Division of Nephrology, Department of Medicine, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama 35294-0007, USA.
J Clin Invest. 2012 May;122(5):1777-85. doi: 10.1172/JCI46490. Epub 2012 Apr 9.
A common renal complication of multiple myeloma is "myeloma kidney," a condition also known as cast nephropathy. The renal lesions (casts) are directly related to the production of monoclonal immunoglobulin free light chains (FLCs), which coprecipitate with Tamm-Horsfall glycoprotein (THP) in the lumen of the distal nephron, obstructing tubular fluid flow. Here, we report that analysis of the binding interaction between FLCs and THP demonstrates that the secondary structure and key amino acid residues on the complementarity-determining region 3 (CDR3) of FLCs are critically important determinants of the molecular interaction with THP. The findings permitted development of a cyclized competitor peptide that demonstrated strong inhibitory capability in the binding of FLCs to THP in vitro. When used in a rodent model of cast nephropathy, this cyclized peptide construct served as an effective inhibitor of intraluminal cast formation and prevented the functional manifestations of acute kidney injury in vivo. These experiments provide proof of concept that intraluminal cast formation is integrally involved in the pathogenesis of acute kidney injury from cast nephropathy. Further, the data support a clinically relevant approach to the management of renal failure in the setting of multiple myeloma.
多发性骨髓瘤的一种常见肾脏并发症是“骨髓瘤肾”，也称为管型肾病。肾脏病变（管型）与单克隆免疫球蛋白游离轻链（FLC）的产生直接相关，这些游离轻链与远曲小管腔中的 Tamm-Horsfall 糖蛋白（THP）共沉淀，阻塞管状液流。在这里，我们报告了对 FLC 与 THP 之间结合相互作用的分析表明，FLC 的互补决定区 3（CDR3）上的二级结构和关键氨基酸残基是与 THP 进行分子相互作用的关键决定因素。这些发现促使开发了一种环状竞争肽，该肽在体外 FLC 与 THP 的结合中表现出很强的抑制能力。当在管型肾病的啮齿动物模型中使用时，这种环化肽构建物作为腔内管型形成的有效抑制剂，并防止了体内急性肾损伤的功能表现。这些实验证明了腔内管型形成是管型肾病引起的急性肾损伤发病机制的一个组成部分。此外，这些数据支持在多发性骨髓瘤背景下对肾衰竭进行临床相关管理的方法。
