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.     

The clinical spectrum of light chain myeloma: A study of 35 patients with special reference to the occurrence of amyloidosis

During a 40 month interval, 35 patients were seen with a plasma cell dyscrasia in which the only detectable monoclonal immunoglobulin abnormality consisted of excess production of either type kappa or type lambda light chains (Bence Jones protein). This group constituted 17.3 per cent of the total number of patients with plasma cell dyscrasias and 25.7 per cent of the patients with myeloma identified during the same period. Variable initial clinical presentation, the absence of a typical monoclonal serum spike and the unreliability of commonly used urine protein tests made recognition of the disorder difficult in many patients. Sulfosalicylic acid and p-toluene sulfonic acid proved valuable in screening for urine protein. Definition of “proteinuria” by quantitative, electrophoretic and immunochemical studies was essential for diagnosis. Bence Jones proteinemia was present in 80 per cent of the patients; panhypogammaglobulinemia and lytic bone lesions were demonstrable in more than 60 per cent. Although no specific morphologic abnormality of marrow plasma cells was evident by light microscopy, the absence of rouleau on peripheral blood smear was a helpful diagnostic clue. Although patients with lambda light chains presented with more Bence Jones proteinuria, this did not correlate with the severity of initial renal functional impairment or with survival when compared to patients with kappa light chains. No other clinical or laboratory observation differentiated the groups with kappa light chains from those with lambda light chains. Amyloid was identified in seven patients. Their course was dominated by the features of primary systemic amyloidosis instead of the usual findings of classic myeloma. Patients with amyloidosis had lower initial serum albumin levels, fewer lytic bone lesions and reduced survival compared to patients without amyloidosis.     

Serum free light-chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma

Using sensitive, automated immunoassays, increased concentrations of either kappa or lambda free light chains (and abnormal kappa/lambda ratios) were detected in the sera of 19 of 28 patients with nonsecretory multiple myeloma. Four other patients had suppression of one or both light chains, and the remaining 5 sera had normal or raised free light-chain concentrations with substantially normal kappa/lambda ratios. Six of the patients with an elevated single free light chain, who were studied during follow-up, had changes in disease activity that were reflected by the changes in free light-chain concentrations. It is concluded that quantification of free light chains in serum should prove useful for the diagnosis and monitoring of many patients with nonsecretory myeloma.     

Amyloidosis: A changing clinical perspective

Primary amyloidosis is a plasma cell dyscrasia characterised by excess production of abnormal immunoglobulin light chains with their subsequent accumulation in kidneys, heart, liver as well as gastrointestinal tract and bone marrow [1–2]. These tissue deposits take the form of a fibrillar protein which damages the involved organ in proportion to the extent of the infiltration and roughly parallels the duration of the disease. Most cases have evidence of the underlying lymphoplasmacytoid neoplasm recognisable in two ways. Firstly, the monoc1one appears in the serum [2]. Secondly is a morphologically and immunohistochemically distinctive cellular infiltrate in the bone marrow [3] that has a specific microscopic and ultrastructural pattern [4–5]. Interestingly occasional patients, who survive long enough, may progress to multiple myeloma [6] but the correlation is variable [7].     

Monoclonal immunoglobulin deposition disease: light chain and light and heavy chain deposition diseases and their relation to light chain amyloidosis. Clinical features, immunopathology, and molecular analysis

Monoclonal immunoglobulin deposition occurs in tissues as Congo Red binding fibrils in light chain amyloidosis, as less structured deposits in light chain deposition disease, and as similar but distinct deposits in light and heavy chain deposition disease. The nonamyloid forms were found in 13 patients who had evidence of plasmacytic dyscrasia by the immunohistochemical detection of immunoglobulin light chains of kappa or lambda class (with or without staining for a single heavy chain isotype) and by the absence of amyloid P component in tissue sections that did not show the birefringence characteristic of amyloid after Congo Red staining. All but two of the patients presented with proteinuria with or without azotemia. Clinical syndromes involving other organ systems were less common but occasionally severe. Four patients had overt multiple myeloma. Three others had hypercalcemia and mild bone marrow plasmacytosis but no lytic lesions. Analyses of immunoglobulin synthesis in bone marrow cells from seven patients showed excess light chains in all and incomplete light chains or heavy chain fragments in six, regardless of whether an intact monoclonal protein or related subunit was in the serum or urine. The fibrillar (amyloidotic) and nonfibrillar forms of monoclonal immunoglobulin deposition occur either in overt multiple myeloma or in the course of less neoplastically aggressive plasmacytic dyscrasias. Bone marrow cells from patients with either type produce immunoglobulin fragments that are related to those deposited in the affected tissues.     

