Experimental models of cardiorenal syndrome: from basic science to the clinic

the interaction between the heart and the kidney is well known. Congestive cardiac failure can be tied to acute renal failure with prerenal origin or, if it is sustained in time, to renal failure. Chronic cardiac disease and chronic kidney disease can both lead to chronic disturbances in the other organ. Lindner et al. published work describing the association between hemodialysis and accelerated atherosclerosis (1). Although the existing relationship between renal failure and cardiovascular risk has been overlooked until recently, it has now become one of the most important issues in nephrology (24). Five types of cardiorenal syndrome have recently been identified—from acute to chronic cardiac and renal conditions (5).

The Acute Dialysis Quality Initiative (ADQI) consensus conference elaborated an executive summary of these cardiorenal syndromes (5). In 1998, a group of experts from the National Kidney Foundation reported an important increase in mortality among patients undergoing dialysis compared with the general population (6). For this reason, different groups of experts recommend that patients with chronic kidney disease (CKD) be considered at high risk for cardiovascular disease (ECV) (6).

Sarnak et al. reported that not only is ECV associated with CKD but also that in patients with CKD the mortality with associated ECV is increased in relation to their base renal pathology (7). This relatively high mortality risk increased several hundredfold compared with the mortality of young patients in the general population and patients of the same age in a hemodialysis program (8). The increase in detection of CKD combined to ECV is a new area of interest in epidemiology, especially in developed countries (7,8).

The definition of CKD (9,10) is important not only with regard to early detection, but also in its association to ECV risk. Therefore, the definition has been associated with renal alterations in the analysis of the patient’s cardiovascular risk (11,12). Compared with the general population, CKD patients have an increase in the prevalence of myocardial ischemic disease, left ventricular hypertrophy, and congestive cardiac failure (10,11). In patients on hemodialysis or peritoneal dialysis, the prevalence of heart disease is approximately 40 percent and 75 percent, respectively, with an annual cardiovascular mortality rate of 4–5 percent. Also well known is the relation between calcification and several nontraditional risk factors (e.g., vitamin D status, activation of the renin-angiotensin-system and cardiovascular risk in CKD) (13,14).

Development of an experimental animal model to study the physiology of the cardiorenal axis and to assess and develop new therapeutics is needed. This review focuses on the major animal models currently used to investigate the cardiorenal axis.

Experimental models

We reviewed four experimental models that analyze the cardiorenal axis in wild type animals and three models of genetically modified (knockout) animals. In a study by Dikow et al., partially nephrectomized rats’ left coronary arteries were ligated for 60 min, followed by reperfusion for 90 min. The researchers measured the nonperfused risk area (total infarction plus penumbra) and the area of total myocardial infarction (MI). They found that a greater proportion of nonperfused myocardium undergoes total necrosis, which is consistent with the hypothesis of reduced ischemic tolerance of the heart in renal failure, independent of hypertension, sympathetic activation, or salt retention, and that these findings could explain the high rate of death from MI in patients with impaired renal function (16).

Van Dokkum et al. studied the effects of MI on mild renal function loss in unilateral nephrectomized rats with sham animals as controls. The rats were separated into two groups according to MI size; less than 20 percent was considered a small MI and greater than 20 percent a moderate MI. There were no animals with MI over 40 percent. In the first experimental group, proteinuria was 55.5 mg/day. In the second group, it was 124.5 mg/day, demonstrating how renal injury due to MI was accelerated. Left ventricular pressure correlated with proteinuria (16). On the other hand, it is clear that microalbuminuria is an independent cardiovascular risk factor, even in the range considered appropriate. Microalbuminuria is a window from the kidney to the vascular system and reflects more than the renal disease; it can reflect generalized endothelial dysfunction or the beginning of vascular remodeling (17).

