Time to Abandon Pre-Transplant Blood Transfusion?

567

anticipate a regression towards the mean if further patients were randomised. Nevertheless, results indicate a substantial reduction in mortality and they are probably better than those of streptokinase (although the ISIS-2 study has not been reported in full). Does the extra expense of APSAC justify its use in preference to streptokinase? (This question may be answered by an ongoing trial in the USA in which the two agents are being compared). If the complete results of the AIMS study, especially the 1-year mortality figures, support the preliminary data, then APSAC is the best agent

thrombolytic therapy myocardial infarction.

at

in

the

for routine withacute

moment

patients

Time to Abandon Pre-Transplant Blood Transfusion? THERE is a political adage "never believe a rumour until it is officially denied". Preparation of the recipient for transplantation and tissue matching with the donor are subjects rife with rumours. Opelz reported that a 1986 literature survey had documented nearly 400 publications on the transfusion effect in both clinical and experimental organ transplantation.1 When we last discussed the topic of blood transfusion and allograft survivaP it was at a time when the benefit of pretransplant blood transfusion had come to be appreciated as the most important single advance in renal transplantation since the introduction of azathioprine and corticosteroids. It was also, by chance, the start of the cyclosporin era. Subsequent data from the Collaborative Transplant’ Society (CTS) showed that actuarial survival rates of first cadaver grafts in patients who had received a transplant in 1982 and 1983 and who had been treated with azathioprine and steroids improved from 50 % in non-transfused to 65% in transfused recipients.’3 The mechanism of this non-specific graft tolerance unknown. It remains unknown. Several attractive hypotheses are still attractive hypotheses--eg, induction of a suppressor cell response, clonal deletion at the time of grafting, and active immunological unresponsiveness induced by anti-idiotypic antibodies.Certainly, transplantation can be successful when pre-existing anti-HLA antibodies are shown to be anti-idiotypic.5 Detailed analysis of the blood transfusion effect showed that, in general, the more blood transfusions given the greater the benefit; however, it was the difference between none and one that was most important, with subsequent transfusions having only a weak additional benefit.’.66

was

1

Opelz G Improved kidney graft survival innontransfused recipients Transplant Proc

After cyclosporin was introduced it remained to be seen whether graft enhancement would still occur. Reports have varied from demonstration of a beneficial effect1,6 to excellent results without transfusion .7,11 Some early accounts suggested no benefit from blood transfusion, but these reports often came from single centres or data pools8 from which results were not as good as the 80% one-year graft survival that one now, at the least, expects. Early data from the CTS showed that there was still a strong positive benefit: in the years 1982 and 1983 cadaver graft survival at one year was 60 % in untransfused and 80 % in transfused recipients.However, in 1986 at the XIth International Congress of the Transplantation Society,Opelz, reporting the CTS results, announced that the blood transfusion effect with cyclosporin seemed to have disappeared. Since 1982, there had been a steady improvement in one-year graft survival from 60 % to 80 % in untransfused patients receiving cyclosporin, so that by 1985 there was no significant difference between transfused and non-transfused recipients. While this result could be understood, it came as something of a surprise to hear that the beneficial effect in recipients treated with azathioprine also seemed to have disappeared. In the same period, the numbers of patients who were receiving azathioprine but not blood transfusions were small, but the first cadaver graft survival times had steadily improved from 50 % to 70 % at one year. What was the

explanation? Although the nephrotoxicity of cyclosporin can hardly be regarded as a benefit, it has meant that episodes of renal graft dysfunction have had to be analysed very carefully and, as a consequence of the difficulties of accurate diagnosis, renal biopsy has become a commonplace investigation. Histological examination often reveals diagnoses other than rejection, even in azathioprine-treated recipients.9 Thus transplantation has become less of an empirical and become

art

1450-55.

of

coupled rejection.

a science, and this transition has with advances in the treatment of

What has become of donor-specific transfusion (DST)? A DST protocol was originally devised by Salvatierra and his colleagues to achieve a better outcome from one-haplotype, mixed lymphocyte culture-reactive donors. Because of the excellent results, DST was extended to zero-haplotype transplants. Graft survival in over 200 zero and one haplotype related grafts, excluding diabetics, was 97 % at one year. The great majority of these recipients were treated with azathioprine and 6

1987, 19: 149-52 2 Editorial Blood transfusion and allograft survival Lancet 1984, i. 830-31. 3 Opelz G. Current relevance of the transfusion effect in renal transplantation Transplant Proc 1985, 17: 1015-25 4 Burlingham WJ, Sollinger HW. Action of donor-specific transfusions—analysis of three possible mechanisms. Transplant Proc 1986; 18: 685-89 5 Reed E, Hardy M, Benevenisty A, Lattes C, et al Effect of antiidiotypic antibodies to HLA on graft survival in renal-allograft recipients N Engl J Med 1987, 316:

more

7

Melzer JS, Husing RM, Feduska NJ, et al The beneficial effect of pretransplant blood transfusions in cyclosporine-treated cadaver renal allograft recipients Transplantation 1987, 43: 61-64 Perloff LJ The role of blood transfusion in the age of cyclosporme Transplant Proc

1986; 18: 29-33. 8 Groth CG There is

no

need

to give

blood transfusions

as

pretreatment for renal

transplantation in the cyclosporine era. Transplant Proc 1987; 19: 153-54 9. Simonton SC, Sibley RK, Fryd DS A comparison of renal biopsies in cyclopsorine and conventionally immunosuppressed renal transplant recipients. Transplant Proc 1987; 19: 1790

