The well-recognized clinical association between acute upper respiratory tract virus infections and acute nephritis, nephrotic syndrome, exacerbations of these diseases and Goodpasture’s syndrome, has never been satisfactorily explained. The association with influenza was reviewed by Thomson and MacAuley’ after the 1917-19 influenza pandemic. Goodpasture’s description’ of the syndrome which bears his name was in association with the same influenza outbreak. Recurrent hemorrhagic nephritis has been clearly associated with influenza A infection,” as has acute renal failure’ and Goodpasture’s syndrome.’ Killed influenza vaccine has been reported to adversely affect pre-existing glomerular disease.‘, A recent review of viral infections and renal disease,’ however, makes only passing reference to a causal relationship between acute respiratory virus infections and renal disease. Several potential pathogenic mechanisms by which respiratory viruses could cause renal pathology have been suggested. They are a direct effect of the virus, intravascular coagulation, and two varieties of immunologically mediated tissue damage. A direct cytopathic effect of virus is possible. Many respiratory viruses grow well and induce cytopathology in cultured renal cells. The myxoviruses, which include influenza and parainfluenza, have a surface neuraminidase. This enzyme splits sialic acid from glycoproteins. Glomerular basement membranes are rich in such proteins” and experimental administration of neuraminidase in mice has been shown to cause alteration of glomerular structure.” However, evidence for viremia or renal infection in all but the most overwhelming respiratory virus infections is lacking.“’ Disseminated intravascular coagulation has followed severe respiratory virus infections” and been associated with catastrophic renal pathology. This may follow agglutination and destruction of platelets after absorption of virus to their surface. Immune complexes could also trigger the coagulation cascade as could hypoxia, acidosis, and non-specific tissue damage. Fibrin degradation products have recently been reported transiently in the urine of healthy normal adults who had suffered trivial upper respiratory tract infections.‘” In this study complement (Cl,) and IgG were also found simultaneously in the urine. It was suggested that a transient immune-complex mediated glomerulitis had occurred. Because of the well-documented experimental nephropathies caused by circulating antigen/antibody complexes and by antibody directed particularly against glomerular (GBM) but also tubular (TBM) basement membrane antigens,” these immunologic entities are frequently sought in renal disease in man. The presence of anti-GBM antibodies, which may cross-react with lung basement membranes, is a definite requirement for the diagnosis of Goodpasture’s syndrome and has followed influenza A infection.’ Studies in animal models of non-lethal respiratory myxovirus infections have thrown
some light on the other possible immunopathologic mechanisms. Immune complexes of viral antigen and antibody have been regularly found in the lungs and frequently in glomeruli and on the TBM of rodents 2 to 12 days after non-lethal primary myxovirus infections.“, li Gross histologic renal damage was not detected. The timing was identical to the urinary findings in man, referred to earlier.” Since about one sixth of the total cardiac output goes through the kidney without an intervening reticula-endothelial barrier, it is not really surprising that immune complexes arising in the lung should frequently be deposited in the kidney. In animals pre-treated with cyclophosphamide, the lung and renal findings were greatly diminished. The presence of immune complexes in lung tissue was invariably associated with complement deposition (unpublished) and, between days 3 to 9, desquamation and necrosis of infected mucosal cells and destruction of bronchial basement membranes (BBM).” Ii Viral antigens were detected in mucosal cells, on the cell membranes, and on BBM. This could clearly lead to the generation of cross-reacting antibodies to cytoplasmic, cell membrane, and basement membrane antigens. In some animal studies there was late and sometimes a progressive appearance of linear IgG staining of GBM and TBM.” Elution studies to determine whether specific antibasement membrane antibodies were present are not complete. In studies in mice there are some preliminary data that genetic make-up played a role in the incidence and severity of both lung and renal lesions” and that transient albuminuria occurred (unpublished). It is also noteworthy that granular glomerular IgG staining often persisted in mice after viral antigens from the infecting virus had disappeared. The antigen in these presumed immune complexes is not known but could be antigens from a different virus (e.g.. chronic murine leukemia virus”‘) or other endogenous antigens. For the hypothesis which follows the most attractive antigen candidates would be derived from basement membrane or mucosal cells. The findings in rodents suggest that the following immunopathological consequences could occur dependent, at least in part, on the genetic background and related immunologic responsiveness of the host and the character and severity of the respiratory virus infection. 1. Early (2 to 10 days) transient renal immune-complex deposition involving the respiratory virus antigens. 2. A later auto-immune response to damaged host bronchial mucosal cells and basement membrane antigens. Immune complex mediated damage with soluble circulating cellular or basement membrane antigens could occur as in the Heymann nephritis model. ‘I Alternatively, or perhaps in addition, cross-reacting anti-GBM or anti-TBM disease could be produced.”
