1283 inol 300 mg orally per day in divided dosage. Laboratory data were in keeping with hyperglycaemic diabetic decompensation and the observed clinical features, but her response to treatment was satisfactory. However, after 2 weeks on allopurinol, serum-urate remained high at 0-84 mmol/1. On June 13, 1977, the patient’s low creatinine clearance (0.99 ml/s, normal range 1.33-2-00) pointed to the need for caution in increasing the dose of allopurinol, to 400 mg per day. On June 16 the patient had an intensely pruritic generalised macular and vesicular eruption. Simultaneously, her white-blood-cell count fell dramatically. All drugs except insulin were withheld. 2 days later no circulating granulocytes remained, and microscopy of bone-marrow aspirate showed severe myeloid depression but reactive erythroid hyperplasia. An earlier sample (June 10) showed reactive myeloid hyperplasia, all other cellular elements being normal. Pseudomonas aruginosa was isolated in blood culture on June 21 and, despite antibiotics, the patient died in acute oliguric renal failure. Just before her death she had small numbers of circulating neutrophils (16% of 0 .3 x 109/1) suggesting marrow recovery. This case has similarities to Greenberg and Zambrano’s,9 including the metabolic derangement, sudden development of rash, suggestion of marrow recovery, and fatal outcome. Both patients showed adverse reactions when allopurinol was increased to 400 mg per day. Allopurinol and its metabolite alloxanthine are excreted mainly in the urine, but this patient was not oliguric until shortly before death. Leith Hospital, Edinburgh EH6 6TH
D. G. WILKINSON
MEASUREMENT OF CREATINE KINASE MB ISOENZYME
SiR,-Dr Roberts and his colleagues (Aug. 13,
p. 319) disfor creatine kinase MB isoen-
radioimmunoassay (R.I.A.) (MB-c.K.) The R.I.A. was claimed to be the method of choice for diagnosis of myocardial infarction since it could detect MB isoenzyme at levels in the 1-10 mi.u./ml range. An alternative column-chromatographic method was noted but it cuss
zyme
was
considered
to
be insensitive
to
MB levels less than 10
mi.u./ml. I agree with Roberts et al. about the need for a sensitive method to detect MB but disagree with their contention that R.I.A. is the only procedure sensitive enough to detect MB isoenzyme in the 1-10 mi.u./ml range. The column method is sensitive to MB isoenzyme activity in this range.2-7 Column measurement involves separation of MB isoenzyme by ionexchange chromatography followed by spectrophotometric kinetic assay of MB-c.K. activity in the MB column effluent. The column method is not only specific and sensitive for MB-c.K. but it is also simple and readily adaptable to clinicalchemistry laboratories, especially when commercial prepacked columns are used (Roche Diagnostics, Hoffmann-La Roche, Nutley, New Jersey). In my laboratory multiple column determinations for MB (up to fifty) are done daily within a threehour period by one technician. Yet Roberts et al. suggest that the column technique is unsuitable for large numbers of
al. suggest that the presence of BB isoenzyme in serum is a possibility. However, raised activities of serum BB isoenzyme (20%) are often found in patients on intensive care8.9 and since the question of myocardial infarction is often considered and MB measurement performed in serum from such patients, the possibility of falsely high MB values due to BB isoenzyme must be thought of when using the R.I.A. procedure. For accurate MB measurement, I recommend the column method which can measure MB isoenzyme free from both MM and BB isoenzymes. remote
