Phosphorus: Chronicles of the epistemology of a vital element.

It was in the philosopher's stone quest that the alchemist Hennig Brand isolated chemiluminescent white phosphorus (P), Greek for "light bearer", from urine in 1669. By 1771 phosphorus was isolated from bone, and in 1777 it was identified by Antoine Lavoisier as a highly reactive element that exists predominantly in nature as ionic phosphate (PO43-) and in solution as phosphoric acid (H3PO4). Early 20th century studies revealed phosphorylated biomolecules as essential components of replicative nuclear material (RNA, DNA), a metabolic source of energy (ATP), and structural components of cellular membrane (phospholipid bilayer). Life on earth began as organophosphates of a self-replicating RNA that evolved into DNA and acquired a membrane to form the original eukaryotes, which eventually joined to form multicellular organisms of the deep sea. Tissue mineralization during transition from the ocean to land generated the endoskeleton, the largest phosphorus stores of evolving vertebrates. Subsequent studies of phosphate homeostasis elucidated its complex regulatory system based on the interaction of the kidney, small intestine, bone, and parathyroid glands, orchestrated by hormones (PTH, calcitriol, FGF23, Klotho), and carried out by phosphate-specific transporters (SLC34 and SLC20 families) all to ensure adequate phosphate for survival and health. Paradoxically, kidney replacement therapy in the 1970s, by prolonging the lives of millions of individuals with kidney failure, revealed the hazards of phosphorus excess. "Phosphorus the light bearer" has become in the eyes of many nephrologists "Phosphorus the cardiovascular toxin".

Cardiorenal Syndrome: An Evolutionary Appraisal.

A recent American Heart Association Scientific Statement and Presidential Advisory recognized a new syndrome, the cardiovascular-kidney-metabolic syndrome. This expands our understanding of what has been called cardiorenal syndrome by incorporating the pathophysiological interrelatedness of metabolic risk factors into the previous concept of cardiorenal syndrome. Importantly, perturbation of cardiac or renal physiology combines to produce significant detrimental outcomes. The cardiorenal syndrome is a significant part of the cardiovascular-kidney-metabolic syndrome and contributes to health care cost, disability, and mortality. It is a vexing malady that has generated considerable interest. To understand the syndrome evaluation of its teleological origins is important. In life's beginning, eukaryotes acquired exocytosis for excretion, formed tubular secretory systems for clearance, and a mesenchymal nucleic acid vasoform for nutritional distribution. Those structures progressed to cardiovascular and renal systems of evolving organisms, whose migration to rivers and land imposed complex, coordinated, homeostatic roles to maintain intravascular stability. Tissue mineralization of vertebrate endoskeleton added renal calcium balance regulation, which in kidney failure results in cardiovascular calcification. Insight into cardiorenal disease can be traced to ancient Egyptian and Chinese medicine, through the Scientific Revolution, and into current insights regarding human physiology and pathophysiology. The post-World War II epidemic of cardiovascular mortality generated considerable information on cardiovascular disease, which being higher in patients with kidney disease, drew increasing health concerns. The cardiorenal syndrome was formally introduced in this setting with a focus on ultrafiltration to manage volume overload. An evolutionary review of insight into cardiorenal syndrome will help us better understand the new cardiovascular-kidney-metabolic syndrome.

Transplant nephropathology: Wherefrom, wherein, and whereto.

