On the Evolution of Pediatrics and the Emergence of Pediatric Nephrology

The Emergence of Pediatrics 

Stories of child sacrifice in antiquity notwithstanding, the care of infants and the care of sick children must have been part of the concerns of populations from the very beginnings of human history. What may have begun as animal instincts was gradually refined into the emotional bonds and natural affections that constitute the very basis of civilization. In time, the care of sick children took shape in shared observations and experiences passed on orally in the priestly and folk medicine of antiquity. By the time recorded medicine began, a body of knowledge already existed that related to the care of children. Most texts of this period center around the care, feeding, and growth needs of infants. However, buried in these early text, and receiving increased attention over time, are descriptions of afflictions of children and reference to how their treatment differs from treatment of the same diseases in adults. Treatments of diseases likely to affect children that appear among the prescriptions listed in the Ebers Papyrus (ca. 1500 B.C.) are those for teething, running nose, ascites, and disorders of the abdomen and urinary tract. Specific recipes are given for the retention of urine, to regulate urination, and for excessive urination.1 Because these ancient writings are consigned to symptoms rather than diseases, speculation on the actual diseases and the treatments administered is not possible.

Hippocrates (459–355 B.C.) devotes several of his Aphorisms (Section III, 24–29) to diseases of children and refers to them in several of his other texts.3 Pertinent to nephrology are his comments on bladder stones: “Children get stone from milk if it is not healthy, but is too hot and bilious … and I say that it is better to give children wine, much diluted, for it has a less heating and drying effect…” The special care of children is mentioned also in extant medical texts of antiquity such as the De Medicina (ca. 50 A.D.) of Celsus (25 B.C.–50 A.D.), which states that “children require to be treated entirely differently than adults” but does not really detail how. Among ancient texts, the first to devote a section (23 chapters) to children is that of the gynecological text of Soranus of Ephesus (98–138 A.D.), in which the care of infants and selected diseases of children receive full attention.4, 5 Two features characterize this milestone text. First is the devotion of most of its text to the rearing of infants and care of the healthy child (feeding, teething, itching, rashes, enuresis, running nose, and ear), a feature that was to remain the major component of most pediatric texts that followed. Second is the association of diseases of children with those of women that was to persist well into the nineteenth century, when pediatrics was still taught in medical schools by professors of obstetrics. Indeed, one of the first journals in the United States dedicated to diseases of children was the American Journal of Obstetrics and Diseases of Women and Children established in 1868.

Rhazes (850–925), famous for his text on smallpox, was the first to write a brief treatise in 24 chapters on diseases of children rather than just providing the traditional advice on the care and nursing of infants. Originally appended to his Almansorem (Al-Mansouri), it was copied and published by subsequent authors as a separate text.1 Rhazes’ equally well-known successor, Avicenna (980–1037) devotes three sections of his Canon to antenatal care, the choice of a wet nurse, and the proper regimen for infants.1, 5 He deals with problems unique to children briefly in Chapter 3 of Book 1 and selectively in other parts of the Canon, such as his description of the surgical removal of bladder stones (Book VII, Chapter 26), in which he specifies that children should be held down “by one, or if necessary two, strong men. The surgeon should be a young man … fearless in character … pitiless. Pitiless in the sense that his desire for the cure of the case he has undertaken, so that he will not be moved by his cry to hurry more than the case demands, nor cut less than needful.”

An increasing number of pediatric texts began to appear in the latter part of the fifteenth century, which, thanks to the earlier invention of the printing press, led to the wider dissemination of knowledge and a revival of learning in the field. The next stage in the expansion and wider diffusion of new knowledge was writing in the vernacular that began in the sixteenth century, so that information became accessible not only to the favored few who knew Latin but also to practitioners in medicine and the learned public in general. This period, a century before the scientific revolution that was to change medicine drastically, also heralded the appearance of daring authors who recorded their own original observations rather than merely recounted and interpreted what their predecessors had reported. One of these original records, published in 1583 by Hieronymus Mercurialis (1530–1606), makes the first mention of hematuria after the use of cantharides “because I have often observed the passage of blood in urine” after its use.5 More pertinent to nephrology is the following quote from 1611 by Franciscus Perez Cascales, who, after dividing suppression of urine into one condition in which the urine cannot be passed from the bladder (obstruction) and another condition in which no urine comes into the bladder (kidney disease), wrote “Many physicians have not the slightest acquaintance with this entire suppression of urine, which must be considered a rare and deadly disorder; but I who deserve to be called the least of physicians, declare, so help me Heaven, that I have seen and cured four patients with complete suppression, no urine entering the bladder.” Whether the suppression of urine he refers to was caused by acute tubular injury or acute glomerulonephritis is impossible to tell. He attributes it to the fact that the body fluids become so thick that excretion is prevented.5

