Portal de Periódicos da CAPES

Franz Volhard and his students' tortuous road to renovascular hypertension

2000; Elsevier BV; Volume: 57; Issue: 5 Linguagem: Inglês

10.1046/j.1523-1755.2000.00068.x

1523-1755

Günter Wolf,

Hemodynamic Monitoring and Therapy

Franz Volhard and his students' tortuous road to renovascular hypertension. Harry Goldblatt's name is irrevocably linked to the phenomenon that renal artery constriction increases blood pressure via renin release, even in the absence of significantly decreased renal function. However, “getting there was more than half the fun.” A lively competition took place earlier in this century elucidating the role of the kidney in hypertension, in which Franz Volhard and his disciples played a major role. I have reviewed the extensive German literature of the time, and observed that Franz Volhard and his young associates made major contributions investigating decreases in renal perfusion and resultant increases in blood pressure. Hessel, Hartwich, 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 still incomplete—knowledge of the kidney, renin-angiotensin system, and blood pressure regulation. Franz Volhard was a colorful figure whose contributions extended far beyond classifying renal diseases. Franz Volhard and his students' tortuous road to renovascular hypertension. Harry Goldblatt's name is irrevocably linked to the phenomenon that renal artery constriction increases blood pressure via renin release, even in the absence of significantly decreased renal function. However, “getting there was more than half the fun.” A lively competition took place earlier in this century elucidating the role of the kidney in hypertension, in which Franz Volhard and his disciples played a major role. I have reviewed the extensive German literature of the time, and observed that Franz Volhard and his young associates made major contributions investigating decreases in renal perfusion and resultant increases in blood pressure. Hessel, Hartwich, 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 still incomplete—knowledge of the kidney, renin-angiotensin system, and blood pressure regulation. Franz Volhard was a colorful figure whose contributions extended far beyond classifying renal diseases. Thomas S. Kuhn observed that science is not a steady, cumulative acquisition of knowledge, but rather is “a series of peaceful interludes punctuated by intellectually violent revolutions… One conceptual world view is replaced by another”1.Kuhn T.S. The Structure of Scientific Revolutions. University of Chicago Press, Chicago1962Google Scholar. Harry Goldblatt, in his seminal articles published between 1934 and 1937, showed that experimentally-induced renal ischemia in dogs with a screw clamp leads to persistent systolic hypertension2.Goldblatt H. Lynch J. Hanzal R.F. Summerville W.W. Studies on experimental hypertension. I. The production of persistent elevation of systolic blood pressure by means of renal ischemia.J Exp Med. 1934; 59: 347-379Crossref PubMed Scopus (1189) Google Scholar, 3.Goldblatt H. Gross J. Hanzal R.F. Studies on experimental hypertension. II. The effect of resection of splanchnic nerves on experimental renal hypertension.J Exp Med. 1937; 65: 233-265Crossref PubMed Scopus (7) Google Scholar, 4.Goldblatt H. Studies on experimental hypertension. III. The production of persistent hypertension in monkeys (macaque) by renal ischemia.J Exp Med. 1937; 65: 671-675Crossref PubMed Scopus (12) Google Scholar, 5.Goldblatt H. Wartman W.B. Studies on experimental hypertension. VI. The effects of section of the anterior spinal nerve roots on experimental hypertension due to renal ischemia.J Exp Med. 1939; 66: 527-534Crossref Scopus (1) Google Scholar. This work is often considered an epochal event initiating such a paradigm shift because of the clear demonstration of the kidney's role in blood pressure regulation6.Goldblatt P.J. The Goldblatt experiment: A conceptual paradigm,.Hypertension: Pathophysiology, Diagnosis, and Management. edited by Laragh JH, Brenner BM. Raven