One important challenge to the understanding of the bidirectional autonomic interactions between the heart and the kidney is the ability to quantify individual regional SNA activity. For this purpose, sympathetic nerve recording techniques and radiotracer-derived measurements of norepinephrine (NE) spillover into the plasma from individual organs have been used. The limitations of each technique have led to the recommendation that they be used together [7]. Microneurography provides instantaneous multiunit or single-fiber recordings of electrical transmission in sympathetic nerves, but assessment may be skewed by interpreter’s bias [8, 9].

The NE spillover method provides objective information on the release of this neurotransmitter from internal organs where microneurography is not feasible [10–12]. During infusion of titrated NE at a constant rate, output of endogenous NE from a given organ (NE “spillover”) can be measured by isotope dilution according to the formula:
where C _V and C _A are the plasma concentrations of NE in the organ’s venous and arterial plasma, E is the fractional extraction of titrated NE while the blood is flowing through the organ, and PF is the organ plasma flow [7].

Computer analysis of heart rate variability (HRV) predominantly reflects selective autonomic control of the heart. Vagal and sympathetic cardiac influences operate on the heart rate in different frequency bands. While vagal regulation has a relatively high cutoff frequency, modulating heart rate both at low and high frequencies (up to 1.0 Hz), sympathetic cardiac control operates only at <0.15 Hz [13–15]. Blood pressure variability is the result of complex interactions between cardiac and vascular neural regulation, mechanical influences of respiration, humoral and endothelial factors, large artery compliance, and genetic influence. Nevertheless, time or frequency domain analysis of either blood pressure or HRV can provide valuable information on autonomic cardiovascular regulation. While often lacking specificity, these measurements can be obtained in clinical practice and are not subject to interpreter’s bias [16]. The ability of HRV and blood pressure fluctuations to reflect autonomic control of the cardiovascular system is improved by use of multivariate models for its assessment. The simplest ones consider the relationship between spontaneous fluctuations in blood pressure and heart rate, either in the time or frequency domain to assess baroreceptor sensitivity (BRS) and its modulation in daily life [17–20]. While spontaneous variations in blood pressure and heart rate clearly depend on autonomic mechanisms, caution is needed in considering them a quantitative measurement of efferent SNA to the heart and vasculature. In fact, in a variety of clinical situations, including HF, low-frequency heart rate spectral power has little or no relation to rates of NE spillover from the heart or sympathetic nerve firing measured by microneurography. Indeed, in HF, low-frequency heart rate spectral power is reduced, but cardiac NE spillover is markedly increased [21].

Cardiac SNA can also be noninvasively assessed by the use of ¹²³I-metaiodobenzylguanidine (MIBG), an analogue of NE, using semiquantitative analyses, namely, early heart-to-mediastinum ratio, late heart-to-mediastinum ratio, and myocardial washout [22]. Data from prospective studies and meta-analyses have shown that patients with decreased late heart-to-mediastinum ratio or increased myocardial ¹²³I-MIBG washout have a worse prognosis than those patients with normal semiquantitative myocardial MIBG parameters [23]. Furthermore, ¹²³I-MIBG has been found to independently predict sudden cardiac death regardless of left ventricular ejection fraction (LVEF) [24]. In addition, the ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) trial demonstrated that ¹²³I-MIBG cardiac imaging provides additional independent prognostic information for risk-stratifying HF patients on top of commonly used markers such as LVEF and B-type natriuretic peptide [25].

Thus, the clinical relevance of information on autonomic cardiac control is supported by the evidence that increased SNA is associated with increased mortality in myocardial infarction and HF patients, and with an increased risk of sudden arrhythmic death.

The kidney is abundantly innervated with both efferent adrenergic and somatic afferent neurons [26, 27] (Fig. 10.2). The efferent neurons terminate at multiple sites within the nephron and independently influence tubular sodium reabsorption, renin secretion, and renal blood flow (RBF). Sodium reabsorption is enhanced at very low stimulation frequencies; higher stimulating frequencies increase renin secretion and lower RBF [28–30]. Thus, under conditions of mild sympathetic activation, sodium reabsorption increases and consequently plasma volume expands. With more intense sympathetic activation, sodium reabsorption is further augmented by the effects of angiotensin II (A II) and aldosterone and vasoconstriction occurs due to the combined vascular effects of NE and A II. Thus, increased efferent renal SNA produces simultaneously an increase in arterial pressure and blood volume and a decrease in RBF. When these compensatory responses to hypotension or hypovolemia become persistent and disproportionate to the cardiovascular abnormalities which initially trigger them, they become maladaptive and directly contribute to the progression of HF. These responses are particularly influential in the CRS where persistent vascular congestion and worsening renal function magnify the mutually detrimental effects of heart and kidney [31]. It should be noted that in addition to the effects of renal sympathetic efferent activation, somatic afferent nerves originating in the kidney act directly on the neural cardiovascular control centers in the midbrain [27]. The activity of these afferent nerves is stimulated by various factors including ischemia and adenosine release, both of which are the result of intense vasoconstriction. A direct neurological connection between the kidney and hypothalamus has been demonstrated in partially nephrectomized rats. In patients with end-stage renal disease (ESRD) and in renal transplant recipients, removal of the native kidney is associated with attenuated muscle SNA [32–35]. Because A II can directly stimulate central sympathetic drive, secretion of renin by the macula densa cells is another mechanism by which the kidney contributes to activation of SNA and of the renin-angiotensin-aldosterone system (RAAS) [36]. Increases in activation of either the afferent or the efferent loop of this “sympathorenal axis” may lead to a self-perpetuating cycle and sustained generalized SNA. However, it should be pointed out that many other reflexes and humoral substances, including natriuretic peptides (NP), can modify sympathetic tone, so that any contribution of the renal sympathetic afferent nerves to this self-perpetuating cycle can be modified by changes in activity of these other controllers [22].

