Abstract

Male dogs with X-linked hereditary nephritis (HN) serve as a model for studying male patients with this disease. In the present study, carrier female dogs were found to resemble female patients in showing a broad range of renal dysfunction. Of 37 carrier female dogs studied, all were healthy up to 5 years of age; however, all had proteinuria develop at 2 to 3 months, and focal segmental glomerulosclerosis (FSGS) was detected after 7 months. After 5 years, 4 of 13 dogs remained healthy and showed mild FSGS on renal biopsy; 4 had mild renal dysfunction develop and their kidneys showed extensive FSGS; 5 died prematurely of renal failure with end-stage kidneys. By immunofluorescence, using antibody to the NC1 domain of collagen type IV, segmental staining of glomerular basement membranes (GBM) was seen in all dogs before 3 to 4 years, and lesions of FSGS were negative. Thereafter, a transition to global staining of GBM was noted and lesions of FSGS became positive. Lens capsule and basement membranes in lung and choroid plexus showed discontinuous staining in two young carrier female dogs and continuous staining in one older carrier female dog. By electron microscopy, multilaminar splitting of some GBM was seen up to 4 years, and thereafter, splitting took on a compressed appearance, with the layers becoming apposed though still detectable. The authors conclude that: 1) carrier female dogs with X-linked HN are mosaics for an abnormality in the NC1 domain of GBM and other basement membranes; 2) FSGS develops in all carrier female dogs in glomerular capillary loops that possess an abnormal NC1 domain, and progresses to a variable extent in different dogs; and 3) the abnormality of NC1 in GBM of carrier female dogs appears to diminish with age, but this does not prevent progression of renal disease. Similar conclusions may apply to females with X-linked HN.