Early Contributors to Nephrology Am J Nephrol 1994;14:371-376 Department of Medicine, University College London Medical School, London. UK John Blackall (1771-1860): Failure to See the Obvious in Dropsical Patients with Coagulable Urine? Key Words Abstract Blackall Dropsy Albuminuria Renal pathology Mercury poisoning Despite his success in publishing a book which was widely read and which drew attention to the fact that some cases of dropsy are associated with coagu lable urine, John Blackall failed to make the link between this phenomenon and disease of the kidneys. Thus, to Richard Bright must go the credit for providing the critical understanding of the phenomenon. The single most probable reason for Bright’s success and Blackall’s failure was that Bright car ried out post mortem examinations of almost all of his patients. In addition, Bright was ruthlessly systematic in documenting his autopsy findings, and not least was the fact that he possessed the rare talent of being objective in looking at his data, without being influenced by the preconceptions of the times. Introduction Identification of the cause of dropsy, i.e. the accumula tion of fluid in the serous cavities and in the interstitia of tissues, intrigued virtually all of the ancient and medieval medical writers. A careful search of the writings on dropsy of such luminaries as Hippocrates, Galen, Areteus, Aetius and Avicenna reveals sporadic case reports of hardened or scirrhous kidneys or kidneys which are altered from their normal appearances [I], A diminution of the volume of the urine was similarly recognized. Similar reports are scattered throughout the literature of the 17th and 18th centuries and these have been elegantly catalogued by Rayer , It is clear, however, that by the beginning of the 19th century it had not been realized that there could be a causal relationship between kidney disease and dropsy. Perhaps the single most important reason for this was the scarcity of post mortem examinations of the internal organs. In 1790 Cotugno ushered in an innovative experimen tal approach to dropsy; he examined the urine of dropsical subjects and found that in some it coagulated on heating . Others had shown that blood and serum may be present in the urine following scarlatina, but this was regarded as a form of bleeding into the urine. Noting that normal serous fluids did not coagulate on heating, Cotu gno found that they did if the serous membranes were inflamed. Extending this principle he performed an ex periment to test whether the dropsical fluid was excreted into the urine: ‘It seemed best to settle this question by a definite experiment, heating the urine. For I had often conclusively shown that the fluid collected beneath the skin of such dropsical cadavers con- Leon G. Fine, FRCP Department of Medicine University College London Medical School 5 University Street London W CIE 6JJ (UK) © 1994 S. Karger AG. Base! 0250-8095/94/0146-0371 $8.00/0 Downloaded by: Vanderbilt University Library 126.96.36.199 - 10/26/2017 9:11:32 AM Leon G. Fine Jennifer A. English tained material capable of coagulation and I hoped that, if the sick man passed such fluid by way of the urine, coagulation would be seen if the material which flowed out were heated, which, as I had anticipated, was proved by experiment. For with two pints of this urine exposed to the fire, when scarcely half evaporated, the remainder made a white mass already loosely coagulated like egg albumen.' Thus it was shown for the first time that urine, which is never coagulable in healthy people, can under some cir cumstances contain a coagulable substance. Cotugno also found coagulable material in the urine of some diabetic subjects. He erred, however, in concluding that the presence of coagulable material signalled recov ery of the disease in that it reflected passage of such co agulable material from the serous fluid of dropsy into the urine. Nevertheless, this seminal work involving genuine experimentation must be heralded as ‘one of the first triumphs of chemistry applied to pathology’ , 372 Finc/English ‘... the kidnies [sic] were much harder than they usually are. The cortical part was thickened and changed in its structure from the deposition of coagulable lymph and there was a small quantity of pus in the pelvis of one of them. I do not conclude, however, from these appearances and those which were found in the former case that the kidnies are always diseased when the urine in dropsy contains much serum." Thus, no relationship between kidney disease and co agulable urine had