Histopathological atlas of renal diseases: light chain deposition disease

Monoclonal diseases of B-cell lineage, often referred to as plasma cell dyscrasias, are characterized by abnormal and uncontrolled proliferation of a single clone of B cells at different maturation stages, with a more or less marked differentiation to immunoglobulin (Ig)-secreting plasma cells. Thus B-cell proliferation is usually associated with the production and secretion in blood of a monoclonal Ig or a fragment thereof. An ominous consequence of secretion of monoclonal Ig products is their deposition in tissue. These proteinaceous deposits can take the form of casts (in myeloma cast nephropathy), cristals (in myeloma-associated Fanconi's syndrome), fibrils (in light-chain [LC] amyloidosis), or granular precipitates (in monoclonal Ig deposition disease [LCDD]).     

Kidney and liver involvement in monoclonal light chain disorders

Monoclonal light chains (LCs) are responsible for a wide spectrum of renal and hepatic diseases, that above all include amyloid light-chain (AL) amyloidosis and light chain deposition disease (LCDD). Amyloid deposits stain for Congo red on light microscopy and have fibrillar aspect on electron microscopy, whereas deposits in LCDD are positive using monotypic LCs on immunofluorescence and have a granular aspect on electron microscopy. Sometimes fibrillar and granular deposits are observed in the same organ or in different organs of the same patient. Kidney and liver involvement is a frequent finding, both in primary amyloidosis (AL amyloidosis) or in LCDD. Renal manifestations include proteinuria, nephrotic syndrome, and progressive renal failure. End-stage renal disease requiring dialysis is observed in about 20% of patients with AL amyloidosis and in 70% of patients with LCDD. The mean survival time is about 12 to 18 months in AL amyloidosis and 34 months in LCDD. The most important prognostic factor is severe cardiac involvement, which reduces the mean survival to only 6 months. Hepatic manifestations include hepatomegaly, portal hypertension, ascites, intrahepatic cholostatic jaundice, and hepatic insufficiency. The mean survival of patients with liver damage is 14 months, but it is reduced to 5 months in patients with cholostatic jaundice. Contemporary kidney and liver involvement is usually observed on histologic examination, less frequently as clinical manifestation. No specific treatment exists for AL amyloidosis and LCDD, and the prognosis remains severe. The aim of treatment is to suppress proliferation of the abnormal clone of plasma cells and remove tissue deposits. The regimens, including melphalan-prednisone (MP) or vincristine-doxorubicin-dexamethasone (VAD), are used both in AL amyloidosis or in LCDD with some effectiveness. New approaches, especially the use of 4'-iodo-4'deoxydoxorubicin, could achieve better results. Dialysis seems to not worsen the outcome in both diseases because survival of patients on dialysis is not different from that of patients not reaching uremia. Also, kidney and liver transplantation is effective, though amyloidosis or LCDD may occur in transplanted organs. The most interesting therapeutic approach is autologous-blood stem-cell transplantation, which may produce a complete remission of the plasma-cell dyscrasia and a substantial improvement of clinical manifestations related to LC deposits.     

Lambda light chain deposition disease in a renal allograft

Light chain deposition disease (LCDD) of the kidney is characterized by deposition of monoclonal light chains predominantly in glomeruli and in tubular basement membranes. The disease is frequently associated with a lymphoproliferative disorder, and the majority of cases are caused by deposition of kappa light chains. Although the occurrence of de novo multiple myeloma after renal transplantation is uncommon, there are several reports of LCDD involving renal allografts, either de novo or in patients with a diagnosis of LCDD prior to transplantation. To the best of our knowledge, all previously described cases in allografts have been in patients with kappa chain deposition. The relative importance of intrinsic properties of the kidney in predisposing to either kappa or lambda light chain deposition is not known. We present a case of LCDD caused by deposition of lambda light chains in a patient who received a cadaveric renal transplant.     

