Table_1_Light Chain Restriction in Proximal Tubules—Implications for Light Chain Proximal Tubulopathy.DOCX

Monoclonal gammopathy (MG) causes various nephropathies, which may suffice for cytoreductive therapy even in the absence of diagnostic criteria for multiple myeloma or B-cell non-Hodgkin lymphoma. The aim of this study was to better understand the significance of light chain (LC) restriction or crystals (LC-R/C) in proximal tubules in the spectrum of LC-induced nephropathies. A consecutive cohort of 320 renal specimens with a history of B-cell dyscrasia was characterized. Special attention was paid to immunohistochemical LC restriction in proximal tubules, tubular crystals or constipation, and ultrastructural findings. Complementary cell culture experiments were performed to assess the role of LC concentrations in generating LC restriction. Light chain restriction or crystals in proximal tubules was found in a quarter of analyzed cases (81/316) and was associated with another LC-induced disease in 70.4% (57/81), especially LC cast-nephropathy (cast-NP) and interstitial myeloma infiltration. LC restriction without significant signs of acute tubular injury was observed in 11.1% (9/81). LC-R/C was not associated with inferior renal function compared to the remainder of cases, when cases with accompanying cast-NP were excluded. Besides crystals, cloudy lysosomes were significantly associated with LC-R/C on an ultrastructural level. In summary, LC-R/C is frequent and strongly associated with cast-NP, possibly indicating that a high load of clonal LC is responsible for this phenomenon, supported by the observation that LC restriction can artificially be generated in cell culture. This and the lack of significant tubular injury in a subgroup imply that in part LC-R/C is a tubular trafficking phenomenon rather than an independent disease process.单克隆丙种球蛋白病（Monoclonal gammopathy, MG）可引发多种肾病，即便未满足多发性骨髓瘤或B细胞非霍奇金淋巴瘤的诊断标准，其所致肾脏病变也足以开展细胞减灭治疗。本研究旨在更清晰地阐明近端肾小管内轻链（light chain, LC）限制性沉积或晶体（LC-R/C）在轻链相关性肾病谱系中的临床意义。本研究对320例有B细胞恶病质病史的肾脏标本组成的连续队列进行了系统表征。研究重点关注近端肾小管的免疫组化轻链限制性沉积、肾小管晶体或管型及超微结构表现。随后开展了补充细胞培养实验，以评估轻链浓度在诱导轻链限制性沉积中的作用。结果显示，四分之一的分析病例（81/316）存在近端肾小管轻链限制性沉积或晶体，其中70.4%（57/81）合并另一种轻链相关性肾病，尤以轻链管型肾病（cast-NP）和间质骨髓瘤浸润最为常见。11.1%（9/81）的病例仅见轻链限制性沉积，无明显急性肾小管损伤征象。若排除伴发轻链管型肾病的病例，轻链限制性沉积或晶体与其余病例的肾功能减退无显著相关性。在超微结构层面，除肾小管晶体外，浑浊溶酶体也与轻链限制性沉积或晶体显著相关。综上，轻链限制性沉积或晶体较为常见，且与轻链管型肾病密切相关，这提示克隆性轻链的高负荷可能是该现象的诱因，而细胞培养实验中可人工诱导轻链限制性沉积的结果也支持这一推论。此外，部分亚组未出现明显肾小管损伤，这表明轻链限制性沉积或晶体在一定程度上属于肾小管转运异常现象，而非独立的疾病进程。