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. 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. In 1856, one of the towering figures of German medicine in the nineteenth century, Ludwig Traube (1818–1856), wrote a major work titled Ueber den Zusammenhang von Herz-und Nieren-krankheiten (The Relationship Between Cardiac and Renal Diseases)1Traube L. Üeber den Zusammenhang von Herz- und Nierenkrankheiten. August Hirschwald, Berlin1856Google Scholar. In this, from clinical observations and physiological experiments, he put forward a comprehensive hypothesis that related cardiac hypertrophy to renal disease, noted first in 1830–1836 by Richard Bright (1789–1858)2Bright R. Cases and observations illustrative of renal disease accompanied with the secretion of albuminous urine.Guy's Hosp Rep. 1836; 1: 338-379Google Scholar. Traube postulated a series of pathophysiological events that have proved uncannily accurate and that still form the basis for thinking in the area today3Cameron J.S. Villain and victim: The kidney and high blood pressure in the nineteenth century.J Roy Coll Phys Lond. 1999; 33: 382-394PubMed Google Scholar. He is justifiably famous for this and many other contributions to medicine. He notes at the end of his article: “I leave aside the combination of heart disease with hemorrhagic infarcts [of the brain], because I have nothing to add to the works of Rokitansky and Senhouse-Kirkes concerning the causal relationship of these maladies” Later, tucked away in an article on pulsus bigeminus presented to the Medical Society of Berlin on March 20th, 1871, and published in the Berliner Klinische Wochenschrift the following year, he states to our amazement4Traube L. Ein fall von pulsus bigeminus nebst bemerkungen ueber die leberschwellungen bei klappenfehlern und ueber acute leberatrophie.Berl Klin Wochenschr. 1872; 9: 185-188Google Scholar: “It was Senhouse-Kirkes who first proposed the tenet that arteriosclerosis is first of all the result of long-lasting high-grade tension of the aortic system. Thus there appeared, I believe, the first allusion to the correct viewpoint not only on the origin of this affection but also its pathological significance … according to Senhouse-Kirkes … the arteriosclerosis would have here the same foundation as the hypertrophy of the left ventricle.” However, today Traube himself is usually credited as having introduced the crucial idea of high intra-arterial pressure as a pathological agent (the word hypertension was still 30 years in the future3Cameron J.S. Villain and victim: The kidney and high blood pressure in the nineteenth century.J Roy Coll Phys Lond. 1999; 33: 382-394PubMed Google Scholar,5Huchard H. Maladies du coeur et des vaisseaux. Doin, Paris1889Google Scholar), but here he gives credit to another physician for the idea. Who was this “Senhouse-Kirkes,” and why has he been all but forgotten, despite the fact that Henri Huchard (1844–1910) writing in his book on hypertension and the heart in 1889 mentions him as well5Huchard H. Maladies du coeur et des vaisseaux. Doin, Paris1889Google Scholar as an original contributor to the field? Kirkes, from his name, seemed likely to be British, but this very name was initially unfamiliar; a search revealed that apart from a brief biography in his own hospital's journal6Anonymous The Kirkes medal.St. Bartholomew's Hosp J. 1911; August: 166-168Google Scholar, almost nothing had been written about Kirkes following his premature death in 1864 at only 42 years of age. The exceptions are a mention in Fishberg's book of 19327Fishberg A.M. Hypertension and Nephritis. (2nd ed). Lea & Febiger, Philadelphia1932: p 538Google Scholar that Kirkes related apoplexy to renal disease, but that misses completely his linking of these two through high arterial pressure, and a brief editorial in JAMA of 19708Anonymous W.S. Kirkes (1823–1864) physician to St. Bartholomew's hospital.JAMA. 1970; 211: 2010-2011Google Scholar. This discusses his important work on embolism from cardiac vegetations published in 18529Kirkes W.S. On some of the principal effects of resulting from detachment of fibrinous deposits from the interior of the heart, and their mixture with the circulating blood.Med Chir Trans. 