On the central role of studies on the kidney in the recognition, conceptual evolution, and understanding of hypertension

The beginning 

The existence of elevated blood pressure had long been surmised from the strength of the pulse. The importance of palpating the pulse as an essential feature of evaluating a patient is described in most recorded medical texts of Antiquity. Monograms elaborating on the intricacies and meaning of changes in the pulse began to appear in the Greco-Roman period, were elaborated upon in Arabic medicine, perpetuated by various authors throughout the Renaissance and Enlightenment, and continued to be published through the Modern period. Methods of making a rough estimation of the arterial pressure by palpating the pulse with 3 or 4 fingers were taught in medical schools well into the 20th century. Indeed, William Osler (1849–1919) had to embark on a campaign to replace it with the mercury manometer that had been introduced in 1896.1, 2

Of all the references to hypertension in the pulse lore of the past, perhaps the most perceptive is that in The Yellow Emperor’s Classic of Internal Medicine: “One should feel the pulse at the place of the cubit…in order to distinguish a gentle pulse and one of low tension from a hard and bounding pulse (Book 2)…The heart is in accord with the pulse…The heart rules over the kidneys…Hence if too much salt is used in food, the pulse hardens, tears make their appearance, and the complexion changes (Book 3)…When the pulse is abundant but tense and hard and full like a cord, there are dropsical swellings (Book 5)…Now one can repress the disease and can administer drugs. If a cure is not achieved the kidneys will pass on the disease to the heart. The muscles (sinews, nerves) and the arteries (veins, pulse) will disunite from each other and an acute illness will develop, which is called convulsions (Book 6).”1 These selected and edited quotes from Chinese medicine, when considered in light of our current understanding of hypertension, which is always a risky undertaking, provide considerable insight into the medical wisdom, accrued over centuries of clinical observation, even when initially tainted by omens and divinations, about a disease that remained unidentified.

Technological foundations 

Actual measurements of arterial pressure with intricate devices began to be introduced in the 17th century, as instrumentation became an integral component of the Scientific Revolution. Reported in qualitative terms, their full significance was not understood. These observations were not limited to medicine. As a stroll through almost any museum reveals, the force with which blood gushes out from the arteries in depictions of beheadings by various artists clearly reflects a reasonable lay notion of arterial pressure.

Stephen Hales (1677–1761) was the first to subject the circulation to hydrostatic laws and coin the term “blood pressure,” when, in 1711, he began a series of experiments measuring intra-arterial pressure in various animals, which he published in his Statical Essays in 1733. Contrary to the popular, but erroneous, illustration showing his recording of the blood pressure from the carotid artery of a horse, he actually measured the pressure by inserting a glass tube into the femoral artery. The subsequent history of devices to measure blood pressure has been recorded in detail and will not be retold here, except to mention 2 devices that stand out. The kymograph, introduced in 1847 by Carl Ludwig (1816–1895), was a multipurpose apparatus devised to trace hemodynamic changes that became a classic experimental tool in physiological studies on hypertension. The transmission sphygmograph, introduced in 1860 by Etienne J. Marey (1830–1904), was the forerunner of indirect of blood pressure measurement techniques and led to the first clinically useful sphygmomanometer by Scipione Riva-Rocci (1863–1937) in 1896.1, 2, 3

The middle: the 19th century 

Clinical research began in earnest in the first half of the 19th century, when hospital-based physicians began to define disease on the basis of postmortem findings that were correlated with the clinical course of the patient. This hospital-based medicine, which began in Paris, was soon imported to England, where Richard Bright (1789–1858), beginning in 1820 and through 1842, concentrated his research on diseases of the kidneys at Guy’s Hospital in London. Apart from differentiating dropsy associated with heat-coagulable urine and diseased kidneys from its other causes and, thereby, pioneering the very creation of nephrology as a specialty of medicine, his work provided the stimulus for the unfolding of the story of hypertension. Although the original report by Bright (1826) made no mention of the pulse or the heart, his subsequent work (1837) linked dropsy, albuminuria, and contracted kidneys with a hard pulse and hypertrophied heart, in the absence of any valvular disease.4, 5, 6