3. An auto-immune response after renal damage caused by directed more precisely at renal antigens. 4. Activation of latent or chronic virus infection with classical immune-complex deposition in the kidney. The viral antigens would not then be derived from the original respiratory virus. If this postulated series of events were to occur, then a sequence of completely different respiratory virus infections could exacerbate renal pathology. induce chronicity, or change the character of the original immunopathological damage. Furthermore, after recovery from the respiratory tract infection. antigens from the infecting virus may never be detected in the kidney. Since adults average 2 to 4 respiratory virus infections each year and children even more, the pathological mechanisms suggested could describe the commonest pathways to acute, recurrent, and chronic renal disease in man. Most infections probably result in acute sub-clinical renal damage. Comprehensive and sophisticated nephrologic and immunologic studies in these common afflictions are both urgently needed and greatly handicapped by the technical lack of promptness and diagnostic precision in respiratory virus infections. It is probable that definitive studies must await future clearly identified respiratory virus epidemics. However, preliminary data could be gathered from studies of patients with clinica1, non-bacterial, upper respiratory tract infections. *Gerald Blandford, M.B., M.R.C.P., F.R.C.P.(C) Toronto Western Hospital Depts. of Medicine and Pathology UniLlersity of Toronto and The Gage Research Institute 223 College Street Toronto, Ontario M5T lR4 Canada *Present address: Dept. of Medicine Akron City Hospital 525 E. Market St. Akron, Ohio 44309 1
Thomson, W. W. D., and MacAuley, an aetiological factor in nephritis, 1920.
H. F.: Influenza as Lancet 198:481,
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Wilson, C. B., and Smith, R. C.: Goodpasture’s syndrome associated with influenza A2 virus infection. Ann. Intern. Med. 76:91, 1972. Schreiner, G. E.: The nephrotic syndrome, in Disease of the Kidney, edited by M.B. Strauss and L.G. Welt. Boston, 1971, Little, Brown & Company, p. 503. Smith, R. D., and Aquino, ,J.: Viruses and the kidney, Med. Clin. North Am 55:89, 1971. Spiro, R. G.: Studies on the renal glomerular basement membrane, J. Biol. Chem. 242:1923, 1967. Hempel, E.. and Geyer, J.: Experimentelle Untersuchungen an der glomerularen Basalmembran in der Niere der Maus, Anat. Anz. 120:84, 1967. Minuse, E., Willis, P. W., Davenport, F. M., and Francis, T.: An attempt to demonstrate viremia in cases of Asian influenza, J. Lab. Clin. Med. 59:1016, 1962. Whitaker, A. N., Bunce, I., and Graeme, E. R.: Disseminated intravascular coagulation and acute renal failure in influenza A2 infection, Med. 3. Aust. 2:196. 1974. Fananapazir, L., Eccleston, M.. Edmond, E., and Anderton d. L.: Raised urinary fibrin-degradation products, complement and IgG during an influenza-like illness, Lancet 1:933, 1977. Unanue, E. R., Dixon, F. J., and Feldman, J. D.: Experimental immunologic diseases of the kidney, in Textbook of immunopathology, ed. Miesher, P. A., and MullerEberhard. H. J.. New York, 1976. Grune & Stratton, Inc., p. 231. Blandford, G.: Studies on the immune response and pathogenesis of Sendai virus infection of mice. III. The effects of cyclophosphamide, Immunology 28:871, 1975. Blandford. G., and Charlton, D.: Studies of pulmonary and renal immunopathology after nonlethal primary Sendai viral infection in normal and cyclophosphamidetreated hamsters, Am. Rev. Resp. Dis. 115:305. 1977. Pascal, R. R.. Koss, M. N., and Kassell, R. L.: Glomerulonephritis associated with immune complex deposits and virus particles in spontaneous murine leukemia. An electron microscopic study with immunofluorescence, Lab. Invest. 29:159, 1973.
Patients with a tight mitral valve stenosis present interesting descriptions of their respiratory difficulties when they walk into the ocean to wade or swim. As they walk into deeper and deeper water and the ocean level rises higher and higher onto their bodies, they feel more and more “congested” or “full” in their chest and become more and more dyspneic. This state often develops before the water level reaches the lower ribs and certainly as the chest begins to be submerged. The dyspnea becomes so distressful that these patients cannot proceed into deeper water and are forced to retreat to the beach to restore comfort. This experience is repeatedly
Goodpasture, E. W.: The significance of certain pulmonary lesions in relation to the etiology of influenza, Am. .J. Med. Sci. 158:863, 1919. Alexander, E. A.: Recurrent hemorrhagic nephritis with exacerbation related to influenza A, Ann. Intern. Med. 62:1022. 1965. Shenouda, A.. and Hatch. F. E.: Influenza A viral infection associated with acute renal failure, Am. d. Med.
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revealed in history taking among patients with mitral valve stenosis. The tighter the stenosis, the less water depth these patients are able to walk into. They, of course, are unable to dive. This phenomenon appears to me to be caused by the water pressing symmetrically upon the superficial veins of the lower extremities and abdomen, squeezing blood rather rapidly into the lungs. Fairly large volumes of blood lodged in the superficial veins are readily squeezed centrally into the right atrium, then into the right ventricle, and finally into the vessels of the lungs since there are no valves in the veins or other obstruc-
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C. V. Mosby