Multiple myeloma (MM) is a malignant plasma cell disorder that has an incidence rate of about 1.1% among all malignancies and constitutes 12-13% of hematologic malignancies in the US. The epidemiology is similar in our veteran population and includes a 3-fold higher prevalence of monoclonal gammopathy of undetermined significance, a premalignant lesion, in African American veterans. Renal dysfunction, determined by serum creatinine elevation = 1.3 mg/dl, is frequently (about 48%) associated with MM, and an increase in the serum creatinine concentration beyond 2.0 mg/dl portends a poor prognosis. One large study concluded that reversibility of renal function was a more important prognostic factor than response to chemotherapy. Recent work has shown that monoclonal immunoglobulin free light chains (FLC) produced in multiple myeloma are biologically active proteins that generate intracellular oxidative stress in the proximal tubule and promote significant changes in epithelial cell biology. The working hypothesis of this renewal application is that monoclonal FLCs promote a pro- fibrotic state in the kidney by generating oxidative stress in the proximal tubule.
Three aims wil be pursued:
Aim 1. Define the mechanism of FLC-induced release of HMGB1 by the proximal tubular epithelium. Hypothesis: release of HMGB1, an Alarmin, is mediated through activation of the JAK2/STAT1 pathway by oxidative stress.
Aim 2. Determine the mechanism of FLC-induced production of Interleukin (IL)-1 by proximal tubular epithelium. Hypothesis: monoclonal FLCs promote a noncanonical inflammasome pathway-mediated activation of IL-1 in proximal tubular epithelium.
Aim 3. Determine how monoclonal FLCs promote renal fibrosis through TGF- in vivo. Hypothesis: monoclonal FLCs promote tubulointerstitial fibrosis by activation of TGF- through the production of IL-1. The proposal will use in vitro and in vivo models to characterize the pathomechanisms by which human monoclonal FLC generate pro-inflammatory and pro-fibrotic growth factors that induce tubulointerstitial renal fibrosis. The lon-term goal of this proposal is to shift clinical practice paradigms in the management of progressive renal failure occurring in the setting of MM, by exploring novel theoretical concepts to devise strategies that limit the development of chronic kidney disease and thereby improve outcomes in MM.
Multiple myeloma constitutes 12-13% of hematologic malignancies in the US and is a significant problem in our aging veteran population. Nearly half of patients with myeloma have an associated kidney dysfunction and at least one large study found that reversibility of renal function was a more important prognostic factor than response to chemotherapy. The present application proposes to address gaps in knowledge in defining the role of immunoglobulin free light chains in the progression of kidney injury. The specific focus will be on the interaction of free light chains with the proximal tubule and the generation of kidney fibrosis in the setting of multiple myeloma.