The microscope, which was greatly improved by the 1830s but not used by Bright, was to provide the next stage of progress, when vascular narrowing and obliteration were observed in the atrophic kidneys of Bright’s disease. In 1856, Ludwig Traube (1818–1876) confirmed the association of increased arterial pulse tension with a contracted kidney and hypertrophy of the left ventricle, which he attributed to cardiac compensation to the blood flow in the obliterated capillaries of the sclerotic kidneys. Especially important in the conceptual evolution of hypertension was the work of George Johnson (1818–1896), who described hypertrophy of the muscular coats of the arteries, initially in the diseased kidneys and subsequently throughout the body, concluding in 1868, that: “It cannot be supposed that the great hypertrophy of the left ventricle, which is often found in Bright’s disease is a direct result solely of the resistance offered by the renal arteries. We must look for the cause of this hypertrophy rather in the fact that the blood…is impeded in its transit through the minute arteries throughout the body. We have evidence of such an impediment in the full, hard, throbbing pulse, which is a very common phenomenon in the advanced stage of chronic Bright’s disease.” Thus, while Johnson characterized diffuse vascular changes manifested clinically by a hard pulse and linked them to cardiac hypertrophy, he considered them a manifestation of kidney disease. Nevertheless, the arguments presented by Bright, Traube, and Johnson were so persuasive that a strong and tense pulse came to be considered a symptom of kidney disease.4, 5, 6, 7, 8

Johnson’s work on widespread arterial changes was confirmed in 1872 by William W. Gull (1816–1890) of Guy’s Hospital and Henry G. Sutton (1836–1891) of London Hospital but differed as to the nature of the alterations by localizing the vascular lesions outside the muscular layer in the “tunica intima.” They described the presence of “hyaline-fibroid material in the minute arteries and “hyalin-granular” material in the capillaries, which they termed “arterio-capillary fibrosis.” Importantly, Gull and Sutton were the first to attribute the “heart much hypertrophied and minute arteries and capillaries much thickened by hyaline-fibroid substance” to a “primary and essential condition” apart from the diseased kidney.7, 8

The next step in progress came from the studies of Frederick Akbar Mahomed (1849–1884), who was the first to actually correlate the morphologic changes of Bright’s disease with actual elevation of the arterial pressure, albeit estimated with a crude modification of Marey’s sphygmograph. Having begun his studies as a student at Guy’s Hospital, Mahomed continued them as a resident medical officer at London’s Fever Hospital, where he studied patients with acute glomerulonephritis after scarlet fever. This work allowed him to describe hypertension in the absence of atrophic or albuminuric kidneys, a condition he termed the “pre-albuminuric stage of Bright’s disease.” Although Mahomed ultimately described a condition in which patients with “high arterial tension,” in whom albuminuria and dropsy were absent, presented with “cerebral hemorrhage, heart disease, lung disease, or sundry diseases” by classifying the patients as in a pre-albuminuric stage of Bright’s disease, he failed to distinguish hypertension from Bright’s disease. Unfortunately, Mahomed died of typhoid fever at a young age, and one of his colleagues, T. Clifford Albutt (1836–1925), went on to differentiate elevated arterial pressure without symptoms of kidney damage, which he termed “hyperpiesis,” from the elevated arterial pressure also found in patients with kidney disease.5, 6, 7, 8

Parallel to these correlative studies, another area that dominated much of the ongoing research through the latter part of the 19th century and early part of 20th century was the classification of Bright’s disease. This endeavor helped solidify the notion of hypertension as a cause of kidney disease, rather than just a result of it, culminating in the work of Franz Wolhard (1872–1950) and Theodor Fahr (1877–1914), who in 1914 classified Bright’s disease as degenerative (parenchymatous, nephrotic), inflammatory (nephritic), and arteriosclerotic (nephrosclerotic) kidneys. The latter was subclassified as “red,” or primary, hypertension and “pale,” or malignant, hypertension.8, 9

Thus, by the beginning of the 20th century, it was well established that, whereas the diseased kidney could cause hypertension, the most common form of elevated arterial pressure was a primary form of hypertension, an entity separate from Bright’s disease, in which hypertension is secondary. Ultimately, with the systematic measurement of blood pressure by utilizing a pneumatic cuff and mercury manometer, the existence and significance of hypertension came to be fully recognized. It was finally named “essential hypertension” in 1911, and its association with cardiac complications, “hypertensive cardiovascular disease,” was named by T. C. Janeway (1872–1917) in 1913.10

