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IMMUNOSUPPRESSION AND RENAL DISEASE
1272
predisposition
to
in Dr. Fialkow’s
autoimmunity ", hypothesis.5
which
was
later elaborated
This work was supported by a grant (GM 11615) from the United States Public Health Service, and a grant from the Children’s Bureau (project 423), United States Department of Health, Education and Welfare. We are indebted to Dr. Grant W. Liddle and Dr. Amos Christie and their staff for referring a number of these patients.
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, U.S.A.
ERIC ENGEL.
MASKING OF ANTIGENS ON TROPHOBLAST SiR,-The objections which Dr. Good raises (May 27, p. 1156) to our paper (April 1, p. 708) are not supported by the many published reports describing the electrochemical properties of cells. His suggestion that the hydration properties of cell-surface monosaccharides determine cell-surface behaviour is at variance with observed data. It has been demonstrated that the abnormal behaviour of malignant cells is dependent upon their high net negative surface charge,6 which can be returned to normal levels by treatment with neuraminidase.7 This enzyme cleaves the o-glycoside link between the monosaccharides and the terminal N-acetylneuraminic-acid moiety. The high charge on malignant cells therefore depends upon the ionised carboxyl group of N-acetyl-neuraminic acid and cannot be related to monosaccharide hydration. Electrostatic repulsion of lymphocytes is well documented in vivo 89 and in vitro,1O and shows that their surface charge may well inhibit contact with cells bearing highly charged sialomucins. We cannot therefore accept Dr. Good’s objections. As Weiss has stated : 11 " ... the charge at the cell periphery may affect ... the magnitude of potential energy barriers, hindering contact between cells." Edgar and Tenovus Laboratory, G. A. CURRIE Fulham Hospital, K. D. BAGSHAWE. St. Dunstans Road, London W.6.
IMMUNOSUPPRESSION AND RENAL DISEASE SIR,-Iwas perturbed to read in your leading article (May 20, p. 1093) your suggestion of prospective trials of single and combined drug programmes using tests of renal function and morphology as criteria. The substance of the review was the article by Michael et al.12 on the use of azathioprine and prednisone in the treatment of glomerulonephritis. To do them justice these workers have stated clearly that despite the results achieved the mode of action of the
There are several good tests for assessing the activity of the but apparently there is reluctance to apply the methods of experimental pathology in clinical medicine. Their use would not only clarify the efficacy of the drugs used, but also allow scientific assessment of therapeutic dosage and help avert the disasters to be expected after total suppression of the immune system. The use of such tests would, I believe, predict the steroid dosage, and the lack of response, or even that patients can be made worse-if suppression of R.E.S. activity means that circulating antigen-antibody complexes are no longer removed by the natural defence mechanism. Just as in physiology, so also in pathology, the kidney cannot be studied in isolation. Royal Victoria Infirmary, E. N. WARDLE. Newcastle upon Tyne 1. R.E.S.
drugs is
not
clear and may
involve immunosuppression, anti-inflammatory effects, or mere reduction of proliferation of endothelial and mesangial cells. Despite experimental models I know of no precise evidence that any human form of glomerulonephritis is " autoimmune " in the sense that antibodies are formed primarily to renal antigens but rather that glomerulonephritis is the result of circulating antigen-antibody complexes or other macromolecules lodging in the glomeruli. This means that, unless such complexes can be destroyed in the circulation, the assessment of therapy of glomerulonephritis rests of the effect of these drugs on the reticuloendothelial system (R.E.S.). It is well recognised that, in the same way as macrophages ingest and dispose of antigen, so the R.E.s. influences antibody synthesis, and indeed phagocytic activity of the R.E.S. is correlated with immunological responsiveness. In human glomerulonephritis phagocytic hyperactivity of the R.E.s. has been demonstrated. 5. Fialkow, P. J. Lancet, 1964, i, 474. 6. Abercrombie, M., Ambrose, G. J. Cancer Res. 1962, 22, 525. 7. Forrester, J. A., Ambrose, G. J., Macpherson, I. A. Nature, Lond. 1962, 196, 1068. 8. Vega, R. E., Singh, L. M., Danese, C., Howard, J. J. Am. med. Ass. 1965, 191, 293. 9. Carey, L. C., Lepley, D. Surg. Forum, 1962, 13, 33. 10. Robinaux, R., Bazin, S. Sang, 1951, 22, 241. 11. Weiss, L. J. Cell Biol. 1965, 26, 735. 12. Michael, A. F., Vernier, R. L., Drummond, K. N., Levitt, J. I., Herdman, R. C., Fish, A. J., Good, R. A. New Engl. J. Med. 1967, 276, 817.
