- Email: [email protected]
REPEAT HLA-DR MISMATCHES IN SECOND TRANSPLANTS
148
Letters
to
the Editor
ETHICAL PROBLEMS OF SCREENING FOR NEURAL-TUBE DEFECTS on Jan. 31, published a letter which I had chairman of an ethical working-group in the Northern Region regarding the proposal to start routine prenatal screening for neural-tube defects. The working-group had been concerned about the pressures on the Department of Health and Social Security to undertake nation-wide screening, while scant attention had been paid to its ethical implications. The study by the working-group of the ethical problems of routine screening has continued, and we wish to report our main conclusion-namely, that each stage of the screening process should be clearly understood to be voluntary. Personal ethical problems associated with routine prenatal screening centre on the fact that the only "treatment" offered, in the event of a positive result, is abortion. For those who believe that abortion is in almost any and every circumstance wrong, the main issue is already foreclosed. For those who find no difficulty in contemplating abortion at 18-20 weeks or even later, the personal implications of screening are relatively minor. For others, who accept abortion as a regrettable necessity only when there seem to be strong reasons for it, the problems are harder, not least because of the narrow dividing line between late abortion and infanticide. Related to this central moral issue are a number of secondary problems. The most serious of these is the unnecessary anxiety and distress which would be caused to expectant mothers to whom abortion, for whatever reason, was unacceptable, and who discovered that they were among the small minority recommended for further investigation after the initial blood-test. This group would have their normal maternal fears of deformity greatly heightened, without having any corresponding relief in knowing that "treatment" was available. There are also questions concerning a pregnant woman’s growing relationship with her child, and the possible damage to this relationship if false hopes have been aroused, or unnecessary guilt or fear engendered. Furthermore, there is the possibility that, in a society where defect was being systematically eliminated by abortion, those who had slipped through the net might find themselves burdened’ by a sense that they were unwanted and ought not to have been born. None of these problems may seem of much significance in comparison with the difficulties of coping emotionally with and caring for the seriously deformed. Cumulatively, however, they articulate the hesitations of those who see the long-term dangers in moves towards a society in which the elimination of a widening variety of those with genetic defects has grown to seem as normal and inevitable as abortion seems today. Some degree of encroachment on the rights of every individual to be born and to receive maximum care, would seem to be justified in view of the already very large medical encroachment on the natural processes of selection and mortality. The question is, how much? and what safeguards is it possible to build into the procedures so that individual wishes are respected and the drift towards centralised decision-making about acceptable types of human being is not allowed to develop too far? The most obvious safeguard would be to ensure that each step, and especially the first one, in the testing process was voluntary, otherwise the patient might face the ethical dilemma for the first time when amniocentesis was offered (on the basis of the screening blood-test). A system of contract-
SIR,-The Times,
written
as
would ensure this, but would have the disadvantage that the social classes most at risk (i.e., iv and v) are those least likely to enter a voluntary scheme, and have the greatest tendency to book late. A system of contracting-out would ensure that a much higher proportion of the population was screened,
but it could put undesirable pressure on individuals to conform unless adequate opportunities were provided for explanation and expert counselling. We believe that, before introducing a screening test, the appropriate health authority should give careful thought to the way in which potential antenatal patients can be informed of all the implications of what, at the outset, appears to be a simple blood-test. Auckland Castle,
Bishop Auckland,
JOHN DUNELM*
Co. Durham DL14 7NR
REPEAT HLA-DR MISMATCHES IN SECOND
TRANSPLANTS
SIR,-We have evidence suggesting that matching for
antigens improves the success-rate of cadaveric renal transplantation,2 indicating that these antigens, like the HLA A and B antigens, may act as histocompatibility antigens. Our findings have been supported by others. 2,3 Many transplant units would not transplant a second kidney which shared at least one mismatched HLA A and B antigen with the first donor, and few surgeons would do a transplant if all the mismatched antigens of the first donor-recipient combination were repeated in the second. Such second transplants have a signifiHLA-DR
RESULTS OF SECOND TRANSPLANTS WHEN A MISMATCHED DR
ANTIGEN OF THE FIRST DONOR WAS REPEATED IN THE SECOND TRANSPLANT
(CASES 1-5) AND WHEN IT WAS (CASES 6-12)
NOT REPEATED
Mismatched DR antigens repeated in the 2nd donor are underlined. * Positive B-cell cross-match with second donor. tNF never functioned; F failure (and day of failure); S Success (and post-transplant day when last seen). =
cantly
=
worse success-rate
than
=
grafts
not
repeating previous
to see whether the fate of second transplants is influenced by a repeat DR antigen mismatch from the first donor. We have done twelve second transplants (all from cadaveric donors) where the recipient and the two donors were DR typed for the seven "official" antigens, DRwl-7. In no case did the second donor share mismatched HLA A and B antigens with the first donor. In five cases, however, the second donor did share the mismatched DR antigen present in the first donor, and four of these grafts have failed (see table). In contrast no failures were seen in the seven patients who received second transplants which did not repeat DR mismatches from their
mismatches.4 We have re-examined
our
data
ing-in
1. 2.
