Fig. 15.1
Types of cardiorenal syndrome. Cardiorenal syndrome can be seen in an acute setting, such as when the hemodynamic changes of heart failure lead to acute kidney injury (type 1). Acute kidney injury such as glomerulonephritis (GN) can lead to heart failure (HF) or myocardial ischemia (type 3). The chronic hemodynamics of heart failure can also lead to chronic kidney disease (type 2), or chronic kidney disease (CKD) can lead to heart failure, commonly with preserved ejection fraction (HFpEF, type 4). Systemic conditions such as sepsis or diabetes can also cause simultaneous heart and kidney failure (type 5)
- 1.
Cardiorenal syndrome type 1 (acute CRS): acute worsening of cardiac function leading to acute kidney injury (AKI) or dysfunction [11]. In this case, acute cardiovascular diseases like acute coronary syndrome, cardiogenic shock, and acute decompensated heart failure are the cause of acute renal dysfunction [10, 11].
- 2.
Cardiorenal syndrome type 2 (chronic CRS): chronic abnormalities in cardiac function causing progressive chronic kidney disease [10].
- 3.
Cardiorenal syndrome type 3 (acute reno-cardiac syndrome): acute kidney injury (abrupt or primary worsening) leading to cardiac dysfunction and/or injury. In this case, acute kidney injury can be related to ischemia or glomerulonephritis that causes acute cardiac injury or dysfunction such as acute decompensated heart failure, arrhythmia, or ischemia [10, 12].
- 4.
Cardiorenal syndrome type 4 (chronic reno-cardiac syndrome): primary chronic kidney disease that leads to chronic cardiac dysfunction including decrease in cardiac function, left ventricular hypertrophy, diastolic dysfunction, or increase in cardiovascular morbidity [10].
- 5.
Cardiorenal syndrome type 5 (secondary CRS): systemic condition (acute or chronic) causing simultaneous heart and kidney dysfunction. Some of these systemic conditions include sepsis, connective tissue disorders such as systemic lupus erythematosus, drugs, toxins, Wegener granulomatosis , diabetes mellitus, sarcoidosis, and amyloidosis [10, 13].
Epidemiology
The incidence of CRS varies by its type. Because cardiorenal syndrome type 5 is a newly recognized entity that may occur in different pathological processes, its incidence, prevalence, and outcomes are not yet well defined [13]. Cardiorenal syndrome type 1 has been the most studied and, thus, the best characterized.
As previously mentioned, initial studies on cardiorenal syndrome were retrospective studies in patients admitted to the hospital with acute decompensated heart failure. Thus, we know that acute worsening of renal dysfunction occurs in 25–45 % of patients with acute decompensated heart failure , especially during the first 3 days after admission [11, 14]. For example, in the Acute Decompensated Heart Failure National Registry (ADHERE) that had more than 105,000 patients with ADHF , renal dysfunction was found in 30 %, and 21 % had a serum creatinine ≥2.0 mg/dl [15]. Less data are available for cardiorenal syndrome type 2, but in chronic heart failure patients, the prevalence of kidney dysfunction has been reported in up to 25 % of these patients (2), and stage III chronic kidney disease (CKD, defined as GFR < 60 ml/min/1.73 m2), has been present in up to 60 % of patients with chronic heart failure [16].
Importantly, renal dysfunction is the most important predictor of mortality in heart failure patients, and worsening renal function is associated with increased hospital stays, cost of complications, and mortality at 5 years [16].
Pathophysiology
Broadly, several factors are thought to contribute to CRS (◘ Fig. 15.2). The pathophysiology of cardiorenal syndrome is still not well understood, and most studies have focused on CRS type 1. Hemodynamic changes and neurohormonal activation have been implicated in the development of all five types of cardiorenal syndrome. Several mediators can play a role in CRS, including a hyperactive sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS), an imbalance between radical oxygen species (ROS) and nitric oxide, and an inflammatory response (◘ Fig. 15.3) [3]. In fact, some studies have shown increased neurohormonal activity associated with tubular and myocardial damage in patients with CRS compared to those with heart failure who did not develop renal failure [17].