1852; 35: 281-324Crossref PubMed Google Scholar, but is illustrated by a picture of a plump middle-aged man with mutton chop whiskers, who, it turns out, is not Senhouse Kirkes at all! Kirkes' 1852 article was also reprinted in Classics in Cardiology10Willius F.A. Keys T.E. Classics of Cardiology. Dover, New York1962Google Scholar, published first in 1941, and is listed in Morton and Garrison's Bibliography of the History of Medicine11Norman J.M. Morton's Medical Bibliography. Scolar Press, London1992Google Scholar. Otherwise, there is nothing. In this article, we describe Senhouse Kirkes' life so far as we have been able to reconstruct it, as well as his contributions to nephrology and cardiology. It appears that one of the main reasons for his being forgotten so quickly is that he died relatively young while still writing his major book on the heart, which was never completed or published. Senhouse Kirkes qualified in 1846 at St. Bartholomew's hospital (life history discussed later in this article), where he practiced for the remainder of his short life. His first published work, together with one of his mentors, the surgeon James (later Sir James) Paget (1814–1899), was a Handbook of Physiology in 1848, which was largely based on Paget's lecture notes12Kirkes W.S. Handbook of Physiology. assisted by J. Paget. Taylor Walton & Maberly, London1848Google Scholar. This work was a great success and went rapidly into two further editions in 1853 and 1856, followed by two further editions in 1859 and 1867 under Kirkes' sole name. After Kirkes' premature death, the publishers John Murray, realizing they had a winning product, recruited first W. Morrant Baker and then V.P. Harris to continue the book. William Halliburton undertook further editions, the latter revision being so thorough that little of Kirkes' original text remained. As Halliburton's Physiology, from the 17th edition in 1896, it continued until the mid-20th century, during which time it had several American as well as many British editions. From 1850 to 1860, Kirkes published papers regularly on a variety of subjects, mostly in the Medical Times and Gazette13Kirkes W.S. Cases, with remarks illustrating the association of chorea with rheumatism and disease of the heart.Trans Abernethian Soc St. Bartholomew's Hosp. 1850; 8: 55-69Google Scholar, 14Kirkes W.S. Coote H. Tubercular inflammation of the brain.Med Times Gaz. 1850; II (86,88,200,203)Google Scholar, 15Kirkes W.S. Coote H. Fatal jaundice: Disorganization of the liver.Med Times Gaz. 1850; II: 539-541Google Scholar, 16Kirkes W.S. Coote H. Hydatid cyst in the pleura.Med Times Gaz. 1851; I: 10-12Google Scholar, 17Kirkes W.S. Coote H. Malignant disease of the lung.Med Times Gaz. 1851; I: 675-676Google Scholar, 18Burrows G. Kirkes W.S. Inflammation of the muscular substance of the heart.Med Times Gaz. 1853; VII: 624-626Google Scholar, 19Burrows G. Kirkes W.S. Affections of the bronchial mucous membrane in chronic renal disease.Med Times Gaz. 1853; VI: 8-11Google Scholar, 20Burrows G. Kirkes W.S. Inflammation of the serous membranes in chronic renal disease.Med Times Gaz. 1853Google Scholar, but clearly one of his main interests was what would now be called cardiology. One of his first articles, which appeared in 1850 while he was still a demonstrator of anatomy working under Paget, was on chorea and rheumatism13Kirkes W.S. Cases, with remarks illustrating the association of chorea with rheumatism and disease of the heart.Trans Abernethian Soc St. Bartholomew's Hosp. 1850; 8: 55-69Google Scholar, a carefully researched clinicopathological analysis of 36 patients, 11 of whom died, published in the local journal of his hospital. Kirkes was not, of course, the first to note the connection: Matthew Baillie (1761–1823) had described the relationship between rheumatism and carditis in 179721Baillie M. The Morbid Anatomy of the Most Important Parts of the Human Body. (2nd ed). J Johnson & G Nichol, London1797: 32-34Google Scholar, as had Corvisart in Paris22Corvisart J.N. Essai Sur Les Maladies et Les Lésions Organiques Du Coeur et Des Gros Vessaux. Migneret, Paris1806Google Scholar. This interest in the nervous system and the heart may have led him to study apoplexy, a subject that was a major preoccupation of another mentor at Bart's, Dr. (later Sir) George Burrows (1801–1887)23Burrows G. On Disorders of the Cerebral Circulation, and on the Connection Between Affections of the Brain and Diseases of the Heart. Longman, Brown, Green & Longman, London1846Google Scholar, and through this route onward to study both the heart and the kidneys. The first of these investigations is his only article that has received any general attention9Kirkes W.S. On some of the principal effects of resulting from detachment of fibrinous deposits from the interior of the heart, and their mixture with the circulating blood.Med Chir Trans. 