The kidney and hypertension: over 70 years of research.

The crucial role of the kidneys in regulation of systemic blood pressure has been known for more than 70 years. A multitude of studies have described the regulatory mechanisms behind this interaction, and elucidate why kidney disease is such a rampant and difficult form of secondary hypertension. Historically, renal hypertension has primarily been described as derangements of the renin-angiotensin-aldosterone system (RAAS), and salt and volume retention. Renally mediated hypertension involves the activation of RAAS leading to angiotensin II-mediated vaso-constriction, and aldosterone-mediated salt retention. The increased sodium retention and volume expansion seen in kidney disease is accompanied by a failure to autoregulate the peripheral vasculature, leading to hypertension. An-giotensin II and aldosterone also cause increased inflammation and endothelial dysfunction, and volume retention leads to the elaboration of ouabain-like compounds that contribute to increased total peripheral resistance. More recently, studies have shown that activation of renal afferent pathways connecting with specific brain nuclei involved in the noradrenergic control of blood pressure appears to play a substantial role. This article will review the classic pa-radigms, as well as new and emerging paradigms linking the kidney with blood pressure.

Antonín vancura and arterial hypertension. 50 years' evolution in the conception of pathogenesis and treatment of the disease.

A historical overview of the important contributions of Prof. Antonin Vancura from Charles University Medical Faculty, Prague, to the broader understanding of the pathogenesis, clinical course and classification of arterial hypertension is given in his pivotal publication and first Czech monography 'High Blood Pressure'. His unique clinical series of 1,096 hypertensive patients with their long-term follow-up after 5, 10 and 15 years made it possible to work out the classification of hypertension not only on the basis of blood pressure readings, but also according to target organ damage--a principle which is close to the 2003 classification of the European Society of Hypertension/European Society of Cardiology (ESH/ESC). In agreement with today's conception, Vancura emphasized already in 1942 the importance of metabolic changes and albuminuria for prognosis of the disease. In spite of the technical, instrumental and laboratory limitations, it is possible to gain from Vancura's publication a modern interpretation of his results given by a long-term follow-up of this large group of patients. In many ways, Vancura outstripped his time and his concepts approached today's standings and so founded one of the important schools of hypertension in Czechoslovakia and Europe.

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

Elevated arterial pressure had long been surmised from the strength of the pulse. Its association with contracted kidneys and hypertrophied hearts was described by Richard Bright (1789-1858). Microscopic observations of the narrowed and obliterated vasculature initially observed in the kidneys of Bright's disease, and subsequently throughout the body, launched clinical research into hypertension. The description of these findings in the absence of symptoms of kidney disease led to the recognition of primary hypertension. Ultimately, the systematic recording of the blood pressure with a pneumatic cuff and mercury manometer established the significance of hypertension as a distinct disease entity. Subsequent experimental studies established the central role of the kidney in hypertension through the renin-angiotensin system and extracellular volume control. This finding provided the basis for the introduction of diuretics and angiotensin converting enzyme inhibitors, two of the most important and valuable antihypertertensive drugs now available. Thus, the study of kidney disease and function 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 medications.

Angiotensin receptors: history and mysteries.

Angiotensin receptors became relatively easy to study when radioactive derivatives of the peptide were synthesized for radioimmunoassays. Binding assays in vitro led to the discovery of receptors in many tissues different from those involved in the classic actions of angiotensin. The physiologic significance of receptors in sites such as the gonads, other endocrine organs, peripheral blood cells, and many regions of the brain is still uncertain. Kinetics of the binding reaction are susceptible to intracellular guanine nucleotides, and extracellular cations, fatty acids, steroids, and eicosanoids. Synthesis of receptors is under equally complex control. Receptor binding assays simplified screening for angiotensin antagonists. Nonpeptide antagonists proved so specific they revealed the existence of receptor subtypes. The two principal subtypes are found in different tissues and trigger different postreceptor cascades. Studies of receptors, the genes that code for them, and the drugs that block them have led to a growing awareness of angiotensin's effects on the structure of the heart, vessels, and kidneys, some of which are pathologic. The existence of receptor subtypes, the different signal transduction cascades they stimulate, the widespread location of receptors, and the range of effects they mediate suggest that the angiotensins are of broad relevance in biology and pathology. This multidimensional matrix also indicates that receptor antagonists may have effects not yet described.