Ting, A., Morris, P. J. Lancet, 1978, i, 575. Albrechtsen, D., Flatmark, A., Jervell, J., Solheim, B., Thorsby, 825.
3. 4.
Martins-da-Silva, B., Vassalli, P., Jeannet, M. ibid. p. 1047. Opelz, G., Terasaki, P. I. Transplantation, 1976, 21, 483.
E. ibid. p.
149 first donor. The difference in the success-rate between these two groups of recipients is highly significant (P=0.01, Fisher’s
exact-probability test). Although preliminary, our results suggest that a second transplant is more likely to fail if a mismatched HLA-DR antigen present in the first donor is repeated in the second donor. Thus this may represent another important application of HLA-DR matching. Nuffield Department of Surgery,
University of Oxford, Radcliffe Infirmary,
ALAN TING PETER J. MORRIS
Oxford OX2 6HE
FROM KIDNEY DONOR TO KIDNEY RECIPIENT a 57-year-old man offered a kidney for his grafting 36-year-old son who was in chronic renal failure due to chronic glomerulonephritis. The father was in good health with normal urinary chemistry, cytology and bacteriology, normal renal function (creatinine clearance 104 ml/min, urinary specific gravity 1.026), and normal pyelogram and renal angiogram. The transplantation was done in July, 1971. The postoperative course was uneventful and the father was discharged after a month. 6 weeks later he had no proteinuria, normal Addis count, a creatinine clearance of 114 ml/min, plasma-creatinine 1.1mg/dl, urinary specific gravity 1.024 and blood-pressure 140/80 mm Hg. He was put under care of his local physician, and nothing was heard of him for 16 months. In March, 1973, he started to have headaches and gastrointestinal symptoms with progressive loss of weight, muscular weakness, and dyspnoea on effort, and was found to have insufficient renal function. In January, 1974, he was admitted to our centre with systolic hypertension, anxmia, decreased tactile perception on lower limbs and cachexia. His creatinine clearance was 9 ml/min, plasma-creatinine 5.6 mg/dl, there was proteinuria of 3 g/day, and an Addis count of 73 million red blood-cells, 1 million of white blood-cells, and 700 000 cylinders. Urine cultures were repeatedly negative. Despite thorough investigation, including intravenous and retrograde pyelography and renal angiography, the cause of his kidney failure was not found; at open biopsy only medullary tissue with non-characteristic morphology was obtained. In August, 1974, regular dialysis treatment was started, and in June, 1975 a cadaver donor kidney was transplanted without autologous nephrectomy. His post-transplant course was difficult but 2 months later he was discharged in good condition and with
SIR,-In 1971 to
good graft function. In June, 1978 (3 years post-transplant) he weighed 30 kg more than with his worst weight shortly after transplantation; his only complaint was intermittent claudication, and his blood-pressure was 140/90 mm Hg. There was no proteinuria, negative urine culture, normal Addis count, and a creatinine clearance of 94 ml/min with 0.8 mg/dl plasmacreatinine. In this case Shakespeare’s "To give away Yourself Yourself still’ (sonnet xvi) takes on a new meaning.
