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Erich Frank (1884-1957): Unsung Pioneer in Nephrology

2011; Elsevier BV; Volume: 58; Issue: 4 Linguagem: Inglês

10.1053/j.ajkd.2011.07.007

1523-6838

Mehmet Şükrü Sever, Arın Namal, Garabed Eknoyan,

Cardiovascular Syncope and Autonomic Disorders

The period between the 2 World Wars was a time of budding interest in renal studies and one that closed in major geopolitical unrest, culminating in World War II. The life of Erich Frank (1884-1957) and his contributions to chronic kidney disease provide considerable insight into this period. Frank began his career in Breslau, Germany. His medical thesis and first publication were on the benign nature of orthostatic proteinuria. He went on to define and differentiate essential from renal hypertension, presented evidence for the role of the posterior pituitary in diabetes insipidus, and studied the first oral hypoglycemic agent. As all clinical scientists then, Frank also contributed to other fields of medicine. When Germany turned to Nazism, Frank moved to Turkey, where he was appointed co-chair of the Department of Medicine of the newly established Istanbul University. For the next 23 years, he trained a new generation of modern physicians and laid the foundation of several medical disciplines in Turkey. As author of the first Turkish textbook of nephrology and a teacher who inspired his students, some of whom went on to become the first generation of Turkish nephrologists, Frank was a pioneer in nephrology who helped establish the discipline in his adopted country. The period between the 2 World Wars was a time of budding interest in renal studies and one that closed in major geopolitical unrest, culminating in World War II. The life of Erich Frank (1884-1957) and his contributions to chronic kidney disease provide considerable insight into this period. Frank began his career in Breslau, Germany. His medical thesis and first publication were on the benign nature of orthostatic proteinuria. He went on to define and differentiate essential from renal hypertension, presented evidence for the role of the posterior pituitary in diabetes insipidus, and studied the first oral hypoglycemic agent. As all clinical scientists then, Frank also contributed to other fields of medicine. When Germany turned to Nazism, Frank moved to Turkey, where he was appointed co-chair of the Department of Medicine of the newly established Istanbul University. For the next 23 years, he trained a new generation of modern physicians and laid the foundation of several medical disciplines in Turkey. As author of the first Turkish textbook of nephrology and a teacher who inspired his students, some of whom went on to become the first generation of Turkish nephrologists, Frank was a pioneer in nephrology who helped establish the discipline in his adopted country. Whereas kidney disease is old, nephrology is a relatively young discipline. The seeds of the study of kidney disease were sown by Richard Bright (1789-1858) in 1827, but it was only in the second half of the 20th century that the study of the kidney as a specialty finally emerged as a budding discipline after the first International Meeting of Nephrology in Evian, France, in 1960. In the interim, and especially in the first half of the 20th century, important contributions to our knowledge of kidney function in health and disease were made by pathologists, physiologists, and internists who worked in and contributed to several other fields of medicine, none of whom considered themselves nephrologists. The major figures who dominated this period have been duly acknowledged for their seminal contributions to the emergence of nephrology.1Peitzman S.J. Nephrology in the United States from Osler to the artificial kidney.Ann Intern Med. 1986; 105: 937-946Crossref PubMed Scopus (19) Google Scholar, 2Peitzman S.J. From dropsy to Bright's disease to end-stage renal disease.Milbank Q. 1989; 67: 16-32Crossref PubMed Scopus (15) Google Scholar The contributions of many others who made it all possible and provided the infrastructure that would spread nephrology worldwide remain unrecognized. One such figure is Erich Frank (1884-1957; Fig 1), better known for his contribution to the understanding of diabetes