Read History of Nephrology: Beginnings

 

George Dunea, MD

Hektoen Institute, Chicago, Illinois, United States

 

Domenico Cotugno

Domenico Cotugno

Coagulable urine

Despite centuries of medical progress, the presence of abnormal amounts of albumin in the urine remains to this day the most sensitive and widely used indicator of renal disease. Described by Hippocrates as “bubbles on the surface of the urine” and known to medieval uroscopists as frothy urine presaging an unfavorable prognosis, it now dominates modern medical thought in the form of micro albuminuria. Already Paracelsus had mentioned in his writings (1527) that adding wine or vinegar could cause some urines to curdle and yield a milky precipitate.1 Others too may have known about this, but credit is traditionally given to the Dutchman Frederick Dekkers of Leyden, who in 1694 reported that certain urines were coagulable by heat.2

Almost a century later, in 1765, Domenico Cotugno (1736–1822), distinguished professor of medicine at the University of Naples, reported coagulable urine in a dropsical patient, a 28-year-old soldier with fever, edema, and anasarca. On further examination “a dense white body like albumen of boiled egg was found in the urine after heating.”2,3 As both urine and edema fluid were coagulable, Cotugno postulated that during diuresis the edema fluid would be discharged in the urine. He lived until the age of 82 and after his death many of his papers and manuscripts were destroyed by his wife, described as an unsuitable woman of good family whose “peculiar mixture of bigotism, prodigality, and stupidity made her detestable.”3 Cotugno was contemporaneous with Rosen von Rosenstein of Upsala, who in 1765 wrote a treatise in Swedish noting that scarlatina could be followed by dropsy and bloody urine, an early description of acute nephritis.2

Further advances

By the end of the 18th century other physicians also reported finding coagulable urine but mostly failed to recognize its significance.2–7 William Cruickshank of St. Thomas’ Hospital in London carried out extensive chemical studies and reported in 1798 that the urines of certain dropsical patients could be coagulated by nitrous acid or by heat, but that “in the dropsy proceeding from diseased liver and other morbid viscera the urine does not coagulate either by nitrous acid or heat.”4

A more extensive report came from William Charles Wells, born in South Carolina, trained in Edinburgh, and also working in London. Between 1806 and 1811 he reported first on scarlatinal edema in children and later on some 78 patients with dropsy and proteinuria, noting at autopsy hard thick renal cortices in one patient and abnormally large and soft kidneys in another.5 John Blackall, physician to the Hospital for Lunatics in Exeter, published in 1813 his Observations on the Nature and Cure of Dropsies, which went through five editions, including an American one in 1820.6,7 He described various groups of patients with edema and coagulable urine, noting that some the kidneys were “unusually firm,” “loaded with blood as if infected,” or “remarkably solid and hard, their structure somewhat confused.”6 His observations lacked the dimension of Richard Bright, who however acknowledged his “most valuable treatise.”2 Yet both Wells and Blackall failed to make the link between edema, proteinuria, and kidney renal disease.5–7

John Bostock, chemist and physician at Guy’s Hospital, also studied the composition of urine, publishing his first paper in 1803. He quantified the albumin in the urine by evaporation, working in collaboration with Richard Bright and being responsible for the analytic studies on the urines of the patients described by the latter.8

 

Richard Bright

Richard Bright

Richard Bright

It remained for Richard Bright (1789–1858) to recognize that albuminuria in the presence of edema meant kidney disease.2,5,6–15 A talented scientist, he had studied in his youth the volcanic terrains in Iceland, was elected to the Geological Society of London, journeyed twice to Hungary and wrote about it, and on his return hastened to Brussels after the Battle of Waterloo to tend the wounded.9 At Guy’s Hospital he later established what has been considered the first medical research unit. He described acute nephritis, nephrotic syndrome, uremia, small shrunken and large swollen kidneys, also noting that some patients had enlarged left ventricles, an indirect evidence of hypertension at a time when sphygmomanometers and chest X-rays were unknown. His unit at Guy’s Hospital consisted of two wards, a male ward of 24 beds and a female ward of 18 beds, a meeting room for physicians and students, and a small laboratory for clinical analyses.10 His observations, published between 1827 and 1842, have been described as “the most wonderful series of papers in medical literature.”10 When several specimens preserved in the Guy’s museum (of which Thomas Hodgkins was curator) were examined some 140 years later, two were found to be examples of membranoproliferative glomerulonephritis, the third of amyloidosis, probably secondary to tuberculosis.10

Richard Bright has been justly called “the greatest physician of his day and one of the five or six great physicians of all time.”10 He died in 1858 at age 70, some say of aortic stenosis.10 According to his niece, however, his colleagues had by 1852 noted “his worn looks, his pallor and swollen feet,” giving rise to rumors that Doctor Bright was suffering from the very disease he had described.

