Background/Purpose: Nephrogenic Systemic Fibrosis (NSF), a generalized progressive fibrotic disorder, occurs in some patients with renal insufficiency exposed to various gadolinium based contrast agents (GdBCA).  Currently, there is no animal model for human NSF.  Some studies using subtotal nephrectomized rats described cutaneous lesions characterized by slight dermal fibrosis and increased infiltration of CD34⁺ cells following systemic GdBCA administration. These lesions, however, failed to reproduce the severe dermal and tissue fibrosis and other histomorphological changes characteristic of human NSF.  One possible reason for this is that although subtotal nephrectomy replicates the decreased filtering capacity of human chronic renal failure, it fails to induce numerous other features that may be necessary for NSF development.  In this study, we treated mice with adenine-induced renal failure by intratracheal instillation of the GdBCA Omniscan to develop a more relevant model of NSF.

Methods: Chronic renal failure was induced in C57BL6/J mice by ad libitum feeding of standard rodent diet supplemented with 3% adenine for 30 days.  A single dose of either the GdBCA Omniscan (25 µL of a 0.5 M solution) or an equal volume of normal saline was administered to mice with normal renal function (controls) or with chronic renal failure by intratracheal instillation.  Mice were sacrificed 28 days post-instillation and tissues were isolated for analysis by histological examination (hematoxyllin/eosin and Masson’s trichrome stains. Assays of collagen content to assess the severity of tissue fibrosis were performed employing a standard hydroxyproline assay of hydrolyzed tissue samples.

Results: Histopathology studies showed mononuclear cell infiltration and fibrosis in lungs isolated from adenine-fed mice instilled with Omniscan but not in lungs from mice with normal renal function instilled with Omniscan nor in mice with either normal or ablated renal function instilled with saline. The pattern of fibrosis was predominantly peribronchial although substantial diffuse interstitial fibrosis was also observed.  Hydroxyproline content was increased ~3 fold in the lungs of renal failure mice treated with Omniscan compared to mice in all other treatment groups.

Conclusion: The present study demonstrates for the first time the ability to induce significant tissue fibrosis and increased collagen deposition in mice with adenine induced renal failure exposed to the gadolinium contrast agent Omniscan.  This inducible model of tissue fibrosis will be a valuable tool in studying the pathogenesis of NSF and other chemically-induced fibrotic disorders.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/intratracheal-instillation-of-omniscan-in-an-adenine-induced-model-of-chronic-renal-failure-a-new-model-of-nephrogenic-systemic-fibrosis/