Keeps
T. TIRKA J. HEJNAL I. RENELTOVÁ
a day. Physical signs and straight X-ray of the abdomen confirmed small-bowel obstruction, and an emergency barium enema revealed a normal colon. Blood-tests showed a hxmoglobin of 15.99
Medicine,
VL. KOČCANDRLE P. MÁLEK
SCLEROSING PERITONITIS IN PATIENT ON TIMOLOL SrtR,-The association of sclerosing peritonitis with the 2-blocker practolol has been clearly established.’ Second-generation 3-blockers have lately appeared and are reputed to have higher cardioselectivity. We report here a case of scleros-
1 Brow n. P., and others Lancet, 1974, ii, 1477.
g/dl,
10 800 white
cells/1
with
a
normal differential
rate of 13 mm/h. and the whole of the small bowel from the duodenojejunal flexure to the ileocaecal valve was matted together in "cocoon-like" adhesions which were responsible for the obstruction. There were no adhesions to the parietal peritoneum (except for a small area around the right lobe of the liver) and the caecum, appendix, colon, bladder, stomach, duodenum, gallbladder, and liver were visibly and palpably normal. Dissection of these adhesions showed what appeared to be two distinct layers. The outer layer was tough and required sharp dissection to divide it between adjacent loops and to peel it off the intestine. A softer inner layer, resembled loose connective tissue and could easily be separated by blunt dissection. During the course of the separation a perforation of the jejunum was found and thought to be iatrogenic. The edge of the jejunum was trimmed before suturing and sent for histology. Samples of the peritoneal adhesions and the liver were also taken for biopsy. On histology the jejunum showed an ischxmic lesion of recent duration associated with a necrotising angiitis. Epithelial regeneration indicated that the lesion was present before surgery. The adhesions showed organising fibrinous peritonitis with fibrosis and leucocyte infiltration. There was slight mesothelial cell proliferation and increased vascularity. The liver biopsy was normal. Apart from a minor wound infection the patient made a satisfactory recovery and was discharged home on the eighteenth postoperative day. The operative findings were similar to those seen after practolol therapy,2 especially since only the small bowel was affected, the other viscera and parietal peritoneum being spared. The histology of the adhesions was not typical of that described after practolol, and histology of the jejunum demonstrated angiitis and a previous perforation which could have been responsible for the organising peritonitis. However, we feel that it was improbable that such dense and localised adhesions could have developed during the 48 h that the patient experienced symptoms. D. C. BAXTER-SMITH I. J. MONYPENNY General Hospital, N. J. DORRICOTT Birmingham B4 6NH count
and
an
erythrocyte-sedimentation
Urgent laparotomy
J. BLÁHA
Transplantation
Research Centre, Institute for Clinical and Experimental 146 22 Prague 4, Czechoslovakia
in a patient taking timolol (’Blocadren’) and feel this may be a side-effect of this drug. A 50-year-old man was admitted as an emergency because of a 48 h history of increasing symptoms of small-bowel obstruction. For 8 years he had been treated for mild proctitis with salazopyrine 2-4 g daily and ’Predsol’ enemas, receiving courses on average three or four times a year. Four barium enemas between 1965 and 1971 had shown no obvious abnormality in the colon. For the 18 months immediately before admission his general practitioner had been treating mild hypertension (200/110 mm Hg) with timolol 10 mg three times
ing peritonitis
was
carried
out
SKIN-TEST ANOMALY
SIR,-Skin testing has been used as a diagnostic tool for allergy for over a hundred years, dating back to Charles Blackley. End-point titration of allergen extracts in the skin of atopics is widely practised and we were surprised when we came upon an anomaly which, we subsequently learned, was first described thirty years ago but not since. Twelve patients seen at a hayfever clinic and having positive skin responses to grass-pollen allergens were prick tested with six ten-fold serial dilutions of five different cocksfoot 2.
Cooke, A. I. M., Foy, P. Ann. R. Coll. Surg. 1976, 58, 473.