Department of Pathology, Montefiore Hospital and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213,
SjR,—We agree with Dr Melville and his colleagues (Nov. 26, p. 1127) that measurement ofMB-c.K. is likely to become routine test in the diagnosis of acute myocardial infarction. It could become a primary diagnostic tool, of value in the diaga
nosis of re-infarction, and have a part to play in determining the extent of an infarct. Although the Merck commercial kit has been developed for use in any medical laboratory and the immunological inhibition of M isoenzyme subunits is said to be almost complete, the Merck kit uses glutathione as activator which has disadvantages such as the possibility of erroneous results with haonolysed samples. We understand Merck intend to use N-acetylcysteine in future.. Boehringer Mannheim produce a kit based on a Mercer column chromatography method. Using the test-combination isoenzyme MB-C.K. and automated analysis kit, with N-acetylcysteine as activator, we have found it suitable for the routine
laboratory. By the manufacturers’ instructions the Merck kits are three times the cost of the Boehringer, however, in practice we can get 90 tests out of a Merck 30-test kit so the cost is comparable. Much work is being done in this area and, although selective activation methods have limited capability, we do not feel it is possible yet to say which method is most suitable for the routine laboratory. Comparing the above kits, in the last 350 duplicate assays, we find very little between them, but marginally prefer the Boehringer. S. J. SURTEES
District General Hospital, Eastbourne BN21 2UD
RENAL TRANSPLANTATION
SIR,-The concluding statement in your editorial on U.K. Transplant (Dec. 10, p. 1213) is both pessimistic and unhelpful. Constructing more dialysis centres, as you suggest, will never succeed in treating all patients in terminal renal failure. As
The R.I.A. procedure is specific not for MB isoenzyme but for the B subunit of C.K. which is present in both C.K. isoenzymes MB and BB. Although the R.I.A. MB procedure does not appear to cross-react with MM isoenzyme, it does react with B subunits found in the BB isoenzyme of C.K. Roberts et
come
23, 504. 7. Fiolet, J. W. T., Willebrands, A. F., Lie, K. I., Welle, H. F. Clin. Chem. Acta, 1977, 80, 23.
M. D. BASTABLE S. SWAN D. G. MODEL T. GIETZEN
Department of Clinical Chemistry,
samples.
1. Mercer, D. W. Clin. Chem. 1974, 20, 36. 2. Mercer, D. W., Varat, M. A. ibid. 1975, 21, 1088. 3. Sax, S. M., Moore, J. J., Giegel, J. L., Welsh, M. ibid. 1976, 22, 87. 4. Yasmineh, W. G., Hanson, N. Q. ibid. 1975, 21, 381. 5. Varat, M. A., Mercer, D. W. Circulation, 1975,51,855. 6. Klein, B., Foreman, J. A., Jeunelot, C. L., Sheehan, J. E. Clin. Chem. 1977,
DONALD W. MERCER
U.S.A.
soon as
the additional spaces
forward, and
were
filled
new cases
would
ever-increasing proportion of doctors and nurses and of the N.H.S. budget would be devoted to dialysis, which would prejudice the treatment of other patients. an
The statement "nor is there much prospect of a substantial increase in the rate of kidney transplantation", is particularly depressing, written at a time when the Department of Health is exhorting the public and the medical profession to increase the number of donors for kidney transplantation. The shortage of kidneys is the cause of the disappointingly small number of kidney transplants not a lack of facilities. Most transplant 8. Mercer, D. W. Clin. Chem. 1977, 23, 611. 9. Coolen, R. B., Pragay, D. A., Chilcote, M. E. ibid. 1. Brent, L., and others. Br. med. J. 1975, i, 251.
1975, 21, 976.
