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Nephrology

The history of renal disease is dominated by the fundamental contribution of Richard Bright (1789-1858). However, while he is often referred to as the ‘father of nephrology’ for establishing the concept of diseases of the kidney, he was not the first to make contributions in this field. Twenty years before Bright’s notable observations, American-born physician Charles Wells (1757-1817) came to London and St Thomas’ Hospital from North Carolina, having been a loyalist during the war of independence. His work on proteinuria in patients with dropsy and scarlet fever from 1805 to 1810 laid the foundations for Bright who wove together clinical observations, chemistry and pathology not only to begin the definition of renal diseases but also to lead the way to modern clinical thinking and methodology.

A succession of Guy’s physicians made further contributions to study of the diseases, notably Frederic Akbar Mahomed (1849-1884) in renal and especially essential hypertension and Sir William Gull (1816-1890) who developed crucial ideas in vascular pathology and hypertension.

At King’s College Hospital, Sir George Johnson (1818-1896) wrote prolifically on renal disease and hypertension, and Sir Nestor Tirard (1853-1928) was one of the earliest experts on renal disease in childhood. In the early years of the twentieth century Ernest Starling (1866-1927) developed his ideas of capillary filtration and exchange, so important in renal function and oedema formation, before leaving Guy’s for University College London.


c3

Two modern histological preparations from an original specimen of one of Richard Bright’s patients, who presented with oedema and proteinuria. Below is a PAS stain showing the features of mesangiocapillary/membranoproliferative glomerulonephritis (x280), and above the immunohistology shows deposition of the complement component C3 (x360).

PASstain

As the techniques of renal biopsy and dialysis developed and the need to treat chronic renal failure became apparent, renal units were formed at Guy’s in the 1960s by Stewart Cameron (b 1934), at King’s College Hospital by Victor Parsons (1929-1995) and at St Thomas’ by Norman Jones (b 1931). A unique opportunity arose at Guy’s as a children’s renal unit had been set up by Richard White (b 1930). This allowed Cameron, and Cyril Chantler (b 1939), White’s successor in 1973, and their colleagues to work at the interface of adult and paediatric nephrology, as well as in their own fields. Cameron’s leadership and scholarship forged a renal unit with an international reputation for linking bedside observations with laboratory work and practice, and for its studies on the immunology, immunopathology and natural history of glomerulonephritis and the development of transplantation. The paediatric renal unit became the largest centre in the UK for children with renal failure and made contributions to preventing growth failure and long-term renal bone disease.

The unit at St Thomas’, as well as developing dialysis and transplantation, played a unique role in the development of the European Registry of Dialysis and Transplantation, through the work of Anthony Wing (b 1933), which provided a matchless source of information on the practice and outcomes of renal replacement. At King’s College Hospital, Victor Parsons pioneered the treatment of endstage renal failure in diabetics at a time when other units were not treating these patients.

For most patients with endstage kidney failure a transplant is the best treatment and in the UK approximately 2,000 are performed annually. Chronic rejection is an important problem, not yet solved, which accounts for the loss of 5-10 per cent of grafts yearly. Research at King’s has shown that complement, representing the innate immune system, plays a major role in transplant rejection. The stimulation of the host’s T-cell response by antigen-presenting cells on the donor kidney is strongly dependent on complement; complement inhibition reduces immune stimulation of the host, with obvious therapeutic implications. Complement has also been shown to contribute to reperfusion damage, which occurs when the newly transplanted kidney receives its blood supply from the host.

Although the range and safe use of immunosuppressive drugs has improved, tailoring immunosuppression to an individual patient still remains a goal. The polymorphism of the genes controlling transport and metabolism of drugs and their effect on drug toxicity is being studied with this aim in view.

Ecoli

Scanning electron microscope picture of E. coli attaching to epithelial surface. E. coli are the commonest organism causing urinary tract infections, and the initial stage in their invasion of the body is to attach to epithelial cells and then enter them. Interfering with this process offers a new line of treatment.


Urinary tract infection is very common, especially in women. However, its pathogenesis has been somewhat neglected in research. E. coli, the commonest organism causing urinary tract infection, invades the urinary tract through its lining epithelial cells. This stage of the infection is complement dependent and the receptor on the epithelial cells which internalizes the bacteria has been identified as the measles receptor (CD55), two findings which could lead to ways to reduce the frequency and severity of infection.