Press, New York1990: 21-32Google Scholar. However, were Goldblatt's experiments really so novel, and was he without any predecessors? I believe that the great German clinician Franz Volhard (1872–1950) and his pupils, Hessel and Hartwich, probably discovered the pathophysiological mechanism of renovascular hypertension before Goldblatt's experiments. Unfortunately, Volhard's contribution to the understanding of hypertension has been barely recognized outside of central Europe. A partial explanation is the fact that Volhard, whose English skills were modest at best, published his work almost exclusively in German. Thus, today's generation of nephrologists, with the exception of his contribution on the classification of glomerulonephritis, may have not heard of this flamboyant personality. Sir George Pickering, the Regius Professor of Medicine at Oxford, delivered the first Volhard Lecture to The 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 handsome and the most impressive men that I have ever met. Outstanding, was his zest and joie de vivre. He noticed everything, and if it was good, enjoyed it hugely. He had a splendid robust and Falstaffian sense of humor and laughed loud and often. It was this that kept him youthful in mind, behavior and experience”7.Pickering G. The first Volhard lecture.Clin Sci Mol Med. 1973; 45: 1S-10SGoogle Scholar. This remarkable person was born in 1872 in Munich as the fourth child of Josefine and Jakob Volhard8.Kronschwitz C. Franz Volhard: Leben und Werk. Sinemis-Verlagsgesellschaft, Frankfurt Am Main1997Google Scholar. Jakob Volhard, who was a famous nephrophile in his own right, was a professor of chemistry in Munich. The elder Volhard was an organic chemist who synthesized numerous new compounds, among them creatinine9.Kaiser W. Die Ära der Volhards in Halle. Zur 100. Wiederkehr des Geburstages von Franz Volhard (1872–1950) am 2. Mai 1972.Zschr Inn Med. 1972; 27: 325-337Google Scholar. In 1882, the Volhard family moved to Halle. Here, the young Franz was ridiculed at the local school because of his Bavarian dialect, and as a result, his father enrolled him in a famous boarding school in Schulpforta, a former cloister10.VOLHARD F: Mein Lebenslauf. Med Welt 23:665–668, 838–840, 958–960, 994–996, 1085–1086, 1233–1234, 1267–1270, 1319–1320, 1405–1406, 1457–1462 (published posthume in 1972; written in 1942)Google Scholar. The discipline had a profound effect. Franz began violin lesions early, and played concertos throughout his school years, and then later with his children, residents and fellows, until the end of his career10.VOLHARD F: Mein Lebenslauf. Med Welt 23:665–668, 838–840, 958–960, 994–996, 1085–1086, 1233–1234, 1267–1270, 1319–1320, 1405–1406, 1457–1462 (published posthume in 1972; written in 1942)Google Scholar. Figure 1 shows Volhard as a student with his violin. While he could have earned a living as a violinist, the study of medicine had an even greater appeal. After brief military service, Volhard studied in Strasbourg, where he attended the lecturers of von Recklinghausen, Naunyn, and Schmiedeberg, among others. Volhard graduated from the University of Halle and wrote his dissertation on the pathogenesis of eclampsia. He examined the effects of serum and urinary extracts from pre-eclamptic patients on blood pressure and renal function in rabbits8.Kronschwitz C. Franz Volhard: Leben und Werk. Sinemis-Verlagsgesellschaft, Frankfurt Am Main1997Google Scholar. After working for a few months with the pathologist von Hansemann in Berlin, Volhard began a residency in internal medicine in Giessen in the department of Franz Riegel11.Luft F.C. Dietz R. Franz Volhard in historical perspective.Hypertension. 