80
increased to 1 in 400 and will therefore require careful counselling and attitude assessment to determine whether this status is acceptable. The effort now being expended worldwide on identification of other mutations should reduce this proportion in the near future. Meanwhile, it seems prudent to instigate pilot studies to determine the best point at which to screen
(eg, antenatal, family planning, or general practice clinic) and to assess how people react to being told their genetic status. Assuming an uptake of 85% among pregnant women (the most likely target group) and 90% among their partners, and detection of 75% of CF mutations, the incidence of CF among those tested could be reduced by over 40%. Since any screening programme will take several years to become fully operational, pilot schemes should be introduced in the very near future. It is important that the mistakes made in the introduction of screening for sickle-cell anaemia are not repeated and that lessons are learnt from the successful screening for p-thalassaemia in Mediterranean populations.16 Detection of heterozygotes carrying the D F 508 mutation is facilitated by the use of polyacrylamide gel electrophoresis, which obviates the need for radioisotopes .’-7,111 Alternatively, the amplification refractory mutation system (ARMS)l9 may prove useful for analysis of this mutation. Thus cloning of the CF gene gives hope for a greater understanding of the disease, for more effective treatment regimens in the long term, and most importantly, for heterozygote screening. Carrier screening should be freely available for two main reasons: (a) it gives prospective parents the chance to make an informed choice, and (b) the reduction in the incidence of CF in the population will free resources for the CF patients alive today. In the UK, screening for the A F508 mutation alone would identify 120 CF fetuses each year out of approximately 700 000 pregnancies in the country as a whole.
11. Stewart AD. Screening for cystic fibrosis. Nature 1989; 341: 696. 12. Ten Kate LP. Carrier screening in CF. Nature 1989; 342: 131. 13. Roderick PJ, Chapple J. Screening for cytstic fibrosis. Lancet 1989; ii: 1403-04. 14. McIntosh I, Lorenzo M-Z, Brock DJH. Frequency of &Dgr;F508 mutation on cystic fibrosis chromosomes in UK. Lancet 1989; ii: 1404-05. 15. Estivill X, Chillon M, Casals T, et al. &Dgr;F508 gene deletion in cystic fibrosis in Southern Europe. Lancet 1989; ii: 1404. 16. The haemoglobinopathies in Europe: combined report on two WHO meetings. Copenhagen: WHO Regional Office for Europe, 1988. 17. Mathew CG, Roberts RG, Harris A, et al. Rapid screening for &Dgr;F508 deletion in cystic fibrosis. Lancet 1989; ii: 1346. 18. Schieffer H, Verlind E, Penninga D, et al. Rapid screening for &Dgr;F508 deletion in cystic fibrosis. Lancet 1989; ii: 1345-46. 19. Newton CR, Heptinstall LE, Summers C, et al. Amplification refractory mutation system for prenatal diagnosis and carrier assessment in cystic fibrosis. Lancet 1989; ii: 1481-83.
in the the numbers
Organ donors
During the past five years services for patients with end-stage renal failure in the UK have improved considerably. By extending the age limits to include the very young and the old, acceptance rates have risen steadilyin 1987, 50 new patients per million of the population (pmp) were taken on for treatment that year.1988 saw a further rise, with some areas, such as Wales, accepting over 70 new patients pmp for treatment.2 Kidney transplant survival rates have also improved to the extent that approximately 80% of first cadaveric kidney transplants can now be expected function for at least a year. Yet there has been no improvement in the supply of cadaveric organs for transplantation. In 1981, Jennett estimated that there were 4000 brainstem deaths annually in the UK,3 and it had been assumed that if sufficient effort was made to identify these individuals as organ donors there would be enough kidneys to supply the dialysis population. However, the annual rate of kidney transplantation only increased from 1443 to 1575 between 1984 and 1988 and transplant activity during 1989 was only marginally better. The waiting list for transplantation continues to increase, and now stands to
at
3684.