Bright’s disease

The concept of Bright’s disease became quickly and widely accepted in England, France, Germany, and the United States. Soon heated arguments broke out as to whether Bright’s disease was one disease or several, and there followed several attempts to subclassify it. In Paris Pierre Rayer, a talented investigator who described renal vein thrombosis and renal anemia, devised a classification that distinguished acute nephritis (nephrite albumineuse aigue), nephrotic syndrome (nephrite albumineuse chronique), and pyelonephritis (pyelite aigue & chronique).12–14 In England Samuel Wilks, also at Guy’s, published a series of 61 patients and concluded that there were two types of Bright’s disease (1853), one with edema and large pale kidneys, the other without edema but with uremia and contracted red kidneys.13

In Germany Friedrich von Frerichs published in 1851 a monograph on “Bright’s disease” in which he supported a unitary theory, maintaining that the various pathological changes seen were stages in the evolution of one disease.13–17 In this he was later supported by Virchow and other pathologists. Frerichs already had use of a microscope (introduced into clinical medicine by Pierre Rayer), allowing him to deduce that the composition of the glomerular filtrate depended on the height of the hydrostatic pressure and the pore size of the glomerular wall, and that Bright’s disease would follow the rupture of capillaries and blood extravasation from increased glomerular pressure.17

Later contributions came from Gottlieb Gluge, who noted “inflammatory globules” on microscopy and concluded that they represented inflammation of the Malpighian bodies, an observation also made by Antoine Becquerel.14 Hugo Hecht and Friedrich Henle (1833) considered tubular degeneration to be the cause of Bright’s disease;14 Ludwig Traube thought that interstitial fibrosis was the primary lesion;14 and Rudolph Virchow promoted the concept of “parenchymatous nephritis” from alterations in the epithelial cells near the Malpighian corpuscle.14 In 1870 Edwin Klebs coined the term glomerulonephritis; and in 1879 Theodor Langhans noted glomerular hypercellularity in this condition.14

High blood pressure and the kidney

In the second half of the 19th century there were lively arguments about the nature of what we now recognize as high blood pressure. Already earlier on Jean-Baptiste Senac (1693–1770) had discussed the relation between cardiac size and its “force,” attributing cardiac hypertrophy to valvular disease.7 John Blackall had noted that a hard pulse in some of his albuminuric patients (1814) was improved by venesection and, as noted earlier, described alterations in the kidneys in some of his patients but attached no significance to these findings.6,7,20 Richard Bright had described cardiac hypertrophy in some of his patients (1827) and later, as microscopic anatomy came into being, collaborated with Joseph Toynbee and noted thickening of small renal vessels in autopsy specimens.18 He thought that altered blood chemistry (i.e., uremia) increased cardiac work either by a direct action on the heart or by increasing peripheral resistance (1836).15–18 In this he was vigorously supported by the influential George Johnson (Guy’s), who also maintained that vascular changes and left ventricular hypertrophy were caused by an alteration in the quality of the blood (1850).7,15–17,20,21

The first hint that hypertension might arise de novo in persons with normal kidneys came from Samuel Wilks, who in 1853 described “cases of diseased arteries and hypertrophic heart without the presence of diseased kidneys.”7,15–17,20,21 In 1872 William Gull and Henry Sutton, also at Guy’s Hospital, concluded that “arteriocapillary fibrosis,” arteriolar thickening, narrowing, and hyaline were the cause rather than the consequence of kidney disease, leading to an acrimonious dispute with Johnson.7,15,16,18,20 None of these authors, however, mentioned the possibility that these vascular changes might be caused by increased pressure in the blood vessels.7,15–21 This dilemma was echoed by Peter Mere Latham (1789–1875), who wrote: “What exact relation diseases of the kidney bears to hypertrophy of the heart, we do not know even yet. But the two are too often coincident in the same subjects for them not to bear some, and that a very important, relation to each other.”

