**3. Previous research on the cardiorenal interactions**

In a recent comprehensive review in *Circulation,* Bock and Gottlieb10 state that:

"…each dysfunctional organ has the ability to initiate and perpetuate disease in the other organ through common hemodynamic, neurohormonal, and immunological/ biochemical pathways." They also write: "…our understanding of the complex physiological, biochemical, and hormonal derangements that encompass the CRS is woefully deficient…".

Despite general acknowledgement of the adverse prognosis of concurrent cardiac and renal disease, many clinicians and researchers are skeptical about the true existence of a specific heart-kidney interaction that goes beyond known physiological interactions. Thus the question was raised whether kidney disease and heart disease simply co-exist or that they indeed worsen each others progression. Clinical studies can not provide the answer to this

of the CRC. The connectors have a modulating effect on hemodynamic control but can also induce cardiovascular damage, thereby mediating further functional deterioration.44 We proposed that activation of the CRC leads to a vicious cycle in which all the connectors become disturbed, synergize and further activate each other. This ultimately results in

A shift in the balance between NO and ROS towards ROS is a central event in many cardiovascular diseases.45 In the SCRS, the balance between NO and the ROS is skewed towards the latter by increased production of ROS, a low anti-oxidant status, and lower availability of NO.46 In the cardiorenal connection, this imbalance may influence sympathetic nervous activity,47 release of renin and angiotensin,48 and promote

Sympathetic nervous activity is also increased in both renal and heart failure. By affecting the other cardiorenal connectors it can play a significant role in the SCRS. It stimulates renin release from the kidneys,50 generates ROS which induces vascular wall growth,51 and

The RAS is activated in both renal and heart failure 53, 54 and angiotensin II affects the other cardiorenal connectors in different ways. It activates the SNS in both heart and kidney failure,55, 56 it generates ROS via nicotinamide adenine dinucleotide phosphate (NADPH)-

Persistent inflammation has been found in both renal and heart failure. By altering the functioning of the RAS,59 and promoting ROS60 and noradrenaline formation,61 inflammation can contribute to the positive feedback loops in the cardiorenal connection. The Severe Cardiorenal Syndrome is thus not a syndrome in which cardiac and renal failure simply co-exist side-by-side. Cardiac and renal failure are intimately linked by the cardiorenal connectors, because failure of either organ can excite the cardiorenal connectors, but the connectors themselves also affect the structure and function of both organs.

oxidase,57 and activates pro-inflammatory gene expression via nuclear factor-κB.58

Logically, the cardiorenal connectors become more pronounced in combined failure.6

"…each dysfunctional organ has the ability to initiate and perpetuate disease in the other organ through common hemodynamic, neurohormonal, and immunological/ biochemical pathways." They also write: "…our understanding of the complex physiological, biochemical, and hormonal derangements that encompass the CRS is

Despite general acknowledgement of the adverse prognosis of concurrent cardiac and renal disease, many clinicians and researchers are skeptical about the true existence of a specific heart-kidney interaction that goes beyond known physiological interactions. Thus the question was raised whether kidney disease and heart disease simply co-exist or that they indeed worsen each others progression. Clinical studies can not provide the answer to this

In a recent comprehensive review in *Circulation,* Bock and Gottlieb10 state that:

**3. Previous research on the cardiorenal interactions** 

worsening of both cardiac and renal damage and failure.

inflammation by oxidative modification of substances.49

**2.1 Summary of the Cardiorenal Connection** 

induces inflammation.52

woefully deficient…".

question because they are observational, lack histological end-points, and are confounded by selection bias, inconsistent definition of end-points, and medication use. Therefore, further exploration of the mechanisms of cardiorenal interactions must rely on animal studies, in which timing and severity of the disease are controlled, progression of disease can be followed, and histological end-points are assessed.

Much of what we know today on the structural cardiac consequences of chronic kidney disease results from the extensive research in rats with CKD by the group of Kerstin Amann and Eberhard Ritz in the late 80's and early 90's.62 Despite numerous cardiac changes, in the rat CKD model of subtotal (5/6th) nephrectomy (SNX) cardiac systolic function is generally maintained.63, 64 Conversely, after MI by ligation of the left coronary artery in rats, renal histological damage or proteinuria is absent although glomerular filtration rate (GFR) may be decreased.65, 66 Thus, it appears that both organs need to be affected to cause acceleration of damage and failure typical for the CRS. Only two animal studies investigated the effect of 'dual damage' to heart and kidneys, with MI following shortly after a renal insult in rats, with conflicting results.65, 67 Different models of nephrectomy exist in mice, but these are not as robust as those in rats, with variable changes in renal function and cardiac abnormalities.68-72

The renal hemodynamic response to heart failure (HF) induced by pacing in dogs has also been investigated,73-75 but whether there is histological damage is unknown. Furthermore, there is no proven model of CKD in dogs. Taken together, there is still a paucity of models that investigate the interaction between kidney and heart failure in a chronic set-up with integrated physiological and histological assessment. From the available data, combining the SNX model of CKD and the coronary ligation model of HF appears to be the most robust option to investigate the SCRS.
