#NephMadness 2017: History of Nephrology Region

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Selection Committee Member for the History Region:

Neil Turner, MD, PhD

Dr. Turner is Professor of Nephrology at the University of Edinburgh in Scotland. His research background in autoimmunity and basement membrane proteins led to clinical interests in anti-GBM disease, Alport Syndrome, proteinuria, and genetic diseases. Dr. Turner has had a long interest in information provision for patients and staff. He is Editor-in-Chief of the Oxford Textbook of Clinical NephrologyAttempting to celebrate rather than repeat the mistakes of history, he started the historyofnephrology blog in 2009. Follow him @neilturn.

Competitors for the History Region

History of the Dipstick U/A vs History of the Kidney Biopsy
History of Hemodialysis vs History of Kidney Transplant

History of the Dipstick U/A vs History of the Kidney Biopsy

Proteinuria was pinned on the kidneys by Richard Bright 190 years ago, and testing for it became a major medical activity almost straight away. It still is! Kidney biopsies on the other hand are only 60 years old; but the development of immunofluorescence and electron microscopy in the 1960s led to a blossoming of disease descriptions and understanding – and occasionally – treatments. So which was more important to nephrology and the world? The public health impact of the simple dipstick, making it easy for everybody to be screened for CKD (and cardiovascular) risk? Or kidney biopsies, without which is difficult to imagine modern nephrology beyond dialysis? History of the Kidney Biopsy versus the History of the Urine Dipstick sees two of the nephrologist’s greatest tools battle it out for a spot in the Saturated Sixteen.

History of the Dipstick U/A

Sometimes the most important and simplest tools are the ones that we don’t even notice. They are so taken for granted that they disappear. But without these tools and techniques the diagnosis and management of kidney disease would break down. The full-court press is the simplest defense imaginable. The technique is easy to understand, “Do not give up one foot of floor space that the offense needs to travel. Fight for every foot.” It is a desperation gambit that underdogs use to disrupt better teams. It is a David move when you are up against Goliath.

Examination of the urine has long been a key tool for physicians to diagnose illness with Hippocrates first observing changes in the odor and color of urine in the presence of fever. He noted that bubbles on the urine surface indicated kidney disease and a poor prognosis (400 BC). In the late 1700s it was noted that in some patients with dropsy (severe generalized edema), heating the urine caused it to coagulate. The discovery and the significance of proteinuria was coming closer. Richard Bright, working at Guy’s Hospital in London, was key in linking kidney disease with dropsy, proteinuria, and nephrotic syndrome, in his ‘Reports of Medical Cases’ (1827):

‘We have, therefore (in dropsy), an example of the blood exhibiting a very great deficiency of albumin at the same time that we observe the mode in which it passes off from the system by means of the kidney’.

Bright’s clinical and pathological observations renewed interest in the examination of urine. Measuring proteinuria, often with assessment for urinary casts, became a routine part of clinical assessment and was recognised very early on as being associated with increased cardiovascular death, such as this report in 1912 of almost 400 otherwise healthy men from New York. Renal disease, and later specifically glomerulonephritides, would bear Bright’s name for the next century.  

Until the 1950s the standard test for proteinuria involved precipitation of protein by acidification or heating the urine. This meant that physicians would carry a spirit lamp, or jars of acid when they rode to see their patients. Attempts to develop dry chemistry that could detect urinary compounds were badly needed. Early attempts included:

  • Sheep’s wool impregnated with stannous chloride. After applying urine and heating with a candle, the wool would turn black in the presence of glucosuria (Jules Maumené, Parisian chemist-1850).
  • In 1883 English physician George Oliver described filter paper (or cloth) tests for glucose and protein.
  • London physician William Pavy developed tablets (‘Pavy’s pellets’) which could be dropped into a tube of urine to test for glucose (copper based) or protein (citrate-ferricyanide).

Fritz Feigl (1891-1971) was a Jewish chemist from Vienna who had served with distinction in World War I. He based his method on the interaction of proteins with hydrogen ions using the dye tetrabromophenol blue in designing his spot test (still used in dipsticks). Protein inhibited the effect of acid on the colour of the compound, so in an acid buffer its color changes from yellow to blue as protein concentration increases. A year after his publication in 1937, Anschluss occurred (the Nazi annexation of Austria) which curtailed his work and buried his report for many years. Despite his war record, he was forced to flee from the Nazi regime. He was temporarily imprisoned in a camp in Vichy France but managed to escape to Andorra, then to Portugal before relocating to Brazil.  A great account of the roles played by Feigl and Oliver can be found here.