It was Ludwig Traube (1818–1876) who is usually credited with the idea that raised intra-arterial pressure was the cause of the vascular disease and left ventricular hypertrophy, thus establishing a clear association between diseases of the heart and kidney. He saw hypertension as a compensatory phenomenon in that the mean pressure of the arterial system had to increase to perfuse diseased kidneys as “shrinking of the renal parenchyma decreases the amount of liquid removed from the arterial system by urinary excretion.”14–21          

Traube was anticipated in his views by William Senhouse-Kirkes (1822–64) an English physician to whom Traube indeed gave appropriate credit: “It was Senhouse-Kirkes who first proposed that “arteriosclerosis is first of all the result of long-lasting high grade tension of the aortic system . . . the arteriosclerosis would then have the same foundation as hypertrophy of the left ventricle.”7,19

 

Frederick Akbar Mahomed

Frederick Akbar Mahomed

Mahomed

Frederick Akbar Mahomed (1849–1884) may justly be deemed the true discoverer of essential hypertension and the originator of the concept that high blood pressure could damage the kidneys and blood vessels. Grandson of an Indian immigrant and physician at Guy’s hospital, he unfortunately died of typhoid fever at the early age of 35. Using a rudimentary modification of Marey’s sphygmograph,7 he was able to measure blood pressure and carried out extensive studies, publishing a series of papers on “Bright’s Disease without Albuminuria.” He used the unfortunate title “Prealbuminuric Bright’s Disease,” partly out of reverence for Richard Bright, but also because he believed that all cases of nephritis went through a prealbuminuric phase.2,16,20,21

In Germany Ritter von Basch further advanced matters by obtaining more accurate blood pressure measurements with an improved apparatus that applied external pressure, making numerous blood pressure estimations, and calling the condition described by Mahomed “latent arteriosclerosis” (1893). In France Henry Huchard also confirmed Mahomed’s findings but called the disease pre-sclerosis or arteriosclerosis (1899).19–21 In England Sir Clifford Allbutt, the influential regius professor at Oxford, [believed to be the model for George Eliot’s Dr. Lydgate in Middlemarch]7 wrote that Mahomed had described a condition that resembles the granular kidney but with the part of Hamlet left out,19 and called it hyperpiesia.7,10,15–17,20,21 In 1911 E. Frank called it essential hypertonia, which later became essential hypertension.7,20

 

Rev. Stephen Hales, 1953

Rev. Stephen Hales, 1953
Joseph F. Doeve

Hypertension landmarks

References to a hard pulse are found in classical Chinese and European writings.7,20 We owe the concept of the heart as a pump to the observations of William Harvey (1578–1657) and Giovanni Borelli (1608–1679).7 The first attempt to measure blood pressure directly has been attributed to the Rev. Stephen Hales (1677–1761), who in 1733 “caused a mare to be tied down. . .” and measured her direct blood pressure by cannulating the carotid artery.7,20,21 Jean Marie Poiseuille (1799–1860) devised a mercury manometer, the "hemodynometer," to measure blood pressure,15,20,21 and John Blake (1815–1895) in London, used it in experiments, concluding that the pressure in the arterial system was nothing but an expression of the force required for the blood to pass through it. In 1856 Jean Faivre adapted the hemodynamometer to measure directly the blood pressure in three people who had suffered amputation of arm or leg.

More practical were instruments allowing indirect blood pressure measurements based on estimating the amplitude of the pulse, such as the “sphygmometer” introduced by Herisson in 1834, in which the radial artery was compressed with a bulb containing mercury and allowing oscillation measurements of the height of the column.15,20 In 1847 Carl Ludwig built the “kymograph,” in which a smoked drum and stylus were used to record the blood pressure. Karl Vierord (1818–1884) used a modified kymograph, and this was followed by Etienne-Jules Marey’s (1830–1904) “sphygmograph,” the first usable machine for clinical purposes, later again modified by Sanderson and also by von Basch.7,15 19–21 In 1896 Riva-Rocci invented the sphygmomanometer,7,15,20 later modified by von Recklinghausen, and soon widely used for indirect blood pressure recordings based on Korotkoff’s description of the sounds heard over the brachial artery (1905). It is sobering to think that even in the early 1900s physicians could measure only systolic blood pressure.