1993; 22: 253-256Crossref PubMed Scopus (10) Google Scholar. Getting a job for Volhard was not easy, since he had decided to marry. William Osler, who did not marry until he was a full professor at Johns Hopkins, had publicly announced, “Medicine is an exacting mistress” and should be more than enough to keep any young man busy12.Osler W. The master-word in medicine,.Aequanimitas with Other Addresses to Medical Students, Nurses and Practitioners of Medicine. P Blakiston's Son, Philadelphia1928: 363-388Google Scholar. This dictum was taken very seriously by German department chairmen of the day. Riegel was interested in gastroenterology, and Volhard concerned himself with gastric juices10.VOLHARD F: Mein Lebenslauf. Med Welt 23:665–668, 838–840, 958–960, 994–996, 1085–1086, 1233–1234, 1267–1270, 1319–1320, 1405–1406, 1457–1462 (published posthume in 1972; written in 1942)Google Scholar,13.Kleeberg J. Zur Entdeckung der Magenlipase durch Franz Volhard (1901).Zschr Gastroenterologie. 1971; 9: 646-647PubMed Google Scholar. Volhard was promoted to faculty rank (“Habilitation”) in 1901 with a summary of these findings14.Volhard F. Ueber das fettspaltende Ferment des Magens.Zschr Klin Med. 1901; 42: 414-429Google Scholar. However, Riegel was also famous as a “pulse” diagnostician and an expert in circulatory diseases. This area of research proved to be more to Volhard's liking. Volhard's interest in renal diseases emerged around 1904 and was accelerated by two events10.VOLHARD F: Mein Lebenslauf. Med Welt 23:665–668, 838–840, 958–960, 994–996, 1085–1086, 1233–1234, 1267–1270, 1319–1320, 1405–1406, 1457–1462 (published posthume in 1972; written in 1942)Google Scholar. 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 190515.Volhard F. Diskussionbemerkungen zum Morbus Brightii.Verh Deutsch Pathol Gesell. 1905; 9: 111-114Google Scholar. At an interdisciplinary session, pathologists and internists discussed the confusing varied clinical and pathological classifications of Bright's disease. In Meran, Friedrich von Muller of Marburg introduced a new antithesis between inflammatory diseases (“nephritis”) and the degenerative form that he called “nephrosis”16.Cameron J.S. The nephrotic syndrome: A historical review,.The Nephrotic Syndrome. edited by Cameron JS, Glassock RJ. Marcel Dekker, New York1988: 3-56Google Scholar, 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 pressure15.Volhard F. Diskussionbemerkungen zum Morbus Brightii.Verh Deutsch Pathol Gesell. 1905; 9: 111-114Google Scholar. Volhard later abandoned this compensatory work theory17.Wolf G. Changing concepts of compensatory renal growth: From humoral pathology to molecular biology.Am J Nephrol. 1992; 12: 369-373Crossref PubMed Scopus (7) Google Scholar; however, his thoughts may be considered an early precursor of Guyton and his concept of pressure natriuresis18.Guyton A.C. Coleman T.G. Cowley A.W. Arterial pressure regulation: Overriding dominance of the kidney in the long-term regulation and in hypertension.Am J Med. 1972; 52: 584-594Abstract Full Text PDF PubMed Scopus (822) Google Scholar. 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 ameliorated10.VOLHARD F: Mein Lebenslauf. Med Welt 23:665–668, 838–840, 958–960, 994–996, 1085–1086, 1233–1234, 1267–1270, 1319–1320, 1405–1406, 1457–1462 (published posthume in 1972; written in 1942)Google Scholar. Volhard also believed early in his career that the kidneys could be “rested” by requiring them to make less urine. He sent patients with chronic renal disease to Egypt, where the hot temperature decreased their urinary production19.Lennert T. Luft F.C. Kidneys on vacation: The notion of renal work and the introduction of nonpharmacological therapies.Am J Kidney Dis. 1997; 29: 777-780Abstract Full Text PDF PubMed Scopus (4) Google Scholar. However, Volhard subsequently changed his opinion after he observed that his patients seldom returned alive from Egypt. In 1904, Volhard took up a new position as head of the department of internal medicine at the city hospital in Dortmund. His clinical workload was formidable, but in addition, he had to performed his own autopsies. He organized and held lectures for students, house staff, and local practitioners and also continued his clinical research. Volhard constructed a simple respirator, which was successfully used in emergency situations. He studied the effects of tuberculin injections8.Kronschwitz C. Franz Volhard: Leben und Werk. Sinemis-Verlagsgesellschaft, Frankfurt Am Main1997Google Scholar,10.VOLHARD F: Mein Lebenslauf. Med Welt 23:665–668, 838–840, 958–960, 994–996, 1085–1086, 1233–1234, 1267–1270, 1319–1320, 1405–1406, 1457–1462 (published posthume in 1972; written in 1942)Google Scholar. He also developed a novel method of preserving whole hearts in paraffin, giving an exact paraffin cast of the specimens. These models provided an impressive display of valvular and congenital defects. However, Volhard's main interest was in the development of tests to assess renal function. von Korányi had already described a water drinking test to evaluate the ability of the kidney to dilute the urine20.von Korányi A. Physiologische und klinische Untersuchungen über den osmotischen Druck thierischer Flüssigkeiten.Zschr Klin Med. 1897; 33: 1-54Google Scholar. Volhard added to this approach, and designed a concentration test in which the patient was thirsted and the specific gravity of the urine was measured. Modifications of the latter test are used to this day to assess patients with polyuric states. Volhard's family grew, as did his clinical and scholarly 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 nonexistent10.VOLHARD F: Mein Lebenslauf. Med Welt 23:665–668, 838–840, 958–960, 994–996, 1085–1086, 1233–1234, 1267–1270, 1319–1320, 1405–1406, 1457–1462 (published posthume in 1972; written in 1942)Google Scholar. Volhard had to battle with the city council almost literally 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 Vorwürfen habe ich Dank erwartet, daß ich aus einem Schweinestall ein Krankenhaus gemacht habe”)10.VOLHARD F: Mein Lebenslauf. Med Welt 23:665–668, 838–840, 958–960, 994–996, 1085–1086, 1233–1234, 1267–1270, 1319–1320, 1405–1406, 1457–1462 (published posthume in 1972; written in 1942)Google Scholar. Parts of Volhard's charming hospital pavilions in Mannheim are still in use. The Mannheim days were extremely eventful for Volhard. He recruited the pathologist Theodor Fahr from Hamburg and began to intensively study renal diseases of all sorts, both clinically and pathologically. This collaborative effort lead to a new classification of Bright's disease and the seminal textbook, Die Brightische Nierenkrankheit. Klinik, Pathologie und Atlas, which was published in 191421.Volhard F. Fahr T. Die Bright'sche Nierenkrankheit. Klinik, Pathologie und Atlas. Julius Springer, Berlin1914Crossref Google Scholar. 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 hypertension22.Kaltenbach M. Mannheim und Frankfurt-Stationen auf dem Lebensweg von Franz Volhard (1872–1950).Zschr Kardiol. 1991; 80: 1-4PubMed Google Scholar. In 1918, Volhard received a call to his alma mater at Halle, his first university faculty job. He was not the faculty's first choice, since his vociferousness was already legendary. The university hospital in Halle was pitiful, even worse than what Volhard had encountered earlier in Mannheim22.Kaltenbach M. Mannheim und Frankfurt-Stationen auf dem Lebensweg von Franz Volhard (1872–1950).Zschr Kardiol. 1991; 80: 1-4PubMed Google Scholar,23.Mark D.E. Franz Volhard als Kliniker.Med Welt. 1963; 14: 13-16Google Scholar. The local government actually wanted to rid itself of the university faculty and convert the hospital into a municipal institution. Volhard's predecessor, who had moved to Bonn, had gutted the department of equipment. In his struggle with the local administration, Volhard was forced to call in the federal ministries for support. Nevertheless, in this modest academic setting, Volhard launched into teaching, research, and clinical practice. His lectures soon became famous for their didactic organization and lively presentations23.Mark D.E. Franz Volhard als Kliniker.Med Welt. 1963; 14: 13-16Google Scholar, 24.Nonnenbruch W. Franz Volhard zum 70. Geburtstage.Münch Med Wochenschr. 