959
Pretransplant Blood-transfusionBad URaeMIC
or
Good?
patients become anaemic and,
in those
who have been maintained on haemodialysis for some time, this anaemia can be extreme. For many years blood was transfused liberally, to make the hemoglobin level as normal as possible; but this sometimes resulted in patients’ becoming immunised to transplantation antigens, with lymphocytotoxic antibodies in the serum. Getting suitable kidneys for these individuals then became very difficult and, even when a cross-match-negative donor could be found, the transplanted kidney was often rejected in the first few weeks. Most dialysis centres then introduced strict policies to reduce transfusions to a minimum. Frozen blood was sometimes used in preference to fresh blood since the freezing and washing procedure removes most of the white blood-cells which constitute the principal antigenic (HL-A) source. But these policies did not improve the overall results of transplantation, and there is some evidence that they were misguided. In laboratory animals, transfusion of donor blood or marrow cells to the recipient at the time of skin or kidney transplantation has sometimes prolonged graft survival. Although first described in rabbits’ and dogs2 with skin-grafts, this effect is more obvious in rats that have received kidney transplants.3 By 1967, enough human kidneys had been grafted to allow analysis of the benefits or ill-effects of blood-trans-4 fusion before transplantation. DossETER et a1.4 found, in a series of 58 cadaver grafts, that the patients who had least rejection were those who had received significantly more blood. HuME, reporting his experience with 102 patients, was unable to show such a clear correlation. Nevertheless, only 1 of 13 patients who received thirty or more units of blood rejected the graft completely. In 1966, KISSMEYER-NIELSON and others6 described 2 cases of "hyperacute" rejection in patients who had acquired cytotoxic antibodies after receiving seventeen and twenty-one units of blood. Three years later PATEL and TERASAKI7 reported an immediatefailure rate of 80% in 30 patients who had circulating cytotoxins and a positive cross match at the time of kidney
transplantation. Thereafter, transplanting centres took much more care to establish the negativity of the cross-match before transplanStark, R. B., Dwyer, A. B. Surgery, 1959, 46, 277. Halasz, N. A. J. surg. Res. 1963, 3, 503. 3. Ockner, S. A., Guttmann, R. D., Lindquist, R. R. Transplantation, 1970, 9, 30. 4 Dosseter, J. B., MacKinnon, K. J., Gault, M. H., Maclean, L. D. ibid. 1967, 5, 844. 5 Hume, D. in Human Transplantation (edited by F. T. Rapaport and J. Dausset). New York, 1968. 6. Kissmeyer-Nielsen, F., Olsen, S., Petersen, V. P., Fjeldborg, O. Lancet, 1966, ii, 662. 7 Patel, R., Terasaki, P. I. New Engl. J. Med. 1969, 280, 735.
1. 2
tation. Nevertheless, even when the cross-match was negative, these patients fared well in the long run.8 The message was clear and the dialysis centres soon took the logical action. Blood-transfusions were restricted to those dialysis patients who had severe symptoms of anaemia and, where possible, frozen or HL-A-compatible blood was used. In 1972 OPELZ, MICKEY, and TERASAKI9 suggested that not all individuals were capable of producing antibodies after blood-transfusion. Those patients who had survived for a year or more on dialysis without developing antibodies could be termed poor responders, and, when they subsequently received cadaver-kidney transplants, 84% had functioning grafts one year later. Those without antibodies who were transplanted within a year of starting dialysis had a one-year graft survival of 50%, whereas only 36% of patients with antibodies had functioning grafts at that time. It would be helpful to identify poor-responder patients at the start of dialysis treatment, since they could then be left on dialysis for a year or more and be given ample blood. The responder group could be transplanted early before antibodies had a chance to appear. Unfortunately there is no test which can identify these two populations-if indeed they are distinct. Cutaneous reactions to dinitrochlorobenzene and other agents are often reduced or absent in urxmic patients. Although WILSON and KIRKPATRICK1 showed that anergic patients have their first rejection episode rather later after transplantation than do the others, there have been no reports to suggest that these individuals do better in the long term. News that depriving a transplant candidate of blood may actually prejudice the survival of his graft came a year ago in another paper from the laboratory of Dr TERASAKI." The Los Angeles workers calculated the one-year graft survival for 93 recipients of cadaver grafts who had had no exposure to transfused white blood-cells, and it was only 28%. This was significantly lower than the 53% graft survival obtained for 197 recipients who had been previously transfused. At a recent meeting of the British Transplantation Society similar results were reported from centres in London and Leiden. What policy should one then adopt? Are the good effects of giving blood to some patients heavily outweighed by the harmful immunising effects in others? Probably not-for immunised patients can apparently be transplanted very successfully.12 The cross-match test has been refined and, in future, the disaster of hyperacute rejection should be avoidable. Incidentally, tissue matching can have Terasaki, P. I., Kreisler, M., Mickey, R. M. Postgrad. med. J. 1971, 47, 89. Opelz, G., Mickey, M. R., Terasaki, P. I. Lancet, 1972, i, 868. Wilson, W. E. C., Kirkpatrick, C. H. in Experience in Renal Transplantation (edited by T. E. Starzl). Philadelphia, 1964. 11. Opelz, G., Terasaki, P. I. Lancet, 1974, ii, 696. 12. National Organ Matching Service. Annual Report for 1974-75. 8. 9. 10.
