Journal of Human Hypertension (2001) 15, 5–16  2001 Macmillan Publishers Ltd All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh REVIEW ARTICLE and Theodor Fahr: achievements and controversies in their research in renal disease and hypertension

A Heidland1, W Gerabek2 and K Sebekova3 1Department of Internal Medicine, 2Institute of History of Medicine, University of Wuerzburg, Germany; 3Institute of Preventive and Clinical Medicine, Bratislava, Slovakia

The clinician, Franz Volhard, and the pathologist, ischaemic (s) contributing – via a vicious circle – Theodor Fahr, worked closely together in Mannheim to a further rise in blood pressure with subsequent reno- from 1909 until 1915 and introduced a novel classi- vascular injury and aggravation of hypertension. This fication of renal diseases. In the monograph entitled ‘Die hypothesis was supported in 1930 by initial experiments Bright’sche Nierenkrankheit, Klinik, Pathologie und of his collaborator, Hartwich (demonstrating in dogs a Atlas’ (1914) they differentiated between degenerative mild rise in blood pressure after ligation of branches of (nephroses), inflammatory (nephritides) and arterio- the renal artery) and definitively proven by Goldblatt sclerotic (scleroses) diseases. Nephrosclerosis was div- (1934) in dogs by induction of severe and persistent ided into the benign and malignant form, of which the hypertension after clamping of both renal arteries. The latter stood the test of time as a new disease entity. Fahr consequent detection of the renin angiotensin system further divided benign nephrosclerosis into the com- was the final confirmation of Volhard’s postulated renal pensated and decompensated form – depending on the pressor substance. In the pathogenesis of red presence or absence of glomerular injury. In the patho- (essential) hypertension, Volhard stressed the role of genesis of malignant nephrosclerosis, Volhard stressed hereditary factors, age, obesity and potentially of severe the decisive role of severe blood pressure elevation, alcoholism. He emphasised a premature reduction of while Fahr postulated an inflammatory mechanism, a vascular distensibility (due to elastosis of the concept later confirmed by Adalbert Bohle for at least a prearterioles), a high cardiac output as well as a damp- minority of patients. A very far reaching concept of ening of baroceptor function. Additionally, Volhard Franz Volhard was his idea that pale (renal) hyperten- made crucial advances in and pneumology. sion results from a pressor substance released from Journal of Human Hypertension (2001) 15, 5–16

Keywords: Franz Volhard; Theodor Fahr; classification of renal diseases; glomerulonephritis; benign nephrosclerosis; malig- nant nephrosclerosis

Introduction attempted to unfold the heterogeneity of Bright’s dis- ease. However, the description of the various renal In the 19th century medicine evolved into a natural lesions by pathologists and clinicians was confusing science, true scientific standards were introduced. In and chaotic. A real breakthrough (‘breath of fresh air’, particular, novel investigative tools had an enormous Sir George Pickering5) was the novel classification by impact: urine analysis (by microscopy and protein 1 Volhard and Fahr in their famous monograph ‘Die determination), estimation of renal function (by Bright’sche Nierenkrankheit, Klinik, Pathologie und measurement of urine osmolarity and determination Atlas’, 1914.6 of blood urea nitrogen),2 indirect measurements of blood pressure (by sphygmomanometry)3 and evalu- ation of the eye ground (by opthalmoscopy).3 Patho- Franz Volhard logical anatomy had been revolutionised by the intro- Was born in Munich on 2 May 1872, the son of the duction of light microscopy combined with new well-known Professor Jacob Volhard, later Director of techniques for tissue staining.4 Numerous studies the Institute of Chemistry at the University of Erlangen and Halle.7,8 He started studying medicine in 1892 at the , where August Ke´k- Correspondence: Dr A Heidland, Department of Internal Medi- cine, University of Wuerzburg, Josef-Schneider-Str. 2, 97080 ule´ and Eduard Pflu¨ ger were among his teachers. He Wuerzburg, Germany continued his studies in with Oskar Min- Received 20 March 2000; revised and accepted 25 July 2000 kowski, , Richard von Rec- Achievements and controversies in renal disease and hypertension A Heidland et al 6 klinghausen and . In 1897 Vol- hard graduated from the University at Halle and subsequently completed his dissertation on ‘Experi- mental and clinical studies on the pathogenesis of eclampsia’. After a short stay at the Pathological Insti- tute in Friedrichsheim/, he was trained in internal medicine at the University of Gieβen (1898– 1905) under the chair of Franz Riegel. This decision was not purely coincidental, since in that clinic being unmarried was not a prerequisite for an assistant’s position – quite in contrast to most other clinics in Germany. During his stay in Gieβen, Volhard started scientific research in various fields, including cardio- vascular, renal and gastroenterological problems. His faculty rank (habilitation) in 1901 concerned the ‘Lipid splitting enzyme of the stomach’. In 1905 Volhard was asked to be Director of the Clinic of Internal Medicine of the Luisenhospital in Dortmund. At this time he had already become specifi- cally interested in and hypertension. Inspired by the cryostatic measurements of the urinary osmoregulatory function by Sandor von Kora´nyi, Vol- hard introduced the urinary concentration and dilution test by measuring specific gravity as an overall para- meter for evaluation of renal function. In 1908 Franz Volhard became Director of the Town Hospital of Mannheim which at the time was in a catastrophic state. Here he attracted the atten- tion of the young pathologist Theodor Fahr, who had very similar scientific interests, in particular of renal vessels. A close partnership developed which was to have an enormous impact on research devel- opment of nephrology and hypertension. Volhard Figure 1 Franz Volhard (1872–1950) as Director of the Clinic of Internal Medicine at the University of Frankfurt/Main (Source: B and his collaborators participated in all autopsies Oslen, MD, Department of Internal Medicine, University of Halle). and in the microscopic evaluation of renal tissues. As a result, their monography on Bright’s disease became the ‘bible of nephrology’ for several decades. Gießen, where he completed his dissertation (1903). In 1918 Volhard was named Director of the Clinic For further training, he moved to Simons and of Internal Medicine at the University of Halle and Deneke in Hamburg and later on to Iljitsch Metsch- in 1927 of the University of Frankfurt/Main (Figure nikow at the Louis Pasteur Institute in Paris. He con- 1). His most important work at this time was the tinued his career at the Institute of Pathology of the publication ‘Kidney and Urinary Tract’ (1826 pages) Hafenkrankenhaus in Hamburg. From 1909 till 1915 in Bergmann and Staehelins’s Handbook of Internal he remained with Volhard in Mannheim, where a Medicine (1931).9 tight collaboration and lasting friendship developed. Volhard was in trouble with the Nazi regime for, Afterwards he returned to the Pathological Institute unfortunately, his independent opinion. As a conse- of the University Hamburg/Eppendorf, where he quence, he was forced to leave his position as Director was given the chair of general pathology in 1924. of the Clinic in 1938 in a humiliating manner. After There he continued his research on diseases of the the end of the Nazi tyranny in 1945, he was reinstated kidney, heart and blood vessels. His most significant as Director and was extremely active until his acciden- publications included the pathological anatomy of tal death (car crash) at the age of 78 in 1950. Volhard, Morbus Bright, kidney tumors and the cardiovascu- the genius scientist, outstanding physician and brilli- lar system. Fahr died in Hamburg in 1945 (Figure 2). ant speaker, had exceptional humanitarian qualities. Among his hobbies, the love of music has to be Elucidating concepts in the acknowledged; Volhard was both an enthusiastic heterogeneity of Bright’s disease in the singer as well as a talented violinist, heading his own family orchestra with his 10 children. 19th century In 1836 Richard Bright (Guys Hospital in London) Theodor Fahr described the association of bilateral diffuse renal Was born in Pirmasens on 3 October 1877 and stud- diseases with albuminuria, oedema and myocardial ied medicine in Munich, Berlin, Kiel and lastly hypertrophy and differentiated them into inflam-

