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Treatment of Steroid-resistant Nephrotic Syndrome
644
Treatment of Steroid-resistant
Nephrotic Syndrome THE nephrotic syndrome has many causes.’2 Apart from its association with certain generalised diseases, it may result from diseases confined to the kidney; and this group of renal conditions is heterogeneous, not only histologically but also in their response to steroids.13 The excellent response to steroids in the nephrotic syndrome when the kidneys are essentially normal under the light microscope makes this the best treatment for these patients-a fact long recognised by paediatricians, and established in children by careful analysis.4 This is the commonest form of nephrotic syndrome in children, though it is not the only childhood form and it can arise throughout life. The response to steroids in the nephrotic syndrome associated with other forms of glomerulonephritis is far less certain, though some reports suggest that proliferative glomerulonephritis, the glomerulonephritis of disseminated lupus erythematosus, the glomerulonephritis of anaphylactoid purpura, and membranous glomerulonephritis may sometimes respond slowly and incompletely to steroids. But doubts have been widely expressed, and the treatment is at best extremely unsatisfactory. If there is no response the outlook for these patients is very grave. A strong case exists therefore for trying other lines of treatment. All these diseases are thought to have an immunological basis, so it is reasonable to try other drugs known to suppress an immune response.ã Most of these drugs are known to act at various points on the pathways of purine and pyrimidine synthesis, which lead to the production ofD.N.A., R.N.A., and protein. It has long been known that nitrogen mustard (an alkylating agent, acting late in the purine synthesis pathway)7 is effective in some forms of nephrotic syndrome 6 though this point has sometimes been overlooked because of the more dramatic effects occasionally produced by steroids. Now that we know the limits of what steroids
can
achieve, this earlier work
must
be
extended, to study the effects of each of the many drugs now available, in each of the types of glomerulonephritis
causing the nephrotic syndrome. All such treatments have their complications, and patients capable of a quick response to the relatively benign steroids should certainly be identified first-either by a trial of steroids (though this entails giving potentially toxic doses of, say, 30-40 mg. of prednisolone daily for at least three months before response can be excluded) or by renal biopsy or differential protein clearances.3Other studies suggest that differential protein clearances are a better guide to steroid response than renal biopsy in both adults and children.9 10 1. 2.
3. 4. 5. 6. 7. 8. 9. 10.
There is probably little likelihood of
Squire, J. R., Blainey, J. D., Hardwicke, J. Br. med. Bull. 1957, 13, 43. Kark, R. M., Pirani, C. L., Pollak, V. E., Muehrcke, R. C., Blainey, J. D. Ann. intern. Med. 1958, 49, 751. Blainey, J. D., Brewer, D. B., Hardwicke, J., Soothill, J. F. Q. Jl Med. 1960, 29, 235. Riley, C. M., Davies, R. A., Fertig, J. W., Berger, A. P. J. chron. Dis. 1956, 3, 640. Berenbaum, M. C. Br. med. Bull. 1965, 21, 140. Chasis H., Goldring, W., Baldwin, D. S. Proc. Soc. exp. Biol. Med. 1949, 71, 565. Kellev, V., Panos, T. C. J. Pediat. 1952, 41, 505. Soothill, J. F. J. Lab. clin. Med. 1962, 59, 859. Joachim, T. R., Cameron, J. S., Schwartz, N., Becker, E. L. J. clin. Invest. 1964, 43, 2332. Cameron, J. S., White, R. H. R. Lancet, 1965, i, 463.
