Franz Volhard and His Students' Tortuous Road to Renovascular

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Kidney International, Vol. 57 (2000), pp. 2156–2166

HISTORICAL ARCHIVES

Franz Volhard and his students’ tortuous road to renovascular hypertension

GUNTER WOLF

Department of Medicine, Division of Nephrology and Osteology, University of Hamburg, Hamburg, Germany

Franz Volhard and his students’ tortuous road to renovascular vascular hypertension before Goldblatt’s experiments. hypertension. Harry Goldblatt’s name is irrevocably linked to Unfortunately, Volhard’s contribution to the under- the phenomenon that renal artery constriction increases blood standing of hypertension has been barely recognized out- pressure via renin release, even in the absence of significantly decreased renal function. However, “getting there was more side of central Europe. A partial explanation is the fact than half the fun.” A lively competition took place earlier in that Volhard, whose English skills were modest at best, this century elucidating the role of the kidney in hypertension, published his work almost exclusively in German. Thus, in which Franz Volhard and his disciples played a major role. today’s generation of nephrologists, with the exception I have reviewed the extensive German literature of the time, and observed that Franz Volhard and his young associates of his contribution on the classification of glomerulone- made major contributions investigating decreases in renal per- phritis, may have not heard of this flamboyant person- fusion and resultant increases in blood pressure. Hessel, Hart- ality. wich, and Volhard made seminal observations in this regard that even preceded those of Goldblatt. A sojourn into this past history gives a revealing insight into our cumulative—albeit WHO WAS FRANZ VOLHARD? still incomplete—knowledge of the kidney, renin-angiotensin system, and blood pressure regulation. Franz Volhard was a Sir George Pickering, the Regius Professor of Medi- colorful figure whose contributions extended far beyond classi- cine at Oxford, delivered the first Volhard Lecture to The fying renal diseases. International Society of Hypertension in 1972. Pickering knew Volhard personally and had visited his department. He observed that “Franz Volhard was one of the most Thomas S. Kuhn observed that science is not a steady, handsome and the most impressive men that I have ever cumulative acquisition of knowledge, but rather is “a met. Outstanding, was his zest and joie de vivre. He no- series of peaceful interludes punctuated by intellectually ticed everything, and if it was good, enjoyed it hugely. He violent revolutions. . . . One conceptual world view is had a splendid robust and Falstaffian sense of humor and replaced by another” [1]. Harry Goldblatt, in his seminal laughed loud and often. It was this that kept him youthful articles published between 1934 and 1937, showed that in mind, behavior and experience” [7]. experimentally-induced renal ischemia in dogs with a This remarkable person was born in 1872 in Munich screw clamp leads to persistent systolic hypertension as the fourth child of Josefine and Jakob Volhard [8]. [2–5]. This work is often considered an epochal event Jakob Volhard, who was a famous nephrophile in his initiating such a paradigm shift because of the clear dem- own right, was a professor of chemistry in Munich. The onstration of the kidney’s role in blood pressure regula- elder Volhard was an organic chemist who synthesized tion [6]. However, were Goldblatt’s experiments really numerous new compounds, among them creatinine [9]. so novel, and was he without any predecessors? I believe In 1882, the Volhard family moved to Halle. Here, the that the great German clinician Franz Volhard (1872– young Franz was ridiculed at the local school because 1950) and his pupils, Hessel and Hartwich, probably dis- of his Bavarian dialect, and as a result, his father enrolled covered the pathophysiological mechanism of reno- him in a famous boarding school in Schulpforta, a former cloister [10]. The discipline had a profound effect. Franz Key words: renin-angiotensin system, blood pressure regulation, hyper- began violin lesions early, and played concertos through- tension, kidney history, classification of renal disease. out his school years, and then later with his children, residents and fellows, until the end of his career [10]. Received for publication August 26, 1999 and in revised form November 11, 1999 Figure 1 shows Volhard as a student with his violin. While Accepted for publication December 1, 1999 he could have earned a living as a violinist, the study of  2000 by the International Society of Nephrology medicine had an even greater appeal. After brief military

2156 Wolf: Franz Volhard 2157