1284 could increase substantially the number of operations without additional staff. A rejected transplant subjects the patient to danger and unhappiness but the quality of life on dialysis leaves much to be desired, both diet and fluid intake being restricted, and the physical and psychological dependence on the machine has to be endured with fortitude by the patients and their relatives. A well-functioning transplant, however, restores the patient fully to the community. One important cause for the shortage of donor kidneys is apathy in the medical profession and this state of mind is apparently shared by you. centres
Department of Surgery, University of Cambridge Clinical School, Addenbrooke’s Hospital,
R. Y. CALNE
Cambridge CB2 2QQ
STATISTICS AND RENAL TRANSPLANTATION
SIR,-We agree with Dr Knapp’s comments (Nov. 19, p. 1068) about misleading statistics on the results achieved by dialysis and by transplantation in the treatment of chronic renal failure. With
few notable exceptions’ most series compare transand dialysis as alternatives, which essentially they are not. Most people now regard dialysis and transplantation as constituents of combined of chronic renal failure rather than as alternatives. Unfortunately, the statistical consequence of this is being learned only very slowly, so conclusions are still being drawn from faulty premises. Transplantation is regarded with suspicion as a life-shortening procedure while home dialysis is made the treatment of choice. The patient in end-stage renal failure with an endogenous creatinine clearance of 3 ml/min has to be treated by dialysis or transplantation. Artificial kidneys are more readily available than cadaver organs, so there is no real choice at the start of treatment. Such a choice does exist for the occasional patient for whom there is a live related donor, but in Europe, more than 85% of renal grafts are from cadavers. So long as donor kidneys are scarce most patients will be dialysed at first (D), transplanted later (T) if a suitable organ becomes available, and eventually dialysed again (D) after rejection (combined treatment, D-T-D). Some patients will be treated by dialysis alone (D) when there is a contraindication to transplantation or no organ available, so the true choice lies between D-T-D and D alone. In Marburg inclusion of transplantation in the management of chronic renal failure did improve the survival-rate over that in patients for whom transa
plantation
management
plantation was not available.2 We are confident that similar conclusions could be drawn from the vast European Dialysis and Transplant Association material if only it were analysed in the proper way, but the E.D.T.A. registry has still to produce the figures. Conventional statistical presentation of data within E.D.T.A. is invaluable as a means of comparison between different centres and should be continued, but for a realistic evaluation of transplantation and dialysis the statistical approach suggested above should be
adopted. Medical Clinic,
University of Marburg, 3550 Marburg, West Germany
H. LANGE R. A. HOFFMANN
MONITORING RENAL FUNCTION AFTER TRANSPLANTATION
SiR,-Dr Knapp and his colleagues (Dec. 3, p. 1183) do service 1. 2.
to
renal
a
transplantation by suggesting the use of serum-
Mathew, T. H., Marshall, V. C., Vibraman, P., Hill, A. V. L., Johnson, W., McOmish, D., Morris, P. J., Kincaid-Smith, P. Lancet, 1975, ii, 137. Lange, H., Claas, G., Hoffmann, R. A., Himmelmann, G., Rodeck, G. Aktuelle Urol. 1976, 7, 297.
creatinine plotted graphically in the assessment of renal-graft function. Graphical representation does allow one to follow trends in changes in renal function as assessed by serumcreatinine. However, I doubt whether plotting serum-creatinine on reciprocal (hyperbolic) graph paper will avoid the pitfalls of assessing renal function by serum-creatinine measurements. The particular area of dispute is the patient with a low serum-creatinine. Changes at this end of the scale are exaggerated by the logarithmic scale. Knapp et al. argue that such a change, which is seen to be significant when plotted logarithmically, indicates rejection or a change in renal function. However, it is with low levels of serum-creatinine that errors in biochemical determination can result in small changes of serum-creatinine which will be magnified by the logarithmic scale. Many of us have struggled over the decision as to whether to institute anti-rejection therapy when the serumcreatinine changes from, for example, 130 to 150 fLmol/l. Those of us who have been restrained from giving therapy have been rewarded by a value of 120 mol/1 the following day. Those who have started anti-rejection therapy have claimed beneficial results from that therapy when the serumcreatinine has fallen. In the example given by Knapp et al. no one would doubt the significance of a rise of serum-creatinine from 130 jjmol/1 on day 9 to 190 p.mol;1 on day 10 and 240 µmol/l on day 11, whether these results are plotted on ordinary graph paper, semilogarithmic graph paper, or simply observed as they are written down. I agree with Knapp et al. that the serum-creatinine should be measured again if there be a suspicious increase. Whether most clinical chemistry departments would agree to carry this out "several times daily" is something which could be put to the test. As a long-established plotter of renal function and hsematological measurements in renal-transplant patients, I support the principle of monitoring function in this way, but I think that Knapp et al. expect too much from the apparent simplification of the plot by the reciprocal (hyperbolic) scale. Nuffield Transplant Unit, Western General Hospital, Edinburgh EH4 2XU