960
considerable impact on the results of kidney transplantation in this group of patients, and, when the two antigens of the HLA-B locus have been matched, 66% of the grafts have survived for more than one year.12 Dialysis centres are unlikely to revert to liberal transfusion, since most have found that patients who have not undergone bilateral nephrectomy will maintain their haemoglobin at acceptable levels. The benefits of transfusion are short-lived and there is always the risk that a patient will acquire the hepatitis-associated antigen. In addition, it would be difficult to ignore completely reports from the European Dialysis and Transplant Association’t3 that transfusion adversely affects cadaver-kidney transplant survival. When antibodies arise as a result of blood-transfusion they are often multispecific and capable of reacting against the antigens of numerous individuals : finding a suitable kidney for an immunised patient is always difficult and may take years. Nevertheless, strong indications for blood-transfusion arise from time to time in dialysis units, and it is reasonable to give blood under these circumstances.
Polyunsaturated Beef-Eaters IF the risk of developing coronary heart-disease is related to serum-cholesterol level, and if this risk is reversible, what might the prudent man do about it? Until lately the answer was to cut out, or cut down on, a number of the normal components of the Western diet. Now, with the arrival of meat and dairy products whose fats have been artificially modified there is an element of choice. 14-16 Is it now going to be possible to live off the fat of the land and run a low serum-cholesterol? Dietary manipulation of serum-cholesterol level has hitherto depended on an overall reduction in the amount of food energy obtained from fat and on replacement of some of the displaced animal products such as meat, lard, milk, and milk products by poultry, fish, and vegetable oils. The reason is that different sorts of fat have different effects on serum-cholesterol level. 17 Dietary cholesterol itself, an animal product, is of debatable importance but does raise the serum level to some extent. Fats containing certain saturated fatty acids increase cholesterol considerably, while polyunsaturated fatty acids have a neutral effect and polyunsaturated fats have a moderate lowering effect. Each foodstuff has a characteristic fat composition. Plants tend to synthesise relatively unsaturated fats which are oily; but the quality of the depot fats of animals is largely determined by the fatty acids reaching their
13. Proc. Europ. Dial. Transplant Ass. 1975, 11. 14. Lake, L. Med. J. Aust. 1975, i, 701. 15. Nestel, P. J. ibid. 1975, ii, 452. 16. Lake, L. ibid. p. 651. 17. Keys, A., Anderson, J. T., Grande, F. Metabolism,
intestines. In those animals that chew the cud, the ruminants, bacteria in the first part of the stomach hydrogenate dietary unsaturated fats before they can be absorbed, so that their body fat and milk contain relatively more hard saturated fats. The saturated fats are then passed on to man, Ruminant meat, milk, and milk products will therefore tend to raise the serum-cholesterol because of the activities of these hydrogenating bacteria. Now ruminant animals are being reared in such a way that this hydrogenation is inhibited. Workers for the Commonwealth Scientific and Industrial Research Organisation in Australia have produced a formaldehyde-casein coating for animal feed which resists bacterial activity.l8 The fatty-acid composition of meat and milk derived from these animals is determined by the amount of this feed that they receive: typically, polyunsaturated fatty acids are increased from 3% to 21% at the expense of both monounsaturated and saturated fatty acids, the latter falling by nearly 10% to just over 40%. The total fat content and cholesterol content remain unchanged.19 Though these products have been labelled polyunsaturated, the reduction in saturated fat is probably more important. In one of a series of metabolic-ward experiments20 21 serumcholesterol fell by an average of 10% in six young volunteers when a diet supplying as much as 45-50% of food energy from these modified animal fats replaced a matched diet of conventional animal fats. An average fall of 10% in cholesterol might, on a formula derived from the