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PERCUTANEOUS DILATATION IN RENAL ARTERY STENOSIS
1123 PERCUTANEOUS DILATATION IN RENAL ARTERY STENOSIS SIR,-Your editorial on renal artery stenosis (March 27, p. 724), giving a case against investigating hypertension, states that "the results of percutaneous transluminal dilatation are disappointing". The reference cited gives results in 37 patients in whom the mean blood pressure fell from 200/120 to 145/90 mm Hg 3 days after dilatation, this mean level being maintained in those patients followed up for two years. Though the "cure" rate was only 35% in atheromatous stenosis, it was 67% in those with fibromuscular dysplasia, and 85% of the total remaining had improved control of their hypertension. 1-4 Recent publications 1-4 on percutaneous angioplasty in renal stenosis results on a total of 158 patients followed-up for give artery up to two years. 40% of patients have been cured (diastolic pressure less than 90 mm Hg on no medication) and a further 43% have significantly improved. As in surgery, the results are better in patients with fibromuscular dysplasia. Recurrent stenosis occurred in 13%; repeat dilatation was successful in 10 of 12 cases in which it was attempted. The complication rate was 10%, complications usually resolved spontaneously, though there were 2 cases of peripheral embolism and 1 of acute thrombosis of the; renal artery. This centre’s experience is small by United States standards and comprises 8 patients: 5 of these have been cured of hypertension in a follow-up period of up to two years, 2 improved, and 1 was unchanged (a patient with stenosis of the artery to the only functioning kidney, there being complete occlusion of the contralateral artery). There have been no complications or recurrences.
The potential complications of angioplasty, though of low incidence, demand appropriate patient selection; apart from this the procedure amounts to little more than a diagnostic angiogram in terms of patient discomfort and rehabilitation time. If there is recurrence, repeat angioplasty usually succeeds, and in the event of failure surgery is very seldom precluded. We consider that the results of percutaneous dilatation in renal artery stenosis are far from disappointing. Though it is, as you state, "unrealistic to recommend routine radiological investigation of all hypertensive - patients", perhaps the investigation of certain groups-for example, young patients or those with poorly controlled hypertension on multiple drug therapy-can be justified. Digital subtraction angiography, in which the renal (and other) arteries can be adequately visualised after intravenous contrast medium, may prove to be of value in this respect, though it is not yet widely available. Department of Radiology and Renal Unit,
Northern General Hospital, Sheffield S5 7AU
D. C. CUMBERLAND P. J. MOORHEAD
STANDARDISATION OF HUMAN CHORIONIC GONADOTROPIN, hCG SUBUNITS, AND PREGNANCY TESTS SIR,-Recent Lancet correspondence about reference materials for human chorionic gonadotropin (hCG) and its subunits (Feb. 13, p. 390, March 13, p. 629) has also involved the problem of specificity of assays (April 3, p. 803), which we believe to be a major contributing factor to the confusion. As stated by Dr Bangham and Dr Storring (Feb. 13), the second International Standard of hCG for Bioassay (2nd IS hCG) is heterogeneous since it contains hCG, its subunits, and other substances,5and for this reason the World Health Organisation
Expert
Committee
on
Biological Standardisationestablished
separate reference preparations of highly purifiedhCG and its subunits7 for use in immunoassay. These preparations are termed the First International Reference Preparation for hCG (lst IRP hCG, 75/537); lst IRP (3hCG, 75/551; and lst IRP ahCG, 75/569. Since only the whole molecule of hCG is biologically active, potency estimations based on bioassay and immunoassay were made only for the 1 st IRP hCG and the preparation was assigned a unitage of 650 IU per ampoule (in terms of the 2nd IS) on the basis of the bioassay results.8 It was pointed out that immunoassay results were discrepant resulting from the lack of specificity of some assays used in the collaborative study. The 1st IRP (3hCG and lst IRP ahCG were each assigned an arbitrary potency of 1 unit per 14g for use in