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Hepatology

The history of liver disease begins at King’s with the work of George Budd (1808-1882). In 1840 he was appointed Professor of Medicine at King’s College London, and made a special study of liver diseases producing one of the earliest books on the topic. His name is perpetuated in the Budd-Chiari syndrome, a disease of progressive liver failure caused by obstruction to the hepatic vein which he described in 1845.

HughDeWardener

Hugh De Wardener
Described as the single most influential nephrologist in the UK in the second half of the last century, Hugh De Wardener (b 1916) is internationally known for his work on salt and its relation to blood pressure, and natriuretic hormones. He qualified from St Thomas’ in 1939 and, after distinguished service in the Royal Army Medical Corps in World War 2, returned there to a lecturer’s post, when his research work on sodium began. It was during this time that he wrote his famous monograph The Kidney which over its several editions influenced many young physicians towards nephrology.


In 1966, Roger Williams (b 1931) established the Liver Unit at King’s College Hospital and Medical School. Two years later the MRC set up within it a ‘Group for Studies into the Metabolism and Haemodynamics of Liver Disease’ and in the same year a collaboration began with Professor Sir Roy Calne in Cambridge to perform the first liver transplants in the UK.

In the early 1970s the first specialist liver intensive care ward for adults in the world was opened at King’s. Over the ensuing twenty-four years and consequent on the strong laboratory base that was set up by Williams (in what became recognised by King’s College London as the Institute of Liver Studies), and with an increasing referral practice, many original contributions were published on the management and outcome of liver failure and liver transplantation as well as on the pathogenesis and treatment of autoimmune liver disease, viral hepatitis and the causes of chronic liver disease.

The appointment of Alex Mowat (1935-1995) in the Department of Child Health enabled a strong and productive link to be established with the Institute of Liver Studies in developing the paediatric liver disease service. Mowat was the first professor of paediatric hepatology in the UK. He made particular contributions to autoimmune liver diseases in children, and with his surgical colleague Edward (Ted) Howard established paediatric liver transplantion.

Today the Department of Liver Studies & Transplantation includes the adult and paediatric liver services and has the largest liver transplant programme in Europe with 2,500 transplants performed since 1990. Several new surgical techniques have been pioneered, such as reduced liver, split-liver and living-related transplantation which effectively increase the supply of donated organs. As an example, one donor liver can provide three grafts – right lobe for an adult, left lateral segment for a child and the remaining tissue for harvesting cells for transplantation. The last is a different approach to transplantation which is being explored at King’s. Using isolated human liver cells (hepatocytes) has several advantages: it reduces reliance on donor organ availability, it can buy time to allow the damaged organ to recover or until a donor organ is available, and it avoids major surgery.

The first requirements for hepatocyte transplantation are for effective isolation of hepatocytes from donor or fetal liver and then preservation. Research has resulted in high yields and viability of 90 per cent being achieved. The second requirement is that the hepatocytes, when infused into the liver, should remain and repopulate the liver, ie succesful engraftment. Methods being investigated to promote this include the application of growth factors and ex vivo gene therapy to induce growth factor production in the hepatocytes themselves.

The first successful human liver transplants in the world using cryopreserved hepatocytes have been performed at King’s College Hospital. The patients were children with various metabolic disorders: the bleeding disorder congenital Factor VII deficiency; ornithine transcarbamylase deficiency, diagnosed antenatally, and usually fatal within weeks; progressive familial intrahepatic cholestasis, which causes severe jaundice. These initial results pave the way for an alternative treatment to transplanting part or whole of the liver. If it becomes widely available it will solve two major problems for patients needing an urgent liver transplant, which are the lack of a hepatic equivalent to dialysis in renal failure and the difficulty with donor organ availability.


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A world first cell transplantation

Cell Transplantation childThe case of Billy (left) shows how liver cell (hepatocyte) transplantation can be life-saving and also buy time for a whole-organ transplant. He was born with severe deficiency of the enzyme ornithine transcarbamylase. This is a rare disease in which toxic levels of ammonia accumulate, as protein is not normally metabolized. Death usually occurs in two weeks. During the first two weeks of life, Billy was given a total of 1.8 billion hepatocytes in several infusions via the umbilical vein, the first frozen hepatocyte transplant in the world. A further 200 million cells were infused directly into the liver at five months. He was able to eat a normal protein diet and maintain normal blood ammonia levels. An auxiliary whole organ transplant was performed at seven months and at 18 months (pictured) progress was satisfactory and he continues to be well.


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