- Email: [email protected]
Renal grafts from non-heart-beating donors
What about the overall safety of clozapine? Of the UK cohort of 6300 individuals exposed to clozapine and registered with the Clozaril Patient Monitoring Service (CPMS) since 1990, only 0-05% per year died of suicide, which is about ten-fold less than the expected rate.9 By the third treatment year, the CPMS reported neutropenia rate is 0-12%, which is similar to that for other phenothiazines. There have been no recorded cases of agranulocytosis after 2 years. There have been 2 deaths due to agranulocytosis in the UK cohort, both in the first of treatment (CPMS database, personal year communication, Karen Atkin). Overall, the prospects for schizophrenics and schizophrenia research are looking up. Robert W Kerwin Section of Clinical Neuropharmacology, Institute of Psychiatry, London, UK 1 2
3
4 5
6 7
8 9
Idanpaan HJ, Alhave E, Olkinnora M, et al. Agranulocytosis during treatment with clozapine. Eur J Clin Pharmacol 1977; 11: 194-98. Coward DM, Imperato A, Urmyler S, et al. Biochemical and behavioural properties or clozapine. Psychopharmacology 1989; 99: S5-12. Kane J, Honigfeld G, Singer J, et al. Clozapine for the treatment resistant schizophrenic: a double blind comparison versus chlorpromazine. Arch Gen Psychiatry 1988; 45: 789-96. Hippius H. The history of clozapine. Psychopharmacology 1989; 99: S3-S5. Carlsson A. Effect of chlorpromazine and haloperidol on formation of 3 methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol 1963; 20: 140-44. Editorial. Atypical treatment for schizophrenia. Lancet 1992; 339: 276-77. Lindstrom LH. The effect of long term treatment with clozapine in schizophrenia: a retrospective study in 96 patients treated with clozapine for up to 13 years. Acta Psychiatr Scand 1988; 77: S24-29. Kane JM, Meltzer HY, Liberman JA. Clozapine 1994. J Clin Psychiatry 1994 (suppl B). Allebeck P, Wistedt B. Mortality in schizophrenia: a ten year follow up based on the Stockholm County inpatient register. Arch Gen Psychiatry
1986; 43: 650-53.
Renal grafts from donors
non-heart-beating
See page 1067 Donation of organs from brain-dead donors seems to have reached a plateau, with little to suggest that numbers of organs from this source can be increased. There is an increasing disparity between supply and need. In many countries the introduction of brain death legislation has allowed the removal of organs from a brain-dead heart-beating donor under the best possible conditions, whereby warm ischaemic time is eliminated. In some countries-eg, Japan-organ removal is permitted only after cardiac arrest, so organs are sometimes removed after a lengthy hypotensive agonal state and a long warm ischaemic period. In Europe, the increasing gap between the number of patients accepted for kidney transplantation and the number receiving transplants has prompted transplant centres to look again at non-heart-beating donors as a source of kidneys for this purpose. Non-heart-beating donors fall into three groups.’ In the first, brain death has been diagnosed but, owing to the lack of brain death legislation, cardiac arrest is confirmed in the operating theatre before the kidneys are removed. The second group comprises donors scheduled for organ removal who have a cardiac arrest before the organised operative procedure-the so-called "controlled" nonheart-beating donor. The third group, or "uncontrolled"
1064
non-heart-beating donors, are those who have a cardiorespiratory arrest just before or soon after admission to hospital. This last group is the focus of efforts to expand the donor pool. Use of these kidneys has been associated with poor results owing to irretrievable kidney damage from warm ischaemia and inadequate flushing during in-situ perfusion. Recently, however, some2,3but not a114 reports have been more encouraging. There are many problems associated with the use of kidneys from these "uncontrolled" or even "controlled" non-heart-beating donors. Llioveras3 reported that in-situ cold perfusion requires pressures of at least 70 mm Hg to be effective. Release of renin and angiotensin is triggered by low flush pressures