Low Molecular Weight Protein Nephrotoxicity

多发性骨髓瘤(MM)是一种恶性浆细胞疾病，发病率为 约占所有恶性肿瘤的1.1%，占中国血液病恶性肿瘤的12%-13% 我们。在我们的退伍军人群体中，流行病学也是相似的，包括高出3倍 未确定意义的单克隆性丙种球蛋白病是一种癌前病变，在 非洲裔美国退伍军人。肾功能障碍，由血肌酐升高≥1.3确定 Mg/dl经常(约48%)与多发性骨髓瘤有关，并且血清肌酐升高。 血药浓度超过2.0 mg/dl预示着预后不良。一项大型研究得出结论， 肾功能的可逆性是比反应更重要的预后因素 化疗。最近的研究表明，单抗免疫球蛋白游离轻链(FLC) 在多发性骨髓瘤中产生的是生物活性蛋白，在细胞内产生 氧化应激在近端小管和促进上皮细胞生物学的重大变化。 这一应用的工作假设是变量的物理化学结构 FLC的结构域决定了肾小管间质肾病的类型和后果 骨髓瘤。 为了解决这一假设，提出了两个目标： 目的1.确定CDR3结构域对蛋白降解的敏感性是否是CAST的决定因素 肾病。FLC可作为肾脏蛋白水解酶的底物；CDR3的切割 域打开循环结构，更改二级结构，从而影响绑定到 THP。假设：CDR3结构域对蛋白酶切割的抵抗力是一个关键 与THP结合的决定因素与管型肾病的发生。 目的2.明确氧化还原信号在进展性肾病发生发展中的作用 管型肾病。假设：肾毒性单克隆性Flc促进一种亲和性- 炎症/纤维化状态，刺激AKI向CKD的转变。 目的2.1确定转录信号转导和激活因子1(STAT1)的功能 在FLC肾毒性中。假设：肾上皮细胞中STAT1的激活产生 IL-1b和转化生长因子-β在急性心肌梗死后慢性肾脏病发生发展中的作用 由于管型肾病。 目标2.2确定是否涉及FLC产生过氧化氢的内在能力 在骨髓瘤肾的发生发展中起重要作用。假设：氢气的产生 在进行性肾损伤的发生过程中，氟碳化合物的过氧化作用是一个关键因素。 该提案将使用体外和体内模型来确定单克隆性Flc如何 产生促炎和促纤维化生长因子，诱导肾小管间质肾 纤维化症。这项提案的长期目标是将临床实践范式 探索新方法治疗多发性骨髓瘤所致进展性肾功能衰竭 制定限制慢性肾脏疾病发展的策略的理论概念 从而改善MM的结果。

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.