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Animals and Medicine

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Jack Howard Botting

II. Development of Life-saving Procedures

8. Development of Dialysis to Treat Loss of Kidney Function

Note de l’auteur

An earlier version of this chapter was published as: Development of dialysis to treat loss of kidney function. RDS News January 1995 8-11.

Texte intégral

1The kidney regulates the water, acid/alkali and ion balance of the body, and removes toxic products of metabolism and ingested poisons. It is thus not surprising that when the kidney fails to function properly the consequences are dire. Urine production falls and toxins build up in the plasma ultimately producing coma. Cardiac arrhythmias may be induced through build-up of potassium ions in the plasma. Death results if the condition is severe and untreated.

2Acute renal failure is a sudden decline in renal function as a result of poisoning or reduced cardiac output (due to severe haemorrhage, shock, septicaemia, myocardial infarction etc.). Chronic renal failure (CRF), due to pyelonephritis, glomerulonephritis, hypertension or diabetes, is characterised by a more gradual loss of function. The chronic disease can be controlled to some extent by a low sodium, low protein diet. But both for acute renal failure, and for the 5,000 patients per year in the UK that develop chronic renal failure, the life-saving technique of dialysis is essential.

Haemodialysis

3The crucial discovery in the development of dialysis techniques was that of Thomas Graham, who in 1854 showed that colloids and crystalloids could be separated in aqueous solution. Graham demonstrated the movement of urea and sodium chloride, but not colloids, through a semipermeable membrane (treated parchment, 1). Over the next 50 years, collodion became the most popular material for the formation of a semipermeable membrane and Richardson must receive credit for being the first to suggest that animal blood could be “dialysed” by passing it through a colloidal tube surrounded by saline (2).

4The first practical demonstration of the continuous dialysis of blood outside the body (i. e. in an “extracorporeal circuit”) was performed by Abel and his co-workers (3). They took blood from arteries of chloretone-anaesthetised dogs and rabbits and passed it through a series of celloidin tubes immersed in saline (celloidin was a brand of collodion). The blood was then returned to the animal via a cannulated vein. The animals made complete recoveries after being subjected to this “vividiffusion” for 2-3 hours.

5Abel did not actually develop the apparatus as a prototype machine for treating renal failure. His main interest was the measurement of the plasma concentration of physiologically active substances such as hormones. Detection of these in the plasma was difficult since they were often lost during precipitation of the plasma proteins, to which they could adhere. Abel thus hoped that this form of dialysis would extract active substances as fast as they entered the blood, without at the same time removing proteins and cells. Nevertheless Abel stated in his paper that the machine might act as an “artificial kidney” which might be used to tide over a dangerous crisis in one of the:

numerous toxic states in which the eliminating organs, more especially the kidneys, are incapable of removing from the body at an adequate rate, either the autochthonous or the foreign substances whose presence in excessive amount is detrimental to life processes.

6Abel prevented coagulation in the extracorporeal circulation by the use of the anticoagulant extracted from leeches, hirudin (Hirudin, at $27.50 per gram, appears to have been the 1913 equivalent of some of the contemporary, expensive recombinant-produced proteins. Abel therefore extracted hirudin for himself from leeches bought from cupping barbers at the rate of $6 per hundred).

Anticoagulants and Cellophane

7It was difficult to extract large quantities of hirudin for use in haemodialysis, and the early preparations were very impure and caused severe cardiovascularrespiratory side effects and allergic reactions. This meant that such preparations could only be used for animal studies. The absence of a suitable anticoagulant to prevent blood clotting in the extracorporeal circuits prevented the clinical use of haemodialysis. The despair and frustration experienced by military physicians during World War I, observing the inevitable death of troops from renal failure following severe traumatic damage, ensured the continued experimental investigation of the technique. More efficient dialysis membranes were prepared, and the design of dialysis machines was modified so that a smaller volume of blood was required to fill the extra corporeal circuit. A significant event was the commercial manufacture of long lengths of cellophane tubing. Although prepared originally as sausage casings, their potential as dialysis membranes in artificial kidney machines was soon recognised.

