Treatment of experimental streptococcal nephritis. I. A preliminary report.
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The principal objective of this investigation was to define the roles of injected and autogenous, kidney-localizing antibodies in the pathogenesis of rat nephrotoxic nephritis by relating data obtained with fluorescent antibody techniques to clinical and histologic observations. Such an analysis of the nephritis that developed in 28 rats after injection with the crude gamma-globulin fraction of nephrotoxic serum has led us to the following conclusions:- The renal localization of nephrotoxic antibodies is primarily and, perhaps, exclusively in the membranes of the glomerular tufts. These antibodies are demonstrable, as antigens, in the glomeruli for up to 3 months after injection. In the acute stage of the nephritis, non-antibody, autogenous globulins are present in the glomerular tufts, probably as components of edema fluid. From 6 and 9 days to 3 months after injection, autogenous antibodies are localized in the glomerular tufts in a pattern that corresponds closely to that of the nephrotoxins. The essential requirements for the operation of the mechanism postulated by Kay are fulfilled in rat nephrotoxic nephritis.
Studies have been carried out to determine the distribution of antigen capable of inducing the formation in rabbits of antibodies nephrotoxic for the rat. The results indicate that the antigen is present both in cortex and medulla of rat kidney. It can be extracted to a limited extent with saline. It is non-dialyzable and destroyed by boiling. The nephrotoxic serum antigen is also present in rat lung and placenta, in amounts roughly comparable to that in kidney, and in a number of other rat organs in smaller amounts. These various tissues not only are capable of stimulating the production of nephrotoxic antibodies, but each tissue is also able to absorb the nephrotoxic antibodies induced by injections of other rat tissues. These studies indicate that the nephrotoxic serum antigen in various rat tissues is the same or closely related. The nephrotoxic serum antigen of the rat is distinct from that of the dog and the rabbit, but there appears to be a cross-reaction between the nephrotoxic serum antigens of the rat and mouse. It is concluded that the nephrotoxic serum antigen is not a specific component of kidney; it is neither limited to kidney in its distribution within the rat, nor is the rat antigen present in kidney tissue of 2 other species examined. Rather, it is probable that the antigen is to a large extent specific for tissue of a given species. The preponderance of renal injury following injections of the anti-organ sera presumably is due to the occurrence in the kidney of large amounts of the antigen in positions of physiological importance in which it is exposed directly to the circulating antibodies.
Experimental uric acid lesions in the kidney of the rabbit have been reinvestigated using the technique of miscrodissection for location of lesions. The maximal initial lesion was found to occur in the first part of the collecting, and not in the ascending Henle and the distal convoluted tubule. Such lesions were only produced by very high dosage (approximately 0.5-1 gm. per kg.). It was concluded that the argument by analogy with the uric acid lesion cannot be used to support a hypothetical toxic damage to the segments of ascending Henle and the distal convolution in the crush syndrome.
The renal lesions of serum sickness were studied with the electron microscope. The most prominent change was a marked swelling and proliferation of glomernlar endothelial cells causing obliteration of the capillary lumen. The basement membrane also showed focal thickenings and excrescences. Deposits of electron-dense material blended into the basement membrane. On the extracapillary side epithelial foot processes were reduced in number and replaced by broad sheets of cytoplasm which were closely applied to the basement membrane. From a comparison of electron and fluorescent microscopic studies of the glomerulus in serum sickness, it would seem that antigen-antibody complexes initiated injury in endothelial cells, although the possibility of the primary reaction occurring on basement membrane cannot be excluded.
Ferritin-conjugated antibody has been used to identify by electron microscopy the sites at which nephrotoxic globulins localize in rat kidney during acute experimental glomerulonephritis. Antibody was concentrated in the glomerular basement membrane and in basement membrane-like material contained in distended cisternae of the endoplasmic reticulum. These data confirm and amplify, at the ultrastructural level, the results of studies obtained with the fluorescent antibody technique, and are consistent with the hypothesis that the cisternae and capillary basement membrane possess common proteins.
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