Journal of Human Hypertension Achievements and controversies in renal disease and hypertension A Heidland et al 7 chronic interstitial and chronic parenchymatous nephritis.13 Parenchymatous nephritis (also known as tubular nephritis or great pale kidney) with oed- ema and proteinuria was attributed to epithelial degeneration and subdivided into the hypertensive and normotensive forms. Interstitial nephritis, asso- ciated with hypertension and heart hypertrophy, was separated into groups with and without renal impairment. In 1904 Sandor von Koranyi coined the term ‘renal insufficiency’, characterised by loss of renal functional variability as determined by urinary osmolarity.19 In another categorisation of Senator (1896) the hematogenous non-purulent nephritides were divided into acute nephritis, chronic non- indurative and chronic indurative nephritis (contracted kidney).20 The French nephrologist Widal21 differentiated between various renal dis- eases with regard to functional disturbances into nephritide´ hydropige´nes and nephritides ure´mi- ge´nes. At the annual congress of the German Society of Pathology in Meran (1905), Friederich von Mu¨ ller23 abandoned Traube’s distinction between paren- chymatous and interstitial nephritis and postulated the term ‘nephritis’ for inflammatory and ‘nephrosis’ for degenerative renal diseases. However, he denied the possibility of separating both forms under clini- cal conditions. Thus the gap between the views of clinicians and pathologists still persisted.8