1942; 89: 403-405Google Scholar, 25.Bock H.E. Franz Volhard.Neue Med Welt. 1950; 1: 835-838Google Scholar. Figure 2 shows Volhard lecturing, with his famous circle diagrams illustrating the classification of renal diseases. Volhard also gained a reputation as a master bedside diagnostician. Oftentimes, he made cardiac diagnoses alone from history, inspection, palpation, and percussion, before applying the stethoscope, much to the amazement of his house staff. In Halle, Volhard established a modest but effective laboratory, not only for clinical but also for research purposes. Volhard and his fellows began trying to isolate vasoconstrictive substances from the blood of hypertensive patients with acute glomerulonephritis. In Vienna in 1923, Volhard introduced his new theory of hypertension in a startling lecture26.Volhard F. Der arterielle Hochdruck.Verh Deutsch Gesell Inn Med. 1923; 35 (Kongr): 134-175Google Scholar. Volhard made the distinction between “pale” hypertension, characterized by generalized intense vasospasm and concomitant renal involvement, and a “red” form of hypertension, in which the patients looked robust and healthy and had normal renal function. The former had a rapid downhill course (malignant hypertension), whereas the latter was deceptively benign until stroke or heart attack ensued (“benign” essential hypertension). Tension with the hospital administration in Halle became so progressively tedious that Volhard accepted the chairmanship at the University of Frankfurt in 1927. This position had been vacant after Gustav von Bergmann had left Frankfurt for Berlin. The intellectual atmosphere and standards of this university were much improved compared with those in Halle, and the Volhards and their 10 children quickly adapted to the city on the Main. The German Society of Internal Medicine met annually since 1882 in nearby Wiesbaden. In 1930, Volhard was president of the society27.Volhard F. Eröffnungsrede zum 42. Internistenkongreß 1930 in Wiesbaden.Verh Deutsch Gesell Inn Med. 1930; 42 (Kongr): 1-6Google Scholar, and there he presented the second edition of his textbook, Die doppelseitigen hämatogenen Nierenerkrankungen, a huge tome of 1826 pages summarizing all of what was known about renal diseases at the time Figure 328.Volhard F. Die doppelseitigen hämatogenen Nierenerkrankungen,.Handbuch der Inneren Medizin. edited by v. Bergmann G, Staehelin R. Julius Springer, Berlin1931: 1-1826Google Scholar. As Volhard's fame grew, he was invited to other countries for lectures and seminars. He visited the United Sates in 1930, where he was very impressed by the research facilities at the Mayo Clinic. He traveled to Egypt in 1935, perhaps in search of his missing patients, and then visited Sweden in 1936. In 1933, Volhard received an honorary doctorate from the Sorbonne. The occasion was all the more momentous for Volhard, since also receiving this honor on that day was none other than Harvey Cushing. Volhard was highly respected and revered by his house staff, perhaps the greatest reward any department chairman can receive. On the occasion of his 65th birthday, Volhard was surprised by a party arranged by H.E. Bock and a gift from his house staff. This gift was a parody on a popular German children's book, the Struwwelpeter (Shock-headed Peter). To become a “Struwwelpeter” is something that well-behaved German children should avoid. The booklet consists of a series of “comic” caricatures, warning children of bad habits. In Figure 4, we see Franz Volhard pointing out the advantages of a low-salt diet to the occasionally naughty house staff “children.” In the strip, Volhard makes the distinction between volume (ECF) and hydration (osmolarity) in terms of salt intake and water intake, an area that still confuses house staff and less experienced physicians to this day. The Nazis found Volhard suspect and deposed him from his chairmanship while he was away on a trip to Argentina in 1938. Although Volhard cannot be considered a member of the resistance, he had argued vociferously against Nazi candidates for faculty positions and against the dismissal of Jewish professors. By this time, Volhard also had a Jewish daughter-in-law. His successor, Nonnenbruch, was elected to Volhard's position solely for political reasons24.Nonnenbruch W. Franz Volhard zum 70. Geburtstage.Münch Med Wochenschr. 