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Inhaled Silica, the Lung, and the Kidney
22
tions. Clearly, dipyridamole will only be beneficial in the presence of circulating prostacyclin (or a substitute). When there is a deficiency of prostacyclin, either because of too high a dose of aspirin or some other form of enzyme inhibition, or because of disease, dipyridamole will be ineffective. Those clinicians conducting trials of aspirin-dipyridamole combinations should examine carefully the dosage of aspirin. Ideally, an assay for blood-levels of prostacyclin would enable the clinician, firstly, to determine whether to use dipyridamole at all and, secondly, to measure the effects of small doses of aspirin. Prostacyclin is chemically unstable, with a half-life in blood at 37°C of 2-3 minutes. Thus, it will largely disappear in the 15-30 minutes taken to process blood into platelet-rich plasma for studies of aggregation in vitro. This explains why there is no demonstrable action in tests of platelet function in vitro in blood-samples taken from sub-
jects receiving dipyridamole.
Inhaled Silica, the
Lung, and the Kidney
PNEUMOCONIOSIS is commonly used as a blanket term, referring to a reaction in the lung to inhaled dust.’ Silicosis is a specific form of pneumoconiosis caused by the inhalation of free silica, and has long been notorious as one of the most serious occupational lung disorders causing fibrosis. now
Sandblasting
particularly high concentrainhalation, and the special recognised when sandblasting was
creates
tions of silica dust for
dangers
were
banned in the U.K. in 1951 and in the E.E.C. in 1966. Unfortunately, sandblasting has been allowed to continue in the U.S.A., and there have now been case-reports describing the unusual lung changes and also evidence of renal effects, including proteinuria and acute renal failure. Such reports reawaken interest in the cellular and immune responses to silica, while reinforcing the need to
strengthen preventive measures. Silica is the major constituent of the earth’s crust. The main danger arises from free silica present mainly as quartz and flint, and as an important constituent of granite, sandstone, and slate. If the quartz is converted into particles of 1-5m by drilling, crushing, or grinding, it can be inhaled and retained within the alveoli. Silicosis, in its usual form, develops after many years of exposure to free silica dust. Workers in the mines, quarries, potteries, and foundries may present with cough, sputum, and breathlessness, but the diagnosis is made from the radiographic changes. Initially the X-rays show a fine nodulation, mainly in the upper zones, but the picture can be complicated by the 1. Parkes, W. R.
Occupational Lung Disorders;
p.
1. London, 1974.
coalescent lesions of progressive massive fibrosis. Eggshell calcification and enlargement of mediastinal lymph-nodes is sometimes seen. Superimposed mycobacterial infection, with Mycobacterium tuberculosis or with atypical organisms such as M. kansasii or M. intracellulare, arises in up to 26%2 and can only be diagnosed by sputum culture ; any X-ray changes may be indistinguishable from the progress of pre-existing silicotic lesions. Silicosis has become less coriimon over the years through better preventive action, and fewer workers are involved in the hazardous industries. Despite this, in 1976, 171 British workers were accepted by the Pneumoconiosis Medical Panels as having silicosis; the figure for coal worker’s pneumoconiosis was 575.3 The heavier the exposure to free silica, the earlier the symptoms and X-ray changes appear. In sandblasters, the socalled acute disease can develop after only 6 months’ exposure, progressing to death within a few months or years from onset of symptoms.4,5 Where tissue has been obtained, at lung biopsy or necropsy, the lung has shown changes resembling alveolar proteinosis, alveoli being filled with
large
proteinaceous
periodic
acid/Schiff-positive