The novel classification of renal Figure 2 Theodor Fahr (1877–1945) as Director of the Institute of Pathology at the University of Hamburg (Source: Historical diseases and blood pressure Archives of the University Hospital Hamburg-Eppendorf, Insti- tute of Medical History, University of Hamburg). ‘One of the milestones of medical history’ (MacMahon)22 was Volhard and Fahr’s6 pathogen- etic classification, based on clinical and pathological matory, degenerative and vascular forms.10 The anatomical findings (Figure 3). An insight into Vol- rapid confirmation of these findings by others domi- hard’s concept8,24: ‘It is not enough to describe the nated the research of the underlying renal lesions structural histological lesions of the moment and to throughout the following decades.4,11,12 characterise the inflammatory, degenerative, or art- Jakob Henle described interstitial fibrosis of con- eriosclerotic processes. The morphological alter- tracted kidneys in 1844 as the primary site of injury ations do not mean the illness, but the reaction upon in Bright’s disease13 – a concept supported parti- the pathological event, which type has to be eluci- cularly by Ludwig Traube.14 On the contrary, Rudolf dated. In this endeavour, from the analysis of all Virchow (1852) favoured the role of inflammatory clinical and histological observations to the syn- processes of the tubules in Bright’s disease.15 thesis, that means to come to the understanding of Theodor Frerichs (1851) recognised ‘the different the nature of the illness, the morphological alter- microscopic appearances of Bright’s disease and dis- ations can only serve us as symptoms. The represen- tinguished the stages of hyperaemia and exudation tations of the disease process will only then be the followed by a stage of metamorphosis of the exu- right, if we succeed in relating the clinical symp- dates and finally of atrophy’.11,16 He also underlined toms to the histological and realize that both are the role of hydrostatic pressure and altered pore size consequences of the same derangement’. of the glomerular capillary wall as a cause of dis- In diagnosing renal disease, patient history, urine turbed transudation – a potential forerunner of the analysis, renal function, blood pressure, heart and concept of glomerular capillary hypertension.11 In eye ground were carefully evaluated. Renal function 1868 Klebs coined the term glomerulonephritis.17 was assessed by Volhard’s concentration and Thereafter Ernst Ziegler (1880) introduced the ‘con- dilution test; isosthenuria was interpreted as severe tracted kidney’ and differentiated the genuine, sec- tubular dysfunction. Renal histology was investi- ondary and atherosclerotic forms.18 Of particular gated either in kidneys obtained from deceased importance became Traube’s classification into patients (at least 2 h post mortem) or from surgical

Journal of Human Hypertension Achievements and controversies in renal disease and hypertension A Heidland et al 8 diseases or scleroses. The latter group was categor- ised into simple benign sclerosis and the ‘Kombina- tionsform’ (combinatory form) or nephritis superim- posed on simple sclerosis. In the presence of hypertension, participation of renal vessels was assumed. In line with this concept, the nephritic group was subdivided into normotensive focal nephritis and the hypertensive diffuse glomeru- lonephritis. The old classification of chronic paren- chymatous and chronic interstitial nephritis was abandoned since the term interstitial nephritis included diffuse glomerulonephritis as well as pri- mary nephrosclerosis, ie, contracted kidneys. Vol- hard and Fahr also rejected the term ‘contracted kid- ney’ in favour of the clinical term ‘renal insufficiency’ (Figure 4). The degenerative diseases, the nephroses (former parenchymatous nephritis) were diagnosed as a genuine disease with proteinuria and oedema, with- out hypertension and haematuria. Proteinuria as well as the characteristic hyaline droplets in the tub- uli initially were assumed a consequence of protein secretion. This concept, however, was later aban- doned by Govaerts and Cordier26 and Randerath27 who demonstrated the fundamental role of leakage of glomerular capillaries for proteins and their consequent reabsorption in the proximal tubules.28 In the 19th century the mechanism for urine for- mation was poorly understood. While Carl Ludwig (1827) postulated the role of glomerular fil- tration,29,30 the dominating idea was the secretion of urine by both the glomeruli and tubules as suggested by Bowman (1842)31 and Heidenhain (1874).32 Figure 3 Front-page of the famous monograph. The inflammatory renal diseases, the nephritides, were divided into three stages: (1) the acute stage, biopsy specimens of nephritic patients after thera- (2) the chronic stage without renal impairment, and peutic kidney decapsulation. (3) the end stage with renal insufficiency. All stages Concerning blood pressure evaluation, the normal could be complicated by proteinuria: nephritis with adult systolic value was assumed to be in the range nephrotic component. In 1942 the two forms of glo- of 110 to 120 mm Hg, while levels exceeding 140 merulonephritis with and without nephrotic compo- mm Hg were regarded as pathologic. Rises in the nent were rediscovered by Ellis33 and called Ellis I upper normal range in young people as well as in and Ellis II in the English speaking world. nephritic patients were given special attention. In so far these criteria are very similar to those of the 6th Therapy of acute and chronic Report of the Joint National Committee on Detec- tion, Evaluation and Treatment of Hypertension glomerulonephritis (1997),25 which stated the optimum systolic blood Acute and chronic nephritis were regarded as seri- pressure to be less than 120 mm Hg and abnormal ous conditions due to hypertension, risk of conges- levels higher than 140 mm Hg, while in renal dis- tive heart failure as well as oedema of the brain, lung ease values even in the upper normal range were and even larynx. To prevent the overfilling of the regarded as being in need of treatment.25 circulatory system and to preclude a chronic course These identical views are reminiscent of Johann of acute nephritis, Volhard recommended an early Wolfgang Goethe: ‘Wer kann was Dummes, wer was and strict therapy with starvation, thirst and bed Kluges denken, was nicht die Vorwelt schon ged- rest. This novel concept was presented on occasion acht’. (‘Who can think something stupid, who can of the Congress of Internal Medicine in Warsaw in think of something clever, which has not been 1916, with an instructional pamphlet on the diag- thought of in the past’.) nosis and therapy of acute nephritis.34 This cam- Volhard and Fahr divided the collective term of paign was a big success and contributed to a marked Bright’s disease into the three major forms: the reduction of the mortality rate of ‘war nephritis’ in degenerative diseases or nephroses, the inflamma- World War I and even World War II. Also in the Red tory diseases or nephritides and the arteriosclerotic Army this kind of therapy was seized upon as life