J. L. ANDERTON
POVIDONE IODINE IN WOUND INFECTION
SIR,-Contrary to the statement by Mr Galland and his colleagues (Nov. 19, p. 1048) povidone iodine has been shown significantly to reduce wound infection in general surgical practice. Sanderson and 11 found that interparietal installation of povidone iodine resulted in a significant reduction in wound in a wide variety of abdominal procedures infection (p
D. G. WILKINSON
MEASUREMENT OF CREATINE KINASE MB ISOENZYME
SiR,-Dr Roberts and his colleagues (Aug. 13,
p. 319) disfor creatine kinase MB isoen-
radioimmunoassay (R.I.A.) (MB-c.K.) The R.I.A. was claimed to be the method of choice for diagnosis of myocardial infarction since it could detect MB isoenzyme at levels in the 1-10 mi.u./ml range. An alternative column-chromatographic method was noted but it cuss
zyme
was
considered
to
be insensitive
to
MB levels less than 10
mi.u./ml. I agree with Roberts et al. about the need for a sensitive method to detect MB but disagree with their contention that R.I.A. is the only procedure sensitive enough to detect MB isoenzyme in the 1-10 mi.u./ml range. The column method is sensitive to MB isoenzyme activity in this range.2-7 Column measurement involves separation of MB isoenzyme by ionexchange chromatography followed by spectrophotometric kinetic assay of MB-c.K. activity in the MB column effluent. The column method is not only specific and sensitive for MB-c.K. but it is also simple and readily adaptable to clinicalchemistry laboratories, especially when commercial prepacked columns are used (Roche Diagnostics, Hoffmann-La Roche, Nutley, New Jersey). In my laboratory multiple column determinations for MB (up to fifty) are done daily within a threehour period by one technician. Yet Roberts et al. suggest that the column technique is unsuitable for large numbers of
al. suggest that the presence of BB isoenzyme in serum is a possibility. However, raised activities of serum BB isoenzyme (20%) are often found in patients on intensive care8.9 and since the question of myocardial infarction is often considered and MB measurement performed in serum from such patients, the possibility of falsely high MB values due to BB isoenzyme must be thought of when using the R.I.A. procedure. For accurate MB measurement, I recommend the column method which can measure MB isoenzyme free from both MM and BB isoenzymes. remote
Department of Pathology, Montefiore Hospital and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213,
SjR,—We agree with Dr Melville and his colleagues (Nov. 26, p. 1127) that measurement ofMB-c.K. is likely to become routine test in the diagnosis of acute myocardial infarction. It could become a primary diagnostic tool, of value in the diaga
nosis of re-infarction, and have a part to play in determining the extent of an infarct. Although the Merck commercial kit has been developed for use in any medical laboratory and the immunological inhibition of M isoenzyme subunits is said to be almost complete, the Merck kit uses glutathione as activator which has disadvantages such as the possibility of erroneous results with haonolysed samples. We understand Merck intend to use N-acetylcysteine in future.. Boehringer Mannheim produce a kit based on a Mercer column chromatography method. Using the test-combination isoenzyme MB-C.K. and automated analysis kit, with N-acetylcysteine as activator, we have found it suitable for the routine
laboratory. By the manufacturers’ instructions the Merck kits are three times the cost of the Boehringer, however, in practice we can get 90 tests out of a Merck 30-test kit so the cost is comparable. Much work is being done in this area and, although selective activation methods have limited capability, we do not feel it is possible yet to say which method is most suitable for the routine laboratory. Comparing the above kits, in the last 350 duplicate assays, we find very little between them, but marginally prefer the Boehringer. S. J. SURTEES
District General Hospital, Eastbourne BN21 2UD
RENAL TRANSPLANTATION
SIR,-The concluding statement in your editorial on U.K. Transplant (Dec. 10, p. 1213) is both pessimistic and unhelpful. Constructing more dialysis centres, as you suggest, will never succeed in treating all patients in terminal renal failure. As
The R.I.A. procedure is specific not for MB isoenzyme but for the B subunit of C.K. which is present in both C.K. isoenzymes MB and BB. Although the R.I.A. MB procedure does not appear to cross-react with MM isoenzyme, it does react with B subunits found in the BB isoenzyme of C.K. Roberts et
come
23, 504. 7. Fiolet, J. W. T., Willebrands, A. F., Lie, K. I., Welle, H. F. Clin. Chem. Acta, 1977, 80, 23.