The ophthalmoscope, invented by Wilhelm von Helmholz in 1851 and later used by Albrecht von Graefe, led to the description by Heymann of the optic changes of malignant hypertension (1858), named albuminuric retinitis by Liebreich in 1858 and more accurately hypertensive neuroretinopathy by Fishberg and Oppenheimer in 1930.15,20 These changes were reclassified in 1939 by Keith, Wagener, and Barker into four groups—a classification still in use at this time.

The role of salt in hypertension was formulated by Fernand Widal, Hermann Strauss, and later by Leon Ambard, who introduced a chloride depletion diet.7,13In 1898 Robert Tigerstedt and Per Bergmann expanded the understanding of the role of the kidney in hypertension by isolating a pressor extract from the kidneys, which they called rennin.15

In 1914 Franz Volhard and Theodor Fahr noted in their famous monograph on Bright’s disease that nephrosclerosis could run two courses, one “benign” (gutartige) and the other “malignant” (bösartige),22 subsequently renamed “malignant hypertension” by Keith, Wagner, and Kernohan (1928). The latter published detailed clinical descriptions of malignant hypertension (1928), as did Klemperer and Otani (1931).

Already in the 1880s several investigators had noted cardiac hypertrophy in cases of prostatic enlargement, obstruction by stone or cancer, or chronic cystitis with ascending infection. But it was Derow and Altschule who showed that hypertension, especially malignant hypertension, could be primary or secondary to renal disease (1935). Between 1926 and 1934 Harry Golblatt (1891–1977) carried out his famous experiments in which he induced hypertension by applying a clamp to the renal artery. Subsequent advances came from Irving Page (and also Braun Menendez), who found in plasma a component that exerted pressor effects when incubated with renin and named it angiotensin.

Extensive research into the nature of hypertension in recent decades has led to descriptions of neurogenic hypertension, baroreptor resetting, the mosaic theory of hypertension, a reevaluation of the role of salt, the discovery of nitric acid, the role of endothelins, and numerous studies of other aspects of hypertension. Landmarks in the therapy of hypertension include the rice diet (Kemper), dorsal sympathectomy (Smithwick), the discovery of potent antihypertensive agents, and a series of therapeutic trials showing the benefits of treating hypertension early and effectively.

Urine microscopy

Microscopes, albeit rudimentary, first became available in the 17th century but had poor resolution and were rarely used. Urine microscopy, so important in modern nephrological practice,23 was at first limited to descriptions of crystals.24 Nicolaus Fabricius de Peiresc (1580–1637) first looked at urine under the microscope and saw “heaps of rhomboidal bricks.”24 Others performing urine microscopy included the Dutchmen Antoni Van Leeuwenhoek (1632–1723) and Hermann Boerhaave (1668–1738), the Dane George Hann (1647–1699), the Englishmen Robert Hooke (1635–1703) and Henry Baker (1698–1774), and the German Martin Frobenius Ledermuller (1719–1769).24–26

 

Thomas Addis

Thomas Addis

It was however Pierre Rayer (1793–1867) and his interne Eugene Napoleon Vigla who introduced urine microscopy into medical practice. Working at the Charitė in Paris, they perfected and popularized the technique of urinary microscopy, describing the appearance of urinary sediments and publishing their results in 1838 in a famous treatise on renal diseases.24,25 Their work was taken up by other investigators such as Alfred Donne and Alfred Becquerel, also from Paris. Gabriel Gustav Valentin (1837) described casts in the urine, as did Johann Simon working in the ward of Schonlein (1839), Fredrich Frerichs (1854), Jacob Henle (1842), Robert Christison (1839), and Golding Bird (1844) in England.24–27

In the 20th century Thomas Addis (1881–1949) reemphasized the importance of urinary microscopy in clinical medicine,23 since “when the patient dies the kidney may go to the pathologist, but while he lives the urine is ours.” He introduced into clinical medicine a quantitative approach to urinary microscopy, his practice of counting red and white cells and cast becoming known as the “Addis count.”23,24

In the 1950s Sternheimer and Malbin used a dye consisting of gentian violet and safranin to distinguish polymorphonuclear cells from tubular and bladder cells. To identify eosinophils in the urine, clinicians used first Wright stain and later Hansel stain. Using immunofluorescent stains, McQueen was able to identify the presence of Tamm Horsfall protein in casts. In their search for better methods of diagnosing urinary infections, Houghton and Pears (1958) carried out timed urinary white blood cell counts, before and after provocative tests with pyrogen or prednisone, an area pursued subsequently by De Wardener and Little (1962), Montgomerie and North, Brumfitt, and Stamey. In the 1960s Robert Kark and his team in Chicago developed the examination of urinary sediment under phase contrast microscopy.