Journal of Human Hypertension Achievements and controversies in renal disease and hypertension A Heidland et al 9

Figure 4 Pathogenetic system of Bright’s renal diseases from Volhard and Fahr’s monograph. saving for many soldiers according to information more, in some patients, working capacity and a con- by a military officer.35 siderable quality of life could be restored for Volhard extended dietary therapy also to hyper- months, or even for 1 or 2 years’. Beneficial effects tensive patients with chronic nephritis and rec- were explained with less retention of toxic products, ommended a low sodium diet (1.5 g NaCl/day) and – which accumulate due to renal failure. A vegetarian at a time when efficient and non-toxic diuretics were diet also retarded the progressive course of renal dis- not available – furthermore a restriction of fluid eases, probably due to indulgence of the kidneys. intake. He stated: ‘In patients with diffuse nephritis Volhard correctly assumed that the excretion of the and with a permanent hypertensive state I have waste products of protein is one of the never seen a measure have such benefit as does main tasks of the kidney. reduction of fluid intake, which I recommend to Protein restriction in prevention and therapy of relax the circulation and to disburden the heart. Its uremic toxicity is still very popular in the form of performance is extremely facilitated by a vegetarian either conventional low protein diet (0.6 g diet’.36 Similarly, in patients with severe hyperten- protein/kg/day) or more rarely very-low-protein diet sion, a low sodium diet was successful and was con- (0.26 g protein/kg/day), supplemented with essen- tinued by the rice diet of Walter Kempner (1944).37 tial amino acids and/or their ketoanalogues. More- over, protein restriction has been demonstrated to Definition and therapy of uraemia retard the progression of renal diseases in experi- mental models as well as in some clinical studies. Volhard classified the clinical symptoms of uraemia into those of true uraemia (resulting from the reten- What remains from the classification of tion of products normally excreted by the kidney) and into pseudo uraemia (symptoms unrelated to glomerulonephritis? renal impairment).6 The latter signs (eclamptic Volhard and Fahr’s grouping of glomerulonephritis attack in toxaemia of pregnancy, convulsions, psy- had been accepted for at least half a century. There- chosis, claudication intermittens, cardiac asthma, after, the widespread use of renal biopsy and renal Raynauds disease, transient blindness) were linked tissue examination by light and electron microscopy to vascular sclerosis (cerebral, coronary and periph- as well as immunohistochemistry ‘became powerful eral vessels), but also frequently induced or aggra- agents in determining the emergence of nephrol- vated by vasospasms. ogy’.38,39 Using these tools, some known types of glo- For therapy of true uraemia, Volhard rec- merulonephritis were confirmed, others newly ommended in 191837 a low protein diet (in parti- defined and some new entities discovered. Concern- cular vegetarian) with a normal caloric supply (2000 ing the frequent post-streptococcal nephritis, a kcal/day). He wrote: ‘In patients with chronic renal remarkable reduction has been observed and attri- failure it is possible to postpone the increase in the buted to the widespread use of antibiotics, better serum urea concentration for a long time by reduc- hygiene and improved nutrition. A decline has also ing the daily nitrogen intake to 3–5 g (20–30 g been observed in focal nephritis, which – according protein). Sometimes we succeeded in reducing even to immunostaining in most patients is a diffuse dis- considerably high serum urea concentrations. ease – in contrast to the former studies with light Consequently, the uremic symptoms disappeared’.9 microscopy alone, which often was of poor qual- In 193136 he added to the previous recall: ‘Further- ity.38,39 On the other hand, a striking rise in lupus