1852; 35: 281-324Crossref PubMed Google Scholar. Published in 1852, it describes cerebral embolism from cardiac vegetations: “On some of the principal effects resulting from the detachment of fibrinous deposits from the interior of the heart, and their admixture with the blood.” This article is justly regarded as a classic10Willius F.A. Keys T.E. Classics of Cardiology. Dover, New York1962Google Scholar. In it, Kirkes describes and explains for the first time embolism from the valves of the heart. It is tempting to speculate both that Virchow may have stimulated his interest in this subject when he was in Berlin (discussed later in this article) and also that his interest in apoplexy led him to make the connection between the heart and the cerebral lesions he observed. By the time Kirkes wrote his article9Kirkes W.S. On some of the principal effects of resulting from detachment of fibrinous deposits from the interior of the heart, and their mixture with the circulating blood.Med Chir Trans. 1852; 35: 281-324Crossref PubMed Google Scholar, René Théophile Laënnec (1781–1826) had made a major contribution to the recognition and understanding of endocarditis24Laennec R.T.H. De L'auscultation Médiate Ou Traité Du Diagnostic Des Maladies Des Poumons et Du Coeur. 1819; 2 (2 vols), Paris, Brosson Chaudé: 334Google Scholar; he suggested that Lazare Rivière (1589–1655), professor of medicine at Montpellier, had been the first to describe aortic endocarditic lesions in his Opera Medica Universa of 1646. During the next two centuries, several physicians made similar observations, including Lancisi and Morgagni in Italy and Vieussens and Sénac in France25Contrepois A. Towards a history of endocarditis.Med Hist. 1996; 40: 25-54Crossref PubMed Scopus (18) Google Scholar. Baillie, cited earlier in this article21Baillie M. The Morbid Anatomy of the Most Important Parts of the Human Body. (2nd ed). J Johnson & G Nichol, London1797: 32-34Google Scholar, noted “a layer of coagulable lymph” on the mitral valve but thought this finding “very uncommon.” Jean Nicholas Corvisart (1755–1821), writing shortly afterward22Corvisart J.N. Essai Sur Les Maladies et Les Lésions Organiques Du Coeur et Des Gros Vessaux. Migneret, Paris1806Google Scholar, applied the enduring term “vegetations” to the outgrowths on the valves. However, it was Laennec's stethoscope, introduced in 1816, that made the diagnosis more available, and the full significance was the work of Jean-Baptiste Bouillaud (1796–1881), who from 1823 onward described and named endocarditis in all its stages, and described the clinical picture in articles culminating in his book on heart diseases of 183526Bouillaud J.B. Traité Des Maladies Du Coeur et Des Gros Vaisseaux. (2 vols). Ballière, Paris1835Google Scholar. However, Bouillaud's endocarditis was a local disease of the heart. Kirkes pointed out that although Rokitansky had described27Rokitansky C: Handbuch der pathologischen Anatomie (3 vols)., Vienna, Braumu¨ ller Seidel, 1842–1846, Bd 1:242Google Scholar“fibrinous deposits” in other vessels in association with valvular diseases, he had attributed the blockage of the vessels to an alteration in the blood produced by the mixture of products of the valvular disease at the site of the thrombus, making the blood more coagulable. Kirkes was in no such doubt: He described four young patients, each with what would now be recognized as subacute bacterial endocarditis, who suffered sudden and ultimately fatal strokes9Kirkes W.S. On some of the principal effects of resulting from detachment of fibrinous deposits from the interior of the heart, and their mixture with the circulating blood.Med Chir Trans. 1852; 35: 281-324Crossref PubMed Google Scholar. At postmortem in every case, there were friable vegetations on the heart valves, often of both the left and right heart. He wrote the following: “The clot in the middle cerebral artery was in this, as in the other cases, directly derived from the vegetations of the left side of the heart…” He describes and discusses the anatomy of the cerebral vessels, pointing out why impaction of a mass of “fibrine” in the middle cerebral artery is so common and so disastrous. The embolism of the kidneys, spleen, and (in the case of tricuspid vegetations) lungs is minutely and accurately described and all attributed to embolism of the vessels (although Kirkes did not use this word, which was introduced by Rudolf Virchow in 185828Virchow R. Die