**1. Introduction**

122 Chronic Kidney Disease

[87] Bongartz LG, Braam B, Verhaar MC, Cramer MJ, Goldschmeding R, Gaillard

kidney disease. *Am J Physiol Regul Integr Comp Physiol* 2010;298:R815-R823. [88] Bidani AK, Schwartz MM, Lewis EJ. Renal autoregulation and vulnerability to hypertensive injury in remnant kidney. *Am J Physiol* 1987;252:F1003-1010. [89] Bongartz LG, Braam B, Verhaar MC, Cramer MJ, Goldschmeding R, Gaillard CA*, et al.*

2010; 299:H2037-H2045.

CA,Doevendans PA, Joles JA. Transient nitric oxide reduction induces permanent cardiac systolic dysfunction and worsens kidney damage in rats with chronic

The Nitric Oxide Donor Molsidomine Rescues Cardiac Function In Rats with Chronic Kidney Disease and Cardiac Dysfunction. *Am J Physiol Heart Circ Physiol*

> Cardiorenal syndrome (CRS) describes the inter-relationship and complex pathophysiological processes by which dysfunction of either the heart or the kidneys is related to dysfunction in the other organ system. Historical definitions may have been overly simplistic; newer definitions have tried to capture the complex interactions and feedback processes which exist between the two organs. These definitions classify the CRS into five discrete categories, based on both the organ system in which the primary dysfunction occurs and the time course of disease development/progression.

> The CRS is more common than many clinicians realize. Over one third of patients in heart failure (HF) registries have evidence of renal dysfunction, and a similar proportion of dialysis patients have symptoms of congestive HF or clinical evidence of left ventricular dysfunction (Adams et al., 2005; Stack & Bloembergen, 2001). Importantly, the presence of the CRS is a strong adverse prognostic marker in patients with either primary cardiac disease or primary renal disease.

> While originally thought to reflect renal hypoperfusion secondary to low cardiac output, it is now understood that the CRS is underpinned by far more complex processes. From a hemodynamic standpoint, it seems likely that venous congestion is at least as important to the pathophysiology of disease progression as is low forward flow. Other contributing factors include activation of neurohormonal axes, including the sympathetic nervous system and the renin-angiotensin-aldosterone system, as well as oxidative injury and endothelial dysfunction (Bock & Gottlieb, 2010). More recently, it has become recognized that anemia may also be intimately involved in the process, both as a consequence and as a causative agent of the CRS. Finally, it is well recognized that many common risk factors for cardiovascular disease and for chronic kidney disease (CKD) co-exist in these patient cohorts.

> Management of the CRS is challenging. Therapies for HF often cause worsening of renal function, while treatment of renal failure commonly involves fluid administration, which may precipitate disease decompensation among those with HF. Unfortunately, most large randomized trials in the HF population have excluded patients with elevated serum creatinine levels, and there is little evidence to guide therapy in this group of patients. Observational studies suggest that there may be a mortality benefit associated with the use

Sub-Types and Therapeutic Management of the Cardiorenal Syndrome 125

Pathophysiologically, Type 1 CRS is characterized by decreased cardiac output with impaired renal perfusion as well as elevated central venous pressures and acute renal edema. Renal ischemia may be mediated by decreased oxygen delivery due to impaired myocardial contractile performance, elevated interstitial pressures in the renal medulla and by peripheral/systemic vasoconstriction which occurs as a compensatory mechanism in the

Historically, decreased forward cardiac flow was thought to be the primary determinant for AKI in this context, however recent clinical trials have suggested this mechanism may not be as important in the development of CRS Type I as previously hypothesized. Specifically, data from ADHERE (Acute Decompensated Heart Failure National Registry) which included over 100,000 patients admitted to hospital in the United States with acute decompensated heart failure (ADHF) showed that <2% of patients had systemic hypotension, a surrogate for low cardiac output, while the vast majority of patients had symptoms/signs of volume overload (Adams et al., 2005). This is corroborated by the findings of the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) Trial in which 433 patients admitted to hospital with ADHF were randomized to pulmonary artery catheterization versus standard care to assess the efficacy of tailored haemodynamic therapy (Binanay et al., 2005). In the ESCAPE Trial, cardiac index was not associated with baseline renal function or deterioration in renal function, however right atrial pressure was weakly correlated with baseline creatinine and

The impact of central venous pressures (CVP) on worsening renal function in the setting of ADHF has been receiving greater attention in recent years. Elevated CVP is more predictive of a decline in renal function than other relevant haemodynamic variables such as cardiac index, blood pressure and pulmonary capillary wedge pressure (Mullens et al., 2009). Moreover, elevated CVP predicts risk of re-hospitalization for HF and death suggesting that it is a potent prognosticator for poor outcomes and a potential target for therapy (Uthoff et al., 2011). Elevated intra-abdominal venous pressures have also been shown to have a similar relationship with GFR at baseline and changes in GFR with therapy (Bock & Gottlieb, 2010; S. E. Bradley & G. P. Bradley). This may be the result of a direct mechanical

Among patients with ADHF, activation of the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS) is a homeostatic mechanism intended to maintain intraglomerular perfusion pressures and preserve GFR. Paradoxically however, systemic vasoconstriction by these mechanisms increases cardiac afterload leading to further decline in cardiac output and renal blood flow. Additionally, these neurohormones have a maladaptive effect on the myocardium resulting in fibrosis and ventricular remodeling. Treatment with β-blockers is relatively contra-indicated in the face of an acute decompensation due to their negative inotropic effects and the relative dependence of cardiac output on heart rate in this patient population; therefore, SNS activation in CRS Type 1 may remain unchecked leading to ischemia of both renal and cardiac tissue beds.

Acute administration of RAAS inhibition may exacerbate renal injury in CRS Type 1 by reducing pressure in Bowman's capsule; this effect may be magnified in the presence of volume shifts associated with diuretics, which remains the mainstay of therapy. Moreover, diuretics may directly result in additional neurohormonal activation and there is now an

effect on renal blood flow or simply a reflection of elevated CVP.

face of low cardiac output.

GFR (Nohria et al., 2008).

of standard HF medications, such as angiotensin converting enzyme inhibitors, angiotensin receptor blockers and beta blockers in patients with HF and CKD, regardless of glomerular filtration rate (GFR) (Berger et al., 2007; Cice et al., 2003).

Many novel therapies for HF have been introduced over recent years, several of which were appealing for treatment of the CRS, given the pathophysiological processes towards which they were directed. Unfortunately, natriuretic peptides, vasopressin antagonists, and adenosine antagonists have all failed to show meaningful clinical benefits in patients with HF (Hernandez, 2010; Konstam et al., 2007; Massie et al., 2010). Other approaches, particularly peripheral ultrafiltration, have shown more promise in this patient population (Costanzo et al., 2005).