material. This may be accompanied by silicotic nodular change with hyaline fibrosis and some granuloma formation. Up to 10% of workers with the rapidly progressive type of silicosis also show clinical evidence of connective tissue disorders such as scleroderma, systemic lupus erythematosus, and rheumatoid arthritis.6 It is now apparent that inhalation of silicon can cause renal disease with no evidence of a widespread connective-tissue disorder. In one patient’ presenting with proteinuria and hypertension, renal biopsy showed a focal glomerulonephritis and degenerative changes in the proximal tubules, although no change in tubular function could be demonstrated. The patient had worked with refractory bricks, and the silicon content of renal tissue was, at 200 parts per million dry weight, some 14 times normal. Surprisingly, chest X-ray was normal. A second reportS describes a sandblaster, with acute pulmonary silicoproteinosis, who died in acute renal failure after a period of massive proteinuria (9-4 g/24 h). Again excessive amounts of silicon were found in the kidney, and histological examination revealed a mild proliferative glomerulonephritis, not judged severe enough to explain the Bailey, W. C., Brown, M., Beuchner, H. A., Weill, H., Ichinose, H., Ziskind, M. Am. Rev. resp. Dis. 1974, 110, 115. 3. Social Security Statistics, 1976. Department of Health and Social Security. London, 1978. 4. Suratt, P. M., Winn, W. C., Brody, A. R., Bolton, W. K., Giles, R. D. Am Rev. resp. Dis. 1977, 115, 521. 5. Xipell, J. M., Ham, K. N., Price, C. G., Thomas, D. P. Thorax, 1977, 32, 2.
104. 6. 7. 8.
Ziskind, M., Jones, R. N., Weill, H. Am. Rev. resp Dis. 1976, 113, 643. Saldanha, L. F., Rosen, V. J., Gonick, H. C. Am. J. Med. 1975, 59, 95. Giles, R. D., Sturgill, B. C., Suratt, P. M., Bolton, W. K. ibid. 1978, 64, 336.
23
and renal failure. Immunofluorescence deposits of immunoglobulin M and C3 complement along the basement membrane, suggesting immune-complex formation, but attempts to identify the antigen in the deposits was unhelpful. A simple toxic effect of silicon on the kidney, perhaps on renal enzymes, has been postulated; but the fact that tubular function is unaffected suggests a major difference from the toxic nephropathies associated with many metals such as gold, cadmium, and mer-
proteinuria showed
cury.’ Silica therefore has curious effects on the tissues. Free silica consists of a crystalline structure of silicon and oxygen atoms, and particles arriving in alveoli are engulfed by alveolar macrophages; silica particles seem particularly toxic, for after being enclosed in phagosomes these cell bodies rupture, releasing lysosomal enzymes, and the macrophages die. The remains of the cells may then be ingested by other macrophages, and the lethal process continues.6 Silica may damage cells by forming hydrogen bonds to protein components of cell membranes and by abstracting these proteins from the membranes.9 It is noteworthy that M. tuberculosis grows more rapidly in macrophages fed sublethal doses of silica."* Immunological changes too have been noted in silicosis. Apart from the increased incidence of connective-tissue disorders, up to 44% of patients have antinuclear antibodies.11 Silicotic lesions may contain plasma cells and immunoglobulins. There is no major evidence of altered cellmediated immunity in silicotic patients.12 An immune reaction may not contribute to the initial killing of macrophages, but it may help to maintain a supply of macrophages at the lesion. The disruption of macrophages stimulates production of collagen by the fibroblasts, resulting in progressive fibrosis, as in the more chronic forms of silicosis. In the more acute silicoproteinosis, macrophage activity is less prominent, but the proteinaceous material contains cells which may be type-2 pneumocytes, shed from the alveolar walls, the damage to the epithelium allowing a proteinaceous exudate.5 It has also been suggested that damage to macrophages may prevent proper clearing of surfactant.44 The pathogenesis of acute and chronic silicosis may still be in doubt, but, as with all occupational diseases, the solution to the disease lies in prevention. The occupational link with respiratory disease is usually a straightforward one, provided a good work history is taken. It now seems necessary to consider inhaled silica dust as a rare cause of renal disease. Once silica has been inhaled, there is little to offer the patient, apart from careful review for 9. Summerton, J., Hoenig, S Exp. mol. Path. 1977, 26, 113. 10. Allison, A. C., Hart, P. D. Br.J exp. Path. 1968, 49, 465. 11 Jones, R. N., Turner-Warwick, M., Ziskind, M., Weill, H. Am. Rev. resp. Dis. 1976, 113, 393 12 Schuyler, M , Ziskind, M., Salvaggio, J. ibid. 1977, 116, 147.