PYELONEPHRITIS OR GLOMERULONEPHRITIS? SIR,-We read with interest your commentary on the problem of chronic glomerulonephritis as a cause of renal failure, but were disturbed by the concluding statements on the prevention of acute glomerulonephritis and its relation to chronic renal disease. The report of Reinstein2 on the 1953 Red Lake epidemic of acute glomerulonephritis is subject to other interpretations than the one that mass penicillin prophylaxis prevented further spread of acute glomerulonephritis. As shown in figure 2 of Reinstein’s paper, four weeks of steady decline in nephritis cases preceded the administration of penicillin. Although prophylaxis apparently reduced the prevalence of group-A streptococci in the population,23 it is likely that the subsidence and possibly the termination of the nephritis outbreak were spontaneous events. A second outbreak of nephritis associated with the same type of streptococcus occurred at Red Lake in the summer of 1966 and terminated spontaneously after a similar period of time.4 The concern of your leading articlewith the prevention of acute glomerulonephritis implies a regular relationship between this disease and chronic glomerulonephritis, a relationship which is questioned by some of the available data. A rather complete follow-up of the children who survived the 1953 epidemic of acute glomerulonephritis at Red Lake uncovered no evidence of chronic renal disease 10 years later.s Another follow-up study in children, in whom the episodes of acute glomerulonephritis were sporadic and less well documented and the follow-up interval more variable, reached essentially the same conclusions.That adults with sporadic acute glomerulonephritis may not escape the development of chronic glomerulonephritis is indicated by two studies with accurate documentation of the acute episode (including supporting streptococcal-antibody data) and with serial renal biopsies.’ However, there is evidence that even adults with epidemic acute glomerulonephritis usually recover without developing chronic renal disease.Finally, as indicated in your leading article, most patients with chronic glomerulonephritis give no history of an initial acute attack of nephritis, which suggests that the relationship is either rare or difficult to approach in this manner. Additional information is badly needed on the prevention and natural history of acute glomerulonephritis, including further documentation on the occurrence of and the explanation for apparent differences in the disease as it occurs under epidemic and sporadic conditions and among children and adults. Pending the availability of such information, there 1. 2. 3. 4.
5. 6. 7.
8.
Lancet, 1966, ii, 1287. Reinstein, C. R. J. Pediat. 1955, 47, 25. Kleinman, H. Minn. Med. 1954, 37, 479. Anthony, B. F., Kaplan, E. L., Chapman, S. S., Wannamaker, L. W. Meeting of Society for Pediatric Research, Atlantic City, New Jersey, April 28-29, 1967 (abstract). Perlman, L. V., Herdman, R. C., Kleinman, H., Vernier, R. L. J. Am. med. Ass. 1965, 194, 63. Lieberman, E., Donnell, G. N. Am. J. Dis. Child. 1965, 109, 398. Jennings, R. B., Earle, D. P. J. clin. Invest. 1961, 40, 1525. McCluskey, R. T., Baldwin, D. S. Am. J. Med. 1963, 35, 213. Rammelkamp, C. H., Jr. in The Streptococcus, Rheumatic Fever and Glomerulonephritis (edited by J. W. Uhr); p. 296. Baltimore, 1964.
predisposition
to
in Dr. Fialkow’s
autoimmunity ", hypothesis.5
which
was
later elaborated
This work was supported by a grant (GM 11615) from the United States Public Health Service, and a grant from the Children’s Bureau (project 423), United States Department of Health, Education and Welfare. We are indebted to Dr. Grant W. Liddle and Dr. Amos Christie and their staff for referring a number of these patients.
