Heart-Kidney Cross-Talk

Predisposing Factors

It is beyond the scope of this chapter to review the broad field of CKD. However, it is important to recognize that the vast majority of heart-kidney cross-talk is believed to occur in the setting of predisposing CKD. In this setting there are a variety of elevated and dysregulated cytokines, in some cases cachexia or obesity, diabetes mellitus and hypertension, proteinuria, uremia, and anemia. There are numerous studies and publications supporting the concept that all of these conditions are probably independently related to the progression of CKD, the development of HF, and the risk of AKI in the setting of AHF.

Subclinical Acute Kidney Injury

It is likely that individuals undergo repeated episodes of either subclinical or unrecognized episodes of AKI over the course of a lifetime. With each episode, there is injury to nephron units with partial recovery of some and permanent death to others. Because of the kidney's ability to alter blood flow and filtration, the clinician would not be able to detect these events with the measurement of serum creatinine. Such AKI events could occur with episodes of extreme dehydration (e.g., with self-limited gastrointestinal or viral syndromes), after elective surgeries, with toxic therapies for other diseases (e.g., chemotherapy, antibiotics), and with the use of iodinated contrast agents for a variety of imaging studies. Thus repeated subclinical AKI in the past may explain why some individuals with seemingly no baseline CKD or risk factors develop CRS in the setting of AHF.

Cardiac and Renal Fibrosis

Increased stress or injury to the myocardium, glomeruli, and renal tubular cells because of uncontrolled hypertension, diabetes mellitus, and other factors discussed in this section have been associated with tissue fibrosis. Responses to acute and chronic damage can involve recruitment of immune cells, production of cell signaling proteins from local pericytes, mast cells, and macrophages, resulting in activation of resident fibroblasts and myofibroblasts, and in the final common pathway, the deposition of procollagen into the extracellular matrix, which is irreversibly cross-linked to collagen, generating cardiac and renal fibrosis.

Galectin-3 (also known as MAC-2 Ag), a regulator of cardiac fibrosis, is one of 14 mammalian galectins and is an approximately 30 kDa glycoprotein that has a carbohydrate-recognition-binding domain of approximately 130 amino acids that enables the binding of β-galactosides. It is encoded by a single gene, LGALS3, located on chromosome 14, locus q21–q22 and expressed in the nucleus, cytoplasm, mitochondrion, cell surface, and extracellular space. Galectin-3 as a paracrine signal is involved in cell adhesion, activation, chemoattraction, growth and differentiation, cell cycle, and apoptosis in multiple diseases, including cancer, liver disease, rheumatologic conditions, and cardiorenal syndromes. In the myocardium and the kidney, angiotensin II and aldosterone is a major stimulus for macrophages to secrete galectin-3, which in turn works as a paracrine signal on fibroblasts to help translate the signal of transforming growth factor-β (TGF-β) to increase cell cycle (cyclin D1) and direct the proliferation of pericytes and fibroblasts and the deposition of procollagen 1. These observations strongly suggest that fibrosis is a critical participant in the pathogenesis and progression of CKD and HF. Because the tissue secretion of galectin-3 is sufficiently high, it can be detected as a signal in blood and thus has been developed as a key advance for the clinical assessment of patients at risk for cardiorenal syndromes.

Hemodynamics and Congestion

In the ADHERE (Acute Decompensated Heart Failure National Registry) registry, 50% of patients who were admitted to the hospital with symptomatic AHF had a systolic blood pressure (BP) of 140 mm Hg or higher, and only 2% had a systolic BP of less than 90 mm Hg. The increase in BP is likely a reflection of sodium retention and sympathetic activation. A dysfunctioning left ventricle is particularly sensible to afterload variations, and therefore an increase in blood pressure can worsen abruptly left ventricular filling pressures, leading to pulmonary congestion irrespective of total intravascular volume. Subsequently, a vicious cycle arises, in which cardiac remodeling leads to functional mitral regurgitation, further increase in left atrial pressure, and pulmonary hypertension. Experimental animal data as far back as the 1930s have demonstrated that temporary isolated elevation of central venous pressure can be transmitted back to the renal veins, resulting in direct impairment of renal function.

Chronic passive congestion of the kidneys results in attenuated vascular reflexes over time. As with the heart, venous congestion is one of the most important hemodynamic determinants of CRS and has been associated with the development of renal dysfunction in the setting of AHF. However, the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial found no relationship with baseline or changes in hemodynamics on renal outcomes. It is observed commonly that coexisting renal dysfunction may complicate the treatment course of HF and that the use of intravenous loop diuretics often alleviates congestion at the cost of worsening renal function within days of hospitalization and is a strong independent predictor of adverse outcomes. Although loop diuretics provide prompt diuresis and relief of congestive symptoms, they provoke a marked activation of the sympathetic and RAAS result in renovascular reflexes and sodium retention and thus are considered a primary precipitant of CRS. This places the patient with AHF at risk for CRS in a narrow therapeutic management window with respect to fluid balance and blood pressure as shown in Fig. 109.2 .