Renal pathology is a relatively recent entry in nephrology. While diseases of the kidney are old, their study began in the 19th century with the report of Richard Bright of the lesions of end-stage kidney disease. Its easy diagnosis from albuminuria soon elevated Bright's nephritis into a leading cause of death. The transformative events in the care of these cases were renal replacement therapy that converted a fatal into a chronic disease, and kidney biopsy that allowed study of the course and pathogenesis of kidney disease. Apart from its fundamental contributions to clinical nephrology, biopsy of renal allografts became an integral component of the evaluation and care of kidney transplant recipients. The Banff transplant pathology conferences launched in 1991 led to developing the classification of allograft pathology into an essential element in the evaluation, treatment, and care of allograft recipients with spirit of discovery. That success came at the cost of increasing complexity leading to the recent realization that it may need the refinement of its consensus-based system into a more evidence-based system with graded statements that are easily accessible to the other disciplines involved in the care of transplanted patients. Collaboration with other medical disciplines, allowing public comment on meeting reports, and incorporation of generative artificial intelligence (AI) are important elements of a successful future. The increased pace of innovation brought about by AI will likely allow us to solve the organ shortage soon and require new classifications for xenotransplantation pathology, tissue engineering pathology, and bioartificial organ pathology.

Interstitial Nephritis: Wherefrom, Wherein, and Whereto.

Abnormalities of the renal interstitium were noted early while identifying chronic kidney disease in 1827; however, interest in glomerular and vascular lesions was then distracted from their further study. As a complication of scarlet fever, interstitial lesions attracted attention in 1859 and came to be defined as acute interstitial nephritis in 1898. The chronic form of interstitial nephritis was traditionally attributed to pyelonephritis until the advent of kidney biopsy in the 1950s, when interstitial lesions were recognized as an independent primary cause of chronic kidney disease from studies of analgesic nephropathy and vesico-ureteral reflux. The term tubulointerstitial nephritis was introduced in 1963 and promoted to denote the role of the tubules in the pathogenesis and the clinical presentation of interstitial nephritis as tubular dysfunction. Studies since then have established that fibrotic tubulointerstitial nephritis lesions correlate best with the severity and progression of kidney diseases independent of their etiology.

Renal osteodystrophy: A historical review of its origins and conceptual evolution.

Long considered an inert supporting framework, bone studies went neglected until the 17th century when they began as descriptive microscopic studies of structure which over time progressed into that of chemistry and physiology. It was in the mid-19th century that studies evolved into an inquisitive discipline which matured into the experimental investigation of bone in health and disease in the 20th century, and ultimately that of molecular studies now deciphering the genetic language of bone biology. These fundamental studies were catalyzed by increasing clinical interest in bone disease. The first bone disease to be identified was rickets in 1645. Its subsequent connection to albuminuric patients reported in 1883 later became renal osteodystrophy in 1942, launching studies that elucidated the functions of vitamin D and parathyroid hormone and their role in the altered calcium and phosphate metabolism of the disease. Studies in osteoporosis and renal osteodystrophy have driven most recent progress benefitting from technological advances in imaging and the precision of evaluating bone turnover, mineralization, and volume. This review exposes the progress of bone biology from a passive support structure to a dynamically regulated organ with vital homeostatic functions whose understanding has undergone more revisions and paradigm shifts than that of any other organ.

Acid-base homeostasis: a historical inquiry of its origins and conceptual evolution.

To a great extent, the conceptual evolution of acid-base homeostasis has been shaped by progress in chemistry. It began with the theoretical consideration of matter by the natural philosophers of antiquity, progressed into an observational craft as chymistry during the Scientific Revolution, evolved into analytical chemistry in the Enlightenment when acid-alkali interactions began to be deciphered, then was clearly exposed in the organic chemistry of the 19th century and ultimately formulated in mathematical precision as the chemical equations of physical chemistry in the 20th century. Two principal transformational changes shaped their clinical application. The first, launched by the Chemical Revolution of Antoine Lavoisier, introduced quantitation, clarified the language and added experimental rigor to chemical studies, which Claude Bernard then introduced into physiology, formulated the concept of regulatory homeostasis, refined experimental medicine and explored the role of the kidney in acid-base balance. The second transformational change in their gradual clinical applicability began in electrochemical studies that revived the atomic composition of matter and introduced the notion of ions and electrolytes that were fundamental in formulating the concept of acid-base ionization by Svante Arrhenius in 1884 and their measurement from hydrogen ion concentration as pH by Søren Sørensen in 1909. Subsequent studies of Lawrence J. Henderson and Donald D. van Slyke introduced these laboratory-based conceptual advances to the bedside in the 20th century. Clinical studies of acidosis and alkalosis that followed over the past few decades have facilitated and refined the clinical recognition, interpretation and treatment of acid-base disorders.