first six years’ data from the Framingham study, be associated with a 24% fall in coronary-disease incidence.22 23 Tables based on domestic purchases of food for 197324 suggest that the average Briton obtained 42% of his food energy from fat (including vegetable fats and oils) and that nearly half of this was saturated and 10% polyunsaturated. Milk, cream, and cheese supplied 26% of this saturated fat, butter alone 21%, and ruminant meat and meat products perhaps 10%. Beef and veal accounted for only 4.5%. Turning the country into a nation of polyunsaturated beef-eaters would therefore have only a marginal effect on the national cholesterol level, unless in addition there was a change in the quantity or quality of butter and dairy products consumed. Over the past twenty years there has been a steady decline in the proportion of food energy obtained from carbohydrate, mainly attributable to a fall in consumption of the traditional 18
Cook, L. J., Scott, T. W., Ferguson, K. A., McDonald I. W Nature. 1970.
228, 178. 19. Havenstein, N. Nutrition, 1974, 28, 255. 20. Nestel P. J., Havenstein, N., Whyte, H M., Engl. J. Med. 1973, 288, 279. 21. Nestel, P. J., Havenstein, N., Scott, T. W.,
Scott, T. W. Cook, L J
Cook,
L
J
Aust N Z
New
Jl Med
1974, 4, 497. 22. Inter Society Commission for Heart Disease Resources circulation, 1970.
42, A 55. 1965, 14,
747.
23. Cornfield, J. Fedn Proc. 1962, 21, suppl. ii, p. 58 24. Household Food Consumption and Expenditure 1973. H M Stationery Office, 1975.
Pretransplant Blood-transfusionBad URaeMIC
or
Good?
patients become anaemic and,
in those
who have been maintained on haemodialysis for some time, this anaemia can be extreme. For many years blood was transfused liberally, to make the hemoglobin level as normal as possible; but this sometimes resulted in patients’ becoming immunised to transplantation antigens, with lymphocytotoxic antibodies in the serum. Getting suitable kidneys for these individuals then became very difficult and, even when a cross-match-negative donor could be found, the transplanted kidney was often rejected in the first few weeks. Most dialysis centres then introduced strict policies to reduce transfusions to a minimum. Frozen blood was sometimes used in preference to fresh blood since the freezing and washing procedure removes most of the white blood-cells which constitute the principal antigenic (HL-A) source. But these policies did not improve the overall results of transplantation, and there is some evidence that they were misguided. In laboratory animals, transfusion of donor blood or marrow cells to the recipient at the time of skin or kidney transplantation has sometimes prolonged graft survival. Although first described in rabbits’ and dogs2 with skin-grafts, this effect is more obvious in rats that have received kidney transplants.3 By 1967, enough human kidneys had been grafted to allow analysis of the benefits or ill-effects of blood-trans-4 fusion before transplantation. DossETER et a1.4 found, in a series of 58 cadaver grafts, that the patients who had least rejection were those who had received significantly more blood. HuME, reporting his experience with 102 patients, was unable to show such a clear correlation. Nevertheless, only 1 of 13 patients who received thirty or more units of blood rejected the graft completely. In 1966, KISSMEYER-NIELSON and others6 described 2 cases of "hyperacute" rejection in patients who had acquired cytotoxic antibodies after receiving seventeen and twenty-one units of blood. Three years later PATEL and TERASAKI7 reported an immediatefailure rate of 80% in 30 patients who had circulating cytotoxins and a positive cross match at the time of kidney
transplantation. Thereafter, transplanting centres took much more care to establish the negativity of the cross-match before transplanStark, R. B., Dwyer, A. B. Surgery, 1959, 46, 277. Halasz, N. A. J. surg. Res. 1963, 3, 503. 3. Ockner, S. A., Guttmann, R. D., Lindquist, R. R. Transplantation, 1970, 9, 30. 4 Dosseter, J. B., MacKinnon, K. J., Gault, M. H., Maclean, L. D. ibid. 1967, 5, 844. 5 Hume, D. in Human Transplantation (edited by F. T. Rapaport and J. Dausset). New York, 1968. 6. Kissmeyer-Nielsen, F., Olsen, S., Petersen, V. P., Fjeldborg, O. Lancet, 1966, ii, 662. 7 Patel, R., Terasaki, P. I. New Engl. J. Med. 1969, 280, 735.