diseases. This area of research proved to be more to Vol- hard’s liking. Volhard’s interest in renal diseases emerged around 1904 and was accelerated by two events [10]. First, Volhard agreed to write a chapter on renal diseases for a new internal medicine textbook, edited by Mohr and Staehelin. This effort required an extensive review of renal literature. Second, Volhard attended a meeting of German pathologists in Meran in 1905 [15]. At an interdisciplinary session, pathologists and internists discussed the confusing varied clinical and pathological clas- sifications of Bright’s disease. In Meran, Friedrich von Muller of Marburg introduced a new antithesis between inflammatory diseases (“nephritis”) and the degenera- tive form that he called “nephrosis” [16], and Volhard discussed the invariable link between renal diseases and hypertension. He supported Bier’s theory that the increased blood pressure in chronic Bright’s disease served as a compensatory mechanism to increase renal filtration pressure [15]. Volhard later abandoned this compensatory work theory [17]; however, his thoughts may be considered an early precursor of Guyton and his concept of pressure natriuresis [18]. As a therapeutic consequence, Volhard recommended reducing dietary salt intake to control extracellular fluid volume. He observed that in that way the paroxysmal nocturnal dyspnoeic attacks of patients with chronic renal disease could be ameliorated [10]. Volhard also believed early in his career that the Fig. 1. Franz Volhard as a 21-year-old medical student with his violin kidneys could be “rested” by requiring them to make in 1893. Volhard preferred Mozart and Beethoven quartets. Not only less urine. He sent patients with chronic renal disease his family, but also his house staff team, was encouraged to participate in music making [8]. to Egypt, where the hot temperature decreased their urinary production [19]. However, Volhard subsequently changed his opinion after he observed that his patients seldom returned alive from Egypt. service, Volhard studied in Strasbourg, where he attended In 1904, Volhard took up a new position as head of the lecturers of von Recklinghausen, Naunyn, and Schmie- the department of internal medicine at the city hospital deberg, among others. Volhard graduated from the Uni- in Dortmund. His clinical workload was formidable, but versity of Halle and wrote his dissertation on the patho- in addition, he had to performed his own autopsies. He genesis of eclampsia. He examined the effects of serum organized and held lectures for students, house staff, and urinary extracts from pre-eclamptic patients on blood and local practitioners and also continued his clinical pressure and renal function in rabbits [8]. research. Volhard constructed a simple respirator, which After working for a few months with the pathologist was successfully used in emergency situations. He stud- von Hansemann in Berlin, Volhard began a residency ied the effects of tuberculin injections [8, 10]. He also in internal medicine in Giessen in the department of developed a novel method of preserving whole hearts Franz Riegel [11]. Getting a job for Volhard was not easy, in paraffin, giving an exact paraffin cast of the specimens. since he had decided to marry. William Osler, who did These models provided an impressive display of valvular not marry until he was a full professor at Johns Hopkins, and congenital defects. However, Volhard’s main inter- had publicly announced, “Medicine is an exacting mis- est was in the development of tests to assess renal func- tress” and should be more than enough to keep any young tion. von Korańyi had already described a water drinking man busy [12]. This dictum was taken very seriously by test to evaluate the ability of the kidney to dilute the German department chairmen of the day. Riegel was urine [20]. Volhard added to this approach, and designed interested in gastroenterology, and Volhard concerned a concentration test in which the patient was thirsted himself with gastric juices [10, 13]. Volhard was promoted and the specific gravity of the urine was measured. Modi- to faculty rank (“Habilitation”) in 1901 with a summary fications of the latter test are used to this day to assess of these findings [14]. However, Riegel was also famous patients with polyuric states. as a “pulse” diagnostician and an expert in circulatory Volhard’s family grew, as did his clinical and scholarly 2158 Wolf: Franz Volhard reputation. He was offered the chairmanship of the internal medicine department in Mannheim in addition to the promise of a “brand new hospital.” The old hospital was a disgrace, and equipment, save for a single rusty syringe for morphine injections, was nonexistent [10]. Volhard had to battle with the city council almost liter- ally to get his new hospital according to his own design, but he eventually succeeded. On one occasion, while fighting city hall, he angrily jumped up, hit with his fist on the table, and exclaimed that the city should raise a statue in his honor rather than