The modern commercialization of these inventions can be attributed to the husband-wife team of Helen Murray and Alfred Free working in the Miles (later Bayer) laboratories in Indiana in the 1950s. The company had modified ‘Pavy’s pellets’ into Clinitest, a tablet test for glucosuria, and then Albutest for albuminuria, employing Feigl’s tetrabromophenol blue method. They quickly moved to using colorimetric paper sticks (or ‘stix’, which caught on commercially) to detect glucose (Dextrostix) using glucose oxidase. Testing for albumin (Albustix) soon followed in 1957, using ‘(T)hick bibulous filter papers…impregnated with a solution containing tetrabromophenol blue’. Over the following 20 years the group devised methods for detecting ketones, hemoglobin, bilirubin, urobilinogen, nitrite, leukocytes and pH to make multi-analyte dipsticks.  

Early physicians recognised the importance of testing the urine, particularly for protein. Modern clinicians still use their methods at the bedside and the office today, although most do not know who the innovators were who developed these crucial assays we take for granted. The history of the urine dipstick is the history of nephrology.

History of the Kidney Biopsy

The kidney biopsy requires patients to be stabbed with a needle. In basketball there is the dagger. First used to describe “The Shot” by Michael Jordan to eliminate the Cleveland Cavaliers in 1989. Since then the Dagger has evolved to refer to a three-point shot that seals a lead and demoralizes an opponent. See: Steph Curry.

Early nephrologists could recognise clinical entities such as acute nephritis, nephrotic syndrome, and chronic uremia but knew nothing of the pathological correlates of these syndromes. Visualizing renal tissue at autopsy was as close as they came to understanding the structural detail of kidney diseases. In the mid-1800s a number of developments occurred, such as technical improvements in the quality of microscope lenses, the ability to cut thin sections of tissue  and embed them in paraffin. This enabled descriptions of pathological post-mortem specimens to be described and illustrated and laid the foundations for doing the same for biopsies from living patients.

The first kidney biopsies were performed in patients with Bright’s disease, during laparotomy usually for renal decapsulation, which was thought to relieve pressure on the swollen organs. An entertaining account by Reginald Harrison in 1896 of some of the first open kidney biopsies can be found here. Harrison considered the biopsies to have therapeutic application by removing ‘tension’ in acute nephritis. Complications were not expanded upon although one 18-year-old with scarlet fever had ‘full discharge of blood and urine from the wound for some days’ after his biopsy. Castleman and Smithwick performed over 100 kidney biopsies taken during sympathectomy operations for severe hypertension. Their report in JAMA in 1943 unsurprisingly demonstrated mostly renal arteriolar disease.

Performing percutaneous biopsies was the next goal, and the liver, being large and accessible, was the organ where this was first developed. An aspiration technique, using a cutting needle with a syringe on the end, was used. Soon, brave clinicians began biopsying that smaller, more vascular and perpetually moving organ, the kidney. Nils Alwall, who was a key player in Team Dialysis with his early innovations with an artificial kidney, began to take aspiration biopsies in 1944. Sweden but didn’t publish his work until 1952. This is likely due to the fact that despite success with his first 13 patients, a fatal complication in one patient led to a drop in his enthusiasm for the procedure. Paul Iversen reported on a series of 133 biopsies in 1951 in Denmark, achieving a 50% success rate in obtaining useful tissue.

Robert Kark with his trusty microscope in 1964 Public archive of National Library of Medicine.