immunoassays. In the early days of hCG immunoassay antisera were frequently raised against the 0 subunit of hCG in the hope of reducing the cross-reaction with the structurally related hLH molecule. These antisera recognise either the (3 subunit alone, the whole molecule alone, or, more frequently, both hCG and (3hCG. In the case of antisera raised against the whole hCG molecule, hCG and/or both of its subunits may be recognised. Regardless of the purity of the reference preparation, in an immunoassay using an antiserum of mixed specificity, the immunopotency of a biological specimen will be calculated on the basis of the displacement of labelled antigen by each of the reactive antigens. Thus, for a specific measurement of hCG or its subunits not only is a highly purified reference preparation required but also a monospecific antibody. With our colleagues K. Payne, S. Razuiddin, K. Vines, and P. A. Underwood we have recently raised a series of monoclonal antibodies of which one identifies only hCG, another identifies only /3hCG, and a third identifies only ahCG. In a radioimmunoassay using the hCG-specific antibody, radiolabelled hCG and not its radiolabelled subunits bind, and the labellled hCG is displaced only by the 2nd IS and the 1 st IRP hCC, but not by the 1 st IRP (3hCG or the lst IS ahCG. Superimposable standard curves are obtained when the 2nd IS and the lst IRP hCG are used on a unitage basis, estimate which was assigned on the basis of confirming the potency 8 biological activity. The (3hCG specific antibody binds radiolabelled (3hCG but not hCG or the a subunit and is displaced by the first IRP /3hCG and the 2nd IS, but not by the 1 st IRP hCG or the 1st IRP ahCG. With this specific (3hCG assay 24 IU 2nd IS hCG are equipotent to 1 IU (=1 lAg) 1st IRP &bgr;hCG. The ahCG specific antibody binds radiolabelled ahCG but not hCG or (3hCG and is displaced by as little as 0 -2ng (=0’2mU) a-hCG and by 500 mIU 2nd IS but not by 500 mU 1st IRP hCG. These data confirm the points made by Bangham and Storring that the international reference preparations of hCG, (3hCG, and ahCG are highly purified preparations and that the 2nd IS is a crude preparation containing hCG and its subunits. Any immunoassay based on an antibody which does not have singular specificity for hCG would be expected to result in different displacement curves for the 2nd IRP and lst IRP hCG. In such an assay, lower hormone levels in the patient’s samples will be reported with the use of the 2nd IS than with the lst IRP hCG. If, on the other hand, the assay has been labelled a "(3hCG" assay it may detect (3 subunits and or the whole molecule, and will again produce quite different serum measurements, depending on the standard used. We believe, and the above data attest to this, that the resolution of the current problem lies in the use of the individual highly purified 1 st International Reference Preparations of hCG and its subunits and in the use of monospecific monoclonal antibodies in hCG
immunoassays. 1. Kuhlmann U, Vetter W, Gruntzig A, Schneider E, Pouliadis G, Steuer J, Siegenthaler W Percutaneous transluminal dilatation of renal artery stenosis: 2 years’ experience. Clin Sci 1981; 61: 4815-35. 2 Schwarten DE, Yune HY, Klatte EC, Grim CE, Weinburger MH. Clinical experience with percutaneous transluminal angioplasty of stenotic renal arteries. Radiology 1980; 135: 601-05. 3 Tegtmeyer CJ, Teates CD, Crigter N, Gandee RW, Ayers CR, Stoddard M, Wellons HA. Percutaneous transluminal angioplasty in patients with renal artery stenosis. Radiology 1981; 140: 323-30. 4. Martin EC, Mattern RF, Baer L, Fankuchen EI, Cazarella WJ. Renal angioplasty for hypertension: predictive factors for long-term success. AJR 1981; 137: 921-24. 5. Bangham DR, Grab B. The second international standard for chononic gonadotrophin. Bull Wld Hlth Org 1964; 31: 111-25.