complete or useful steroid response if the proteinuria is not highly selective. Steroids may therefore provide the best criterion for selecting patients for alternative treatments ; and, indeed, failure of highly selective proteinuria to respond to steroids should prompt a careful search for the cause of such failure (for example, hidden infection or failure to take or absorb the steroids). All reports of non-steroid treatment in patients selected in this way must give the fullest details of the diagnostic investigations, including renal biopsy, and of the control treatment by accurate measurements of renal function (at least daily 24-hour proteinuria and repeated determinations of red-cell excretion and creatinine clearance). A single drug should be given in sustained dosage until patterns of response are recognised; for, as BERENBAUM argues concerning the actions of these drugs on graft rejection, though there are theoretical reasons for using combinations, the response to two or more drugs together can be interpreted only with a knowledge of the effect of each drug alone. The first such report in fully investigated patients with the nephrotic syndrome due to glomerulonephritis recorded 11 some success with 6-thioguanine (which blocks the purine synthesis pathway earlier than the mustards), but only in patients who also responded well A response to nitrogen mustard was to steroids. observed in steroid-resistant nephrotic syndrome due to trimethodione,I2 and LAGRUE et al. 13 noted that various types of steroid-resistant glomerulonephritis responded to immunosuppressant drugs, including what is probably the least toxic of the alkylating agents, chlorambucil. SHEARN x4 now describes the effects of 6-mercaptopurine (another inhibitor of purine synthesis) in 10 patients with the nephrotic syndrome who had failed to respond to 60 mg. or more a day of prednisone for from three to twelve weeks. 2 out of 3 patients with " lipoid nephrosis " responded at least for a while (though information on why and how they failed to respond to steroids is incomplete); 2 out of 4 with lupus nephritis showed some response, and so did another patient with nephrotic syndrome associated with HenochSchonlein purpura. The 2 patients with membranous glomerulonephritis did not respond at all. The series is unusual in that it included no patients with proliferative glomerulonephritis, the commonest cause of the nephrotic syndrome3 and a condition in which the response to steroids is by no means constant. The dose was increased in the non-responders until toxic effects were produced, so the frequency of such effects cannot be estimated from this report, though it is clear that they will be difficult to avoid if maintenance treatment is required. Nevertheless, this study with its good followup data represents the right kind of first-stage report in the next generation of work on the treatment of nephrotic syndrome. Larger series are needed, using the alkylating agents, cyclophosphamide or the less toxic chlorambucil, 11. 12. 13. 14.
Goodman, H. C., Wolff, S. M., Carpenter, R. R., Andersen, B. R., Brandriss, M. W. Ann. intern. Med. 1963, 59, 388. Talamo, R. C., Crawford, J. D. New Engl. J. Med. 1963, 269, 15. Lagrue, G., Barietz, J., de Kérautem, Y., Samarcq, P., Fritel, D., de Boisdeffre, B., Milliez, P. J. Urol. Néphrol. 1964, 70, 156. Shearn, M. A. New Engl. J. Med. 1965, 273, 943.
645
and inhibitors of pyrimidine synthesis, such as methotrexate. Other drugs that may help, such as heparin 15 and hydroxy chloroquine , 16 also need further examination. Later will come comparisons between different drugs and combination of drugs. Treatments shown to be effective should then be tried in the much larger group of patients with progressive nephritis not associated with the nephrotic syndrome. Large enough series can be collected and adequately investigated only by specialised renal units in large medical centres, so patients must be referred there to get the full benefit of these
developments.
Treatment of Cardiac Shock IN acute cardiac infarction sudden death from cardiac arrest or ventricular fibrillation is not uncommon; little can be done about it unless chance permits rapid massage or defibrillation of the heart, and we have discussed 1’the growing importance of these measures. In other patients severe hypotensive shock quickly develops, and more than half who reach hospital die in a day or two. Can anything useful be done to maintain the circulation until the heart recovers ? Anticoagulants have no value in shock, and digitalis is of little use. Vasopressor drugs such as noradrenaline may be harmful because the increased vasoconstriction aggravates tissue anoxia and increases heart-load. Cardiac shock is accompanied by hypoxaemia, acidosis, and other secondary effects which may be deleterious to the circulation.18 Oxygen is often given, but