Journal of Human Hypertension Achievements and controversies in renal disease and hypertension A Heidland et al 10 nephritis, various forms of vasculitis (in particular as a new morphological entitiy was rather poor, Wegener’s granulomatosis) and especially of dia- even from Volhard. It took nearly 50 years till DBN betic nephropathy have been noted in the last dec- was confirmed by the German pathologist Adalbert ades – after the introduction of insulin therapy as Bohle and his collaborators. After an initial obser- well as modern antihypertensive treatment. vation in a patient with renovascular hypertension Unchanged to this day is Volhard and Fahr’s clini- in 1972, they found similar processes in many other cal differentiation of nephritis according to the time patients. In 1989 they reported a total of 251 cases course and severity of the disease into acute (which of DBN as compared to 765 cases of CBN.45 In the mostly can be healed), subacute (corresponding to DBN patients the signs of glomerular hyperperfusion the extracapillary form with enlarged pale or col- injury were stressed, which primarily affected the oured kidneys), subchronic (corresponding to intra- juxtamedullary glomeruli, while the intermediate capillary nephritis with enlarged or small kidneys) and subcapsular glomeruli followed later. In com- and chronic nephritis (developing to contracted parison to CBN patients, the clinical picture of DBN kidney). was characterised by higher levels of blood pressure, serum creatinine and proteinuria and a clear preva- Nephrosclerosis lence of males as opposed to females (ratio 5.5:1). The importance of this severe renovascular dis- In distinguishing inflammatory renal diseases, Vol- ease is underlined by a recent biopsy study in hard and Fahr (1914) separated the hypertensive patients with chronic renal insufficiency, where patients with nephrosclerosis into two categories: nephrosclerosis was the cause of renal failure46 at the large group of benign nephrosclerosis least in 10% of cases. Thus the term ‘benign’ (corresponding to the arteriocapillary fibrosis of Gull nephrosclerosis is absolutely misleading, also with and Suton) and the smaller one of malignant regard to the enhanced cardiovascular morbidity nephrosclerosis. In the first group hypertension was and mortality. of long duration; deaths of these patients occurred in most instances from cardiac or cerebrovascular Malignant nephrosclerosis disease, while renal failure in general was not observed. ‘Proteinuria may be completely absent in Morphology of malignant nephrosclerosis was benign nephrosclerosis over many years and may characterised by Volhard and Fahr (1914) by severe develop only in traces for years’.6 This description degenerative changes of afferent arterioles (in parti- is truly identical to that of Frederik Akhbar Ma- cular fibrinoid necrosis), proliferative alterations of homed,40,41 who stated in 1874: ‘It is very common interlobular and arcuatae arteries with marked to meet with people apparently in good health, who thickening of the intima (oedema and/or concentric have no albumin in the urine or any other sign of onion-skin like alterations), as well as inflammatory organic disease, who constantly present a condition and degenerative reactions of many glomeruli. The of high arterial tension, when examined by the aid combination of the severe arteriosclerosis and glom- of the sphygmograph’. erulitis was defined as ‘Kombinationsform’ and The second group of malignant nephrosclerosis regarded as a single disease entity. Later the terms was clinically characterised by an excessive rise in ‘malignant nephrosclerosis’ and ‘malignant scler- blood pressure, neuroretinopathy with or without osis’ were coined. Finally, the terms ‘malignant or papilloedema, albuminuria, haematuria, progressive accelerated hypertension’ were introduced, since impairment of renal function and weight loss.6 Inter- renal damage is not obligatory in this disease. estingly, the majority of these patients were younger (average age 40–50 years, even including children) Optic fundi in malignant nephrosclerosis than those with the benign form, which at first mani- fests itself at the age of 60–70 (Fahr, 1919).42 Patients Volhard (1914) was fascinated by investigations of with malignant nephrosclerosis died from renal the eye ground as a clinical tool for evaluation of insufficiency in particular.42 the vascular system and especially of that of the kid- ney. He was convinced that ‘The eye opens our eyes’ Benign nephrosclerosis and stated: ‘How much the study of visible retinal changes could improve our comprehension of the According to Fahr’s thorough investigations, benign invisible processes occurring in the kidney’. With nephrosclerosis – primarily affecting interlobular regard to the extreme narrowing of retinal vessels arteries and afferent arterioles – was associated with and the consequent exudates in severe renal dis- segmental hyalinosis, probably due to extravasation eases, he coined the term ‘retinitis angiospastica’, of plasma macromolecules through the endo- instead of the former ‘retinitis albuminurica’ (1921). thelium. In 1925 and 1934 Fahr divided benign The presence of papilloedema was interpreted by nephrosclerosis into the compensated (CBN) and the increased intracranial pressure. In Volhard’s opi- more severe decompensated form (DBN) with glom- nion, manifestation of retinitis angiospastica was the erular injury (focal/segmental hyalinosis and point at which nephrosclerosis was no longer sclerosis).43,44 In contrast to CBN, acceptance of DBN benign.

