P-glycoprotein and Steroid-Resistant Nephrotic Syndrome

DESCRIPTION (provided by applicant): Nephrotic Syndrome (NS) is one of the most common kidney diseases in children, and although treatment with corticosteroids can induce remission in most patients, more than 20% fail to respond. These patients are at increased risk for developing complications such as end-stage renal disease, which occurs in at least 50% of patients with corticosteroid-resistant NS. Precisely how corticosteroids work in NS is unclear, but the prevailing theory is that these agents modify immune function at the level of the lymphocytes for most non-genetic causes of NS. The underlying reason for corticosteroid unresponsiveness in some patients is unclear, but the fact that high-dose corticosteroids induce remission in some previously resistant patients suggests that the disease itself is not inherently resistant to corticosteroids. One potentially vital determinant of corticosteroid responsiveness is the drug efflux pump, p-glycoprotein (Pgp). As a result of its location on the surface of lymphocytes and its ability to bind to and efflux corticosteroids, Pgp is thought to play a key role in regulating corticosteroid response. By limiting intralymphocyte corticosteroid concentrations, Pgp is capable of limiting the ability of corticosteroids to bind to their receptors and exert their effects. In fact, studies in other corticosteroid-responsive diseases, such as Systemic Lupus Erythematosus and Inflammatory Bowel Disease, have identified a relationship between increased lymphocyte Pgp expression and corticosteroid resistance. Based on these data, we hypothesize that the Pgp drug efflux pump is an important determinant of corticosteroid responsiveness in pediatric patients with NS. The aims of this study are to compare the expression and activity of Pgp in lymphocytes, as well as the DNA sequence for the gene encoding Pgp, between pediatric patients with corticosteroid-resistant NS and those with corticosteroid-responsive NS. Blood samples will be collected from 50 patients with NS (25 with cortisteroid-resistant NS and 25 with corticosteroid-sensitive NS) and analyzed to determine (1) lymphocyte Pgp protein and mRNA expression, (2) Pgp activity, and (3) DNA sequence for the gene encoding Pgp. Identification of a correlation between lymphocyte Pgp and corticosteroid resistance would not only improve our understanding of corticosteroid resistance (both specific to nephrotic syndrome as well as overall), but also reveal novel opportunities to detect and overcome the corticosteroid resistance in NS.