Hepatorenal syndrome: a historical appraisal of its origins and conceptual evolution.

The hepatorenal syndrome (HRS), a progressive but potentially reversible deterioration of kidney function, constitutes a serious complication of hepatic decompensation. Coexistence of liver/kidney damage, mentioned in the dropsy literature, was highlighted by Richard Bright in 1827 and confirmed in 1840 by his contemporary nephrology pioneer Pierre Rayer. Cholemic nephrosis was described in 1861 by Friedrich Frerichs, and the renal tubular lesions of HRS by Austin Flint in 1863. The term "acute hepato-nephritis" was introduced in 1916 by Paul Merklen, and its chronic form was designated HRS by Marcel Dérot in 1930s. HRS then was applied to renal failure in biliary tract surgery and to cases of coexistent renal and hepatic failure of diverse etiology. The pathogenesis of HRS was elucidated during the 1950 studies of renal physiology. Notably, studies of salt retention in edema and its relation to regulating the circulating plasma volume by John Peters and subsequently Otto Gauer defined the concept of "effective blood volume" and the consequent elucidation of ascites formation in liver failure. Parallel studies of intrarenal hemodynamics demonstrated severe renal vasoconstriction and preferential cortical ischemia to account for the functional renal dysfunction of HRS. Dialysis and liver or combined liver-kidney transplantation transformed the fatal HRS of old into a treatable disorder by the 1970s. Elucidation of the pathogenetic mechanisms of renal injury and refinements in definition, classification, and diagnosis of HRS since then have allowed for earlier therapeutic intervention with combined i.v. albumin and vasoconstrictor therapy, enabling the continued improvement of patient outcomes.

A historical perspective of how public policy shaped dialysis care delivery in the United States.

Broadly defined public policy has been said to be whatever "governments choose to do or not to do" As applied to healthcare, public policy can be traced back to the 4000-year-old Code of Hammurabi. As it applies to dialysis care its history is barely 50 years old since national coverage for end-stage renal disease (ESRD) was legislated as Public Law 92-603 in 1972. As with most healthcare policy changes, it was a result of medical progress which had changed renal function replacement by dialysis from its rudimentary beginnings during the Second World War into an experimental acute life-saving procedure in the 1950s and to an established life-sustaining treatment for the otherwise fatal disease of uremia in the 1960s that was limited by its costs. Since 1973, the Medicare ESRD Program has saved the lives of thousands of individuals, a compassionate achievement that has come at increasing costs which have exceeded all estimates and evaded containment. Apart from cost containment, policy changes in dialysis care have been directed at improving its safety and adequacy. Some of the results of these changes are evident as one compares the outcomes and complications of dialysis encountered in the 1970s to those in the present; others, particularly those related to vascular access and hospitalization rates have improved modestly. This article recounts the historical background in which national coverage for dialysis care was developed, legislated and has evolved over the past 50 years.