chastising. After all, he had created a modern hospital out of a pigsty (Volhard said, “Statt Vorwu¨rfen habe ich Dank erwartet, daß ich aus einem Schweinestall ein Krankenhaus gemacht habe”) [10]. Parts of Volhard’s charming hospital pavilions in Mannheim are still in use. The Mannheim days were extremely eventful for Vol- hard. He recruited the pathologist Theodor Fahr from Hamburg and began to intensively study renal diseases of all sorts, both clinically and pathologically. This collab- orative effort lead to a new classification of Bright’s disease and the seminal textbook, Die Brightische Nieren- krankheit. Klinik, Pathologie und Atlas, which was published in 1914 [21]. This textbook made Volhard and Fahr well known, even in non–German-speaking countries. In Mannheim, Volhard also studied clinical aspects of uremia and began the first experiments to investigate the pathogenesis of hypertension [22]. In 1918, Volhard received a call to his alma mater at Halle, his first university faculty job. He was not the Fig. 2. Volhard lecturing to students. On the board are Volhard’s famous circle diagrams separating the various forms of Bright’s disease, faculty’s first choice, since his vociferousness was already with and without hypertension. Volhard points to the group with essen- legendary. The university hospital in Halle was pitiful, tial “red” hypertension [79]. even worse than what Volhard had encountered earlier in Mannheim [22, 23]. The local government actually wanted to rid itself of the university faculty and convert 1923, Volhard introduced his new theory of hypertension the hospital into a municipal institution. Volhard’s pre- in a startling lecture [26]. Volhard made the distinction decessor, who had moved to Bonn, had gutted the department of equipment. In his struggle with the local between “pale” hypertension, characterized by general- administration, Volhard was forced to call in the federal ized intense vasospasm and concomitant renal involve- ministries for support. Nevertheless, in this modest aca- ment, and a “red” form of hypertension, in which the demic setting, Volhard launched into teaching, research, patients looked robust and healthy and had normal renal and clinical practice. His lectures soon became famous function. The former had a rapid downhill course (malig- for their didactic organization and lively presentations nant hypertension), whereas the latter was deceptively [23–25]. Figure 2 shows Volhard lecturing, with his fa- benign until stroke or heart attack ensued (“benign” mous circle diagrams illustrating the classification of re- essential hypertension). nal diseases. Volhard also gained a reputation as a master Tension with the hospital administration in Halle be- bedside diagnostician. Oftentimes, he made cardiac diag- came so progressively tedious that Volhard accepted the noses alone from history, inspection, palpation, and per- chairmanship at the University of Frankfurt in 1927. This cussion, before applying the stethoscope, much to the position had been vacant after Gustav von Bergmann amazement of his house staff. had left Frankfurt for Berlin. The intellectual atmosphere In Halle, Volhard established a modest but effective and standards of this university were much improved laboratory, not only for clinical but also for research compared with those in Halle, and the Volhards and purposes. Volhard and his fellows began trying to isolate their 10 children quickly adapted to the city on the Main. vasoconstrictive substances from the blood of hyperten- The German Society of Internal Medicine met annually sive patients with acute glomerulonephritis. In Vienna in since 1882 in nearby Wiesbaden. In 1930, Volhard was Wolf: Franz Volhard 2159

Fig. 4. Cartoon prepared by Bock and others [8] commemorating Fig. 3. The two huge volumes of the second edition of Volhard’s renal Volhard’s 65th birthday. The booklet was a parody on the popular handbook. The work from 1931, by a single author, approaches in bulk German children’s book of the day, Der Struwwelpeter (Shock-headed the multi-authored nephrology textbooks that are published and used Peter, originally written by the physician Heinrich Hoffmann). Der today. Struwwelpeter (analogous to the “Pigpen” character in the American “Peanuts” comic strip drawn by Charles Schultz) was an anti-role model for “good” German children. In the text, Volhard advises a low-salt diet to promote volume contraction and to rest the heart. Clearly, president of the society [27], and there he presented Volhard was aware of the distinction between volume (salt) homeostasis and water (osmolarity) homeostasis, a point not clear to many clinicians the second edition of his textbook, Die doppelseitigen to this day. ha¨matogenen Nierenerkrankungen, a huge tome of 1826 pages summarizing all of what was known about renal diseases at the time (Fig. 3) [28]. As Volhard’s fame grew, he was invited to