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A finding in the autopsy of John Paul Jones, the American Revolutionary War naval hero, may explain his terminal illness. During his last 2 years, he had a persistent productive cough and dyspnea. Ten days before death, he developed rapidly progressive dependent edema and ascites. He died in France in 1792. His body, preserved in alcohol in a lead coffin, was, in 1905, removed to the United States. Glomerulonephritis was noted on an autopsy, performed in France, but there was no comment then or since about ventricular wall thickness being the same in both ventricles at 5-6 mm. Hypertrophy and dilatation with biventricular failure followed by tissue shrinkage during 113 years in alcohol could have resulted in these ventricular wall findings. Systemic hypertension and left ventricular failure are consistent with his respiratory symptoms complicated perhaps by pulmonary emboli, right ventricular failure with tricuspid regurgitation, peripheral congestion, and jaundice., (© 2015 American Academy of Forensic Sciences.)

In the early 1990s, an international working group of experienced renal pathologists, the Renal Histology group, set up a scoring system for biopsies with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis. This scoring system subdivided glomerular, interstitial and vascular lesions and served as a tool for the evaluation of all renal biopsies from studies of the European Vasculitis Study Group (EUVAS). Histopathological studies gave new insights into the prediction of renal outcome in patients with ANCA-associated glomerulonephritis. Percentage of normal glomeruli and a selected number of interstitial parameters were reliable predictors of long-term follow-up glomerular filtration rate in all studies. Out of these results, a histopathological classification distinguishing focal, crescentic, mixed and sclerotic classes of ANCA-associated glomerulonephritis was developed. Until today, 13 studies have validated this classification system. Future studies will try to determine if and how renal histology could be helpful in guiding treatment of ANCA-associated glomerulonephritis., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

The name of Thomas Addis (1881-1949) is linked to several aspects of nephrological practice: from the "Addis count" of urinary elements, to the history of diet in chronic kidney diseases. He was accustomed to working with limited funds, and developed his theories with relatively simple means, combined with the careful, long-term observation of single cases. His political ideas were progressive; his outlook on life was optimistic. This is deeply reflected in his Glomerular Nephritis: Diagnosis and Treatment, a book worth reading in the era of chronic kidney disease (CKD), as it contains sharp analyses of the organizational aspects, and accurate comments on the role of the physician - all subjects of interest for the present times and challenges. One of Addis' ingenious ideas was to follow his patients throughout their lifelong disease, thus anticipating the theories of continuum of care and of therapeutic alliance between patients and physicians. He used to tailor his prescriptions and frequency of controls to each patient and phase of the disease, thus anticipating the tailored therapies and the patient empowerment presently considered as fundamental in chronic diseases. Furthermore, he suggested that physicians should work outside the hospital in small coordinated teams, in which volunteers, dietitians and laboratory technicians would play a crucial role. Patient-centered care and the importance of nonmedical team members are clear from the first lines of his book. As far as we know, he was the first physician to stress the role of volunteers in CKD, anticipating by decades nonprofit organizations such as the National Kidney Foundation.

Thomas Addis is an important figure in the history of nephrology. Born in Scotland and trained in Edinburgh, he came to San Francisco in 1911 to the new Stanford School of Medicine to run the clinical laboratory. Over the next 38 years, he made many contributions to renal physiology, the investigation of the structure and function of the kidneys in Bright's disease, and studies of kidney growth, hypertrophy and protein metabolism. Largely forgotten today, he was one of the first to use urea clearance as a measure of kidney function and was the first to systematize examination of the urinary sediment - the Addis count. He was also a leader in the use of diet and rest in the treatment of Bright's disease. Unknown to most nephrologists, before he came to the United States during the first 6 years following his graduation, he became one of the leading clinical investigators in hematology. His special interests were the mechanism of blood clotting and hemophilia. He was the first to transfuse fresh blood into a hemophiliac patient and show that this shortened the patient's clotting time. Addis was a great, if eccentric, personality as well as a great scientist. He was beloved by his many colleagues and students and was honored in his lifetime both in the United States and Great Britain.

