Hippocrates: “Those whose urine is merely blood-stained have suffered in the veins. When urine is thick, and there are passed with it small pieces of flesh like hair, you must know that these symptoms result from the kidneys and arthritic complaints.” Bubbles appearing on the surface of the urine indicate disease of the kidneys and a prolonged illness. Diseases of the kidneys or bladder are difficult to cure in the aged. The sudden appearance of blood in the urine indicates that a small renal vessel has burst.

Aristotle: “Very often the kidneys are found to be full of stones, growths, and small abscesses; so is the liver, and the lung, and especially the spleen.” (De partibus animalium III, 4,667b, cit. in Am J Nephrol 14:305)

Aretaeus of Cappadocia: “Certain persons pass blood periodically … they are very pale, without appetite. They are languid and relaxed in their limbs … their eyes become dull, dim, and rolling: hence may become epileptic; others are swollen, misty, dropsical; and others again are affected with melancholy and paralysis.”

Many ancient Greek and medieval Byzantine medical writers have described the clinical features of acute renal failure. An illuminated manuscript from the Byzantine era shows a physician holding up a urinal as symbol of his trade. Treatment was generally nonspecific, consisting of bleeding, diuretics, enemas, and purgatives (J Roy Soc Med 86;290).

Rufus of Ephesus in about 100 AD wrote a treatise on diseases of the kidneys and bladder, noting that sclerosis of kidneys was not painful, but might cause dropsy. He recommended rest, enemas, cupping of the loins, baths, ”refrigerant and sedative medicines” given internally.

Paul of Aegina (625–690): “When hardness occurs in the kidneys it does not cause pain … but the limbs lose their strength, little urine is passed, and the whole habit resembles that of dropsical persons.” Treatment as above, but if it fails, try boiled squill in wine and honey, or ox dung dried and drunk daily to the amount of one spoonful every day.

Aetios of Amida (502–575) mentioned hardening of the kidneys in his Tetrabiblion.

Theophilus Protospatharius, a seventh century physician in Byzantium, first had the idea of heating the urine and precipitating its proteins as a means of diagnosing diseases.

Paracelsus (1493–1541) later achieved the same effect by adding vinegar and noting it curdled the urine and produced a precipitate. He wrote voluminous medical manuscripts, including comments on urinalysis, proteinuria, hematuria, and edema. He introduced the use of mercury to treat patients with dropsy – a therapy continued in a modified form until the late 1950s (Kidney Int 71:384; Nephrol Dial Transpl 11:1388).

Maimonides (1135–1204) : “Black urine and black sediment are extremely malignant and indicate serious illness. They occur in association with what resembles the death of natural resources … I have never seen anyone who urinated black urine who survived” (Am J Nephrol 14:312).

Nicolaus Fabricius de Peiresc (1580–1637) is believed to have been the first to carry out microscopic observations on urine. He noted in a sample of “sandy urine” a “heap of rhomboidal bricks” and thought that their shape could explain the pain caused by their passage along the urinary system (Kidney Int 50:1058).

Marcello Malpighi (1628–1694), founder of microscopical anatomy, was professor of medicine at Messina and Bologna. Using the microscope as avant garde technology of his time, he noted the pyramids of the medulla, the collecting ducts, and the glomerulus—to this day still called the Malpighian corpuscle. “To see these corpuscles the artery of the kidney has to be injected with a black liquid [and then] one can see the small corpuscles which have turned black … hanging like apples from the blood vessels which, swollen with the black fluid, look like a beautiful tree.” (1666) (Am J Nephrol 13:223; Nephrol Dial Transpl 12:2191)

Solon, 1838, Paris: “If, in renal cases, urea be detected in the blood, the patient should be restrained from too animalised a diet.”

John Blackall of Exeter, England, noted in 1814 the presence of a hard pulse, diminished by venesection, in some albuminuric patients. He also observed that some kidneys at autopsy “were remarkably solid and hard, their appearance somewhat confused,” but attached no significance to this finding (JR College Physicians 33:383; Am J Nephrol 14:371).

