Correspondence to: L.C. Paul Division of Nephrology St Michael's Hospital 30 Bond Street Toronto, Ontario M5B 1W8
Key Words: glomerulosclerosis; glomerular capillary pressure; anti-mesangial cell antibodies
With the introduction of powerful immunosuppressive drugs, the focus in clinical renal transplantation has shifted from improvement in the 1-year graft survival rate to prevention of late graft attrition. Elucidation of the mechanism(s) leading to late graft failure is needed to design the proper strategies to improve the long-term outcome. Several clinical studies have emphasized the correlation between acute rejection episodes and late graft dysfunction or chronic rejection but it is unknown whether these entities are causally related.
Proteinuria, the clinical hallmark of glomerular pathology, correlates with an adverse long-term prognosis . The glomeruli in grafts with chronic dysfunction may show a variety of abnormalities, including wrinkling and collapse of the glomerular tuft , glomerular hypertrophy , mesangial matrix expansion with partial or complete collapse of the tuft, or focal glomerulosclerosis . Although some of these lesions may result from recurrent or de-novo glomerulonephritis or from graft ischemia or cyclosporin exposure, most glomerular lesions seem related to chronic rejection. Hamburger et al were the first to describe rejection glomerulonephritis , a lesion characteristic of chronic rejection, that has also been named transplant glomerulopathy . The early lesions are characterized by enlargement of the glomeruli, hypercellularity, mesangiolysis with widening of subendothelial zones and interposition of mesangial matrix and cells. Immunofluorescence staining show in most cases nonspecific segmental deposits of IgM and fibrin, sometimes associated with trace amounts of C3 albeit that some cases have transient linear deposits of IgG along the glomerular basement membrane (GBM) . Immunohistochemistry with antibodies against extra-cellular matrix proteins has shown peripheral glomerular expansion of collagen type IV and fibronectin .
The pathophysiology of transplant glomerulopathy has remained elusive. We have recently demonstrated in rats the presence of antibodies against donor type glomerular basement membranes  and glomerular hypertension  in grafts with chronic rejection but the pathogenetic significance of these findings is unknown. Current experiments were designed to test the hypothesis that lowering of the intraglomerular pressure has a beneficial effect on the graft glomerular structure and function in chronic rejection.
These data, as well as recent data from other investigators , are consistent with the hypothesis that glomerular hypertension is an important determinant of post-transplant glomerulosclerosis, which in turn seems closely associated with graft prognosis. Glomerular hypertension emerges as a result of loss of auto-regulatory capacity of the afferent arteriole in conjunction with glomerular hyperfiltration, as observed after loss of renal mass. However, the extent of graft glomerulosclerosis 4 or 8 weeks after transplantation of F344 kidneys into LEW recipients is more extensive than found 12 to 16 weeks after straightforward renal ablation, suggesting that glomerular hypertension alone cannot explain allograft glomerulosclerosis . Consistent with this hypothesis is the observation that the degree of glomerulosclerosis observed in syngeneic F344 grafts is far less than in F344 grafts removed from allogeneic LEW recipients although syngeneic F344 grafts are also exposed to glomerular hypertension . We recently found alloantibodies against cell surface antigens of cultured mesangial cells in LEW rats after transplantation of a F344 kidney . Studies in the Thy-1.1 model of mesangial-proliferative glomerulonephritis in rats has shown that antibodies against mesangial cell surface antigens can produce many of the glomerular features of transplant glomerulopathy such as mesangiolysis, influx of mononuclear cells and glomerulosclerosis. The combination of immune reactivity against allogeneic determinants of glomerular mesangial cells, glomerular extracellular matrix proteins, and glomerular hypertension, possibly in conjunction with other factors such as hyperlipidemia, may lead to the tissue remodelling characteristic of transplant glomerulopathy and chronic rejection .
Figure 1. Photomicrograph of a F344 glomerulus removed from a LEW recipient on day 50 after transplantation. There is mesangiolysis affecting a segment of the glomerulus. PAS x 200.