Kidney damage in multiple myeloma and other monoclonal gammopathies

Multiple myeloma typically damages the skeleton in the form of osteolytic lesions or diffuse osteoporosis and causes a decrease in blood production. Renal insufficiency is diagnosed immediately at the onset of illness when establishing diagnosis in up to 20% of patients. Where patients suffer from an advanced form of the illness, it occurs in up to 40%. The predominant cause of damage to the kidneys is the monoclonal light chains. Most frequently, nephropathy is caused by the precipitation of light chains with the Tamm-Horsfall protein in the distal part of the loop of Henle and subsequent tubular ruptures and the creation of fibrous changes in the interstitium. Less frequently, there is clinically serious damage to tubular functions without indication of renal insufficiency. In some patients monoclonal immunoglobulin induces changes in the glomeruli. A rare type of damage is deposits of light chains in the form of AL-amyloid and subsequent nephritic syndrome. A very rare form is the deposition of monoclonal immunoglobulin in the form of amorphous matter (light-chain deposition disease) or in the form of crystals within tissue histiocytes (crystal storing histiocytosis). Both of these disorders cause renal insufficiency and less frequently nephritic syndrome such as AL amyloidosis. With timely and intensive treatment of multiple myeloma, which quickly suppresses the creation of light chains, a significant proportion of patients experience reparative changes and improved kidney function. The benefit of plasmapheresis for patients with severe kidney damage has not been confirmed by randomised studies. At the present time the first positive results are becoming available from tests of the use of pre-emptive haemodialysis with special columns that are permeable for light chains. The aim of the text is to provide information on the various forms of nephropathy whose closer analysis can reveal multiple myeloma and contribute to the timely diagnosis of the cause of the nephropathy.     

Renal disease in multiple myeloma

Multiple myeloma is a malignant tumor of B (plasma) cells that is characterized by monoclonal immunoglobulin production. The incidence of myeloma is increasing worldwide, particularly among individuals of advanced age. Renal impairment at diagnosis is present in approximately 20% of patients with myeloma, and uremia is the cause of death in about 15%. Several renal disorders may be present in myeloma. Bence Jones cast nephropathy (BJCN), acute tubular necrosis, and “nonspecific” tubulointerstitial nephritis are related to nephrotoxic light chains in urine. Hypercalcemia potentiates the toxicity of urinary light chains. The tissue deposition of light chains leads to renal AL-amyloidosis or light chain deposition nephropathy (LCDN). In necropsy series, the incidence of BJCN, renal AL-amyloidosis, and LCDN is about 30%, 10%, and 4%, respectively. Clinically, urinary nephrotoxic light chain-associated disorders and LCDN are usually manifested in chronic or acute renal failure. The nephrotic syndrome is commonly due to renal AL-amyloidosis. Most cases of end-stage renal failure are due to BJCN and LCDN. The basic therapy of renal impairment is hydration, forced diuresis, and initiation of chemotherapy. Diphosphonates are effective new tools for the correction of hypercalcemia, and decrease the incidence of pathological fractures. In acute renal failure, plasma exchange in association with forced diuresis, dialysis, and chemotherapy may improve renal function. End-stage renal failure requires maintenance renal replacement therapy. In myeloma patients with advanced age, the limits of medical intervention should be judged individually. Particular attention should be paid to the supportive care of the patients.     