By the eighteenth century, an increasing number of books (75 as compared with 21 in the seventeenth century) and almanacs that provided practical information on the care of children and their diseases began to appear.6, 7 Because of greater concern for the welfare of children, infant consultation clinics were founded and were soon followed by the establishment of hospitals for sick children.1, 5, 6, 7 Actually, hospices for children had existed since the sixteenth century. However, these early hospices were a place to die rather than recover. By the end of the century, as physicians were assigned to these institutions to supervise the care and treatment of children, hospitals for “curabiles” began to spring up alongside those for the “incurabiles,” which had served for the isolation of lepers, epileptics, and dying children. The founding of pediatric hospitals in earnest dates from the first half of the nineteenth century (Paris 1802, Vienna 1837, Prague 1842, Berlin 1843, Turin 1845, London 1852, and Philadelphia 1855). By the mid-1800s, concomitant with increased interest in the care of children, hospitals for sick children were being established in growing numbers, and general hospitals opened special wards for children.6, 7, 8 The establishment of hospitals now allowed the correlation of clinical observations made at the bedside to morbid anatomy changes detected postmortem in assorted cases. As a result, diseases of children were studied and analyzed in larger numbers of cases. Diseases were described in greater detail, and new ones recognized. This outcome was not unique to pediatrics and corresponds to the period when the study of the pathological anatomy of hospitalized patients was the cornerstone of advances in medicine in general, and it is during this time that Richard Bright (1789–1858) described the disease that was to be named after him.

Unfortunately, given the limited treatments available, little curing occurred during that time, and the mortality of hospitalized patients was high. The now famous Boston Floating Hospital at Tufts-New England Medical Center was actually a ship, which put to sea daily with loads of sick babies and their parents and returned at nightfall with a handful of survivors; the others having been buried at sea.7, 9 This situation was to change during the latter half of the nineteenth century, when developments in the biological sciences and in chemistry, especially biochemistry, began to provide a sound basis for the study of diseases that was to provide the groundwork for their treatment. These clinical investigations in the new hospitals for children assured the institutionalization of pediatrics by laying the foundations on which the new specialty organized itself into a discipline. Two figures stand out in this evolutionary period in the United States: Job L. Smith (1827–1897), who helped establish the American Pediatric Society in 1888, and Abraham Jacobi (1830–1919), who founded the Section on Pediatrics of the American Medical Association (AMA) in 1880. The rudiments of medicine as it related to children that had been part of general teaching in medical schools began to receive increased emphasis. As a result, by the turn of the twentieth century, half the medical schools in the United States had dedicated chairmen of pediatrics.1, 5, 7

Diseases of Children and Emergence of Nephrology 

The single most common cause of hospital mortality during this evolutionary period was diarrhea of childhood, which had a mortality as high as 80% to 90%. Actually, the problem was an ancient one mentioned by Hippocrates in one of his aphorisms: “They that often pass bloody and indigested stools from the belly are specially liable, amongst the symptoms of fever, to drowsiness.”3 The study of diarrheal diseases of children that had begun in the eighteenth century, assumed increased urgency at the end of the nineteenth century. Because a considerable amount of blood (200 mL) was needed for chemical analysis, analysis of the whole body of infants postmortem was done instead, but this approach failed to detect chemical abnormalities, and death came to be attributed to such causes as “decomposition” that resulted from “intestinal intoxication,” or, in their original German, “toxikosis” caused by “coma dyspepticum.”1, 5 The changes in the urine of these patients had been noted and recorded in 1752 by Rosenstein (1706–1773): “The urine in a diarrhea, is in much less quantity than before, and is also redder than usual; it is therefore a good sign, when it is discharged in a greater quantity, and its color is clear. This shews a less flux towards the intestines, and a more equal division of the fluids, in order that they also dilute the urine. By this we learn the reason of our being obstipated by drinking mineral water when it is carried off too soon.”10

Analysis of the composition of urine and blood of these cases was to come much later. In the meantime, the symptoms of diarrhea had come to be attributed to “acid intoxication” and treated with alkali.11 Ultimately, it was the solution of what came to be known as the “Milk Question” that provided chemical answers.6, 7, 8 In the closing years of the nineteenth century, social, economic, and cultural forces consequent to increased urbanization had prompted mothers to substitute bottle-feeding for breast-feeding in the era before refrigeration and pasteurization. The subsequent conflict between physicians in general, and pediatricians in particular, concerned over the high mortality among bottle-fed infants and mothers seeking self-control was resolved by advances in the pediatric sciences and by public policy that instituted pasteurization and sterile sealing of milk in the 1930s,12 a period that corresponds to the increased professionalization of pediatrics. Of the many institutions and pediatricians who participated in the resolution of the Milk Question, three names stand out. The first is John Howland (1873–1926), founder of the first department of pediatrics in the United States in the medical school at Johns Hopkins University. His studies of diarrhea introduced quantitative analytical techniques to pediatrics. Importantly, Howland’s vision in recruiting the second key player, James Gamble (1883–1959), led to an important part of the solution to the Milk Question and, in the process, contributed to the foundation of renal physiology that preceded the emergence of nephrology.13, 14