insipidus.3Eknoyan G. A history of diabetes insipidus: paving the road to internal water balance.Am J Kidney Dis. 2010; 56: 1175-1183Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar His life and many other contributions to the leading causes of chronic kidney disease (diabetes, hypertension, and proteinuria) provide considerable insight into the formative years of nephrology during a period of great social and political turmoil that preceded its emergence as a discipline after World War II. To quote from the subtitle of Steven Shapin's4Shapin S. Never Pure: Historical Studies of Science as if It Was Produced by People With Bodies, Situated in Time, Space, Culture, and Society, and Struggling for Credibility and Authority. The Johns Hopkins University Press, Baltimore, MD2010Google Scholar book, Never Pure, the life work of Frank represents a historical study in the understanding of kidney disease as it was produced by “people with bodies, situated in time, space, culture, and society, and struggling for credibility and authority” and in his case for survival. His work represents the evolving understanding of kidney disease as much as it does that of the major geopolitical changes affecting Europe at the time, as well as that of the emergence of the new Republic of Turkey, which provided him safe haven to continue the work he had started in his native Germany. Frank was born on June 28, 1884, in Berlin to a Jewish mother (Dorothea) and a Christian father (Albert) who was a teacher at a local gymnasium (the upper level of secondary school, which prepared students for admission to university).5Gahagan Frank S. My father.in: Ulutin O. Ord. Prof. Dr. Erich Frank'ın Dünya Tıbbındaki Yeri ve Türk Tıbbına Katkıları. Nobel Tıp Kitabevleri, Istanbul, Turkey2007: 81-87Google Scholar, 6Gaedicke G. Ein jüdischer Arzt aus Deutschland als modernisierer der akademischen Medizin in der Türkei Prof. Erich Frank's Wirken an der Universität Istanbul.in: Heidel C.P. Jüdische Medizin- Jüdisches in der Medizin- Medizin der Juden? Mabuse Verlag, Frankfurt am Main, Germany2011: 255-265Google Scholar After his secondary education, Frank began his medical studies in 1902 at the University of Breslau (now the University of Wrocław, Poland). This was a period in which research was venerated and the system of medical education encouraged good students to find their way into research. A written thesis of original research that usually was published was a requirement for obtaining a medical degree in Germany. Thus, it was as a medical student that Frank embarked on the study of albuminuria in Breslau. In 1907, he passed the Staatsexamen (National Medical Examination) and transferred to the University of Strasbourg (then known as the Kaiser Wilhelm Medical Faculty), where he presented his thesis on “orthostatic albuminuria” (Fig 2) and was granted a medical degree in 1908.7Kandan S. Prof. Dr. Erich Frank'ın Türk ve dünya tıbbına katkısı Atatürk'ün 1933 üniversite reformu ve Türk-Avrupa Tıbbi ilişkileri simpozyumu bildirileri.in: Türk Tıp Tarihi Yıllığı (Acta Turcica Historiae Medicinae VII). 2001: 97-100Google Scholar From 1908 to 1911, Frank worked as an assistant to Wilhelm Weintraud (1866-1920). Weintraud, a trainee of Felix Hoppe-Seyler (1825-1895), had been recruited by the head of the medical department of the University of Breslau and Oskar Minkowski (1858-1931), famous for his research on diabetes mellitus and the first to show its relationship to the pancreas.8Luft R. Oskar Minkowski: discovery of the pancreatic origin of diabetes, 1889.Diabetologia. 1989; 32: 399-401Crossref PubMed Scopus (20) Google Scholar In Breslau, Frank studied salvarsan, one of the magic bullets of Paul Ehrlich (1854-1915; another graduate of Breslau and Strasbourg), and wrote his well-known paper on diabetes insipidus.9Frank E. Uber Beziehungen der Hypophyse zum diabetes insipidus.Berliner Klin Wochenschr. 1912; 9: 1-15Google Scholar In 1911, Frank began his academic career as a resident in internal medicine at the University of Strasbourg and worked at Wiesbaden Hospital, which was affiliated with the university. In 1913, he was promoted to associate professor, and in 1919, to professor of internal medicine in Breslau, where he served as the head of internal medicine of the Wenzel-Hancke Municipal Hospital in 1926-1933. In Breslau in 1918, Frank married Erna Führich, who was born in Katowice, Poland, in 1889. From this marriage, they had a daughter, Sabine, born in 1919, and a son, Ernst Frank, born in 1925.10Bilhan N. Frank Hoca.Diabet. 