Fig. 15.2
Schematic summary of key factors leading to cardiorenal syndrome (CRS). CO cardiac output
Fig. 15.3
Schematic representation of some of the factors involved in the cardiac-renal interactions. GFR glomerular filtration rate, F(x) function, ROS reactive oxygen species, NO nitric oxide, RAAS renin-angiotensin-aldosterone system, SNS sympathetic nervous system, MAP mean arterial pressure, CO cardiac output
Hemodynamic Abnormalities
- 1.
Low cardiac output : The low cardiac output state seen in patients with heart failure, especially those with systolic dysfunction and related hypovolemia, leads to activation of arterial and intrarenal receptors in the kidneys. Activation of these receptors will cause non-osmotic release of arginine vasopressin that, in turn, leads to activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system. Activating both the RAAS and SNS results in water and sodium retention that causes systemic hypertension. This increase in systemic pressures in conjunction with increased renal arteriolar resistance results in decreased glomerular filtration rate (GFR). This is important because in patients with heart failure, GFR is an important predictor of survival [18]. Several medications used in heart failure can impact renal hemodynamics, causing worsening renal function. Thus, diuretic therapy increases the production of angiotensin II and leads to worsening renal hemodynamics, especially when the use of diuretics is related to hemoconcentration. In that case, patients experience a fivefold increase in worsening renal function [11, 19]. Also, medications such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists (ARBs), and aldosterone receptor antagonists can directly lead to worsening renal function in these patients.
- 2.
Vascular congestion : Vascular congestion has been associated with poor prognosis in heart failure patients and with worsening renal function. Mullens et al. [20] observed that patients admitted with acute decompensated heart failure had central venous pressure higher than 18 mmHg at admission. This increased central venous pressure is transmitted to the renal vein with a subsequent decrease in GFR and an associated decrease in sodium excretion, decrease in renal flow, and an increase in renal interstitial pressure that is associated with tissue hypoxia [20–22]. In addition, the authors found a limited contribution of impaired cardiac index at admission in the development of worsening renal function in these patients, similar to a sub-analysis of the Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke (ESCAPE) trial, where 193 patients were treated with pulmonary artery catheter-based therapy. Although the cardiac index improved in these patients, there was no significant improvement in renal function, and there was no correlation between pulmonary wedge pressure, systemic vascular resistance, and cardiac index with serum creatinine or GFR [16].
- 3.
Increase in intra–abdominal pressure : An increase in intra-abdominal pressure equal to or higher than 8 mmHg has been associated with worsening renal function in patients with ADHF [23]. In a very small cohort, the same authors [Mullens et al.] showed that removing intra-abdominal fluid either by ultrafiltration (UF) or paracentesis is linked to improvement in renal function without a significant alteration in hemodynamic parameters [24]. The increase in intra-abdominal pressure is related to abdominal perfusion pressure (APP). Abdominal perfusion pressure is the difference between mean arterial pressure (MAP) and intra-abdominal pressure (IAP); APP = MAP − IAP [25].
Thus, patients with acute decompensated heart failure associated with congestion and who normally have a low MAP but experience an increase in IAP will have a low abdominal perfusion pressure, resulting in reduced perfusion to the abdominal organs [25]. Some studies have shown that APP is an independent predictor of adverse events in patients with intra-abdominal hypertension. An APP of at least 50 mmHg was shown to be a good predictor of survival in patients with abdominal trauma (sensitivity, 76 %; specificity, 57 %) [26].
Non-hemodynamic Factors
In addition to the hemodynamic changes seen during acute decompensated heart failure, other mechanisms have been implicated in the development of CRS type 1. Besides activation of the RAAS and SNS, other factors, including increased inflammatory response, apoptosis, and imbalance between reactive oxygen species and nitric oxide (NO) production, play a role [27]:
- 1.
