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Obstructive Protein Cast Nephropathy in Cynomolgus Monkeys Treated with Small Organic Molecules

Drug Safety Research and Development, Pfizer Global Research and Development, Groton, CT¹

Abstract

We have observed a renal toxicity consistent with an obstructive protein cast nephropathy in cynomolgus macaques but not in other species treated with different therapeutic candidates having a common carboxylic acid moiety, suggesting a species-specific sensitivity. Here, we present renal toxicity findings consistent with a protein cast nephropathy in a 2-week safety study in cynomolgus monkeys. Light microscopic changes consisted of intratubular cast formation, tubular dilatation, interstitial inflammation, and expansion of the medullary interstitium. Tubular cast material was identified as Tamm-Horsfall protein (THP) and, on ultrastructure, crystalloid material was present in vacuoles of tubular epithelium. It is hypothesized that microcrystal formation in the urinary tubular spaces induces aggregation of THP protein and cast formation in monkeys. Drug-induced obstructive nephropathy is not identified as a major problem in humans; thus, the clinical relevance of the above findings in monkeys is not clear.

Key words: Carboxylic acid; cynomolgus; kidney; Tamm-Horsfall.

Request reprints from Dr. Roberto E. Guzman, Pfizer Global Research and Development, Eastern Point Road Groton, MI 06340 (USA). E-mail: johnmerc{at}cancerboard.ab.ca.