8The discovery of the anticoagulant that occurred naturally in mammals, heparin, was a turning point in the clinical use of dialysis. Heparin was isolated from dog liver by McLean in 1916, when he was actually trying to prepare clotting factors (4). Haas produced a batch of heparin in 1925 and showed that it performed well during dialysis in his animal studies (5). But as with hirudin, the early extracts of heparin were very impure and could not be used in patients. However, the relative abundance of heparin, large amounts of which could be extracted from beef liver and lung, meant that biochemists were free to experiment with purification techniques. In 1937 Murray (6), using purified extracts (250 units/mg) produced by Charles and Scott, showed that injection of heparin into dogs, rabbits, guinea pigs and mice rendered their blood incoagulable for long periods with no apparent ill effects. A sample of double the purity (500 units/mg) was then administered to patients with “no deleterious effects” (6).

  • 1 “One of my first patients was a young man suffering from chronic nephritis and slowly dying of rena (...)

9Heparin was thus used as the anticoagulant in the first successful treatment of a patient in acute renal failure by the Dutchman Willem Kolff in 1945.1 Although she was completely comatose when the treatment was initiated, the use of the artificial kidney designed by Kolff brought her out of the coma. Renal function improved and she survived. The life-saving potential of dialysis was realised (5).

10Heparin must still be prepared from animal sources, viz the lungs of oxen or the intestinal mucosa of oxen, sheep or pigs. Like many substances extracted from animal tissue, the safety of each batch must be ensured by testing samples on an anaesthetised animal to ensure the absence of substances that may lower blood pressure (7).

Alternative Anticoagulants

11Even in the presence of heparin, blood platelets can deposit on the dialysis membranes and thus cause a thrombocytopenia (fall in platelet levels) in the patient. Some low molecular weight fragments of heparin are anticoagulant and are said to produce less of a fall in platelet levels. Such compounds may be of use in dialysis in patients with a high bleeding risk.

12Epoprostenol (prostacyclin) is an endogenous prostanoid made by the innermost cells of the blood vessels. Its ability to prevent platelet aggregation in vivo was demonstrated in a number of species (8). Epoprostenol was shown to be capable of replacing heparin in dialysis in anaesthetised dogs (9). Subsequent tests in dialysis patients showed that with small amounts of epoprostenol, the dose of heparin could be reduced to avoid problems in high-bleeding-risk patients. Epoprostenol thus has a guaranteed place in the management of dialysis where haemorrhage may be a problem.

13Rather belatedly, highly purified samples of the first anticoagulant, hirudin, have now become available. Studies in dogs, rabbits and rats showed hirudin to be well-tolerated with low toxicity. The cardiovascular-respiratory effects seen in dogs with the partially purified hirudin were not seen with the highly purified preparations (10). Subsequent tests of the purified hirudin samples in healthy volunteers showed that they were also innocuous to humans (11). (It is of interest that the pharmacokinetic data, i. e. plasma half-life and urinary excretion of unchanged hirudin, were virtually the same in both animal and human studies).

14Since hirudin can now be produced in recombinant form, it is possible that it may, after 100 years, find a use in dialysis.

Peritoneal Dialysis

15Wegner, in 1877, was the first to conduct experiments into the effect of placing solutions of various concentrations into the peritoneal space (12). He noted that if a particular volume of a concentrated sugar solution was injected into the peritoneum of rabbits, a larger volume could be subsequently withdrawn.

16Changes in volume and osmotic pressure of fluids placed in the peritoneal space were further studied by Starling and his co-workers between 1894 and 1895. In the same species they noted that on injection of hypotonic solutions their volume in the peritoneum decreased within hours, but when an isotonic solution was used, the volume remained the same for 2-3 hours (actually the fluid began to be absorbed after this time). The inevitable conclusion was that the serous surfaces of the peritoneum behaved as an inert membrane, the volume of fluid within the peritoneal cavity being dependent on the osmotic pressure on either side of the membrane (13).