and sympathy as the disease progresses. Financial compensation may be available, but prevention is a better solution.
complicating tuberculosis,
SCREENING FOR REFLUX
"Pyelonephritic" scarring of a kidney is generally associated with vesicoureteric reflux in childhood. Many authorities believe the association to be causal-urinary tract infection damaging the kidneys of children who have reflux. Conversely damage by infection is unlikely in the absence of reflux. This has led to a desire to screen children for vesicoureteric reflux. The sure way of detecting reflux is by a voiding cystourethrogram (micturating cystogram). It is an unpleasant procedure which requires skilled radiographers and radiologists, and the incidence of reflux is unlikely to warrant general population screening. The exact incidence is unknown; for obvious reasons there have been few studies of well children. Of 66 premature infants and 24 full-term neonates none had reflux;2,3 of 100 children (mainly under 5 years of age) who had normal urine and no urinary-tract symptoms 1 had reflux.4 Therefore it is unlikely that much more than 1% of unselected children would be found to have reflux. In selected groups the prevalence could be much higher. Of the 1-2% of schoolgirls who have bacteriuria,5,7about a quarter have reflux. Another approach is to consider the familial nature of reflux. Many families have been reported in which several members had reflux. The modes of inheritance have varied, some being confined to males," others apparently being governed by autosomal dominant inheritance,9 while the bulk of familial cases seem to involve both boys and girls. The Burgersl° have suggested that for this large group there is a multifactorial genetically controlled anomaly of the vesicoureteric junction, and that the functional expression depends upon several factors including sex, age, urine infection, and bladder pressure. The likelihood of kidney damage may vary with the type of inheritance. In some families severe reflux has been the rule, associated with gross renal damage (or is it congenital renal dysplasia?) and yet little or no urine infection.8 In other families reflux and urine infection have been prominent and radiological evidence of kidney damage rare. De Vargas and others" have just reported a useful family study of vesicoureteric reflux. Lumping all children with reflux together (which may not be the ideal) they found reflux in 3 out of 20 well siblings under the age of 5-a 15% prevalence. Similarly the preva1. 2.
Hodson, C. J., Edwards, D. Clin. Radiol. 1960, 11, 219. Peters, P. C., Johnson, D. E., Jackson, J. H. J. Urol. 1967, 97, 259. 3. Lich, R., Jr., Howerton, L. W., Jr., Groode, L. S., Davis, L. A. ibid. 1964, 92, 436. 4. Jones, B. W., Headstream, J. W. ibid. 1958, 80, 114. 5. Kunin, C. M., Deutscher, R., Paquin, A. J. Medicine, 1964, 43, 91. 6. Meadow, S. R., White, R. H. R., Johnston, N. M. Br. Med. J. 1969, iii, 81. 7. Savage, D. C. L., Wilson, M. I., McHardy, M., Dewar, D. A. E., Fee, W. M.Archs Dis. Childh. 1973, 48, 8. 8. Middleton, G. W., Howards, S. S., Gillenwater, J. Y. J. Urol. 1975, 114, 36. 9. Lewy, P R., Belham, A. B. J. Pediat. 1975, 86, 851. 10. Burger, R. H., Burger, S.E. Urol. Clins N Am. 1974, 1, 419. 11. De Vargas, A., Evans, K., Ransley, P., Rosenberg, A. R., Rothwell, R., Sherwood, T., Williams, D. I., Barratt, T. M., Carter, C. O. J. med. Genet. 1978, 15, 85.