The
1. Rommens JM, lanuzzi MC, Kerem B, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989; 245: 1059-65. 2. Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989; 245: 1066-73. 3. McIntosh I, Raeburn JA, Curtis A, Brock DJH. First trimester prenatal diagnosis of cystic fibrosis by direct gene probing. Lancet 1989; ii: 972-73. 4. Boat TF, Welsh MJ, Beaudet AL. Cystic fibrosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease, 6th ed. New York: McGraw-Hill, 1989: 2649-80. 5. Goodfellow PN, ed. Cystic fibrosis. Oxford: Oxford University Press, 1989. 6. Higgins C. Protein joins transport family. Nature 1989; 341: 103. 7. Kerem B, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989; 245: 1074-80. 8. Cappechi MR. The new mouse genetics: altering the genome by gene targetting. Trends Genet 1989; 5: 70-76. 9. Danielson H. Gene therapy in man. Lancet 1988; i: 1271-72. 10. Wu CH, Wilson JM, Wu GY. Targeting genes: delivery and persistent expression of a foreign gene driven by mammalian regulatory elements in vivo. J Biol Chem 1989; 264: 16985-87.
UK—getting right
1988
represents just 29 kidney which is less than half the rate transplants year pmp, required to match the annual accrual of patients with renal failure. Dr Gore and her colleaguess have lately reported the results of an audit that was carried out in 278 intensive care units in England. Of 2853 deaths recorded during the first quarter of 1989, only 148 patients (5%) became organ donors-ie, 12 donors or
figure
a
24 kidneys pmp. Realisation that the supply of cadaver kidneys might have reached a ceiling has prompted much debate, since, if true, the long-term objectives for the management of patients with renal failure may have to be revised (and recosted). A symposium on organ donation was held in November at the Department of Health, and further discussions took place at a similar symposium in Cardiff, and at the autumn meeting of the British Transplantation Society. At the symposia, some preliminary and as yet unpublished findings were presented from an audit of hospital deaths that had just beeP
81
completed in South Wales by Dr I. Harvey, Dr S. Frankel, and Dr M. Salih in the Department of Epidemiology and Community Medicine in Cardiff. The results of this study are awaited with considerable interest because its approach has been methodologically different from that of the English audit. These researchers looked for possible organ donors among hospital deaths, not merely those occurring within intensive care units, and sought to identify, in addition to conventional donors with brainstem death, unventilated patients dying outside intensive care units with primary and progressive cerebral disease. For such patients to become organ donors, they would need ventilation as soon as breathing had ceased to preserve circulation while the transplant team was notified and consent was sought from the relatives and the coroner. There were considerable differences of opinion at the symposia as to whether it was practical or indeed ethical to ventilate someone purely for the purpose of organ donation. Moreover, would patients "resuscitated" in this way fulfil all the criteria of brainstem death, when formally tested afterwards? Those with catastrophic cerebrovascular accidents might well, whereas those dying slowly of brain tumours might not. The Glasgow neurosurgical unit has a policy of not electively ventilating patients for the purpose of organ donation. Physicians and surgeons in Exeter, however, have taken the opposite view, and organ donation rates have doubled there as a result.6
Kidney transplantation rates in the UK are similar to those reported from much of Europe. In Sweden, Austria, and Belgium, however, there were approximately 40 transplants pmp done in 1988 compared with 28 pmp for the UK.The group from Leuven, Belgium, have suggested that the high donation rates in their country and in Austria that underlie these figures have been the result of an opting-out law.8 Nevertheless, there may be other reasons-eg, the high rate of fatal accidents in the two countries. In 1987, Austria and Belguim had 188 and 192 fatal traffic accidents pmp, respectively;9 in the UK, the figure was 91 pmp, and this fell to 89 pmp in 1988.’° Victims of road traffic accidents make up 30 % of the total number of cadaveric kidney donor population.1 Donation rates within the regions of the UK vary considerably. In 1988, Wales achieved the highest rate of 20 donors (40 kidneys) pmp,t possibly as a result of a locally organised opting-in donor scheme. This observation would suggest that accident rates are not a critical factor, and that donation levels equivalent to those reported from Austria and Belgium can still be achieved. At first sight the gap between the annual accrual rate for patients with renal failure in the UK (which is about 60 pmp) and the current number of cadaveric kidneys (28 pmp) would seem unbridgeable. This is not necessarily the case, because the equation is profoundly influenced by the proportion of dialysis patients who are placed on the transplant waiting list. In the UK this figure is approximately 45 % .1 It is often the patient’s wish not to have a transplant; the age of the patient or the presence of medical contraindications can also explain why patients are excluded. By international comparisons, the UK has a
good record of offering transplantation to its dialysis population. In West Germany, France, and Belgium the proportions of dialysis patients on the transplant waiting list are 20%, 16%, and 14%, respectively. The expected failure of approximately 10 % of kidney transplants per year means that there will be an additional of group patients requiring If is to retransplantation. transplantation keep pace with the accrual of all suitable kidney transplant candidates, 2700 grafts will have to be carried out each year-a 72 % increase on the figure of 1575 achieved in 1988.