and leads to reactive vasospasm and poor core cooling. Use of a double balloon catheter with cold perfusion for 3 min at a constant pressure of 70-90 mm Hg and a flow rate of 250-300 mL/min was effective. Matsuno et a 15 reported that addition of machine perfusion of the kidneys after in-situ cooling in non-heart-beating donors improved early graft function when the cold ischaemic time extended beyond 8 h. Even when several grafts have been excluded on the basis of macroscopic appearance and microscopic examination, there is still a high risk of primary graft nonfunction or delayed graft function with the use of nonheart-beating donors. Histological evidence of rejection is significantly higher in patients with delayed graft function than in those with immediate graft function. One suggestion is that ischaemic injury induces altered major histocompatibility complex gene expression and/or lymphocytes are exposed to tissue antigens from tissue destruction and this sequence of events does not occur in the absence of acute tubular necrosis.6 In this issue Wijnen et al report their 12-year experience with the use of non-heart-beating donor kidneys; they were able to increase the number of available kidneys in their area by 20%. They compared the outcome of the kidneys transplanted from these "asystolic" donors with a control group of donor kidneys obtained from heart-beating donors. There was a higher percentage of delayed function in the non-heart-beating kidney group (60% vs 35%), and this was associated with longer hospital stay. Nevertheless, results of long-term graft and patient survival were similar in the two groups. Risk factors with a negative predictive value on graft or patient survival when non-heart-beating donor kidneys were transplanted were donor serum creatinine, donor age, and cold ischaemia time. There are obvious logistic difficulties in the use of asystolic donors with respect to consent from the family and, where necessary, legal authority in the case of unnatural death. These drawbacks, together with technical problems, were instrumental in the nonavailability of more than one-third of the kidneys. This report should challenge other groups to assess the potential of this procedure. A basic requirement is a dedicated well-trained team available immediately to assess the potential donor, initiate in-situ perfusion, obtain the necessary consent, and carry out organ removal. To achieve a worthwhile result, there is an obligatory haste to the whole procedure. Will this have a negative impact on transplant programmes? Respect for the
’--...
recently dead should
is
a
cultural and moral tradition. The dead
other ends. The regarded issues are not the exclusive responsibility of doctors or health professionals; they are the responsibility of the society on whom these pace-setting activities are thrust. To maintain trust, acquiescence of the community is essential. Meanwhile transplant surgeons must control their activities or the presumed social benefit will be not
be
as mere means to
negated. Russell W Strong Princess Alexandra Hospital, Australia 4102
Woolloongabba, Brisbane, Qld,
1 Valero R, Manyalich M, Cabrer C, Salvador L, Garcia-Fages LC. Organ procurement from non-heart-beating donors by total body cooling. Transplant Proc 1993; 25: 3091-92. 2 Varty K, Veitch PS, Morgan JDT, Kehinde EO, Donnelly PK, Bell PRF. Response to organ shortage: kidney retrieval programme using non-heart beating donors. BMJ 1994; 308: 575. 3 Llioveras J, Ping JM, Cerdà M, et al. Optimisation of in situ renal perfusion of non-heart beating donors: four lumen catheter developed for continuous perfusion pressure determination. Transplant Proc 1993; 25: 3169-70. 4 Phillips AO, Snowden SA, Hillis AV, Bewick M. Renal grafts from non-heart beating donors. BMJ 1994; 308: 575-76. 5 Matsuno N, Sakurai E, Uchiyama M, Kozaki K, Tamaki I, Kozaki M. Use of in situ cooling and machine perfusion preservation for nonheart beating donors. Transplant Proc 1993; 25: 3095-96. 6 Howard RJ, Pfaff WW, Brunson ME, et al. Increased incidence of rejection in patients with delayed graft function. Clin Transpl 1994; 8: 527-31.
