肾脏白细胞趋化因子2型淀粉样变性的临床病理特点

Clinicopathological characteristics of renal amyloid leukocyte chemotactic factor 2 amyloidosis

目的探讨肾脏白细胞趋化因子2型淀粉样变性(leukocyte chemotactic factor 2 amyloidosis,ALECT2)患者的临床病理表现特点。方法回顾性选取2001年1月至2021年10月在北京大学第一医院、山西医科大学第二医院和山西白求恩医院经肾活检病理检查确诊的ALECT2患者为研究对象,根据其是否合并其他肾脏疾病分为单纯ALECT2组和ALECT2合并其他肾脏病组,比较两组患者临床病理表现的差异。用光镜、免疫荧光及免疫电镜等方法观察肾组织病理改变;质谱分析法分析肾组织淀粉样沉积物质的成分;基因测序法分析患者外周血白细胞趋化因子2(leukocyte chemotactic factor 2,LECT2)基因序列。结果16例ALECT2患者入选本研究,9例合并其他肾脏病。患者发病年龄(65.00±8.45)岁,男女比例为7∶9,汉族15例,其中8例患者为山西省籍。15例患者有蛋白尿,中位尿蛋白量为2.16(1.07,4.72)g/24 h;5例表现为肾病综合征;11例有肾功能不全;12例有镜下血尿。12例患者合并高血压,6例合并糖尿病。与单纯ALECT2组相比,合并其他肾脏病组患者肾病综合征占比较高(5/9比0/7,P=0.034)。肾组织病理检查结果显示,16例患者肾皮质间质均有淀粉样物质沉积,均伴有不同程度的炎性细胞浸润和纤维化,多数患者伴有肾小球(12/16)、小动脉壁(14/16)淀粉样物质沉积。刚果红染色呈强阳性,免疫组化结果显示LECT2阳性。淀粉样物质沉积半定量分析结果显示,合并其他肾脏病组患者的肾小球淀粉样物质沉积和肾脏淀粉样物质总沉积评分显著低于单纯ALECT2组(均P<0.05)。16例患者电镜下见直径8~12 nm无分支的细纤维结构无序分布。8例患者肾组织质谱分析检测到LECT2肽段,7例患者基因检测显示LECT2存在纯合子G等位基因。13例完整随访资料结果显示,2例死亡,1例肾活检时已进展为终末期肾病,其余大部分患者(8/10)肾功能进展缓慢。结论肾脏ALECT2患者临床表现以蛋白尿为主,肾功能不全、血尿及合并其他肾脏病的发生率高。肾组织病理改变特征为淀粉样物质主要沉积于肾皮质间质。

Objective To investigate the clinicopathological characteristics of renal leukocyte chemotactic factor 2 amyloidosis(ALECT2).Methods The patients with renal ALECT2 diagnosed by renal biopsy in Peking University First Hospital,Shanxi Medical University Second Hospital and Shanxi Bethune Hospital from January 2001 to October 2021 were retrospectively enrolled.According to whether the patients had concurrent glomerular diseases,they were classified into two groups:isolated ALECT2 group and ALECT2 with concurrent renal diseases group.Clinicopathological data of the two groups were compared.Light microscopy,immunofluorescence and immunoelectron microscopy were applied to investigate pathological characteristics of renal tissues.Mass spectrometry was used to analyze the composition of renal amyloid deposits.Gene sequencing was employed to detect the leukocyte chemotactic factor 2(LECT2)gene sequence in peripheral blood of the patients.Results Sixteen patients with ALECT2 were enrolled in this study and nine of them had concurrent renal diseases.The age of 16 patients was(65.00±8.45)years old.The sex ratio of males to females was 7 to 9.Most of patients were Han ethnicity(15/16).Eight patients came from Shanxi province.Fifteen patients presented with varying degree of proteinuria[2.16(1.07,4.72)g/24 h];5 patients had nephrotic syndrome;11 patients had renal insufficiency;12 patients had microscopic hematuria.Part of patients also had hypertension(12/16)and diabetics(6/16).Compared with isolated ALECT2,the ALECT2 group with concurrent renal diseases had a higher proportion of nephrotic syndrome(5/9 vs 0/7,P=0.034).Renal biopsy results showed that all patients(16/16)had amyloid deposits in the interstitium of renal cortex with varying degree of inflammatory cell infiltration and fibrosis,and glomeruli(12/16)and arterioles(14/16)were involved by amyloid deposits.The amyloid deposits were strongly congophilic and immunohistochemistry for LECT2 was positive.By semi-quantitative analysis,the proportions of glomerular and overall amyloid loads in ALECT2 with concurrent renal diseases group were lower than those in isolated ALECT2 group(both P<0.05).Electron microscopy revealed randomly oriented and non-branching fibrils with a diameter of 8-12 nm.The LECT2 peptides were detected by mass spectrometry in renal amyloid deposits of 8 patients,and homozygous G allele of LECT2 was found in 7 patients by gene sequencing.Complete follow-up data of 13 patients showed that 2 patients died,1 patient developed end-stage renal disease at the time of renal biopsy,and most of the rest patients had stable renal function(8/10).Conclusions Patients with renal ALECT2 mainly present with proteinuria,along with a high incidence of renal insufficiency,microscopic hematuria,and concurrent renal diseases.The pathologic feature is the preferential deposition of amyloid in renal cortical interstitium.