(Dactylis
Letters
to
the Editor
ETHICAL PROBLEMS OF SCREENING FOR NEURAL-TUBE DEFECTS on Jan. 31, published a letter which I had chairman of an ethical working-group in the Northern Region regarding the proposal to start routine prenatal screening for neural-tube defects. The working-group had been concerned about the pressures on the Department of Health and Social Security to undertake nation-wide screening, while scant attention had been paid to its ethical implications. The study by the working-group of the ethical problems of routine screening has continued, and we wish to report our main conclusion-namely, that each stage of the screening process should be clearly understood to be voluntary. Personal ethical problems associated with routine prenatal screening centre on the fact that the only "treatment" offered, in the event of a positive result, is abortion. For those who believe that abortion is in almost any and every circumstance wrong, the main issue is already foreclosed. For those who find no difficulty in contemplating abortion at 18-20 weeks or even later, the personal implications of screening are relatively minor. For others, who accept abortion as a regrettable necessity only when there seem to be strong reasons for it, the problems are harder, not least because of the narrow dividing line between late abortion and infanticide. Related to this central moral issue are a number of secondary problems. The most serious of these is the unnecessary anxiety and distress which would be caused to expectant mothers to whom abortion, for whatever reason, was unacceptable, and who discovered that they were among the small minority recommended for further investigation after the initial blood-test. This group would have their normal maternal fears of deformity greatly heightened, without having any corresponding relief in knowing that "treatment" was available. There are also questions concerning a pregnant woman’s growing relationship with her child, and the possible damage to this relationship if false hopes have been aroused, or unnecessary guilt or fear engendered. Furthermore, there is the possibility that, in a society where defect was being systematically eliminated by abortion, those who had slipped through the net might find themselves burdened’ by a sense that they were unwanted and ought not to have been born. None of these problems may seem of much significance in comparison with the difficulties of coping emotionally with and caring for the seriously deformed. Cumulatively, however, they articulate the hesitations of those who see the long-term dangers in moves towards a society in which the elimination of a widening variety of those with genetic defects has grown to seem as normal and inevitable as abortion seems today. Some degree of encroachment on the rights of every individual to be born and to receive maximum care, would seem to be justified in view of the already very large medical encroachment on the natural processes of selection and mortality. The question is, how much? and what safeguards is it possible to build into the procedures so that individual wishes are respected and the drift towards centralised decision-making about acceptable types of human being is not allowed to develop too far? The most obvious safeguard would be to ensure that each step, and especially the first one, in the testing process was voluntary, otherwise the patient might face the ethical dilemma for the first time when amniocentesis was offered (on the basis of the screening blood-test). A system of contract-
SIR,-The Times,
written
as
would ensure this, but would have the disadvantage that the social classes most at risk (i.e., iv and v) are those least likely to enter a voluntary scheme, and have the greatest tendency to book late. A system of contracting-out would ensure that a much higher proportion of the population was screened,
but it could put undesirable pressure on individuals to conform unless adequate opportunities were provided for explanation and expert counselling. We believe that, before introducing a screening test, the appropriate health authority should give careful thought to the way in which potential antenatal patients can be informed of all the implications of what, at the outset, appears to be a simple blood-test. Auckland Castle,
Bishop Auckland,
JOHN DUNELM*
Co. Durham DL14 7NR
REPEAT HLA-DR MISMATCHES IN SECOND
TRANSPLANTS
SIR,-We have evidence suggesting that matching for
antigens improves the success-rate of cadaveric renal transplantation,2 indicating that these antigens, like the HLA A and B antigens, may act as histocompatibility antigens. Our findings have been supported by others. 2,3 Many transplant units would not transplant a second kidney which shared at least one mismatched HLA A and B antigen with the first donor, and few surgeons would do a transplant if all the mismatched antigens of the first donor-recipient combination were repeated in the second. Such second transplants have a signifiHLA-DR
RESULTS OF SECOND TRANSPLANTS WHEN A MISMATCHED DR
ANTIGEN OF THE FIRST DONOR WAS REPEATED IN THE SECOND TRANSPLANT
(CASES 1-5) AND WHEN IT WAS (CASES 6-12)
NOT REPEATED
Mismatched DR antigens repeated in the 2nd donor are underlined. * Positive B-cell cross-match with second donor. tNF never functioned; F failure (and day of failure); S Success (and post-transplant day when last seen). =
cantly
=
worse success-rate
than
=
grafts
not
repeating previous
to see whether the fate of second transplants is influenced by a repeat DR antigen mismatch from the first donor. We have done twelve second transplants (all from cadaveric donors) where the recipient and the two donors were DR typed for the seven "official" antigens, DRwl-7. In no case did the second donor share mismatched HLA A and B antigens with the first donor. In five cases, however, the second donor did share the mismatched DR antigen present in the first donor, and four of these grafts have failed (see table). In contrast no failures were seen in the seven patients who received second transplants which did not repeat DR mismatches from their
mismatches.4 We have re-examined
our
data
ing-in
1. 2.