Cellularpathologie. A. Hirschwald, Berlin1858Google Scholar). Kirkes realized the role of preceding rheumatic inflammation, but at no point mentions infection (or any other cause) as a component of the friable vegetations: Throughout, they are referred to as being made of “fibrine.” It was not until the work of Norwegian Emmanuel Winge (1817–1894) in 1870 that microorganisms were identified in the vegetations29Winge E. Endocarditis (nycosis endocardii).Nord Med Ark. 1870; 14: 15-16Google Scholar. The summary of Kirkes' article deserves reproduction: “1st the general fact that fibrinous concretions on the valves of the interior of the heart admit of being easily detached during life, and mingled with the circulating blood. 2ndly that if detached and transmitted in large masses they may suddenly block up a large artery, and so cut off the supply of blood to an important part; if in smaller masses they may be arrested in vessels of much less size, and give rise to various morbid appearances in internal organs… 3rdly that the effects produced will in great measure be determined by the side of the heart from which the fibrinous masses have been detached; for if the right valves have furnished the source of the fibrine, the lungs will bear the brunt of the secondary mischief; but if as is far more commonly the case, the left valves are affected, the mischief is more widely spread, and may fall on any systemic part, but especially on those organs with which, such as the brain, spleen and kidneys, are largely and directly supplied with blood from the left side of the heart.” Kirkes' observations on the embolic nature of the systemic lesions in endocarditis were amply confirmed within the next decade by a number of observers, particularly Jean-Martin Charcot (1825–1893) and Alfred Vulpian (1826–1887), who were in Paris25Contrepois A. Towards a history of endocarditis.Med Hist. 1996; 40: 25-54Crossref PubMed Scopus (18) Google Scholar. This article of 1852 serves as a prologue to the work of central interest to our subject, that of 1855 “On apoplexy in relation to chronic renal disease” Figure 130Kirkes W.S. On apoplexy in relation to chronic renal disease.Med Times Gaz. 1855; 24: 515-517Google Scholar. Again, the brain, the heart, and the kidney are the principal players, but with a different script. Kirkes' article was one of the first of several major steps in advancing the understanding of this relationship that took place later during the 1850s3Cameron J.S. Villain and victim: The kidney and high blood pressure in the nineteenth century.J Roy Coll Phys Lond. 1999; 33: 382-394PubMed Google Scholar: the first measurement of the blood pressure in humans, the introduction of the sphygmograph and the ophthalmoscope, the description of the retinal changes associated with Bright's disease (“retinitis albuminurica”), and finally Traube's speculations about the genesis of high arterial tension in renal patients with renal diseases1Traube L. Üeber den Zusammenhang von Herz- und Nierenkrankheiten. August Hirschwald, Berlin1856Google Scholar. However, all these were to come when Kirkes did his work. The hard, wiry artery whose pulse was difficult to compress had been recognized since classical times in Europe and even before this in China, and the spurting of blood from a cut artery must have been known since prehistoric times. Only by the end of the 17th century, however, did modern concepts of the circulation appear. These concepts were founded on the work of William Harvey (1578–1657). Giovanni Borrelli (1608–1679) was the first to realize that as a pump, the heart performed work, and this work could be calculated, a task performed by the Reverend Stephen Hales (1677–1761)31Hales S: Statistical Essays: Containing Haemostaticks (2 vols), London, W. Innys & R. Manby II:1, 1733Google Scholar. Thomas Young (1773–1829), physicist and physician, discussed in his surprisingly modern Croonian lectures of 180932Young T. The Croonian lecture: On the functions of the heart and arteries.Phil Trans Roy Soc Lond. 1809; I: 1-31Crossref Google Scholar the model of a circulation as a hydraulic system and calculated the resistance of the periphery, showing that the majority of this must occur in the small vessels. Hypertrophy of the heart was known by the beginning of the eighteenth century. Jean-Baptiste Sénac (1693–1770) clearly described the relationship between cardiac size and its “force,” discussing hypertrophy in terms of the fibers of the heart growing stronger33Sénac J-B Traité de La