1962; 4: 10-16Google Scholar As Germany turned to Nazism, the University of Breslau came under the influence of Nazi ideology, and there followed an aggressive policy for the eviction of university faculty of Jewish heritage. As a result, together with thousands of other citizens and many renowned scientists and scholars, Frank sought asylum away from his country.5Gahagan Frank S. My father.in: Ulutin O. Ord. Prof. Dr. Erich Frank'ın Dünya Tıbbındaki Yeri ve Türk Tıbbına Katkıları. Nobel Tıp Kitabevleri, Istanbul, Turkey2007: 81-87Google Scholar It is in this context that in September 1933, Albert Einstein (1879-1955) sent a letter to İsmet İnönü (1884-1973), then Prime Minister of Turkey, asking permission “to allow forty professors and physicians from Germany to continue their scientific and medical work in Turkey”, adding that “in accepting this request, your government not only will perform an act of high humanity, but will also bring profit to your own country” (Fig 3).11Bardakci M. Bugün erkeğin kadınla tokalaşmasını tartışan Türkiye'den bir zamanlar Einstein bile iş ricasında bulunuyordu. Hurriyet Daily, October 29, 2006http://hurarsiv.hurriyet.com.tr/goster/ShowNew.aspx?id=5335137Google Scholar The letter was referred to the Ministry of National Education, where it was considered incompatible with existing laws and initially was rejected.11Bardakci M. Bugün erkeğin kadınla tokalaşmasını tartışan Türkiye'den bir zamanlar Einstein bile iş ricasında bulunuyordu. Hurriyet Daily, October 29, 2006http://hurarsiv.hurriyet.com.tr/goster/ShowNew.aspx?id=5335137Google Scholar About this time, the new Turkish Republic founded by Kemal Atatürk (1881-1938) was keen in modernizing its education system. In 1932, Albert Malche (1876-1956) of Switzerland, who was a pedagogy professor, had been invited to prepare a report on reforming the Turkish educational system.12Widman H. Atatürk ve Üniversite Reformu. Kabalci Yayinevi, Istanbul, Turkey1999Google Scholar Among other suggestions, Malche had proposed a major infusion of academic talent from abroad. A Western style of higher education had long been sought by the Ottomans, leading to the establishment in 1846 of Darülfünun (House of Sciences) in Istanbul. Despite repeated attempts at reform, Darülfünun remained a mediocre institution until 1933, when, on the basis of the Malche report, it was transformed to Istanbul University.12Widman H. Atatürk ve Üniversite Reformu. Kabalci Yayinevi, Istanbul, Turkey1999Google Scholar By the direct personal intervention of Atatürk, the new university became host to a number of Jewish educators fleeing Germany, including the 40 mentioned in Einstein's letter, most of whom (including Frank) accepted the offer and emigrated to Turkey. As a consequence, more than two-thirds of the faculty of Darülfünun was relieved of their duties and replaced by new faculty. By the following academic year (1933-1934), all directors of the 12 institutions of Istanbul University were German refugee scholars.13Reisman A. Turkey's Modernization Refugees From Nazism and Atatürk's Vision. New Academia Publishing, LLC, Washington, DC2006Google Scholar This was an opportunity for Frank to leave behind the threatening environment of his native country to pursue his academic career in a safer place. He was invited to take the position of co-chair of the Department of Internal Medicine of the new Istanbul University. Joining him on the medical faculty were other distinguished scholars, such as Rudolf Nissen (1896-1981) from Charité in Berlin to head surgery; Wilhelm Liepmann (1878-1939) from Berlin University to head obstetrics; Joseph Igersheimer (1879-1965) from Frankfurt University to head ophthalmology; and Friedrich Dessauer (1881-1963), also from Frankfurt University, to head radiology.13Reisman A. Turkey's Modernization Refugees From Nazism and Atatürk's Vision. New Academia Publishing, LLC, Washington, DC2006Google Scholar Frank was assigned to head the medical services of the Vakıf Gureba