Classification and Pathophysiology of Cardiorenal Syndrome

Acute worsening of heart function leading to kidney injury and/or dysfunction

This is a syndrome of worsening renal function (WRF) as a complication of acute heart failure and/or acute coronary syndrome (ACS). Between 27 and 40 percent of patients hospitalized for acute decompensated heart failure appear to develop acute kidney injury (AKI) (1), which generally occurs early after presentation to the hospital. These patients experience higher mortality and morbidity and increased length of hospitalization.

In acute decompensated heart failure, the effects of vasoconstricting and sodium-retaining neurohormones such as angiotensin II, norepinephrine, endothelin, adenosine, and arginine vasopressin are counterbalanced by vasodilatory and natriuretic hormones such as natriuretic peptides, prostaglandins, bradykinin, and nitric oxide. The imbalance between the vasoconstriction/sodium retention and vasodilatation/natriuresis in favor of the former is pivotal in CRS and in sodium retention in these patients (4). Increased cardiac preload is associated with renal venous congestion, which is an important hemodynamic factor driving AKI in patients with acute decompensated heart failure (5).

In patients admitted to the intensive care unit with acute decompensated heart failure, AKI is associated with greater central venous pressure (CVP) on admission and after intensive medical therapy. This finding is consistent after adjusting for systemic blood pressure, pulmonary capillary wedge pressure, cardiac index, and estimated glomerular filtration rate (GFR)(5). Elevated adenosine levels in acute heart failure decrease GFR by vasodilatation of efferent capillaries, vasoconstriction of afferent capillaries, and by activating tubuloglomerular feedback. This creates the appearance of pre-renal azotemia in a patient who is clearly volume overloaded. The use of iodinated radiocontrast agents, nonsteroidal anti-inflammatory agents, and other nephrotoxic drugs can further exacerbate renal dysfunction. Vasodilators and loop diuretics widely used in treatment of acute decompensated heart failure can also contribute to reductions in GFR, and in some cases, may be the direct precipitants of CRS.

Chronic abnormalities in heart function leading to kidney injury and/or dysfunction

This subtype refers to a more chronic state of kidney disease complicating chronic heart disease. Chronic cardiorenal syndrome is common and has been reported in 63 percent of patients hospitalized with heart failure (6). Chronic kidney disease (CKD) is associated with higher all-cause and cardiac-specific mortality (6). A “dose-response” or graded association between decline in GFR and worsening clinical outcome is generally noted.

An example of type 2 CRS is chronic heart failure, where chronic cardiac dysfunction can result in adaptive alterations in kidney perfusion and neurohormonal activation. In a study of 1102 adult patients with heart failure, over 50 percent had evidence of kidney dysfunction. Nine percent had GFR <60 mL/min/1.73 m², and this was associated with a threefold increase in mortality (7). It is recognized that patients may transition between type 1 and type 2 CRS at various stages in their disease.

Initiation of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) may cause a mild increase in serum creatinine but does not contribute to CRS. Other causes contributing to real decline of renal function include excessive diuresis, persistent hypotension, prescriptions for nephrotoxic agents, vasodilators, and underlying renovascular disease. Anemia is a common finding in patients with type 2 CRS as a result of relative or absolute erythropoietin deficiency combined with a functional decrease in iron utilization as a result of increased hepcidin levels, which block iron transfer to hematoblasts. Correction of the anemia may improve symptoms but has not been shown to reduce clinical endpoints or mortality.

Acute worsening of kidney function leading to heart injury and/or dysfunction

This subtype refers to abnormalities in cardiac function secondary to AKI. The pathophysiologic mechanisms contributing to acute dysfunction of the heart likely go beyond simple volume overload to include uremic changes, electrolyte derangements, humoral mediators, and mediators of inflammation. Untreated uremia depresses myocardial contractility and contributes to pericardial inflammation. Hyperkalemia can precipitate arrhythmias and cardiac arrest, while acidemia results in negative inotropic effects and an increased risk of arrhythmias. Renal ischemia itself may precipitate activation of systemic oxidative stress leading to apoptosis of cardiomyocytes.