Journal of Human Hypertension Achievements and controversies in renal disease and hypertension A Heidland et al 11 In the pathogenesis of retinitis angiospastica, Vol- later on (1925, 1934)43,44 in the arteriae interlobu- hard underlined the critical role of severe hyperten- laris and vasa afferentia. This concept was also sion for its development.6 He stated that, in prin- underIined by casual observations in young individ- ciple, this could evolve in the absence of azotemia. uals, who developed malignant nephrosclerosis However, a rather high incidence in patients with even without previous hypertension. In a re-evalu- chronic glomerulonephritis and renal impairment ation of the renal histology of Fahr’s collection of was found.9 These observations are in accordance malignant nephrosclerosis, Schu¨ rmann und with our own eye ground studies47 in patients with McMahon (1934)50 confirmed his findings and renoparenchymal hypertension (based on histologi- showed that the disease ‘represented a broad and cal proof of various forms of glomerulonephritis) as uninterrupted spectrum reaching from severe forms compared to patients with essential hypertension. In of arteriosclerosis showing onion-like thickening of both groups we found a direct relationship between the intima on the one hand to the most fulminating severe hypertensive retinopathy (corresponding forms of arteritis on the other’.22 In the United States with the earlier fundus hypertonicus stages III and Klemperer and Otani (1931)51 were the first to con- IV of Keith and Wagner) and mean arterial blood firm a malignant nephrosclerosis as a disease entity pressure. However, its incidence was – as in Vol- and differentiated between an accelerated arterio- hard’s observations – significantly higher in the sclerotic and an arteritic group. (Figures 5 and 6). nephritis patients with impaired renal function. In Germany Fahr’s inflammatory hypothesis was Therefore, renal insufficiency seems to be an corroborated by Bohle and his associates (1976).52 In important co-factor for the development of severe single individuals with a negative history of hyper- hypertensive retinopathy. According to animal stud- tension and normal blood pressure, they clearly ies, the leakage of plasma proteins and fibrin depo- demonstrated the development of acute malignant sition – the characteristic features of malignant nephrosclerosis with stenosing oedema of the intima retinopathy – occurs in the dilated segments of the and progressive renal failure. In most patients ‘pri- retinal vessels as a consequence of loss of endo- mary malignant nephrosclerosis’ was associated thelial integrity. with haemolytic uremic syndrome, frequently pre- ceded by trivial virus infections. Further causes Potential mechanisms in the were postpartum renal failure in women, use of con- pathogenesis of malignant traceptive drugs, renal cortical thrombotic microangiopathy and vascular transplant rejec- nephrosclerosis tion.52,53 Thus Fahr’s inflammatory concept could Whereas Volhard and Fahr6 were in concord about finally be confirmed for a minority of patients. The malignant nephrosclerosis as a new disease entity, pathogenesis of vascular endothelial damage with they disagreed concerning its aetiology and patho- the resulting insudation of plasma constituents – genesis.22 While Fahr postulated the decisive role of assumed by Fahr to be triggered by a toxic factor – inflammatory changes, Volhard was convinced that is as yet still unknown. One important vasculotoxic the severe alterations in renal blood vessels and glo- element seems to be the local activation of the renin meruli were caused by hypertension alone. He angiotensin system: thus angiotensin II increases the stressed the role of initial vasospasms (with conse- permeability of vascular endothelium.54 quent prolonged ischaemia) as the cause of repara- In summary, the differentiation between benign tive reactions in focal glomeruli as well as develop- and malignant nephrosclerosis was Volhard and ment of nephrosclerosis of the subsequent rise of Fahr’s most important contribution in the eluci- blood pressure. dation of the different forms of Bright’s disease. As The definite proof for the crucial role of severe the pertinent evaluation of their common work, Sir hypertension in the pathogenesis of malignant George Pickering (1972)5 substantiated: ‘The most nephrosclerosis was provided in rats with Goldblatt- challenging of all innovations of the 1914 classi- hypertension (two kidney, one clip model). In these fication was the differentiation into two %.was the investigations Wilson and Byrom (1939)48 and later distinction between the benign and malignant Helmchen et al (1984)49 demonstrated the develop- courses of essential hypertension, the most revol- ment of gross hypertension with the full picture of utionary of Volhard and Fahr’s innovations, has benign and malignant nephrosclerosis in the intact stood the test of time and is now indeed at last kidney, while the clipped kidney was without sig- understood’. nificant alterations. Nowadays it is assumed that in malignant nephrosclerosis, the fibrinoid necrosis of Pathogenesis of hypertension: the red the arterioles and the proliferative endarteritis is a direct consequence of hypertension-induced mech- and pale form anical stress. The sites of vascular damage are the Volhard (1923)55 spoke against the dogma of the gen- dilated vessel segments with consequent hyperper- eral vasoconstriction in the pathogenesis of hyper- meability to plasma proteins. tension and differentiated between the pale and red From the beginning, Fahr emphasised the forms. In case of the latter, reflecting essential hyper- inflammatory reactions in the glomeruli (1914) and tension, initially no signs of enhanced peripheral

Journal of Human Hypertension Achievements and controversies in renal disease and hypertension A Heidland et al 12

Figure 5 (figure 83 from the monograph). Magnification × 400; haematoxylin-eosin stain. Combination form with marked degenerative and inflammatory features, diffuse fibrosis with small cell infiltration; most of the glomeruli are intact (GI.), one glomerulus (GI. e.), with marked epithelial proliferation and desquamation (Case of a 45-year-old merchant, who consulted his physician because of severe headache, urine investigation initially normal, later albuminuria (3/4 bis 2 ‰), no red cells in sediment later systolic blood pressure 238 mm Hg, neuroretinitis albuminurica, progressive renal insufficiency (BUN 100 mg/dl). The patient died 3 years after his first symptoms from lung oedema. At autopsy, shrunken kidneys, heart hypertrophy, severe cerebral and coronary arteriosclerosis.

vascular resistance were found, while large vessel and growth of the capillary endothelial cells. At compliance was assumed to be decreased. In its present it is well known that – in contrast to Vol- pathogenesis the importance of inheritance (in parti- hard’s thinking – in acute nephritis renal blood flow cular for nephrosclerosis), age, obesity, intensity of is enhanced and not reduced. life style (stress) as well as alcohol abuse were dis- Volhard emphasised that the enhanced vaso- cussed.6,9,55 constriction in pale hypertension is caused by a On the contrary, in pale hypertension, Volhard humoral factor, that is released from the kidney fol- emphasised a general vasoconstriction as docu- lowing its ischaemia. He stated: ‘Pale hypertension mented by pallor of the skin, narrowed retinal ves- is caused by the kidney and acts humorally. sels as well as hypocirculation of the kidney. He Thereby, a vicious circle is induced with the conse- assumed that hypertension in acute and chronic quent aggravation of hypertension and nephro- renal disease is a consequence of diffuse involve- sclerosis’. To prove this concept, his scholar Hart- ment of renal vessels. He wrote: ‘It is undisputed wich (1930)56 performed in rabbits and dogs an that with acute diffuse glomerulonephritis almost all experimental reduction of renal blood flow by lig- glomeruli of both kidneys are found, so to speak, ation of branches of the renal arteries. In fact, in empty of red blood cells, not seldomly also the vasa these experiments, they could induce a transient afferentia. Only some isolated glomeruli are still rise in blood pressure. filled with blood%. I have reason to assume that a Full confirmation of Volhard’s hypothesis was contraction of the kidney vessels – possibly caused possible through the experiments of Goldblatt et al allergically – is a primary factor, ie, a functional (1934).57 Using an improved screw-clamp tech- occurrence. Supporting this is the fact that, after nique, partial constriction of both renal arteries in dying, the glomeruli are easily filled with and the dogs was followed by a severe and persistent hyper- vasa afferentia are often found empty of blood’.6 tension.57 Five years later Goldblatt’s detection of Fahr, on the other hand, assumed that the disturb- renal hypertension was supported by the discovery ance of renal circulation is not a functional one but of the renin angiotensin system by Page (1939)58 and results from an endocapillaritis through swelling Braun-Menendez (1939).59 Thereby, the same