Hospital, which was a vakıf (foundation) charity hospital that accepted the gureba (poorest) patients from all over Turkey. It was one of the teaching hospitals of Istanbul University located in the Marmara region of the Fatih district of Istanbul. It was built in 1843 during the reign of Sultan Abdülmecid I (1823-1861) by a grant from his mother Bezmiâlem Valide Sultan (1807-1853); hence the full name of the hospital, the Valide Vakıf Gureba Hospital. (A fictionalized version of the sultan and his mother appears in Jason Goodwin's novels, The Bellini Card and The Janissary Tree.) A modern hospital with the same name now stands on the site of the old hospital. Frank's first contract extended from September 1, 1934, until August 31, 1939, at a salary of 600 Turkish liras per month (Fig 4). The contract also allowed for the hiring of a laboratory chief and a dietician, if their need could be documented. Frank petitioned for these positions shortly after his arrival, convincing the authorities to recruit Kurt Steinitz (1907-1966) as laboratory chief and Elisabeth (Elsa) Wolff (1894-?) as dietician. Steinitz was a medical graduate of Leipzig and Heidelberg Universities with an interest in chemistry, and he had collaborated with Frank in Breslau at the Wenzel-Hancke Municipal Hospital. He moved to Turkey in October 1934, where he took the position of laboratory chief of the Vakıf Gureba Hospital. Steinitz organized the laboratory, taught medical students clinical pathology, and embarked on the investigation of kidney function in humans. In the years that he worked at the hospital, Steinitz conducted studies on the determination of glomerular filtration by endogenous creatinine clearance 14Steinitz K. Turkand H. The determination of the glomerular filtration by the endogenous creatinine clearance.J Clin Invest. 1940; 19: 285-298Crossref PubMed Google Scholar and on glucose excretion in humans15Steinitz K. Studies on the conditions of glucose excretion in man.J Clin Invest. 1940; 19: 299-305Crossref PubMed Google Scholar that were published in the Journal of Clinical Investigation in 1940 and are quoted by Homer Smith (1895-1962) in his classic book The Kidney: Structure and Function in Health and Disease.16Smith H.W. The Kidney: Structure and Function in Health and Disease. Oxford University Press, Oxford, NY1951Google Scholar In the first article, Steinitz showed the hyperbolic increase in serum creatinine level with progressive loss of kidney function in humans. In both articles, Steinitz expresses his indebtedness and acknowledges the encouragement of Frank in conducting these basic investigations. Steinitz's contract expired in 1943, whereupon he left for Palestine, where he became the first physician to develop an artificial kidney and the first to dialyze a patient in Israel.17Namal A. Zwischen Emigration aus dem NS- Einflussbereich und Ankunft in Palästina bzw Israel: Jüdische Wissenschaftler an der Universität Istanbul.in: Heidel C.P. Der Einfluss des Zionismus auf Medizin und Gesundheitswesen [Medizin und Judentum Band 8]. Mabuse Verlag, Frankfurt a Main, Germany2006: 121-145Google Scholar, 18Levy N. Dr. Kurt Steinitz (1907–1966) and the 60th anniversary of the first hemodialysis in the Middle East.Harefuah. 2010; 149: 108-110PubMed Google Scholar Elsa Wolff was born in Loslau, now Wodzisław Śląski in southern Poland. Upon graduation in nursing from Breslau in 1922, she worked in Frank's clinic until 1928. After 2 years of working in Switzerland and Poland, she returned to work for Frank in Breslau until 1933. As one of the few representatives of modern dietetics, on moving to Turkey, she organized the first hospital-based dietary department in the country. She was instrumental in the training of many nurses as dieticians, who later went on to serve in other hospitals as dietary experts. With Frank, she wrote a popular diet book in Turkish on the dietary management of patients.19Wolf E. Pratik Diyetetik Muhtelif Hastalıkları Perhizle Tedavi Usulleri. Marifet Basımevi, Istanbul, Turkey1942Google Scholar The book includes 20 chapters, the 4th of which is on diet in diabetes; the 8th, on diet in kidney diseases; and the 14th, on that of kidney and bladder stones. After 32 years of service in Turkey, Elsa retired in 1965 and returned to Germany.20Namal A. Eine deutsche Vorreiterin in der türkischen Diätetik Diätschwester Elisabeth Wolff-32 hochgelobte Dienstjahre.NTM. 2004; 12: 161-181Crossref PubMed Scopus (2) Google Scholar Shortly after assuming his position, Frank submitted a petition to the Dean of Istanbul University School of Medicine, Nureddin Ali Berkol (1880-1955), requesting the following: 1. Personnel: 2 additional residents in addition to the 4 assigned to his service; one to work in the outpatient clinic, and the other, in the research laboratory. Two more nurses to allow for continuous 24-hour nursing coverage of hospital wards. 