CAMERON 19 did not find that it saved life: he observed no difference in the early mortality or in fatal arrhythmia among men admitted within twenty-four hours of myocardial infarction whether they were treated with hyperbaric oxygen or atmospheric oxygen, or without oxygen. On p. 611 Dr. McGowAN and Dr. WALTERS refer to the different clinical and haemodynamic forms of shock. In cardiac shock, as in many other forms, cardiac output and venous return are reduced, the arterial pressure is often low, and the peripheral resistance is high owing to vasoconstriction. In shock due to other causes, means are being sought to maintain perfusion at the tissue level, and last year we discussed 20 the use of antiadrenergic drugs combined with intravenous infusion (to maintain effective blood-volume) in irreversible shock following haemorrhage, trauma, burns, and bacterial infection. Can lives be saved in cardiac shock by treatment aimed at increasing peripheral blood-flow ? Experiments by BLOCH et al. 21 22 throw some light on this question. Using the experimental model devised by AGRESS et al.23 they produced diffuse infarction Vassolli, P., Morris, R. H., McCluskey, R. T.J. exp. Med. 1963, 118, 467. Soothill, J. F., Hardwicke, J. Int. Congr. Nephrol. 1964, p. 164. Lancet, 1965, ii, 730. MacKenzie, G. J. Proc. R. Soc. Med. 1965, 58, 103. Cameron, A. J. V. ibid. p. 106. Lancet, 1965, i, 255. 21. Bloch, J. H., Pierce, C. H., Manax, W. G., Lyons, G. W., Lillehei, R. C. Archs Surg., Chicago, 1965, 91, 77. 22. Bloch, J. H., Pierce, C. H., Manax, W. G., Lillehei, R. C. Surgery, St. Louis, 1965, 58, 197. 23. Agress, C. M., Glassner, H. F., Binder, M. J. Fields, J. J. appl. Physiol. 1957, 10, 469. 15. 16. 17. 18. 19. 20.
of the myocardium in dogs by plastic microspheres introduced into the coronary arteries. Some dogs died quickly, and others not shocked survived; but the majority went quickly into shock with an initial fall in cardiac output of 50% or more, significant hypotension, and the electrocardiographic changes of myocardial damage. Without treatment the mortality was 80% within twenty-four hours, and the administration of noradrenaline did little to improve this figure, even though arterial pressure was raised and cardiac output temporarily restored. But phenoxybenzamine, an antiadrenergic vasodilator, and low-molecular-weight dextran gave encouraging results. With phenoxybenzamine, cardiac output and heart-work were not different from the controls; but 5 out of 6 shocked dogs survived more than forty-eight hours, and 4 were well by a week. The significant effects were the combating of vasoconstriction, an increase in superior-mesenteric and renal blood-flow and in urine output, and normal central venous filling and right atrial pressure. Phenoxybenzamine plus noradrenaline also gave good results, but no better than phenoxybenzamine alone. After
infusion of 15% low-molecular-weight dextran, 7 out of 9 shocked dogs survived for more than forty-eight hours: benefit was attributed to maintenance of peripheral systemic and pulmonary blood-flow. Despite vasoconstriction renal and mesenteric flow were maintained; and, though central venous and right atrial pressure rose, pulmonary oedema did not develop. Maintenance of peripheral blood-flow was attributed to decreased blood viscosity produced by the dextran. Of course, infusion of hypertonic dextran rapidly increases plasma-volume by more than the amount infused; and, although that effect is short-lived because the low-molecular-weight dextran is rapidly excreted, much of the decreased viscosity is due to plasma dilution. This is in accord with the results of GROTH and THORSEN 24 who found that the decreased blood-sedimentation rate produced by low-molecular-weight dextran was largely the effect of plasma dilution, though an anti-aggregating effect on red cells may have contributed. The benefit of both and low-molecular-weight dextran thus be ascribed to increased peripheral perfusion, the former acting on constricted vessels and the latter on the blood. Studies on the use of plasma and fluids other than dextran with and without vasodilators are
phenoxybenzamine can
required. naturally cautious about transfusing damaged heart, especially when jugular patients venous pressure is raised. According to LILLEHEI,25 reduces a raised venous pressure by phenoxybenzamine vascular increasing capacity even in patients with pulmonary oedema. In cardiac shock he advocates giving phenoxybenzamine first and then transfusion, which the patient would tolerate until venous pressure rose again. Despite traditional caution, controlled trials in selected patients seem worth undertaking, since the outlook in cardiac shock is so bleak. Intensive care and study units Clinicians
with
24. 25.
are a
Groth, C. G., Thorsen, G. Acta chir. scand. 1965, 130, Lillehei, R. C. Surgery, St. Louis, 1965, 58, 213.
