The role of podocyte injury in the pathogenesis of focal segmental glomerulosclerosis

The podocyte has diverse functions including glomerular filtration, biosynt hesis and maintenance of the glomerular capillary architecture. It discharg es these functions by virtue of a unique morphology, an intimate relationsh ip with the capillary wall, and diverse synthetic and membrane specializati ons. Despite the complex role that it plays in glomerular function, the cli nical manifestations of podocyte dysfunction are limited to proteinuria and renal insufficiency. Recurrent focal segmental glomerulosclerosis (FSGS) i n renal transplants provides a unique opportunity to study the pathogenesis of FSGS in human beings, because the patients are monitored carefully to i dentify the onset of disease, the recurrence is presumed to have the same e tiology as the primary disease, renal biopsy is a tool to study the pathoge nesis of the lesion, and therapeutic intervention provides a mechanism to t est pathogenesis. Pathologic studies have identified a proliferative lesion of the podocytes as the first sign of recurrent disease. The glomerular le sions evolve to form segmental glomerular scars with time. These findings a nd studies in experimental models of FSGS implicate podocyte injury in the pathogenesis of the recurrent disease. The cellular lesion (similar to the proliferative lesion of podocytes in recurrent FSGS), seen early in the cou rse of primary FSGS suggests that the pathogenic sequence in recurrent FSGS also applies to primary FSGS. A soluble circulating factor that increases glomerular permeability and correlates with recurrence of FSGS has been ide ntified in the pretransplant serum of patients with end-stage FSGS, but the mechanism of podocyte injury by this factor remains speculative. In any ca se, podocytes in the cellular lesion undergo morphologic changes and lose s pecialized functions seen in the normal mature cell, and these structural a nd functional abnormalities cause the permeability changes associated with proteinuria and destruction of glomerular filtration surface by scarring as sociated with loss of glomerular function.