轻链足细胞病伴轻链肾小管病

老年女性患者,临床表现肾脏及血液系统为主的多系统损害,肾脏损害以中等量蛋白尿、低白蛋白血症为主要症状.肾外有轻度贫血及血小板减少,血清免疫固定电泳提示κ型IgG单克隆免疫球蛋白条带.肾活检组织学改变为肾小球足细胞及肾小管上皮细胞肿胀,胞质内见结晶样物质;免疫病理示κ轻链阳性,电镜下见菱形、圆形、梭形等多种形状的结晶,免疫胶体金技术证实上述结晶κ轻链阳性.该患者最终诊断为轻链足细胞病伴轻链肾小管病,考虑浆细胞异常增生性疾病所致.     

伴单克隆IgG1沉积的增生性肾小球肾炎

61岁女性,病程10个月,临床表现尿检异常、低补体血症伴贫血、血游离轻链比值异常,免疫固定电泳见Ig G-λ单克隆免疫球蛋白条带,肾脏体积增大,骨髓浆细胞7. 5%、未见原始和幼稚浆细胞,肾活检示膜增生性肾小球肾炎(结节样病变),Ig G1++、λ轻链+颗粒状沉积于系膜区及血管袢,Ig G2、Ig G3、Ig G4、κ轻链阴性;诊断为伴单克隆Ig G1沉积的增生性肾小球肾炎。给予沙利度胺联合地塞米松治疗1年,蛋白尿完全缓解,补体上升,血游离轻链比值恢复正常,血清M蛋白转阴。     

轻重链沉积病合并轻链淀粉样变性

中年女性,临床表现为血清肌酐升高,中等量蛋白尿、大量镜下血尿,无高血压,轻度贫血,免疫固定电泳图谱见λ型Ig G单克隆免疫球蛋白条带,骨髓细胞学检查浆细胞比例为8%。肾活检示肾小球系膜区轻~中度增宽,肾血管壁刚果红染色阳性,免疫荧光染色Ig G及λ轻链呈线状沉积于肾小球毛细血管袢及肾小管基膜,间质血管壁λ轻链阳性,超微结构见肾小球基膜内侧缘、系膜区、肾小管基膜外侧缘细沙样高密度的电子致密物沉积,免疫电镜下见电子致密物Ig G、λ轻链染色胶体金颗粒阳性,间质动脉壁淀粉丝分布;皮肤脂肪活检刚果红染色阳性。最终诊断为轻重链沉积病(Ig G-λ型)合并AL型系统性淀粉样变性(累及肾脏、皮肤、心脏)。     

伴多核巨细胞浸润的轻链型肾淀粉样变性

64岁男性患者,临床表现为肾病综合征,无高血压及肾功能损害,血免疫固定电泳检查示λ型IgA单克隆免疫球蛋白条带,血游离轻链检查示κ/λ比值下降;骨髓流式细胞学见4.52%单克隆增生的浆细胞,外院肾活检诊断轻链型肾淀粉样变性。患者化疗后临床达非常好的部分缓解,经重复肾活检后诊断为罕见的伴多核巨细胞浸润的轻链型肾淀粉样变性。     

肾脏轻-重链沉积病

中年男性,病程3年,临床表现为中等量蛋白尿、少量镜下血尿、高血压、肾功能不全,伴贫血、白细胞减低,血清免疫固定电泳见λ型IgA单克隆免疫球蛋白条带,骨髓细胞学检查浆细胞比例5%。组织学改变为肾小球结节样病变,免疫荧光染色IgA及单一λ轻链均呈线状沉积于肾小球毛细血管袢及肾小管基膜,超微结构见肾小球基膜内侧缘及肾小管基膜外侧缘细沙状、高电子密度的致密物沉积。最终诊断为轻-重链沉积病(IgA-λ型)。     