Protective efficacy of vaccination
hepatitis
B
See 1089 The latest results achieved by The Gambia Hepatitis Intervention Study (reported in this issue) confirm the long-term efficacy of immunisation in preventing carriage of the hepatitis B virus (HBV) and hence its sequelaechronic hepatitis, cirrhosis, and, most important, hepatocellular carcinoma. This is heartening news because there are some 300 million carriers of the virus in the world today and they account for as much as 80% of the more than 310000 new cases of hepatocellular carcinoma that occur each year.’ Most carriers live in the Far East or in Africa and they become infected with HBV early in childhood. Their lifetime relative risk of hepatocellular carcinoma exceeds 100, and 40-50% die from the tumour, cirrhosis, or both diseases.2 Apart from the very high incidence in the Far East and Africa, other reasons why prevention of hepatocellular carcinoma is a priority are the rarity with which the tumour is resectable when symptomatic and its unresponsiveness to conservative forms of treatment, the often fulminant course, and the grave prognosis. The protective efficacy of hepatitis B vaccination against both uncomplicated infection and carriage remains high in Gambian vaccinees even after eight years and despite rapidly decreasing serum concentrations of neutralising antibody. A small proportion of vaccinated children still become infected. Most of these episodes result from failure to finish the course of injections or to respond to the vaccine, or from infection before immunisation is completed.3 The first explanation is especially worrying in rural parts of Africa where immunisation programmes run without the financial and logistic support that is available to The Gambia Hepatitis Intervention Study have had unacceptably high failure
°
-.."
--<.-.,.- --....-’’;’.:,
rates, as judged by receipt of the second and especially the third injections.4 When an individual becomes infected despite successful vaccination (breakthrough infection), titres of protective antibody to HBV have usually declined to a low level. Fortunately, these infections seldom result in carriage because persistence is far less likely when infection is acquired after the first year of life.s A few breakthrough infections do occur in the presence of high circulating concentrations of neutralising antibody, and may result from the production of antibodies of low affinity6 or from infection with vaccine escape mutants of HBV.’ Escape mutants have been detected among vaccinees in Europe, the Far East, and North America, as well as The Gambia.7-9 In unvaccinated children in the Far East, early infection with HBV leading to a carrier state results mainly from perinatal transmission of the virus from replicative carrier mothers.’° To prevent this mode of infection the first dose of the vaccine must be given very soon after birth, and should ideally be supplemented by passive immunisation. Carriage in Asian children has already been substantially reduced by use of this approach: for example, at the age of 6 years, Taiwanese vaccinees have a carrier rate of only 1-7% compared with 10-6% in unvaccinated children (D-S Chen, personal communication). This pattern of transmission contrasts with that in Africa, where the predominant route of spread is horizontal, especially between siblings,"-’3 and where there is less urgency in initiating immunisation. With predominantly horizontal transmission and the high levels of infectivity of recently infected children," vaccination of all seronegative African children aged 1-5 years at the same time that immunisation of infants is begun would be expected to improve the overall protective efficacy of the vaccine. This was the case in The Gambia, where less than half the expected number of breakthrough infections occurred. Our main objectives must now be the universal inclusion of hepatitis B vaccination in the Expanded Programme of Immunisation and the global implementation of the latter, with a view to eventual eradication of this virus and its life-threatening consequences.
Michael C Kew MRC Molecular Hepatology Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa 1 2
3
4
Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 1993; 54: 594-606. Beasley RP. Hepatitis B virus: the major etiology of hepatocellular carcinoma. Cancer 1988; 61: 1942-56. Fortuin M, Chotard J, Jack AD, et al. Efficacy of hepatitis B vaccine in the Gambian expanded programme on immunisation. Lancet 1993; 341: 1129-31. Schoub BI, Johnson S, McAnerney JM, et al. Integration of hepatitis B vaccination into rural African primary health care programmes. BMJ
1991; 302: 313-15. 5
6
7 8
Coursaget P, Yvonnet B, Chotard J, et al. Age- and sex-related study of hepatitis B virus chronic carrier state in infants from an endemic area (Senegal). J Med Virol 1987; 22: 1-5. Brown SE, Howard CR, Zuckerman AJ, Steward MW. Affinity of antibody responses in man to hepatitis B vaccine determined with synthetic peptides. Lancet 1984; ii: 184-87. Carman WF, Zanetti AR, Karayiannis P, et al. Vaccine-induced escape mutant of hepatitis B virus. Lancet 1990; 336: 325-29. Okamoto H, Yano K, Nozaki Y, et al. Mutations within the S gene of hepatitis B virus transmitted from mothers to babies immunised with hepatitis B immune globulin and vaccine. Pediatr Res 1992; 32: 264-68.
