1. What is the relationship between the decrease in the glomerular filtration rate and cardiovascular disease?

Patients with chronic kidney disease (CKD) have a substantial increase in risk for death from cardiovascular disease. Even small decreases in kidney function, as measured by the estimated glomerular filtration rate (eGFR), are associated with this higher risk, and it increases progressively as kidney function declines. Patients with CKD are substantially more likely to die from heart disease than progress to dialysis. In patients with end-stage kidney disease (ESKD), the risk for death is 10- to 100-fold higher than age- and gender-matched individuals without kidney disease. Conversely, in patients with known heart disease (like coronary artery disease or heart failure), the greater the severity of kidney disease, the worse the patient outcome, including higher mortality and, in patients hospitalized for non-ST segment elevation myocardial infarction, a longer length of stay.

2. What is the relationship between albuminuria/proteinuria and cardiovascular disease?

The presence of albuminuria is also associated with a higher risk of death from cardiovascular disease. This risk begins even when the amount of urine albumin is not enough to meet the criteria for the diagnosis of microalbuminuria. As the amount of urine albumin increases, so does the risk for death from heart disease—the risk is higher in individuals with microalbuminuria and even higher among those with overt proteinuria.

3. Why is the risk for cardiovascular disease increased in CKD?

Both traditional and nontraditional risk factors are important contributors to cardiovascular disease. Diabetes mellitus and hypertension are the two most common causes of CKD—both are also known cardiovascular risk factors. Moreover, diseases like hypertension are more severe in the setting of CKD. However, traditional risk factors are insufficient to explain the high cardiovascular risk seen with CKD. A large number of nontraditional risk factors have been identified, such as systemic inflammation, high serum phosphorus, and oxidative stress (among others). However, at this time, it remains unclear if any of the traditional or nontraditional risk factors can be modified to reduce the risk of heart disease ( Table 21.1 ).

4. What types of cardiovascular disease are seen in patients with CKD?

There are two major overlapping categories of cardiovascular disease associated with CKD: disorders of cardiovascular perfusion, which includes atherosclerotic cardiovascular disease; and disorders of cardiac function, such as congestive heart failure and left ventricular hypertrophy. Disorders of vascular perfusion include coronary artery disease, cerebrovascular disease, peripheral vascular disease, and renovascular disease.

5. Are there other forms of cardiovascular disease seen in patients with CKD?

Cardiovascular calcification is a frequent contributor to cardiovascular disease in CKD; it can occur either in heart valves, the tunica intima, or the tunica media of the blood vessels. Calcified blood vessels can often be seen on plain x-rays in patients with CKD, particularly among the elderly or those being treated with dialysis. Though not fully understood, during vascular calcification, the smooth muscle cells of vessels express osteocytic phenotypes and the calcium phosphate deposition resembles hydroxyapatite seen in bone. The greater the severity of vascular calcification, the greater the risk of death. There are many reasons why patients with CKD develop vascular calcification; an increase in serum phosphorus is considered to be an important contributor, and this may be a potentially modifiable risk factor. Hence, the management of elevated phosphorus levels may reduce the risk for heart disease; however, this approach remains unproven.

Calciphylaxis, or cacificic uremic arteriolopathy, is an accelerated form of vascular calcification typically seen in patients with CKD stage 5. Risk factors include warfarin therapy, altered mineral metabolism, and obesity. The process can lead to nonhealing wounds and is often fatal. Parathyroidectomy and/or sodium thiosulfate therapy may be of benefit.

6. What are the clinical manifestations of cardiovascular disease in CKD?

Manifestations of cardiovascular disease include angina pectoris, myocardial infarction, congestive heart failure, stroke, peripheral vascular disease, arrhythmias, and sudden cardiac death. In advanced CKD, cardiovascular disease is often manifested by left ventricular hypertrophy, diastolic dysfunction, and heart failure. The national registry for dialysis patients—the United States Renal Data System—reports that about 30% of patients with CKD over 66 years of age have congestive heart failure. Left ventricular hypertrophy may be accompanied by left ventricular remodeling and fibrosis, and these changes, with or without coronary artery disease (in addition to electrolyte shifts and volume expansion), may contribute to the high incidence of sudden cardiac death in this population. Indeed, sudden cardiac death is the most common cause of death in dialysis patients.

The clinical manifestations of acute coronary syndrome are also atypical in patients with CKD, and the electrocardiographic findings may be obscured by the presence of left ventricular hypertrophy.