Manifestations of systemic light chain deposition

In two patients with terminal renal failure, manifestations of disease developed in multiple organ systems. One had a previous diagnosis of multiple myeloma with kappa light chain proteinemia and proteinuria. The other had idiopathic lobular glomerulonephritis. Hepatic and neurologic abnormalities developed in both; in the latter gastrointestinal, cardiac and endocrine disease developed as well. Clinical and pathologic correlations suggest that the retention and tissue deposition of light chains produced the organ dysfunction, inasmuch as free kappa light chain determinants were demonstrated histologically in the clinically affected organs. The deposition in these patients may be an extreme example of a common but previously unrecognized form of plasma cell dyscrasia.     

Amyloidosis: a changing clinical perspective

Primary amyloidosis is a plasma cell dyscrasia characterised by excess production of abnormal immunoglobulin light chains with their subsequent accumulation in kidneys, heart, liver as well as gastrointestinal tract and bone marrow 1-21, 2. These tissue deposits take the form of a fibrillar protein which damages the involved organ in proportion to the extent of the infiltration and roughly parallels the duration of the disease. Most cases have evidence of the underlying lymphoplasmacytoid neoplasm recognisable in two ways. Firstly, the monoclone appears in the serum [2]. Secondly is a morphologically and immunohistochemically distinctive cellular infiltrate in the bone marrow [3] that has a specific microscopic and ultrastructural pattern 4-54, 5. Interestingly occasional patients, who survive long enough, may progress to multiple myeloma [6] but the correlation is variable [7].     

Clonal immunoglobulin light chain variable region germline gene use in AL amyloidosis: association with dominant amyloid-related organ involvement and survival after stem cell transplantation

AL (primary or immunoglobulin light chain) amyloidosis (AL) differs from myeloma per se in that tissue deposits of amyloid are found, typically in association with small numbers of clonal plasma cells producing lambda light chains, and also in that AL patients typically present with a predominantly dysfunctional organ-system. This constellation of features - fibrillar deposits comprised of light chains, lambda light chain predominance, and organ-system tropism and dysfunction - remains unexplained. Select patients with AL respond to haemopoietic stem cell transplantation (SCT) with clinical improvement and extended survival, particularly those who do not have cardiac involvement. In order to ascertain whether the organ-system tropism of AL was associated with immunoglublin light chain variable region (Ig VL) germline gene utilization, we attempted to clone, sequence and assign germline donors to the clonal Ig VL genes of 62 AL patients, all of whom were treated with SCT. We succeeded in 39 cases, identifying clonal AL genes derived from donors of the lambdaI (n = 10), lambdaII (n = 5), lambdaIII (n = 6), lambdaVI (n = 11) and KI (n = 7) subtypes. The majority of the donors (IGLV6S1, DPL5, DPL2, DPL23 and LFVK431) were genes that appear in the expressed repertoire <5% of the time, suggesting an intrinsic propensity to form amyloid under certain conditions. Patients whose clones derived from the lambdaVI IGLV6S1 donor uniformly presented with dominant renal involvement while those with other Vlambda or unknown donors often had dominant cardiac or other organ involvement, particularly patients whose clones derived from the lambdaI DPL2 donor. In addition, both early (<3 months) and overall post-SCT survival were significantly better in lambdaVI IGLV6S1 patients compared to patients with other Vlambda donors. These findings indicate that there are important associations in AL amyloidosis among Ig VL gene utilization, organ-system tropism and post-SCT survival.     

Use of continuous venovenous hemofiltration for acute renal failure due to multiple myeloma cast nephropathy

Renal insufficiency is associated with high morbidity and mortality in multiple myeloma. One of the common causes for acute renal failure in multiple myeloma is cast nephropathy. It is important to reduce the levels of light chains to improve renal failure and also the overall outcome. Plasmapheresis has failed to show any significant improvement in renal failure due to cast nephropathy as demonstrated in a recent randomized control trial. Here, we present a case series of three patients who were treated with continuous venovenous hemofiltration as a modality to remove these free light chains. There was improvement in renal failure in these patients with decrease in the levels of free light chains. These patients remained off hemodialysis on follow-up and two of them were able to undergo hematopoietic stem cell transplantation.     

Plasmapheresis in the treatment of acute renal failure in multiple myeloma.

Three patients with multiple myeloma and severe acute renal failure were treated by repeated plasmapheresis. Recovery of renal function was observed in all. The pathogenetic role of light chains and the possible mechanisms responsible for renal damage are discussed. It is suggested that the removal of light chains by plasmapheresis may be of therapeutic value in this condition.     

