PATHOPHYSIOLOGY OF AIDS GLOMERULOPATHY

慢性肾小球损伤已被描述在患者

A chronic glomerular injury has been described in patients with AIDS. To determine its incidence we will screen urine of 500 AIDS patients with a sensitive immunochemical technique for subclinical as well as overt elevation of albuminuria. Twenty-five AIDS patients with heavy proteinuria will then be examined with physiologic, morphometric and cell biologic techniques to elucidate the pathogenesis and extent of the glomerular injury. Because the idiopathic nephrotic syndrome (INS) is associated with a similar alteration of glomerular epithelial cells with or without focal and segmental glomerulosclerosis, 25 patients with INS will be examined in identical fashion. Fractional clearances of uncharged dextrans of graded size and of anionic dextran sulfate will be used to define the magnitude of injury to the size- and charge-selective barriers in the glomerular filter. Morphometric determinations, including glomerular filtration surface area and epithelial filtration slit density will be correlated with lowered GFR and ultrafiltration capacity (Kf). Monoclonal antibodies will be used to determine levels of various cytokines in supernates of cultured lymphocytes, so as to relate such levels to the magnitude of glomerular injury. Recombinant interferons and other selected cytokines will be infused into the Munich Wistar rat and micropuncture and morphometric techniques used to determine whether the foregoing human glomerular injuries can be replicated. Rat kidney will also be examined with monoclonal antibodies to identify cytokine- mediated alteration of expression on renal cells of MHC and other antigens, and these alterations will be sought for in human biopsy material. To define the course of the injury, differential solute clearances and cytokine levels will be repeated before and after an attempt to inhibit the latter with cyclosporine, and then at regular intervals over a 5 year period. The filtration data will be analyzed with a model that treats the glomerular capillary wall as a heteroporous membrane with an effective concentration of fixed negative charges. The membrane parameters derived from serial examinations will be used to monitor the injury and define either remission of irrevocable progression. By obtaining a more guantitative description of AIDS-related glomerulopathy, we hope to determine whether it represents a non-specific or unique injury to glomerular epithelial cells, perhaps mediated by cytokines. Enhancement of our understanding of its pathogenesis and pathophysiology could lead to the development of efficacious therapy.