levels were independently predictive of cardiovascular events.
Hypertension is a complex phenotype because neurohumoral factors such as angiotensin II, norepinephrine, and other cytokines, as well as chronic volume overload, exert inflammatory and growth-promoting effects in the cardiovascular system. Angiotensin II is a proinflammatory substance and a recognized growth promoter. The sympathetic system not only is a major regulator of cardiovascular function but also affects immune response, as does angiotensin II. It is interesting to note that in patients with CKD, circulating levels of norepinephrine are directly related to the muscular component of the left ventricle. Norepinephrine levels are also a strong and independent predictor of death from cardiovascular causes. Chronic volume overload is a major stressor, and in the long run, the deleterious effects of volume overload depend on the fact that hemodynamic burden activates a series of adaptive processes that modify the very structure of the myocardium.
The aforementioned factors—together with retention of toxins, increased calcium intake, and decreased phosphate excretion; abnormalities in bone mineral metabolism; and poor nutrition state—all increase inflammatory markers and potentiate vascular disease.
Risk in Community-Based Populations
CKD itself is a major risk factor for cardiovascular events. In many cohort studies, risk for coronary heart disease (CHD) has been assessed in relation to changes in CKD stage. The findings of these studies have led to the formation of recommendations from both The National Kidney Foundation and the American College of Cardiology/American Heart Association that CKD be considered as a CHD risk equivalent. Many physicians may not be aware that increases in risk for CHD parallel reductions in GFR, highest risk being at GFR values lower than 45 mL/min.
The Framingham Heart Study is one prospective, community-based study of the burden of CVD in patients with kidney disease. The study has revealed that the majority of patients with mild to moderate CKD are older, are more likely to be obese, have lower levels of high-density lipoprotein (HDL), and higher triglyceride levels. They also have a high prevalence of hypertension, diabetes, and elevated levels of low-density lipoprotein (LDL). The CKD population is less likely to achieve optimal control of blood pressure and controlled hemoglobin A1c concentrations of less than 7%.
Another large cohort study involved the Kaiser Permanente Renal Registry. Among 1,120,295 adults within a large, integrated system of health care delivery, the GFR was estimated. After adjustment, the risk of death increased as the estimated GFR decreased below 60 mL/min/1.73 m 2 . The adjusted hazard ratio for cardiovascular events also increased inversely with the estimated GFR. The adjusted risk of hospitalization with a reduced estimated GFR followed a similar pattern. The findings highlighted the clinical and public health importance of CKD. In the Atherosclerosis Risk in Communities (ARIC) study, participants with a GFR of 15 to 59 mL/min/1.73 m 2 (hazard ratio, 1.38; 95% confidence interval, 1.02 to 1.87) and 60 to 89 mL/min/1.73 m 2 (hazard ratio, 1.16; 95% confidence interval, 1.00 to 1.34) had an increased adjusted risk for atherosclerotic CVD events, in comparison with subjects with normal GFR levels, after a mean follow-up of 6.2 years.
In the National Health and Nutrition Examination Survey (NHANES), rates of CVD-related mortality were 4.1, 8.6, and 20.5 deaths per 1000 person-years among participants with estimated GFRs of higher than 90, 70 to 89, and lower than 70 mL/min/1.73 m 2 , respectively. Those with an estimated GFR lower than 70 mL/min/1.73 m 2 had significantly higher relatively risks of death from cardiovascular disease (1.7; 95% confidence interval, 1.3 to 2.1) and from all causes.
Cardiovascular Risk Factors in Patients with Chronic Kidney Disease
CVD is the major cause of morbidity and mortality among patients with CKD. Most patients share risk factors, including diabetes, hypertension, obesity, lipid abnormalities, and smoking (see Table 6-1 ). Even people with early stage 3 nephropathy (i.e., estimated GFR < 60 mL/min/1.73 m 2 ) have a higher risk of mortality than those with a GFR above 60 mL/min/1.73 m 2 .
Diabetes is the most common cause of CKD, accounting for nearly 50% of all new cases of renal replacement therapy. In a cohort of Chinese patients with type 2 diabetes who did not have macrovascular disease or end-stage renal disease, all-cause mortality increased from 1.2% to 18.3% as kidney function deteriorated from stage 1 to stage 4. Hypertension is another modifiable risk for CVD. The degree and duration of hypertension strongly influence outcomes and also accelerate CKD progression. Most patients with CKD have both hypertension and diabetes as comorbid conditions, and the effect on CVD risk is more than additive.