been established in the early 19th cen tury. In France, Fourcroy (1800), Nysten (1811) and Chapotain (1812) described coagulable urine in patients with dropsy, with Nysten even noting that it: ‘foamed strongly on shaking and remained frothy for a long time’, but none of these authors appears to have been drawn to the kid neys to explain the phenomenon . John Blackall and Dropsical Patients Downloaded by: Vanderbilt University Library 188.8.131.52 - 10/26/2017 9:11:32 AM Fig. 1. John Blackall ( 17 7 1- 1860). Cruikshank deserves the credit for being the first to attempt, in 1798, to separate those dropsies in which the urine is coagulable from those in which it is not , Writ ing in Rollo’s Cases o f Diabetes Mellitus he suggests that the presence of coagulable material implies that the drop sy is dependent on ‘morbid viscera’, which at the time meant a diseased liver or spleen. Again the kidney did not merit a mention! The foregoing remarks show that by the early 19th cen tury there was a tenuous understanding that some cases of dropsy were associated with abnormal kidneys and that some cases were associated with coagulable urine. What now seems to be an obvious association, i.e. the relation ship between diseased kidneys and coagulable urine, was obviously not intuitive at the time. It was arrived at, indi rectly, through the writings of William Wells in 1812. In his paper to the Society for the Improvement of Medical and Surgical Knowledge , he not only demonstrated that the red colour of the urine in dropsies associated with scarlatina was due to the red matter of the blood (red blood corpuscles had not yet been discovered), but also that this urine contained the serous portion of blood, i.e. serum. Using both heat and nitric acid he showed that fioccules appeared. To quantify the amount of serum in the urine, he mixed different proportions of serum and normal urine. Out of 138 cases of scarlatina he found ‘se rum’ in the urine of 78. Importantly, he noted that when serum was added to urine, the urine may have a perfectly normal appearance, and indeed he found that ‘serum’ was present in the urine of 23 of 29 cases of dropsy not associ ated with scarlatina. Once again he was limited by his inability to examine the viscera of such patients after death. He records 1 case in which: OBSERVATIONS The P octor, in Ins obser vations oil this rase, is inclined to lay m eat stress on the coagulability o f the ON T H E N A T U R E AND C U R E O F urine by b eat, IDMOPSIIES, AND PARTICU LA RLY OX THE PRESENCE OF THE COAGILABLE PART OF T nE BLOOD IN DROPSICAL URINE; TO H U1C B I S 'A D D B D , AN APPENDIX, C O N T A IN IN G SEVERAL CASES OF ANGINA PECTORIS, W IT H DISSECTIONS, (fc. JOHN BLACKALL, M. D. PHYSICIAN TO I B B DEVON AN D AND TO T H E LUNATI C AS YLUM, EXETER NEAR li e says, “ The extraordinary coagulability o f the urine fot ms a peculiar feature o f the complaint. It was principally this circum stance which determ ined me to bleed, notw ithstanding the ap parently hopeless condition of the pa tient and the obscurity o f the pulse as a guide. 1 have never h esitated, when the urine coagulates, to bleed in dropsies, and I have never yet had reason to believe the practice injudi cious ; and I cannot help expressing here my opinion, that the profession are highly indebted to Dr. TIi .ackam ., for so pointedly directing onr a tte n tion to this condition of th a t dis charge. 1 am not, Indeed, prepared to ad mit, that the sensible qualities o f the urine form a principle upon which to found a practical division of dropsies, hut 1 feel assured that the coagulabi lity of the urine w ill almost invariably w arran t tile practice o f bloodletting. The ap pearance of the blood draw n incoutrovertihly proved, in this in stance, the iiillanimatory tendency, iu d the propriety of the practice." HOSPITAL, EXETER. LONDON: M IN T E D FOR LONOHAN, HU RST, REES, O R M E, AND B R O W N , PATERN09T1R-R0W. Fig. 2. Title page of the 1st edition of John Blackall’s book on dropsy. Fig. 3. Extract from a review of the book Clinical Reports on Dropsies by Robert Venables, which appeared in the Lancet of 18 December 1824. The recognition that was accorded to Blackall’s work on dropsy is evident from the remarks of the reviewer. Cure o f Dropsies John Blackall (fig. 1) was born in 1771 in Exeter, England, and educated at Exeter Grammar School and Balliol College, Oxford. He received his BA degree in 1793 and his MD degree in 1797. He received a second MD degree from St. Bartholomew’s Hospital in 1801. He gained his MRCP in 1814 and