It is believed that Richard Bright (1789–1858) may have suffered from the disease which he himself originally described. By the winter of 1852, according to his niece, his colleagues had noted “his worn looks, his pallor and swollen feet.” Little is actually known about his illness, but there were “strong rumors circulating that Bright had fallen victim to his own specialty” (Am J Kidney Dis 21:63 and 655).

Ludwig Traube, in 1871, proposed that hypertension is a compensatory phenomenon that would explain the rise in blood pressure that occurs when the kidneys are grossly diseased. He suggested that “the shrinking of the renal parenchyma will … act by decreasing the amount of liquid which is removed from the arterial system by urinary excretion. As a result … the mean pressure of the arterial system must increase” (Kidney Int 50:717).

William Bowman published studies in 1842 in which he elucidated the structure of the glomerulus by examining the kidneys of parrots, boa constrictors, horses, and frogs. He showed that the glomerulus consisted of a rounded mass of minute vessels invested by a cyst or capsule (Bowman’s capsule) similar to the basement membrane of the tubules (LG Fine, Nephrol Dial Transpl 10:2147).

Although Samuel Wilks (1826–1912) had suggested that hypertension might arise de novo in persons with normal kidneys, it was his pupil Frederick Akhbar Mahomed (1849–1884) who put forward the idea that high blood pressure itself could damage kidneys and bloood vessels. He described the natural history of essential hypertension as “chronic Bright’s disease without albuminuria” setting it apart from renal disease with secondary hypertension. His untimely death at age 35 from typhoid fever accounts for his contributions being forgotten for so long (JS Cameron, Nephrol Dial Transpl 10:1244).

William Gull (1816–1890), one of the most prominent London physicians of his time, described arteriolar thickening, narrowing, and hyaline formation in patients with chronic renal disease. He called these changes “arterio-capillary fibrosis,” found them in organs throughout the body, and believed they were the cause rather than the consequence of kidney disease (Nephrol Dial Transpl 14:1327).

The thirteen year old girl described by Dr. Davies Colley in 1883 probably represents the first ever description of renal rickets or osteodystrophy. The girl had lived mostly indoors in a dark low kitchen and was noticed to be pale and undersized, walking with a peculiar gait and manifesting florid signs of rickets. She was admitted repeatedly to Guy’s Hospital because of pathological fractures and at autopsy had dilated ureters and chronic obstructive suppurative pyelonephritis (Am J Nephrol 13:293).

Friedrich von Frerichs (1819–1885), one of the most distinguished German physicians of his time, performed microscopic studies on kidneys from patients with Bright’s disease and wrote the first German textbook of nephrology. He made many important observations, including descriptions of uremia that are quite modern, and took the position that Bright’s disease was a single disease that passed through three stages, hyperemia, exudation, and fibrosis or atrophy (Am J Nephrol 22:596).

Many of the important advances in nephrology at the turn of the last century were made in Berlin. They include the discovery of the cystoscope (1877), one of the earliest attempts at transplantating a kidney from monkey to man (1910), the development of retrograde pyelography (1905), and the use of iodinate dyes for intravenous urography (1923) (Am J Nephrol 12:442).

Also in Berlin, H. Strauss opened up the field of clinical chemistry by inventing the venesection needle (1898-1902). Before that time “blood was obtained by either cutting a superficial vein or making multiple small incisions at the site of cupping.” Subsequently Strauss (and also Widal in Paris) revolutionized prevailing views on renal disease by showing that edema was due to the retention of sodium chloride and not of urea (Kidney Int 43:1385).

“In the cure of nephritis our chief reliance is to be placed on blood-letting, both general and local, assisted by fomentations, the use of a warm bath, and emollient clysters … The patient is to be directed to drink plentifully of mild diluents, such as barley-water, thin gruel, whey, linseed, or marshmallow tea. In nephritis the application of blisters would be improper. They are apt to affect the urinary organs and vessels, and to occasion much irritation, and would consequently increase the inflammation” (Robert Thomas, The Practice of Physic, 1821, p. 194–5).