Lupus nephritis: A historical appraisal of how a skin lesion became a kidney disease
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"Lupus nephritis", a serious complication of systemic lupus erythematosus (SLE), is an entity of recent vintage. The term "lupus", derived from Latin for wolf, was introduced in the Middle Ages to denote nondescript erosive skin lesions which resembled wolf bites that were known theretofore by their Greek name of "herpes esthiomenos", used in the Hippocratic Corpus for the spread of the lesions like a crawling snake. The specific dermatologic features of lupus were characterized as an "erythematous" butterfly rash in 1828 and dubbed "lupus erythematosus" in 1850. Their association with systemic manifestations was described in 1872 and termed "disseminated lupus erythematosus" by the close of the century. A preference for "systemic" rather than "disseminated" was suggested in 1904 but would not prevail until the 1960s. The generic term "nephritis", denoting "inflammation of the kidnies" dating to the 1580s, was first used to describe the renal lesions of SLE in 1902. Although albuminuria and abnormal urine sediment were often noted in SLE patients, the early study of their renal changes was limited to postmortem studies. Refinements in their identification came in the late 1950s after the introduction of kidney needle biopsies and refined thereafter by immunofluorescent and electron microscopic studies. Subsequent lupus nephritis studies paralleled the emerging discipline of immunology that identified autoimmunity as the cause of SLE. The varied lesions observed were classified by glomerular changes in 1975 and refined in 2003. Advances in genetic and molecular profiling have enriched the management of lupus nephritis based on kidney biopsies.

Uremia: A historical reappraisal of what happened
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Urea was identified as a urinary salt in 1662 and was the first organic bodily product to be synthesized in vitro in 1828. This heralded the end of an era that defined disease as an imbalance between vital life forces, and catalyzed the merging of organic chemical sciences into clinical medicine. The term urée (urea) was introduced in 1803, its accumulation in blood was dubbed urémie (uremia) in 1847, and the procedure for its removal from urine across semi-permeable membranes designated dialysis in 1861. The advent of modern dialysis in the 20th century provided lifesaving replacement therapy for the universally fatal disease that progressive uremia had been theretofore. Today, the clearance of urea is no longer used as a marker to identify patients with kidney disease; rather it has been adopted as a measure of the adequacy of dialysis, and the "urea toxicity" of yesteryears has been replaced by that of dialyzable "uremic toxins". As a result, the use of the term uremia has become non-uniform and is now applied to variable scenarios ranging from "azotemia" to "kidney failure" and to the symptoms persisting in patients receiving maintenance hemodialysis. In the process, the quest for variably dialyzed uremic toxins has overshadowed the consideration that dialysis is an invasive non-physiologic process that operates counter to normal homeostasis and itself may be toxic.
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A History of Uremia Research.

The history of uremia research begins with the discovery of urea and the subsequent association of elevated blood urea levels with the kidney disease described by Richard Bright, a well told story that needs no recounting. What this article highlights is how clinical and laboratory studies of urea launched the analysis of body fluids, first of urine and then of blood, that would beget organic chemistry, paved the way for the study of renal function and the use of urea clearance to determine "renal efficiency," provided for the initial classification of kidney disease, and clarified the concepts of diffusion and osmosis that would lead to the development of dialysis. Importantly and in contrast to how the synthesis of urea in the laboratory heralded the death of "vitalism," the clinical use of dialysis restored the "vitality" of comatose unresponsive dying uremic patients. The quest for uremic toxins that followed has made major contributions to what has been facetiously termed "molecular vitalism." In the course of these major achievements derived from the study of urea, the meaning of "what is life" has been gradually liberated from its past attribution to supernatural forces (vital spirit, archaeus, and vital force) thereby establishing the autonomy of biological life in which the kidney is the master chemist of the living body.

Nephrology: As It Was Then, But Is Not Now.

Diseases of the kidney are old, but the discipline dedicated to their study, nephrology, is barely more than 50 years old. As recounted in this recollection of those events, the rudiments of what would become nephrology emerged in the time between the 2 World Wars from basic studies of normal kidney function and flourished after the integration of their methodologies into clinical medicine thereafter. Although shaped by studies of kidney function in the 1960s, it was the subsequent advent of dialysis that fueled the growth of nephrology well into the 21st century. Although to some extent this growth was a product of technical developments (micropuncture, dialysis, biopsy, etc), it was the paradigm shifts they engendered that brought about the revolutionary changes that stimulated the growth of nephrology from its formative years in the 1960s. Notable among those was the classification of chronic kidney disease on the basis of kidney function, calculated from serum creatinine level as estimated glomerular filtration rate, that has expanded nephrology's interaction with and integration into other disciplines and begat the recent outpouring of epidemiologic and interventional studies, thereby establishing it as a leading discipline dedicated to improving outcomes for individuals with kidney disease worldwide.