became FRCP in 1815. He worked as a physician in Totnes, Devon, from 1801 to 1807, after which he returned to Exeter. In 1812 he became physician to the Hospital for Lunatics. In 1813 he published his Observations on the Nature and Cure o f Dropsies  (fig. 2) which went through 5 editions (1813, 1814,1818,1820,1824) including an American edition in 1820 based on the 3rd London edition. This work was widely regarded as a significant contribution to the medi cal literature (fig. 3). Blackall was highly regarded as a physician: ‘His information on medical matters, singularly extensive and accurate, had been qualified by a wide and varied research from many departments of human knowledge; his diagnostic powers were of the highest order’ , He practised until the age of 80 years and died aged 88 years in 1860. 373 Downloaded by: Vanderbilt University Library 184.108.40.206 - 10/26/2017 9:11:32 AM John Blackall and Observations on the Nature and Dropsy Urine differs little from the healthy state Without bloody sediment Related to administration of mercutials Fig. 4. Schematic overview of the catego ries of dropsy described by Biackall. Blackall’s single work (no other publications by him have been traced) has a title that raises the possibility that he may have made the seminal discovery for which Richard Bright later received the credit. This article examines whether this was the case or not. His book was fully titled Observations on the Nature and Cure o f Drop sies and Particularly on the Presence o f the Coagulable Part o f the Blood in Dropsical Urine and contained 15 chapters and An Appendix Containing Several Cases o f Angina Pectoris with Dissections, etc. Biackall indicates in the introduction that he was aware of previous reports of coagulable urine in dropsy and cites the writings of Fordyce, Darwin, Cotunnius (Cotugno), Vauquelan, Fourcroy and Cruikshank. His interest in the topic seems to have been stimulated by a single case under the care of his preceptor Dr Latham. It is difficult to follow a simple pattern of thought through the book, so a simple description of its contents would be confusing. Figure 4 categorizes, in a simplified fashion, the different forms of dropsy that Biackall con sidered. What follows describes his experience with each. Dropsy in Which the Urine Differs Little from the Healthy State In this general category Biackall describes individual cases of anasarca without any unique or distinguishing features, in which the urine is described as pale, crude and apparently diluted. He notes that this is not very common in dropsy. In none of the patients was a coagulum pro duced by heat or nitrous acid but in 2 cases oxymuriate of mercury detected a small amount of ‘albumen’. For no obvious reason, he concludes that this form of dropsy is connected with ‘great and irretrievable injury of internal 374 Scanty volume Fine/English Urine coagulable by heat With blood} sediment Unrelated to to medication organs’. He regarded digitalis as being of little use in the treatment of these patients, and indeed felt that the poly uria was a very bad sign as it precluded the use of many diuretics. He described another group of cases in which the only difference seems to be that the volume of urine was small. Here for the first time he alludes to the ‘bad effects of mercury’, which he regarded as being far more common than generally suspected, as is discussed below. Dropsy in Which the Urine Is Not Coagulable. Is Scanty. High Coloured and Deposits a Sediment Biackall includes a variety of cases of ascites, hydrotho rax, pericardial effusion and anasarca in this category. He refers to the sediment in the urine as ‘lateritious’ (brickcoloured). The sediment in many cases was pink. Of the 21 case reports provided, most are very brief and in only 2 (cases 11 and 21) were autopsies performed. In 1 case the liver was hard and small. Biackall attempted to define the nature of the sedi ment. It was precipitated by ‘the infusion of galls’ but not nitrous acid, suggesting that it was not protein. Oxymu riate of mercury occasionally produced a coagulum re sembling the effect of heat. Biackall concluded that this was: ‘in a great measure at least, albumen'. He further concluded that the pinkish material was: ‘pure ammonia, the muriate of barytes and acetate of lead [and] a large proportion of saline matters’. Despite the fact that he paid such attention to this pinkish sediment, he is objective enough to conclude that it is not always present in dropsy associated with a scirrhous liver, as Cruikshank had pro posed, nor did its absence allow any conclusions to be drawn about the cause of the dropsy. John Biackall and Dropsical Patients Downloaded by: Vanderbilt University Library 220.127.116.11 - 10/26/2017 9:11:32 AM Copious volume Urine not coagulable by heat but scanty, high coloured and deposits a sediment ‘... the kidneys were rather soft and flaccid and more loaded with fat than could have been suspected after so long an illness, but in other respects quite natural.’ Of interest is the fact that this particular case, while included in the chapter on scarlatina, did not have scarla tina but an erysipelatous inflammation of the lower extremities. Couched in modern terms this case is likely to have been secondary infection of grossly oedematous legs, while the renal appearance is consistent with ‘lipoid nephrosis’. As far as the bloody urine sediment is concerned, Blackall had no doubt that this was true haemorrhage, as ‘its appearance could hardly deceive’. Dropsy in Which the Urine Is Coagulable by Heat: Associated with Administration o f Mercurial Compounds Throughout the book Blackall alludes to the potentially deleterious effects of mercury (calomel). He seems to have had little respect for a therapy which, if continued, led to the gums becoming sore and greatly debilitated the pa tient. The refrain: ‘I cannot help fearing that mercury had some share in thus changing the type of disease’ (chapter 4, case 8) is chanted in one form or another repeatedly. Blackall was impressed with the long-term adverse effects of mercurials, and when complicated by continued saliva tion, he believed the underlying disease to be more speedi ly fatal. One autopsy was performed on a patient who suc cumbed to general debility, severe oedema of the legs and a sloughing ulcer of the leg. The urine was coagulable by heat. Post mortem examination showed pleuropericarditis was present and the: ‘kidneys [were] unusually firm’. Another autopsy was performed on a patient who re ceived mercurials for treatment of diarrhoea, which turned out to be related to ileocaecal tuberculosis, and in this case: ‘the kidneys [were] remarkably loaded with blood as if infected’. Dropsy in Which the Urine Is Coagulable by Heat: Associated with Drinking Cold Water when Heated and Fatigued. Exposure to Cold. Intemperance. Cachexia and Scurvy This is a heterogeneous collection of cases of anasarca, ascites, or leg swelling in which scanty, coagulable urine was found. No insight into involvement of the kidneys was provided. Dropsy in Which the Urine Is Coagulable by Ileal: Associated with Hydrothorax, Ascites and Hydrocephalus It is not at all clear what this group of 9 patients with ‘hydrothorax’ represents, because examination of the chest using percussion and auscultation had not been described. In one case the autopsy revealed a unilateral hydrothorax, atelectasis of the underlying lung and the: ‘kidneys [were] remarkably small and sound’. Similarly, in an autopsy on 1 case of ascites with copious coagulable urine, a hardness and enlargement of the right lobe of the liver was found, firmly resisting the knife. The other viscera were sound: ‘except the kidneys, which were remarkably solid and hard, their stmeture somewhat confused’. Blackall recognized this appearance of the kidneys to be very uncommon and remarks that he is not aware that: ‘such a hardness approaching to scir rhous has ever been attributed to the use of mercury’, but contradicts this statement by referring to 1 of the cases described above. Blackall’s Overview In his defence it must be said that any failure of Black all to recognize the association of coagulable urine with kidney disease can be attributed to the very small number of post mortem examinations which he performed on his patients. But he did fail to recognize the association! In attempting to summarize his findings, he is obtuse and vague in the extreme. Indeed, he indicates that coagulable urine: ‘is not connected exclusively with any particular situation’. He did attempt to address the nature of the coagulable substance that he recognized as ‘serum’, noting that both heat and nitrous acid produced the coagulum. It appears that it was commmonly accepted at the time that oxymuriate of mercury could be used to detect very min ute quantities of albumin, but Blackall considered this test to be unhelpful: ‘since it acts on the urine in many other cases of dropsy’, i.e. also those that do not have coagulable urine. This statement confirms that he thought that the coagulum was some component of serum other than albu min. 375 Downloaded