Hyaline Droplet Accumulation in Rodent Kidney Proximal Tubules: An Association with Histiocytic Sarcoma

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Abstract
Since recognition during the last decade that certain renal carcinogens can initially cause an accumulation of hyaline (protein) droplets in proximal tubules of male rats, it has become appropriate to establish whether this phenomenon of protein overload can also occur in rodent kidneys unrelated to chemical treatment. Kidney tissue from a number of selected rodent studies held in the National Toxicology Program (NTP) or Food and Drug Administration (FDA) archives were evaluated for hyaline droplet accumulation in proximal tubules. The survey concentrated on rats and mice of both sexes bearing hematopoietic tumors, as our preliminary observations had suggested this direction of study. The tissues of 101 Sprague-Dawley, 25 Osborne-Mendel, and 70 Fischer 344 rats and 96 B6C3F1 mice were examined. These animals provided an assortment of tumors including histiocytic sarcoma, lymphocytic lymphoma, mononuclear cell leukemia, and sarcoma. Hyaline droplet accumulation, primarily involving the P2 segment of proximal tubules, was diagnosed in 96% of rats with histiocytic sarcoma (74/77 cases in Sprague-Dawley, 17/18 in Osborne-Mendels, 7/7 in Fischers) and in 55% of B6C3F1 mice with histiocytic sarcoma (18/33 cases). There appeared to be a qualitative correlation between hyaline droplet accumulation and degree of tumor burden. Thus, in cases negative for hyaline droplets, the tumor was often confined to a single location, while increasing involvement of proximal segments beyond P2 occurred with more extensive multi-organ dissemination of the tumor. By immunohistochemistry on 11 cases of rat and 8 cases of mouse histiocytic sarcoma, the protein in hyaline droplets was identified as lysozyme, a known major secretory product of monocytes and macrophages. The hyaline droplets were negative for α1-antitrypsin, α2u-globulin, rat or mouse immunoglobulin, and albumin. More sparsely scattered droplets and granules present in proximal tubules of Fischer rats with mononuclear cell leukemia were negative for lysozyme but positive for either iron or lipofuscin pigment. The study establishes a clear association between renal tubule hyaline droplet and lysozyme accumulation in rats and mice with histiocytic sarcoma. Hyaline droplets secondary to neoplasia should be distinguished from chemically-induced hyaline droplet nephropathy in the male rat involving α2u-globulin.