Enter Robert Kark, a native South African and keen rugby player, of Guy’s Hospital, London. He had been a fellow at Harvard and developed an interest in nutrition where he worked on fortifying bread with B vitamins and the discovery of vitamin K. In World War II, he used this expertise to help develop K-rations, joined the Royal Canadian Air Force, and foiled a sabotage plot against a plane to be used by Winston Churchill. Following the war, he moved to Rush-Presbyterian-St Luke’s Medical Center in Chicago where he became an expert in kidney diseases. He met Iversen at a conference in 1950 and they worked to improve the biopsy technique. Kark and Muehrcke adopted cutting needle (modified Vim Silverman needle) and used the modern prone position, instead of sitting, which appears to have coincided with a higher success rate and fewer complications. In the pre-ultrasound era, the procedure was performed ‘blind’, using anatomical landmarks to locate the kidney, with the oscillation of the needle with respiration indicating successful placement. The technique was rapidly adopted and soon large case series of hundreds of biopsies were being reported.

Complementary to the development of the biopsy technique was the evolution of renal histopathology as a specialty, a tale told by Weening and Jennette. Immunofluorescence and electron microscopy were first applied to kidney biopsies in 1955 and 1957, allowing increased understanding of the pathogenesis of glomerular disease in particular. It became apparent that immunoglobulins were often deposited in glomerulonephritis, and a myriad of descriptive diseases and classifications soon followed. In patients with nephrosis but ‘minimal change’ on low power light microscopy, electron microscopy revealed ‘distortion of the organization of the epithelial foot processes’. Early adopters of the electron microscope for renal pathology marvelled at the fenestrated endothelium, multi-layered glomerular basement membrane and the exquisite, interdigitating, podocyte foot processes. The CIBA Foundation Symposium on Renal Biopsy in London is often quoted as a landmark event in the development of renal histopathology. Pioneering renal pathologists from worldwide were in attendance, including Robert H. Heptinstall, who later published the first modern textbook of renal pathology, Pathology of the Kidney (1966).

The kidney biopsy technique evolved with ultrasound guidance becoming routine in the developed world and the incorporation of spring-loaded biopsy needles. The field of renal histopathology also continued to grow over the decades. Diseases continue to be re-classified in the modern era based on novel techniques and discoveries of relating to disease pathogenesis, built on the innovations of early nephrologists and pathologists. The renal biopsy has come a long way in the past century.

History of Hemodialysis versus History of Kidney Transplant

There are lots of classic rivalries in college basketball.

  • Indiana vs Purdue, the respective homes to Bob Knight, the worst temper in basketball and Gene Keady, the worst toupee in basketball.
  • Kentucky vs Louisville. A rivalry so intense that the state legislature mandates that the teams play each other every year.It is a rivalry so intense that dialysis patients came to blows over it:

A Kentucky fan hooked up to a dialysis machine got punched the other day by a Louisville fan who, waiting for treatment, declared that his Cardinals were going to whup ’em some ass Saturday. The Kentucky fan flipped off the guy. That’s when the discussion turned physical. Police in the mid-state city of Georgetown responded to the dialysis duel. Détente was achieved before handcuffs were necessary.

But those rivalries are all in the backseat while the parents of college basketball bicker in the front seat. We are talking, of course, about Duke vs UNC, the granddaddy of them all. This rivalry has hosted some of the biggest names in college basketball: Dean Smith, Coach Krzyzewski, Michael Jordan, Christian Laettner, James Worthy, Grant Hill, J.J. Redick, Tyler Hansbrough, Roy Williams, etc. The list goes on and on. All of these legends played in home stadiums just 15 miles apart on Tobacco Road. They have played each other 243 times (UNC leads the series 134-109) but have never met in March Madness. UNC and Duke are the Dialysis and Transplant of College Basketball.

The History of Maintenance Hemodialysis versus the History of Kidney Transplantation pits two bitter rivals against each other in the first round of the contest. Both teams have exciting backstories and have competed with each other for decades. Team Dialysis has a longer history but both teams made the big leagues in the 1960s when they became mainstream. Imagine it’s 1963 and you have ESKD. Nobody knows whether there was any long term hope for Scribner’s crazy initiative in Seattle, to use machines designed for acute renal failure to keep people alive longer. Many centres didn’t even have machines for acute renal failure; and it was expensive, with tiny numbers of patients taken on, and fewer surviving a year. Intermittent peritoneal dialysis, every few weeks or months, was a short-term holding option for some. But transplantation is not necessarily better – azathioprine was first used in 1962, and 50% graft survival beyond 1 year wasn’t reported till 1965, after probably hundreds of deaths. Ten-year graft survival passed 50% only 20 years later. Failures rarely returned to dialysis in the early days. At times these rivals have traded team members (see John P. Merrill below) and appeared to be complementary options, but don’t be fooled, there is no love lost between these two heavyweights of nephrology.