轻链κ/λ比值测定对多发性骨髓瘤诊断的临床应用

目的:探讨血清、尿液轻链含量及κ/λ比值差异在鉴别诊断多发性骨髓瘤(MM)中的临床应用价值。方法:回顾性分析9 120例各类型MM患者血清轻链含量及κ/λ比值数据,并将其中合并肾损伤和无肾损伤MM患者的血、尿轻链及κ/λ比值分别与38例肾病者及100例正常对照者进行比较分析。结果:各类型MM患者所属血清κ型轻链及κ/λ比值显著升高,所属λ型及κ/λ比值显著降低,合并肾损伤检出率约占MM的49.57%,肾损伤MM者血清轻链含量及κ/λ比值均低于无肾损伤MM者(P0.05),但尿液中所属轻链含量显著升高(P0.01)。肾损伤MM患者中同一轻链型多发性骨髓瘤(LCMM)血清与尿液轻链含量及κ/λ比值比较差异有统计学意义(P0.01),而非LCMM血清与尿液轻链含量及κ/λ比值比较差异无统计学意义(P0.05),与肾病者及正常对照者比较差异有统计学意义(P0.01)。结论:血清、尿液轻链含量尤其κ/λ比值差异,对MM的诊断、分型、早期肾损伤及肾病的鉴别诊断有重要的临床应用价值。     

轻链沉积病肾损害的临床和病理分析

目的：了解轻链沉积病(LCDD)肾损害的临床和病理特征。方法：回顾性分析26例经临床和肾活检确诊的LCDD患者的临床和病理改变。结果：26例LCDD患者起病时的平均年龄为49.4岁(27—72岁)，其中男性21例，女性5例。8例确诊为多发性骨髓瘤(MM)，2例伴有浆细胞异常增生，另有16例病因不明。临床表现为急性肾衰3例(11．5％)，慢性肾衰17例(65．4％)，肾病综合征17例(65．4％)，15.4％的患者起病时即需行肾脏替代治疗。实验室检查发现血清和尿液游离κ、λ轻链的阳性率分别为56．5％和91．7％。肾脏病理改变以系膜结节样病变多见，占53．8％，2例表现为膜增生样病变、1例为膜性病变，中—重度小管间质慢性化病变为本组患者较特征性的病变(92．3％)。肾组织中以λ轻链沉积为主者占65．4％(17例)，κ轻链沉积占34．6％(9例)。18例患者行肾组织电子显微镜检查，均显示肾小球和(或)肾小管基膜内(外)侧不规则的纤细颗粒样电子致密物。结论：LCDD患者临床以肾功能不全伴肾病综合征多见，部分患者合并浆细胞增生性疾病。病理以系膜结节样伴严重的小管间质病变为特征。血清、尿液以游离λ轻链增高多见，肾组织中也以λ轻链沉积居多。     

伴单克隆免疫球蛋白IgA沉积的膜增生性肾小球肾炎

中年男性患者,反复发作双下肢皮肤紫癜16年,肾脏损害表现为肾病综合征,大量镜下血尿,血压及血清肌酐升高,轻度贫血。2009年曾行肾活检诊断为"过敏性紫癜性肾炎";2016年5月发现血M蛋白阳性(λ-IgA),重复肾活检为膜增生性肾小球肾炎,免疫荧光提示IgA++,轻链染色λ++、κ-,电镜下见晶格状电子致密物沉积;最终诊断为浆细胞病,伴单克隆λ-IgA沉积的膜增性肾小球肾炎,予沙利度胺治疗效果欠佳,硼替佐米治疗后病情好转。     

血、尿中轻链κ和轻链λ含量变化、κ/λ比值在骨髓瘤性肾病和慢性肾脏疾病鉴别诊断中的意义

目的探讨检测血、尿中轻链κ和轻链λ含量及κ/λ比值在骨髓瘤性肾病和慢性肾脏疾病鉴别诊断中的意义。方法利用美国Beckman公司全自动蛋白分析系统,采用速率散射比浊法测定血、尿中本周氏蛋白轻链κ和轻链λ的含量并计算κ/λ比值。结果97例慢性肾脏疾病患者血中轻链κ和λ均下降,而尿中轻链κ和λ均升高,与对照组比较有显著性差异(P<0.01),但κ/λ比值与对照组比较无显著性差异(P>0.05),78例骨髓瘤性肾病患者血、尿中轻链κ或λ升高与对照组比较有显著性差异(P<0.01)。且κ/λ比值与对照组比较有显著性差异(P<0.01)。结论骨髓瘤性肾病患者血中轻链κ或λ升高,且尿中相应轻链κ或λ升高,κ/λ比值显著变化。慢性肾脏疾病患者血中轻链κ和λ下降,而尿中轻链κ和λ均升高,但κ/λ比值没有显著变化。     

