History Of Anaemia

Renal anaemia is not new. In 1836, Richard Bright stated ‘after a time, the healthy colour of the countenance fades’ eluding to­the anaemia­of chronic renal­failure

But the first significant description of renal anaemia was made by Sir Robert Christison, in Edinburgh, in his 1839 book 'On granular degeneration of the kidnies [sic] and its connexion [sic] with dropsy, inflammations and other diseases': ‘thus then, in the advanced stage of granular disorganization the proportion of haematosin in the blood is invariably and greatly reduced ... I am acquainted with no natural disease, at least of a chronic nature, which so closely approaches haemorrhage in its power of impoverishing the red particles of the blood’

In 1878, Paul Bert and Denis Jourdanet proposed that the symptoms of anaemia and mountain sickness resulted from hypoxia.­In 1890, Viault noted a 60% increase in red blood cell numbers after a brief expedition at 13,000 feet elevation

In 1906, Paul Carnot and C Deflandre, two scientists at the University of Paris, took the understanding of haemoglobin one step further. By injecting the serum of bleeding rabbits into otherwise healthy animals, they were able to demonstrate an increase in the red cell concentrations of the transfused animals. Thus they described the existence of a hormone responsible for erythropoiesis: “We have observed, with Mlle. Deflandre, that regeneration of blood after bloodletting is under the influence of a humoral process (a process controlled by a substance in the blood) …we give this substance the generic name Hemopoietin.”

In 1948, Eva Bonsdorff E and Eeva Jalavisto, in Finland,­gave this humoral factor that stimulates red cell production (previously called ‘hemopoietine’), the name ‘Erythropoietin’.­

Reissmann, in 1950, reported when one partner in parabiotic rat experiments was exposed to hypoxia, while the other breathed normal air, that an increase in erythroid cells occurred in the bone marrows and an increase in hemoglobin and reticulocytes in peripheral blood of both partners – providing strong support for a humoral factor being produced by the hypoxic partner which passed over through the parabiotic circulation to stimulate erythropoiesis in the partner breathing normal air

Allan Erslev, in 1953, confirmed an erythropoietic-stimulating activity in the plasma of anaemic rabbits, which he theorised would be of potential therapeutic value if isolated. In 1955, Plzak­ developed the first quantitative and specific assay for EPO when they demonstrated stimulation of radioactive iron incorporation in red cells following injection of plasma from anemic rats into normal rats.

But it was not until 1957 that the kidneys were identified as the major site of EPO production in the adult mammal by Leon Jacobson and Eugene Goldblasser (Jacobson and Goldwasser, 1957); they found that bilateral nephrectomy in rats prevented the rise in erythropoietin in plasma after a bleeding stimulus

The first purification of EPO was from plasma of anaemic sheep in 1971 (Goldwasser and Kung, 1971). Despite an extensive procedure, the yield and specific activity of the product were extremely low (0·4% and 8250 U/mg protein respectively). In 1977, the same procedure was used with 2550 litres of urine from anaemic humans, generating a product with a specific activity of 74 000 U/mg protein (Miyake, 1977)

 Eugene Goldwasser (Chicago, USA)‚Äč

But it was not until the mid 80s, that progress re the large scale production of erythropoietin (EPO) was made. The human erythropoietin gene was isolated by Fu-Kuen Lin (Chicago) and Kenneth Jacobs (Boston) in 1985. Soon afterwards,­in 1985, in Seattle, Eshbach gave the first treatment to a dialysis patient, initially with 2.5 units/kg on dialysis - with no response. With an increased dose of 15 units/kg was used, there was a good response.

Recombinant human erythropoietin (rHuEPO) therapy was introduced in 1986-7 (Winearls, 1986; Eschbach, 1987). In 1989, the US FDA approved recombinant EPO for use in chronic renal failure patients on dialysis. Then, a year later, the FDA approved recombinant EPO for use in chronic renal failure without dialysis and other non renal causes

In 1988, Koury­reported the localisation of EPOmRNA in interstitial cells in the mouse kidney. In the same year Lacombe found EPOmRNA in peritubular cells in the mouse kidney

This article­by Bradley Benker in 2004­is a good summary of the history, development and use­of erythropoietin. Stewart Cameron, in 1999, and Fisher, in 2009, also summarised the history of renal anaemia and EPO respectively. Cameron has also emphasised (in 2007) the work of Sir Robert Christison (1797–1882) in Edinburgh