Pierre Rayer (1793–1867) on chronic Bright’s disease: “When one examines under the microscope the blood of dropsical individuals suffering for a long time from chronic albuminuric nephritis, the red blood cells appear less numerous than in healthy blood” (Nephrol Dial Transpl 14[Suppl 2]:10).

“Both kidneys were invested by a cellular membrane of an inch thick, and infiltrated with a brown turbid fluid; their tissue was pale-red an opened up. Every one of the calyces was occupied by a calcareous concretion of a wart-like shape and as large as a split pea.” (Autopsy protocol of Ludwig van Beethoven, 1827) (Am J Kidney Dis 21: 643).

“The autopsy description of Beethoven’s nephropathy … of symmetrical soft calyceal concretions, like a pea cut across the middle, is so typical of papillary necrosis concretions that the diagnosis is as near to certain as is possible, in the absence of a histological examination … It is proposed that the cause was an acute onset diabetes mellitus, complicating chronic pancreatitis,” wrote P.J. Davies from Melbourne, Australia (J Roy Soc Med 86:159). Beethoven, however, had in addition a complicated non-renal medical history, almost certainly dying of liver failure and probably also having gram negative septicemia. Additional diagnoses considered by medical historians include tuberculosis, sarcoidosis, lupus, ulcerative colitis, Paget’s disease, and otosclerosis (ibid 83:640 and 64:493).

Sir Walter Scott in his journal: “Within these last three days I have passed (you may alter the vowel A to the vowel I) a formidable quantity of blood. When a man makes blood instead of water, he is tempted to think of the possibility of his soon making earth” (quoted by Sir Douglas Black, BMJ, 1960,1:667).

Peter Mere Latham (1789–1875): “What exact relation diseases of the kidney bears to hypertrophy of the heart, we do not know even yet. But the two are too often coincident in the same subjects for them not to bear some, and that a very important, relation to each other.”

“In 1849, Dr. Bright was consulted by a physician of five-and forty who suffered from a pronounced and persistent albuminuria. Dr. Bright is said to have expressed the opinion that the patient could not live for more than two years. The physician thereupon abandoned his practice and betook himself to the country, where he lived comfortably for forty-three years, dying of cerebral hemorrhage in 1892 at the age of eighty-eight. The albuminuria persisted throughout his life” (Hawkins, 1892 – as quoted by R.M. Kark, Med Clin North Amer 44:49).

“Protein restriction for renal failure was suggested as early as 1869.” Reviewing its history and its waxing and waning popularity over the years, A.G. Wasserstein contrasts its current lukewarm acceptance with the enthusiastic use of coronary bypass grafting “long before its appropriate use was defined by controlled studies” (Ann Intern Med 119:84).

A patient presenting to a doctor 100 years ago with edema and albuminuria would have been treated with warm baths, fomentations or poultices, julap root enemas, and by tapping the fluid from his legs with a scarficator (multi-blade knife). He may have also received kidney nostrums containing alcohol, digitalis, lithium carbonate, podophyllin, methylene blue, and extract of buchu to induce a diuresis and sterilize the urine (Dial and Transpl 26:326).

“Those who have once suffered from an inflammation of the kidneys are very liable to it again; to prevent a recurrence of the attack, they should abstain from wine and stimulants, use moderate exercise; avoid exposure to wet and cold; eat of food light and easy of digestion; not lie too much on the back, and on a mattress in preference to a bed” (from Dr. Chase’s Recipes: Treatment of Diseases, p. 252).

“A six year old girl was given up to die by her family physician, who said she had Bright’s disease, which has never been known to be cured. He told the mother to give the girl anything she wanted and make her as comfortable as possible while she lived. As the girl cried constantly for beans, the mother cooked some quickly and gave them to her to eat. The girl went to sleep and from that time began to improve. She became mother of two children, and has not been troubled with the disease unless she takes a severe cold; and when that happens she at once uses her old remedy, and it is always effective” (from Dr. Chase’s Recipes: Treatment of Diseases, p. 154, c. 1870).

Notwithstanding the item above, a London physician reported in the Lancet that he had cured 16 out of 19 patients with 15 grains of powdered valerian four times a day and supporting diet. If not effective “it had better be tried, and may, with the beans, as above, cure more than without them” (Ibid.).