M. D. BASTABLE S. SWAN D. G. MODEL T. GIETZEN
Department of Clinical Chemistry,
samples.
1. Mercer, D. W. Clin. Chem. 1974, 20, 36. 2. Mercer, D. W., Varat, M. A. ibid. 1975, 21, 1088. 3. Sax, S. M., Moore, J. J., Giegel, J. L., Welsh, M. ibid. 1976, 22, 87. 4. Yasmineh, W. G., Hanson, N. Q. ibid. 1975, 21, 381. 5. Varat, M. A., Mercer, D. W. Circulation, 1975,51,855. 6. Klein, B., Foreman, J. A., Jeunelot, C. L., Sheehan, J. E. Clin. Chem. 1977,
DONALD W. MERCER
U.S.A.
soon as
the additional spaces
forward, and
were
filled
new cases
would
ever-increasing proportion of doctors and nurses and of the N.H.S. budget would be devoted to dialysis, which would prejudice the treatment of other patients. an
The statement "nor is there much prospect of a substantial increase in the rate of kidney transplantation", is particularly depressing, written at a time when the Department of Health is exhorting the public and the medical profession to increase the number of donors for kidney transplantation. The shortage of kidneys is the cause of the disappointingly small number of kidney transplants not a lack of facilities. Most transplant 8. Mercer, D. W. Clin. Chem. 1977, 23, 611. 9. Coolen, R. B., Pragay, D. A., Chilcote, M. E. ibid. 1. Brent, L., and others. Br. med. J. 1975, i, 251.
1975, 21, 976.
1284 could increase substantially the number of operations without additional staff. A rejected transplant subjects the patient to danger and unhappiness but the quality of life on dialysis leaves much to be desired, both diet and fluid intake being restricted, and the physical and psychological dependence on the machine has to be endured with fortitude by the patients and their relatives. A well-functioning transplant, however, restores the patient fully to the community. One important cause for the shortage of donor kidneys is apathy in the medical profession and this state of mind is apparently shared by you. centres
Department of Surgery, University of Cambridge Clinical School, Addenbrooke’s Hospital,
R. Y. CALNE
Cambridge CB2 2QQ
STATISTICS AND RENAL TRANSPLANTATION
SIR,-We agree with Dr Knapp’s comments (Nov. 19, p. 1068) about misleading statistics on the results achieved by dialysis and by transplantation in the treatment of chronic renal failure. With
few notable exceptions’ most series compare transand dialysis as alternatives, which essentially they are not. Most people now regard dialysis and transplantation as constituents of combined of chronic renal failure rather than as alternatives. Unfortunately, the statistical consequence of this is being learned only very slowly, so conclusions are still being drawn from faulty premises. Transplantation is regarded with suspicion as a life-shortening procedure while home dialysis is made the treatment of choice. The patient in end-stage renal failure with an endogenous creatinine clearance of 3 ml/min has to be treated by dialysis or transplantation. Artificial kidneys are more readily available than cadaver organs, so there is no real choice at the start of treatment. Such a choice does exist for the occasional patient for whom there is a live related donor, but in Europe, more than 85% of renal grafts are from cadavers. So long as donor kidneys are scarce most patients will be dialysed at first (D), transplanted later (T) if a suitable organ becomes available, and eventually dialysed again (D) after rejection (combined treatment, D-T-D). Some patients will be treated by dialysis alone (D) when there is a contraindication to transplantation or no organ available, so the true choice lies between D-T-D and D alone. In Marburg inclusion of transplantation in the management of chronic renal failure did improve the survival-rate over that in patients for whom transa