tions. Clearly, dipyridamole will only be beneficial in the presence of circulating prostacyclin (or a substitute). When there is a deficiency of prostacyclin, either because of too high a dose of aspirin or some other form of enzyme inhibition, or because of disease, dipyridamole will be ineffective. Those clinicians conducting trials of aspirin-dipyridamole combinations should examine carefully the dosage of aspirin. Ideally, an assay for blood-levels of prostacyclin would enable the clinician, firstly, to determine whether to use dipyridamole at all and, secondly, to measure the effects of small doses of aspirin. Prostacyclin is chemically unstable, with a half-life in blood at 37°C of 2-3 minutes. Thus, it will largely disappear in the 15-30 minutes taken to process blood into platelet-rich plasma for studies of aggregation in vitro. This explains why there is no demonstrable action in tests of platelet function in vitro in blood-samples taken from sub-
jects receiving dipyridamole.
Inhaled Silica, the
Lung, and the Kidney
PNEUMOCONIOSIS is commonly used as a blanket term, referring to a reaction in the lung to inhaled dust.’ Silicosis is a specific form of pneumoconiosis caused by the inhalation of free silica, and has long been notorious as one of the most serious occupational lung disorders causing fibrosis. now
Sandblasting
particularly high concentrainhalation, and the special recognised when sandblasting was
creates
tions of silica dust for
dangers
were
banned in the U.K. in 1951 and in the E.E.C. in 1966. Unfortunately, sandblasting has been allowed to continue in the U.S.A., and there have now been case-reports describing the unusual lung changes and also evidence of renal effects, including proteinuria and acute renal failure. Such reports reawaken interest in the cellular and immune responses to silica, while reinforcing the need to
strengthen preventive measures. Silica is the major constituent of the earth’s crust. The main danger arises from free silica present mainly as quartz and flint, and as an important constituent of granite, sandstone, and slate. If the quartz is converted into particles of 1-5m by drilling, crushing, or grinding, it can be inhaled and retained within the alveoli. Silicosis, in its usual form, develops after many years of exposure to free silica dust. Workers in the mines, quarries, potteries, and foundries may present with cough, sputum, and breathlessness, but the diagnosis is made from the radiographic changes. Initially the X-rays show a fine nodulation, mainly in the upper zones, but the picture can be complicated by the 1. Parkes, W. R.
Occupational Lung Disorders;
p.
1. London, 1974.
coalescent lesions of progressive massive fibrosis. Eggshell calcification and enlargement of mediastinal lymph-nodes is sometimes seen. Superimposed mycobacterial infection, with Mycobacterium tuberculosis or with atypical organisms such as M. kansasii or M. intracellulare, arises in up to 26%2 and can only be diagnosed by sputum culture ; any X-ray changes may be indistinguishable from the progress of pre-existing silicotic lesions. Silicosis has become less coriimon over the years through better preventive action, and fewer workers are involved in the hazardous industries. Despite this, in 1976, 171 British workers were accepted by the Pneumoconiosis Medical Panels as having silicosis; the figure for coal worker’s pneumoconiosis was 575.3 The heavier the exposure to free silica, the earlier the symptoms and X-ray changes appear. In sandblasters, the socalled acute disease can develop after only 6 months’ exposure, progressing to death within a few months or years from onset of symptoms.4,5 Where tissue has been obtained, at lung biopsy or necropsy, the lung has shown changes resembling alveolar proteinosis, alveoli being filled with
large
proteinaceous
periodic
acid/Schiff-positive