Double myeloma. Production of both IgG type lambda and IgA type lambda myeloma proteins by a single plasma cell line

Monoclonal immunoglobulins G (IgG) and A (IgA) of the lambda light chain type were present in the serum of a patient with multiple myeloma. Three populations of myeloma cells were seen by immunofluorescence of bone marrow; those containing either IgG or IgA and those staining for both IgG and IgA. Idiotypic determinants present on the variable regions of the two myeloma proteins were immunologically identical and all the myeloma cells contained the same idiotypic determinant. The idiotypic specificity was related more closely to the variable region of the heavy chain than to the light chain. Structural and electrophoretic analysis confirmed that the light chains of the two myeloma proteins were identical. The myeloma in this patient appears to have arisen from a single clone of cells that was capable of synthesizing the constant portions of both the IgG and IgA heavy chain but only a single light and heavy chain variable region. These findings suggest that current concepts of antibody synthesis involving the sequential production of immunoglobulin M (IgM) and IgG antibodies may apply to certain cell lines synthesizing IgG and IgA antibodies as well.     

Intracytoplasmic crystals and Fanconi syndrome in a patient with IgA kappa myeloma

A 45 year old man with IgA-Kappa myeloma had adult Fanconi Syndrome. Examination of renal biopsy revealed lesions in proximal tubules without glomerular lesions and without intratubular casts. By electron microscopy cytoplasmic crystalline inclusions were observed in renal proximal tubular epithelium. Increased plasma cells (28%) in bone marrow aspiration also contained crystalline inclusions. The treatment of myeloma produced partial remission of proliferative disease and Fanconi syndrome. We discuss the pathogenesis of Fanconi syndrome induced by light chains as well as the composition of crystalline deposits and the effects of treatment on Fanconi Syndrome.     

Rapidly progressive silicon nephropathy

Rapidly progressive renal failure developed in four patients with silica exposure. Three presented with manifestations of a connective tissue disorder. All had abnormal proteinuria, hypoalbuminemia and active urinary sediments. Histologically, a distinct constellation of findings was present, consisting of glomerular hypercellularity and sclerosis, crescents, interstitial cellular infiltrates and tubular necrosis with red cell casts as seen on light microscopy. On electron microscopy there was foot process obliteration, characteristic cytoplasmic dense lysosomes, microtubules and dense deposits. Despite vigorous treatment, two patients died of the systemic illness and one is on hemodialysis. The fourth is improved after pulse methylprednisolone therapy. We propose that silica induced this multisystem disease through activation of the immune system and a direct tissue toxic effect.     

Nucleolus-associated J chains in myeloma cells

Bone marrow aspirates from 10 patients with multiple myeloma (6 IgG myeloma, 3 IgA myeloma, 1 Bence Jones myeloma) were examined for nucleolus-associated localization of J chains. On light microscopy using the PAP method, almost all or a significant number of myeloma cells exhibited intranuclear spots stained with anti-J chains in 3 (IgG myeloma) out of the 8 cases positive for cytoplasmic J chains. In contrast, the nucleus of myeloma cells examined was constantly negative for anti-heavy and -light chains. Immunoelectron microscopically, J chain was identified as dicrete round electron-dense precipitates, corresponding to the whole nucleolus, and as sparsely distributed, small electron-dense deposits in the nucleus. In addition, some connections were found between nuclear and nucleolar electron-dense precipitates. Several possible explanations have been proposed to account for this localization of J chains.     

Polymeric Bence Jones Proteins in Serum in Myleoma Patients with Renal Insufficiency

ABSTRACT The polymeric forms of Bence Jones protein (BJ) in serum and the influence on renal function were investigated in 59 patients with multiple myeloma and 2 with Waldenström's macroglobulinemia. Eight of 35 patients with kappa and 26 with lambda type BJ protein had decreased renal function. The investigation showed a considerable variation between patients in serum concentrations of tetrameric (T), dimeric (D) and monomeric (M) forms of BJ protein. A significantly higher fraction of D forms of BJ protein resulting in a high D/M ratio was found in the myeloma patients compared with polyclonal light chains in 10 normal controls. The renal function in multiple myeloma was, however, not correlated to the D/M ratio or to the BJ protein tetramers. This suggests that the nephrotoxicity of BJ proteins is not associated with polymerization of BJ proteins in serum. BJ proteins of aberrant size were found in 3 patients with rapidly decreasing renal function. Histological investigation in 2 of these patients revealed nodular glomerulosclerosis.     

