Clinicopathological characteristics of renal light chain deposition disease coexisted with cast nephropathy

Objective To investigate the clinicopathological characteristics of renal light chain deposition disease coexisted with cast nephropathy (LCDD&LCN). Methods Patients with LCDD&LCN (n=10), isolated LCDD (I-LCDD, n=21) and isolated LCN(I-LCN, n=17) diagnosed by renal biopsy in Peking University First Hospital from January 1, 2000 to March 31, 2018 were enrolled, and all cases were examined by light microscopy, immunofluorescence (IF) (including light chain) and electron microscopy (EM). The semi-quantitative evaluation of the main features of renal pathology was performed. The clinical manifestations and pathological features were reviewed and compared. Results LCDD&LCN was more prevalent in middle-aged males. Nine patients showed acute renal insufficiency with small molecular proteinuria (97.1%) and microscopic hematuria. The hematologic diseases included 9 patients of multiple myeloma. The type of monoclonal light chain in serum and urine by immunofixation electrophoresis showed λ dominant (5/8). By light microscopy, glomerular lesions presented with mild mesangial proliferation in most patients, and only one of them displayed mesangial nodular sclerosis. At the same time, acute tubular injury with light chain casts was the prominent feature, and the clinical manifestations and histological features of LCDD&LCN were similar to that of I-LCN. IF revealed linear staining of monoclonal light chain along the glomerular basement membrane (GBM), tubular basement membrane (TBM) and Bowman's capsule, and also positive in tubular casts. By electron microscopy, diffuse powder-like or granular electron-dense deposits located in the inner side of the GBM, the outer layer of the TBM, renal interstitium and arteriolar walls were observed. Conclusions Patients with LCDD&LCN manifest as acute renal insufficiency, and the majority have multiple myeloma. The pathology of LCDD&LCN possesses the features of both I-LCDD and I-LCN. The IF stain of light chains(κ, λ) and ultrastructural examination by electron microscopy are the inevitable methods for the diagnosis of LCDD&LCN.     

Coexistent light chain deposition disease,light chain cast nephropathy,and vascular light chain amyloidosis in a patient with IgD lambda multiple myeloma

International Urology and Nephrology -     

Combination of bortezomib-based chemotherapy and extracorporeal free light chain removal for treating cast nephropathy in multiple myeloma

Besides amyloidosis and light chain deposition disease, themost common histological type of renal lesion is cast nephropathyin 30% of patients with multiple myeloma [2]. In contrast toamyloidosis, cast nephropathy is believed to be potentiallyreversible when circulating light chains are rapidly reduced.We report on three patients with multiple myeloma and cast nephropathytreated with a bortezomib-based chemotherapy in addition toa newly developed high-cutoff polyflux® haemofilter. Reductionin serum free light chain levels was achieved within 10–12days, with all three patients improving their renal function.     

Membranous nephropathy with light chain restricted deposits

The literature on membranous nephropathy (MN) with monoclonal deposits on immunofluorescence (IF) and their outcome is very scarce. We report our experience of managing five patients with this clinical entity. The mean age of the patients was 33.2 ± 6.55 years. The mean proteinuria, serum albumin and serum creatinine was 5.73 ± 2.17 g/day, 2.86 ± 0.51 g/dL and 1.34 ± 1.19 mg/dL, respectively. None of the patients had a lymphoproliferative disorder. Only one patient had an elevated free light chain ratio. Four (80%) patients were M‐type phospholipase A2 receptor (PLA2R) negative (tissue and serum), and one (20%) was PLA2R related. Three (60%) cases had monoclonal IgG3/k, one IgG3/λ, whereas one patient with PLA2R positivity had an IgG3/IgG4k subtype. Two (67%) patients treated with cyclical cyclophosphamide and steroids (cCYC/GC) achieved complete remission and one patient (33%) with elevated baseline creatinine had a reduction in serum creatinine with persistent proteinuria at the end of the 12th month of follow‐up. One patient with PLA2R positive MN was treated with Rituximab and is in complete remission. The patient with an elevated free light chain at baseline was treated with Bortezomib/Thalidomide/Dexamethasone, had complete remission at 12 months, however, had a progressive rise in creatinine over the next 40 months of follow‐up. The current series, though limited by numbers, documents the efficacy of conventional therapies in non‐malignant associated MN with monoclonal deposits on IF.     