An Atypical Case of POEMS Syndrome with IgG Kappa M Protein and End Stage Renal Failure

POEMS syndrome is a rare plasma cell dyscrasia which is characterized by small amounts of monoclonal protein, and a multisystem complex manifested by various combinations of polyneuropathy, organomegaly, endocrinopathy and skin changes. Here, we presented an atypical case of POEMS syndrome with IgG kappa monoclonal protein, chronic demyelinating polyneuropathy, hepatosplenomegaly, hypothyroidism, gynecomastia and severe renal impairment. The finding of IgG kappa type of monoclonal protein in our patient was interesting because the majority of cases were reported to have lambda light chain. Also, the absence of typical skin and bone lesions were atypical. Though speculative, these atypical features may account for the unusual presentation of this case. Our patient rapidly progressed to end-stage renal failure and died of cachexia. Renal involvement in POEMS syndrome is rare but may show substantial clinical and pathological variations. Proteinuria, hematuria, renal dysfunction and renal failure requiring hemodialysis can be seen. The pathogenesis of renal dysfunction is unclear. As a conclusion, POEMS syndrome may present with diverse clinicopathologic manifestations. In this syndrome, renal involvement may lead to end stage renal failure and the course may be fatal due to severe polyneuropathy and wasting.     

轻链沉积病肾损害的诊断与治疗

轻链沉积病(LCDD)为单克隆免疫球蛋白轻链在肾脏、心脏、肝脏等组织的沉积。LCDD肾损害起病时多伴有慢性肾功能不全。典型的LCDD肾损害有相对特殊的临床表现,血、尿蛋白电泳及游离轻链定量有助于诊断,确诊需行肾组织病理学检查,包括光镜、荧光显微镜及电镜等检查。LCDD肾损害的治疗应综合考虑B细胞增殖程度和单克隆免疫球蛋白对肾功能造成的损害。应积极控制B细胞增殖,但治疗时应选择肾毒性较小的药物如硼替佐米,必要时改用大剂量马法兰＋周围血干细胞移植(HDM/ASCT)方案。     

Recurrence of light chain deposit disease after renal allograft transplantation: potential role of rituximab?

Light chain deposit disease (LCDD) is a monoclonal plasma cell disorder characterized by tissue deposition of nonamyloid immunoglobulin light chains, predominantly kappa chains, causing renal insufficiency. LCDD reoccurs almost invariably after renal grafting, leading to early graft loss, usually within a time span of months to years. We describe a female patient with LCDD who lost her first living donor graft after 1 year due to extensive recurrence of kappa chain deposition. Rituximab was administered on the seventh day after her second transplantation with a graft from a deceased donor, in order to prevent early recurrence of LCDD. The 2-year protocol biopsy - similarly to the completely normal 1-year protocol biopsy - revealed persistent absence of light chain deposition on light microscopy but immunohistochemical staining and electron microscopy showed very mild recurrence of light chain deposits. A second 4-week course of rituximab was repeated because of these electron microscopic findings. Subsequently, free kappa light chain concentration decreased from 693 to 74 mg/l and remained low 4 months after completion of therapy. Rituximab could be considered for delaying early LCDD recurrence in patients in whom treatment of the underlying bone marrow disorder failed or is contraindicated, but maintenance therapy is apparently necessary to consolidate this response.     

Rapid deterioration of renal function in a patient with multiple myeloma associated with amyloid and light chain depositions

Here we report a 75-year-old man with multiple myeloma who developed acute deterioration of renal function. Systemic AL amyloid deposition was found in the stomach, duodenum and brachial artery. A small amount of proteinuria without significant abnormal urinary sediments, increased excretion of urinary low-molecular-weight proteins and Bence Jones protein were observed. Significant renal Ga-67 uptake suggested acute tubulointerstitial lesions. Renal necropsy after sudden death 40 days after introduction of hemodialysis revealed mesangial expansion with glomerular basement membrane thickening, tubular basement membrane thickening with or without tubular atrophy and massive tubulointerstitial fibrosis. Slight amyloid depositions in the mesangium and vessels, and massive granular electron-dense deposits and deposition of monoclonal light chain λ in renal basement membranes and vessels were found, indicating the rare condition of co-existence of amyloidosis and light chain deposition disease (LCDD). The rapid progression of renal failure may have been caused by massive deposition of monoclonal light chains in our patient.     