The early death of the composer Wolfgang Amadeus Mozart on 5 December 1791 has fascinated the world for more than 2 centuries. It has been suggested that his final illness was caused by poisoning, renal failure, Henoch-Schönlein purpura, trichinosis, and many other conditions. The official daily register of deaths in Mozart's Vienna was evaluated to provide an epidemiologic framework into which the observations of contemporary witnesses of his death can be integrated. All recorded deaths in Vienna during November and December 1791 and January 1792 were analyzed, together with the corresponding periods in 1790 to 1791 and 1792 to 1793. The deaths of 5011 adults (3442 men, 1569 women) were recorded over these periods. The mean ages of death were 45.5 years (SD, 18.5) for men and 54.5 years (SD, 19.9) for women. Tuberculosis and related conditions accounted for the highest number of deaths; cachexia and malnutrition ranked second, and edema was the third most common cause. According to eyewitness accounts, the hallmark of Mozart's final disease was severe edema. Deaths from edema were markedly increased among younger men in the weeks surrounding Mozart's death compared with the previous and following years. This minor epidemic may have originated in the military hospital. Our analysis is consistent with Mozart's last illness and death being due to a streptococcal infection leading to an acute nephritic syndrome caused by poststreptococcal glomerulonephritis. Scarlet fever, which represents the same underlying disease from an etiologic perspective, is a less likely possibility.

Glomerulopathies are the third most common cause of end-stage renal failure. Immunosuppressive treatment of glomerulonephritis in a systematic way was introduced in Poland by Professor Tadeusz Orłowski in the early 1960s. The studies were conducted at the First Department of Medicine and at the Transplantation Institute of the Medical Academy in Warsaw in the years 1962-1988. This paper critically reviews the results of studies on the use of combined, triple-drug (prednisone/chlorambucil/azathioprine), immunosuppressive protocol in various pathological forms of glomerulopathies. We conclude that immunosuppressive protocols pioneered by Tadeusz Orłowski continue to be the backbone of the treatment of glomerulonephritis, especially the one with nephrotic syndrome, progressive impairment of kidney function and poor prognosis.

Glomerulonephritis refers to a collection of primary renal disorders and those secondary to a systemic disease, all characterized by inflammation within the glomerulus. Given the underlying immunologic nature of these disorders, they are routinely treated with corticosteriods and various cytotoxic agents. Although in many instances such therapies are successful, they are associated with significant morbidity; as such, alternatives are clearly necessary. Our understanding of the pathogenesis of immunologic glomerular diseases has grown remarkably, in large part from the study of rodent disease models. Fundamental to each disorder is the development of an antigen-specific immune response followed by the effector stage of inflammation. To block the immune response, antigen-specific therapy can be used to induce tolerance, such as through the use of double-stranded DNA molecules in lupus nephritis. Since other antigen systems are less well characterized, inducing a more generalized impairment in the immune response by blocking costimulatory molecules CD40-CD154 and CD28-CD80/86 is a growing approach to treat various immunologic disorders and transplantation. To reduce glomerular inflammation, a variety of effector systems have been targeted, including complement, cytokines/chemokines, adhesion molecules, and mediators of cellular proliferation. Of these, antibodies targeting C5 in the complement system, and antibody and receptor antagonists of tumor necrosis factor-alpha (TNF-alpha) have already been used in glomerular disorders with some promise. Less specific blockade of receptor-mediated events stimulated by platelet-derived growth factors and cell cycle proteins may soon be applied to glomerulonephritis. Finally, interruption of fibrosing pathways, which lead to glomerulosclerosis and interstitial fibrosis common to the end-stage of all glomerulonephritis, is the subject of intense effort which may yield effective biologic therapies. In spite of all these advances, we still are dependent on steroids and cytotoxics to treat glomerulonephritis. To get past this, we must devote significant resources to take observations made in basic research laboratories to develop therapeutics and prove their utility in human disease.

Elevated arterial pressure had long been surmised from the strength of the pulse. Its association with contracted kidneys and hypertrophied hearts was described by Richard Bright (1789-1858). Microscopic observations of the narrowed and obliterated vasculature initially observed in the kidneys of Bright's disease, and subsequently throughout the body, launched clinical research into hypertension. The description of these findings in the absence of symptoms of kidney disease led to the recognition of primary hypertension. Ultimately, the systematic recording of the blood pressure with a pneumatic cuff and mercury manometer established the significance of hypertension as a distinct disease entity. Subsequent experimental studies established the central role of the kidney in hypertension through the renin-angiotensin system and extracellular volume control. This finding provided the basis for the introduction of diuretics and angiotensin converting enzyme inhibitors, two of the most important and valuable antihypertertensive drugs now available. Thus, the study of kidney disease and function has played a pivotal role in the conceptual evolution of the understanding of hypertension as a disease, the identification of its mechanisms, and the development of clinically useful antihypertensive medications.