Careful
study of the English audit
has provided some clues as to how organ donation might be increased. Consent to donation was refused by the relatives of 30 % of the donors. Although in some cases the relatives may have been acting upon the expressed wishes of the donor, in many instances a negative response from the relatives is the result of indecision. When the potential donor has registered his consent on a donor card, the relatives are usually willing to comply with that request. The acceptance rate by relatives, therefore, could be modified by further promoting the donor card scheme and by encouraging the establishment of local registries for opting-in, as already exist in Wales, Manchester, and Birmingham. It is also important that the relatives are approached by someone who is suitably trained and experienced. Transplant coordinators have often found that senior nursing staff on the intensive care units are the most successful in obtaining consent. In the English audit, failure to seek consent occurred in 14 cases, or 6% of the potential donors,s and recent reports from the intensive care unit at Addenbrooke’s Hospital, Cambridge," and the Glasgow neurosurgical unit12 have provided similar figures. It is crucially important that the view of the relatives is sought in every case. There is a much larger pool of patients-17% of brainstem dead patients in the English audit-in whom brain death was diagnosed but who were not considered suitable for organ donation. Although in many instances there may have been good medical reasons for excluding these patients as donors (eg, overwhelming sepsis), both the English and Welsh audits have identified a mismatch between the criteria being applied by the donating hospitals and those currently recommended by the transplant teams. As a result, many donors were excluded by intensive care unit staff on grounds that the transplant teams would not have considered valid. There is clearly scope for increasing donor numbers by improving communications between the transplant teams and the contributing hospitals; this is the prime function of transplant coordinators, and their rapid appointment to all regions in the UK is an urgent requirement. Many donors are lost when circulatory collapse occurs before brainstem testing can be completed. This is sometimes occasioned by clinicians wishing to wait a full 24 hours before initiating the second set of tests. In the code of practice circulated in 1983, the
82
period between tests is not stipulated but is "a matter for discussion" by the two doctors diagnosing brainstem death.13 Donor numbers could probably be increased if the interval between the tests of brainstem function were shortened in potential donors who were cardiovascularly unstable. Sometimes the circulation can be improved by use of antidiuretic agents and hormones in addition to the more usual methods. Intensive care units should be able to obtain advice on these manoeuvres from the transplant coordinators. If the circulation collapses and asystole develops in the potential donor, it may still be possible to salvage the organs if the transplant team is on hand. "1n the English audit, five successful donations occurred under these circumstances.S Finally, there is a large group of patients who die in hospital with a possible diagnosis of brainstem death, in whom formal testing of brainstem function is never considered. In the English audit, such patients comprised 26% of those with possible brainstem death who died in intensive care units. Additionally, the Welsh audit has pointed to the existence of a large number of potentially suitable patients who die, unventilated, outside intensive care units. If such patients were to have become donors (which may well have been their wish), they would have needed to be ventilated and formally tested for brainstem death as already mentioned. In most hospitals the intensive care units are very busy and would have great difficulty in taking on this task. Ventilation, however, could take place in a high-dependency unit or even in a cubicle on a general ward. Since the potential for increasing donor numbers is greatest in this area, acute hospitals should be provided with funds to increase their facilities for ventilating patients. How then might the numbers work out? Improved measures for identifying and obtaining donors from intensive care units could raise the annual donation rate by 3 donors pmp. A rise of this order, albeit brief, is often observed when there has been nationwide publicity on the need for donor organs.14 The use of potential .donors dying on medical wards might provide another 5 donors pmp and this figure, when added to the current rate of donation, would give a total of 22 donors or 44 kidneys pmp. Such a figure is not too far removed from the perceived annual need of 48 kidneys pmp as calculated earlier. There is still a problem of finding kidneys for the large pool of patients already on the transplant waiting list. Some of this shortfall could be made up by increasing the use of