多发性骨髓瘤伴继发性红细胞增多症一例

患者女，72岁。因面红3个月，检查发现红细胞增高伴骨髓浆细胞增多1个月收住入院。患者无明显诱因于2005年下半年出现面红、结膜充血，无眩晕、视力下降、乏力、盗汗、骨痛、鼻及牙龈出血、体重减轻等不适。在外院检查发现Hb明显增高。血象Hb208g／L，RBC7．83×10^12／L，红细胞压积（HCT）0．636，WBC7．14×10^9／L，PLT130×10^9／L。血清碱性磷酸酶（AKP）积分14，骨髓检查示红系增生活跃，占0．36，浆细胞明显增生，可见双核及多核浆细胞占0．14。考虑真性红细胞增多症（真红）伴浆细胞明显增高。骨髓细胞染色体核型46XX。尿本周蛋白阳性，X线检查示未见明显骨质破坏及骨质疏松。尿检尿λ轻链879mg／L，κ轻链8．22mg／L，尿κ／λ比值：0．01。尿量2600ml／24h，λ轻链2．29g／24h。血清免疫电泳提示：IgD未见，λ在中γ区可见异常浓集区带；结论：游离λ轻链。予羟基脲口服降低红细胞。     

IgA-kappa type multiple myeloma affecting proximal and distal renal tubules

A 45-year-old male was admitted because of chest pain, lumbago, and bilateral ankle pain. Examination disclosed hypophosphatemic osteomalacia, acquired Fanconi syndrome, and abnormalities in distal nephron such as distal renal tubular acidosis and renal diabetes insipidus. Further exploration revealed IgA kappa multiple myeloma excreting urinary Bence Jones protein (kappa-light chain). Renal biopsy revealed thick basement membranes and elec-tron-dense crystals in proximal tubular epithelial cells. Immunofluorescent studies revealed deposition of kappa-light chain in renal tubular epithelial cells that caused the renal tubular damage. Although the osteomalacia was relieved by medical treatment, the urinary Bence Jones protein and the renal tubular defects were not improved by the chemotherapy for the myeloma. The patient died of exacerbation of multiple myeloma at 50 years of age.     

A novel type of familial transthyretin amyloidosis,ATTR Asn124Ser,with co-localization of κ light chains

A 68-year-old Italian woman who had a clinical history of thyroidectomy in 2002 presented with slowly progressing renal insuffiency and non-nephrotic proteinurea in 2004. A renal biopsy showed the occurrence of amyloid; the thyroid biopsy previously taken also revealed amyloid infiltration. Other amyloid-containing tissues included bone marrow and heart. The plasma cell level in the bone marrow was found to be less than 5% and both serum and urine samples were positive for a monoclonal κ light chain band. DNA analysis unexpectedly revealed the presence of a novel transthyretin (TTR) mutation, ATTR Asn124Ser. Histologically, amyloid deposits in the thyroid had a homogeneous appearance with moderate Congophilia. In immunohistochemistry, a κ light chain antiserum showed positive immunoreactivity with amyloid deposits in the thyroid. Furthermore, a TTR antiserum, anti-TTR50-127, also recognized a number of amyloid deposits stained positive with the κ light chain antiserum. Overall, the κ light chain antiserum reacted with most of the amyloid deposits in the thyroid, whereas TTR immunoreactivity was scarcer, with a scattered appearance. In contrast, only the anti-TTR50-127 antiserum labeled amyloid in the kidney, albeit not all deposits. In this study, we report a patient having a novel TTR variant, ATTR Asn124Ser, with co-localization of κ light chains in the amyloid deposits in the thyroid tissue.     

Renal epithelial cells rapidly bind and internalize calcium oxalate monohydrate crystals.

Renal tubular fluid is supersaturated with calcium and oxalate ions, which can nucleate to form crystals of calcium oxalate monohydrate (COM), the most abundant constituent of kidney stones. However, the mechanisms by which nascent crystals are retained in the nephron and then grow into kidney stones are unclear. An interaction of COM crystals with the surface of renal epithelial cells could be a critical initiating event in nephrolithiasis. To investigate this possibility we used cultures of monkey kidney epithelial cells (BSC-1 line) as a model system and found that [14C]COM crystals bound to the cell surface within seconds. Scanning electron microscopy revealed that crystals bind first to apical microvilli, which subsequently migrate over the crystalline surface. When visualized by transmission electron microscopy, intracellular crystals were located within vesicles. Cytoskeletal responses to crystal uptake were sought by immunofluorescence microscopy, which revealed concentration of F-actin at sites of crystal contact as well as a generalized reorganization of the intermediate filament network containing cytokeratin 8. Uptake of COM crystals did not adversely affect renal epithelial cell growth, and internalized crystals were apparently distributed to daughter cells during division. Rapid adherence of COM crystals to the apical surface of tubular epithelial cells could promote crystal retention in the kidney. Elucidation of factors that regulate this process may provide insight into the pathogenesis of nephrolithiasis.     