Background: Richard Bright (1789-1858) discovered that edema and proteinuria are linked with renal disease. Friedrich Theodor von Frerichs (1819-1885) performed microscopic studies on Bright's disease and wrote the first German textbook of nephrology. The present contribution analyzes Frerichs' work., Methods: Frerichs' career and his book Die Bright'sche Nierenkrankheit und deren Behandlung are examined in terms of contemporary medical knowledge., Results: Frerichs conducted clinical and microscopic studies that led him to conclude that Bright's disease is a single pathological entity with many possible causes. Frerichs identified three stages through which the condition progresses. Although an oversimplification, Frerichs' various stages are reflected in the current notion that chronic renal disease, irrespectively of its etiology, relentlessly progresses to end-stage renal failure with common features of tubulointerstitial fibrosis and tubular atrophy. After writing his monograph, Frerichs never touched on renal disease again and is actually better known for his contributions to hepatology. Frerichs was a volatile and difficult person who was not always fair to his students and colleagues., Conclusion: Frerichs put the study of renal diseases on the map in Germany and made the novel observation that chronic renal diseases follow similar morphological patterns despite multiple origins., (Copyright 2002 S. Karger AG, Basel)

Though the term 'nephritis' first appeared in the 19th century, this word did not bear the same meaning as it does today; indeed, for many years it was used to indicate 'renal diseases' (in the sense of Bright's disease) in a larger sense. This review summarizes the long gestation of the concept of 'glomerulonephritis' from the prehistory of medicine up to the beginning of the second half of the 20th century with emphasis on Italy and, in particular, on Torino, which was the capital of the Kingdom of Italy from 1861 to 1865. To the best of our kowledge, this is the first study reporting an epidemiology survey of Bright's disease in Italy from 1880 up to 1960. Towards the end of the 19th century, Bright's disease accounted for 26 deaths/year/10(5) population (in comparison with more than 200 from tuberculosis) in Italy, roughly paralleling that reported in the USA. At the beginning of the 20th century, Bright's disease was the seventh cause of death (almost 1% of total deaths) in Italy. Furthermore, in Italy, as elsewhere, autopsy studies showed a higher percentage of deaths attributed to Bright's disease (5-7%) in comparison with those obtained from vital statistics. In 1960, just before the beginning of renal replacement therapy, Bright's disease accounted for 15.7 deaths/year/10(5) population (= 1.46% of all deaths), roughly paralleling that reported in the United Kingdom (13.8/10(5) population = 1.25% of deaths). Probably, it was difficult to recognize the real incidence of chronic renal diseases leading to death in the 1960s, and vital statistics were able to furnish only approximate estimates. However, noteworthy is the fact that these values were very close to those estimated as being the annual need for renal replacement therapy (10-20 cases/year/10(5) population).

Mozart, perhaps one of the greatest geniuses of modern age, died mysteriously at the age of 35 in Vienna in 1791. The causes of his death are still somewhat obscure and debated since we do not have any documentation acceptable by current scientific standards. Inevitably, the conclusions reached are highly debatable. In the present article the various interpretations of Mozart's death are taken into consideration-from his possible poisoning to causes of death more acceptable by the present diagnostic criteria. We suggest that the terminal cause of death was brain hemorrhaging or stroke, complicated by broncopneumonia and associated with renal failure induced by proliferative glomerulonephritis and glomerulosclerosis.

Professional historians generally treat the phrase 'what if' with pardonable scorn. It is a speculation which necessarily will never be tested in the real world. Nevertheless, there is a reasonable likelihood that, if typhoid fever had not carried off Frederick Akbar Mahomed at the age of 35, clinical research in Britain would have been both stronger and more highly developed at the beginning of the 20th century. Indeed, if he had lived to continue his most ambitious project, we would have had access to a unique source of clinical and epidemiological data 70 years before anything similar was contemplated.

Bright's work led to the recognition that coagulable protein in the urine indicated macroscopic kidney disease. After light microscopy was introduced, Simon, Nasse, Henle and Frerichs identified the major constituents of urinary sediment. By 1896, Senator had deduced that hyalin cylinders arise in the kidney tubules, and only the discovery of the Tamm-Horsfall protein in the next century separated him from the modern concept. Chemical analysis of urine also advanced greatly. Recognition of the pressure-volume relationship by Traube was probably the most brilliant achievement related to renal disease, and became the basis of the later pressure-natriuresis relationship. Traube also linked left ventricular hypertrophy with renal disease, recognizing that it maintained circulatory homeostasis at a higher level of pressure. The concept of nephritis changed considerably with technical progress, and Gluge was the first to see inflamed Malpighian bodies or glomeruli. The primary site of damage was disputed by many, including Henle, Pfeufer, Virchow, Reinhardt and Frerichs, but all these workers had to reconstruct the sequence of events leading to the autopsy findings. The term glomerulonephritis was first coined by Klebs, and the classification of nephritis adopted by Senator in 1896 led directly to the classic monograph of Volhard and Fahr (1914) on Bright's disease.