Van Dokkum et al. also looked at an experimental model of renal damage induced by 5/6 nephrectomy plus a ligature of the coronary artery a week after surgery. They evaluated endothelium-dependent relaxation to acetylcholine in vitro in small arteries isolated from the extirpated 5/6 nephrectomy. After the MI, the nephrectomized rats gradually developed proteinuria in a range varying from 20 to 507 mg/day at week 16, with an average systolic blood preassure of 131±7 mm Hg. They found that individual renal endothelial function of the healthy rats predicted the extent of renal damage in terms of proteinuria (r = -0.62, p = 0.008) and focal glomerulosclerosis (r = -0.70, p = 0.003) (18).

Fedulov et al. studied serum levels of TGF

β1 and TNFβ in rats with cardiac fibrosis during chronic renal failure. They performed a unilateral nephrectomy and electrocoagulation of 25 percent of the cortex of the remnant kidney. The cardiac collagen correlated with both serum TGFβ1 levels and time from onset of follow-up at two, four, and six months (19). Finally, Wong et al. evaluated whether mild and severe renal failure shortens cardiac telomeres and excessively shortens telomeres after MI in rats subjected to sham, unilateral, or 5/6 nephrectomy to induce no, mild, or severe renal failure, and left coronary artery ligature to induce MI. They concluded that severe renal failure, but not mild renal failure, leads to shortening of cardiac telomeres to a similar extent as found after MI, and that renal failure did not induce excessive telomere shortening after MI (20).

Brymora et al. assessed the systemic inflammatory response (defined as the seric haptoglobin level), local inflammation (through use of monocytes chemoattractant protein MCP-1 levels), and the arterial response to phenilephrine in different stages of renal failure. For this purpose they performed a nephrectomy in rats divided into four groups: control, half nephrectomy, 3/5 nephrectomy, and 5/6 nephrectomy. The investigators found a lower arterial contraction in the 5/6 nephrectomized group. Systemic inflammation was evident in the half nephrectomized group with no evidence in the advanced stages of renal desease. Local inflammation increased progressively with renal failure.

It is clear that inflammation affects smooth muscle cells of the vessels and plays a key role in the final vascular tone (21). We proposed a rat model in three stages: First we perfomed a 5/6 nephrectomy in the left kidney; a week later, nephrectomy of the contralateral kidney; and finally, a ligature of the coronary artery to achieve mild MI. Sham controls in each group underwent the same technique as treated rats. It would be interesting to study the cardiorenal axis with different levels of renal insufficiency and with and without myocardial infarction (22,23).

There are three transgenic models in mice: knockout (KO) apolipoprotein E (APOE-/-) mice with accelerated atherosclerosis in uremia (24), KO mice for the LDL receptor (LDL-/-) (25), and AT1 KO mice (26).

In the first two models, APOE-/- and LDL-/-, hyperphosphatemia and vascular calcification was found, and animals with chronic renal disease had a worse prognosis. Those treated with bone morphogenetic protein-7 (BMP-7) in the LDL model improved (25).

The third model of Li et al. assessed the molecular pathway mediated by AT1A in cardiac dysfunction and renal dysfunction. They used wild mice and AT1 KO mice. In both cases they performed a 5/6 nephrectomy. The observed effects in the wild group (hypertrophy, dilatation, fibrosis, and a reduction in the capillary density) were significantly less important in the AT1 KO group. The valsartan treatment in the wild type mice improved the cardiac function to a level as good as that in the AT1 KO group (26).

Increasing evidence links the kidney and the heart through different humoral stimulus.This has not only been proven at an experimental level, but also in day-to-day clinical pratice. A better understanding of this tight relationship and consideration of the kidney and the heart as an axis will allow future development of drugs that can intervene in such an axis in an integrated way, thus achieving a more rational therapeutics of the cardiorenal and renocardial conditions that affect thousands of patients worldwide. The goal of these experimental models is to find the underlying mechanism enabling improved protection for both kidneys and heart.

Susana Pérez, Alejandro Bernasconi, and C. Jordi Bover are with the Fundació Puigvert, Universidad Autónoma de Barcelona, Spain. Carlos Musso is with the nephrology division, Hospital Italiano de Buenos Aires, Argentina.



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