1. 2
tation. Nevertheless, even when the cross-match was negative, these patients fared well in the long run.8 The message was clear and the dialysis centres soon took the logical action. Blood-transfusions were restricted to those dialysis patients who had severe symptoms of anaemia and, where possible, frozen or HL-A-compatible blood was used. In 1972 OPELZ, MICKEY, and TERASAKI9 suggested that not all individuals were capable of producing antibodies after blood-transfusion. Those patients who had survived for a year or more on dialysis without developing antibodies could be termed poor responders, and, when they subsequently received cadaver-kidney transplants, 84% had functioning grafts one year later. Those without antibodies who were transplanted within a year of starting dialysis had a one-year graft survival of 50%, whereas only 36% of patients with antibodies had functioning grafts at that time. It would be helpful to identify poor-responder patients at the start of dialysis treatment, since they could then be left on dialysis for a year or more and be given ample blood. The responder group could be transplanted early before antibodies had a chance to appear. Unfortunately there is no test which can identify these two populations-if indeed they are distinct. Cutaneous reactions to dinitrochlorobenzene and other agents are often reduced or absent in urxmic patients. Although WILSON and KIRKPATRICK1 showed that anergic patients have their first rejection episode rather later after transplantation than do the others, there have been no reports to suggest that these individuals do better in the long term. News that depriving a transplant candidate of blood may actually prejudice the survival of his graft came a year ago in another paper from the laboratory of Dr TERASAKI." The Los Angeles workers calculated the one-year graft survival for 93 recipients of cadaver grafts who had had no exposure to transfused white blood-cells, and it was only 28%. This was significantly lower than the 53% graft survival obtained for 197 recipients who had been previously transfused. At a recent meeting of the British Transplantation Society similar results were reported from centres in London and Leiden. What policy should one then adopt? Are the good effects of giving blood to some patients heavily outweighed by the harmful immunising effects in others? Probably not-for immunised patients can apparently be transplanted very successfully.12 The cross-match test has been refined and, in future, the disaster of hyperacute rejection should be avoidable. Incidentally, tissue matching can have Terasaki, P. I., Kreisler, M., Mickey, R. M. Postgrad. med. J. 1971, 47, 89. Opelz, G., Mickey, M. R., Terasaki, P. I. Lancet, 1972, i, 868. Wilson, W. E. C., Kirkpatrick, C. H. in Experience in Renal Transplantation (edited by T. E. Starzl). Philadelphia, 1964. 11. Opelz, G., Terasaki, P. I. Lancet, 1974, ii, 696. 12. National Organ Matching Service. Annual Report for 1974-75. 8. 9. 10.
960
considerable impact on the results of kidney transplantation in this group of patients, and, when the two antigens of the HLA-B locus have been matched, 66% of the grafts have survived for more than one year.12 Dialysis centres are unlikely to revert to liberal transfusion, since most have found that patients who have not undergone bilateral nephrectomy will maintain their haemoglobin at acceptable levels. The benefits of transfusion are short-lived and there is always the risk that a patient will acquire the hepatitis-associated antigen. In addition, it would be difficult to ignore completely reports from the European Dialysis and Transplant Association’t3 that transfusion adversely affects cadaver-kidney transplant survival. When antibodies arise as a result of blood-transfusion they are often multispecific and capable of reacting against the antigens of numerous individuals : finding a suitable kidney for an immunised patient is always difficult and may take years. Nevertheless, strong indications for blood-transfusion arise from time to time in dialysis units, and it is reasonable to give blood under these circumstances.