IgD Heavy-Chain Deposition Disease: Detection by Laser Microdissection and Mass Spectrometry

Monoclonal Ig deposition disease (MIDD) is a rare complication of monoclonal gammopathy characterized by deposition of monoclonal Ig light chains and/or heavy chains along the glomerular and tubular basement membranes. Here, we describe a unique case of IgD deposition disease. IgD deposition is difficult to diagnose, because routine immunofluorescence does not detect IgD. A 77-year-old man presented with proteinuria and renal failure, and kidney biopsy analysis showed a nodular sclerosing GN with extensive focal global glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Immunofluorescence was negative for Ig deposits, although electron microscopy showed deposits in the glomeruli and along tubular basement membranes. Laser microdissection of glomeruli and mass spectrometry of extracted peptides showed a large spectra number for IgD, and immunohistochemistry showed intense glomerular and tubular staining for IgD. Together, these findings are consistent with IgD deposition disease. Bone marrow biopsy analysis showed 5% plasma cells, which stained for IgD. The patient was treated with bortezomib and dexamethasone, which resulted in improvement of hematologic parameters but no improvement of renal function. The diagnosis of IgD deposition disease underscores the value of laser microdissection and mass spectrometry in further evaluating renal biopsies when routine assessment fails to reach an accurate diagnosis.     

Mechanisms and consequences of sympathetic hyperactivity in renal disease

Kidney impairment of different origins can lead within a short time to structural and functional maladaptations of the kidney, which may culminate in end-stage renal failure. The most common causes of chronic renal failure are due to hypertensive and diabetic renal impairment [Moore et al. 1999, Ritz et al. 1999]. Moreover, an inadequate blood pressure control in primary renal diseases further accelerates the decline of renal function. In spite of improved therapeutic measures the number of patients with chronic renal failure continues to increase dramatically [Mailloux and Haley 1998]. Cardiovascular morbidity and mortality in patients with chronic renal failure are extraordinarily high and are more frequent than that observed in the general population [Vita et al. 1999]. Measures, which can reduce the high incidence of cardiovascular complications, have priority in the treatment of chronic renal failure patients. ACE-inhibitors have been shown to be the best choice in this case. Until now a possible role for sympathetic hyperactivity has not been seriously considered although there is very good clinical and experimental evidence for such a role. This overview will give a summary of the currently known experimental and clinical findings about the role of the sympathetic nervous system in hypertension and renal disease and to expound possible therapeutic strategies.     

Glomerulonephritis with organized immunoglobulin deposits

Glomerulonephritis with organized immunoglobulin deposits are heterogeneous and may be encountered in a variety of renal disorders. It is particularly important to determine the exact types of immunoglobulin deposited and their monotypy/monoclonality, using specific anti-light chain conjugates and in some instances, anti-heavy chain subclass conjugates. The histologic pattern and identification of monotypic Ig deposits in renal tissue are in some cases sufficient for the diagnosis of AL amyloidosis, type I cryoglobulinic glomerulonephritis or "Randall-type" monoclonal immunoglobulin deposition disease (MIDD). Electron microscopy is particularly valuable for the precise localization of Ig deposits and for determing the pattern of deposition: organized, homogeneous (non-organized or granular) or mixed. New entities in the broad spectrum of Ig deposition diseases are emerging from electron microscopy studies of renal diseases. We propose here a comprehensive classification for diseases featuring the organized deposition in tissues of Ig.     

Monoclonal gammopathy of renal significance with light‐chain deposition disease diagnosed postrenal transplant: a diagnostic and therapeutic challenge

Patients with light‐chain deposition disease (LCDD) frequently do not meet criteria for myeloma. In such cases, despite low tumor burden, the circulating monoclonal immunoglobulins cause renal damage, are responsible for post‐transplant recurrence, and are rightly categorized as monoclonal gammopathy of renal significance (MGRS) requiring chemotherapy. A 65‐year male with uncharacterized nodular glomerulopathy presented with proteinuria 3 years postrenal transplant. His allograft biopsies were diagnostic of light‐chain deposition disease (likely recurrent), and in the absence of myeloma, he was labeled as MGRS. Based on the limited literature available, he was treated with bortezomib which resulted in normalization of serum‐free light‐chain ratios and resolution of proteinuria. He, however, later succumbed to complications of chemotherapy. This case highlights the diagnostic difficulties in LCDD, the importance of an accurate pretransplant diagnosis, and treatment of the malignant clone, in the absence of which post‐transplant management of recurrence is challenging with poor outcomes.     

