Fig. 27.1
Increasing number of publications in PUBMED regarding cardiorenal syndrome
The term syndrome derives from the Greek συνδρομή (sundromē) that means “concurrence of symptoms, concourse” and reflects the presence of various common disorders. Although no genetic factors that encompass all traits of the syndrome have been identified, synergism between two epidemiologic trends may support the construct of the CRS, namely the population ageing and the epidemics of obesity and diabetes.
In the entirety of recorded human history, the world has never seen as aged a population as currently exists globally, and the UN predicts that the rate of population aging in the twenty-first century will exceed that in the 20th. Population aging has profound implications for many facets of human life affecting simultaneously the cardiac and renal function. Elderly individuals have the highest incidence of coronary heart disease and hypertension, which constitute the two most powerful risk factors for heart failure. The prevalence of CKD also rises dramatically with age. Based on the results of the NHANES 1999–2004, more than one-third of those aged 70 or older have moderate or severe CKD defined as an eGFR <60 ml/min/1.73 m2. Thus, parallel aging of the cardiovascular system and the kidney is at least in part the common soil for CRS in our time.
In addition, overweight and obesity have grown to pandemic proportions in industrialized countries during the past 50 years. For example, from 1960–1962 to 2005–2006, the prevalence of obesity increased from 13.4 to 35.1 % in U.S. adult age 20–74. Obesity increases the likelihood of type 2 diabetes, whose incidence is increasing in correlation with the rise in obesity. The American Diabetes Association estimates that about 21 million people have diabetes, with another 54 million people diagnosed with pre-diabetes. Diabetic patients carry an increased risk of coronary heart disease, hypertension, heart failure and nephropathy, in other words components of the CRS [6, 7].
Despite inconsistencies in the definition of anemia cases, most studies indicate that the prevalence of anemia is increased in CHF populations with co-existing kidney disease, advanced age, hypertension and more severe symptoms (range, 30–61 %) when compared with less symptomatic ambulatory populations (range, 4–23 %). Of note, even in patients with CHF and preserved ejection fraction, who represent the most common form of heart failure in westernized cultures anemia is also highly prevalent.
Since obesity and diabetes seem to be the driving force behind the development of heart disease and CKD, conditions with high prevalence of anemia, the term CRS has been enriched by many researchers to encompass anemia (cardiorenal anemia syndrome, CRAS) and metabolic syndrome (cardiorenal metabolic syndrome), in an effort to improve the practical utility, as a diagnostic and management tool among cardiologists, endocrinologists, nephrologists, hematologists and intensivists [8, 9].
Various pathophysiological pathways link cardiac and renal function and mediate clinical outcomes in CRS, including sympathetic and the renin-angiotensin aldosterone axis activation, vasopressin oversecretion, nitric oxide bioavailability, inflammation and overproduction of reactive oxygen species [10]. This very complex interaction of various processes is reflected in the great diversity of biomarkers used for detection of the concurrent kidney injury and heart failure by Palazzuoli et al. [11]:
NT-proBNP. BNP: Hemodynamic overload, neurohormonal activity. Troponins: Myocardial injury, hemodynamic overloads KIM-1, NGAL: Ischemia and nephrotoxins. NHE 3: Ischemia, pre-and post renal acute kidney injury. Cytokines (IL-6, 8, 18): Delayed graft function inflammatory activity. Actin, actin depolymerizing factor: Ischemia and delayed graft function. Cystatin-C: proximal tubule injury.
Among various therapeutic modalities introduced to interrupt those pathways and modulate morbidity and mortality, inactivation of rennin angiotensin system (RAS) has emerged, as the cornerstone treatment decision introduced by major guideline developers in cardiovascular, renal and endocrine medicine. An almost unexplored idea is that RAS inhibition, although benefiting heart failure, further deteriorates renal function and anemia in patients with CRS. If we accept this basic idea then wide use of RAS inhibition in large subsets of patients may be considered an iatrogenic cause of CRS with anemia.