1942; 89: 403-405Google Scholar. Volhard spent the war working in a private sanitarium in nearby Bad Nauheim. Volhard was reinstated in his former position by the military government in 1945 and immediately began to rebuild his devastated department. Volhard's 75th birthday brought many honors, including the honorary citizenship of the city, which was celebrated in an official ceremony. Despite his age, Volhard remained active in clinical and investigative work29.Volhard F. Blutdruck und Niere.in: Becher E. Jena, Gustav Fischer. 1944: 318-339Google Scholar. Volhard was severely injured in an automobile accident and died of complications (pulmonary embolism) on May 24, 1950. As evidenced by various obituary addresses, he was widely mourned by many friends, colleagues, house staff, and students30.Sarre H. Franz Volhard.Klin Wschr. 1950; 28: 487-493Crossref PubMed Google Scholar, 31.Hildebrand K.H. Franz Volhard.Deutsch Med Wochenschr. 1950; 75: 1196-1199Crossref PubMed Scopus (3) Google Scholar, 32.Nonnenbruch W. Nachruf auf Professor Dr. Franz Volhard.Münch Med Wochneschr. 1950; 97: 626Google Scholar. Volhard was aware of an ancient Chinese textbook describing observations that the “pulse hardens,” and its reference to renal disease29.Volhard F. Blutdruck und Niere.in: Becher E. Jena, Gustav Fischer. 1944: 318-339Google Scholar. He also carefully noted Richard Bright's observations on the relationship between cardiac hypertrophy and chronic renal disease33.Bright R. Tabular view of the morbid appearances in 100 cases connected with albuminous urine.Guy's Hosp Rep. 1836; 1: 380-489Google Scholar,34.Fine L.G. Pathological specimens of the kidney examined by Richard Bright.Kidney Int. 1986; 29: 779-783Abstract Full Text PDF PubMed Scopus (303) Google Scholar. Bright had reasoned that, “the altered quality of the blood so affects the minute and capillary circulation as to render greater action necessary to force the blood through the distal division of the vascular system”33.Bright R. Tabular view of the morbid appearances in 100 cases connected with albuminous urine.Guy's Hosp Rep. 1836; 1: 380-489Google Scholar. However, Bright had no means of measuring the blood pressure in the 1830s35.Cameron J.S. Villain and victim: The kidney and high blood pressure in the nineteenth century.J R Coll Physicians Lond. 1999; 33: 382-394PubMed Google Scholar. Traube, who was influenced by suggestions from William Senhouse Kirkes (as emphasized more recently35.Cameron J.S. Villain and victim: The kidney and high blood pressure in the nineteenth century.J R Coll Physicians Lond. 1999; 33: 382-394PubMed Google Scholar), assumed that an increase in circulating blood volume contributes to hypertension36.Lupu A.N. Experimental hypertension: Some historical aspects.Urol Clin North Am. 1975; 2: 223-226PubMed Google Scholar,37.Traube L. Ueber den Zusammenhang von Herz- und Nierenkrankheiten. A. Hirschwald, Berlin1856Google Scholar. He speculated that Bright's disease, by leading to shrunken kidneys, may destroy many small intrarenal vessels. As a consequence, less blood flows from the arterial system into the veins, resulting in decreased urine production and an increase in circulating fluid volume. The final result is hypertension leading to cardiac hypertrophy37.Traube L. Ueber den Zusammenhang von Herz- und Nierenkrankheiten. A. Hirschwald, Berlin1856Google Scholar. An alternative view, provided Gull and Sutton in 1872, suggested that renal and cardiac disease are the consequences of a common underlying disease. This view may be considered as the first description that essential hypertension can cause cardiac as well as renal disease38.Gull W. Sutton H. On the pathology of the morbid state commonly called chronic Bright's disease with contracted kidney (“arterio-capillary fibrosis”).Med Chir Trans. 1872; 55: 325-371Google Scholar,39.Newton N.M. Fine L.G. Inference of the existence of high blood pressure as a cause of renal disease in the mid-19th century: Observations on vascular structures in the kidney.Am J Nephrol. 