From "Heart and Reins" to Clinical Syndromes: Origin and Evolution of Cardio-Renal Disease.

The term “Cardiorenal syndromes” has recently been adopted to refer to the disorders of heart and kidney where acute or chronic dysfunction in one of the organs may induce acute or chronic dysfunction in the other.[12] Nonetheless, the relationship between the heart and kidney has long been recognized.[3]

In September 2008, a consensus conference on cardio-renal syndromes was held in Venice Italy, under the auspices of the Acute Dialysis Quality Initiative.[2] An expert panel reviewed available literature and produced a definition and clinical classification structure for cardiorenal syndromes. Based on the organ presumed to be the primary precipitant and the time course of progression (i.e., acute or chronic), cardiorenal syndromes were then categorized into five types: Acute CRS (type 1): acute worsening of heart function (AHF-ACS) leading to kidney injury and/or dysfunction. Chronic cardiorenal syndrome (type 2): chronic abnormalities in heart function (CHF-CHD) leading to kidney injury and/or dysfunction; Acute reno-cardiac syndrome (type 3): acute worsening of kidney function (AKI) leading to heart injury and/or dysfunction; Chronic reno-cardiac syndrome (type 4): chronic kidney disease leading to heart injury, disease, and/or dysfunction; Secondary CRS (type 5): systemic conditions leading to simultaneous injury and/or dysfunction of the heart and kidney [Table 1].

Table 1

Cardiorenal syndrome classification

Type	Definition
CRS Type I (acute CRS)	Abrupt worsening of cardiac function (e.g., acute cardiogenic shock, acute decompensation of chronic heart failure, or acute coronary syndrome) leading to acute kidney injury
CRS Type II (chronic CRS)	Chronic abnormalities in cardiac function (e.g., chronic heart failure) causing progressive chronic kidney disease
CRS Type III (acute renocardiac syndrome)	Abrupt worsening of renal function (e.g., acute kidney failure due to volume depletion or glomerulonephritis) causing acute cardiac disorder (e.g., heart failure, arrhythmia, and pulmonary edema)
CRS Type IV (chronic reno cardiac syndrome)	Chronic kidney disease (e.g., chronic glomerular disease) contributing to decreased cardiac function, cardiac hypertrophy, and/or increased risk of adverse cardiovascular events
CRS Type V (secondary CRS)	Systemic condition (e.g., diabetes mellitus and sepsis) causing both cardiac and renal dysfunction

CRS: Cardiorenal syndrome

These recent classifications are clearly articulated and very useful in diagnosing and treating patients who have developed cardiorenal syndrome from these different mechanisms. The special link between the heart and the kidneys has, however, featured in literature from a number of different societies and civilizations going back over 3500 years.

In Ancient Egypt, the value of the heart and the kidneys and probably their interaction for the passage into the afterlife was evidenced by the fact that these were the only two organs left inside the body during the process of mummification. In addition, since the blood vessels are well preserved in mummies, it has been possible to show that cardiovascular disease involving the heart and kidneys was not an uncommon finding.[4] Additionally, the first known texts that mentioned the heart and kidneys in parallel was in the Egyptian “Book of the Dead” (1600-1240 B. C.) [Figure 1], which served as a reference work to assist the deceased in the afterlife: “Homage to thee, O my heart! Homage to you, O my kidneys!”[4].

Figure 1

Luxor Book of the Dead

In the Bible, the kidneys were mentioned more than thirty times, and in five times as the organs examined by God to pass judgment on a person.[5] Kidneys were referred to as “Reins” and were believed to be the seat of longing and desire. As a consequence, they were often mentioned either before or after in parallel with the heart. Some examples are: “O Lord of hosts, that judgest righteously, that triest the reins and the heart, let me see thy vengeance on them.” (Jeremiah 11:20); “I, the Lord, search the heart, I try the reins, even to give every man according to his ways, and according to the fruit of his doings” (Jeremiah 17:10); Oh let the wickedness of the wicked come to an end; but establish the just: for the righteous God trieth the hearts and reins” (Psalm 7:9); “Examine me, O Lord, and prove me; try my reins and my heart” (Psalm 26:2).”