Immune response : Growing evidence supports activation of the immune system as part of development of heart failure [28–30]. Similarly, abnormalities in the immune system have been proposed as part of the mechanism leading to cardiorenal syndrome. In vitro studies of patients with CRS type 1 have shown significantly higher monocyte apoptosis and activation of caspase cascade in patients with heart failure who developed acute kidney injury compared with controls. In addition, patients with CRS type 1 have higher levels of inflammatory cytokines produced by monocytes, including interleukin-16 (IL-6) and IL-18 as well as tumor necrosis factor (TNF)-α [31]. These cytokines promote renal tubular epithelium injury and death leading to tubular damage that, similar to GFR, has been associated with worsening outcomes in heart failure patients [27, 32].
- 2.
Oxidative stress imbalance : Heart failure patients have an increase in oxidative stress mediated by RAAS and SNS activation and related to a metabolic shift in the cardiomyocytes. The activation of radical oxygen species is associated with cardiac damage and is related with negative effects on contractility, ion transport, and calcium handling in the cardiomyocytes [33]. The RAAS stimulates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation that results in ROS formation. This increase in ROS generation in response to RAAS activation is also related to kidney damage. Increased oxidative stress brings a decrease in NO and an increase in vasoconstrictor molecules including cyclooxygenase-mediated production of thromboxane A2. ROS also induces tissue fibrosis by promoting mesangial cell apoptosis and cellular hypertrophy. Finally, ROS causes loss of normal epithelial cell function in the tubules. This epithelial cell dysfunction is characterized by loss of cell adhesion, disruption of tubular basement membrane, and cell migration with invasion into the interstitium. Ultimately, chronic inflammation present in patients with heart failure and kidney dysfunction leads to a vicious cycle where increased inflammatory cytokines and persistent activation of RAAS and SNS lead to a continuous production of ROS and an oxidative stress imbalance that perpetuates the damage not just in the heart but also in the kidney [17].
It appears that CRS type 2 is the result of a vicious cycle among poor hemodynamics, persistent congestion, and neurohormonal abnormalities. These chronic changes lead to an increase in vasoconstrictive mediators, altered response to vasodilators, and a persistent inflammatory process marked by elevated cytokines, apoptosis, and ROS generation as well as vascular dysfunction manifested by arterial stiffness [10, 34]. In fact, some studies have shown that patients with cardiorenal syndrome type 2 have glomerular damage with evidence of podocyte damage [35].
This cross talk between the kidneys and the heart works both ways—implying that CRS type 3 also uses pathways similar to those of CRS type 1. Thus, in the presence of acute kidney injury, there is also activation of inflammatory cascades, oxidative stress with ROS generation, and caspase-mediated apoptosis that can cause distal organ damage [36]. In the setting of acute injury, tubular epithelial cells play an active role in handling inflammatory mediators and enable them to reach the systemic circulation. In addition, the renal vascular endothelial cells initiate inflammatory responses with an increase in endothelial permeability that facilitates leukocyte infiltration of the renal parenchyma. These functional abnormalities affect leukocyte trafficking, adhesion, and tissue extravasation in other organs including the heart—causing CRS type 3 [27].
However, immune and neurohormonal factors are not the only ones that cause cardiac injury in the setting of AKI. Indirect mechanisms that can lead to cardiac injury in these patients include fluid overload caused by renal dysfunction (leading to sodium and water retention with cardiac overload, venous congestion, and hypertension that could cause myocardial dysfunction and neurohormonal activation), electrolyte imbalance that can cause arrhythmias, acidemia that can disturb the cardiac metabolism, and uremic toxins that can lead to myocardial ischemia and organ dysfunction (◘ Fig. 15.4) [37].