Chemistry and physiology

The 18th century witnessed the earliest advances in chemistry with the identification of many solid substances and gases.27 Clinical chemistry at first centered on understanding the composition of renal stones. Several investigators, including the Reverend Stephen Hales, had made preliminary attempts to identify the composition of renal stones, but the first meaningful breakthrough came in 1776, when Karl Scheele described at the Academy of Sciences in Stockholm that bladder stones contained an acid substance he first named lithic acid but was later renamed uric acid.27 Subsequent advances came from several other chemists, including George Pearson and William Wollaston in England, and Antoine Francois Fourcroy and Nicolas Vauquelin in France, so that by the early 1800s the composition of most urinary calculi had been worked out.27–29

The story of the identification of urea begins around 1750 with the isolation of a “soapy substance” from the urine by Hilaire-Marin Rouelle, and also by Hermann Boerhaave.28 This substance was isolated at the time of the French Revolution (1790) by Francois Foucroy and Nicholas Vauquelin,2,27,28 and about the same time in England by William Cruickshank (1798), who named it urea.4,27,28 J. N. Comhaire in 1803 carried out experiments to show increased urea levels in the blood after nephrectomy; only two out of 65 dogs survived, but he reported that these smelled of urine.28 More successful were J. L. Prevost and J. B. Dumas, who in 1820 repeated these experiments with improved surgical techniques and were indeed able to demonstrate high urea concentrations in the blood of nephrectomized animals.28   

In 1828 Friedrich Wohler synthesized urea from cyanic acid and ammonia;29 then in 1822 Segalas showed that injecting urea into a Basset hound induced polyuria.28,30 In 1856 J. Picard, working as an intern in Strasbourg, improved the method of measuring blood urea;28 and around 1870 V. Feltz and E. Ritter showed that potassium was a uremic poison.28 In 1868 Adolph Fick calculated the glomerular filtration rate from urea excretion.28,31                               

 

Jacob Henle

Jacob Henle

Structure and function

The development of microscopes with higher resolution in the first half of the 19th century led to parallel developments in the study of renal morphology and function. In 1842 William Bowman, newly elected to the Royal Society at the tender age of 25, improved on Marcello Malpighi’s earlier observations by publishing his investigations on the kidneys of parrots, boa constrictors, horses, and frogs. In his classical paper “On the Structure and Use of the Malpighian Bodies of the Kidney, with Observations on the Circulating Through That Gland,” he showed that the glomerulus was a rounded mass of minute vessels invested by a capsule continuous with the basement membrane of the tubules. He described the entire structure of the nephron, with its afferent and efferent arterioles, and used injection techniques to show that the glomerulus communicated directly with the renal tubules.30,34–36

In Germany Jacob Henle, perhaps the most respected morphologist of his time, took advantage of the introduction of better microscopes to study epithelial tissues, and around 1860 published his observations on the loop arrangement of the medullary tubules (loop of Henle), which eventually led the way to the discovery of the countercurrent system.15,31–33 These advances in renal morphology led to several theories attempting to explain the mechanism of urine formation. Carl Ludwig, eventually professor of physiology at a famous institute in Leipzig and inventor of the kymograph for measuring blood pressure, proposed that urine was produced by filtration at the glomerulus and reabsorption by the renal tubules.2,13,15,30,31,33   

Rudolph Heidenhein, professor of physiology and histology in Breslau, carried out careful injection studies leading him to conclude in 1883 that proximal tubular secretion was the principal transport process involved in urine formation.13,30,31,33,36 In 1917 Arthur Cushny published the The Secretion of Urine, in which “without having contributed any original data of a substantial nature to the field"36 he proposed a “modern view” of the production of urine that combined filtration, tubular reabsorption, and secretion.2,30,36