Light chain nephropathy

In 13 specimens of renal tissue from 11 patients, deposits of monoclonal immunoglobulin light chains and continuous granular electron-dense material within tubular basement membranes and in association with the glomerular basement membrane were identified. All but one patient were men in the fifth to seventh decades of life, and each presented with azotemia and features of glomerular rather than tubulointerstitial disease. Osteolytic bone lesions occurred in only three patients, and a bone marrow plasmacytosis >30 percent consistent with plasma cell myeloma was identified in only four patients.Light chain distribution in the nephron was confirmed with immunoelectron microscopy and was not associated with deposition of other serum proteins such as immunoglobulin heavy chains, complement, transferrin, alpha₂ macroglobulin and albumin. The electron dense deposits differed in distribution and character from those associated with membranoproliferative glomerulonephritis type II (dense deposit disease), amyloidosis, cryoglobulinemla, macroglobulinemia and benign monoclonal gammopathy. Serum from six of these patients did not bind to normal human or rat renal parenchyma in vitro. Kappa light chain nephropathy was characterized by predominant linear tubular basement membrane κ deposits, and nodular mesangial and linear glomerular basement membrane κ immunostaining. Lambda light chain nephropathy was characterized by linear λ glomerular basement membrane and tubular basement membrane immunostaining.Manifestations of glomerular dysfunction dominated the clinical presentation of light chain nephropathy, and most patients did not have typical features of multiple myeloma. The diagnosis was predicated upon thorough immunohistologic assessment of renal biopsy material.     

Pathogenetic role of Arg-Gly-Asp-recognizing integrins in acute renal failure. off.

Reorientation of the alpha 3 subunit of integrins from predominantly basal to the apical cell surface of cultured renal tubular epithelial cells subjected to oxidant stress has previously been demonstrated. The present study was designed to assess functional competence of ectopically expressed apical integrins. Cell-cell adhesion assay revealed enhanced cytoatractant properties of stressed cells. Stressed epithelial cells exhibited specific recognition and binding of laminin-coated latex beads. These processes were inhibited with the peptide Gly-Arg-Gly-Asp-Asn-Pro (GRGDNP) suggesting a role of RGD-recognizing integrins in augmented adhesion to stressed cells. Given that such enhanced adhesion in in vivo acute renal failure may govern tubular obstruction by desquamated epithelium, a physiological marker of patency of tubular lumen, proximal tubular pressure, was monitored in rats subjected to 60 min of renal ischemia followed by reperfusion. Proximal tubular pressure increased 2-fold after 2 hr of reperfusion in animals that had undergone 60 min of ischemia. Infusion of GRGDNP into the renal artery during reperfusion period virtually abolished an increase in proximal tubular pressure observed in ischemic acute renal failure. These in vitro and in vivo findings are consistent with the hypothesis that RGD-recognizing integrins play an important role in the pathogenesis of tubular obstruction in ischemic acute renal failure.     

骨髓细胞参与甘油引起的小鼠急性肾小管坏死修复的实验观察

目的：观察骨髓来源的细胞能否分化成肾小管上皮细胞。方法：15只绿色荧光蛋白（GFP）标记的C57BL／6转基因小鼠提供骨髓细胞，64只同种无荧光标记的C57BL／6小鼠随机分为正常对照组（N组）、全身照射组（TBI组）、骨髓移植组（BMT组）、骨髓移植＋甘油注射组（B＋G组），每组16只。各组小鼠于不同时间点取血检测血常规、尿素氮及血肌酐，并取肾行H-E染色检查肾脏病理变化。流式细胞仪可以明确受体鼠骨髓细胞中CFP阳性细胞的比例，利用荧光显微镜及激光共聚焦显微镜采用荧光组织化学、免疫组织化学等方法观察GFP阳性细胞在受体鼠肾脏的分布及数量。结果：致死剂量^60Co照射虽然引起血常规三系减少，但并未对肾脏的组织结构及功能造成损伤。BMT组受体鼠在骨髓移植后第56天、84天时，肾小管中有少量GFP阳性细胞的存在，B＋G组受体鼠于上述同样时间点时肾小管中的GFP阳性细胞增多。激光共聚焦显微镜进一步证实了这些GFP阳性细胞位于肾小管上皮，并且荧光组织化学显示，这些GFP阳性细胞表达肾小管上皮细胞特异性功能蛋白Megalin。结论：骨髓细胞可以向肾小管上皮细胞分化．参与肾小管上皮细胞的更新。并且损伤可以使骨髓细胞的肾向分化率增加。     