Structure Du Coeur, de Son Action, et Ses Maladies. Chez Briasson, Paris1749Google Scholar, thus laying the basis for the clinical diagnosis of this hypertrophy by Jean Nicholas Corvisart des Marets (1775–1821), physician to Napoleon I26Bouillaud J.B. Traité Des Maladies Du Coeur et Des Gros Vaisseaux. (2 vols). Ballière, Paris1835Google Scholar. However, in almost all instances, this cardiac hypertrophy was recognized as a consequence of valvular disease. At that time, the Paris schools were coming to their peak, and thus, it was again in Paris that Jean-Léonard Marie Poiseuille (1799–1869) repeated Hales' work in dogs in 1828, but introduced a mercury manometer for measurement34Poiseuille J.L.M. Recherches Sur La Force de La Coeur Aortique. Didot, Paris1828Google Scholar, developing further Sénac and Corvisart's ideas of the force of the heart. Poiseuille's “hemodynamometer” was used by a number of investigators to study the blood pressure in animals during the next few years, especially by James Blake of London from 1839 onward35Blake J. Observations on the physiological effects of various agents introduced into the circulation as indicated by the haemodynamometer.Edinb Med Surg J. 1839; 51: 330-345Google Scholar. Thus, the idea of a varying pressure within the normal arterial circulation was well established during the century from 1750 to 1850. However, arterial pressure made no entry into clinical thinking during this period, despite observations by Blackall, Bright, Barlow and Rees, Toynbee, Simon, and others on cardiac hypertrophy and vessel changes3Cameron J.S. Villain and victim: The kidney and high blood pressure in the nineteenth century.J Roy Coll Phys Lond. 1999; 33: 382-394PubMed Google Scholar, 36Mann W.N. Bright's disease: The changing concept of a century.Guy's Hosp Rep. 1958; 107: 323-347PubMed Google Scholar, 37Rault R. Enigma of granular kidney: A chapter in the history of nephrology.Am J Nephrol. 1991; 11: 402-408Crossref PubMed Scopus (8) Google Scholar, 38Harlos J. Heidland A. Hypertension as cause and consequence of renal disease in the 19th century.Am J Nephrol. 1994; 14: 436-442Crossref PubMed Scopus (16) Google Scholar, 39de wardener H.E. Hypertension artérielle et artérioles rénales: De Bright à aujou d'hui.Néphrologie d'Hier et dAujou d'hui. 1994; 4: 15-21Google Scholar. In particular, George (later Sir George) Robinson (1818–1896) of King's College Hospital misinterpreted his histologic descriptions of the arterial changes in small renal vessels40Johnson G. On the proximate cause of albuminous urine and dropsy and on the pathology of the renal blood vessels in Bright's disease.Med Chir Trans. 1850; 33: 107-120Crossref PubMed Google Scholar, being convinced that what he regarded as the hypertrophy of the muscle of the vessel wall was analogous to that of the cardiac hypertrophy in cases of chronic Bright's disease and had a propulsive effect on the blood. In his article of 1855, Kirkes pointed out that there had been little emphasis on the frequency of apoplexy in association with Bright's disease30Kirkes W.S. On apoplexy in relation to chronic renal disease.Med Times Gaz. 1855; 24: 515-517Google Scholar, quoting Bright's Reports (volume II) of 183141Bright R. Reports of Medical Cases, Etc. (vol 2). Longman Green etc, London1831Google Scholar and Robert Christison in his Diseases of the Kidnies, Etc., (sic) of 183942Christison R. On Granular Degeneration of the Kidnies, and Its Connexion with Dropsy, Inflammations, and Other Diseases. Adam and Charles Black, Edinburgh1839Google Scholar. He also cites his mentor Burrows for his On Disorders of the Cerebral Circulation, Etc., of 184623Burrows G. On Disorders of the Cerebral Circulation, and on the Connection Between Affections of the Brain and Diseases of the Heart. Longman, Brown, Green & Longman, London1846Google Scholar, crediting him with having described cardiac hypertrophy in those dying of strokes, although French descriptions had been available from the time of Corvisart, as Burrows himself had noted23Burrows G. On Disorders of the Cerebral Circulation, and on the Connection Between Affections of the Brain and Diseases of the Heart. Longman, Brown, Green & Longman, London1846Google Scholar. Then Kirkes goes on to note that in his series of patients with apoplexy, disease of the kidneys and of the arteries was frequent: in 22 cases who died and in whom a complete autopsy was available (not just the brain), 12 showed abnormalities of all three of the cerebral vessels, the heart, and