Obesity is a major global health concern and may precede the development of many CVD risk factors, including diabetes, hypertension, and dyslipidemia. In the Framingham Heart Study, obesity was noted to be associated with increased risk of developing stage 3 CKD during nearly 20 years of follow-up. This finding suggests that the association of obesity with stage 3 CKD may be mediated by vascular disease risk factors.
Patients with CKD are at high risk for insulin resistance and other features of the classical metabolic syndrome. The association of higher body mass index (BMI), insulin resistance, hyperglycemia, and hypertriglyceridemia supports the notion that early in the disease state, other well-known CVD risk factors are present and may be magnified by the presence of advanced CKD.
Overweight and obesity are also associated with increased risk of proteinuria and risk of worsening kidney function, inasmuch as increased levels of proteinuria are associated with faster CKD progression. Conversely, in patients undergoing dialysis, the relationship is different: The greater the BMI with better nutrition, the lower the incidence of CVD events. In short, survival is higher in patients with end-stage kidney disease who have higher BMIs.
The sequelae of CKD, such as anemia and low active vitamin D levels, may also contribute to the increased risk for CVD. In a registry cohort study of 5549 adults hospitalized with acute myocardial infarction or unstable angina, profound anemia was independently associated with increased mortality rate (hazard ratio, 1.8 for hemoglobin levels of <9 vs. >12 g/dL) among patients with an estimated GFR of 30 to 59.
Elevated cholesterol levels are very prevalent among people with estimated GFR values lower than 60 mL/min/1.73 m 2 . Lowering cholesterol levels in people who have diabetes and an estimated GFR higher than 60 mL/min/1.73 m 2 is beneficial, as observed in the Scandinavian Simvastatin Survival Study (4S), in which patients with type 2 diabetes had a 2.5-fold greater risk for coronary artery disease than did nondiabetic patients. Ongoing trials are currently being conducted to examine the benefit of lowering cholesterol levels in early- to moderate-stage CKD ; however, it is clear that lowering cholesterol levels in patients with advanced-stage CKD who are undergoing dialysis does not alter CVD outcomes. Thus, early use of statins slows nephropathy progression and reduces CVD risk, whereas late use once dialysis has been instituted fails to alter CVD risk ( Table 6-2 ).
| Trial | Design | Population | Sample Size | Intervention | Duration | Outcome |
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| Pravastatin Pooling Project (PPP) | Post hoc subanalysis of West of Scotland Coronary Prevention Study (WOSCOPS), Cholesterol and Recurrent Events (CARE), and Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) | Moderate CKD (CG-GFR, 30-59 mL/min/1.73 min 2 | 4491 | Pravastatin, 40 mg/day | ≈5 years | Decile risk (HR, 0.77) of adjusted incidence of primary outcome |
| Heart Protection Study (HPS) | Post hoc subanalysis | CKD (serum creatinine clearance >110 µmol/L for women and >130 µmol/L for men but <200 µmol/L) | 1329 | Simvastatin, 40 mg/day | 5 years | Decile risk (HR, 0.72) of major vascular events |
| Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA) | Post hoc subanalysis | Renal dysfunction (microalbuminuria, proteinuria) | 6571 | Atorvastatin, 10 mg/day | 3.3 years | Decile risk (HR, 0.61) of primary endpoint |
| Veterans’ Affairs High Density Lipoprotein Intervention Trial (VA-HIT) | Post hoc, subanalysis | Predialysis CKD | 1046 | Gemfibrozil, 1200 mg/day | 5.3 | Decile risk (HR, 0.73) of primary outcome and decile risk (HR, 0.74) of combined outcome of coronary death, nonfatal MI, or stroke |
| Study of Heart and Renal Protection (SHARP) | Prospective double-blind RCT | Predialysis status Hemodialysis Peritoneal dialysis | 9000 (6000 before dialysis and 3000 undergoing dialysis) | Simvastatin, 20 mg, and ezetimibe, 10 mg | 4 years | Major vascular events, rates of progression to ESR in patients before dialysis |
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