living related kidney donors. Raising the rate of kidney donation would also provide more hearts, heart-lungs, and livers for transplantation. The need for these organs is as great as for kidneys; at the end of October, 1989, 232 patients were waiting for heart transplants, 213 for heart-lungs, and 47 for liver transplants.4 The prospects for transplantation in the 1990s are not as bleak as the figures would at first suggest and there are practical ways by which donor numbers can be increased. Acute hospitals should look to how this
goal can be achieved in their own locality. Kingdom Transplant Service 1989 Annual Report. Obtainable from UKTS, Southmead Hospital, Bristol BS10 5NB. 2. Smith WGJ, Cohen DR, Asscher AW. Evaluation of renal services m Wales 1989. Report to the Welsh Office. 3. Jennett B. Brain death. Br J Anaesth 1981; 53: 1111-19. 4. Data from United Kingdom Transplant Service, Southmead Hospital, Bristol BS10 5NB. 5. Gore SM, Hinds CJ, Rutherford AJ. Organ donation from intensive care units in England. Br Med J 1989; 299: 1193-97. 6. Collins C. Organs for transplantation. Br Med J 1989; 299: 1463. 7. Combined report on regular dialysis and transplantation in Europe XIX. EDTA, 1988. 8. Vanrenterghem Y, Waer M, Roels T, et al. Shortage of kidneys, a solvable problem? The Leuven experience. Clinical transplants 1988. In: Terasaki P, ed. Los Angeles: UCLA Tissue Typing Laboratory, 1989. 9. Eurotransplant Newsletter no 69, November, 1989. 10. Road accidents. Great Britain 1988—The Casualty Report. London: HM Stationery Office, 1989. 11. Bodenham A, Berridge JC, Park GR. Brain stem death and organ donation. Br Med J 1989; 299: 1009-10. 12. Jennett B, Gentleman D. Brain stem death and organ donation. Br Med J 1989; 299: 1398-99. 13. Cadaveric organs for tranpslantation. A code of practice including the diagnosis of brain death. London: Department of Health, 1983. 14. United Kingdom Transplant Service bulletin no 68, 1989. Obtainable from UKTS, Southmead Hospital, Bristol BS10 5NR. 1. United
CHEMOTHERAPY: TOPOISOMERASES AS TARGETS An obvious goal of molecular studies in oncology is the identification of biochemical processes so characteristic of malignant cells that it will be possible to design and develop drugs with specific and predictable anti-cancer effects. This may be some way off in practice; most of the drugs in use today have evolved through empirical, even serendipitous, observation followed by chemical manipulation of a parent molecule and systematic screening until the most useful analogues have been identified. Somewhere between these two approaches comes the detailed study of compounds of proven value in cancer chemotherapy. The answers to the question "How do they work?" can be remarkably illuminating. Thus several drugs formerly regarded as
DNA-intercalating or chromosome-fragmenting agents are now known to act as topoisomerase "poisons". Two classes of DNA topoisomerase (types I and II) are recognised in mammalian cells and, in man at least, each is probably encoded by a single gene.1.2 The function of these enzyme systems appears to be to facilitate the
relaxation,
unwinding, controlled cleavage, and rejoining of the DNA helix during replication and transcription. DNA is such a large and unwieldy molecule that without topoisomerases it would be unable to participate in many biochemical reactions and would degenerate into an irretrievable tangle. Not surprisingly, topoisomerase activity tends to be high in cells that are metabolically very active, especially in those from rapidly dividing tissues. While much remains to be learned about the details of topoisomerase activity and the differences between types I and II, it seems clear that both are required for long-term cell survival. Topoisomerase I can cleave only a single DNA strand whereas type II cleaves both strands of the helix. The enzyme forms a protein bridge across the ends of the divided DNA molecule until continuity is restored, but topoisomerase poisons stabilise the DNA/protein complex so that the normally process of strand division, disentangling, and rejoining is