History of Hemodialysis

The term ‘dialysis’ was coined by Thomas Graham, Professor of Chemistry in Glasgow, in 1861 when he observed crystalloids diffusing through a semipermeable membrane (vegetable parchment coated with albumin). He used this method to extract urea from urine and others refined the process to create what they termed an ‘Artificial Kidney’ in 1913. John Jacob Abel, along with his colleagues at Johns Hopkins, Benjamin Turner, and Leonard Rowntree, employed nitrocellulose tubing to circulate blood from an animal through a saline-dextrose solution contained in a rotating drum. They used hirudin, obtained from leeches’ heads, as an anticoagulant. Although their technology was never used to treat a human, they saw the potential application for acute dialysis:

…this apparatus might be applied to human beings suffering from certain toxic states, especially if due to kidney damage, in the hope of tiding a patient over a dangerous chemical emergency.

The first human treatment occurred in Germany, where George Haas performed 15 minutes of complication-free dialysis on a terminally uremic patient in 1924. Willem Kolff refined the technology further and famously made the application of therapeutic dialysis practical. All the more remarkable is that this occurred in a small hospital in Kampen in the midst of the Nazi-occupied Netherlands during World War II. He had moved from Groningen to escape the attentions of Nazi sympathizers and developed his rudimentary rotating drum dialysis machine using cellulose (sausage skin) tubing that wound around a wooden slat drum, which dipped into the dialysate bath of at the bottom of its turn. Rotation of the drum powered the movement of blood, as there was no blood pump. Dialysate was made by adding known quantities of salts to tap water and ultrafiltration could be achieved by adding glucose to the bath, although this was unpredictable. He published his work in the seminal report ‘New Ways of Treating Uraemia’, with patient descriptions including the first survivor, patient 17.

Kolff moved to the USA in 1947 where pioneering nephrologist John P. Merrill and others modified his machine in Boston. The Kolff-Brigham machine was used to provide dialysis for acute renal failure in a small number of centers and during the Korean War (1950-1953). More innovations followed, with others improving on the technique. These included:

  • Nils Alwall developed a machine in Sweden with controllable ultrafiltration, by enclosing the artificial kidney inside a stainless steel canister. This allowed the removal of fluids by applying a negative pressure to the outside of the canister.
  • Blood clotting was a big problem with early hemodialysis techniques. Although Abel had used hirudin as an anticoagulant, it was only when hirudin and later heparin became more widely available that hemodialysis became practical.
  • Twin coil dialyzer with an inlet (arterial) and outlet (venous) bloodline allowed for disposable dialyzers (circa 1956). Kolff and Watschinger modified the concept based on the principles of the Alwall machine. 

Despite these improvements, in the early days of haemodialysis, it was considered a laborious, dangerous treatment and achieved no better results than strict conservative care. It was not considered a treatment for end-stage uremia until Quinton and Scribner, from the University of Washington, described an arterio-venous shunt in 1960. The AV fistula, created by Brescia & Cimino (1966), did not require exteriorised plastic and was a further advancement. Maintenance dialysis programs, which had started in Seattle in 1960, were now popping up in many centers.

In these early programs, it was generally young, fit, functional patients who were selected to receive hemodialysis. Criteria often stipulated an age limit (<50 years), emotional stability, absence of disabling comorbidity, and sometimes availability of a living donor. ‘Life and death’ committees were set up to decide who would be eligible for this new and expensive treatment, with John Darraghs account of being on the Seattle committee from 1962-1970 is required reading. Also well worth a watch is the inaugural episode of Tomorrow’s World on the BBC describing hemodialysis for end stage renal disease (ESRD) in 1965 (UK visitors only unfortunately).

Hemodialysis sessions were typically 12 hours in length but shortened to about 6 hours, twice weekly, when disposable dialyzers became available (approximately 1972 in Edinburgh). The management of ESRD was rapidly evolving in the 1960s from palliation to long term maintenance dialysis. Further changes would occur including refinement of vascular access, development of home hemodialysis and intermittent peritoneal dialysis and US Congress creating the Medicare ESRD Program. For further reading, see this remarkable interview with a remarkable patient. An English medical student who moved to Seattle for dialysis with Belding Scribner in 1963, becomes a dialysis technician and graduates in medicine. The nice review of the history of chronic hemodialysis from the Seattle perspective can also be found here.