other coun- (Shock-headed Peter). To become a “Struwwelpeter” is tries for lectures and seminars. He visited the United something that well-behaved German children should Sates in 1930, where he was very impressed by the re- avoid. The booklet consists of a series of “comic” carica- search facilities at the Mayo Clinic. He traveled to Egypt tures, warning children of bad habits. In Figure 4, we in 1935, perhaps in search of his missing patients, and see Franz Volhard pointing out the advantages of a low- then visited Sweden in 1936. In 1933, Volhard received salt diet to the occasionally naughty house staff “children.” an honorary doctorate from the Sorbonne. The occasion In the strip, Volhard makes the distinction between vol- was all the more momentous for Volhard, since also ume (ECF) and hydration (osmolarity) in terms of salt receiving this honor on that day was none other than intake and water intake, an area that still confuses house Harvey Cushing. staff and less experienced physicians to this day. Volhard was highly respected and revered by his house The Nazis found Volhard suspect and deposed him staff, perhaps the greatest reward any department chair- from his chairmanship while he was away on a trip to man can receive. On the occasion of his 65th birthday, Argentina in 1938. Although Volhard cannot be consid- Volhard was surprised by a party arranged by H.E. Bock ered a member of the resistance, he had argued vocifer- and a gift from his house staff. This gift was a parody ously against Nazi candidates for faculty positions and on a popular German children’s book, the Struwwelpeter against the dismissal of Jewish professors. By this time, 2160 Wolf: Franz Volhard

Volhard also had a Jewish daughter-in-law. His succes- strings [41]. Despite severe technical problems, Lewinski sor, Nonnenbruch, was elected to Volhard’s position observed cardiac hypertrophy in five of six dogs; how- solely for political reasons [24]. Volhard spent the war ever, he had not measured blood pressure [41]. He working in a private sanitarium in nearby Bad Nauheim. thought that unknown humoral substances, normally ex- Volhard was reinstated in his former position by the creted by the kidneys, might affect the heart and cause military government in 1945 and immediately began to vasoconstriction of small vessels [41]. rebuild his devastated department. Tigerstedt and Bergmann made a giant step in 1898. Volhard’s 75th birthday brought many honors, includ- They observed that extracts of the rabbit renal cortex ing the honorary citizenship of the city, which was cele- produce a pronounced and sustained increase in blood brated in an official ceremony. Despite his age, Volhard pressure when injected intravenously [42]. They also remained active in clinical and investigative work [29]. found that blood from renal veins exerted a small pres- Volhard was severely injured in an automobile accident sure action when infused into another animal [42]. The and died of complications (pulmonary embolism) on vasoactive substance was destroyed by alcohol and was May 24, 1950. As evidenced by various obituary addresses, named “renin” by the authors [42]. This novel approach he was widely mourned by many friends, colleagues, to hypertension was likely based on current studies of house staff, and students [30–32]. the Paris school, and Charles Brown-Se´quard promoted the novel concept that internal organs, including the kidney, had an “internal secretion” [35]. However, con- EARLY OBSERVATIONS ON firming Tigerstedt and Bergmann’s observations proved RENAL HYPERTENSION difficult, probably because the original extraction proto- Volhard was aware of an ancient Chinese textbook col was not carefully followed. Pa¨ssler and Heinecke, in describing observations that the “pulse hardens,” and its 1905, performed 5/6 nephrectomy experiments in dogs reference to renal disease [29]. He also carefully noted and found that systolic blood pressure increased by 15 Richard Bright’s observations on the relationship be- mm Hg at the level of the femoral artery [43]. They tween cardiac hypertrophy and chronic renal disease also identified cardiac hypertrophy. Volhard was at their [33, 34]. Bright had reasoned that, “the altered quality presentation and raised the possibility that hyperfiltra- of the blood so affects the minute and capillary circulation tion in remaining nephrons required an increase in blood as to render greater action necessary to force the blood pressure under these circumstances [15]. Shortly thereaf- through the distal division of the vascular system” [33]. ter, Katzenstein used rubber bands to partially occlude However, Bright had no means of measuring the blood the renal arteries of rabbits and dogs. He also applied pressure in the 1830s [35]. Traube, who was influenced torsion of the renal pedicle to occlude the renal blood by suggestions from William Senhouse Kirkes (as em- flow completely [44]. Katzenstein observed an increase phasized more recently [35]), assumed that an increase in systolic blood pressure by 10 to 30 mm Hg during in circulating blood volume contributes to hypertension partial constriction of the renal artery, whereas complete [36, 37]. He speculated that Bright’s disease, by leading occlusion was without a blood pressure-raising effect. to shrunken kidneys, may destroy many small intrarenal Alwens performed renal compression experiments vessels. As a consequence, less blood flows from the in 1909 and found that such compression decreased re- arterial system into the veins, resulting in decreased urine nal blood flow and promptly elevated blood pressure production and an increase in circulating fluid volume. [45]. Interestingly, renal denervation experiments did not The final result is hypertension leading to cardiac hyper- change this response. Since Alwens also found an in- trophy [37]. crease in blood pressure when he exerted external pres- An alternative view, provided Gull and Sutton in 1872, sure on other abdominal organs such as the spleen and suggested that renal and cardiac disease are the conse- liver, he wrongly concluded that the observed effects were quences of a common underlying disease. This view may caused by a passive transduction of the applied external be considered as the first description that essential hyper- pressure to the arterial system [45]. Rauterberg pertension can cause cardiac as well as renal disease [38, 39]. formed a temporary unilateral ureteral ligation for three Possible connections between renal perfusion and blood weeks in rabbits and subsequently removed the contra- pressure were examined during the 19th century. Graw- lateral kidney [46]. He also observed a considerable and itz and Israel occluded one renal artery of the rabbit for permanent increase in systolic blood pressure (to 171 short periods and directly measured blood pressure in mm Hg) and sclerotic changes in the aorta [46]. The the carotid artery using a newly constructed device [40]. kidneys of his animals revealed a mixture of “regenera- Although Grawitz and Israel could not detect an increase tive and atrophic” processes with an increase in intersti- in blood pressure, they found evidence of “compensa- tial connective tissue. tory” cardiac hypertrophy [40]. Lewinski constricted re- In 1911, Senator used direct liquid paraffin injections nal arteries of both kidneys in dogs using silk or catgut into the renal arteries of cats to induce a bilateral partial Wolf: Franz Volhard 2161 obstruction [47]. Senator found no increase in systolic early in glomerulonephrits, before renal failure devel- blood pressure in these heavily anesthetized cats, and oped [56]. A variant on this theme was Volhard’s distinc- erroneously concluded that diseased kidney with re- tion between “pale” or malignant hypertension, with duced arterial flow could not produce the vasoactive severe vasospasm and endorgan damage, and the more substance described by Tigerstedt and Bergman [47]. indolent “red” hypertension, which had less end organ Lichtwitz totally rejected the hypothesis that the kidneys damage but nevertheless was a risk for subsequent com- release vasoactive substances because he reasoned that plications [25, 26]. Volhard was misled to believe that the release must be continuous, a task beyond the abili- vasoconstriction was largely responsible for the decrease ties of diseased kidneys [48, 49]. Without supplying data, in renal function occurring in glomerulonephritis. This Lichtwitz alternatively proposed that a renal artery dila- view was laid to rest by Volhard’s resident, Sarre, who tion leads to a “compensatory reflex mechanism” in re- later showed that vasoconstriction is not a feature of sponse to secondary increases in peripheral vascular re- Masugi nephritis [57]. sistance [49]. These citations illustrate the lively nature Volhard was convinced that Tigerstedt and Bergmann of this area of research prior to the arrival of Volhard had made correct observations and that humoral factors and Goldblatt on the scene. played a role in hypertension. Working in Volhard’s laboratory, his resident, Hu¨ lse, began a series of studies in the 1920s to test this notion [58, 59]. Hu¨ lse studied VOLHARD’S CONTRIBUTIONS patients with acute and chronic glomerulonephritis and Above all, Volhard was a clinician, and his initial ob- hypertension. Hu¨ lse found that sera from patients with servations stemmed from the bedside [50]. Volhard’s “pale,” but not from patients with “red,” hypertension puzzle was how Bright’s disease could result in retinitis, sensitized animals to the blood pressure-raising effects cerebral dysfunction, and cardiac hypertrophy. He rea- of epinephrine. Hu¨ lse thought that these “sensitizing” soned that hypertension must be responsible. Volhard agents were protein-degradation products. Hartwich was was not satisfied with