Clinicopathological significance of light chain deposition in IgA nephropathy

Background

Clinicopathological significance of light chain deposition in IgA nephropathy and the relation of monotypic IgA deposition to bone marrow abnormalities are important issues to be clarified.

Methods

We retrospectively investigated light chain deposition in 526 patients with IgA nephropathy. We divided the patients into 5 groups according to the balance of intensity of both light chain deposition: lambda monotypic, lambda dominant, polytypic, kappa dominant and kappa monotypic. Clinicopathological parameters were compared among the groups. The relation of monotypic IgA deposition to hematological malignancy was also evaluated.

Results

The prevalence of monotypic IgA deposition was 6.3%, 33 patients (21 lambda and 12 kappa). Thirty-two (4.0%) and 10 patients (1.9%) were classified into lambda and kappa dominant groups, respectively. Polytypic IgA deposition was observed in 455 patients (85.7%). Age of onset, age at biopsy, urinary protein creatinine ratio, the percentage of global glomerulosclerosis, and the degree of IgA and C3 deposition were different among the groups. However, there was no gradual difference according to the groups. No patient with monotypic IgA deposition showed hematological abnormality at biopsy and during follow-up.

Conclusions

The prevalence of IgA monotypic deposition was extremely low. Clinicopathologically, we could not differentiate patients with monotypic IgA deposition from those with polytypic one and no hematological disorder was documented in patients with monotypic IgA deposition. Whether IgA nephropathy with monotypic IgA deposition and that with polytypic one is the same entity or not, and relation between monotypic IgA deposition and hematological malignancy should be clarified by further investigations.

     

Predominant synthesis of IgA with lambda light chain in IgA nephropathy

The nature of the light chains in mesangial IgA deposits and serum IgA was studied in patients with IgA nephropathy. Immunofluorescence (IF) studies using murine monoclonal antibodies, rabbit and goat anti-human monospecific antisera were performed in kidney sections from 15 IgA nephritic patients with only IgA isotype detected in the renal biopsy. Lambda light chain IF was demonstrated in all biopsy specimens and kappa light chain IF in 11 renal biopsy specimens. The majority of renal biopsies showed a predominance of lambda light chain IF staining in the mesangial deposits. The concentration of individual immunoglobulins and their light chain fractions, and the kappa/lambda ratio were determined in the serum and the supernate from peripheral blood mononuclear cells culture of 30 IgA nephritic patients and 30 age-matched healthy controls. The IgA nephritic patients had a higher serum concentration of total IgA (P less than 0.001) and a significantly lower IgA kappa/lambda ratio (P less than 0.001) compared with the controls. The kappa/lambda ratio of supernatant IgA from IgA nephritic patients (N = 20) was also significantly lower than that of the normal subjects (N = 14), both in the unstimulated (P less than 0.01) and pokeweed mitogen stimulated, peripheral blood mononuclear-cell culture (P less than 0.05). Our results showed that patients with primary IgA nephropathy displayed a unique immunologic response characterized by a predominance of IgA with lambda light chain in circulation.     

轻链肾病和轻链型淀粉样变肾脏损害的临床和病理

目的：总结轻链肾病（LCN）和轻链型淀粉样变（AL）肾脏损害临床和病理改变。方法：回顾性分析1990－2000年25例AL及6例LCN患者临床、实验室及组织病理检查结果。结果：首发症状多为水肿。96％AL和66．7％LCN出现蛋白尿,其中75％为肾病综合征（NS）。肾功能不全见于56％AL和83．3％LCN。约50％患者肾脏体积增大。肾小管功能不全发生率较高（＞60％）。肾外改变以贫血和肝脾肿大最为常见。LCN光镜主要呈肾小球系膜结节性硬化（4例）,6例LCN标本均见单克隆轻链（k4例,λ2例）在肾小管基底膜及部分肾小球内沉积。所有AL标本见肾小球、小管间质及小叶间动脉淀粉样物质沉积,刚果红染色（＋）,偏光显微镜下呈苹果绿双折光,高锰酸钾预处理试验不褪色（10例）,免疫组化AA蛋白（－）。6例AL伴多发性骨髓瘤,骨髓浆细胞＞15％。2例LCN合并异常增高IgM单株峰,病理亦支持巨球蛋白血症诊断。结论：AL和LCN并非少见病,临床以蛋白尿和NS最常见,肾功能受累发生率高,肾外表现多见。病理检查尤其特殊病理检查对诊断和鉴别有重要作用。     