rapid
increased to 1 in 400 and will therefore require careful counselling and attitude assessment to determine whether this status is acceptable. The effort now being expended worldwide on identification of other mutations should reduce this proportion in the near future. Meanwhile, it seems prudent to instigate pilot studies to determine the best point at which to screen
(eg, antenatal, family planning, or general practice clinic) and to assess how people react to being told their genetic status. Assuming an uptake of 85% among pregnant women (the most likely target group) and 90% among their partners, and detection of 75% of CF mutations, the incidence of CF among those tested could be reduced by over 40%. Since any screening programme will take several years to become fully operational, pilot schemes should be introduced in the very near future. It is important that the mistakes made in the introduction of screening for sickle-cell anaemia are not repeated and that lessons are learnt from the successful screening for p-thalassaemia in Mediterranean populations.16 Detection of heterozygotes carrying the D F 508 mutation is facilitated by the use of polyacrylamide gel electrophoresis, which obviates the need for radioisotopes .’-7,111 Alternatively, the amplification refractory mutation system (ARMS)l9 may prove useful for analysis of this mutation. Thus cloning of the CF gene gives hope for a greater understanding of the disease, for more effective treatment regimens in the long term, and most importantly, for heterozygote screening. Carrier screening should be freely available for two main reasons: (a) it gives prospective parents the chance to make an informed choice, and (b) the reduction in the incidence of CF in the population will free resources for the CF patients alive today. In the UK, screening for the A F508 mutation alone would identify 120 CF fetuses each year out of approximately 700 000 pregnancies in the country as a whole.
11. Stewart AD. Screening for cystic fibrosis. Nature 1989; 341: 696. 12. Ten Kate LP. Carrier screening in CF. Nature 1989; 342: 131. 13. Roderick PJ, Chapple J. Screening for cytstic fibrosis. Lancet 1989; ii: 1403-04. 14. McIntosh I, Lorenzo M-Z, Brock DJH. Frequency of &Dgr;F508 mutation on cystic fibrosis chromosomes in UK. Lancet 1989; ii: 1404-05. 15. Estivill X, Chillon M, Casals T, et al. &Dgr;F508 gene deletion in cystic fibrosis in Southern Europe. Lancet 1989; ii: 1404. 16. The haemoglobinopathies in Europe: combined report on two WHO meetings. Copenhagen: WHO Regional Office for Europe, 1988. 17. Mathew CG, Roberts RG, Harris A, et al. Rapid screening for &Dgr;F508 deletion in cystic fibrosis. Lancet 1989; ii: 1346. 18. Schieffer H, Verlind E, Penninga D, et al. Rapid screening for &Dgr;F508 deletion in cystic fibrosis. Lancet 1989; ii: 1345-46. 19. Newton CR, Heptinstall LE, Summers C, et al. Amplification refractory mutation system for prenatal diagnosis and carrier assessment in cystic fibrosis. Lancet 1989; ii: 1481-83.
in the the numbers
Organ donors
During the past five years services for patients with end-stage renal failure in the UK have improved considerably. By extending the age limits to include the very young and the old, acceptance rates have risen steadilyin 1987, 50 new patients per million of the population (pmp) were taken on for treatment that year.1988 saw a further rise, with some areas, such as Wales, accepting over 70 new patients pmp for treatment.2 Kidney transplant survival rates have also improved to the extent that approximately 80% of first cadaveric kidney transplants can now be expected function for at least a year. Yet there has been no improvement in the supply of cadaveric organs for transplantation. In 1981, Jennett estimated that there were 4000 brainstem deaths annually in the UK,3 and it had been assumed that if sufficient effort was made to identify these individuals as organ donors there would be enough kidneys to supply the dialysis population. However, the annual rate of kidney transplantation only increased from 1443 to 1575 between 1984 and 1988 and transplant activity during 1989 was only marginally better. The waiting list for transplantation continues to increase, and now stands to
at
3684.