material. This may be accompanied by silicotic nodular change with hyaline fibrosis and some granuloma formation. Up to 10% of workers with the rapidly progressive type of silicosis also show clinical evidence of connective tissue disorders such as scleroderma, systemic lupus erythematosus, and rheumatoid arthritis.6 It is now apparent that inhalation of silicon can cause renal disease with no evidence of a widespread connective-tissue disorder. In one patient’ presenting with proteinuria and hypertension, renal biopsy showed a focal glomerulonephritis and degenerative changes in the proximal tubules, although no change in tubular function could be demonstrated. The patient had worked with refractory bricks, and the silicon content of renal tissue was, at 200 parts per million dry weight, some 14 times normal. Surprisingly, chest X-ray was normal. A second reportS describes a sandblaster, with acute pulmonary silicoproteinosis, who died in acute renal failure after a period of massive proteinuria (9-4 g/24 h). Again excessive amounts of silicon were found in the kidney, and histological examination revealed a mild proliferative glomerulonephritis, not judged severe enough to explain the Bailey, W. C., Brown, M., Beuchner, H. A., Weill, H., Ichinose, H., Ziskind, M. Am. Rev. resp. Dis. 1974, 110, 115. 3. Social Security Statistics, 1976. Department of Health and Social Security. London, 1978. 4. Suratt, P. M., Winn, W. C., Brody, A. R., Bolton, W. K., Giles, R. D. Am Rev. resp. Dis. 1977, 115, 521. 5. Xipell, J. M., Ham, K. N., Price, C. G., Thomas, D. P. Thorax, 1977, 32, 2.
104. 6. 7. 8.
Ziskind, M., Jones, R. N., Weill, H. Am. Rev. resp Dis. 1976, 113, 643. Saldanha, L. F., Rosen, V. J., Gonick, H. C. Am. J. Med. 1975, 59, 95. Giles, R. D., Sturgill, B. C., Suratt, P. M., Bolton, W. K. ibid. 1978, 64, 336.
23
and renal failure. Immunofluorescence deposits of immunoglobulin M and C3 complement along the basement membrane, suggesting immune-complex formation, but attempts to identify the antigen in the deposits was unhelpful. A simple toxic effect of silicon on the kidney, perhaps on renal enzymes, has been postulated; but the fact that tubular function is unaffected suggests a major difference from the toxic nephropathies associated with many metals such as gold, cadmium, and mer-
proteinuria showed
cury.’ Silica therefore has curious effects on the tissues. Free silica consists of a crystalline structure of silicon and oxygen atoms, and particles arriving in alveoli are engulfed by alveolar macrophages; silica particles seem particularly toxic, for after being enclosed in phagosomes these cell bodies rupture, releasing lysosomal enzymes, and the macrophages die. The remains of the cells may then be ingested by other macrophages, and the lethal process continues.6 Silica may damage cells by forming hydrogen bonds to protein components of cell membranes and by abstracting these proteins from the membranes.9 It is noteworthy that M. tuberculosis grows more rapidly in macrophages fed sublethal doses of silica."* Immunological changes too have been noted in silicosis. Apart from the increased incidence of connective-tissue disorders, up to 44% of patients have antinuclear antibodies.11 Silicotic lesions may contain plasma cells and immunoglobulins. There is no major evidence of altered cellmediated immunity in silicotic patients.12 An immune reaction may not contribute to the initial killing of macrophages, but it may help to maintain a supply of macrophages at the lesion. The disruption of macrophages stimulates production of collagen by the fibroblasts, resulting in progressive fibrosis, as in the more chronic forms of silicosis. In the more acute silicoproteinosis, macrophage activity is less prominent, but the proteinaceous material contains cells which may be type-2 pneumocytes, shed from the alveolar walls, the damage to the epithelium allowing a proteinaceous exudate.5 It has also been suggested that damage to macrophages may prevent proper clearing of surfactant.44 The pathogenesis of acute and chronic silicosis may still be in doubt, but, as with all occupational diseases, the solution to the disease lies in prevention. The occupational link with respiratory disease is usually a straightforward one, provided a good work history is taken. It now seems necessary to consider inhaled silica dust as a rare cause of renal disease. Once silica has been inhaled, there is little to offer the patient, apart from careful review for 9. Summerton, J., Hoenig, S Exp. mol. Path. 1977, 26, 113. 10. Allison, A. C., Hart, P. D. Br.J exp. Path. 1968, 49, 465. 11 Jones, R. N., Turner-Warwick, M., Ziskind, M., Weill, H. Am. Rev. resp. Dis. 1976, 113, 393 12 Schuyler, M , Ziskind, M., Salvaggio, J. ibid. 1977, 116, 147.