507.
Treatment of Steroid-resistant
Nephrotic Syndrome THE nephrotic syndrome has many causes.’2 Apart from its association with certain generalised diseases, it may result from diseases confined to the kidney; and this group of renal conditions is heterogeneous, not only histologically but also in their response to steroids.13 The excellent response to steroids in the nephrotic syndrome when the kidneys are essentially normal under the light microscope makes this the best treatment for these patients-a fact long recognised by paediatricians, and established in children by careful analysis.4 This is the commonest form of nephrotic syndrome in children, though it is not the only childhood form and it can arise throughout life. The response to steroids in the nephrotic syndrome associated with other forms of glomerulonephritis is far less certain, though some reports suggest that proliferative glomerulonephritis, the glomerulonephritis of disseminated lupus erythematosus, the glomerulonephritis of anaphylactoid purpura, and membranous glomerulonephritis may sometimes respond slowly and incompletely to steroids. But doubts have been widely expressed, and the treatment is at best extremely unsatisfactory. If there is no response the outlook for these patients is very grave. A strong case exists therefore for trying other lines of treatment. All these diseases are thought to have an immunological basis, so it is reasonable to try other drugs known to suppress an immune response.ã Most of these drugs are known to act at various points on the pathways of purine and pyrimidine synthesis, which lead to the production ofD.N.A., R.N.A., and protein. It has long been known that nitrogen mustard (an alkylating agent, acting late in the purine synthesis pathway)7 is effective in some forms of nephrotic syndrome 6 though this point has sometimes been overlooked because of the more dramatic effects occasionally produced by steroids. Now that we know the limits of what steroids
can
achieve, this earlier work
must
be
extended, to study the effects of each of the many drugs now available, in each of the types of glomerulonephritis
causing the nephrotic syndrome. All such treatments have their complications, and patients capable of a quick response to the relatively benign steroids should certainly be identified first-either by a trial of steroids (though this entails giving potentially toxic doses of, say, 30-40 mg. of prednisolone daily for at least three months before response can be excluded) or by renal biopsy or differential protein clearances.3Other studies suggest that differential protein clearances are a better guide to steroid response than renal biopsy in both adults and children.9 10 1. 2.
3. 4. 5. 6. 7. 8. 9. 10.
There is probably little likelihood of
Squire, J. R., Blainey, J. D., Hardwicke, J. Br. med. Bull. 1957, 13, 43. Kark, R. M., Pirani, C. L., Pollak, V. E., Muehrcke, R. C., Blainey, J. D. Ann. intern. Med. 1958, 49, 751. Blainey, J. D., Brewer, D. B., Hardwicke, J., Soothill, J. F. Q. Jl Med. 1960, 29, 235. Riley, C. M., Davies, R. A., Fertig, J. W., Berger, A. P. J. chron. Dis. 1956, 3, 640. Berenbaum, M. C. Br. med. Bull. 1965, 21, 140. Chasis H., Goldring, W., Baldwin, D. S. Proc. Soc. exp. Biol. Med. 1949, 71, 565. Kellev, V., Panos, T. C. J. Pediat. 1952, 41, 505. Soothill, J. F. J. Lab. clin. Med. 1962, 59, 859. Joachim, T. R., Cameron, J. S., Schwartz, N., Becker, E. L. J. clin. Invest. 1964, 43, 2332. Cameron, J. S., White, R. H. R. Lancet, 1965, i, 463.
