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 application is that the physicochemical structure of the variable domain of the FLC determines the type and consequences of tubulointerstitial renal disease in myeloma. To address this hypothesis, two aims are proposed:
Aim 1. Determine if susceptibility of the CDR3 domain to proteolysis is a determinant of cast nephropathy. FLC may serve as substrates for kidney proteases; cleavage of the CDR3 domain opens the loop structure, changing the secondary structure, which affects binding to THP. Hypothesis: resistance of the CDR3 domain to protease cleavage is a critical determinant of binding to THP and development of cast nephropathy.
Aim 2. Define the role of redox signaling in the development of progressive kidney disease in cast nephropathy. Hypothesis: nephrotoxic monoclonal FLCs promote a pro- inflammatory/fibrotic state that stimulates an AKI to CKD transition.
Aim 2. 1 Determine the function of Signal Transducer and Activator of Transcription 1 (STAT1) in FLC nephrotoxicity. Hypothesis: STAT1 activation in kidney epithelium produces IL-1b and TGF-b and plays a critical role in the development of CKD following AKI due to cast nephropathy.
Aim 2. 2 Determine if the intrinsic ability of the FLC to generate hydrogen peroxide is involved in the development of myeloma kidney. Hypothesis: the production of hydrogen peroxide by FLCs is a critical element in the generation of progressive kidney injury. The proposal will use in vitro and in vivo models to determine how monoclonal FLCs generate pro-inflammatory and pro-fibrotic growth factors that induce tubulointerstitial renal fibrosis. The long-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, especially those exposed to Agent Orange. 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. !