Journal of Human Hypertension Achievements and controversies in renal disease and hypertension A Heidland et al 13

Figure 6 (figure 84 from the monograph). Stronger magnification of the former tissues specimen, haematoxylin-eosin stain. Illustration of an inflamed glomerulus (GI. e.), with proliferation of endothelial cells and crescent formation; marked hyaline thickening of the vas afferens with narrowing of the lumen, leucocytes (L.) in capsular space. Fibrin (F) precipitation. pressor substance, formerly detected by Tigerstedt ure, while in patients with essential hypertension and Bergmann (1898),60 was fully confirmed: it was this effect was less pronounced – ‘due to physical their merit to demonstrate the blood pressure raising changes in the arterial wall, which lowers the ability of a renal tissue extract of rabbits that they stretch of nerve endings’.5 As a consequence of this named renin.60 dampening of the baroceptor reflexes, an increased Volhard’s historical contribution to the eluci- sympathetic nervous tone – possibly mediated via dation of renal hypertension, in particular upon the central nervous system – has been postulated as clinical observations, was recognised by the Nobel- a pathogenetic factor. However, the resetting of alt- Prize Winner, A Houssay. He wrote in the preface ered baroceptor function is not specific for essential of Braun-Menendez ‘Renal hypertension’ (1946): hypertension, ie the tonic regulation of the cardio- ‘Much credit is due to the indefatigable investi- vascular system occurs at a higher level, probably in gations of Volhard, who was convinced that a all forms of chronic hypertension.62 vasospastic factor existed in the so-called pale According to Volhard, red hypertension over time hypertension, as was indicated by ocular and cer- leads to decreased renal blood flow through a tonus ebral symptoms and by blanching of the vessels of increment of the vessels as well as through the skin. Since he believed that the exaggerated con- arterio/arteriolosclerosis. These disorders gradually traction of these vessels was due to a substance cir- tend towards pale hypertension. In 194263 Volhard culating in the plasma, he devoted himself with the wrote: ‘If the humoral mechanism of renally help of his students to a search for its presence%’. induced pale hypertension adds to red hyperten- In the late 1940s Volhard and his students concen- sion, high blood pressure is henceforth to be trated their work on the pathogenesis of red hyper- described as malignant. The progressive course of tension. Its manifestation was interpreted by both a renal insufficiency is unavoidable, since the humor- rise of cardiac output and a premature reduction of ally caused general and renal vasoconstriction vascular distensibility, both of which could be gen- (induced by decreased renal blood flow) will further etic. Furthermore, involvement of altered baroceptor aggravate the disturbed circulation in the kidney – function was documented. Thus Volhard’s assistant a true vicious circle just as with chronic nephritis, Lampen61 showed for the first time that an anaes- whose progression is to be understood only in this thesia of the carotid sinus by novocain in healthy manner. Evident is the visible change of the back- individuals resulted in a marked rise in blood press- ground arteries of the eye. The later development of