Extracorporeal treatment of cast nephropathy

Acute kidney injury (AKI) is common in patients with multiple myeloma (MM), most commonly caused by cast nephropathy resulting from precipitation of free light chains (FLC) in renal tubules. AKI may be irreversible and require dialysis and predicts a poor prognosis. Reduction in serum FLC concentration is thought to be associated with improved likelihood of kidney function recovery in MM patients with AKI. Plasma exchange (PE), by removing circulating FLC, has been used as a treatment modality to improve kidney function in MM, although its efficacy remains uncertain. Extracorporeal treatment with extended high cutoff hemodialysis (HCO-HD) has also recently been studied as a potentially more effective means of FLC removal. Both PE and HCO-HD may be beneficial in some patients, but only when used as adjuncts to successful chemotherapy. Further research is necessary to establish the specific efficacy of each of these extracorporeal methods in the treatment of cast nephropathy.     

Renal transplantation in a patient with multiple myeloma and light chain nephropathy

A case of multiple myeloma in a 41-year-old white man that resulted in chronic renal failure is discussed. During the period of hemodialysis treatment, remission of the patient's myeloma was induced by chemotherapy. Thereafter a transplanted cadaver kidney functioned well for 3.5 years despite episodes of sepsis, administration of nephrotoxic chemotherapeutic agents, and recurrence of the myeloma with intermittent excretion of Bence Jones protein in the urine. The results of this fully documented case, as well as two other cases we have previously reported, support the strategy of offering cadaver renal transplantation to carefully selected individuals who require long-term dialysis and whose myeloma is in remission after chemotherapy.     

磷酸化肌球蛋白轻链在大鼠慢性移植肾肾病早期病变中的作用及其机制

目的 探讨磷酸化肌球蛋白轻链(pMLC)在慢性移植肾肾病(CAN)中的作用与机制.方法 依照标准的CAN大鼠模型进行左肾原位移植,受者为LEW大鼠,供者为F344大鼠,另取雄性F344大鼠和LEW大鼠仅行单肾切除术,分别作为对照.分别于术后4、8及12周时,收集各组大鼠的24 h尿量,并检测其尿肌酐水平,计算肌酐清除率.然后取各组大鼠血液标本,测定血清肌酐水平.采用Banff分级标准评定各组肾小球肾病、肾小管萎缩、间质纤维化及血管内膜增厚程度.采用免疫组织化学法和采用蛋白质印迹法检测肾组织中磷酸化MLC(pMLC)和整合素连接激酶(ILK)的表达部位及表达水平.结果 移植组大鼠术后4周时肾间质可见单个核细胞浸润,12周时可见血管平滑肌细胞的移行与增殖.移植组大鼠各时相肾组织pMLC和ILK表达水平显著高于Lewis对照组及F344对照组,且随着移植时间的延长有逐渐增高趋势.大鼠移植肾组织中pMLC表达水平与24 h尿蛋白定量、血清肌酐水平、肾间质单个核细胞浸润、肾小动脉血管平滑肌细胞数量、Banff评分等呈显著正相关,相关系数(r)分别为0.273(P＜0.05)、0.434(P＜0.01)、0.525(P＜0.01)、0.676(P＜0.01)、0.570(P＜0.01),在移植后4周时,pMLC表达水平与肾小管间质ILK表达水平呈显著正相关,r=0.778(P＜0.01).结论 pMLC在慢性移植肾病早期病理变化中发挥重要作用,移植肾肾小管间质及肾小动脉中pMLC表达上调与ILK的作用机制相关.