An example of type 3 CRS is the development of an ACS, arrhythmia, or acute decompensated heart failure after the onset of AKI such as acute glomerulonephritis or acute tubular necrosis. Another common scenario is cardiac surgery-associated AKI (CSA-AKI) with a reported incidence between 0.3 and 29.7 percent (8). In this condition, AKI contributes to fluid overload and worsened left ventricular pump mechanics. It is appreciated that CSA-AKI may also represent type 1 CRS.

Some patients with contrast-induced AKI develop progressive renal failure, volume overload, and acute decompensated heart failure requiring intensive care treatment and/or transient and sometimes permanent dialysis (9). Solomon et al. (10) showed that patients with contrast-induced acute kidney injury were almost twice as likely to suffer subsequent adverse cardiovascular events in the year following the contrast exposure, indicative of the serious consequences of type 3 CRS.

Chronic kidney disease leading to heart injury, disease, and/or dysfunction

This subtype refers to disease or dysfunction of the heart that occurs secondary to CKD. Cardiac disease in CKD patients is common, and cardiac-specific mortality rates are ten- to 20-fold higher compared with age and sex-matched non-CKD populations (11). Several observational studies have found a graded increase in the prevalence of CVD and heart failure, along with a higher risk of subsequent cardiac events associated with the degree of decline in kidney function (12). This dose-response trend also translates into similar trends for the risk of cardiac-specific and all-cause mortality (12).

Type 4 CRS involves the progression of CKD, often due to diabetes mellitus and hypertension, with accelerated calcific atherosclerosis, anemia, progressive left ventricular hypertrophy, and the development of diastolic and systolic dysfunction. Sodium retention occurs in progressive CKD from reduced renal excretion, and in patients on hemodialysis due to dietary noncompliance, inappropriately high dialysate sodium, and the inability to achieve target or “dry” weight. The dialysis procedure itself has been implicated in chronic myocardial injury and the activation of multiple proteinases that could be destabilizing to atherosclerotic plaque. However, it has been observed that most of the cardiac mortality in dialysis patients is not attributed to coronary ischemia but is more consistent with pump failure or lethal arrhythmias as the terminal event.

Systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney

In secondary CRS, both organs are simultaneously affected by systemic illnesses, either acute or chronic. Examples include sepsis, systemic lupus erythematosus, diabetes mellitus, amyloidosis, or other chronic inflammatory conditions. Sepsis is common and its incidence is increasing, with an estimated mortality of 20–60 percent. Approximately 11–64 percent of septic patients develop AKI that is associated with a higher morbidity and mortality (13). Abnormalities in cardiac function are also common in sepsis.

Observational data have found that approximately 30–80 percent of septic patients have elevated cardiac-specific troponins that often correlate with reduced left ventricular function. Currently there is an incomplete understanding of the pathophysiologic mechanisms causing such changes, but they may involve the effect of tumor necrosis factor (TNF) and other inflammatory mediators on both organs (14,15). Systemic inflammation and cellular injury leads to the liberation of small quantities of labile iron from organelles, and this acts as the critical substrate for the generation of oxygen free radicals, which propagate tissue injury (16). Myocardial depression leading to decreased cardiac output can further deteriorate renal function. Renal ischemia may induce further myocardial injury. Treatment of the primary illness in general improves both heart and kidney function.

The classification of CRS presented will allow development of a clinical and research framework for improved recognition and treatment of CRS in the future.

Saurabh Goel, MD, is a fellow with the division of nephrology, department of internal medicine, and Keith Bellovich, DO, is program director of the department of nephrology, St. John Hospital and Medical Center in Detroit. Peter McCullough, MD, is consultant cardiologist and chief, division of nutrition and preventive medicine, Oakland University William Beaumont School of Medicine, William Beaumont Hospital, in Royal Oak, MI.