Journal of Human Hypertension Achievements and controversies in renal disease and hypertension A Heidland et al 14 vascular changes, including thickening of the arteri- diseases. With this unique store, Volhard attended oles, could finally result in the development of various international congresses, such as in London, pale hypertension’. New York and Cairo. In the field of lung disease, In the past few years the renal origin of primary Volhard developed the first apparatus for artificial hypertension has been demonstrated in cross-trans- respiration and a bedside method for assessing peak plantation experiments in rats. Thus a rise in blood flow in patients with emphysema. pressure in normotensive recipients has been observed after transplantation of a kidney from a hereditary hypertensive strain, while kidney trans- Honours of Franz Volhard plantation from normotensive animals to the hyper- 64 The time spent in Frankfurt brought Franz Volhard tensive strain reduced their blood pressure. Mean- many honours and successes, for example the while, similar observations were also made in honorary doctorate at Sorbonne University in Paris. patients with essential hypertension and endstage Also the Universities of Go¨ttingen and Freiburg renal failure after transplantation of a kidney from a awarded him an honorary doctor title. In the Nu¨ rem- normotensive or hypertensive donor. This suggests, berg Doctors’ Trial, he finally took over the esteemed that after transplantation, a drop or rise in blood task of a medical expert. Since 1952 the Medical pressure may be dependent on whether the trans- Faculty of the University of Frankfurt/M organises planted kidney comes from a normotensive or a gen- regular Volhard Lectures. Similarly, the Inter- etic hypertensive donor, probably due to an 65 national Society of Hypertension created – accord- inherited sodium-retaining effect. ing to a proposal by Franz Gross – the famous Vol- hard Lectures, to honour scientists for outstanding Volhard’s work in diseases of the heart contributions in the field of hypertension. The first and lung presentation was given by Sir George Pickering in 1972. The Gesellschaft fu¨ r Nephrologie awards the Franz Volhard also attained international acclaim as 5,8,66 Volhard Prize and Volhard Medal to scientists for a heart and lung researcher. During his years as excellent achievements in kidney research. More- assistant to the clinician Franz Riegel in Gießen, over, in Volhard’s honour, the German government there was neither an apparatus to measure blood founded a clinic for cardiovascular and renal pressure nor an electrocardiograph, yet one was still research in Berlin-Buch. able to diagnose heart diseases and especially valve dysfunctions. From Riegel, Volhard learned how to judge arterial and venous pulse exactly as well as References how to estimate arterial pressure, merely through palpation. 1 Ritz E, Ku¨ ster S, Zeier M. Clinical nephrology in 19th In Gießen, Volhard wrote important cardiological century in Germany. Am J Nephrol 1994; 14: 443–447. works, for example concerning the relationship of 2 Hierholzer K. Carl Ludwig, Jacob Henle, Hermann Helmholtz, Emil DuBois-Reymond and the scientific heart block to Adams Stoke’s syndrome and also development of nephrology in Germany. Am J Nephrol regarding the distinction between pulsus alternans 1994; 14: 344–354. and pseudo alternans. At this time Volhard also 3 Cameron JS, Hicks J. The introduction of renal biopsy learned how to evaluate the heart’s action by close into nephrology from 1901 to 1961: A paradigm of the inspection of the jugular veins, enabling him to diag- forming of nephrology by technology. Am J Nephrol nose even rare heart diseases in the quickest poss- 1997; 17: 347–358. ible time. Wilhelm Nonnenbruch (1887–1955) once 4 Cameron JS. Villain and victim: the kidney and high remarked very fittingly about Volhard: ‘He seemed blood pressure in the nineteenth century. J R Coll to have a cymographion in his head which func- Physicians Lond 1999; 33: 382–394. tioned with infallible certainty’. In addition, it was 5 Pickering G. The first Volhard lecture. Franz Volhard, 1872–1972. Clin Sci Mol Med 1973; 45: 1S–10S. likewise Franz Volhard (as one of the first) who 6 Volhard F, Fahr T. Die Brightsche Nierenkrankheit. pointed out the meaning of the peripheral circu- Klinik, Pathologie und Atlas. Springer: Berlin, 1914. lation for compensation of heart failure. Further- 7 Volhard F. Mein Lebenslauf. Med Welt. 1972; 23:665– more he gave the description of the leading clinical 668, 838–840, 958–960, 994–996, 1085–1086, 1233– symptoms of concretio pericardii, based on the dis- 1234, 1267–1270, 1319–1320, 1405–1406, 1457–1462 tended and pulsating veins in the neck, enlargement (Text prepared by Volhard in 1942). of the liver with ascites and small heart with 8 Kronschwitz C. Franz Volhard. Leben und Werk. reduced apex beat (Volhard’s triade). Following this Sinemis Verlag: Frankfurt, 1997, 1–328. diagnostic approach, concretio pericardii became a 9 Volhard F, Suter F. Nieren und ableitende Harnwege. treatable entity by pericardectomy, first performed In: Handbuch der Inneren Medizin, Hrsg. G. v. 67 Bergmann und R. Staehelin. Springer: Berlin, 1931, pp by Schmieden. Another great achievement was the 1–2137. development of a method for preserving the anat- 10 Bright R. Tabular view of the morbid appearances in omy of the heart by fixing it in a standard position, 100 cases connected with albuminous urine. Guy’s followed by dehydration and impregnation with hot Hosp Rep 1836; 1: 380–400. paraffin. This allowed him a collection of rare heart 11 Ritz E, Zeier M, Lundin P. French and German nephro-

Journal of Human Hypertension Achievements and controversies in renal disease and hypertension A Heidland et al 15 logists. The impact of Richard Bright on the continent. 34 Volhard F. Merkblatt u¨ ber die Behandlung der akuten Am J Nephrol 1989; 9: 167–172. diffusen Nierenentzu¨ ndungen. Mu¨ nchner Med Wschr 12 Harlos J, Heidland A. Hypertension as cause and 1916; 63: 1346. consequence of renal disease in the 19th century. Am 35 Kaiser W. Die halleschen Ordinariatsjahre von Franz J Nephrol 1994; 14: 436–442. Volhard. Med Welt 1972; 23: 694–701. 13 Henle J, Pfeuffer C. Morbus Bright, klinische Mitteil- 36 Kempner W. Treatment of kidney disease and hyper- ungen. Z Rationelle Med Zu¨ rich 1844. tensive vascular disease with rice diet. Med J North 14 Traube L. Zur Pathologie der Nierenkrankheiten. Ges Carolina 1944; 5: 125–133. Beitr 1870; 2: 966 (originally published in Allge Med 37 Volhard F. 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