the then current explanation that another Volhard fellow who performed studies in dogs an attenuated renal secretory function was responsible. [60, 61]. He showed that complete ligation of three out He therefore developed clinical tests to better assess of four branches of the renal artery in dogs leads to a renal function [51, 52]. He was greatly influenced by the significant increase in blood pressure without the devel- physical chemistry approach developed by von Korańyi opment of renal insufficiency [60]. Hartwich next re- [20, 53]. von Korańyi was interested in the notion of renal moved the stenotic kidney after three days and prepared work and studied the kidney’s ability to excrete osmoti- a “pressed juice” extract (“Preßsaft”). He injected this cally active substances by employing freezing point de- preparation into normal dogs, in which it caused hyper- pression [54, 55]. von Korańyi observed that chronically tension [60]. He subsequently showed that this response diseased kidneys excreted a urine with a freezing point was independent of central nervous system activity and depression similar to that of plasma [55]. He termed this was organ specific [60]. There was no increase in blood situation “asthenuria.” pressure if the ischemic kidney was removed or if the Volhard introduced the term “isosthenuria” and relied renal vein was also ligated. Hartwich speculated that on the simpler determinations of specific gravity to re- renin might be responsible. flect the osmolarity. von Korańyi speculated on the evo- Hessel and Hartwich later meticulously characterized lutionary meaning of his findings and drew analogies to vasoactive factors from autolytic kidneys 1932 [61]. They sea water and fresh water fishes, an area later revisited found that an additional vasoconstrictive substance with by Homer Smith. Armed with dilution and concentration biochemical properties distinct from renin was extracted tests, as well as measurements to reflect glomerular fil- with various organic solvents. This new substance was tration, Volhard systematically studied clinical hyperten- fundamentally different from renin, because it remained sion with and without renal disease. Volhard soon discov- active after precipitation with ammonium sulfate or boil- ered that hypertension occurred early in some renal ing and also displayed a lower molecular weight than diseases, such as glomerulonephritis. He also identified renin [61]. This substance was also nondialyzable, indi- patients with no decrease in renal function who neverthe- cating that it was not identical to small catecholamines. less had retinitis and cerebral dysfunction. In these pa- Interestingly, more substance could be isolated if the tients, endorgan damage was highly correlated with the kidneys were subjected to prolonged autolysis, indicating severity of hypertension [50]. These astute bedside ob- that the vasoactive principle was formed during the decay servations prompted Volhard to introduce the notion of process. Finally, Hessel and Hartwich described that “uremic” and “nonuremic” hypertension. after injecting isolated vasoactive factors, the increase Volhard visualized the retinal vessels and their caliber in blood pressure is occasionally delayed. They con- directly and concluded that vasospasm was independent cluded that the factor may be protein bound and require of the renal functional impairment and occurred very release in the circulation to exert their effects [61]. 2162 Wolf: Franz Volhard

What was really the nature of this “novel” vasoactive became a pathologist [6]. He was aware that hyperten- factor? The resistance to boiling suggests that the sub- sion and uremia were not necessarily correlated [66], and stance could not be identical to glycoproteins such as began working on the problem in the late 1920s. Goldblatt renin or angiotensinogen, which would be likely inacti- used an adjustable silver clamp to narrow the main renal vated by prolonged heating. On the other hand, the non- artery in dogs. He presented his findings at the 1932 meet- dialyzable character of the substance and the precipita- ing of the Academy of Medicine in Cleveland (abstract; tion with ammonium sulfate would argue for a larger Goldblatt et al, Bull Acad Med Cleve 16:6, 1932). The peptide hormone. Although one would argue that angio- results were published in a series of outstanding papers tensin I and angiotensin II would be probably easily starting in 1934 [2–5]. Goldblatt constricted one or both degraded in the autolytic kidney, it is also possible that renal arteries to various degrees in a total of 11 dogs using more angiotensin peptides are formed from intrarenal his newly constructed adjustable clamps [2], and in each angiotensinogen. Thus, although the precise chemical dog performed several direct blood pressure measure- nature of Hessel and Hartwich’s pressure substance re- ments under defined conditions [2]. Goldblatt also as- mains obscure, there is some evidence that is was indeed sessed renal function before and after application of the identical to angiotensins. clamps using urea clearance, excretion of phenolsulfo- Hessel further investigated the properties of this novel nephthalein, and measurements of nitrogen, creatinine, vasoactive factor [62, 63]. In contrast to Tigerstedt and and guanidine in the blood [2]. The adrenal glands were Bergmann, Hessel was also able to isolate renin in a additionally removed in one animal. Goldblatt noted that relatively pure preparation. Microgram quantities of his “the constriction of the main arteries of both kidneys of material were sufficient to increase blood pressure in dogs was followed invariably by elevation of systolic blood normal animals [62, 63]. Hessel later extracted his vaso- pressure, determined in a carotid artery, which persisted active material from normal kidneys directly frozen in for as long as 15 months” [2]. In contrast, constriction liquid nitrogen, suggesting that renin is preformed and of one renal artery was followed by only a moderate, stored in the kidney [62]. In contrast to in vivo injection, the isolated renin was a much weaker vasoconstrictor temporary rise in blood pressure. Furthermore, Gold- than epinephrine for small vessels in an organ bath. blatt summarized his findings: “When the constriction of These results also indicated that renin was not a direct both main renal arteries is made only moderately severe vasoconstrictor in its own right in the absence of other in the beginning, the elevation of systolic blood pressure factors [62]. is unaccompanied by signs of materially decreased renal In additional experiments highly relevant to Gold- function. Almost complete constriction of both main renal blatt’s contribution, Hessel partly constricted the renal arteries, from the beginning, results in great elevation of artery of dogs with a band made of silver wire [62, 63]. systolic blood pressure which is accompanied by severe After the development of chronic hypertension, he in- disturbance of renal function and uremia” [2]. Goldblatt jected venous blood obtained from the ischemic kidney concluded, “It is hoped that these investigations will afford into normal dogs and showed that these animals exhib- a means of studying the pathogenesis of hypertension that ited an increase in blood pressure during injection. A is associated with renal vascular disease” [2]. This modest representative example is shown in Figure 5. An injection hope was profoundly realized. of blood obtained directly from the artery of the ischemic Goldblatt repeated his experiments with similar results kidney or from normal dogs was without effect [62]. in monkeys, and also showed that destruction of splanch- Hessel also injected renin daily for five weeks into rabbits nic nerves or cutting of the lumbar anterior spinal nerve and induced a permanent hypertension, which even per- roots were without any effect on the hypertension [3, 4]. sisted without renin until the death of the animal [62]. Together with an ophthalmologist, Goldblatt further ex- Volhard published a collection as a book of several lec- ploited the original series of his hypertensive dogs and tures under the title, Nierenerkrankungen und Hoch- reported opthalmoscopic alterations of retinal vessels druck, in 1942, again illustrating his profound penetra- and histologic changes of the eyes [67]. Similar to Volhard, tion of this subject [50]. Figure 6 shows the first page of Goldblatt remained very active in his later years and pub- this book with Volhard’s portrait and signature on the lished articles in his mid-eighties on the effect of high- frontispiece. After the war, Volhard published additional salt intake on blood pressure and renin. Both topics were articles summarizing his view of renal hypertension; how- on the cutting edge of hypertension research [68–71]. ever, neither he nor his coworkers provided any addi- After Goldblatt’s unambiguous demonstration that con- tional new experimental insights into the problem [64, 65]. striction of the renal artery causes hypertension, angiotensin was independently discovered by Page and Braun- THE TORTUOUS ROAD TO Meneńdez and colleagues early in the 1940s [72, 73]. RENOVASCULAR HYPERTENSION In his initial article, Goldblatt mentions the earlier Harry Goldblatt (1891–1977) graduated from McGill German literature including the work of Katzenstein, University and was first trained as a surgeon before he Senator, Alwens, and also referenced a textbook article Wolf: Franz Volhard 2163

Fig. 5. Original femoral arterial blood pressure tracings of an anesthetized dog [62]. (A) A baseline tracing. (B) The blood pressure increase during infusion of blood obtained from the renal vein of a dog with a constricting silver band on its renal artery. (C) The blood pressure recording after the infusion was terminated.