Ting, A., Morris, P. J. Lancet, 1978, i, 575. Albrechtsen, D., Flatmark, A., Jervell, J., Solheim, B., Thorsby, 825.
3. 4.
Martins-da-Silva, B., Vassalli, P., Jeannet, M. ibid. p. 1047. Opelz, G., Terasaki, P. I. Transplantation, 1976, 21, 483.
E. ibid. p.
149 first donor. The difference in the success-rate between these two groups of recipients is highly significant (P=0.01, Fisher’s
exact-probability test). Although preliminary, our results suggest that a second transplant is more likely to fail if a mismatched HLA-DR antigen present in the first donor is repeated in the second donor. Thus this may represent another important application of HLA-DR matching. Nuffield Department of Surgery,
University of Oxford, Radcliffe Infirmary,
ALAN TING PETER J. MORRIS
Oxford OX2 6HE
FROM KIDNEY DONOR TO KIDNEY RECIPIENT a 57-year-old man offered a kidney for his grafting 36-year-old son who was in chronic renal failure due to chronic glomerulonephritis. The father was in good health with normal urinary chemistry, cytology and bacteriology, normal renal function (creatinine clearance 104 ml/min, urinary specific gravity 1.026), and normal pyelogram and renal angiogram. The transplantation was done in July, 1971. The postoperative course was uneventful and the father was discharged after a month. 6 weeks later he had no proteinuria, normal Addis count, a creatinine clearance of 114 ml/min, plasma-creatinine 1.1mg/dl, urinary specific gravity 1.024 and blood-pressure 140/80 mm Hg. He was put under care of his local physician, and nothing was heard of him for 16 months. In March, 1973, he started to have headaches and gastrointestinal symptoms with progressive loss of weight, muscular weakness, and dyspnoea on effort, and was found to have insufficient renal function. In January, 1974, he was admitted to our centre with systolic hypertension, anxmia, decreased tactile perception on lower limbs and cachexia. His creatinine clearance was 9 ml/min, plasma-creatinine 5.6 mg/dl, there was proteinuria of 3 g/day, and an Addis count of 73 million red blood-cells, 1 million of white blood-cells, and 700 000 cylinders. Urine cultures were repeatedly negative. Despite thorough investigation, including intravenous and retrograde pyelography and renal angiography, the cause of his kidney failure was not found; at open biopsy only medullary tissue with non-characteristic morphology was obtained. In August, 1974, regular dialysis treatment was started, and in June, 1975 a cadaver donor kidney was transplanted without autologous nephrectomy. His post-transplant course was difficult but 2 months later he was discharged in good condition and with
SIR,-In 1971 to
good graft function. In June, 1978 (3 years post-transplant) he weighed 30 kg more than with his worst weight shortly after transplantation; his only complaint was intermittent claudication, and his blood-pressure was 140/90 mm Hg. There was no proteinuria, negative urine culture, normal Addis count, and a creatinine clearance of 94 ml/min with 0.8 mg/dl plasmacreatinine. In this case Shakespeare’s "To give away Yourself Yourself still’ (sonnet xvi) takes on a new meaning.