Garvan Institute of Medical Research, St Vincent’s Hospital, Darlinghurst, N.S.W. 2010, Australia
M. C. STUART L. LAZARUS
6. Twenty-sixth report of WHO Expert Committee on Biological Standardisation. WHO Tech Rep Ser 1975, no 565. 7. Canfield RE, Ross GT. A new reference preparation of human chorionic gonadotrophin and its subunits. Bull Wld Hlth Org 1976, 54: 463-70. 8. Storring PL, Gaines Das RE, Bangham DR. International reference preparation of
human chorionic gonadotrophin for immunoassay: Potency estimates m various bioassay and protein-binding assay systems and internationalreference preparations of the &agr; and &bgr; subunits of human chorionic gonadotrophin for immunoassay. J Endocrinol 1980; 84: 295-310.
The potential complications of angioplasty, though of low incidence, demand appropriate patient selection; apart from this the procedure amounts to little more than a diagnostic angiogram in terms of patient discomfort and rehabilitation time. If there is recurrence, repeat angioplasty usually succeeds, and in the event of failure surgery is very seldom precluded. We consider that the results of percutaneous dilatation in renal artery stenosis are far from disappointing. Though it is, as you state, "unrealistic to recommend routine radiological investigation of all hypertensive - patients", perhaps the investigation of certain groups-for example, young patients or those with poorly controlled hypertension on multiple drug therapy-can be justified. Digital subtraction angiography, in which the renal (and other) arteries can be adequately visualised after intravenous contrast medium, may prove to be of value in this respect, though it is not yet widely available. Department of Radiology and Renal Unit,
Northern General Hospital, Sheffield S5 7AU
D. C. CUMBERLAND P. J. MOORHEAD
STANDARDISATION OF HUMAN CHORIONIC GONADOTROPIN, hCG SUBUNITS, AND PREGNANCY TESTS SIR,-Recent Lancet correspondence about reference materials for human chorionic gonadotropin (hCG) and its subunits (Feb. 13, p. 390, March 13, p. 629) has also involved the problem of specificity of assays (April 3, p. 803), which we believe to be a major contributing factor to the confusion. As stated by Dr Bangham and Dr Storring (Feb. 13), the second International Standard of hCG for Bioassay (2nd IS hCG) is heterogeneous since it contains hCG, its subunits, and other substances,5and for this reason the World Health Organisation
Expert
Committee
on
Biological Standardisationestablished
separate reference preparations of highly purifiedhCG and its subunits7 for use in immunoassay. These preparations are termed the First International Reference Preparation for hCG (lst IRP hCG, 75/537); lst IRP (3hCG, 75/551; and lst IRP ahCG, 75/569. Since only the whole molecule of hCG is biologically active, potency estimations based on bioassay and immunoassay were made only for the 1 st IRP hCG and the preparation was assigned a unitage of 650 IU per ampoule (in terms of the 2nd IS) on the basis of the bioassay results.8 It was pointed out that immunoassay results were discrepant resulting from the lack of specificity of some assays used in the collaborative study. The 1st IRP (3hCG and lst IRP ahCG were each assigned an arbitrary potency of 1 unit per 14g for use in
immunoassays. In the early days of hCG immunoassay antisera were frequently raised against the 0 subunit of hCG in the hope of reducing the cross-reaction with the structurally related hLH molecule. These antisera recognise either the (3 subunit alone, the whole molecule alone, or, more frequently, both hCG and (3hCG. In the case of antisera raised against the whole hCG molecule, hCG and/or both of its subunits may be recognised. Regardless of the purity of the reference preparation, in an immunoassay using an antiserum of mixed specificity, the immunopotency of a biological specimen will be calculated on the basis of the displacement of labelled antigen