Sir William Osler wrote in his first edition of The Principles and Practice of Medicine (1892) that chronic Bright’s disease was “an incurable affliction, as beyond the reach of medicines as wrinkled skin or gray hair, but compatible with the enjoyment of life for many years.” He recommended a quiet life without mental worry, gentle but not excessive exercise, keeping the bowels regular, the skin active by a daily tepid bath, and the urinary secretion free by drinking daily a definite amount of either distilled water or some pleasant mineral water. Alcohol was strictly prohibited; and the diet was to be nourishing, but patients were to be warned not to eat excessively and not to take meat more than once a day. Patients in good circumstances were “to be urged to go away during the winter months, to move altogether to a warm equable climate, or to pay an annual visit to certain mineral springs.”

“Councilman has described an acute interstitial nephritis occurring chiefly in children after fevers, characterized by the presence of cells similar to those described by Unna as plasma cells. He thinks that these cells are formed in other organs, chiefly the spleen and bone marrow, and are carried to the kidneys in the blood-current” (Osler’s Principles and Practice of Medicine, 7^th edition, 1909).

Thomas Addis (1881–1949): “All we know for certain about the kidney is that it makes urine.” “When the patient dies the kidney may go to the pathologist, but while he lives the urine is ours. It can provide us day by day, month by month, and year by year with a serial story of the major events going on within the kidney. The examination of the urine is the most essential part of the physical examination of any patient with Bright’s disease.” “Any clinician who really wants to find out something about a patient with Bright’s disease must himself look at the urine. If he is content to derive his information from laboratory reports he is in the same position as a specialist on diseases of the chest who hires someone to give him a report on auscultation and percussion, or a cardiologist who asks someone to give him an account of the heart sounds of a patient.”

John P. Peters (1887–1955), professor of medicine at Yale, was a “compleat physician” who made many contributions to nephrology. He introduced the flame photometer into clinical medicine, popularized balance studies, formulated the concept of effective plasma volume, enhanced our understanding of edema, renal failure, acid base and electrolyte disturbances, and toxemias of pregnancy. He showed that “the kidneys react to change in the volume of the circulating blood, but are largely indifferent to changes in the volume of body fluids at large…” He objected to bladder catheterization for the convenience of the staff, and recognized the futility of trying to reverse the early catabolic reaction of the acutely ill patient by giving artificially high intakes of protein (Am J Kidney Dis 37:1113; Amer J Nephrol 22:1192).

Josep Trueta, Spanish military surgeon, carried out between 1936 and 1939 experiments to discover the reason for the post-traumatic oliguria seen in combat casualties. He induced ischemic myopathy by applying tourniquets to the legs of rabbits and used angiography to demonstrate renal cortical vasoconstriction and ischemia, the first documentation of acute vasomotor nephropathy (Am J Med 19:343).

Dr. Louis Tobian, an outstanding clinician and investigator, was one of the first to recognize the role of sodium and of the juxtaglomerular apparatus in hypertension, and of high potassium diets in protecting against stroke. He also showed that diuretics reduced blood pressure at least in part by leaching sodium and water from blood vessels and making them less sensitive to sympathetic stimuli (J Clin Hyperten 8:690).

Several heads of state in history are recorded to have suffered from kidney disease. Oliver Cromwell is believed to have had pyonephrosis secondary to calculous urinary tract obstruction, with septicemia and renal insufficiency. Napoleon III died in exile in London from uremia due to calculous disease and obstructive uropathy. His more illustrious uncle, Napoleon I, also had kidney stones. President Chester Arthur died from kidney failure (1886), and two recent heads of state, Ferdinand Marcos and Yuri Andropov, developed uremia and underwent dialysis for some time.

Dr. Irving Page, who died in his 90^th year in 1991, is remembered for his many contributions to our understanding of hypertension. He played an important role in the discovery and characterization of angiotensin and serotonin, in the description of neurogenic hypertension and baroreptor resetting, and in formulating the mosaic theory of hypertension. Clinicians know him best for his description of hypertension induced by external compression of the kidney, the Page kidney (Hypertension 34:1177).