Keeps
T. TIRKA J. HEJNAL I. RENELTOVÁ
a day. Physical signs and straight X-ray of the abdomen confirmed small-bowel obstruction, and an emergency barium enema revealed a normal colon. Blood-tests showed a hxmoglobin of 15.99
Medicine,
VL. KOČCANDRLE P. MÁLEK
SCLEROSING PERITONITIS IN PATIENT ON TIMOLOL SrtR,-The association of sclerosing peritonitis with the 2-blocker practolol has been clearly established.’ Second-generation 3-blockers have lately appeared and are reputed to have higher cardioselectivity. We report here a case of scleros-
1 Brow n. P., and others Lancet, 1974, ii, 1477.
g/dl,
10 800 white
cells/1
with
a
normal differential
rate of 13 mm/h. and the whole of the small bowel from the duodenojejunal flexure to the ileocaecal valve was matted together in "cocoon-like" adhesions which were responsible for the obstruction. There were no adhesions to the parietal peritoneum (except for a small area around the right lobe of the liver) and the caecum, appendix, colon, bladder, stomach, duodenum, gallbladder, and liver were visibly and palpably normal. Dissection of these adhesions showed what appeared to be two distinct layers. The outer layer was tough and required sharp dissection to divide it between adjacent loops and to peel it off the intestine. A softer inner layer, resembled loose connective tissue and could easily be separated by blunt dissection. During the course of the separation a perforation of the jejunum was found and thought to be iatrogenic. The edge of the jejunum was trimmed before suturing and sent for histology. Samples of the peritoneal adhesions and the liver were also taken for biopsy. On histology the jejunum showed an ischxmic lesion of recent duration associated with a necrotising angiitis. Epithelial regeneration indicated that the lesion was present before surgery. The adhesions showed organising fibrinous peritonitis with fibrosis and leucocyte infiltration. There was slight mesothelial cell proliferation and increased vascularity. The liver biopsy was normal. Apart from a minor wound infection the patient made a satisfactory recovery and was discharged home on the eighteenth postoperative day. The operative findings were similar to those seen after practolol therapy,2 especially since only the small bowel was affected, the other viscera and parietal peritoneum being spared. The histology of the adhesions was not typical of that described after practolol, and histology of the jejunum demonstrated angiitis and a previous perforation which could have been responsible for the organising peritonitis. However, we feel that it was improbable that such dense and localised adhesions could have developed during the 48 h that the patient experienced symptoms. D. C. BAXTER-SMITH I. J. MONYPENNY General Hospital, N. J. DORRICOTT Birmingham B4 6NH count
and
an
erythrocyte-sedimentation
Urgent laparotomy
J. BLÁHA
Transplantation
Research Centre, Institute for Clinical and Experimental 146 22 Prague 4, Czechoslovakia
in a patient taking timolol (’Blocadren’) and feel this may be a side-effect of this drug. A 50-year-old man was admitted as an emergency because of a 48 h history of increasing symptoms of small-bowel obstruction. For 8 years he had been treated for mild proctitis with salazopyrine 2-4 g daily and ’Predsol’ enemas, receiving courses on average three or four times a year. Four barium enemas between 1965 and 1971 had shown no obvious abnormality in the colon. For the 18 months immediately before admission his general practitioner had been treating mild hypertension (200/110 mm Hg) with timolol 10 mg three times
ing peritonitis
was
carried
out
SKIN-TEST ANOMALY
SIR,-Skin testing has been used as a diagnostic tool for allergy for over a hundred years, dating back to Charles Blackley. End-point titration of allergen extracts in the skin of atopics is widely practised and we were surprised when we came upon an anomaly which, we subsequently learned, was first described thirty years ago but not since. Twelve patients seen at a hayfever clinic and having positive skin responses to grass-pollen allergens were prick tested with six ten-fold serial dilutions of five different cocksfoot 2.
Cooke, A. I. M., Foy, P. Ann. R. Coll. Surg. 1976, 58, 473.
(Dactylis