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.

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".

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
.

"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
.

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.
.

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
.

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.
.

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.

Beginnings-The Kidney and Nephrology in Ancient Mesopotamian Culture.

A defining period in the history of civilization occurred in ancient Mesopotamia. While some of Mesopotamian contributions to knowledge (writing, mathematics, astronomy) have been recognized, those made to medicine are just beginning to be studied and appreciated. The medicine of the time developed in a theocratic society where local gods controlled all aspects of life and their healers were learned scribes who established the priestly medicine of old. For their use of prayers and incantations as a component of therapy Mesopotamian medicine has been belittled and relegated to magic. In fact, the Mesopotamian healers established the basic medical skills of observation, diagnosis, prognosis and treatment and, over time, systematically produced an expanding corpus of medical knowledge that had not existed theretofore. The kidney as an organ, the components of the urogenital tract, some signs and symptoms of renal diseases, and the art of urinalysis were first conceptualized, studied, and codified in Mesopotamia. In doing so, the Mesopotamians set the foundations of rational medicine that would follow after the introduction of the phonetic alphabet and the Socratic method of questioning and debate to stimulate critical analysis.

A forgotten chapter in the history of the renal circulation: the Josep Trueta and Homer Smith intellectual conflict.

This article reviews the pioneering and visionary contributions of the Catalan surgeon Josep Trueta (1897­1977) to the changes in renal circulation that contribute to the pathogenesis of acute renal failure (ARF). An erudite scientist with eclectic interests in physiology, orthopedics, politics, and medical history, Trueta's initial involvement in wound healing as a trauma surgeon during the Spanish Civil War and the London Blitz is what prompted him to postulate that a trauma-induced "neural effect" on the renal vasculature, with resultant renal arterial constriction could cause ARF. To test his hypothesis, Trueta assembled an experienced radiologist, a renowned physiologist, and a renal pathologist to study ARF in Oxford. They investigated the renal circulation of rabbits in response to diverse traumatic conditions by injecting a radio-opaque substance, using cine-radiography to visualize the flow of blood through the renal vasculature. Trueta's suggestion of renal cortical ischemia and diversion of blood to the less resistant medullary circulation (Trueta shunt) was criticized by Homer Smith and coworkers. In contrast to Homer Smith's data, which were derived from clearance studies and renal arteriovenous oxygen, Trueta used the diametrical opposite method of "direct" observation of the renal circulation. Their differing methodologies, direct visualization of the renal circulation as opposed to inferred computations from clearance studies, accounts for some of their conflicting theories. Nevertheless, the proposal of disparate renal flow compartments focused attention on intrarenal hemodynamics. Trueta's focus on renal cortical ischemia was ultimately validated by the studies of Barger in the dog and Hollenberg and Epstein in human subjects.

The Scientific Revolution--The Kidney and Nephrology in and about the Seventeenth Century (Part 1).

In the history of the evolution of the medical sciences, it is in the 17th century that the conscious, deliberate, and systematic study of the workings of the human body began. It was a product of the radical changing attitudes of this insurgent century when mathematical reasoning and mechanistic philosophy replaced the teleological outlook of earlier times. It was then that meticulous observation, reproducible quantification, experimental validation, and mathematical exactitude in the quest for truths launched the Scientific Revolution. The effect on medicine was a transformative change from a descriptive to an explanatory body of knowledge during the course of which rigorous anatomical dissections were used for the mechanical explanation of organ function, when morbid changes observed at postmortem began to be related to clinical features of disease, and when the secretive analytical methods of alchemy began to be refined for the study of chemical changes in living matter. Essentially what began with meticulous observations of anatomical features begat physiology and laid the foundations of pathology and chemistry. As a result, studies of organ structure, function, and changes in disease in general, and of the kidney in particular, were clarified and progressed at a rate never achieved theretofore.

Clinical trials in uremia-time to reappraise.

The construct of any road map of the progress of medical knowledge reveals a long and tortuous road, full of errors, misapprehensions, blind alleys, and a perpetual shuffling between authority, heresy, and reason; but one of continuous growth and steady progress, albeit at variable pace and achievement at different periods of history. Numerous factors account for this cumulative progress, notable among which are the transmission, scientification, and mathematization of medical knowledge that ultimately account for the progressive evolution of medical care over time, from its primitive beginnings in antiquity to its present sophisticated state of accomplishment. It was the mathematical precision provided by quantification and statistical analysis that established certainty in medicine and ultimately changed the conjectural art of clinical practice to a disciplined science founded on clinical investigation, especially in therapeutics. Randomized clinical trials (RCTs) introduced in the 1950s have since been instrumental in establishing certainty in the practice of medicine. Regrettably, the proliferation of RCTs driven by biased hypotheses and pharmaceutical-industrial interests have created serious flaws in the results of the onslaught of new RCTs that need to be reappraised. Another unfortunate trade-off during this evolution has been neglect of the individual patient's inborn biological variation from the norm, mean, or median, an omission that has come to erode the personal in medical care.

The early modern kidney--nephrology in and about the nineteenth century (part 2).

Two basic science specialties that matured in the nineteenth century were instrumental in the transformation of medicine into a scientific discipline and in the process of establishing the evidentiary basis of the fundamental role of the kidney in maintaining homeostasis, whose continued exploration would lead to the emergence of nephrology in the following century. The first specialty was that of chemistry, which progressed from a descriptive to an analytical, organic, biological, and physical science that progressively eroded the animism of the "vital" forces of old and replaced it with the physicochemical forces and laws of chemical reactions that govern the "matters of life". The second specialty was that of cell biology, which established the cell as the structural and functional unit of living organisms, be they plant or animal. Refined microscopic technologies then helped to identify the structural components of the cell, amongst which the plasma membrane emerged as the most important in regulating the separation of the intracellular machinery from its external environment and thereby maintaining the internal milieu of cells. The interaction of these two specialties (chemistry, cell biology) clarified the functions of the cell in health and disease and extended it to the study of epithelial cell transport. This transforming turn of events established the role of the renal tubules in the vital function of the kidney of maintaining body homeostasis, a function well beyond that of the passive excretory filter of wastes and excess fluids it had been considered theretofore.

Music, musicians, medicine, and the kidney.

The relationship between music, medicine and nephrology is ancient; ranging from musicians afflicted with kidney disease, contributors to nephrology who were musicians, and the use of music to treat renal maladies. Musicians have long been afflicted by diseases of the kidney, particularly nephrolithiasis, for which Marin Marais in 1725 composed a unique piece for the viol detailing the harrowing experience of 'cutting for stone.' Beethoven and Mozart were afflicted by kidney disease, as are several current musicians. Where past musicians succumbed to their failing kidneys, the advent of renal replacement therapy has given today's musicians, such as James DePreist and Natalie Cole, the opportunity to continue performing and composing. Several notable physicians of old have excelled as musicians; one example is Jacob Henle (1809-1885), for whom the loop of Henle is named, another is Robert Christison, a contemporary of Richard Bright, who is considered a 'founder of nephrology'. Importantly, music therapy, as used in the times of Hippocrates and King David, has evolved from an empiric to a well-established scientific discipline. Given the recent enlarging body of scholarly studies of music therapy, its rudimentary role in nephrology deserves further exploration.