complete or useful steroid response if the proteinuria is not highly selective. Steroids may therefore provide the best criterion for selecting patients for alternative treatments ; and, indeed, failure of highly selective proteinuria to respond to steroids should prompt a careful search for the cause of such failure (for example, hidden infection or failure to take or absorb the steroids). All reports of non-steroid treatment in patients selected in this way must give the fullest details of the diagnostic investigations, including renal biopsy, and of the control treatment by accurate measurements of renal function (at least daily 24-hour proteinuria and repeated determinations of red-cell excretion and creatinine clearance). A single drug should be given in sustained dosage until patterns of response are recognised; for, as BERENBAUM argues concerning the actions of these drugs on graft rejection, though there are theoretical reasons for using combinations, the response to two or more drugs together can be interpreted only with a knowledge of the effect of each drug alone. The first such report in fully investigated patients with the nephrotic syndrome due to glomerulonephritis recorded 11 some success with 6-thioguanine (which blocks the purine synthesis pathway earlier than the mustards), but only in patients who also responded well A response to nitrogen mustard was to steroids. observed in steroid-resistant nephrotic syndrome due to trimethodione,I2 and LAGRUE et al. 13 noted that various types of steroid-resistant glomerulonephritis responded to immunosuppressant drugs, including what is probably the least toxic of the alkylating agents, chlorambucil. SHEARN x4 now describes the effects of 6-mercaptopurine (another inhibitor of purine synthesis) in 10 patients with the nephrotic syndrome who had failed to respond to 60 mg. or more a day of prednisone for from three to twelve weeks. 2 out of 3 patients with " lipoid nephrosis " responded at least for a while (though information on why and how they failed to respond to steroids is incomplete); 2 out of 4 with lupus nephritis showed some response, and so did another patient with nephrotic syndrome associated with HenochSchonlein purpura. The 2 patients with membranous glomerulonephritis did not respond at all. The series is unusual in that it included no patients with proliferative glomerulonephritis, the commonest cause of the nephrotic syndrome3 and a condition in which the response to steroids is by no means constant. The dose was increased in the non-responders until toxic effects were produced, so the frequency of such effects cannot be estimated from this report, though it is clear that they will be difficult to avoid if maintenance treatment is required. Nevertheless, this study with its good followup data represents the right kind of first-stage report in the next generation of work on the treatment of nephrotic syndrome. Larger series are needed, using the alkylating agents, cyclophosphamide or the less toxic chlorambucil, 11. 12. 13. 14.
Goodman, H. C., Wolff, S. M., Carpenter, R. R., Andersen, B. R., Brandriss, M. W. Ann. intern. Med. 1963, 59, 388. Talamo, R. C., Crawford, J. D. New Engl. J. Med. 1963, 269, 15. Lagrue, G., Barietz, J., de Kérautem, Y., Samarcq, P., Fritel, D., de Boisdeffre, B., Milliez, P. J. Urol. Néphrol. 1964, 70, 156. Shearn, M. A. New Engl. J. Med. 1965, 273, 943.
645
and inhibitors of pyrimidine synthesis, such as methotrexate. Other drugs that may help, such as heparin 15 and hydroxy chloroquine , 16 also need further examination. Later will come comparisons between different drugs and combination of drugs. Treatments shown to be effective should then be tried in the much larger group of patients with progressive nephritis not associated with the nephrotic syndrome. Large enough series can be collected and adequately investigated only by specialised renal units in large medical centres, so patients must be referred there to get the full benefit of these
developments.
Treatment of Cardiac Shock IN acute cardiac infarction sudden death from cardiac arrest or ventricular fibrillation is not uncommon; little can be done about it unless chance permits rapid massage or defibrillation of the heart, and we have discussed 1’the growing importance of these measures. In other patients severe hypotensive shock quickly develops, and more than half who reach hospital die in a day or two. Can anything useful be done to maintain the circulation until the heart recovers ? Anticoagulants have no value in shock, and digitalis is of little use. Vasopressor drugs such as noradrenaline may be harmful because the increased vasoconstriction aggravates tissue anoxia and increases heart-load. Cardiac shock is accompanied by hypoxaemia, acidosis, and other secondary effects which may be deleterious to the circulation.18 Oxygen is often given, but