The Histopathology of Kidney Changes in Rats and Monkeys Following Intravenous Administration of Massive Doses of FCE 26184, Human Basic Fibroblast Growth Factor

Abstract

Intravenous administration of human basic fibroblast growth factor up to 100 μg/kg/day to Sprague-Dawley rats caused changes in the kidneys that included enlargement, vacuolation, and karyomegaly of podocytes in glomeruli, dilatation and cast formation in tubules, thickening of the media in the lobular arteries, and hyperplasia of the epithelium of the papilla and collecting ducts. In cynomolgus monkeys there was hyperplasia of the parietal epithelium of Bowman's capsule in the glomeruli, tubular dilatation, and minimal arteriopathy. These changes were only seen at 100 μg/kg/day. The development and eventual recovery over time were investigated in a sequence of sacrifices. In monkeys the first changes were seen after 7 days of treatment, but in rats only after 16 days. In both species the changes had partially resolved after 30 days of recovery and were considered to return to normal after 60 days without treatment. The morphological changes were accompanied by functional alterations that included proteinuria and raised blood urea. Changes that occurred in other tissues including bone, red blood cells, adrenals, ovaries, liver, gall bladder, spleen, mesenteric lymph nodes, thymus, aorta, salivary glands, and injection site are not described in this paper.

Engineering vascular networks in porous polymer matrices

“…Using a localized sustained release system for growth factors may greatly enhance the desired formation of local blood vessels, while eliminating the risk of toxic side effects 12 and unwanted blood vessels developing at other sites in the body. Localized delivery as opposed to systemic delivery limits the VEGF's area of effect because large masses of VEGF do not enter the circulation.…”

“…These approaches to delivery of growth factor risk promoting unwanted blood vessel formation (e.g., at the site of quiescent tumors) and toxic side effects. [10][11][12] In addition, the bolus administration of growth factor cannot maintain a consistent concentra-tion at the desired site of angiogenesis, as demonstrated by vascular endothelial growth factor (VEGF), which has been shown to have an elimination half-life of less than 1 h following injection. 8 Delivering angiogenic growth factors utilizing controlled drug delivery strategies, 13,14 offers the potential to promote angiogenesis at a specific site while leaving the circulation free from high concentrations of growth factor.…”

Exported 18-kDa Isoform of Fibroblast Growth Factor-2 Is a Critical Determinant of Bone Mass in Mice

“…There were no differences in any of these parameters between VTg and 18-kDa TgFGF2 mice (data not shown). Histologic examination of hematoxylin and eosin-stained sections of the kidneys showed that targeted overexpression of 18-kDa FGF2 in bone did not cause enlargement, vacuolation and karyomegaly of podocytes in glomeruli, dilatation and cast formation in tubules, thickening of the media in lobular arteries, or hyperplasia of the epithelium of the papilla and collecting ducts (24).…”

A 20-year history of childhood HIV-associated nephropathy

“…In addition, circulating FGF-2 does not induce the proliferation of normal tissues containing vessels with an intact endothelium [91,92]. Only in the presence of endothelial/tissue injury [41,93,94] or when extremely large doses of FGF-2 are infused for a prolonged period of time [94,95,96] is FGF-2 capable of inducing renal changes similar to those seen in patients with HIVAN. It should be noted that both control and HIV-Tg 26 kidneys transplanted into HIV-Tg 26 or wild type mice, respectively, developed compensatory renal hypertrophy [44], and that these changes per se may accelerate the progression of the renal disease [97] in renal tissues injured by the expression of HIV-1 genes.…”