Among the investigators who had stimulated a better understanding of renal physiology in the second half of the 19th century, a place of honor goes to Claude Bernard, who postulated that all vital mechanisms of the body have only one object, namely to preserve the internal environment, the “milieu interieur.”30,33 Attempts to understand the mechanisms of polyuria and its relation to the solute concentration in the blood as determined by its freezing point depression culminated in the work of Sandor Koranyi, who developed tests to measure the kidney’s ability to maximally concentrate the urine, showing that this is defective in some patients, and introducing the functional concept of isosthenuria in renal insufficiency (1897).13,28–30,37 Further advances became possible in 1898 when H. Strauss in Berlin invented a needle for sampling blood from a vein for analysis in the laboratory.13,28

Tests of renal function and structure

Dye excretion tests came into being in 1897 with the demonstration by Achard and Castaigne that the excretion of injected methylene blue was delayed in patients with renal failure,28 enabling them to make a distinction between uremia and edema by showing that the urinary excretion of methylene blue was low in uremia but normal in edematous states.28 This concept was further confirmed by H. Strauss in Berlin and F. Widal in Paris (1903–5), who likewise established that edema was due to the retention of sodium and not of urea.13,28 Also in that period Ernest Starling described hormones, formulated his “law of the heart,” and distinguished between colloid and hydrostatic pressure and the relation between the two.36

Early modern studies of renal function were based on attempts to work out relations between the retained urea in the blood and that excreted in the urine.23 One of the earliest formulations was the Ambard coefficient, a complex relationship between urine and blood urea with a correction for urine flow. Thomas Addis at Stamford and Donald Van Slyke at the Rockefeller Institute built on the work of Ambard, using modifications of the urine/plasma urea ratio, a direct precursor of the urea clearance as conceptualized by George D. Barnett around 1920.23,28,38,39 In the 1940s Thomas Addis advocated using the serum creatinine as a clinical indicator of renal function,23 and about the same time the inulin clearance came into use following the work of Benjamin F. Miller.

Further developments ushered in the modern era of physiology and include micropuncture (A. N. Richards),23,28 modern renal function tests (Homer Smith, John P. Peters, Robert Pitts),23,30,38 the intact nephron theory (Robert Platt, Neil Bricker) and hyperfiltration (Bary Brenner). New techniques included renal perfusion, medullary dye transit times, microspheres, AGBM antibodies, cell culture (1982), in-vitro perfusion of isolated glomeruli, and most recently the revolutionary developments in molecular medicine and recombinant technology.

Imaging techniques

Indirect means of visualizing the urinary tract during life became available only at the end of the 19th century. In 1877 Maximilian Nietze of Berlin designed a cystoscope after attending a demonstration of a similar instrument used to examine the nasal sinuses.40,41 Later he also built an irrigating cystoscope. The first ureter cystoscope was designed in Berlin in 1894 by Leopold Casper.40,41 The use of radio-opaque dyes to outline the kidneys date back to Fritz Voelcker and Alexander von Lichtenberg (Heidelberg)], who in 1905 used colloidal silver for retrograde pyelography, but found it toxic. Later E. D. Osborne and L. G. Rowntree treated syphilitics with a large dose of iodides and observed that the kidneys rapidly excreted the dye. In 1923 Rowntree reported that iodinated dyes could be used for intravenous urography. Several other dyes were later synthesized, and then introduced by Moses Swick into urologic practice, eventually with compression of the ureters to obtain better visualization.40,41

In the 1960s it was shown that larger quantities of dye could be used to visualize the kidneys of patients with renal insufficiency. This has now been replaced by ultrasonography (Dussik, et al., from 1942), computed tomography (Hounsfield, 1929), and magnetic resonance imaging (Pauli, Bloch Purcell, et al., from 1923).41 Arteriography, first performed by Egon Moniz, is now being largely replaced by improved methods that use less dye, such as subtraction arteriography or spiral computed tomography. Radioisotope scans for evaluation of renal function, mainly in hypertension and after transplantation, were first introduced by Dubovsky, et al., in 1982.41

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GEORGE DUNEA, MD, FACP, FRCP, FASN is the president and CEO of the Hektoen Institute of Medicine. He is also a professor of medicine at University of Illinois at Chicago, the medical director of Chicago Dialysis Center, and founding chairman emeritus, Division of Nephrology, Stroger Hospital of Cook County. He also serves as Editor-in-Chief of Hektoen International.

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