Fig. 15.4
Acute kidney injury (AKI) leads to a number of consequences, such as increased reactive oxygen species (ROS), which have an adverse impact on cardiac function
Diagnosis
The diagnosis of cardiorenal syndrome remains a challenge, especially in CRS type 1 where the increase in SCr sometimes reflects a preexisting kidney injury, and clinicians cannot prevent further renal injury.
Although measuring the glomerular filtration rate is commonly used to evaluate renal function, it may not adequately reflect the renal function in patients with cardiorenal syndrome. We have to remember that GFR is not reliable in acute states, given that the formulas used to estimate GFR have been validated in patients with stable renal function. In addition, other markers of renal function, such as serum creatinine, are influenced by several factors including age, sex, and muscle mass and reflect the GFR but not the tubular function. Then, using GFR or serum creatinine to assess renal function in patients with ADHF can be misleading and can sometimes lead to delay in diagnosis.
Early identification of cardiorenal syndrome certainly is important; several new biomarkers have been shown to be useful for this purpose, including neutrophil gelatinase-associated lipocalin (N-GAL) and cystatin C [3]. N-GAL is obtained using genomic and protein microarray technology [38]. It indicates accumulation of nephrotoxins and renal ischemia 48–72 h before the increase in serum creatinine is noted in children with AKI and in adults before AKI or after cardiac surgery [38–40]. More importantly, N-GAL levels correlate with the degree of renal tubular damage and also are an early marker of renal injury in children admitted to the intensive care unit [41], in patients with contrast-induced nephropathy after percutaneous intervention [42], and in patients with acute pulmonary embolism [43].
In patients with cardiorenal syndrome, N-GAL , blood urea nitrogen (BUN), and BUN/creatinine levels were found to be significantly higher compared to patients with normal renal function and heart failure, so it helps to discriminate between patients with CRS and those without renal injury [17].
Cystatin C is a cysteine protease inhibitor (non-glycosylated protein) produced at a constant rate for almost all nucleated cells [44]. Its levels are not affected by age, sex, race, or muscle mass, which makes it more reliable than creatinine [44]. Cystatin C is also freely filtered by the kidney due to its low molecular weight, and it is neither secreted nor reabsorbed in the kidney, which makes it better for estimating GFR with a greater sensitivity than serum creatinine (93.4 % vs. 86.8 %) [44, 45]. Also, cystatin C has been found to be an independent predictor of adverse cardiovascular events in heart failure patients—even in patients with preserved renal function [46]. However, although cystatin C is more accurate than N-GAL , N-GAL provides earlier estimates of renal dysfunction [47].
In addition, several markers of inflammation found in heart failure patients have also been suggested to be related to development of cardiorenal syndrome. These inflammatory markers are myeloperoxidase [48], cytokines [49], and urine IL-18 [50]. Readers are directed to a review on the topic for more information on the role of biomarkers in the cardiorenal syndrome [51].
These newly recognized biomarkers are still experimental for diagnosing cardiorenal syndrome, and the most important tool for diagnosing CRS remains the clinical assessment. This assessment should be based on the presence of either acute or chronic heart failure with preserved or reduced ejection fraction associated with biochemical findings of renal dysfunction, including elevated SCr, worsening calculated GFR, or the presence of additional findings of renal damage including proteinuria with other simultaneous biomarkers that improve accuracy of the diagnosis (Nt-proBNP and N-GAL ) [52, 53].
Management
Because patients with cardiorenal syndrome have been excluded from many heart failure trials, literature supporting appropriate management and treatment of cardiorenal syndrome is lacking and remains largely empirical. Most treatment plans focus on improving hemodynamic abnormalities and congestion (◘ Fig. 15.5).