plantation
management
plantation was not available.2 We are confident that similar conclusions could be drawn from the vast European Dialysis and Transplant Association material if only it were analysed in the proper way, but the E.D.T.A. registry has still to produce the figures. Conventional statistical presentation of data within E.D.T.A. is invaluable as a means of comparison between different centres and should be continued, but for a realistic evaluation of transplantation and dialysis the statistical approach suggested above should be
adopted. Medical Clinic,
University of Marburg, 3550 Marburg, West Germany
H. LANGE R. A. HOFFMANN
MONITORING RENAL FUNCTION AFTER TRANSPLANTATION
SiR,-Dr Knapp and his colleagues (Dec. 3, p. 1183) do service 1. 2.
to
renal
a
transplantation by suggesting the use of serum-
Mathew, T. H., Marshall, V. C., Vibraman, P., Hill, A. V. L., Johnson, W., McOmish, D., Morris, P. J., Kincaid-Smith, P. Lancet, 1975, ii, 137. Lange, H., Claas, G., Hoffmann, R. A., Himmelmann, G., Rodeck, G. Aktuelle Urol. 1976, 7, 297.
creatinine plotted graphically in the assessment of renal-graft function. Graphical representation does allow one to follow trends in changes in renal function as assessed by serumcreatinine. However, I doubt whether plotting serum-creatinine on reciprocal (hyperbolic) graph paper will avoid the pitfalls of assessing renal function by serum-creatinine measurements. The particular area of dispute is the patient with a low serum-creatinine. Changes at this end of the scale are exaggerated by the logarithmic scale. Knapp et al. argue that such a change, which is seen to be significant when plotted logarithmically, indicates rejection or a change in renal function. However, it is with low levels of serum-creatinine that errors in biochemical determination can result in small changes of serum-creatinine which will be magnified by the logarithmic scale. Many of us have struggled over the decision as to whether to institute anti-rejection therapy when the serumcreatinine changes from, for example, 130 to 150 fLmol/l. Those of us who have been restrained from giving therapy have been rewarded by a value of 120 mol/1 the following day. Those who have started anti-rejection therapy have claimed beneficial results from that therapy when the serumcreatinine has fallen. In the example given by Knapp et al. no one would doubt the significance of a rise of serum-creatinine from 130 jjmol/1 on day 9 to 190 p.mol;1 on day 10 and 240 µmol/l on day 11, whether these results are plotted on ordinary graph paper, semilogarithmic graph paper, or simply observed as they are written down. I agree with Knapp et al. that the serum-creatinine should be measured again if there be a suspicious increase. Whether most clinical chemistry departments would agree to carry this out "several times daily" is something which could be put to the test. As a long-established plotter of renal function and hsematological measurements in renal-transplant patients, I support the principle of monitoring function in this way, but I think that Knapp et al. expect too much from the apparent simplification of the plot by the reciprocal (hyperbolic) scale. Nuffield Transplant Unit, Western General Hospital, Edinburgh EH4 2XU
J. L. ANDERTON
POVIDONE IODINE IN WOUND INFECTION
SIR,-Contrary to the statement by Mr Galland and his colleagues (Nov. 19, p. 1048) povidone iodine has been shown significantly to reduce wound infection in general surgical practice. Sanderson and 11 found that interparietal installation of povidone iodine resulted in a significant reduction in wound in a wide variety of abdominal procedures infection (p