568

prednisolone.11 After DST, unfortunately, warm cytotoxic T-cell antibodies to the donor may develop in the recipients even when concomitant azathioprine is given." The question now is whether cyclosporin-treated one-haplotype transplants will do as well as those prepared by DST. Although in this single centre exceptional results have been obtained, CTS data from one-haplotype transplants showed no difference when third-party transfusions were compared with DST, with both groups achieving 90% one-year graft survival.3 Per-operative transfusions do not confer any benefit on first grafts, but may have a small beneficial effect on regrafts treated with cyclosporin.12 Should the practice of blood transfusions be continued? Although the Scandinavian multicentre studies have reported excellent results without transfusion, their patients were beneficially matched.8 In a recent single-centre study the benefit of blood transfusion was most conspicuous in grafts that were poorly matched.6 It remains to be seen from detailed analysis of CTS data whether the improvement in non-transfused recipients is independent of beneficial matching. Many units now achieve excellent results, with one-year graft survival of 80-85 %, and they will want to see more evidence before they change their existing regimens. But the risks of blood transfusion have never been more visible and renal units will be happy to avoid them if possible. INFANT NUTRITION AND CARDIOVASCULAR

DISEASE THE MRC Environmental Epidemiology Unit holds periodic conferences leading to scientific reports on topics that have ranged from the carcinogenicity of wood-dust to the aetiology of acute appendicitis. The latest publication in this series follows a meeting in 1986 on infant nutrition and cardiovascular disease chaired by Dame Barbara Clayton. The starting point, outlined by Prof David Barker, was the unit’s own observation of strong correlations-about 0-7-between infant mortality rates in the early 1920s and mortality from ischaemic heart disease (IHD) in men and women forty or fifty years later in the 212 areas into which the Registrar General divides England and Wales. There was also a strong association between maternal mortality during the second decade of the century and mortality from stroke between 1968 and 1978. Only three other conditions-chronic bronchitis, stomach cancer, and chronic rheumatic heart disease-show geographical relationships with past infant mortality similar to that of IHD. These disorders, like IHD, are associated with low 10 Salvatierra

O, Melzer J, Vincenti F, et al. Donor-specific blood transfusions versus cyclosporine—the DST story Transplant Proc 1987; 19: 160-66 11. Anderson CB, Tyler JD, Sicard GA, et al. Pre-treatment of renal allograft recipients with immunosuppression and donor-specific blood Transplantation 1984; 38: 664-68

12

Tokunaga K, Terasaki PI. Kidney transplant regraft results improved by peroperative

blood transfusions. Lancet 1986; ii: 634-35 1 Scientific report no 8 Infant nutrition and cardiovascular disease. Southampton: MRC Environmental Epidemiology Unit, 1987. 2. Forsdahl A Are poor living conditions in childhood and adolescence an important risk factor for arteriosclerotic heart disease? Br J Prev Soc Med 1977; 31: 91-95

socioeconomic status. The Unit’s hypothesis, first suggested by Forsdahl in 1977,2 is that adverse influences in childhood increase susceptibility to other circumstances associated with affluence that are encountered in later life and that predispose to IHD. Dr Clive Osmond, also from the unit, considered national time trends in stroke and IHD and how far changes in susceptibility, as indicated by infant mortality, predict changes in these diseases. The decline in mortality from stroke in both men and women during the past 40 years follows a fall in both neonatal and maternal mortality in the earlier years of the century, although there may of course be other explanations for the declinein stroke. The possibility that the earlier decline in IHD in the United States and Australia might be explained by earlier improvements in infant mortality is alluded to, and is certainly a point on which more detailed analyses would be valuable. In general, the correlations between changes in susceptibility-ie, in infant mortality- and subsequent changes in IHD rates are consistent with the unit’s hypothesis. The decline in mortality from IHD in some countries could perhaps be explained along the lines suggested by the unit as well as by changes in adult lifestyle, as generations that have experienced striking contrasts between childhood deprivation and later affluence have been replaced by others not exposed to such extremes. Several contributors reviewed the extent to which alterations in infant feeding might explain later susceptibility to IHD, and everyone agreed to avoid the preconception that breastfeeding would necessarily confer the most favourable outcome. Dr Roger Whitehead of the MRC Dunn Nutritional Laboratory summarised changes in infant feeding patterns since the 1920s. The proportion of mothers breastfeeding declined between 1920 and 1970, after which it rose again. In the 1930s, breastfeeding may have been more common in manual than professional classes, although this pattern has almost certainly been reversed since 1945. Changes in the composition of bottled milks have contributed to a pronounced rise in the intake of linoleic acid since about 1970. Between 1920 and 1970, the daily intake of sodium by babies almost doubled, although it has since declined. Dr Alan Lucas, also from the Dunn Nutritional Laboratory, considered the effects of diet on short-term health and the extent to which diet in infancy has demonstrable effects on morbidity in later life. "Programming" refers to the long-term effects of stimuli at particularly sensitive points in development. Agents that may be involved include hormones, growth factors, sensory experiences, and different nutrients. In animals, there is little doubt that programming occurs. Lipid metabolism, obesity, and regulatory enzyme activities are among a range of conditions or processes affected. For example, very high energy intakes in baboons during the first four months of life lead to progressive weight gain and body fat deposition in females, particularly during adolescence. In man, there is some evidence that breastfeeding in infancy prevents obesity in adolescence. The Dunn Unit is studying nearly 1000 preterm infants in a randomised comparison of a nutrientenriched preterm infant formula and an unfortified diet, either as sole diets or as supplements to their mothers’ own milk. In the short term, babies on the enriched formula grow and gain head circumference more quickly and may do better in terms of mental and motor development. Prof June Lloyd concluded that although the diet in early infancy, and specifically the type of fat, clearly influences the plasma cholesterol concentration, there is no firm evidence that