Myeloma-like cast nephropathy caused by human recombinant soluble CD4 (sCD4) in monkeys

Abstract

CD4 is the receptor for human immunodeficiency virus (HIV) on lymphocytes and macrophages. Soluble CD4 (sCD4), a recombinant truncated form of CD4, has been shown to inhibit HIV-1 in vitro and is being tested as a therapy for AIDS. Preclinical studies in cynomolgus monkeys revealed a protein cast nephropathy after four daily intravenous doses of 100 mg/kg/day. Renal lesions were not found in monkeys that received 10 mg/kg/day. The renal lesions consisted of proteinaceous tubular casts associated with multinucleate giant cells and neutrophils located in the tubules of the distal nephron. The affected tubules were surrounded by an interstitial mixed inflammatory cell infiltrate. By electron microscopy, the casts were composed of moderately electron dense, paracrystalline material. Immunostaining demonstrated that the casts contained sCD4-derived material and Tamm-Horsfall protein. Moreover, biochemical analysis of urine showed that a portion of sCD4 was excreted as intact protein. Because infection with HIV-1 can be associated with clinically significant nephropathy, these data suggest that renal function should be closely monitored in patients receiving soluble forms of CD4.