1065
3
4 5
6 7
8 9
Idanpaan HJ, Alhave E, Olkinnora M, et al. Agranulocytosis during treatment with clozapine. Eur J Clin Pharmacol 1977; 11: 194-98. Coward DM, Imperato A, Urmyler S, et al. Biochemical and behavioural properties or clozapine. Psychopharmacology 1989; 99: S5-12. Kane J, Honigfeld G, Singer J, et al. Clozapine for the treatment resistant schizophrenic: a double blind comparison versus chlorpromazine. Arch Gen Psychiatry 1988; 45: 789-96. Hippius H. The history of clozapine. Psychopharmacology 1989; 99: S3-S5. Carlsson A. Effect of chlorpromazine and haloperidol on formation of 3 methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol 1963; 20: 140-44. Editorial. Atypical treatment for schizophrenia. Lancet 1992; 339: 276-77. Lindstrom LH. The effect of long term treatment with clozapine in schizophrenia: a retrospective study in 96 patients treated with clozapine for up to 13 years. Acta Psychiatr Scand 1988; 77: S24-29. Kane JM, Meltzer HY, Liberman JA. Clozapine 1994. J Clin Psychiatry 1994 (suppl B). Allebeck P, Wistedt B. Mortality in schizophrenia: a ten year follow up based on the Stockholm County inpatient register. Arch Gen Psychiatry
1986; 43: 650-53.
Renal grafts from donors
non-heart-beating
See page 1067 Donation of organs from brain-dead donors seems to have reached a plateau, with little to suggest that numbers of organs from this source can be increased. There is an increasing disparity between supply and need. In many countries the introduction of brain death legislation has allowed the removal of organs from a brain-dead heart-beating donor under the best possible conditions, whereby warm ischaemic time is eliminated. In some countries-eg, Japan-organ removal is permitted only after cardiac arrest, so organs are sometimes removed after a lengthy hypotensive agonal state and a long warm ischaemic period. In Europe, the increasing gap between the number of patients accepted for kidney transplantation and the number receiving transplants has prompted transplant centres to look again at non-heart-beating donors as a source of kidneys for this purpose. Non-heart-beating donors fall into three groups.’ In the first, brain death has been diagnosed but, owing to the lack of brain death legislation, cardiac arrest is confirmed in the operating theatre before the kidneys are removed. The second group comprises donors scheduled for organ removal who have a cardiac arrest before the organised operative procedure-the so-called "controlled" nonheart-beating donor. The third group, or "uncontrolled"
1064
non-heart-beating donors, are those who have a cardiorespiratory arrest just before or soon after admission to hospital. This last group is the focus of efforts to expand the donor pool. Use of these kidneys has been associated with poor results owing to irretrievable kidney damage from warm ischaemia and inadequate flushing during in-situ perfusion. Recently, however, some2,3but not a114 reports have been more encouraging. There are many problems associated with the use of kidneys from these "uncontrolled" or even "controlled" non-heart-beating donors. Llioveras3 reported that in-situ cold perfusion requires pressures of at least 70 mm Hg to be effective. Release of renin and angiotensin is triggered by low flush pressures and leads to reactive vasospasm and poor core cooling. Use of a double balloon catheter with cold perfusion for 3 min at a constant pressure of 70-90 mm Hg and a flow rate of 250-300 mL/min was effective. Matsuno et a 15 reported that addition of machine perfusion of the kidneys after in-situ cooling in non-heart-beating donors improved early graft function when the cold ischaemic time extended beyond 8 h. Even when several