The
1. Rommens JM, lanuzzi MC, Kerem B, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989; 245: 1059-65. 2. Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989; 245: 1066-73. 3. McIntosh I, Raeburn JA, Curtis A, Brock DJH. First trimester prenatal diagnosis of cystic fibrosis by direct gene probing. Lancet 1989; ii: 972-73. 4. Boat TF, Welsh MJ, Beaudet AL. Cystic fibrosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease, 6th ed. New York: McGraw-Hill, 1989: 2649-80. 5. Goodfellow PN, ed. Cystic fibrosis. Oxford: Oxford University Press, 1989. 6. Higgins C. Protein joins transport family. Nature 1989; 341: 103. 7. Kerem B, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989; 245: 1074-80. 8. Cappechi MR. The new mouse genetics: altering the genome by gene targetting. Trends Genet 1989; 5: 70-76. 9. Danielson H. Gene therapy in man. Lancet 1988; i: 1271-72. 10. Wu CH, Wilson JM, Wu GY. Targeting genes: delivery and persistent expression of a foreign gene driven by mammalian regulatory elements in vivo. J Biol Chem 1989; 264: 16985-87.
UK—getting right
1988
represents just 29 kidney which is less than half the rate transplants year pmp, required to match the annual accrual of patients with renal failure. Dr Gore and her colleaguess have lately reported the results of an audit that was carried out in 278 intensive care units in England. Of 2853 deaths recorded during the first quarter of 1989, only 148 patients (5%) became organ donors-ie, 12 donors or
figure
a
24 kidneys pmp. Realisation that the supply of cadaver kidneys might have reached a ceiling has prompted much debate, since, if true, the long-term objectives for the management of patients with renal failure may have to be revised (and recosted). A symposium on organ donation was held in November at the Department of Health, and further discussions took place at a similar symposium in Cardiff, and at the autumn meeting of the British Transplantation Society. At the symposia, some preliminary and as yet unpublished findings were presented from an audit of hospital deaths that had just beeP
81
completed in South Wales by Dr I. Harvey, Dr S. Frankel, and Dr M. Salih in the Department of Epidemiology and Community Medicine in Cardiff. The results of this study are awaited with considerable interest because its approach has been methodologically different from that of the English audit. These researchers looked for possible organ donors among hospital deaths, not merely those occurring within intensive care units, and sought to identify, in addition to conventional donors with brainstem death, unventilated patients dying outside intensive care units with primary and progressive cerebral disease. For such patients to become organ donors, they would need ventilation as soon as breathing had ceased to preserve circulation while the transplant team was notified and consent was sought from the relatives and the coroner. There were considerable differences of opinion at the symposia as to whether it was practical or indeed ethical to ventilate someone purely for the purpose of organ donation. Moreover, would patients "resuscitated" in this way fulfil all the criteria of brainstem death, when formally tested afterwards? Those with catastrophic cerebrovascular accidents might well, whereas those dying slowly of brain tumours might not. The Glasgow neurosurgical unit has a policy of not electively ventilating patients for the purpose of organ donation. Physicians and surgeons in Exeter, however, have taken the opposite view, and organ donation rates have doubled there as a result.6
Kidney transplantation rates in the UK are similar to those reported from much of Europe. In Sweden, Austria, and Belgium, however, there were approximately 40 transplants pmp done in 1988 compared with 28 pmp for the UK.The group from Leuven, Belgium, have suggested that the high donation rates in their country and in Austria that underlie these figures have been the result of an opting-out law.8 Nevertheless, there may be other reasons-eg, the high rate of fatal accidents in the two countries. In 1987, Austria and Belguim had 188 and 192 fatal traffic accidents pmp, respectively;9 in the UK, the figure was 91 pmp, and this fell to 89 pmp in 1988.’° Victims of road traffic accidents make up 30 % of the total number of cadaveric kidney donor population.1 Donation rates within the regions of the UK vary considerably. In 1988, Wales achieved the highest rate of 20 donors (40 kidneys) pmp,t possibly as a result of a locally organised opting-in donor scheme. This observation would suggest that accident rates are not a critical factor, and that donation levels equivalent to those reported from Austria and Belgium can still be achieved. At first sight the gap between the annual accrual rate for patients with renal failure in the UK (which is about 60 pmp) and the current number of cadaveric kidneys (28 pmp) would seem unbridgeable. This is not necessarily the case, because the equation is profoundly influenced by the proportion of dialysis patients who are placed on the transplant waiting list. In the UK this figure is approximately 45 % .1 It is often the patient’s wish not to have a transplant; the age of the patient or the presence of medical contraindications can also explain why patients are excluded. By international comparisons, the UK has a
good record of offering transplantation to its dialysis population. In West Germany, France, and Belgium the proportions of dialysis patients on the transplant waiting list are 20%, 16%, and 14%, respectively. The expected failure of approximately 10 % of kidney transplants per year means that there will be an additional of group patients requiring If is to retransplantation. transplantation keep pace with the accrual of all suitable kidney transplant candidates, 2700 grafts will have to be carried out each year-a 72 % increase on the figure of 1575 achieved in 1988.