17It was natural to assume that small molecules might cross the peritoneal membranes, the rate of passage depending on the relative concentrations in the blood or the peritoneal fluid. From the 1920s to 1930s, experiments on rabbits, dogs and monkeys showed that the peritoneal membranes were permeable to most low molecular weight substances (including urea) and even some proteins (13). Warming the solutions placed in the peritoneum, and increasing the movement of the gut were found to accelerate the diffusion of substances out of the blood into the fluid in the peritoneum.

18The conclusion derived from these animal experiments was that if fluid was placed in the space surrounding the highly vascular intestines, the membranes between the blood and the injected solution acted in the same way as the artificial membrane in vividiffusion. That is, they allowed low molecular weight substances to diffuse across to an area of low concentration.

Peritoneal Dialysis in Uraemic Animals

19It was a natural assumption that it would be possible to remove waste products from the blood into suitable solutions injected into the peritoneum. Experiments were therefore performed on uraemic animals. Solutions were either placed in the peritoneum, left for a sufficient time and then replaced with a fresh solution, or a continuous method was used. In this case the solution was caused to flow into the peritoneum through one catheter and allowed to drain out through a second.

20Ganter in 1923 performed peritoneal dialysis on guinea pigs and rabbits with anuria (and hence uraemia) induced by ligation of the ureters. Constant, intraperitoneal injection of 50 ml samples of a physiological salt solution produced a marked clinical improvement. The animals became less lethargic and began walking around in search of food (14).

21Later investigations were virtually restricted to tests on bilaterally nephrectomised dogs. Such experiments clearly demonstrated that peritoneal dialysis could prolong the life of uraemic dogs from a control level of 3-5 days, to 13 (15), 70 (16) and even 111 days (17). Through such experiments the optimal formulations of the dialysis solutions were derived and possible complications of the procedure exposed. One such was peritonitis, and as a consequence antibiotics were added to dialysis fluids used for patients from 1957 onwards.

22These early animal experiments laid the basis for the use of peritoneal dialysis for the removal of toxins from the blood of patients. The use of peritoneal dialysis gradually intensified from 1945 onwards with constant refinements being added to the technique. Continuous ambulatory peritoneal dialysis (CAPD), in which waste products and water are continuously removed whilst patients carry on with their normal activities, became freely available in the UK in 1980.

Fig. 8.1 In the 1960s, the NHS only supplied dialysis for acute kidney failure; patients with chronic kidney failure had to pay about £7,000 for machines and technical support. However, today kidney dialysis machines like these are widely available. © Science Photo Library, all rights reserved.

Anaemia During Dialysis: Erythropoietin

23Another problem associated with renal failure is anaemia. This is not secondary to the dialysis, but to the fact that the diseased kidney is not able to produce a factor that normally promotes the maturation of red blood cells, erythropoietin (EPO). Our knowledge of the importance of EPO and other agents in the prevention of anaemia stems originally from studies of the circulating haemopoietic factors that appear in the blood of anaemic rabbits (18). The kidney was shown to be the main site of formation of EPO after experiments in rats and rabbits which demonstrated a sharp fall in plasma EPO activity after nephrectomy, but no change after removal of other organs (19). Defective production of EPO in patients in chronic renal failure can render some patients dependent on regular blood transfusions. EPO can now be prepared by recombinant methods and it is highly effective for the treatment of the anaemia of chronic renal failure, removing the requirement for transfusion within weeks.

24Dialysis without question saves the lives of patients with acute and chronic renal failure. The basic animal research, performed around the turn of the century, exposed the possibility of removal of toxic metabolites from the blood by diffusion across semipermeable membranes. Without those experiments, the 100 patients per million population per annum (20) that develop CRF would have no future. However, while dialysis is life-saving, the treatment for CRF with the best prognosis is a kidney transplant (21). Transplantation is also the most cost effective treatment (20).