27.2 RAS Inhibition May Further Deteriorate Renal Function in the Cardiorenal Syndrome
RAS inhibition has provided a major improvement in the management of CHF, resulting in both amelioration of symptoms and an increase in survival. In addition, angiotensin converting enzyme (ACE) inhibitors (ACEi) or angiotensin receptor blockers (ARB) are recommended for primary prevention of HF in patients with coronary artery disease, peripheral vascular disease, stroke, and diabetes with another major risk factor, such as smoking or microalbuminuria. RAS inhibition is also recommended for patients with reduced LVEF, regardless of symptoms.
RAS inhibition has been shown to be effective in slowing the progressive decay of GFR in diabetic nephropathy in both diabetes mellitus type 1 and type 2, as well as in non-diabetic individuals with CKD and proteinuria >1,000 mg/day. Intense RAS blockade in subjects with cardiovascular disease and relatively preserved renal function by a combination of high-dose ACE inhibitor and ARB therapy worsened GFR despite improving proteinuria in the ONTARGET study [11]. A high burden of renal vascular atherosclerosis, preexisting CKD not revealed by serum creatinine or both may have contributed to these outcomes. Of note, RAS inhibition in patients with CRS has not been established as yet to be renoprotective. On the contrary, RAS inhibition could further deteriorate renal function in CRS and somehow diminish the beneficial effect anticipated from the studies in patients with CHF.
Animal studies by several laboratories, most notably that of B. Brenner, have revealed that the glomerular capillary pressure and proteinuria depends on arterial perfusion pressure and the constriction of efferent arteriole, the dominant site of angiotensin II action. Consequently, RAS inhibition exerts its renoprotective effect by reducing arterial pressure and relaxing the efferent arteriole. These effects of RAS inhibition on renal hemodynamics vary widely depending on the preexisting physiologic and pathologic state of the kidneys. RAS inhibition is usually well tolerated in patients with normal cardiac function or mild heart failure and preserved renal perfusion. However, in cardiac patients with moderate-to-severe heart failure or systemic hypotension and sodium and fluid depletion due to high dose diuretic therapy, renal perfusion pressures may already be at or near the autoregulatory breakpoint and GFR could be maintained due to angiotensin II-mediated selective vasoconstriction of the efferent arteriole of the glomerulus. Complete or sustained RAS inhibition with the longer-acting agents regularly administered in our days in cardiac patients may be detrimental to renal function, especially if coexisting renal impairment exists, in other words in patients with CRS [12, 13].
Although ACEi and ARBs are not nephrotoxic drugs per se, they must be used with extreme caution because severe hyperkalemia and acute deterioration of renal function may occur in patients with CRS. In the management of such patients, especially if the eGFR is less than 30–40 mL/min/1.73 m2, it is of paramount significance to commence these agents with the smallest dose and carefully and slowly titrate the dose to the highest dose tolerated. However, many physicians still rely on serum creatinine, as an index of renal function, and not on the considerably more precise estimates of the GFR and therefore, tend to underestimate the severity of renal dysfunction, particularly in elderly women, who may have severely compromised renal function despite a serum creatinine concentration within the normal range. Those physicians usually prescribe ACE inhibitors or ARBs in the “recommended” dosage. As a result, a vicious cycle begins to operate because the higher the RAS inhibition, the worse the deterioration of the renal function, leading to even higher accumulation of the ACEi or ARBs administered [14].
27.3 RAS Inhibition May Increase Incidence of Anemia in Cardiorenal Syndrome
The discovery of ACEi and ARB’s at the beginning of 80s and 90s, respectively, and the finding that RAS inhibition reduces morbidity and mortality in patients with CHF, created the basis for most authorities worldwide to develop guidelines introducing this type of therapy, as the cornerstone therapy in CHF. Despite the inconsistencies in the definition of anemia cases, most studies indicate that the prevalence of anemia is increased in CHF populations with co-existing kidney disease, the so called CRS, advanced age, and more severe symptoms (range, 30–61 %) when compared with less symptomatic ambulatory populations (range, 4–23 %). Anemia is more common in CHF than could be accounted for by age or the degree of renal dysfunction. The few published reports in patients with CHF and preserved ejection fraction indicate that anemia is also highly prevalent. In most cases of anemia in heart failure no specific etiology can be found [15–17].
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