Careful
study of the English audit
has provided some clues as to how organ donation might be increased. Consent to donation was refused by the relatives of 30 % of the donors. Although in some cases the relatives may have been acting upon the expressed wishes of the donor, in many instances a negative response from the relatives is the result of indecision. When the potential donor has registered his consent on a donor card, the relatives are usually willing to comply with that request. The acceptance rate by relatives, therefore, could be modified by further promoting the donor card scheme and by encouraging the establishment of local registries for opting-in, as already exist in Wales, Manchester, and Birmingham. It is also important that the relatives are approached by someone who is suitably trained and experienced. Transplant coordinators have often found that senior nursing staff on the intensive care units are the most successful in obtaining consent. In the English audit, failure to seek consent occurred in 14 cases, or 6% of the potential donors,s and recent reports from the intensive care unit at Addenbrooke’s Hospital, Cambridge," and the Glasgow neurosurgical unit12 have provided similar figures. It is crucially important that the view of the relatives is sought in every case. There is a much larger pool of patients-17% of brainstem dead patients in the English audit-in whom brain death was diagnosed but who were not considered suitable for organ donation. Although in many instances there may have been good medical reasons for excluding these patients as donors (eg, overwhelming sepsis), both the English and Welsh audits have identified a mismatch between the criteria being applied by the donating hospitals and those currently recommended by the transplant teams. As a result, many donors were excluded by intensive care unit staff on grounds that the transplant teams would not have considered valid. There is clearly scope for increasing donor numbers by improving communications between the transplant teams and the contributing hospitals; this is the prime function of transplant coordinators, and their rapid appointment to all regions in the UK is an urgent requirement. Many donors are lost when circulatory collapse occurs before brainstem testing can be completed. This is sometimes occasioned by clinicians wishing to wait a full 24 hours before initiating the second set of tests. In the code of practice circulated in 1983, the
82
period between tests is not stipulated but is "a matter for discussion" by the two doctors diagnosing brainstem death.13 Donor numbers could probably be increased if the interval between the tests of brainstem function were shortened in potential donors who were cardiovascularly unstable. Sometimes the circulation can be improved by use of antidiuretic agents and hormones in addition to the more usual methods. Intensive care units should be able to obtain advice on these manoeuvres from the transplant coordinators. If the circulation collapses and asystole develops in the potential donor, it may still be possible to salvage the organs if the transplant team is on hand. "1n the English audit, five successful donations occurred under these circumstances.S Finally, there is a large group of patients who die in hospital with a possible diagnosis of brainstem death, in whom formal testing of brainstem function is never considered. In the English audit, such patients comprised 26% of those with possible brainstem death who died in intensive care units. Additionally, the Welsh audit has pointed to the existence of a large number of potentially suitable patients who die, unventilated, outside intensive care units. If such patients were to have become donors (which may well have been their wish), they would have needed to be ventilated and formally tested for brainstem death as already mentioned. In most hospitals the intensive care units are very busy and would have great difficulty in taking on this task. Ventilation, however, could take place in a high-dependency unit or even in a cubicle on a general ward. Since the potential for increasing donor numbers is greatest in this area, acute hospitals should be provided with funds to increase their facilities for ventilating patients. How then might the numbers work out? Improved measures for identifying and obtaining donors from intensive care units could raise the annual donation rate by 3 donors pmp. A rise of this order, albeit brief, is often observed when there has been nationwide publicity on the need for donor organs.14 The use of potential .donors dying on medical wards might provide another 5 donors pmp and this figure, when added to the current rate of donation, would give a total of 22 donors or 44 kidneys pmp. Such a figure is not too far removed from the perceived annual need of 48 kidneys pmp as calculated earlier. There is still a problem of finding kidneys for the large pool of patients already on the transplant waiting list. Some of this shortfall could be made up by increasing the use of