1999; 19: 323-332Crossref PubMed Scopus (7) Google Scholar. Possible connections between renal perfusion and blood pressure were examined during the 19th century. Grawitz and Israel occluded one renal artery of the rabbit for short periods and directly measured blood pressure in the carotid artery using a newly constructed device40.Grawitz P. Israel O. Experimentelle Untersuchung über den Zusammenhang zwischen Nierenerkrankungen und Herzhypertrophie.Arch Path Anat. 1879; 77: 315-325Crossref Scopus (8) Google Scholar. Although Grawitz and Israel could not detect an increase in blood pressure, they found evidence of “compensatory” cardiac hypertrophy40.Grawitz P. Israel O. Experimentelle Untersuchung über den Zusammenhang zwischen Nierenerkrankungen und Herzhypertrophie.Arch Path Anat. 1879; 77: 315-325Crossref Scopus (8) Google Scholar. Lewinski constricted renal arteries of both kidneys in dogs using silk or catgut strings41.Lewinski L. Ueber den Zusammenhang zwischen Nierenschrumpfung und Herzhypertrophie.Zschr Klin Med. 1880; 1: 561-582Google Scholar. Despite severe technical problems, Lewinski observed cardiac hypertrophy in five of six dogs; however, he had not measured blood pressure41.Lewinski L. Ueber den Zusammenhang zwischen Nierenschrumpfung und Herzhypertrophie.Zschr Klin Med. 1880; 1: 561-582Google Scholar. He thought that unknown humoral substances, normally excreted by the kidneys, might affect the heart and cause vasoconstriction of small vessels41.Lewinski L. Ueber den Zusammenhang zwischen Nierenschrumpfung und Herzhypertrophie.Zschr Klin Med. 1880; 1: 561-582Google Scholar. Tigerstedt and Bergmann made a giant step in 1898. They observed that extracts of the rabbit renal cortex produce a pronounced and sustained increase in blood pressure when injected intravenously42.Tigerstedt R. Bergmann P.G. Niere und Kreislauf.Scand Arch Physiol. 1898; 8: 223-271Crossref Scopus (501) Google Scholar. They also found that blood from renal veins exerted a small pressure action when infused into another animal42.Tigerstedt R. Bergmann P.G. Niere und Kreislauf.Scand Arch Physiol. 1898; 8: 223-271Crossref Scopus (501) Google Scholar. The vasoactive substance was destroyed by alcohol and was named “renin” by the authors42.Tigerstedt R. Bergmann P.G. Niere und Kreislauf.Scand Arch Physiol. 1898; 8: 223-271Crossref Scopus (501) Google Scholar. This novel approach to hypertension was likely based on current studies of the Paris school, and Charles Brown-Séquard promoted the novel concept that internal organs, including the kidney, had an “internal secretion”35.Cameron J.S. Villain and victim: The kidney and high blood pressure in the nineteenth century.J R Coll Physicians Lond. 1999; 33: 382-394PubMed Google Scholar. However, confirming Tigerstedt and Bergmann's observations proved difficult, probably because the original extraction protocol was not carefully followed. Pässler and Heinecke, in 1905, performed 5/6 nephrectomy experiments in dogs and found that systolic blood pressure increased by 15 mm Hg at the level of the femoral artery43.Pässler D. Heinecke L. Versuche zur Pathologie des Morbus Brightii.Centralbl Allgemein Pathol Anat. 1906; XVI: 99-117Google Scholar. They also identified cardiac hypertrophy. Volhard was at their presentation and raised the possibility that hyperfiltration in remaining nephrons required an increase in blood pressure under these circumstances15.Volhard F. Diskussionbemerkungen zum Morbus Brightii.Verh Deutsch Pathol Gesell. 1905; 9: 111-114Google Scholar. Shortly thereafter, Katzenstein used rubber bands to partially occlude the renal arteries of rabbits and dogs. He also applied torsion of the renal pedicle to occlude the renal blood flow completely44.Katzenstein M. Experimenteller Beitrag zur Erkenntnis der bei Nephritis auftretende Hypertrophie des linken Herzens.Virchows Arch. 1905; 182: 327-337Crossref Scopus (5) Google Scholar. Katzenstein observed an increase in systolic blood pressure by