The prehistory of haemodialysis as a treatment for uraemia.

Less is generally known about the ideas, events and personalities which drove developments permitting the evolution of haemodialysis as a clinically useful form of palliation and treatment, than its subsequent success and failures. This pre-history of haemodialysis is summarized here. One must remember that with hindsight we can now discern connections between ideas and developments which were not perceptible in their time, and that progress towards any new idea, material or piece of hardware was usually random and undirected, and outcomes uncertain. We must also remember the many blind alleys we can now safely ignore, to give a spurious continuity to the development of ideas. The prehistory of dialysis begins with study of the diffusion of solute and solvent in osmosis in living systems and experimental settings, and the retention of potentially toxic substances in kidney failure, during the 18th and early 19th centuries. These two areas came together in work in the mid-19th century on diffusion of gases and liquids, and showed that natural and synthetic membranes could selectively hinder different solutes. This explained osmosis and allowed semi-permeable membranes to be used and designed. These ideas underpinned the subsequent history of both dialysis using body cavities such as the peritoneum (not discussed here) and ex vivo dialysis of blood. To perform this, new membranes and anticoagulants were needed. These led to the first attempts in animals in 1912-3, and human patients in 1924-8, but only the purification and synthesis of newer materials such as cellulose and heparin allowed practical and successful haemodialysis to evolve in the 1940s.

A history of urine microscopy.

The naked-eye appearance of the urine must have been studied by shamans and healers since the Stone Age, and an elaborate interpretation of so-called Uroscopy began around 600 AD as a form of divination. A 1000 years later, the first primitive monocular and compound microscopes appeared in the Netherlands, and along with many other objects and liquids, urine was studied from around 1680 onwards as the enlightenment evolved. However, the crude early instruments did not permit fine study because of chromatic and linear/spherical blurring. Only after complex multi-glass lenses which avoided these problems had been made and used in the 1820s in London by Lister, and in Paris by Chevalier and Amici, could urinary microscopy become a practical, clinically useful tool in the 1830s. Clinical urinary microscopy was pioneered by Rayer and his pupils in Paris (especially Vigla), in the late 1830s, and spread to UK and Germany in the 1840s, with detailed descriptions and interpretations of cells and formed elements of the urinary sediment by Nasse, Henle, Robinson and Golding Bird. Classes were held, most notably by Donné in Paris. After another 50 years, optical microscopy had reached its apogee, with magnifications of over 1000 times obtainable free of aberration, using immersion techniques. Atlases of the urinary sediment were published in all major European countries and in the US. Polarised light and phase contrast was used also after 1900 to study urine, and by the early 20th century, photomicroscopy (pioneered by Donné and Daguerre 50 years previously, but then ignored) became usual for teaching and recording. In the 1940s electron microscopy began, followed by detection of specific proteins and cells using immunofluorescent antibodies. All this had been using handheld methodology. Around 1980, machine-assisted observations began, and have dominated progress since.

Nephrotic syndrome redux.

Redux: brought back, resurgent (Wikipedia free dictionary). This essay traces the history of the concepts that led to the usage of the term 'nephrotic syndrome' beginning ∼90 years ago. We then examined the various definitions used for this syndrome and modified them to conform to contemporary standards. Remarkably, only minor modifications were required. This analysis of a common clinical entity may be helpful in ensuring appropriate evaluation of patients suffering from nephrotic syndrome and nephrotic-range proteinuria.

IgA nephropathy: progress before and since Berger.

Immunoglobulin A nephropathy (IgAN) is linked inextricably to the name Jean Berger, the Parisian pathologist who published the first description of IgAN in 1968. We reflect on the significance of Berger's first report and consider 40 years of progress in our understanding of IgAN since it was published. We also look back to the days before Berger, when IgAN could not have been identified (because there were no techniques for detecting IgA deposits), classification of glomerulonephritis was even more contentious and confusing than it is today, and it is likely that the literature describing focal glomerulonephritis contained many of the cases we would now identify as IgAN.

Nephrologist extraordinary--Michael Darmady (1906-1989).

Michael Darmady (1906-1989) is now largely forgotten, although he played a major role in several areas of Nephrology in the early days of the speciality, both as a clinician and as a pathologist. His contributions to the early understanding of acute renal failure and of the use of haemodialysis during the 1940s have been particularly neglected. His nephron microdissection work achieved some influence around 1960, but today he is remembered principally for his classical work on the morphology of the ageing kidney, and on being the first to point out the poorer outlook of kidneys transplanted from older donors, in 1974.

Uric Acid and renal disease.