The ancient Chinese physicians used the Five Element theory to study the connections between the pathology and physiology of the paired (Yin/Yang) organs and tissues and the natural environment.[6] According to the theory, the qualities of Wood, Fire, Earth, Metal, and Water may be used to describe the basic elements of the material world. The heart represents fire and is a “yang” organ, whereas the kidney represents water and is considered a “yin” organ [Figure 2].

Figure 2

The Five Elements theory of traditional Chinese medicine and the relationships between the organs

In the Chinese Five Element theory, the kidney not only regulates the urinary system but also controls the endocrine, reproductive, and nervous systems. “The heart resides in the vessels. It rules the kidney network, not via a controlling position in the restraining circle of relationship between the organ networks, but simply because it is the general master of all organ networks. Before the heart fire can harmoniously blend with the kidney water, however, the kidney water must be sufficient. Otherwise the heart fire will flare out of control, and all kinds of heart and kidney ailments will arise.” (Dr. Shen's Compendium of Honoring Life [Shen Shi Zunsheng Shu], 1773).

Importantly, a disorder representing the first documented description of the cardiorenal syndrome called “Heart and kidney failing to link” was presented in the five elements network of Chinese medicine. This disorder resulted in a range of symptoms ranging from palpitations and restlessness to dark, scanty urination or nocturia, and dizziness.

Another more accurate description of cardiorenal syndrome symptoms appears in the Chinese medicine: “When the kidney fails to evaporate fluid which then floods and ascends to depress the function of heart “yang,” there may be clinical manifestations such as edema, chills, and cold limbs, accompanied by palpitations, shortness of breath, and stuffiness in the chest, indicating retained water affecting the heart.”[7]

In the middle ages, Gentilis de Fulgineo considered to be the first Western “cardio-nephrologist” in his commentary on “De pulsibus” (About Pulses) composed by Aegidius Corboliensis,[8] stressed the relationship between the fast pulse rate and urine output and the importance of heart disease on modulating the colour and output of urine [Figure 3].

Figure 3

Gentilis de Fulgineo (1272–1348)

Around 500 years later, William Senhouse Kirkes (1822–1864), an English physiologist, noted for his reference work “Kirkes' Physiology” which first appeared in 1848, reviewed 14 autopsy cases of apoplexy and diseased kidneys, of which all but one had an enlarged heart.[9] The observations of the connection between heart and kidney disease continued during the Industrial Revolution, when both Richard Bright (1789–1858) and Ludwig Traube (1818–1876) documented that cardiac hypertrophy was a common anomaly resulting from chronic renal disease.[1011]

Alfred Stengel (1868–1939), an American surgeon, first proposed a definition of “cardio-renal disease” in 1914.[12] Stengel wrote “The clinician encounters many cases, mainly in persons of middle age or older, in which evidences of cardiac weakness and other circulatory disturbances, such as high pressure, are associated with signs of failure of renal function or urinary indications of renal disease. When this combination of symptoms is of such character that the observer cannot readily assign to either the cardiovascular system or to the kidneys the preponderance of responsibility, the term “cardio-renal disease” is often employed. The term comprises cases of combined cardiovascular and renal disease without such manifest predominance of either as to justify a prompt determination of the one element as primary and important and the other as secondary and unimportant.”

After that, the evidence of the cardio-renal renal connection continued to accumulate in the medical literature. In 2003, a statement from several councils from the American Heart Association was published in hypertension and circulation emphasizing the problem of increased cardiovascular risk in patients with chronic kidney disease.[13] In 2004, at the National Heart, Lung, and Blood Institute, a working group of investigators defined the “Cardiorenal syndrome” as a state in which therapy to relieve heart failure symptoms is limited by further worsening renal function.[14]

For centuries, the relationship between the heart and kidneys has intrigued scientists and physicians. The very early metaphorical links between the heart and the kidney have now been developed into connections between these diseases in these organs, resulting in clearly defined subgroups of cardiorenal syndrome, described above. The recent definition and classification of the different subtypes of cardiorenal syndromes clarifies the connection between cardiac and renal disease and provides a clinically relevant construct to raise the awareness and prompt consideration of the management approaches.

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