Focal segmental glomerulosclerosis refers to a set of particular histopathologic lesions in which steroid-resistant podocyte injury leads to patchy adhesions between the glomerular tuft and Bowman's capsule, followed by progressive glomerulosclerosis and proteinuric renal failure. Because of the nonspecific nature of this lesion, it has been difficult to classify the various forms of primary nephrotic syndrome in children. However, with the recognition of hereditary FSGS caused by mutations podocyte slit diaphragm genes, it is increasingly clear that the steroid-resistant form of FSGS that recurs in the renal allografts (R-FSGS) constitutes a distinct clinical entity. Capitalizing on recent studies in which patients have been screened for slit diaphragm gene mutations, this review focuses on the natural history and pathogenesis of R-FSGS. 1. R-FSGS in the Context of Steroid-Resistant Nephrotic Syndrome A recent population-based study in the Gironde region of France reported an incidence of about 2.3 pediatric cases of idiopathic nephrotic syndrome for every 100,000 children <15 years of age . The majority (91%) of these children exhibited a classical steroid-responsive relapsing disease, in which there may be podocyte foot process effacement noted on renal biopsy but no progressive renal insufficiency. Estimates of steroid-responsiveness are somewhat lower (80%) in referral populations or cohorts that include adults . Among those who fail to respond to daily steroid therapy for 4 weeks, renal biopsies usually reveal a progressive lesion in which early podocyte detachment from the glomerular basement membrane is associated with segmental hyalinosis of the glomerular capillary tuft and, eventually, fibrotic adhesions to Bowman's capsule. It is the patchy distribution of these lesions within the glomerulus and the initial sparing of some glomeruli that warrant the pathologic descriptor, focal segmental glomerulosclerosis (FSGS). In New York City, about two thirds of steroid-resistant nephrotic syndrome (SRNS) patients display FSGS on renal biopsy . In the setting of SRNS, these lesions are associated with high risk of progressive renal failure . Collectively, these children comprise nearly 15% of the dialysis and renal transplant population in North America. However, the FSGS lesion is not pathognomonic for a specific clinical entity but rather reflects any process that leads to patchy irreversible podocyte injury. In addition to the many disorders that cause “secondary” glomerulosclerosis, children with steroid-sensitive nephrotic syndrome
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