Jan Brod (1912–1985), eminent clinician, teacher, and scientist, is remembered as one of the founders of academic nephrology in the years following World War II. Born in Moravia (later Czechoslovakia and more recently the Czech Republic), he published some 200 articles and two major textbooks on kidney disease while working first in Prague and later in Germany. He was one of the first to use the creatinine clearance, and also worked on interstitial nephritis and its causes, on water and sodium metabolism and edema, and on the hemodynamic response in renal disease and hypertension (Nephrol Dial Transpl 19:1374).

Priscilla Kincaid-Smith made numerous contributions to our understanding of malignant hypertension, chronic pyelonephritis, analgesic nephropathy, glomerulonephritis, hypertension, reflux nephropathy, and renal transplantation (Kidney Int 44, Suppl 42:71).

Claus Brun: “Because liver biopsy was a standard procedure in the department … it was no big mental jump to attempt the same technique on the kidney … Our first biopsy – on May 19, 1949 – was made with the patient in the sitting position and without any serious attempt to localize the kidney by x-ray. We had the very good luck of obtaining a few millimeters of renal tissue, and Iverson and I carried it proudly to the local pathology department where our enthusiasm was not shared – key hole pathology was not their cup of tea” (quoted in J Amer Soc Nephrol 8:1778).

Frederic C. Bartter et al.: “Hyperplasia and hypertrophy of the juxtaglomerular apparatus, and primary aldosteronism with hypokalemic alkalosis were found associated with normal blood pressure in two patients. This coexistence of a histologic lesion not previously described with a rare disease entity suggests an association between them; the appearance of these disorders in two patients who have never had hypertension appears to represent a new syndrome” (Amer J Med 33:811).

In the 18th century physicians were puzzled that patients with bilateral atrophy of the kidneys could still excrete large quantities of urine. The initial steps toward understanding the phenomenon of osmotic diuresis were experiments showing that bilateral nephrectomy increased the blood urea, and later that injecting urea into a Basset hound induced polyuria (Kidney Int 45:1241).

Several 19th century physicians, including Richard Bright, had commented on the frequent association between glomerular disease and alcoholism. Two reviews of patients with postinfectious glomerulonephritis, one in Germany and the other in France, likewise revealed that about half of such patients were alcoholics and that many had cirrhosis of the liver. Alcoholism, known to impair the immune response in a variety of ways, appears to affect the prognosis unfavorably in these patients (Quart J Med 87;97 and Abstract ASN 94P in JASN 5:356).

Trench nephritis was the name given to the epidemic illness that swept through Western Europe during World War One and affected 35,000 British and 2000 American soldiers. Presenting with dyspnea, edema, headache, sore throat, albuminuria, it caused over 500 deaths. Many causes were considered – including streptococcal infection – but as stated in the official war record “The ultimate cause of war nephritis has not been discovered” (Kidney Int 70:635).

Heymann nephritis was first induced in 1959 by immunizing rats with antigens derived from proximal tubule brush border. In this model circulating antibodies bind to an antigenic complex located at the base of the glomerular epithelial foot processes. This complex consists of two proteins, the glycoprotein megalin and a smaller receptor associated protein or RAP (M.G. Farquhar et al., JASN 6:35 and 61).

Henry A. Christian: “It is not possible to diagnose accurately during life the anatomical changes that will be found in the kidney after death” (Bright’s Disease, Oxford University Press, New York 1948).

“At the age of 54 in 1935 President Franklin D Roosevelt had a blood pressure of 136/78. It was 162/98 in 1937 and 188/105 by 1941, rising to 226/118 shortly before the invasion of Normandy and to 260/150 before the Yalta conference in February 1945. It was 300/190 fifteen minutes after he had his cerebral hemorrhage. There is no doubt that FDR had quite severe and extensive arteriosclerosis, and it is likely superimposed hypertension, accelerated his death” (NEJM 332:1038).