grafts have been excluded on the basis of macroscopic appearance and microscopic examination, there is still a high risk of primary graft nonfunction or delayed graft function with the use of nonheart-beating donors. Histological evidence of rejection is significantly higher in patients with delayed graft function than in those with immediate graft function. One suggestion is that ischaemic injury induces altered major histocompatibility complex gene expression and/or lymphocytes are exposed to tissue antigens from tissue destruction and this sequence of events does not occur in the absence of acute tubular necrosis.6 In this issue Wijnen et al report their 12-year experience with the use of non-heart-beating donor kidneys; they were able to increase the number of available kidneys in their area by 20%. They compared the outcome of the kidneys transplanted from these "asystolic" donors with a control group of donor kidneys obtained from heart-beating donors. There was a higher percentage of delayed function in the non-heart-beating kidney group (60% vs 35%), and this was associated with longer hospital stay. Nevertheless, results of long-term graft and patient survival were similar in the two groups. Risk factors with a negative predictive value on graft or patient survival when non-heart-beating donor kidneys were transplanted were donor serum creatinine, donor age, and cold ischaemia time. There are obvious logistic difficulties in the use of asystolic donors with respect to consent from the family and, where necessary, legal authority in the case of unnatural death. These drawbacks, together with technical problems, were instrumental in the nonavailability of more than one-third of the kidneys. This report should challenge other groups to assess the potential of this procedure. A basic requirement is a dedicated well-trained team available immediately to assess the potential donor, initiate in-situ perfusion, obtain the necessary consent, and carry out organ removal. To achieve a worthwhile result, there is an obligatory haste to the whole procedure. Will this have a negative impact on transplant programmes? Respect for the
’--...
recently dead should
is
a
cultural and moral tradition. The dead
other ends. The regarded issues are not the exclusive responsibility of doctors or health professionals; they are the responsibility of the society on whom these pace-setting activities are thrust. To maintain trust, acquiescence of the community is essential. Meanwhile transplant surgeons must control their activities or the presumed social benefit will be not
be
as mere means to
negated. Russell W Strong Princess Alexandra Hospital, Australia 4102
Woolloongabba, Brisbane, Qld,
1 Valero R, Manyalich M, Cabrer C, Salvador L, Garcia-Fages LC. Organ procurement from non-heart-beating donors by total body cooling. Transplant Proc 1993; 25: 3091-92. 2 Varty K, Veitch PS, Morgan JDT, Kehinde EO, Donnelly PK, Bell PRF. Response to organ shortage: kidney retrieval programme using non-heart beating donors. BMJ 1994; 308: 575. 3 Llioveras J, Ping JM, Cerdà M, et al. Optimisation of in situ renal perfusion of non-heart beating donors: four lumen catheter developed for continuous perfusion pressure determination. Transplant Proc 1993; 25: 3169-70. 4 Phillips AO, Snowden SA, Hillis AV, Bewick M. Renal grafts from non-heart beating donors. BMJ 1994; 308: 575-76. 5 Matsuno N, Sakurai E, Uchiyama M, Kozaki K, Tamaki I, Kozaki M. Use of in situ cooling and machine perfusion preservation for nonheart beating donors. Transplant Proc 1993; 25: 3095-96. 6 Howard RJ, Pfaff WW, Brunson ME, et al. Increased incidence of rejection in patients with delayed graft function. Clin Transpl 1994; 8: 527-31.