and sympathy as the disease progresses. Financial compensation may be available, but prevention is a better solution.
complicating tuberculosis,
SCREENING FOR REFLUX
"Pyelonephritic" scarring of a kidney is generally associated with vesicoureteric reflux in childhood. Many authorities believe the association to be causal-urinary tract infection damaging the kidneys of children who have reflux. Conversely damage by infection is unlikely in the absence of reflux. This has led to a desire to screen children for vesicoureteric reflux. The sure way of detecting reflux is by a voiding cystourethrogram (micturating cystogram). It is an unpleasant procedure which requires skilled radiographers and radiologists, and the incidence of reflux is unlikely to warrant general population screening. The exact incidence is unknown; for obvious reasons there have been few studies of well children. Of 66 premature infants and 24 full-term neonates none had reflux;2,3 of 100 children (mainly under 5 years of age) who had normal urine and no urinary-tract symptoms 1 had reflux.4 Therefore it is unlikely that much more than 1% of unselected children would be found to have reflux. In selected groups the prevalence could be much higher. Of the 1-2% of schoolgirls who have bacteriuria,5,7about a quarter have reflux. Another approach is to consider the familial nature of reflux. Many families have been reported in which several members had reflux. The modes of inheritance have varied, some being confined to males," others apparently being governed by autosomal dominant inheritance,9 while the bulk of familial cases seem to involve both boys and girls. The Burgersl° have suggested that for this large group there is a multifactorial genetically controlled anomaly of the vesicoureteric junction, and that the functional expression depends upon several factors including sex, age, urine infection, and bladder pressure. The likelihood of kidney damage may vary with the type of inheritance. In some families severe reflux has been the rule, associated with gross renal damage (or is it congenital renal dysplasia?) and yet little or no urine infection.8 In other families reflux and urine infection have been prominent and radiological evidence of kidney damage rare. De Vargas and others" have just reported a useful family study of vesicoureteric reflux. Lumping all children with reflux together (which may not be the ideal) they found reflux in 3 out of 20 well siblings under the age of 5-a 15% prevalence. Similarly the preva1. 2.
Hodson, C. J., Edwards, D. Clin. Radiol. 1960, 11, 219. Peters, P. C., Johnson, D. E., Jackson, J. H. J. Urol. 1967, 97, 259. 3. Lich, R., Jr., Howerton, L. W., Jr., Groode, L. S., Davis, L. A. ibid. 1964, 92, 436. 4. Jones, B. W., Headstream, J. W. ibid. 1958, 80, 114. 5. Kunin, C. M., Deutscher, R., Paquin, A. J. Medicine, 1964, 43, 91. 6. Meadow, S. R., White, R. H. R., Johnston, N. M. Br. Med. J. 1969, iii, 81. 7. Savage, D. C. L., Wilson, M. I., McHardy, M., Dewar, D. A. E., Fee, W. M.Archs Dis. Childh. 1973, 48, 8. 8. Middleton, G. W., Howards, S. S., Gillenwater, J. Y. J. Urol. 1975, 114, 36. 9. Lewy, P R., Belham, A. B. J. Pediat. 1975, 86, 851. 10. Burger, R. H., Burger, S.E. Urol. Clins N Am. 1974, 1, 419. 11. De Vargas, A., Evans, K., Ransley, P., Rosenberg, A. R., Rothwell, R., Sherwood, T., Williams, D. I., Barratt, T. M., Carter, C. O. J. med. Genet. 1978, 15, 85.