2. Resources: 2,500 Turkish liras to establish a dietary service and obtain new instruments for the diagnosis and treatment of patients. 3. Revision of medical education: Frank considered the quality of medical education inadequate and made several recommendations for improving the training of medical students, suggesting the incorporation of a combination of French and German medical principles to improve education and health care services in Turkey. In the years that followed, Frank and his team completely reorganized internal medicine services at Istanbul University, treated thousands of patients, educated hundreds of medical students, and trained many house officers as physicians and investigators.21Ulutin O. Ord. Prof. Dr. Erich Frank'ın Dünya Tıbbındaki Yeri ve Türk Tıbbına Katkıları.in: Ulutin O. Ord. Prof. Dr. Erich Frank'ın Dünya Tıbbındaki Yeri ve Türk Tıbbına Katkıları. Nobel Tıp Kitabevleri, Istanbul, Turkey2007: 27-66Google Scholar Frank also collaborated with Turkish academicians and contributed to their careers, acquiring in the process the loyalty and support of colleagues throughout the country. In short, his work was central to the development of modern medicine in Turkey. His efforts were appreciated by not only his students, colleagues, and patients, but also by the Turkish government, which remained favorably responsive to his requests for the support and expansion of medical services. In 1951, Frank launched a new medical journal titled Istanbul Contribution to Clinical Science, of which he served as Editor-in-Chief until his death in 1957. The inaugural issue of the journal contained 4 articles. The first, written by Frank, was a review titled “An update on the pathogenesis of essential hypertension.”22Frank E. Esansiyel hipertansiyon bilgisinin bugünkü durumu Tecrübi ve esansiyel hipertansiyonun aynı oluşuna dair Goldblatt'ın tezi.Istanbul Contrib Clin Sci. 1951; 1: 3-39Google Scholar The other 3 were prospective clinical trials, one of which was a study of the effect of oral potassium loads in healthy volunteers. Thus, of the 4 inaugural articles, 2 were related to nephrology. After his death, his fellow Orhan Ulutin (b. 1924) became Editor-in-Chief of the journal, which in 1962 was reorganized as the Turkish Journal of Hematology, the official publication of the Turkish Society of Hematology. After World War II, Frank received several offers for academic positions from various countries, especially the United States and Germany. However, he was content with his job in his adopted homeland and always grateful for the invitation to Istanbul University in his most difficult and insecure days. Unlike most of those who had sought refuge in Turkey with him, Frank refused these attractive offers and elected to continue his work and teaching in the Istanbul University, surrounded by his students, assistants, and patients. He retired from the university in 1953 and died on February 13, 1957, after a fulminant illness, probably hepatic failure.23Berker F. Erich Frank.in: Ulutin O. Ord. Prof. Dr. Erich Frank'ın Dünya Tıbbındaki Yeri ve Türk Tıbbına Katkıları. Nobel Tıp Kitabevleri, Istanbul, Turkey2007: 66-75Google Scholar Frank had the hallmarks of a true scientist: a profound analytical ability, a keen intellect, an all-embracing mind, and humility and humanity. As a graduate of the German medical system, he was a clinical scientist. As a trainee of Breslau, he had a special interest in diabetes mellitus. As an informed investigator, he kept abreast of the accumulating new studies of the kidney in health and disease. His scientific contributions encompassed several branches of