Renal Fibrin Deposition Associated with Isoimmune Haemolysis in Monkeys: Observation by Light, Electron and Immunofluorescence Microscropy

Following control renal biopsies, five cynomolgus monkeys received an infusion of incompatible isoimmune plasma. Renal biopsies were obtained at 2 or 4 hr, 24 hr, and 7 days after infusion and were examined by light and electron microscopy, as well as immunofluorescence microscopy for platelet antigens and fibrinogen related antigen(s) (FRA). Test animals receiving incompatible plasma showed evidence of haemolysis and disseminated intravascular coagulation. Renal tissue changes varied according to the severity of the transfusion reaction and the time of biopsy. Light microscopy revealed mild glomerular and tubular changes. In early biopsies, immunofluorescence studies showed deposition of FRA in glomerular capillaries and tubule cells. By day 7, glomerular FRA was no longer present, and tubule cell FRA had been displaced into the renal interstitium. Platelet antigen was not seen in any biopsy. Electron microscopy demonstrated proximal tubule cell damage with phosphotungstic acid positive staining granules, intravascular clot formation, and foot process fusion. Two control monkeys received compatible plasma and showed no evidence of renal injury. It appears that renal fibrin deposition and tubule cell damage occur even during mild haemolytic transfusion reactions. This study provides evidence for local fibrinolysis of glomerular fibrin and the transfer of FRA from tubular lumens to the interstitium. In addition, tubule cell FRA appears to be associated with structural damage.     

第474例——贫血,骨痛,蛋白尿

患者女,49岁,临床主要表现为骨痛和蛋白尿。因间歇性头晕、疲倦7年,症状加重并伴骨痛4个月余入院。患者在当地医院被诊断为贫血,并疑诊多发性骨髓瘤(MM)。实验室和影像学检查结果提示为获得性范科尼综合征(FS)伴有冒烟型多发性骨髓瘤(SMM),经肾活检、电子显微镜检查和反复入院检查证实为轻型近端肾小管病(LCPT)。LCPT常引起近端肾小管功能障碍,其特征是近端小管中结晶,多为kappa单克隆轻链的胞质内结晶状沉积。具有FS和LCPT特征的MM患者在临床上较少见,且难以准确诊断。希望通过此病例的分析,使临床医生关注LCPT等类型的有肾脏意义的单克隆球蛋白病(MGRS),以及与浆细胞病(如MM)的鉴别诊断。     

The morphology of "acute tubular necrosis" in man: analysis of 57 renal biopsies and a comparison with the glycerol model.

Renal biopsies from 24 patients with oliguric "acute tubular necrosis" (ATN) and 26 patients with non-oliguric ATN were compared with biopsies from 7 patients who had recently recovered from ATN and 20 control patients. Many morphologic changes were present in the biopsies of patients with ATN and absent in controls, but only two lesions were significantly more severe in patients who had ATN at the time of the biopsy compared with patients who had recently recovered from ATN. These two lesions, necrosis of individual tubular epithelial cells and loss of brush border in proximal tubules, may play a role in the pathogenesis of renal functional failure in ATN. Necrosis of individual tubular epithelial cells appeared to be a continuing process. In the patients with non-oliguric acute renal failure there was a positive correlation between duration of renal failure and severity of tubular necrosis. This was not observed in the patients with oliguric acute renal failure, but otherwise there were no identifiable morphologic differences between the two groups. The glycerol model of acute renal failure in the rabbit was found to differ in several significant ways from ATN in man. Despite the fact that the rabbits had significantly less severe renal failure, their kidneys showed much more severe tubular necrosis and much more prominent presence of tubular casts than was the case in biopsies from patients with ATN. Loss of brush border in proximal tubules was not an important feature of the glycerol model of acute renal failure in the rabbit. We suggest that the glycerol model is not analogous to human ATN and may have an entirely different pathogenesis.