Protective efficacy of vaccination
hepatitis
B
See 1089 The latest results achieved by The Gambia Hepatitis Intervention Study (reported in this issue) confirm the long-term efficacy of immunisation in preventing carriage of the hepatitis B virus (HBV) and hence its sequelaechronic hepatitis, cirrhosis, and, most important, hepatocellular carcinoma. This is heartening news because there are some 300 million carriers of the virus in the world today and they account for as much as 80% of the more than 310000 new cases of hepatocellular carcinoma that occur each year.’ Most carriers live in the Far East or in Africa and they become infected with HBV early in childhood. Their lifetime relative risk of hepatocellular carcinoma exceeds 100, and 40-50% die from the tumour, cirrhosis, or both diseases.2 Apart from the very high incidence in the Far East and Africa, other reasons why prevention of hepatocellular carcinoma is a priority are the rarity with which the tumour is resectable when symptomatic and its unresponsiveness to conservative forms of treatment, the often fulminant course, and the grave prognosis. The protective efficacy of hepatitis B vaccination against both uncomplicated infection and carriage remains high in Gambian vaccinees even after eight years and despite rapidly decreasing serum concentrations of neutralising antibody. A small proportion of vaccinated children still become infected. Most of these episodes result from failure to finish the course of injections or to respond to the vaccine, or from infection before immunisation is completed.3 The first explanation is especially worrying in rural parts of Africa where immunisation programmes run without the financial and logistic support that is available to The Gambia Hepatitis Intervention Study have had unacceptably high failure
°
-.."
--<.-.,.- --....-’’;’.:,
rates, as judged by receipt of the second and especially the third injections.4 When an individual becomes infected despite successful vaccination (breakthrough infection), titres of protective antibody to HBV have usually declined to a low level. Fortunately, these infections seldom result in carriage because persistence is far less likely when infection is acquired after the first year of life.s A few breakthrough infections do occur in the presence of high circulating concentrations of neutralising antibody, and may result from the production of antibodies of low affinity6 or from infection with vaccine escape mutants of HBV.’ Escape mutants have been detected among vaccinees in Europe, the Far East, and North America, as well as The Gambia.7-9 In unvaccinated children in the Far East, early infection with HBV leading to a carrier state results mainly from perinatal transmission of the virus from replicative carrier mothers.’° To prevent this mode of infection the first dose of the vaccine must be given very soon after birth, and should ideally be supplemented by passive immunisation. Carriage in Asian children has already been substantially reduced by use of this approach: for example, at the age of 6 years, Taiwanese vaccinees have a carrier rate of only 1-7% compared with 10-6% in unvaccinated children (D-S Chen, personal communication). This pattern of transmission contrasts with that in Africa, where the predominant route of spread is horizontal, especially between siblings,"-’3 and where there is less urgency in initiating immunisation. With predominantly horizontal transmission and the high levels of infectivity of recently infected children," vaccination of all seronegative African children aged 1-5 years at the same time that immunisation of infants is begun would be expected to improve the overall protective efficacy of the vaccine. This was the case in The Gambia, where less than half the expected number of breakthrough infections occurred. Our main objectives must now be the universal inclusion of hepatitis B vaccination in the Expanded Programme of Immunisation and the global implementation of the latter, with a view to eventual eradication of this virus and its life-threatening consequences.
Michael C Kew MRC Molecular Hepatology Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa 1 2
3
4
Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 1993; 54: 594-606. Beasley RP. Hepatitis B virus: the major etiology of hepatocellular carcinoma. Cancer 1988; 61: 1942-56. Fortuin M, Chotard J, Jack AD, et al. Efficacy of hepatitis B vaccine in the Gambian expanded programme on immunisation. Lancet 1993; 341: 1129-31. Schoub BI, Johnson S, McAnerney JM, et al. Integration of hepatitis B vaccination into rural African primary health care programmes. BMJ
1991; 302: 313-15. 5
6
7 8
Coursaget P, Yvonnet B, Chotard J, et al. Age- and sex-related study of hepatitis B virus chronic carrier state in infants from an endemic area (Senegal). J Med Virol 1987; 22: 1-5. Brown SE, Howard CR, Zuckerman AJ, Steward MW. Affinity of antibody responses in man to hepatitis B vaccine determined with synthetic peptides. Lancet 1984; ii: 184-87. Carman WF, Zanetti AR, Karayiannis P, et al. Vaccine-induced escape mutant of hepatitis B virus. Lancet 1990; 336: 325-29. Okamoto H, Yano K, Nozaki Y, et al. Mutations within the S gene of hepatitis B virus transmitted from mothers to babies immunised with hepatitis B immune globulin and vaccine. Pediatr Res 1992; 32: 264-68.
1065