Fig. 15.5
Treatment of cardiorenal syndrome consists of optimizing hemodynamics and maintaining effective decongestion. MAP mean arterial pressure, CO cardiac output, CVP central venous pressure
Congestion Relief
Almost half of the patients admitted with a diagnosis of heart failure present with signs and symptoms of congestion [15], which plays an important role in the development of CRS. Consequently, it is critical to accurately assess the volume status of patients presenting with heart failure and worsening renal function. However, it is also vital to understand that, for some patients, there is a disconnection between the cardiac filling pressures and the intravascular volume. In the latter case, patients will present with no significant increase in weight but with a significant increase in filling pressures, likely secondary to changes in the splanchnic venous pool. These changes are caused by a persistent sympathetic activation that leads to vasoconstriction of the venous pool with the subsequent volume shift to the systemic circulation and an increase in filling pressures [54]. When that happens, the clinician should use decongestion measures with caution to avoid intravascular volume depletion and worsening renal failure.
Regarding decongestion, several volume-control strategies have been attempted in patients with acute decompensated heart failure. These strategies include:
- (a)
Diuretics : Loop diuretics remain the most-used therapy for patients with ADHF, as demonstrated in the Acute Decompensated Heart Failure National Registry (15). Use of diuretics has been associated with improvement in symptoms, hemodynamics, and, in some cases, renal function, when they are tailored to relieve congestion [55]. However, there are not enough studies that formally evaluated the optimal dose, route of administration, and safety of diuretics. The Diuretic Optimization Strategies Evaluation in Acute Heart Failure (DOSE AHF) trial is probably the only large randomized clinical trial that evaluated the use of diuretics in heart failure patients. This trial failed to show any difference in symptoms or in change in renal function between patients who received continuous infusion vs. bolus of diuretics and those who received high dose vs. low dose [56].
The use of diuretics in ADHF has several caveats. First, some heart failure patients present with diuretic resistance, most likely due to a decrease in diuretic efficiency in the setting of a kidney dysfunction and low cardiac output that leads to poor renal perfusion. Some authors have proposed combination therapy with other diuretics like thiazides to decrease resistance and achieve progressive and gradual diuresis instead of aggressive diuresis to reduce hypovolemia [3]. Second, diuretics have been associated with worsening renal function in patients with acute decompensated heart failure and may increase the risk of complications when used in conjunction with other medications like angiotensin-converting enzyme (ACE) inhibitors [57].
Additional limitations of loop diuretics are related to neurohormonal activation mediated by an increase in RAAS activation, norepinephrine release, and electrolyte imbalance [58, 59]. Despite these limitations, recent studies like the CARRESS trial showed that stepwise pharmacological therapy with diuretics was as effective as ultrafiltration in managing congestion in ADHF patients [60]. In a post hoc analysis from CARRESS-HF and DOSE trials, neither a high dose nor a low dose of diuretics showed significant RAAS activation, and the plasma renin activity in the diuretic therapy group was lower than in the ultrafiltration group. This is important because the degree of RAAS activation has been related to worsening renal function and worse outcomes [61].
- (b)
Ultrafiltration: The main goal of ultrafiltration is mechanical removal of isotonic fluid from the venous compartment. Ultrafiltration is not associated with electrolyte imbalance or neurohormonal activation and could be beneficial in patients with diuretic resistance [62–64]. However, the role of ultrafiltration is controversial. Although some studies like the RAPID trial [65] and the UNLOAD [66] trial showed that UF can safely remove more fluid than high-dose diuretics, and with more weight loss and decrease in admissions for heart failure at 90 days, neither therapy showed a significant clinical benefit in terms of dyspnea or renal function. Ultrafiltration also was not beneficial in patients admitted to the intensive care unit with pulmonary catheter-guided therapy, and it was associated with a higher incidence of transition to renal replacement therapy and high in-hospital mortality despite improvement in hemodynamics [67]. In addition, the CARRESS-HF trial showed that the pharmacological therapy algorithm was superior to ultrafiltration for preserving renal function with less adverse events [60]. One explanation for these findings in the CARRESS-HF trial is that the ultrafiltration rate was constant in patients undergoing ultrafiltration. This could lead to transient episodes of intravascular volume depletion, which can also explain the higher levels of plasma renin activity in these patients compared those undergoing diuretic therapy [61]. Given that the results from ultrafiltration studies are contradictory, there is no clear consensus about the appropriateness of using ultrafiltration over diuretic therapy in ADHF patients.