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, U.S.A.
ERIC ENGEL.
MASKING OF ANTIGENS ON TROPHOBLAST SiR,-The objections which Dr. Good raises (May 27, p. 1156) to our paper (April 1, p. 708) are not supported by the many published reports describing the electrochemical properties of cells. His suggestion that the hydration properties of cell-surface monosaccharides determine cell-surface behaviour is at variance with observed data. It has been demonstrated that the abnormal behaviour of malignant cells is dependent upon their high net negative surface charge,6 which can be returned to normal levels by treatment with neuraminidase.7 This enzyme cleaves the o-glycoside link between the monosaccharides and the terminal N-acetylneuraminic-acid moiety. The high charge on malignant cells therefore depends upon the ionised carboxyl group of N-acetyl-neuraminic acid and cannot be related to monosaccharide hydration. Electrostatic repulsion of lymphocytes is well documented in vivo 89 and in vitro,1O and shows that their surface charge may well inhibit contact with cells bearing highly charged sialomucins. We cannot therefore accept Dr. Good’s objections. As Weiss has stated : 11 " ... the charge at the cell periphery may affect ... the magnitude of potential energy barriers, hindering contact between cells." Edgar and Tenovus Laboratory, G. A. CURRIE Fulham Hospital, K. D. BAGSHAWE. St. Dunstans Road, London W.6.
IMMUNOSUPPRESSION AND RENAL DISEASE SIR,-Iwas perturbed to read in your leading article (May 20, p. 1093) your suggestion of prospective trials of single and combined drug programmes using tests of renal function and morphology as criteria. The substance of the review was the article by Michael et al.12 on the use of azathioprine and prednisone in the treatment of glomerulonephritis. To do them justice these workers have stated clearly that despite the results achieved the mode of action of the
There are several good tests for assessing the activity of the but apparently there is reluctance to apply the methods of experimental pathology in clinical medicine. Their use would not only clarify the efficacy of the drugs used, but also allow scientific assessment of therapeutic dosage and help avert the disasters to be expected after total suppression of the immune system. The use of such tests would, I believe, predict the steroid dosage, and the lack of response, or even that patients can be made worse-if suppression of R.E.S. activity means that circulating antigen-antibody complexes are no longer removed by the natural defence mechanism. Just as in physiology, so also in pathology, the kidney cannot be studied in isolation. Royal Victoria Infirmary, E. N. WARDLE. Newcastle upon Tyne 1. R.E.S.
drugs is
not
clear and may
involve immunosuppression, anti-inflammatory effects, or mere reduction of proliferation of endothelial and mesangial cells. Despite experimental models I know of no precise evidence that any human form of glomerulonephritis is " autoimmune " in the sense that antibodies are formed primarily to renal antigens but rather that glomerulonephritis is the result of circulating antigen-antibody complexes or other macromolecules lodging in the glomeruli. This means that, unless such complexes can be destroyed in the circulation, the assessment of therapy of glomerulonephritis rests of the effect of these drugs on the reticuloendothelial system (R.E.S.). It is well recognised that, in the same way as macrophages ingest and dispose of antigen, so the R.E.s. influences antibody synthesis, and indeed phagocytic activity of the R.E.S. is correlated with immunological responsiveness. In human glomerulonephritis phagocytic hyperactivity of the R.E.s. has been demonstrated. 5. Fialkow, P. J. Lancet, 1964, i, 474. 6. Abercrombie, M., Ambrose, G. J. Cancer Res. 1962, 22, 525. 7. Forrester, J. A., Ambrose, G. J., Macpherson, I. A. Nature, Lond. 1962, 196, 1068. 8. Vega, R. E., Singh, L. M., Danese, C., Howard, J. J. Am. med. Ass. 1965, 191, 293. 9. Carey, L. C., Lepley, D. Surg. Forum, 1962, 13, 33. 10. Robinaux, R., Bazin, S. Sang, 1951, 22, 241. 11. Weiss, L. J. Cell Biol. 1965, 26, 735. 12. Michael, A. F., Vernier, R. L., Drummond, K. N., Levitt, J. I., Herdman, R. C., Fish, A. J., Good, R. A. New Engl. J. Med. 1967, 276, 817.