The clinical aspects of biclonal gammopathies. Review of 57 cases

Between 1966 and 1979, biclonal gammopathy was recognized in 57 patients. Clinical and laboratory features differentiated three groups: biclonal gammopathy of undetermined significance, 37 cases (65 percent); multiple myeloma, nine cases (16 percent); and lymphoproliferative disease--including lymphoma, macroglobulinemia, chronic lymphocytic leukemia and unclassified lymphoproliferative disorders--11 cases (19 percent). With biclonal gammopathy of undetermined significance, symptomatic multiple myeloma developed after two years in one patient; the others remained stable. One patient with multiple myeloma had osteosclerotic myeloma and a severe sensorimotor peripheral neuropathy, and another presented with plasma cell leukemia. In the remainder response to therapy and survival were much the same as in patients with multiple myeloma with a monoclonal protein. Patients with lymphoproliferative disease responded to chemotherapy like that for monoclonal gammopathy. Of the 57 patients, 30 (53 percent) had IgG and IgA components, 15 (26 percent) had IgG and IgM, six had two IgG components, three had IgA and IgM, one had IgA proteins, one had IgA and IgE and 1 had triclonal gammopathy. Of the 115 light chains, 70 percent were kappa; the chains were both kappa and lambda in 63 percent of biclonal pairs. In many cases, serum electrophoresis produced only a single band on the acetate strip, and the biclonal gammopathy was not recognized until immunoelectrophoresis was done. Although the clinical features of biclonal gammopathy and its response to therapy are similar to those of monoclonal gammopathy, this subject is of importance because of the lack of clinical data in the literature.     

血管壁淀粉样蛋白沉积型淀粉样变性肾病六例临床和病理分析

目的 通过报告6例血管壁淀粉样蛋白沉积型淀粉样变性肾病(VADAN)的临床和病理特性,以提高对VADAN的诊治水平.方法 收集6例VADAN患者行免疫病理、光镜及电镜检查,并进行淀粉样蛋白的分型.结果 6例患者均为中老年(52～73岁)患者,男女各3例.其中2例为多发性骨髓瘤.多数病例仅呈轻度的蛋白尿和血尿.1例因合并微小病变型肾病,呈现肾病综合征表现;1例因合并IgA肾病,呈现蛋白尿和血尿;1例因骨髓瘤管型肾病,呈现急性肾衰竭.经肾活检证实,淀粉样蛋白仅沉积于小叶间动脉.6例患者均为原发性系统性淀粉样变性肾病,2例多发性骨髓瘤继发者,为κ型,其余为λ型.结论 VADAN属于少见的淀粉样变性肾病类型,临床表现不同于常见的淀粉样变性肾病,肾活检有助于其鉴别诊断.

Abstract：

Objective To analyze clinical and pathologic features of a rare vascular amyloid deposits of amyloid nephropathy ( VADAN) in 6 patients, so as to improve its diagnosis and treatment. Methods All patients received immunopathology, microscopy and electron microscopy examination, and amyloid types were analyzed. Results There were 3 males and 3 females with ages ranging from 52 to 73 years. Two patients suffered from multiple myeloma. Majority patients had slight albuminuria and hematuria. One patient combined with minimal change glomerular disease presented nephrotic syndrome. One patient combined with IgA nephropathy had albuminuria and hematuria. And one patient had myeloma cast nephropathy with acute renal failure. Kidney biopsy proved amyloid deposits along interlobular arterial wall only in all 6 patients. Two cases secondary from multiple myeloma were κ amyloid, and the rests were λ amyloid. Conclusions VADAN is a rare type of amyloid nephropathy. Its clinical manifestation is different from common amyloid nephropathy. Kidney biopsy will benefit its differential diagnosis.