Bibliographie

References

1) Graham T (1854) Osmotic force. Philo Trans Roy Soc. London 144 177-228.

2) Richardson B (1889) Practical studies in animal dialysis. Asclepiad 6 331-32.

3) Abel J, Rowntree L, Turner B (1914) Plasma removal with return of corpuscles (Plasmaphaeresis). J Pharmacol Exp Ther 5 275-316.

4) Beck E. (1984) The treatment of thrombosis, in Discoveries in Pharmacology, vol. 2, eds Parnham M & Bruinvels J. Amsterdam: Elsevier.

5) McBride P (1980) The Development of hemodialysis and peritoneal dialysis, in Clinical Dialysis, eds Nissenson A, Fine R & Gentile D. Englewood Cliffs: Prentice-Hall.

6) Murray D, Jaques M, Perrett T & Best C (1937) Heparin and thrombosis of veins following surgery. Surgery 2 163-87.

7) Department of Health The British Pharmacopoeia. London: Stationery Office Books 1993.

8) Gryglewski R, Botting R & Vane J (1988) Mediators produced by the endothelial cell. Hypertens 12 530-548

9) Woods H, Ash G, Weston M, Bunting S, Moncada S & Vane J (1978) Prostacyclin can replace heparin in haemodialysis in dogs. The Lancet 2 1075-77.

10) Markwardt F, Hauptmann J, Nowak G, Klessen C & Walsmann P (1982) Pharmacological studies on the antithrombotic action of Hirudin in experimental animals. Thromb Haemostas 47 226-29.

11) Markwardt F, Nowak G, Stuerzebecher J Griessbach U, Walsmann P & Vogel G (1984) Pharmacokinetics and anticoagulant effect of hirudin in man. Thromb Haemostas 52 160-63.

12) Wegner G (1877) Chirurgische Bemerkungen über die Peritonealhöhle, mit besonderer Berücksichtigung der Ovariotomie. Arch f klin Chir 20 51-55.

13) Boen S (1964) Peritoneal Dialysis in Clinical Medicine. Springfield: Charles Thomas.

14) Ganter G (1923) Ueber die Beseitigung giftiger Stoffe aus dem Blute durch Dialyse. Muench Med Wochschr 70 1478.

15) Bliss S, Kastler A, Nadler S (1931) Peritoneal lavage. Effective elimination of nitrogenous wastes in the absence of kidney function. Proc Soc Exp Biol and Med 29 1078-79.

16) Grollman A, Turner L & Mclean J (1951) Intermittent peritoneal lavage in nephrectomised dogs and its application to the human being. Arch Int Med 87 379.

17) Houck C, More A, ElksonW & Gilmer R (1954) Intestinal intussusception in chronic nephrectomised dogs maintained by peritoneal dialysis. Science June 11 845.

18) Carnot P & Deflandre O (1906) Sur l’activite hemopoietique du serum. Compt rend Acad d Sc Par 143 384-86.

19) Jacobson L, Goldwasser E, Fried W & Plzak L (1957) Role of the kidney in erythropoiesis. Nature 179 633-34.

20) West R (1991) Organ Transplantation. London: Office of Health Economics.

21) Minerva (1993) Br Med J 307 880.

Notes

1 “One of my first patients was a young man suffering from chronic nephritis and slowly dying of renal failure. He was hypertensive, had headaches, 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.” Dr Willem Kolff, the first person to treat a patient with an artificial kidney. Written in a letter to Dr F. D. Moore, quoted in F. D. Moore, Give and Take: The Development of Tissue Transplantation. Philadelphia: Saunders.

Table des illustrations

Légende Fig. 8.1 In the 1960s, the NHS only supplied dialysis for acute kidney failure; patients with chronic kidney failure had to pay about £7,000 for machines and technical support. However, today kidney dialysis machines like these are widely available. © Science Photo Library, all rights reserved.
URL http://books.openedition.org/obp/docannexe/image/1980/img-1.jpg
Fichier image/jpeg, 103k

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