History of Kidney Transplantation

Image courtesy of The Francis A. Countway Library Creative Commons License

You can have a kidney graft, ….. But they’re not successful.

Chronic hemodialysis patient commenting on what happens if you cannot get a place on an artificial kidney program (‘Tomorrow’s World’ inaugural episode on the BBC in 1965).

That kidney transplantation is the optimum treatment for ESKD is an often quoted opening sentence in many transplant manuscripts. It wasn’t always so.

Pioneering work in xenotransplantation had been performed by Emerich Ullmann in 1902 when he transplanted a kidney between 2 dogs which lasted for a number of days. Around this time, Alexis Carrel was working on methods of vascular anastomoses, with the end-to-side Carrel patch still bearing his name. A number of surgeons transplanted animal kidneys into humans with terminal uraemia. These included:

  • Jaboulay in France using pig kidneys (1906)
  • Unger in Berlin using en-bloc monkey kidneys (1909)
  • Harold Neuhof at Mount SInai Hospital using lambs’ kidneys (1923)

All of these attempts ended in catastrophe and understandably, enthusiasm for transplantation waned over the next couple of decades.

Russian surgeon Yuriy Voronoy performed the first human deceased donor kidney transplant in 1933. The ABO incompatible allograft was implanted into the recipients leg and the patient expired 2 days later. The first intra-abdominal kidney transplant for a patient with ESKD (polycystic kidney disease) occurred in Chicago on 17th June 1950. Richard Lawler performed his first and only kidney transplant on 44-year-old Ruth Tucker. The ABO-compatible allograft lasted 10 months but the patient lived a further 5 years, apparently with her small residual renal function. The first living donor kidney transplant was performed by Jean Hamburger at the Necker in Paris in 1952 but allograft failure occurred at 3 weeks. The first successful live donor transplant was famously performed by Joseph E. Murray with the assistance of John P. Merrill at the Brigham in 1954. Ronald Herrick donated one of his kidneys to Richard Herrick his identical twin who was suffering from chronic nephritis. Richard lived for 8 additional years.

The UK’s first successful transplant, also between monozygotic twins, was performed in Edinburgh by Michael Woodruff in 1960. Further reading about the first twins transplants, including proving monozygosity and predicting tolerance with skin grafting, can be found here. At this time in the early 1960s, hemodialysis despite its scarcity and technical problems, seemed a much more attractive option for patients with advanced uremia. But all that was about to change.

John Merrill explains the artificial kidney to the Herrick brothers, Richard (recipient) and Ronald (donor) on the far right. Wikipedia.

Peter Medawar and Frank Burnet won the 1960 Nobel Prize in Medicine for work that defined rejection, immune tolerance, and early attempts at immunosuppression. Whole-body irradiation was sporadically used and then unsurprisingly abandoned due to poor tolerability. Cyclophosphamide, thiopurine, and high-dose steroids were used before azathioprine and lower-dose steroids were found to show efficacy with a reasonable side effect profile. Learning to use these drugs was difficult, but by 1965 1-year allograft survival rates was over 60%, with living related grafts even higher. Thomas Starzl, who sadly passed away this week aged 90, performed the first liver transplant, adopted dual therapy of azathioprine and steroids and treated acute renal rejection with some success. Transplantation was still plagued by technical and immunological failures but given the ongoing scarcity of dialysis, it was slowly becoming a therapeutic option.

Further advances in the 1960’s included the development of anti-lymphocyte preparations and Paul Terasaki’s seminal experiments leading to tissue typing and cross-matching to predict and prevent rejection and prolong graft survival. Cyclosporin was adopted in the 1980s and led to a further impressive reduction in early rejection rates. Logistical and legislative changes throughout the world allowed for deceased donation and facilitated kidney transplantation becoming a mainstream therapeutic option for ESKD.

Please see RenalMed for an entertaining and detailed telling of the history of kidney transplantation.

– Post written and edited by Paul Phelan (@paulphel).

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