by each of the reactive antigens. Thus, for a specific measurement of hCG or its subunits not only is a highly purified reference preparation required but also a monospecific antibody. With our colleagues K. Payne, S. Razuiddin, K. Vines, and P. A. Underwood we have recently raised a series of monoclonal antibodies of which one identifies only hCG, another identifies only /3hCG, and a third identifies only ahCG. In a radioimmunoassay using the hCG-specific antibody, radiolabelled hCG and not its radiolabelled subunits bind, and the labellled hCG is displaced only by the 2nd IS and the 1 st IRP hCC, but not by the 1 st IRP (3hCG or the lst IS ahCG. Superimposable standard curves are obtained when the 2nd IS and the lst IRP hCG are used on a unitage basis, estimate which was assigned on the basis of confirming the potency 8 biological activity. The (3hCG specific antibody binds radiolabelled (3hCG but not hCG or the a subunit and is displaced by the first IRP /3hCG and the 2nd IS, but not by the 1 st IRP hCG or the 1st IRP ahCG. With this specific (3hCG assay 24 IU 2nd IS hCG are equipotent to 1 IU (=1 lAg) 1st IRP &bgr;hCG. The ahCG specific antibody binds radiolabelled ahCG but not hCG or (3hCG and is displaced by as little as 0 -2ng (=0’2mU) a-hCG and by 500 mIU 2nd IS but not by 500 mU 1st IRP hCG. These data confirm the points made by Bangham and Storring that the international reference preparations of hCG, (3hCG, and ahCG are highly purified preparations and that the 2nd IS is a crude preparation containing hCG and its subunits. Any immunoassay based on an antibody which does not have singular specificity for hCG would be expected to result in different displacement curves for the 2nd IRP and lst IRP hCG. In such an assay, lower hormone levels in the patient’s samples will be reported with the use of the 2nd IS than with the lst IRP hCG. If, on the other hand, the assay has been labelled a "(3hCG" assay it may detect (3 subunits and or the whole molecule, and will again produce quite different serum measurements, depending on the standard used. We believe, and the above data attest to this, that the resolution of the current problem lies in the use of the individual highly purified 1 st International Reference Preparations of hCG and its subunits and in the use of monospecific monoclonal antibodies in hCG
immunoassays. 1. Kuhlmann U, Vetter W, Gruntzig A, Schneider E, Pouliadis G, Steuer J, Siegenthaler W Percutaneous transluminal dilatation of renal artery stenosis: 2 years’ experience. Clin Sci 1981; 61: 4815-35. 2 Schwarten DE, Yune HY, Klatte EC, Grim CE, Weinburger MH. Clinical experience with percutaneous transluminal angioplasty of stenotic renal arteries. Radiology 1980; 135: 601-05. 3 Tegtmeyer CJ, Teates CD, Crigter N, Gandee RW, Ayers CR, Stoddard M, Wellons HA. Percutaneous transluminal angioplasty in patients with renal artery stenosis. Radiology 1981; 140: 323-30. 4. Martin EC, Mattern RF, Baer L, Fankuchen EI, Cazarella WJ. Renal angioplasty for hypertension: predictive factors for long-term success. AJR 1981; 137: 921-24. 5. Bangham DR, Grab B. The second international standard for chononic gonadotrophin. Bull Wld Hlth Org 1964; 31: 111-25.
Garvan Institute of Medical Research, St Vincent’s Hospital, Darlinghurst, N.S.W. 2010, Australia
M. C. STUART L. LAZARUS
6. Twenty-sixth report of WHO Expert Committee on Biological Standardisation. WHO Tech Rep Ser 1975, no 565. 7. Canfield RE, Ross GT. A new reference preparation of human chorionic gonadotrophin and its subunits. Bull Wld Hlth Org 1976, 54: 463-70. 8. Storring PL, Gaines Das RE, Bangham DR. International reference preparation of
human chorionic gonadotrophin for immunoassay: Potency estimates m various bioassay and protein-binding assay systems and internationalreference preparations of the &agr; and &bgr; subunits of human chorionic gonadotrophin for immunoassay. J Endocrinol 1980; 84: 295-310.