by: Vanderbilt University Library 18.104.22.168 - 10/26/2017 9:11:32 AM Dropsy in Which the Urine Is Coagulable by Heat: Associated with Scarlatina Blackall devotes almost 140 pages to this topic. In most cases the dropsy appeared weeks or months after the attack of scarlatina, and in half of these cases Blackall found a blood-stained urine sediment. Most were treated with digitalis; indeed, Blackall states: ‘I know of no instance where digitalis has failed’. A few cases developed erysipelas of a limb at the time that dropsy was present. In only 1 case was an autopsy done and in this: In some cases, he considered the urine to be deficient in urea (a substance isolated in 1797 by Fourcroy and Vauquelin ), acidic, ‘unanimalized’ and resistant to putrefaction. He was unable to determine from his experi ence whether coagulable urine ever precedes the onset of dropsy. He confirmed Wells’ observation that a bloody sediment is found after an attack of scarlatina and sus pected that the use of calomel aggravated this state. Perhaps Blackall’s single most important contribution, when viewed with hindsight, was his demonstration that mercurials were being abused and that the ‘mercurial hab it’ caused irritation and inflammation, and also dropsy. He further ascribed some cases of fevers of children to the excessive use of calomel. In reviewing the 9 autopsies that he described in his book, Blackall concluded that the urinary organs are often free from any appearance of unsound structure, despite the great fault in their secretion and that, in 2 mercurial cases, the kidneys were firmer than normal. Finally, Blackall posed the obvious question: where does the coagulable part of the urine come from? He refered to the earlier contention of Erasmus Darwin that it enters the bladder by an inverted motion of the lym phatic system, but is quick to refute this by saying that it has: ‘no kind of support from anatomy’. Could the dropsi cal accumulations supply the albumin in the urine, he asks? As it is hardly ever found other than with dropsy, and as the fluid is wholly unfit for the purposes of circula tion, he concluded that it is appropriate that it should be discharged. He argued that the kidneys, from their ‘com parative simplicity of secretion’, are probably the ‘glands’ most suited for this purpose, as: ‘they appear to be pos sessed of a sort of selective power capable of separating the blood from whatever is hurtful to it’. On the other hand, he contended that this understanding does not account for the presence of blood in the urine and noted that, occasionally, coagulated urine had been observed in patients without dropsy or in hydrocephalus where the amount of accumulated fluid was small. Most important ly, the excretion of the coagulable substance increased precisely when the disease was worst and decreased when relief was obtained, contrary to his expectation that recov ery should be associated with an ‘unloading’ of the materi al into the urine. Blackall was forced to conclude that he was uncertain about whether the serum found in the urine was derived from dropsical accumulations. At no point does disease of the kidney as a cause of the coagulable urine rear its head! Acknowledgements The authors are appreciative of having been provided with an unpublished English translation by Professor J.S. Cameron of Pierre Rayer’s writings on the history of renal disease, which was invaluable in the preparation of this paper. References 376 4 Cruikshank WG: Experiments on urine and sugar by Mr Cruikshank; in Rollo J (ed): Cases of Diabetes Mellitus. London. J Dilly, 1798. pp 443-451. 5 Wells WC: Observations on the dropsy which succeeds scarlet fever. Trans Soc Improvement Med Surg Knowledge 1812;3:167-186. 6 Blackall J: Observations on the Nature and Cure of Dropsies and Particularly on the Pres ence of the Coagulable Part of the Blood in Dropsical Urine. London, Longman, Hurst, Rees. Orme and Brown. 1813. Finc/English 7 Harris JD: The Royal Devon and Excter Hos pital. Exeter. Eland Bros, 1922. 8 Fourcroy AF. Vauquelin N: Mémoire pour ser vir à l'histoire naturelle clinique et médicale de l’urine humaine. Mémoires de l’Institut 1797: 2:431-437. John Blackall and Dropsical Patients Downloaded by: Vanderbilt University Library 22.214.171.124 - 10/26/2017 9:11:32 AM 1 Southey R: The Lectures on Bright’s Disease. Br Med J 1881;1:541-546, 587-589.625-627. 669-672,713-715. 2 Rayer P: Traité des Maladies des Reins. 3 vol with atlas. Paris, Ballière, 1839. 3 Cotugno D: De Ischiade Nervosa Commentarius. Vienna. R Graffer, 1790.