**3.1 The role of nitric oxide in the Severe Cardiorenal Syndrome**

We developed a model of the SCRS based on CKD and depletion of NO availability. The rationale for these investigations was that the pathogenesis of CKD (in the presence of hypertension, diabetes or aging) is associated with low NO availability,76,77 while experimental SNX induces nephron number reduction in a healthy animal. Furthermore, in SNX, cardiac systolic function generally remains preserved, while in patients left ventricular dysfunction (LVSD) develops during the course of CKD progression.78

Reduced NO availability is considered a hallmark of CKD.46, 79 NO can function as an effector of the CRC by way of its vasodilatory action. It also modulates GFR and tubuloglomerular feedback.80 Reduced NO availability will result in tissue damage by oxidative stress. In extension to our proposal of the Cardiorenal Connection,44 we postulated that the balance between NO and ROS is a key modulator of the other cardiorenal connectors.81 Many effects of the other CRCs may be mediated by changes in the redox-balance and NO availability.82, 83

Also, it has been shown that constitutive NO production supports basal cardiac function.84 Apart from its role in endothelial dysfunction, NO availability also modulates cardiac contractility, as NO synthase (NOS) inhibition reduces cardiac output, and causes cardiac damage in high doses.85, 86

Origins of Cardiorenal Syndrome and the Cardiorenal Connection 117

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We thus hypothesized that a reduction in NO availability would accelerate the development of cardiac dysfunction. Indeed, treatment with an oral NO synthase (NOS) inhibitor (L-NNA), at a very low dose, induced NO depletion and severe cardiac dysfunction.87 Furthermore, proteinuria, severe glomerulosclerosis and cardiac interstitial fibrosis were worsened compared to rats with CKD without NOS inhibition. Another remarkable finding was that the effects on cardiorenal dysfunction but also on systemic NO production were irreversible after cessation of the NOS inhibitor, during a 7 week follow-up. A five times higher dose of NOS inhibition in control rats, which caused a similar level of hypertension and NO depletion, induced LVSD that was not as severe as in the CRS rats. Furthermore, all effects on blood pressure, cardiac function and NO availability were completely reversible, and had no effect on kidney structure and function. Combining NOS inhibition with SNX also, worsened kidney injury. The more severe hypertension and direct effects of NOS inhibition may have played a role in this.

We concluded that during CKD development the heart is very sensitive to depression of systemic NO availability. Compared to the normal kidney, the damaged kidney is more sensitive to alterations of NO availability as well, possibly because of a loss of autoregulation.88 Thus, maintaining adequate NO availability appears to be very important for progression of cardiorenal failure during progression of CKD, and the combination of CKD and NO depletion appears to produce a functional model of the SCRS in which cardiac function is further compromised.

That supplementation of NO is useful as a rescue therapy was shown in a subsequent study, where treatment with the oral tolerance-free NO donor molsidomine (MOLS) significantly improved cardiac diastolic and systolic function, abrogated mortality, and also slightly improved kidney function and injury.89 The cardiac effect of MOLS appeared to be a combination of reduced cardiac loading and improved contractility and relaxation. Systolic blood pressure was only mildly reduced and GFR was even slightly improved. Thus, MOLS appears to be an attractive and safe therapeutic option for CKD patients suffering from cardiac dysfunction of non-ischemic origin. The pathophysiology of the continuing low NO production in this model is likely very complex and may include low NOS expression or activity, substrate deficiency, high oxidative stress levels, and increased amounts of endogenous NOS inhibitors.79

In conclusion, the cardiorenal connection has intrigued scientists and physicians for centuries. The existence of a specific cardiorenal syndrome has been suggested since the start of the 20th century, but has recently gained widespread attention in the scientific literature. We proposed the Severe Cardiorenal Syndrome, in which CKD and HF induce derangements to cause a vicious cycle of cardiovascular damage and progression of failure of both organs. Understanding of pathophysiological mechanisms is expanding and animal models provide an invaluable tool to investigate the bidirectional nature of cardiorenal interactions.

#### **4. References**

[1] Parfrey PS, Harnett JD, Barre PE. The natural history of myocardial disease in dialysis patients. *J Am Soc Nephrol* 1991;2:2-12.

We thus hypothesized that a reduction in NO availability would accelerate the development of cardiac dysfunction. Indeed, treatment with an oral NO synthase (NOS) inhibitor (L-NNA), at a very low dose, induced NO depletion and severe cardiac dysfunction.87 Furthermore, proteinuria, severe glomerulosclerosis and cardiac interstitial fibrosis were worsened compared to rats with CKD without NOS inhibition. Another remarkable finding was that the effects on cardiorenal dysfunction but also on systemic NO production were irreversible after cessation of the NOS inhibitor, during a 7 week follow-up. A five times higher dose of NOS inhibition in control rats, which caused a similar level of hypertension and NO depletion, induced LVSD that was not as severe as in the CRS rats. Furthermore, all effects on blood pressure, cardiac function and NO availability were completely reversible, and had no effect on kidney structure and function. Combining NOS inhibition with SNX also, worsened kidney injury. The more severe hypertension and direct effects of NOS

We concluded that during CKD development the heart is very sensitive to depression of systemic NO availability. Compared to the normal kidney, the damaged kidney is more sensitive to alterations of NO availability as well, possibly because of a loss of autoregulation.88 Thus, maintaining adequate NO availability appears to be very important for progression of cardiorenal failure during progression of CKD, and the combination of CKD and NO depletion appears to produce a functional model of the SCRS in which cardiac

That supplementation of NO is useful as a rescue therapy was shown in a subsequent study, where treatment with the oral tolerance-free NO donor molsidomine (MOLS) significantly improved cardiac diastolic and systolic function, abrogated mortality, and also slightly improved kidney function and injury.89 The cardiac effect of MOLS appeared to be a combination of reduced cardiac loading and improved contractility and relaxation. Systolic blood pressure was only mildly reduced and GFR was even slightly improved. Thus, MOLS appears to be an attractive and safe therapeutic option for CKD patients suffering from cardiac dysfunction of non-ischemic origin. The pathophysiology of the continuing low NO production in this model is likely very complex and may include low NOS expression or activity, substrate deficiency, high oxidative stress levels, and increased amounts of

In conclusion, the cardiorenal connection has intrigued scientists and physicians for centuries. The existence of a specific cardiorenal syndrome has been suggested since the start of the 20th century, but has recently gained widespread attention in the scientific literature. We proposed the Severe Cardiorenal Syndrome, in which CKD and HF induce derangements to cause a vicious cycle of cardiovascular damage and progression of failure of both organs. Understanding of pathophysiological mechanisms is expanding and animal models provide an invaluable tool to investigate the bidirectional nature of cardiorenal

[1] Parfrey PS, Harnett JD, Barre PE. The natural history of myocardial disease in dialysis

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inhibition may have played a role in this.

function is further compromised.

endogenous NOS inhibitors.79

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**8**

*Canada* 

**Sub-Types and Therapeutic**

Margot Davis and Sean A. Virani

*University of British Columbia* 

**Management of the Cardiorenal Syndrome** 

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

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

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

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

dysfunction occurs and the time course of disease development/progression.

**1. Introduction** 

disease or primary renal disease.

cohorts.