medicine, including diabetes, nephrology, hematology, and neurology (Box 1). What follows is a review of his contributions to nephrology and a brief summary of his contribution to other fields in medicine.Box 1Principal Scientific Contributions of Frank to MedicineNephrology•Description of orthostatic proteinuria (1908)•Concept of essential and renal parenchymal hypertension (1911)•Concept of hypertensive nephrosclerosis (1911)•Description of renal glycosuria (1913)•Textbook of Nephrology (1941) (in Turkish)Other Fields of Medicine•Micromethod for blood glucose determination (1910)•Pathogenesis of diabetes insipidus (1912)•Pathogenesis of aplastic anemia and essential thrombocytopenia (1915)•Role of thrombocytes in anticoagulation (1915)•Description of hypersplenism (1915)•Discovery of an oral antidiabetic: Synthaline B (1925)•Description of factor VIII and pathogenesis of hemophilia (1927) Nephrology•Description of orthostatic proteinuria (1908)•Concept of essential and renal parenchymal hypertension (1911)•Concept of hypertensive nephrosclerosis (1911)•Description of renal glycosuria (1913)•Textbook of Nephrology (1941) (in Turkish) Other Fields of Medicine•Micromethod for blood glucose determination (1910)•Pathogenesis of diabetes insipidus (1912)•Pathogenesis of aplastic anemia and essential thrombocytopenia (1915)•Role of thrombocytes in anticoagulation (1915)•Description of hypersplenism (1915)•Discovery of an oral antidiabetic: Synthaline B (1925)•Description of factor VIII and pathogenesis of hemophilia (1927) Frank's interest in the kidney can be traced to his student years in Breslau. His medical thesis, prepared under the supervision of Weintraud, was on orthostatic proteinuria and was published in 1908 as Über den genuinen orthostatischen Typus (Genuine Orthostatische Albuminurie) (Fig 2).24Frank E. Uber den genuen orthostatische Typus (Genuine orthostatische Albuminurie), Eis.-Lothr. Druckerei, Strassburg, Germany1908: 1-74Google Scholar After Richard Bright's landmark report of the kidney in dropsical patients and its differentiation from other causes of dropsy by the presence of albuminous urine, albuminuria came to be considered the manifestation of a serious inflammatory lesion of the kidneys termed “nephritis.” Debate during the ensuing decades centered on whether nephritis could exist in the absence of dropsy and whether albuminuria could be present without progressive loss of kidney function. To address this latter issue, Frank undertook his thesis work in an attempt to differentiate benign from serious kidney disease, with its focus on orthostatic albuminuria as a benign disorder that required no treatment and might improve with exercise. In his report, Frank emphasized that the pathogenesis of this type of albuminuria was not orthostatism per se, but rather the lordotic position of the patient,24Frank E. Uber den genuen orthostatische Typus (Genuine orthostatische Albuminurie), Eis.-Lothr. Druckerei, Strassburg, Germany1908: 1-74Google Scholar, 25Frank E. Dahili Böbrek Hastalıkları Klinigi.in: Istanbul University Press, Istanbul, Turkey1941Google Scholar and thus he measured urinary albumin excretion in 2 positions. First, he placed a pillow under the lumbar region of supine volunteers in bed to create a lordotic position, noting that albuminuria appeared after 1 hour and disappeared several hours later when the volunteer returned to the normal flat position at rest. Next, he asked a standing patient to bend forward, assuming a kyphotic position, and noted that albuminuria disappeared shortly thereafter. Thus, he emphasized again that it was the lordotic position and not merely orthostatism that produced albuminuria. Frank also measured glomerular filtration rate and renal blood flow in these individuals and found that both parameters decreased in the lordotic position. He commented that these changes possibly were related to changes in intrarenal hydrostatic pressure secondary to a positional reflex constriction of the renal artery. His first publications after graduation addressed ongoing studies of kidney disease that were to lead to the coherent scheme of Franz Volhard (1872-1950) and Theodor Fahr (1877-1945) in framing the classification of kidney disease. This was a time when the kidney as a