PYELONEPHRITIS OR GLOMERULONEPHRITIS? SIR,-We read with interest your commentary on the problem of chronic glomerulonephritis as a cause of renal failure, but were disturbed by the concluding statements on the prevention of acute glomerulonephritis and its relation to chronic renal disease. The report of Reinstein2 on the 1953 Red Lake epidemic of acute glomerulonephritis is subject to other interpretations than the one that mass penicillin prophylaxis prevented further spread of acute glomerulonephritis. As shown in figure 2 of Reinstein’s paper, four weeks of steady decline in nephritis cases preceded the administration of penicillin. Although prophylaxis apparently reduced the prevalence of group-A streptococci in the population,23 it is likely that the subsidence and possibly the termination of the nephritis outbreak were spontaneous events. A second outbreak of nephritis associated with the same type of streptococcus occurred at Red Lake in the summer of 1966 and terminated spontaneously after a similar period of time.4 The concern of your leading articlewith the prevention of acute glomerulonephritis implies a regular relationship between this disease and chronic glomerulonephritis, a relationship which is questioned by some of the available data. A rather complete follow-up of the children who survived the 1953 epidemic of acute glomerulonephritis at Red Lake uncovered no evidence of chronic renal disease 10 years later.s Another follow-up study in children, in whom the episodes of acute glomerulonephritis were sporadic and less well documented and the follow-up interval more variable, reached essentially the same conclusions.That adults with sporadic acute glomerulonephritis may not escape the development of chronic glomerulonephritis is indicated by two studies with accurate documentation of the acute episode (including supporting streptococcal-antibody data) and with serial renal biopsies.’ However, there is evidence that even adults with epidemic acute glomerulonephritis usually recover without developing chronic renal disease.Finally, as indicated in your leading article, most patients with chronic glomerulonephritis give no history of an initial acute attack of nephritis, which suggests that the relationship is either rare or difficult to approach in this manner. Additional information is badly needed on the prevention and natural history of acute glomerulonephritis, including further documentation on the occurrence of and the explanation for apparent differences in the disease as it occurs under epidemic and sporadic conditions and among children and adults. Pending the availability of such information, there 1. 2. 3. 4.
5. 6. 7.
8.
Lancet, 1966, ii, 1287. Reinstein, C. R. J. Pediat. 1955, 47, 25. Kleinman, H. Minn. Med. 1954, 37, 479. Anthony, B. F., Kaplan, E. L., Chapman, S. S., Wannamaker, L. W. Meeting of Society for Pediatric Research, Atlantic City, New Jersey, April 28-29, 1967 (abstract). Perlman, L. V., Herdman, R. C., Kleinman, H., Vernier, R. L. J. Am. med. Ass. 1965, 194, 63. Lieberman, E., Donnell, G. N. Am. J. Dis. Child. 1965, 109, 398. Jennings, R. B., Earle, D. P. J. clin. Invest. 1961, 40, 1525. McCluskey, R. T., Baldwin, D. S. Am. J. Med. 1963, 35, 213. Rammelkamp, C. H., Jr. in The Streptococcus, Rheumatic Fever and Glomerulonephritis (edited by J. W. Uhr); p. 296. Baltimore, 1964.