The middle: the 20th century 

As organized laboratory investigation replaced clinical research in the 20th century, so did research into hypertension. Several investigators undertook the quest for vasoconstrictive substances in earnest, but once again work on the kidney provided some of the key answers.1, 11

In 1898, Robert Tigerstedt (1853–1923) and Per G. Bergman (1874–1955) had shown that saline extracts of rabbit kidneys produced a prolonged rise in blood pressure in rabbits. They named the active principle “renin.” Yet, the existence of renin remained suspect, because others could not reproduce readily the results of Tigerstedt and Bergman. Nevertheless, the focus of developing an experimental model of hypertension, albeit unsuccessful, remained the kidney (Table 1). Success came in 1934, when Harry Goldblatt (1891–1977) and his coworkers demonstrated that persistent hypertension could be reproduced in dogs by constricting both renal arteries or one renal artery if the opposite kidney had been removed. They went on to show that mild constriction of the renal arteries produced a lesion resembling “benign nephrosclerosis,” whereas severe constriction resulted in “malignant hypertension” with cardiac hypertrophy, and hypertension persisted if the constrictive clamp was removed several months later. This discovery was to provide a reproducible model of hypertension that led to the next step of the now rapidly unfolding story.11, 12

Table 1. Experiments to Determine the Renal Origin of Hypertension

	1. Bilateral nephrectomy 1912, 1916, 1930–1936
	2. Partial ablation of the kidneys 1879, 1916, 1925–1935
	3. Ligation of branches of the renal arteries 1908–1930
	4. Unilateral nephrectomy with ligation of branches of the renal artery to the contralteral kidney 1924, 1931
	5. Radiation of the kidneys 1925, 1935
	6. Kidney infarction by multiple emboli 1911, 1924, 1930
	7. Occlusion of one main renal artery 1929, 1930
	8. Occlusion of both renal arteries 1905, 1925, 1926
	9. Occlusion of renal arteries, veins, and ureters 1926, 1936
	10. Partial occlusion of renal arteries 1905, 1918
	11. Constriction of renal vein of one kidney 1927, 1933
	12. Constriction of kidneys with an oncometer 1909
	13. Permanent obstruction of ureters 1929, 1930, 1936
	14. Temporary occlusion of ureters 1910
	15. Toxic injury to the kidneys 1928, 1935–1937
	16. Calibrated occlusion of renal arteries with a clamp—Goldblatt kidneys 1932

Note: Data from Goldblatt.12

Within 5 years, a team in Buenos Aires headed by Eduardo Braun-Menendez (1903–1959) and another in Cleveland headed by Irvine H. Page (1901–1991) showed that renin isolated from the renal vein of “Goldblatt kidneys,” when incubated with plasma, produced a potent vasoconstrictor, which the former group termed “hypertensin” and the latter group termed “angiotonin.” It was to become “angiotensin,” which, over the ensuing 2 decades was purified and synthesized, and its functions were clarified.13 Simultaneously, several groups were exploring another role of the kidney in hypertension, specifically its regulation of extracellular fluid volume control through sodium excretion, which was ultimately integrated and clarified by Arthur Guyton (1920–2003) by the latter part of the 20th century.14

While still a long way from identifying the cause of hypertension, these two apparently disparate areas of investigation on the role of the kidney in hypertension also provided the basis for the development of our most useful antihypertensive medications: diuretics, whose importance in treating hypertension and preventing cardiovascular disease was recently reemphasized by the ALLHAT study, and angiotensin-converting enzyme inhibitors, whose ability to retard the progressive loss of kidney function and improve cardiovascular events continues to be documented.

Conclusion 

Beginning with the 19th century, the study of the kidney and its diseases has played a pivotal role in the conceptual evolution of the understanding of hypertension as a disease, the identification of its mechanisms, and the development of clinically useful antihypertensive drugs. What we now face in the 21st century is the epidemic of hypertension whose increasing prevalence has come to be termed a disease of civilization, and an aspect of the disease that neither Richard Bright nor any of the luminaries mentioned in this brief account had anticipated: hypertension in patients whose kidneys have failed and are now on replacement therapy. These are the stories that will have to be told in the future. The present issue of Advances in Chronic Kidney Disease explores the roots of one of them: hypertension in the patient on renal replacement therapy.