living related kidney donors. Raising the rate of kidney donation would also provide more hearts, heart-lungs, and livers for transplantation. The need for these organs is as great as for kidneys; at the end of October, 1989, 232 patients were waiting for heart transplants, 213 for heart-lungs, and 47 for liver transplants.4 The prospects for transplantation in the 1990s are not as bleak as the figures would at first suggest and there are practical ways by which donor numbers can be increased. Acute hospitals should look to how this
goal can be achieved in their own locality. Kingdom Transplant Service 1989 Annual Report. Obtainable from UKTS, Southmead Hospital, Bristol BS10 5NB. 2. Smith WGJ, Cohen DR, Asscher AW. Evaluation of renal services m Wales 1989. Report to the Welsh Office. 3. Jennett B. Brain death. Br J Anaesth 1981; 53: 1111-19. 4. Data from United Kingdom Transplant Service, Southmead Hospital, Bristol BS10 5NB. 5. Gore SM, Hinds CJ, Rutherford AJ. Organ donation from intensive care units in England. Br Med J 1989; 299: 1193-97. 6. Collins C. Organs for transplantation. Br Med J 1989; 299: 1463. 7. Combined report on regular dialysis and transplantation in Europe XIX. EDTA, 1988. 8. Vanrenterghem Y, Waer M, Roels T, et al. Shortage of kidneys, a solvable problem? The Leuven experience. Clinical transplants 1988. In: Terasaki P, ed. Los Angeles: UCLA Tissue Typing Laboratory, 1989. 9. Eurotransplant Newsletter no 69, November, 1989. 10. Road accidents. Great Britain 1988—The Casualty Report. London: HM Stationery Office, 1989. 11. Bodenham A, Berridge JC, Park GR. Brain stem death and organ donation. Br Med J 1989; 299: 1009-10. 12. Jennett B, Gentleman D. Brain stem death and organ donation. Br Med J 1989; 299: 1398-99. 13. Cadaveric organs for tranpslantation. A code of practice including the diagnosis of brain death. London: Department of Health, 1983. 14. United Kingdom Transplant Service bulletin no 68, 1989. Obtainable from UKTS, Southmead Hospital, Bristol BS10 5NR. 1. United
CHEMOTHERAPY: TOPOISOMERASES AS TARGETS An obvious goal of molecular studies in oncology is the identification of biochemical processes so characteristic of malignant cells that it will be possible to design and develop drugs with specific and predictable anti-cancer effects. This may be some way off in practice; most of the drugs in use today have evolved through empirical, even serendipitous, observation followed by chemical manipulation of a parent molecule and systematic screening until the most useful analogues have been identified. Somewhere between these two approaches comes the detailed study of compounds of proven value in cancer chemotherapy. The answers to the question "How do they work?" can be remarkably illuminating. Thus several drugs formerly regarded as
DNA-intercalating or chromosome-fragmenting agents are now known to act as topoisomerase "poisons". Two classes of DNA topoisomerase (types I and II) are recognised in mammalian cells and, in man at least, each is probably encoded by a single gene.1.2 The function of these enzyme systems appears to be to facilitate the
relaxation,
unwinding, controlled cleavage, and rejoining of the DNA helix during replication and transcription. DNA is such a large and unwieldy molecule that without topoisomerases it would be unable to participate in many biochemical reactions and would degenerate into an irretrievable tangle. Not surprisingly, topoisomerase activity tends to be high in cells that are metabolically very active, especially in those from rapidly dividing tissues. While much remains to be learned about the details of topoisomerase activity and the differences between types I and II, it seems clear that both are required for long-term cell survival. Topoisomerase I can cleave only a single DNA strand whereas type II cleaves both strands of the helix. The enzyme forms a protein bridge across the ends of the divided DNA molecule until continuity is restored, but topoisomerase poisons stabilise the DNA/protein complex so that the normally process of strand division, disentangling, and rejoining is
rapid