Increased plasma NE, muscle SNA, and total body, cardiac, and renal NE spillovers have been documented in patients with congestive HF [12, 37]. For more than three decades, plasma NE has been known to be a strong predictor of outcomes in HF patients [38]. The success of beta-blockers in decreasing mortality in HF patients convincingly supports the notion that excessive SNA directly contributes to HF progression [39].

However, the use in HF patients of moxonidine, an inhibitor of presynaptic NE release, was associated with increased mortality presumably due to hypotension caused by a precipitous fall in plasma NE levels [40]. Data are lacking on whether a more gradual reduction in NE levels would have produced different results in HF patients.

There is little doubt that renal NE spillover is, together with cardiac NE spillover, a major contributor to the total excess of sympathetic drive in HF patients [12]. Indeed, it has recently been shown that renal SNA, as measured by renal NE spillover, was highly predictive of outcomes despite concomitant therapy with anti-neurohormonal drugs [39]. In addition in an experimental myocardial infarction model, renal sympathetic denervation was associated with improved outcomes [41]. The enhanced efferent sympathetic signaling to the kidney seen in HF presumably has the same effects it has in hypertension (enhanced sodium retention, decreased RBF and activation of the RAAS). These effects are even more harmful in HF because volume expansion and increased arterial pressure will aggravate myocardial loading conditions and, together with the direct actions of NE, A II, and aldosterone, worsen myocardial remodeling. The SNA-related sodium avidity and renal hemodynamic abnormalities may be especially deleterious in the CRS, because persistent congestion may itself contribute to further deterioration of renal function [31]. Kidney dysfunction often occurs during intensive treatment with loop diuretics. This event is not surprisingly because loop diuretics are known to further stimulate SNA either directly or through activation of the RAAS [42]. Augmentation of afferent signaling from the kidney may then contribute to perpetuate the global sympathetic overdrive in HF, completing the sympathorenal loop [39] (Fig. 10.3).

Many critically important changes occur in the kidney in the setting of cardiac dysfunction and neurohormonal activation (Fig. 10.3). When RBF decreases as a result of decreased cardiac output (CO), neurohormonally induced efferent arteriolar vasoconstriction, or increased central venous pressure (CVP), the kidney strives to maintain glomerular filtration rate (GFR) by increasing filtration fraction (FF) [43]. In normal conditions, FF is approximately 20–25 %, increases above this value in HF, and can rise above 50 % when congestion is complicated by increased intra-abdominal pressure. As explained below, increased FF in itself augments sodium reabsorption, an event which is magnified by increased SNA and RAAS activation. Different transporters mediate active transfer of sodium across the luminal side of proximal tubular cells. However, because the proximal tubules have a highly permeable epithelium, sodium can easily return to the lumen so that net sodium reabsorption is governed by passive Starling forces between the peritubular capillaries and renal interstitium. In congestive HF, because of an increased FF, the oncotic pressure in the peritubular capillaries (πPC) is higher, which stimulates sodium and water reabsorption into the vasculature. Because the kidney is an encapsulated organ, when congestion is present, the interstitial fluid hydrostatic pressure (PIF) and the peritubular capillaries hydrostatic pressure (PPC) are both increased, whereas the interstitial fluid oncotic pressure (πIF) drops because of increased lymph flow, which removes interstitial proteins. This also favors net sodium and water reabsorption into the vasculature [44–51]. Abnormally high-sodium reabsorption in the proximal tubule has profound consequences on the rest of the nephron. Under normal circumstances, the macula densa senses increased sodium chloride delivery because active chloride transport requires ATP, which is ultimately converted to adenosine. This substance, which is released from cells of the macula densa, has a paracrine vasoconstrictive effect on the afferent arteriole. This effect, known as tubuloglomerular feedback (TGF), protects the glomerulus from hyperfiltration injury. In congestive HF, due to increased sodium chloride reabsorption in the proximal tubule, chloride delivery to the macula densa is reduced and intracellular chloride levels are low. This stimulates NOS I and COX-2 activation and release of NO and PGE2. Both NO and PGE2 stimulate the granulosa cells of the afferent arteriole to secrete renin which activates angiotensin II, thus perpetuating a vicious cycle of neurohormonal activation and worsening congestion. It is also important to consider that loop diuretics, which are used in large numbers of ambulatory and in the majority of hospitalized HF patients, inhibit the Na+/K+/2Cl− co-transporter in the thick portion of the ascending loop of Henle, further reducing macula densa uptake of sodium chloride and escalating neurohormonal activation [43]. The distal convoluted tubules and collecting ducts reabsorb ≤10 % of the total amount of sodium filtered by the glomerulus. In contrast to the part of the nephron proximal to the macula densa, where net fractional sodium reabsorption is kept relatively constant under normal circumstances, distal fractional sodium reabsorption rates are highly variable depending on tubular flow rate, and levels of aldosterone and arginine vasopressin [52–54]. Therefore, it is the distal nephron which determines the urinary sodium concentration and osmolality. However, a prerequisite for the ability of the distal nephron to maintain a neutral sodium balance is adequate delivery of sodium. In congestive HF, because of increased fractional reabsorption in the proximal tubules and often decreased GFR in individual nephrons, tubular flow might be low in the distal part of the nephron despite significant systemic fluid excess. In addition, the increased levels of aldosterone and arginine vasopressin further stimulate reabsorption of the remaining tubular fluid. It is the decreased distal tubular flow which causes aldosterone breakthrough, which leads to secondary hyperaldosteronism despite therapy with adequate doses of RAAS inhibitors [55, 56]. Furthermore, prolonged exposure to loop diuretics produces adaptive hypertrophy of distal tubular cells, which increases local sodium reabsorption and aldosterone secretion. Indeed, experimental data shows that distal tubular cells adaptation to loop diuretics can be significantly attenuated by administration of aldosterone antagonists or thiazide diuretics [55, 57].