Gamble had begun research in 1915 and spent most of his life in the laboratory studying diarrheal dehydration. As a student of Lawrence J. Henderson (1878–1959), he was well prepared for the task. The processes of preserving constancy of the environment surrounding cells and tissues was conceived and developed by Henderson in his physicochemical description of acid–base balance, which finally began to provide an explanation to what had been termed the “acid intoxication” of diarrhea.11 Gamble adapted this structural model to the study of volume depletion, which he depicted in his now classic bars that became famous as Gamblegrams and are still used to illustrate changes of urine and blood electrolytes in metabolic-balance studies. His initial report was on the blood and urine changes of four children with epilepsy who were treated with fasting, then with a traditional therapy to induce acidosis.15 This study and his subsequent studies began the unraveling of the then mysterious adaptation of the kidneys, lungs, and extracellular volume to changes induced by dehydration. Gamble was the first to use the flame photometer, which he helped develop.9, 13, 15, 16, 17

The third key figure was Daniel C. Darrow (1885–1965), who established the principle that water is freely permeable across cell membranes and that the shift caused by osmotic changes accounts for hyponatremia-induced increase and hypernatremia-induced decrease in cell volume. Importantly, he was the one to describe potassium deficiency and the extracellular alkalosis and hyponatremia associated with volume depletion. The studies of Darrow and Gamble in the 1920s to 1930s, at a time that Homer Smith (1895–1962) was defining glomerular filtration and the tubular functions of the kidney, were the basis of the corpus of information that was to form the core of the then emerging science of nephrology.13

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Fig 1. A man and a child presenting their urine samples for examination by a doctor, surrounded by his attendants and students. Inspection of the gross characteristics of the urine in the special flask (matula) shown in the figure was one of the most common methods (uroscopy) for the diagnosis of disease in adults and children. In the Middle Ages, the matula became the symbol of the doctor. By the end of the seventeenth century, uroscopy began to be replaced by urine microscopy, although urine microscopy was not widely practiced. In 1909, Abraham Jacobi, a proponent of urine microscopy in children, lamented the failure to recognize glomerular nephritis in children as “deplorable as the diagnosis at any age is readily made by the examination of urine.”

The other disease of childhood that contributed to the emergence of nephrology is the nephrotic syndrome. The discovery of adrenal cortical tropic hormone (ACTH) and steroids after World War II led to their successful use in the nephrotic syndrome of children. The prohibitive cost of these therapies at the time led to the foundation in 1948 of the Nephrosis Foundation, which was to become the National Kidney Foundation (NKF) in 1950, the first organization in the United States dedicated to the support and dissemination of knowledge on diseases of the kidney. The Scientific Advisory Board of the NKF was the nidus around which the American Society of Nephrology was founded in 1969 and, after dialysis became available, helped introduce Public Law 72-93, which provided funding for ESRD, probably the most important factor that led to the blossoming of nephrology.14, 18

The emergence of pediatric nephrology from these beginnings closes the circle that began with the emergence of nephrology from its foundations in the studies of childhood diarrhea and treatment of the nephrotic syndrome. The founders of pediatrics had foreseen the branching of their discipline when they adopted the plural term, pediatrics, as the name their new specialty. The first recorded application of a name to the discipline was “pedenemice,” used by Gabriel Miron, physician to Louis XII of France, in 1544, to avoid use of such unwieldy phrases as management or treatment of diseases of childhood that had been used theretofore.1, 5, 6 In 1722, Theodor Zuringer (1658–1724) first used the term “Paedo-Iatrea” (Paedo, Greek for child and Iatreia, Greek for physician), the linear ancestor of pediatrics.5 However, pedenemice remained in vogue, and its derivatives “pedology’ for the science and “pediatrist” for the practitioners were used well into the early twentieth century. Instrumental in the ultimate adoption of pediatrics was Abraham Jacobi, who, in his contributions to the teachings of the new specialty, popularized the use of the term pediatrics, a welcome change from the phonetic confusion that pedenemice and its derivatives could have caused otherwise.

Among the topics that Jacobi helped popularize was that of the then little known childhood glomerular nephritis and its uremic complications, a condition he described as “deplorable as the diagnosis at any age is readily made by the examination of urine.” 6, 19 (Fig 1). Much has happened in the century since Jacobi lamented the state of the art in 1910. This issue of Advances in Chronic Kidney Disease presents the current state of knowledge of chronic kidney disease of children accrued over the relatively short period of time since pediatric nephrology emerged as a discipline.