the kidneys, and in another two cases, either the heart or the cerebral vessels were affected together with the kidneys. Thus, of 14 patients with apoplexy and diseased kidneys, only one did not have an enlarged heart. The direct observation of “rupture of the small blood vessels in the brain, and the consequent occurrence of sanguineous apoplexy” must have been a powerful stimulus to his thinking. Pierre Piorry (1794–1879) in Paris had just described and named “uraemia”43Piorry R. Traité de Médecine Pratique. Balliere, Tome III Chapitre XII, Paris1847: 430-440Google Scholar, giving substance to Bright's earlier speculations as to alterations of blood in kidney failure. Kirkes points out that the “… detention of the excretory principles of the urine is capable of explaining many of the complex and often serious nervous phenomena that are apt to occur in advanced disease of the kidney, but it cannot be supposed to explain [them], at least directly.” Having reviewed the data, Kirkes asks these questions: “First, what relation do the renal cardiac and arterial diseases bear to each other? Secondly, what share do they severally take in the production of apoplexy?” and he provides these answers: “… I believe that the affection of the kidneys is the primary disease… [it] has among its most frequent and permanent accompaniments an hypertrophied condition of the left ventricle … of the various explanations of this pathological fact the most probable perhaps is that which regards the blood as so far altered from its normal constitution … as to move with less facility through the systemic capillaries, and thus to require increased pressure, and consequently increased growth of the left ventricle, to effect its transmission.” He also speculates that the “impeded transit of blood” through the renal circulation may contribute directly. Kirkes then goes on to consider the second question, noting that the coats of the cerebral arteries were altered by the “well known yellowish white thickening and deposit”44Cottet J. Lenoir M. Deux mille ans d'etude historique des mots: Athérome, athérosclérose, arteriosclérose.Bull Acad Nat Méd. 1992; 176: 1385-1390PubMed Google Scholar and goes on to speculate the following: “It may be held as highly probable, that the disease or degeneration [of the vessels] in question is in great measure the result of the continued over-distension and straining to which the arteries are subjected by the unwonted energy with which the hypertrophied heart propels the blood along them. Stretched and weakened … by long continued pressure … it may be that before degenerating, the coats undergo a sort of protective hypertrophy to resist the increased pressure on their walls.” He adds at this point a case description of a girl of 14, who had a fit followed by a hemiplegia after “having spent a day of unusual pleasure and excitement.” Four months later she died, and postmortem examination revealed (apart from her cerebral hemorrhage) a tiny right kidney, and “enormous” left ventricular hypertrophy without any valvular disease. However, the analysis of this case reveals what we would now judge to be a flaw in Kirkes' otherwise impeccable reasoning: “Something at an earlier period of the child's life had occurred to inflict irreparable damage on one kidney; and the other had not with sufficient rapidity to supply its place; the elimination of urine had been imperfectly effected, and the elements of this excretion had accumulated in the blood; the left ventricle of the heart had become hypertrophied in consequence of the continued impurity of the blood; to resist the increased pressure on their walls, resulting from the hypertrophied heart, the coats of the aorta had gradually increased in size and thickness … the walls of the ventricle and aorta growing in proportion to the increasing demand upon them … and the delicate vessels of the brain yielded to the excessive pressure.…” Thus, Kirkes here returns to the first of Bright's hypotheses of 18362Bright R. Cases and observations illustrative of renal disease accompanied with the secretion of albuminous urine.Guy's Hosp Rep. 1836; 1: 338-379Google Scholar: that of a direct action of “uraemic” blood on the left ventricle to produce hypertrophy. Today, we prefer his second explanation. Kirkes was pushed in this direction by previous work of his mentor James Paget (1814–1899)45Paget J. On obstructions of the pulmonary artery.Med Chir Trans. 1844; 27: 162-188Crossref PubMed Google Scholar and particularly by studies of