Induction of diabetes in PVG/c strain rats by manipulation of the immune system

A combination of thymectomy and sublethal irradiation (Tx-X) consistently induced diabetes in female rats of the PVG/c strain. The incidence of diabetes varied from 10.7% to 53.4% in seven successive Tx-X groups (mean 29.7%). Both clinical and subclinical disease was observed with the majority of affected animals developing the former condition. This was acute in onset, rapidly fatal (1-4 days) and characterized by ketosis and lipidemia. Overtly diabetic rats had markedly raised plasma glucose concentrations compared to normal rats of the same strain and plasma immunoreactive insulin concentrations were correspondingly depressed in this group. Histopathological change within the islets of Langerhans correlated with clinical status and ranged from diffuse atrophy in the majority of the acutely diabetic rats to mild and focal lymphocytic insulitis in a proportion of the non-diabetic rats. Islet cell autoantibodies were demonstrated by indirect immunofluorescence in approximately 25% of clinically diabetic animals. The majority of diabetic rats were found to be responsive to insulin and the clinical signs could be reversed by daily parenteral insulin administration. These observations implicate the immune system in diabetes generation and are consistent with an immune mediated pathogenesis as the underlying cause of the islet cell destruction. This syndrome may thus be a potentially useful animal model for type 1 (insulin dependent) diabetes in man

Hereditary nephritis in the bull terrier: evidence for inheritance by an autosomal dominant gene

A high prevalence of renal failure has been reported in bull terriers in Australia. The pattern of inheritance was analysed in a family of 33 bull terriers in which 10 dogs had renal disease manifested by proteinuria, ultrastructural abnormalities in the glomerular basement membrane, renal failure, or 'end stage' kidneys. The presence of at least one affected parent for each affected offspring, the approximately equal male/female ratio and the apparent absence of 'generation-skipping', strongly supported an autosomal dominant mode of inheritance, assuming a fully penetrant single major gene locus. Further evidence was not compatible with either an autosomal recessive or X-linked inheritance pattern. This contrasts with the X-linked inheritance shown in Alport's-type human hereditary nephritis and hereditary glomerulopathy in the samoyeds. Hereditary nephritis in the bull terrier should be a useful model for non-Alport's-type human hereditary nephritis, which is also reported to have an autosomal dominant inheritance pattern

Correlation of histopathological features and renal impairment in autosomal dominant Alport syndrome in Bull terriers

Background. Bull terrier hereditary nephritis represents a model for autosomal dominant Alport syndrome, as affected dogs have the characteristically lamellated glomerular basement membrane and demonstrate vertical male‐to‐male disease transmission. Methods. This study compared the histopathological features in kidneys from affected Bull terrier neonates, puppies, and adult dogs with normal or impaired renal function, with the histopathological appearance of kidneys from age‐ and size‐matched normal dogs. Results. There were fewer glomeruli per unit area of cortex in kidneys from affected neonatal kidneys (P<0.05), increased numbers of fetal glomeruli in affected puppy kidneys (P<0.05), and a separate population of glomeruli with larger renal corpuscles and glomerular tufts in kidneys from affected adult dogs with normal renal function (both P<0.0001) compared with normal dogs. Other histological features that are characteristic of human X‐linked and autosomal recessive Alport syndrome and that were present included hypercellular glomeruli, occasional crescents, segmental and global glomerular sclerosis, periglomerular fibrosis, interstitial fibrosis without significant cellular infiltrates and cystic dilatation of Bowman's capsular space and tubules. In dogs with renal impairment, the tubular index was the best predictor of increased urinary protein:creatinine (r=0.92) compared with glomerular, interstitial and vascular indices (r=0.77, 0.88 and 0.81), and medullary fibrosis correlated best with serum creatinine (r=0.72, P=0.0002). Conclusions. The demonstration in Bull terrier kidneys of fewer nephrons in neonates increased fetal glomeruli, and a separate population of glomeruli with larger corpuscles and tufts reflects the effects of the underlying genetic mutation that are first manifest antenatally. The major determinant of renal impairment in adult affected Bull terriers is, however, progressive tubulointerstitial damage after birth

Proteinuria as an indicator of early renal disease in bull terriers with hereditary nephritis

A group of non‐azotaemic bull terriers from families with hereditary nephritis had significant subclinical renal disease. Of the renal function tests carried out, proteinuria, almost exclusively albumin, was a reliable and early indicator of glomerular abnormality. While 24‐hour urinary protein excretion (24 UPE) in the bull terriers was significantly higher than in a group of normal dogs of other breeds, urinary protein excretion (UPE) was also significantly higher when measured by simple single sample tests such as the urinary protein to urinary creatinine ratio (UP/C). UPE in bull terriers was correlated with increasing age, in contrast to lack of correlation in the normal dogs. The degree of proteinuria in affected bull terriers from which renal biopsies were taken correlated with the severity of histopathological changes which mainly affected glomeruli. Light microscopic examination revealed segmentally thickened glomerular and tubular basement membranes, thickened Bowman's capsules and adhesions between glomerular capillaries and Bowman's capsules. Other renal function tests were performed but failed to detect subclinical disease. It is suggested that hereditary nephritis (HN) in bull terriers is similar to that seen in samoyeds, dober‐mann pinschers and humans