Abstract：

Objective To investigate the role and mechanism of phosphate myosin light chain (pMLC) in the rat kidney of chronic allograft nephropathy (CAN) model. Methods The left donor kidneys from Fisher (F344) rats were orthotopically transplanted into Lewis recipients. Meanwhile, the F344 rats and LEW rats with resection of the right kidney served as control groups. Animals were harvested respectively at the 4th, 8th and 12th week after transplantation. The creatinine clearance rate (CCr) was calculated by urine creatinine of 24-h urine. Blood samples were collected from rats for determination of serum creatinine. The expression of pMLC was detected by using Western blotting and immunohistochernistry, and that of integrin-linked kinase (ILK) by using immunohistochemistry. Results Mononuclear cells infiltration of allografts was markedly aggravated as compared to the controls. Allografts got severe interstitial fibrosis and tubular atrophy at 12th week after transplantation. The expression of pMILC and ILK was up-regulated in the kidney of CAN rats after transplantation, and increased more significantly as the time went on. The expression of pMILC was significantly correlated with 24-h urine protein excretion (r= 0. 273, P＜0. 05), serum creatinine levels (r = 0. 434, P＜0. 01 ), the number of tubulointerstitial infiltrated mononuclear cells (r = 0. 525, P＜0. 01 ), the number of smooth muscle cells (SMC) in vascular wall (r= 0. 676, P＜0. 01 ) and the extent of interstitial fibrosis (r= 0. 570, P＜0. 01 ).There was a significantly positive correlation between ILK and pMLC in CAN rats at the 4th week after transplantation (r= 0. 778, P＜0. 01 ). Conclusion pMLC might play an key role in CAN, and the over-expression of ILK might be involve in the pathogenesis of CAN.     

Renal transplantation in light chain nephropathy: case report and review of the literature

A successful cadaveric transplantation in a patient with irreversible renal insufficiency due to light chain nephropathy is reported. Remission of the monoclonal gammopathy was induced with melphalan and prednisone and after 4.5 years of hemodialysis a cadaveric kidney transplantation was performed, which resulted in excellent renal function up to 3.5 years after transplantation. Along with 8 previously reported patients in the literature this case demonstrates that renal transplantation can no longer be withheld from this category of patients, when they are in remission and no other major complications of their monoclonal gammopathy are present.     

Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains

Cast nephropathy is the most common cause of renal disease in multiple myeloma, however, treatment with plasma exchange remains controversial even after 3 randomized controlled studies. We sought to determine the importance of diagnostic confirmation and goal directed therapy in the treatment of cast nephropathy in forty patients with confirmed multiple myeloma and renal failure who underwent plasma exchange. A positive renal response was defined as a decrease by half in the presenting serum creatinine and dialysis independence. No baseline differences were noted between eventual renal responders and non-responders. Three quarters of the patients with biopsy proven cast nephropathy resolved their renal disease when the free light chains present in the serum were reduced by half or more but there was no significant response when the reduction was less. The median time to a response was about 2 months. In patients without cast nephropathy, renal recovery occurred despite reductions in free light chain levels of the serum. No association was found between free light chains in the serum, urinary monoclonal proteins, overall proteinuria and cast nephropathy. We found that the relationship between renal recovery and free light chain reduction was present only in patients with biopsy proven cast nephropathy showing the importance of extracorporeal light chain removal in this disease.     

Lambda light chain induced nephropathy: A rare cause of the Fanconi syndrome and severe osteomalacia

The Fanconi syndrome is a generalized disorder of proximal renal tubular transport characterized by wasting of phosphate, amino acids, glucose, bicarbonate, and uric acid. The association of the acquired Fanconi syndrome with lambda light-chain proteinuria is rare. We report the third case in the English language literature. A 65-year-old man presented with severe pelvic pain. Investigations showed an elevated serum creatinine level, and a 24-hour urine collection contained 2.56 g protein. The Fanconi syndrome was diagnosed, with findings of phosphaturia, glycosuria, and aminoaciduria. Bence Jones protein (lambda sub-type) was present in the urine at a concentration of 0.58 g/L. Monocytic cells in the bone marrow and proximal tubular cells in the kidney contained cytoplasmic crystalline inclusions. Undecalcified bone sections confirmed the clinical diagnosis of osteomalacia. The patient was treated with phosphate, calcium, and ergocalciferol and experienced significant symptomatic improvement. The Fanconi syndrome caused by light-chain deposition in proximal tubular cells is well described in the literature. However, it is rare for the light chains to be of the lambda subtype. This may reflect differences in the physicochemical properties of kappa and lambda light chains. (Am J Kidney Dis 1998 Dec;32(6):E3)