High blood pressure and the kidney: the forgotten contribution of William Senhouse Kirkes.

The realization of the key role for raised intra-arterial pressure as a pathogenetic agent in hypertension is usually credited to Ludwig Traube, but Traube in his writings gives credit for the idea to a little-known English doctor, William Senhouse Kirkes (1822-1864). Kirkes' main interest was in cardiology and vascular disease, and he gave the first account of embolism from vegetations in infective endocarditis in 1852. Three years later, he published a study of apoplexy in Bright's disease, in which he pointed clearly to the role of raised intra-arterial tension in the causation of arterial disease, a point that had eluded Bright, Johnson, and other contemporaries. Kirkes died at the age of only 42 while working on a book summarizing his work on cardiology and renal disease, and the neglect of his contribution probably resulted from his early death. We have traced his life history from the few available records; as a boy, Kirkes was apprenticed to become a surgeon and only later trained as a physician. We place his contributions within the setting of the development during the 19th century of understanding of the relationship between the kidney, vascular disease, and high blood pressure.

Hypertension as cause and consequence of renal disease in the 19th century.

The pioneering work of Richard Bright, who introduced the concept of the renal origin of cardiovascular disease, initiated the continuous unfolding of knowledge on renal disease and its close interrelationship with arterial hypertension in the 19th century. Hypertension as a clinically and pathologically defined entity, however, was not established. The partial elucidation of the problem that the diseased kidney was sometimes the cause and sometimes the consequence of elevated blood pressure is not only fascinating but also remarkable, given the crude techniques available to physicians at that time. Subsequent workers came to regard 'Bright's disease' as consisting of several conditions differing in clinical manifestation and pathology. In particular, Johnson and Gull and Sutton drew attention to the small blood vessels in renal disease. Only the invention of a clinically applicable method of measuring blood pressure indirectly allowed Mahomed and Allbutt to show that hypertension may occur in the absence of renal disease. They paved the way for a clear separation of hypertensive renal disease from other forms of 'Bright's disease', culminating in the classification introduced by Fahr and Volhard.

Hypertension and the kidney.

From our perspective, Priscilla Kincaid-Smith's major achievement in the field of hypertension relates to the pathogenesis of vascular lesions. Our own studies of the hypertension of renal parenchymal disease have suggested a role for impairment of the cortisol-cortisone shuttle and decreased activity of the enzyme complex 11-beta-hydroxy-steroid dehydrogenase. We have defined the renal functional consequences of steroid-induced hypertension and shown that the rise in blood pressure produced by steroids with predominant glucocorticoid activity is not dependent on volume shifts or sodium status, although the magnitude of the rise is modulated by dietary sodium content. We have shown that normal pregnant women adapt readily to extremes of sodium intake while women with pre-eclampsia retain sodium, and have shown enhanced capillary permeability. Recent studies have defined an abnormal aldosterone:renin ratio, dopaminergic inhibition of aldosterone, elevations of plasma atrial natriuretic peptide and reduced urinary prostacyclin:thromboxane ratios in women with pre-eclampsia.

Enigma of contracted granular kidney: a chapter in the history of nephrology.

British successors of Richard Bright came to regard the disease which bore his name as consisting of several distinct clinical and pathological types, one of which was referred to as contracted granular kidney. The insidious nature of this form of the disease, the lack of clear-cut precipitating factors and, above all, the associated cardio-circulatory disorders gave rise to much speculation and debate. Whether the renal disease or the vascular disease was the primary and essential change was a question which sharply divided eminent Victorian physicians and gave rise to a bitter quarrel between Sir George Johnson and Sir William Gull. The anser to this conundrum, that the kidney was sometimes the cause and sometimes the consequence of circulatory disease was suggested by Mahomed's discovery of essential hypertension but confirmation had to await the invention of a clinically useful sphygmomanometer.