Polyunsaturated Beef-Eaters IF the risk of developing coronary heart-disease is related to serum-cholesterol level, and if this risk is reversible, what might the prudent man do about it? Until lately the answer was to cut out, or cut down on, a number of the normal components of the Western diet. Now, with the arrival of meat and dairy products whose fats have been artificially modified there is an element of choice. 14-16 Is it now going to be possible to live off the fat of the land and run a low serum-cholesterol? Dietary manipulation of serum-cholesterol level has hitherto depended on an overall reduction in the amount of food energy obtained from fat and on replacement of some of the displaced animal products such as meat, lard, milk, and milk products by poultry, fish, and vegetable oils. The reason is that different sorts of fat have different effects on serum-cholesterol level. 17 Dietary cholesterol itself, an animal product, is of debatable importance but does raise the serum level to some extent. Fats containing certain saturated fatty acids increase cholesterol considerably, while polyunsaturated fatty acids have a neutral effect and polyunsaturated fats have a moderate lowering effect. Each foodstuff has a characteristic fat composition. Plants tend to synthesise relatively unsaturated fats which are oily; but the quality of the depot fats of animals is largely determined by the fatty acids reaching their
13. Proc. Europ. Dial. Transplant Ass. 1975, 11. 14. Lake, L. Med. J. Aust. 1975, i, 701. 15. Nestel, P. J. ibid. 1975, ii, 452. 16. Lake, L. ibid. p. 651. 17. Keys, A., Anderson, J. T., Grande, F. Metabolism,
intestines. In those animals that chew the cud, the ruminants, bacteria in the first part of the stomach hydrogenate dietary unsaturated fats before they can be absorbed, so that their body fat and milk contain relatively more hard saturated fats. The saturated fats are then passed on to man, Ruminant meat, milk, and milk products will therefore tend to raise the serum-cholesterol because of the activities of these hydrogenating bacteria. Now ruminant animals are being reared in such a way that this hydrogenation is inhibited. Workers for the Commonwealth Scientific and Industrial Research Organisation in Australia have produced a formaldehyde-casein coating for animal feed which resists bacterial activity.l8 The fatty-acid composition of meat and milk derived from these animals is determined by the amount of this feed that they receive: typically, polyunsaturated fatty acids are increased from 3% to 21% at the expense of both monounsaturated and saturated fatty acids, the latter falling by nearly 10% to just over 40%. The total fat content and cholesterol content remain unchanged.19 Though these products have been labelled polyunsaturated, the reduction in saturated fat is probably more important. In one of a series of metabolic-ward experiments20 21 serumcholesterol fell by an average of 10% in six young volunteers when a diet supplying as much as 45-50% of food energy from these modified animal fats replaced a matched diet of conventional animal fats. An average fall of 10% in cholesterol might, on a formula derived from the first six years’ data from the Framingham study, be associated with a 24% fall in coronary-disease incidence.22 23 Tables based on domestic purchases of food for 197324 suggest that the average Briton obtained 42% of his food energy from fat (including vegetable fats and oils) and that nearly half of this was saturated and 10% polyunsaturated. Milk, cream, and cheese supplied 26% of this saturated fat, butter alone 21%, and ruminant meat and meat products perhaps 10%. Beef and veal accounted for only 4.5%. Turning the country into a nation of polyunsaturated beef-eaters would therefore have only a marginal effect on the national cholesterol level, unless in addition there was a change in the quantity or quality of butter and dairy products consumed. Over the past twenty years there has been a steady decline in the proportion of food energy obtained from carbohydrate, mainly attributable to a fall in consumption of the traditional 18
Cook, L. J., Scott, T. W., Ferguson, K. A., McDonald I. W Nature. 1970.
228, 178. 19. Havenstein, N. Nutrition, 1974, 28, 255. 20. Nestel P. J., Havenstein, N., Whyte, H M., Engl. J. Med. 1973, 288, 279. 21. Nestel, P. J., Havenstein, N., Scott, T. W.,
Scott, T. W. Cook, L J
Cook,
L
J
Aust N Z
New
Jl Med
1974, 4, 497. 22. Inter Society Commission for Heart Disease Resources circulation, 1970.
42, A 55. 1965, 14,
747.
23. Cornfield, J. Fedn Proc. 1962, 21, suppl. ii, p. 58 24. Household Food Consumption and Expenditure 1973. H M Stationery Office, 1975.