7. What should be the goal blood pressure for the treatment of hypertension in patients with CKD?

Long-term follow-up of participants with nondiabetic CKD in the Modification of Diet in Renal Disease study showed that aggressive control of blood pressure was associated with slowing in the rate of loss of kidney function. However, the results of other studies examining the association of intensity of blood pressure control on the progression of kidney disease has not been consistent, and a recent meta-analyses of clinical trials in patients with nondiabetic kidney disease was not able to show the benefit as seen in the Modification of Diet in Renal Disease study. The results of the Systolic Blood Pressure Intervention Trial (SPRINT) trial have recently been published and show that targeting blood pressure <120 mm Hg systolic, measured using a standardized approach distinct from how measurements are made in clinical practice, was associated with a 25% lower risk for the composite primary outcome of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. The benefit was the same in patients with and without kidney disease; the results of the effect of aggressive control of blood pressure on the rate of loss of kidney function are awaited. Given the results of this landmark study, it seems prudent to target lower blood pressure in patients with CKD, which has not been the norm recently.

8. Does reduction in proteinuria decrease cardiovascular risk?

The greater the proteinuria, the higher the cardiovascular risk. A reduction in urine protein excretion is associated with long-term slowing in the loss of kidney function. However, whether or not reduction in proteinuria will reduce cardiovascular risk is unclear at this time. Nevertheless, given the benefit of the slowing rate of decline of the GFR, attempts should be made to reduce urine protein excretion to at least <1.0 g/day.

There are two broad strategies for reducing urine protein excretion:

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  Therapies specific to the underlying disease (like that for glomerular diseases)

  
  
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  Nonspecific therapies. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are the most effective nonspecific anti-proteinuric therapies and should be the first-line antihypertensive therapies as long as there are no contraindications for their use. The combined use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers is no longer recommended, as it is associated with a higher risk for clinically meaningful acute worsening of kidney function.

9. What is the role of lipid management in CKD?

The greater the amount of proteinuria, the worse the abnormalities in the lipid panel. Patients with proteinuria generally have elevated total cholesterol and low-density lipoprotein cholesterol, as well as low levels of high-density lipoprotein cholesterol. Patients with diabetes may have, in addition, elevated triglyceride levels.

Lipid-lowering therapies are as effective in lowering cholesterol levels in patients with CKD as in the general population. No dosage adjustments are required for statins, bile acid sequestrants, niacin, or ezetemibe. Fibrates do require a dosage adjustment for kidney function. However, the magnitude of effect of these drugs on reducing cardiovascular disease may not be as large as that seen in the general population. Two large, randomized, controlled trials have been unable to show any significant reduction in fatal and/or nonfatal cardiovascular events in dialysis patients. The Study of Heart and Renal Protection (SHARP) study demonstrated that treatment of patients with CKD with simvastatin/ezetimibe was associated with a significant reduction in cardiovascular events; however, there was no effect on cardiovascular or all-cause mortality. The results were the same whether or not the patients were undergoing dialysis. These data indicate that the benefit with lipid lowering in patients with CKD may not be as large as that seen in patients without kidney disease.

10. What is the relationship between anemia and its management to the cardiovascular mortality in CKD?

Anemia is a cardinal manifestation of CKD and it generally is apparent when the eGFR is <30 mL/min per 1.73 m ² . Observational studies have shown that the greater the severity of anemia, the higher the risk for death. However, several randomized, controlled trials have failed to demonstrate a reduction in mortality risk with erythropoietin therapy, the cornerstone of anemia management in patients with CKD. In fact, some of these studies have shown a higher risk for stroke and/or death when the treatment was targeted to achieve a hemoglobin level of 13 g/dL. Hence, erythropoietin therapy should not be started unless the hemoglobin level decreases to between 9.0 and 10.0 g/dL, and care should be exercised to prevent it from increasing to above 12.0 g/dL.

11. Can serum troponin be used in the diagnosis of myocardial infarction in patients with kidney disease?

The use of biomarkers for the diagnosis of myocardial infarction in patients with CKD can be problematic. Serum troponin has been found to be elevated in patients with CKD who have no clinical suspicion of acute myocardial injury. It is not absolutely clear why this is the case. This may have to do with subclinical myocardial ischemia or decreased clearance of troponin degradation products because of kidney disease.

Baseline elevations in troponin are associated with the higher risk of cardiovascular death in these patients. Troponin I is a more specific marker of infarction that troponin T in these patients. Even so, whether or not an elevation in serum troponin in a given patient indicates acute myocardial injury, it is necessary to take into account the patient’s clinical presentation and change in the blood levels of troponin over time. For example, a rising troponin level in a patient who presents with typical chest pain would be consistent with the diagnosis of acute myocardial infarction. On the other hand, small and unchanging elevations in an otherwise asymptomatic patient would portend a poor long-term prognosis but are unlikely to be of any immediate import.