Cardiovascular Problems in Acute Kidney Injury

Cardiovascular Complications in Chronic Kidney Disease

It is well appreciated that the cardiovascular mortality rate is excessively high in end-stage renal disease (ESRD) as a result of accelerated arteriosclerosis and vascular calcifications. The disease process leading to these complications, however, starts during much earlier stages of chronic kidney disease (CKD), and even mild to moderate CKD is associated with increased cardiovascular morbidity and mortality. The evidence is becoming increasingly clear that renal dysfunction not only carries the risk for development of cardiovascular diseases but also is a significant independent risk factor for adverse events in patients with acute illnesses such as myocardial infarction. It has been demonstrated that the presence of mild to moderate renal impairment in these patients increases the rate of adverse outcomes and that the mortality risk increases with declining renal function. For patients with a glomerular filtration rate (GFR) below 81.0 mL/min per 1.73 m ² of body surface, each 10-unit reduction in baseline estimated GFR is associated with a 10% increase in the relative risk of death or nonfatal cardiovascular complications. Furthermore, rates of reinfarction, congestive heart failure, stroke, and resuscitation are significantly higher in patients with GFRs less than 45 mL/minute per 1.73 m ² than in those with better renal function. Therefore, among patients who have had a myocardial infarction, any degree of preexisting renal impairment has to be considered a potent and independent risk factor for cardiovascular complications.

The typical cardiovascular problems associated with CKD include vascular and valvular calcifications, left ventricular hypertrophy, left ventricular dilatation, congestive heart failure, arrhythmias, and sudden cardiac death. The exact mechanisms by which chronic renal dysfunction increases the cardiovascular risk are currently under investigation. The progressive increase in cardiovascular risk with worsening GFR is at least partly explained by factors associated with the decline in renal function, such as anemia, oxidative stress, disturbances of calcium-phosphate homeostasis, inflammation, and conditions promoting coagulation. All of these factors are associated with accelerated atherosclerosis and endothelial dysfunction. Another factor, almost unrecognized until recently, is the dialysis procedure. Elegant studies indicate that conventionally administered HD results in recurrent circulatory stress, including myocardial, cerebral, and intestinal hypoperfusion and tissue hypoxia, caused at least in part by a composite loss of individual organ vasoregulatory reserve. The repetitive nature of this injury has a cumulative effect, leading to fixed reductions in left ventricular systolic function and conferring an increased risk of cardiac events, arrhythmia, and mortality.

Cardiovascular Complications in Acute Kidney Injury

The occurrence of AKI increases the risk for cardiovascular complications and in-hospital death. For a long time it was assumed that the high mortality rate in septic patients with AKI was due mainly to the consequences of sepsis alone and that AKI was only an expression of an aggravated course of the disease. However, it has been recognized that the relationship between sepsis and AKI is more complex than has been appreciated previously. The prognosis for patients in whom AKI develops during an intensive care unit (ICU) stay is worse than that for patients with ESRD referred to ICUs. These differences in outcome between patients with these two forms of kidney disease are not explained by differences in disease severity but rather reflect the additional risk conferred by AKI on top of sepsis. Compared with sepsis patients without AKI, those with AKI have a higher incidence of hemodynamic instability and leukocytosis. Hemodynamic instability is one of the most common cardiovascular problems seen in patients with AKI. Other problems include the wide spectrum of conditions and disorders leading to cardiac and pulmonary dysfunction, which are among the most common causes of death in patients with AKI ( Box 104.1 ). Patients with AKI more frequently require vasoactive medication, mechanical ventilation, cardiopulmonary resuscitation, and treatment of acid-base disturbances. Hypotension, congestive heart failure, respiratory failure, plasma potassium levels, and plasma bicarbonate levels have been shown to be of significant prognostic value for in-hospital death of AKI patients. From several studies examining outcomes and prognostic factors in AKI, it can be concluded that the development of cardiovascular dysfunction in patients with AKI has an important impact on survival in the ICU. Furthermore, dialysis-requiring AKI alone is associated with a 1.7-fold higher risk of coronary events, which is similar to the risk conferred by diabetes alone. ⁸⁷ This complex array of cardiovascular problems in patients with AKI does not necessarily reflect an increased severity of the underlying illness but rather is mediated by traditional and nontraditional complications of AKI.

The traditional cardiovascular complications of AKI are those related to direct consequences of renal dysfunction, such as hyperkalemia, acidosis, uncontrolled uremia, or volume overload. Hyperkalemia can cause life-threatening dysrhythmias, whereas severe acidosis may impair cardiac contractility, reduce vasopressor responsiveness, and contribute to the susceptibility for arrhythmias. Volume overload, which is considered the main factor contributing to patient mortality and morbidity in AKI, is associated with a number of adverse events, including increased intraabdominal pressure, which may delay kidney function recovery, pulmonary edema, which may predispose to lung inflammation and pneumonia, and gut edema, which may lead to bacterial translocation and sepsis. Uncontrolled uremia, on the other hand, may cause pericarditis or upper gastrointestinal bleeding because of impaired platelet function. The mutual “end points” of these traditional adverse cardiovascular events in AKI include myocardial infarction, stroke, and heart failure.

Although traditional complications can be managed by modern renal replacement therapy (RRT), it is the nontraditional complications of AKI that appear to be mainly responsible for the high mortality rate. These nontraditional complications include respiratory failure, cardiac complications, and sepsis, all of which mainly occur in the context of a systemic inflammatory response syndrome (SIRS) triggered or potentiated by AKI. Similar to other systemic illnesses, induction of SIRS eventually results in a dysregulation of the immune system. The inflammatory response to AKI may induce direct injury to the lung capillary endothelium and promote fluid extravasation into the interstitium. In addition to the traditional cardiovascular effects, AKI also may have direct deleterious effects on the heart, inducing acute LV dilatation and alterations of various functional parameters, including LV relaxation times and fractional shortening. Experimental studies have described cardiac histologic changes such as cellular apoptosis and capillary vascular congestion after renal ischemia reperfusion injury or glycerol-induced rhabdomyolysis; AKI also has been shown to lead to cardiac hypertrophy and increased cardiac macrophage accumulation. Cardiocyte apoptosis has been suggested to play a role in promoting these changes along with increased mitochondrial fragmentation and stimulation of inflammatory mediators. These effects likely contribute to short- and long-term deleterious cardiac complications associated with AKI.

Taken together, AKI has to be viewed as a systemic disease affecting multiple organs including lung, heart, liver, intestines, and brain. Traditional and nontraditional complications together lead to a diverse array of complications such as sepsis, respiratory failure, and heart failure that contribute to the increased mortality in AKI patients.

Pathophysiology of Cardiopulmonary Dysfunction in Acute Kidney Injury

In health, a strong physiologic interaction between renal and cardiovascular function operates to control extracellular fluid volume and arterial blood pressure. Renal failure modifies most of the factors regulating cardiovascular function through direct hemodynamic effects, neurogenic reflexes, and circulating hormones. The main players involved in these interactions are the renin-angiotensin system (RAS), nitric oxide (NO), and the sympathetic nervous system (SNS). AKI affects each of these systems separately, with consequences for cardiovascular function.