The escalating congestion resulting from the cardiorenal interactions outlined above has profound implications for all abdominal vascular systems, including the splanchnic, intestinal, hepatic, and splenic circulations [58]. In the splanchnic microcirculation, net filtration rate is determined by Starling forces, (PC -PIF) – (πC- πIF), which favor filtration throughout the entire length of the capillary bed. When capillary hydrostatic pressure increases as a result of congestion, filtration pressure is even higher [58]. Because the interstitium has low compliance, the excess filtrated fluid is drained directly into lymphatic capillaries, so that there is only a slight increase in interstitial fluid volume. Splanchnic lymphatic flow can increase as much as 20 times its normal value [59]. Because increased lymphatic flow removes interstitial proteins, the drop in interstitial oncotic pressure reduces filtration and the accumulation of fluid in the interstitium. Once lymphatic flow cannot increase further and interstitial compliance increases, interstitial fluid begins to accumulate [60]. When lymph flow can no longer adequately remove interstitial proteins, protein-rich edema accumulates to the point of compressing lymphatic vessels which further impairs lymph flow.

The intestinal microcirculation is characterized by a countercurrent system that enables extensive exchange of oxygen (O₂) between arterioles and venules. This O₂ “short circuit” creates a gradient with the lowest partial O₂ pressure at the villus tip [61–63]. During congestive HF, low perfusion, venous congestion, and sympathetically mediated arteriolar vasoconstriction in the splanchnic microcirculation stimulate O₂ exchange between arterioles and venules, exaggerating the O₂ gradient between the villus base and tip. This causes villus tip ischemia which is responsible for epithelial cells dysfunction and loss of intestinal barrier function. As a result, lipopolysaccharide or endotoxin, produced by gram-negative bacteria residing in the gut lumen, enters the systemic circulation and contributes to escalate the HF inflammatory milieu [61–63].

In the liver, hepatocytes continuously produce adenosine from the breakdown of ATP. Adenosine accumulates in the perisinusoidal space, which is drained by the lymphatic system. When portal blood flow is reduced because of α receptor–mediated vasoconstriction, lymph flow decreases and intrahepatic adenosine concentration increases. Adenosine then stimulates hepatic afferent nerves, which have synaptic connections with renal efferent sympathetic nerves. These events intensify renal vasoconstriction and sodium retention [58].

The splenic sinusoids are freely permeable to plasma proteins. As a result, their colloid osmotic pressure is the same as that of the surrounding lymphatic matrix. Therefore, fluid transport between the two spaces is dictated by differences in hydrostatic pressure. Transient congestion of the splanchnic venous system results in increased hydrostatic pressure inside the splenic sinusoids so that more fluid is transferred to the lymphatic matrix and buffered inside the lymphatic reservoirs of the spleen [64]. In congestive HF, increased cardiac filling pressures increase the production of atrial natriuretic peptide (ANP) which produces splenic arterial vasodilatation and venous vasoconstriction. These hemodynamic changes promote the shift of fluid into the perivascular third space of the spleen. Storage of large amounts of fluid in the spleen may lead to perceived central hypovolemia which further stimulates neurohormonal activity and perpetuates the vicious circle of congestion-driven SNA and RAAS enhancement. Moreover, when the splenic lymphatic circulation becomes overloaded, additional accumulation of interstitial edema occurs [58].

According to a widely accepted definition, the cardiorenal syndrome is a pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ. On the basis of this definition, five types of the cardiorenal syndrome have been identified and each has unique aspects of autonomic crosstalk between the heart and the kidney [65].