The interrelationship between uric acid and renal disease is reviewed in a historical context. Four phases can be distinguished--the descriptions of uric acid stones and gravel in the eighteenth century, of chronically scarred kidneys containing urate crystals in the nineteenth, the appearance of the syndrome of acute urate nephropathy following tumour lysis in the mid twentieth century, and finally the realization that soluble urate affects both systemic and glomerular blood vessels, and may play a role in both hypertension and chronic renal damage.

Time's arrow in nephrology: the discovery of the kidney.

Time is a unique dimension of the universe, along with perhaps 10 dimensions of space, according to superstring theory. Our brain and its associated consciousness perceive time as a continuous unidirectional stream. Even though we appear to be able to move freely in three dimensions of space; time's arrow for us points only one way, the present eroding into the future to leave the past behind. For two millennia, time has been likened to a stream or river. In the West, for the past two centuries, time and change have been equated almost automatically with the idea of progress. However, change always brings with it loss as well as gain, and progress is far from inevitable. This remains true in the history of medicine. The history of any subject is full of blind alleys, which, although important at the time, generally become edited out in retrospect.

Hereditary hyperuricemia and renal disease.

Hyperuricemia and gout have long been known to run in families. As well as an apparently multifactorial genetic component to classic gout itself, 2 rather unusual sex-linked single-gene disorders of purine biosynthesis or recycling have been defined: deficiency of the enzyme hypoxanthine-guaninephosphoribosyl transferase (HPRT), and overactivity of PPriboseP synthase. Both result in overproduction of urate, hyperuricemia, and secondary overexcretion that may lead to acute or chronic renal damage. Familial juvenile hyperuricemic nephropathy (FJHN) and autosomal-dominant medullary cystic kidney disease (ADMCKD) are more common but less well-defined hyperuricemic conditions resulting from a decrease in the fractional excretion of filtered urate, with normal urate production. Although having features in common, ADMCKD is distinguished in particular by the presence of medullary cysts. One major group of both disorders is associated with mutations in the gene for uromodulin, but this accounts for only about one third of cases, and genetic heterogeneity is present. Whether the genes involved in these latter disorders contribute to the polygenic hyperuricemia and urate underexcretion of classic gout remains unexplored.

Focal segmental glomerulosclerosis in adults.

The lesion of focal segmental glomerulosclerosis (FSGS) presents even greater problems of definition, interpretation and treatment in adults than it does in children, to the point where the specificity and utility of the appearance can even be questioned. The histological diagnosis of FSGS in adults can be interpreted only if the clinical circumstances are known, but a group of nephrotic patients with FSGS can be separated from a much larger group of non-specific, probably secondary but similar lesions arising in many circumstances. This group appears even so to have a diverse aetiology, the majority being idiopathic, but a significant minority showing a family history and/or mutations in genes relating to several intracellular or surface podocyte proteins, as discussed in other articles in this symposium. This heterogeneity makes conclusions with regard to prognosis and treatment difficult to draw. Today, in contrast to 20 or even 10 years ago, it seems useful to treat all adult nephrotic patients with FSGS using an adequate course of corticosteroids lasting at least 4-6 months to establish whether they fall or not into the 20-30% who will respond to this treatment with decrease or loss of proteinuria. The prognosis of such responders (who may well suffer relapse) is relatively benign with regard to renal function, but the majority of the remainder evolve into renal failure. Their management remains a source of controversy in the absence of a proper database of randomized trials: more prolonged (up to 24 months) use of lower-dose corticosteroids with cyclosporine for 12 months or more has support from uncontrolled studies, but cyclophosphamide appears to be of less obvious benefit.

Sir Robert Christison (1797-1882): a neglected founder of nephrology.

Although Robert Christison (1797-1882) of Edinburgh was one of the three main pioneers of modern nephrology along with Bright and Rayer, his name much is less well known than his compatriots, even in his native Scotland. Amongst many contributions to an amazingly wide variety of medical fields in a long and distinguished career, he confirmed and extended Bright's work on the nature and origins of albuminuria and dropsy, showed that these states might be completely reversible, suggested a relationship between acute nephritis, large white and granular kidneys, discovered the basis for understanding uremia whilst applying chemistry to the study of blood and urine in patients with renal disease, described and quantified the anemia of renal failure for the first time, made early microscopical examinations of the kidney and urine, and finally described the syndrome of acute renal failure from intrinsic renal involvement in response to outside noxious stimuli or poisons. Today, it is not easy to discern why he has been so overlooked. Possibily, the fact that he had such an enormous output in other fields, particularly pharmacology and jurisprudence, on which his fame principally rests today, whilst he studied renal diseases for only 25 years of his long career. In addition, only one year after his own book on granular kidney was published, Pierre Rayer brought out his enormous treatise and even though he quoted Christison's results, subsequently tended to be cited even by British physicians. Finally, he left no school of pupils to honour and advertize his achievements to subsequent generations.