Fig. 6. Frontispiece from Volhard’s 1942 textbook, Nierenerkrankungen und Hochdruck. This book was published after Volhard had been dismissed from his post due to political conflict with the Nazi regime. The work contains several of his key lectures delivered in the early and late 1930s dealing with hypertension and the kidney. 2164 Wolf: Franz Volhard by Fahr; however, he did not cite any work of Volhard The best example is the work of Sarre, whose experimen- or his disciples [2]. Nevertheless, in his 1938 Harvey tal results totally contradicted Volhard’s theory of vaso- Lecture, Goldblatt gave a concise history of the relation- constriction in acute glomerulonephritis without any ob- ship between the kidney and hypertension in form of a vious consequence for Sarre’s personal career [57]. table and there gave due recognition to the work of Volhard accepted Goldblatt findings and conclusions. Volhard’s group [74]. Goldblatt acknowledged that “in However, Volhard expressed in several talks and lectures some of the earlier investigations mentioned in the sum- his opinion that Goldblatt had extended his group’s find- mary the hypertension that was observed was usually ings, implying that credit also goes to his pupils, Hartwich slight and lasted from only a few hours to several days. and Hessel [50, 65]. Volhard correlated Goldblatt’s suc- Some of the later investigators reported the development cess with the better opportunities of American scientists of hypertension of moderate degree and of short duration with better equipment and larger laboratories [10]. This while others succeeded in producing moderate or severe point, on the other hand, was unfair, since Goldblatt hypertension of longer duration” [74]. certainly did not perform his work under the optimal The experimental work on renin by Hessel and Hart- laboratory conditions that Volhard had seen at the Mayo wich was not held in high esteem by the giants of early Clinic during his 1930 visit. Goldblatt’s laboratory sup- American hypertension research. For example, Page port was surprisingly modest. Volhard’s indirect priority wrote in 1951, “Unfortunately, many claims are unsup- claims were posthumously supported by some of his dis- ported by evidence. My personal experience with Dr. Hes- ciples and others [52, 76]. sel leads me to believe that probably most of the claims have some, although not complete, validity” [75]. How- ever, Page admitted, “Our own work was begun in 1931, POSTSCRIPT stimulated by Hessel, and later by the announcement of Osler pointed out that “in science the credit goes to the production of reproducible hypertension without a the man who convinces the world, not to the man to reduction in renal function by Goldblatt in 1934” [75]. whom the idea first occurs” [77]. In this regard, Goldblatt Similarly, Fishberg failed to mentioned the contributions certainly convinced the world by his very clear experi- of Volhard and his coworkers, despite some lengthy de- mental approach and the publication of his findings in scriptions of the various mechanisms of renal hyperten- English. However, the fundamental work of Volhard and sion [48]. Fishberg acknowledges Volhard’s clinical sepa- his pupils on the pathophysiology of renal hypertension, ration of hypertension into “pale” and “red” forms, although Fishberg did not appear to be enamored of the ultimately derived from Volhard’s clinical acumen, un- concept [48]. questionably paved the road for Goldblatt’s elegant ex- Pickering also issued criticism of Volhard’s students. periments. Volhard and his students accumulated new He wrote that “Hartwich and Hessel claimed to have evidence inconsistent with the existing paradigm of that rediscovered renin in the autolyzed pressed juice of the time. The final hit that changed the then existing para- kidney” in 1932. However, the pressor substance they got digm was Goldblatt’s work. The time was ripe for this was alcohol soluble and heat stable. It was almost certainly experimental approach. Thus, the discovery of the patho- a mixture of putrefactive amines, and completely different physiological mechanism underlying renal hypertension from the alcohol insoluble and heat labile renin of Ti- may fit into Kuhn’s model of scientific progress. gerstedt and Bergmann. Hu¨lse claimed that there was an Volhard was one of the few clinical investigator giants epinephrine-like substance present in the blood of patients in European medicine of the 20th century’s first half, a with pale but not red hypertension, and Bohn also ex- species said to be endangered in Germany and elsewhere tracted a pressor substance in pale but not in red hyperten- [78]. Volhard’s pupils held almost all leading academic sion. It took many man-hours of work in the United positions in German nephrology [79], indicating Volhard’s Kingdom and in the United States to demonstrate that fundamental influence on this field. Today, university de- these results were fallacious. It was not Volhard’s fault. partments in Berlin and Halle bear Volhard’s name. Vol- At that time, it was not uncommon in some universities hard’s ingenious scientific contributions, particularly to to find that those who proved the ideas of the professor the pathophysiology of hypertension, are underappreci- to be right were promoted, and those proved them to be ated and deserve a broader recognition in non-European wrong lost their jobs” [7]. This was not a very fair state- countries. ment, taking into consideration that the meticulous work of Hartwich and Hessel with the isolation of their sub- ACKNOWLEDGMENTS stance with different properties than renin may have indeed been the discovery of angiotensin II. Further- I am supported by a Heisenberg Fellowship of the Deutsche Forschungsgemeinschaft. I appreciate the helpful advice of Friedrich more, nobody was obliged to confirm the hypothesis of C. Luft, M.D. (Berlin-Buch), who is a long-time admirer of both Harry the chief in Volhard’s department to become promoted. Goldblatt and Franz Volhard. Wolf: Franz Volhard 2165

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