The kidney in sickle hemoglobinopathies
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With improvements in the care of patients with sickle hemoglobinopathies, sickle cell disease (SCD) has evolved from a disease that was fatal in childhood into one in which most survive past their 5th decade and some into old age. As a result, the renal complications of sickle hemoglobinopathies, which are age dependent, have emerged as a common and serious complication of SCD. Approximately 14 - 18% of mortality in SCD is attributed to chronic kidney disease (CKD), which develops in 1/3 of individuals with SCD and progresses to end-stage renal disease in 4 - 18% of them. Importantly, the presence of CKD increases the risk of the other systemic complications of SCD, with the median survival of SCD estimated at 51 years, declining to 29 years in those with CKD. The obstructive vasculopathy of SCD affects the glomerulus, tubules, and medulla of the kidney. Albuminuria and inability to concentrate the urine precede the onset of renal failure, and, along with other tubular dysfunctions, are early warning signs of sickle cell nephropathy (SCN). This is a review of the historical background SCN, the pathophysiology of the renal lesions, their varied clinical and pathologic manifestations, and available treatment options.
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Why the history of nephrology?

Nephrology is a relatively new discipline that emerged at a time when the writing of the history of medicine was changing drastically. While the merits of medical history were valued since antiquity, it was only in the 18th century that the actual historiography of medicine began. It was nurtured, matured and appreciated enough that by the late 19th and early 20th centuries, medical history was incorporated into the medical curriculum and presented at national meetings. Unfortunately, the merits of medical history and its inclusion in medical education have come under increasing scrutiny over the past few decades. Ironically, the erosion began at about the same time that scholarly work on the history of medicine was flourishing whilst that of scientific discovery and innovation in medicine was accelerating. The demands of rigorous research into the history of medicine gradually led to the emergence of medical history as an independent discipline within academic departments of history. Simultaneously, the exponential growth of new information generated by medical research led to an overflow of medical knowledge in which the inclusion of medical history was contested and dismissed. That is just about the time that nephrology emerged in the 1960s. Whereas initially the quest for origins led renal journals to publish historical articles, the more recent quest to increase impact factors has led to the exclusion of historical articles from consideration for publication. This manuscript examines the reasons that brought about the separation of nephrology from its history and proposes potential solutions to their rapprochement.

Stephen Hales: the contributions of an Enlightenment physiologist to the study of the kidney in health and disease.

Stephen Hales (1677-1761) was an English clergyman who made major contributions to a wide range of scientific topics such as botany, chemistry, pneumatics, and physiology. Early in his career he developed a keen interest in medicine through his association with his younger physician friend at Cambridge, William Stukeley (1687-1765), with whom he dissected animals and attended experiments in the laboratory of Isaac Newton. His fame as a scientist grew and by the end of his life he had achieved an international reputation as a major scientist of the Enlightenment. He is best known for his 1733 Statical Essays, in the second part of which he describes his studies in animal physiology. Most famous amongst those are his assessments of the force of the blood, which he measured in horses and dogs. Less well known and often unrecognized are his studies on the kidney in health and disease, which are the focus of this review. Amongst others Hales described the effects of hemorrhagic shock which he observed as he bled his animals while measuring their blood pressure; he then studied the effect of increasing saline perfusion pressures on the renal secretion of urine; and delved into biochemistry in exploring the composition of and solutions to dissolve bladder stones. His 1733 statement in the introduction to his hemodynamic studies that the healthy State of the Animal principally consists, in the maintaining of a due Equilibrium between the body solids and fluids literally predicts the milieu intrieur that would ultimately be formulated in 1854 by Claude Bernard (1813-1878).