CAMERON 19 did not find that it saved life: he observed no difference in the early mortality or in fatal arrhythmia among men admitted within twenty-four hours of myocardial infarction whether they were treated with hyperbaric oxygen or atmospheric oxygen, or without oxygen. On p. 611 Dr. McGowAN and Dr. WALTERS refer to the different clinical and haemodynamic forms of shock. In cardiac shock, as in many other forms, cardiac output and venous return are reduced, the arterial pressure is often low, and the peripheral resistance is high owing to vasoconstriction. In shock due to other causes, means are being sought to maintain perfusion at the tissue level, and last year we discussed 20 the use of antiadrenergic drugs combined with intravenous infusion (to maintain effective blood-volume) in irreversible shock following haemorrhage, trauma, burns, and bacterial infection. Can lives be saved in cardiac shock by treatment aimed at increasing peripheral blood-flow ? Experiments by BLOCH et al. 21 22 throw some light on this question. Using the experimental model devised by AGRESS et al.23 they produced diffuse infarction Vassolli, P., Morris, R. H., McCluskey, R. T.J. exp. Med. 1963, 118, 467. Soothill, J. F., Hardwicke, J. Int. Congr. Nephrol. 1964, p. 164. Lancet, 1965, ii, 730. MacKenzie, G. J. Proc. R. Soc. Med. 1965, 58, 103. Cameron, A. J. V. ibid. p. 106. Lancet, 1965, i, 255. 21. Bloch, J. H., Pierce, C. H., Manax, W. G., Lyons, G. W., Lillehei, R. C. Archs Surg., Chicago, 1965, 91, 77. 22. Bloch, J. H., Pierce, C. H., Manax, W. G., Lillehei, R. C. Surgery, St. Louis, 1965, 58, 197. 23. Agress, C. M., Glassner, H. F., Binder, M. J. Fields, J. J. appl. Physiol. 1957, 10, 469. 15. 16. 17. 18. 19. 20.
of the myocardium in dogs by plastic microspheres introduced into the coronary arteries. Some dogs died quickly, and others not shocked survived; but the majority went quickly into shock with an initial fall in cardiac output of 50% or more, significant hypotension, and the electrocardiographic changes of myocardial damage. Without treatment the mortality was 80% within twenty-four hours, and the administration of noradrenaline did little to improve this figure, even though arterial pressure was raised and cardiac output temporarily restored. But phenoxybenzamine, an antiadrenergic vasodilator, and low-molecular-weight dextran gave encouraging results. With phenoxybenzamine, cardiac output and heart-work were not different from the controls; but 5 out of 6 shocked dogs survived more than forty-eight hours, and 4 were well by a week. The significant effects were the combating of vasoconstriction, an increase in superior-mesenteric and renal blood-flow and in urine output, and normal central venous filling and right atrial pressure. Phenoxybenzamine plus noradrenaline also gave good results, but no better than phenoxybenzamine alone. After
infusion of 15% low-molecular-weight dextran, 7 out of 9 shocked dogs survived for more than forty-eight hours: benefit was attributed to maintenance of peripheral systemic and pulmonary blood-flow. Despite vasoconstriction renal and mesenteric flow were maintained; and, though central venous and right atrial pressure rose, pulmonary oedema did not develop. Maintenance of peripheral blood-flow was attributed to decreased blood viscosity produced by the dextran. Of course, infusion of hypertonic dextran rapidly increases plasma-volume by more than the amount infused; and, although that effect is short-lived because the low-molecular-weight dextran is rapidly excreted, much of the decreased viscosity is due to plasma dilution. This is in accord with the results of GROTH and THORSEN 24 who found that the decreased blood-sedimentation rate produced by low-molecular-weight dextran was largely the effect of plasma dilution, though an anti-aggregating effect on red cells may have contributed. The benefit of both and low-molecular-weight dextran thus be ascribed to increased peripheral perfusion, the former acting on constricted vessels and the latter on the blood. Studies on the use of plasma and fluids other than dextran with and without vasodilators are
phenoxybenzamine can
required. naturally cautious about transfusing damaged heart, especially when jugular patients venous pressure is raised. According to LILLEHEI,25 reduces a raised venous pressure by phenoxybenzamine vascular increasing capacity even in patients with pulmonary oedema. In cardiac shock he advocates giving phenoxybenzamine first and then transfusion, which the patient would tolerate until venous pressure rose again. Despite traditional caution, controlled trials in selected patients seem worth undertaking, since the outlook in cardiac shock is so bleak. Intensive care and study units Clinicians
with
24. 25.
are a
Groth, C. G., Thorsen, G. Acta chir. scand. 1965, 130, Lillehei, R. C. Surgery, St. Louis, 1965, 58, 213.
507.