The pioneering work of Richard Bright, who introduced the concept of the renal origin of cardiovascular disease, initiated the continuous unfolding of knowledge on renal disease and its close interrelationship with arterial hypertension in the 19th century. Hypertension as a clinically and pathologically defined entity, however, was not established. The partial elucidation of the problem that the diseased kidney was sometimes the cause and sometimes the consequence of elevated blood pressure is not only fascinating but also remarkable, given the crude techniques available to physicians at that time. Subsequent workers came to regard 'Bright's disease' as consisting of several conditions differing in clinical manifestation and pathology. In particular, Johnson and Gull and Sutton drew attention to the small blood vessels in renal disease. Only the invention of a clinically applicable method of measuring blood pressure indirectly allowed Mahomed and Allbutt to show that hypertension may occur in the absence of renal disease. They paved the way for a clear separation of hypertensive renal disease from other forms of 'Bright's disease', culminating in the classification introduced by Fahr and Volhard.

Pierre Rayer, in a day of purely descriptive medicine, devised a method for the scientific study of diseases affecting the kidney and urinary tract. He first assembled vivid illustrations of a wide range of disorders of the kidney found in specimens obtained at autopsy. The resulting Atlas won him widespread praise and is still often cited. His Treatise (Traité des Maladies des Reins et des Altérations de la Sécrétion Urinaire), in which he integrated data from pathological anatomy with urinary biology and clinical manifestations, was ahead of its time. Hence it was poorly understood and, like the work of many other innovators, was largely ignored. Nevertheless, his 2100 page Traité which begins with a description of his innovative and highly disciplined method of study, most unusual at this time, is by no means lacking in interest for today's nephrologists. Rayer's was a landmark contribution, affording, as it did, a comprehensive approach to the clinical problems of nephrology a century before the diseases themselves could be understood. Could a contemporary of Rayer tell that he was an inventor of scientific methodology before the proof of his rigorous demonstrations was carried out? That has been the achievement of clinical nephrology in the past forty years...one century later.

Within a few years of its occurrence, American clinicians became aware of the discovery by Bright in 1827 that albuminuria in edematous patients was associated with granular degeneration of the kidney. Yet, there was a paucity of important original observations in nephrology from American in the first half of the 19th century. By the mid-19th century, however, the primitive concepts of clinical nephrology, renal physiology, and renal pathology were becoming established in the United States, after enlightenment from Europe. Because of the dreadful course of anasarca and uremia and stimulated by the advantages of innovations in microscopy, renal disease began at that time to attract the attention of eminent American clinician-pathologists. Their early observations would add to the knowledge base on which later developments such as bacteriology, radiology, clinical chemistry, and other scientific advances would build.

British successors of Richard Bright came to regard the disease which bore his name as consisting of several distinct clinical and pathological types, one of which was referred to as contracted granular kidney. The insidious nature of this form of the disease, the lack of clear-cut precipitating factors and, above all, the associated cardio-circulatory disorders gave rise to much speculation and debate. Whether the renal disease or the vascular disease was the primary and essential change was a question which sharply divided eminent Victorian physicians and gave rise to a bitter quarrel between Sir George Johnson and Sir William Gull. The anser to this conundrum, that the kidney was sometimes the cause and sometimes the consequence of circulatory disease was suggested by Mahomed's discovery of essential hypertension but confirmation had to await the invention of a clinically useful sphygmomanometer.

Clinical concepts--labels placed on categories of sickness--are essential to both the physician's and the patient's understanding of a disease. The changing use of labels in renal medicine reflected how physicians and others thought about kidney disease, each new label suggesting increasing complexity in the encounter of renal patient and physician. While dropsy referred to symptoms easily perceived by the patient as well as the physician, Bright's disease focused mainly on microscopic pathology invisible to the patient. Most removed from palpable symptoms is end-stage renal disease, a diagnosis often uncovered by autoanalyzer, defined by the need for dialysis, and formally bestowed by government. This process of definition and redefinition demands the attention of scholars because it reveals much about the evolution of medical thought and practice.

Modern knowledge of renal physiology, kidney disease, and the body fluids in American medicine was established largely by Donald D. Van Slyke, Thomas Addis, John P. Peters, Homer W. Smith, and Alfred Newton Richards. Only two of these men were physicians, and through this group future nephrology was shaped by a dominant interest in metabolic problems and pathophysiology. Acute renal failure emerged as a new syndrome during World War II and fostered interest in hemodialysis and renal biopsy. Dialysis, when applied to chronic renal failure, eventually spawned an army of renal clinicians; and biopsy provided a specialist's nosology of what had once enjoyed the unity of "Bright's disease." A society and subspecialty board came late to nephrology and have been directed largely by renal academicians of the metabolic tradition. Nephrology is in the 1980s a bipartite subspecialty, its senior leaders still cherishing the metabolic-physiologic tradition, and a growing army of dialysis practitioners mostly looking after patients with chronic and acute renal failure.