Basnayake, Kolitha Indika (2012)
Ph.D. thesis, University of Birmingham.
Monoclonal immunoglobulin free light chains (FLCs) cause a range of disorders in the kidney. In multiple myeloma, FLCs can activate the proximal tubule to release MCP-1, an important cytokine in renal fibrosis. Distal tubular cast formation can also occur when FLCs co-precipitate with uromodulin. However a pathogenic role for the elevated polyclonal FLC concentrations seen in chronic kidney disease has not been assessed to date. This thesis explores the biology of monoclonal FLCs as well as polyclonal FLCs. Detailed histological analyses demonstrated that in multiple myeloma, interstitial fibrosis can progress rapidly in situ and indicated that intratubular cast numbers might be linked to potential for renal recovery. The functional basis of this fibrosis was explored by in vitro studies, which showed that upon endocytosis of FLCs, oxidative stress activated redox signalling, resulting in MCP-1 production. Further in situ analyses showed that in chronic kidney disease, polyclonal FLCs co-localised with uromodulin in distal tubular casts. Relationships between these casts and markers of progression of chronic kidney disease were demonstrated. In vitro analyses then showed that polyclonal FLCs bind to uromodulin and promote aggregation. These findings: (i) further delineate the pathways for proximal tubular injury in myeloma and (ii) indicate a potential pathogenic role for polyclonal FLCs in the distal nephron.
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