- (c)
Vasopressin receptor antagonists: Vasopressin receptor antagonists can act on V2 and V1a receptors. V2 receptors are located in the distal tubules and collecting ducts; their function is increasing aquaporin-mediated water reabsorption [68]. V1a receptors, located in the peripheral vasculature, cause vasoconstriction [69]. Thus, V2 receptor blockers have a natriuretic effect, while V1a receptor antagonists affect the blood pressure. Tolvaptan is a V2 receptor-antagonist that was tested in the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF) [70] and Efficacy of Vasopressin Antagonism in HF Outcome Study with Tolvaptan (EVEREST ) [71] trials. In both studies, tolvaptan showed a beneficial effect on body weight loss, dyspnea, and edema as well as improvement of hyponatremia. However, there was no difference on primary end points including mortality and readmission rate for heart failure. Thus, although tolvaptan has not delivered a long-term beneficial effect in these patients, it has shown benefit in high-risk patients, including those presenting with poor prognostic factors such as hyponatremia. Conivaptan is a V1a/V2 receptor-antagonist that has shown an increase of diuresis in patients with ADHF without significant effect on blood pressure or heart rate [72]. However, despite these promising results, due to its lack of effect on mortality and heart failure readmissions, neither tolvaptan nor conivaptan has been approved for use in ADHF patients.
- (d)
Adenosine antagonists : Adenosine interacts with A1 receptors in several organs including the kidney (causing afferent arteriole vasoconstriction and tubuloglomerular feedback) and the heart (causing cardiac fibrosis and altered calcium handling) [73]. Initial studies with adenosine antagonists have shown their capacity to prevent further reduction in GFR and enhance the diuretic effect of furosemide [74]. However, the PROTECT trial did not show any benefit in reduction of primary end points, including readmission or death for heart failure, worsening heart failure symptoms, or renal impairment, and was associated with an increase in secondary effects including seizures and stroke [75]. The PROTECT trial was a placebo-controlled randomized study of the selective A1 adenosine receptor-antagonist KW-3902 for patients hospitalized with acute heart failure and volume overload to assess treatment effect on congestion and renal function .
- (e)
Natriuretic peptides: Brain natriuretic peptide (BNP ) is a native peptide available for therapeutic use (nesiritide) and commonly used for diuretic resistance. Concerns were raised about its impact on renal function and mortality, but the A Study Testing the Effectiveness of Nesiritide in Patients With Acute Decompensated Heart Failure (ASCEND-HF) trial found a lack of impact on death, rehospitalization, or renal function in patients hospitalized for acute decompensated heart failure [76, 77]. Furthermore, a substudy found that nesiritide did not increase urine output in patients with ADHF [78]. With the clinical challenge of cardiorenal syndrome and diuretic resistance, interest in natriuretic peptides remains high in light of their combination of vasodilatory and natriuretic properties [79].
Improvement of Hemodynamics
As mentioned, patients with heart failure undergo significant hemodynamic changes. These changes contribute to worsening renal perfusion and activation of inflammatory responses that lead to glomerular and tubular damage in CRS. As important as relieving congestion, improving the patient’s hemodynamics avoids worsening renal failure and breaks the vicious cycle that perpetuates kidney damage. To do so requires:
- (a)
Decreasing intra–abdominal pressure: An increase in intra-abdominal pressure is usually related to third-space accumulation of fluid leading to ascites. Therefore, paracentesis in patients with ADHF presenting with ascites has been associated with improvement in renal function and should be considered, especially in those patients refractory to medical treatment [25].
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