The principles of dialysis were first enunciated by “Thomas Graham, a Scotsman, who took two Greek words, ‘dia’ meaning through and ‘lyien’ to loose. He used these to describe the separation of crystalloids and colloids in solution by unequal diffusion through membranes. Thomas Graham used a thin parchment to demonstrate the difference in diffusion rates between crystalloids represented by salt and colloids represented by protein” (George E. Schreiner, ASAIO Journal 39:828).

In 1913, Abel, Rowntree, and Turner built “the first extracorporeal device that permitted the diffusion of substances from the blood.” Working at Johns Hopkins University they treated salicylate intoxicated dogs using a membrane made from collodion and hirudin extracted from leeches as the anticoagulant (ASAIO Journal 45:238; Contemp Dialysis & Nephrology 20:9).

The credit for performing the first ever hemodialysis in man belongs to George Haas (1886–1971) of Giessen, Germany. In 1923, he extracted and purified hirudin from leeches for anticoagulation and used collodion membranes which he synthesized, prepared, and sterilized himself for this purpose. Although “he clearly put hemodialysis on the map as a clinical procedure,” he eventually abandoned work on dialysis because of technical difficulties and “lack of recognition of his breakthrough by the medical community” (Dial Nephrol Transpl 9;1829).

Willem J Kolff: “One of my first patients was a young man suffering from chronic nephritis and slowly dying of renal failure. He was hypertensive, became blind, and was vomiting every day. His old mother was the wife of a poor farmer, her back bent by hard work, dressed in her traditional Sunday black dress, but with a very pretty white lace cap. I had to tell her that her only son was going to die, and I felt very helpless. Gradually the idea grew in me that if I could only remove 20 g of urea and other retention products per day we might relieve this man’s nausea, and that if we did this from day to day life might still be possible. This was in 1938…” (Ann Intern Med 62:608).

In 1959 Richard Ruben in San Francisco first used peritoneal dialysis successfully for a patient with chronic renal failure who survived for six months. Two years later, in Seattle, Fred Boen developed an automatic cycling machine, and by 1964 reported having maintained one patient for two years and another for eleven months (Am J Kidney Dis 49:482).

During his many years at the University of Washington in Seattle, Dr. Belding Scribner (1921–2003) made many contributions to the treatment of uremia, notably the external (Quinton-Scribner) shunt that made long term hemodialysis possible. He pioneered outpatient and home dialysis, intermittent peritoneal dialysis, the Tenkhoff catheter, the use of acetate in the dialysate, as well as many technological advances and new approaches to treating anemia, bone disease, and assessing dialysis adequacy. He will be remembered as one of the great figures of nephrology (Kidney Int 64:1155; Nephrol Dial Transpl 119:507,509; Hemodialysis Int 8:4,6).

Belding H Scribner, 1960: “The development of a technique for permanent indwelling teflon cannulatation of radial artery and forearm vein has made it possible to perform an unlimited number of dialyses on patients with chronic renal failure. The technique … essentially … consisted of placement of indwelling teflon canulae in the radial artery and vein. When not in use for dialysis, a small arterio-venous teflon bypass shunts blood from artery to vein. The patients have become ambulatory … Each dialysis has lasted for approximately 24 to 60 hours. The interval between dialysis varied from 4 to 21 days.”

“After the first use of the subclavian route for hemodialysis by Shaldon in 1961, this technique was adapted by Josef Erben from the former Czechoslovakia, using the infraclavicular route (1969). During the following two decades the subclavian approach was the preferred route for temporary vascular access by central venous catheterization. Today, time has come to abandon subclavian cannulas in patients with chronic renal disease, since phlebographic studies revealed a 50% stenosis or occlusion rate at the site of cannulation. This predisposes to edema of the arm, especially after creation of an arteriovenous fistula (Nephrol Dial Transpl 20:2629).

M.J. Brescia, J.E. Cimino et al.: “We have successfully used a combination of a surgically created fistula between radial artery and vein and venipuncture using 14-gauge, thin-walled needles for over 800 dialyses in 13 patients. We believe that this technic provides a dependable method for repeated access to vessels for hemodialysis and largely removed the clinical and psychologic problems associated with external Silastic-Teflon shunts” (N Engl J Med, 1966, 275:1089).