cause or culprit in hypertension was actively debated. In 1911, Frank published 2 reports in which he defined and described the terms hypertonische diathese and nephrogene hypertonie; in other words, essential hypertension and hypertension due to renal parenchymal disease.22Frank E. Esansiyel hipertansiyon bilgisinin bugünkü durumu Tecrübi ve esansiyel hipertansiyonun aynı oluşuna dair Goldblatt'ın tezi.Istanbul Contrib Clin Sci. 1951; 1: 3-39Google Scholar, 26Frank E. Ueber die Beziehungen zwischen Niere, Nebenniere und hohen Blutdruck in der menschlichen Pathologie (Hypertonische Diathese und nephrogene Hypertonie).Berliner Klin Wochenschr. 1911; 14: 1-11Google Scholar, 27Frank E. Bestehen Beziehungen zwischen chromaffinem System und der chronischen Hypertonie des Menschen?.Deutsches Arch F Klin Med. 1911; 103: 397-412Google Scholar, 28Kolta S. Das wissenschaftliche Werk von Erich Frank (1884-1957).in: Terzioğlu A. Proceedings of the Second Turkish-German Medical Relations Symposium (September 24-25, 1981). FGV Mambas, Istanbul, Turkey1981: 103-108Google Scholar Based on the autopsy findings of a 46-year-old woman with severe hypertension (in whom rather than the expected small sclerotic kidneys, the kidneys showed minimal abnormalities and no sclerosis), he argued that the hypertension in this patient certainly was different from nephrogene hypertonie, suggesting that her hypertension was due to primary increased vascular tone (hypertonische diathese).26Frank E. Ueber die Beziehungen zwischen Niere, Nebenniere und hohen Blutdruck in der menschlichen Pathologie (Hypertonische Diathese und nephrogene Hypertonie).Berliner Klin Wochenschr. 1911; 14: 1-11Google Scholar He emphasized that clinically, this disorder usually begins in the early 40s and can result in cardiac and renal failure if untreated. He acknowledged that the cause of essential hypertension was unknown, but could be due to reflex activation originating from the kidneys or its release of “renin,” but that these remained to be determined. In a subsequent publication, he considered other causes of hypertension, such as a higher set point for blood pressure control in the nervous system, sex hormones, and genetic factors.22Frank E. Esansiyel hipertansiyon bilgisinin bugünkü durumu Tecrübi ve esansiyel hipertansiyonun aynı oluşuna dair Goldblatt'ın tezi.Istanbul Contrib Clin Sci. 1951; 1: 3-39Google Scholar Another interest of Frank was renal glycosuria, specifically in pregnancy, which he began to address in 1913. He considered this “renal diabetes” a harmless condition due to a lower renal threshold for glucose absorption. However, he acknowledged that it could appear at the onset of diabetes or turn into diabetes subsequently.29Frank E. Über experimentelle und klinische Glycosurien renalen Ursprungs.Arch Experimentelle Pathol Pharmakol. 1913; 72: 387-443Google Scholar In addition, Frank contributed several articles on kidney function and disease to the Istanbul Contribution to Clinical Science that were detailed reviews of the literature. Importantly, he wrote the first Turkish textbook on the kidney and its diseases, titled Dahili Böbrek Hastalıkları Kliniği (Medical Kidney Diseases Clinics),25Frank E. Dahili Böbrek Hastalıkları Klinigi.in: Istanbul University Press, Istanbul, Turkey1941Google Scholar which was published in 1941 by Istanbul University. This 277-page book was divided into 9 chapters and was a state-of-the-art text on kidney function and disease (Box 2; Fig 5).25Frank E. Dahili Böbrek Hastalıkları Klinigi.in: Istanbul University Press, Istanbul, Turkey1941Google ScholarBox 2Table of contents of Frank's textbook of nephrology “Medical Kidney Diseases Clinics” (Dahili Böbrek Hastalıkları Kliniği, 1941)25Frank E. Dahili Böbrek Hastalıkları Klinigi.in: Istanbul University Press, Istanbul, Turkey1941Google Scholar1Pathophysiology of kidney disease. Reviews glomerular filtration and tubular function in health and disease.2Evaluation of kidney function. Concentrates on urea and creatinine clearance and their measurement.3Orthostatic proteinuria. Devoted to his long-standing interest in the subject.4Acute glomerulonephritis. On the cause, pathogenesis, clinical, and laboratory findings in acute glomerulonephritis.5Specific types of kidney disease. I