Pulmonary light chain deposition disease: report of five cases and review of the literature

Light chain deposition disease (LCDD) in the lung is a rare occurrence. We describe 5 new cases of this entity, review the literature, and compare pulmonary light chain deposits to pulmonary amyloidosis. In addition, we identified 17 patients with pulmonary LCDD in the literature with sufficient clinical information to allow evaluation of clinical presentation, laboratory findings, histologic appearance, and disease progression. In these 22 patients, 2 different histologic patterns were appreciated: diffuse and nodular. A parallel with the diffuse and nodular forms of pulmonary amyloidosis is suggested. The 10 patients with nodular LCDD had an overall better prognosis compared with the 12 patients with diffuse pulmonary LCDD. However, when compared to what is reported in the literature for nodular pulmonary amyloidosis, the patients with nodular LCDD had a higher incidence of an associated lymphoproliferative and/or plasma cell dyscrasia and renal failure. Light chain deposits in the lung are histologically similar to amyloid but are not Congophilic. Their electron microscopic appearance is distinctly different with fibrils in amyloid and granular deposits in LCDD. As the diffuse forms of LCDD and amyloidosis have a similarly poor prognosis, differentiating the 2 entities is probably not critical. However, when present as nodules, LCDD is more frequently associated with an underlying plasma cell dyscrasia or renal failure than is amyloidosis, and therefore the distinction may be clinically important.     

Recurrence from primary and secondary glomerulopathy after renal transplant

Glomerulonephritis is the primary cause of end-stage renal failure in 30-50% of kidney transplant recipients and recurrence of the initial disease is an important determinant of long-term graft outcome after transplantation. Although renal transplantation remains the best treatment option for patients with end stage renal diseases in most cases, diagnosis and management of recurrences of glomerulopathies are critical for the optimization and improvement of long-term kidney transplant graft survival and provide a unique opportunity to explore the pathogenesis of native kidney disease. This review aims to update knowledge for a large panel of recurrent primary and secondary glomerulonephritis after kidney transplantation, excluding diabetic nephropathy including primary focal and segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, membranoproliferative glomerulonephritis, lupus, vasculitis but also less usual secondary nephropathy related to sarcoidosis, AA and AL amyloidosis, monoclonal immunoglobulin deposition disease, and fibrillary glomerulonephritis.     

Heavy chain deposition disease: an overview

Heavy chain deposition disease (HCDD) is one of three entities of monoclonal immunoglobulin deposition disease, characterized histopathologically by the presence of nodular glomerulosclerosis and glomerular and tubular deposition of monoclonal heavy chains without associated light chains. Although HCDD is an extremely rare disease, >30 cases have been reported to date in the literature. Of these cases, only three cases have been reported in Japan. The majority of the patients presents with nephrotic syndrome, hematuria, and hypertension, and develop progressive renal failure with or without the complication of multiple myeloma. Some cases have been treated successfully using chemotherapy. Because of its rarity, a thorough understanding of HCDD is essential for both accurate diagnosis and adequate subsequent treatment.     

The ultrastructural basis of renal pathology in monoclonal gammopathies

The kidney is frequently involved in the course of monoclonal gammopathies (MG). Renal involvement presents different clinical-morphological patterns, which can occur either at the onset or in a late phase of the hematological disease, as well as after chemotherapy. The reasons for the organ tropism of monoclonal immunoglobulins (Igs) are still unknown. Currently, it is well known that some primary structure alterations in monoclonal Igs and/or in their segments correlate to nephrotoxicity. On the other hand, it is impossible to predict the pathogenicity and the clinical manifestations induced by a specific monoclonal Ig based on its specific conformational modifications. Pathogenicity and organ tropism are probably complex phenomena, which involve specific protein factors, patient factors, target organ characteristics and monoclonal plasmacellular mass entities. However, aminoacidic sequence analysis of nephrotoxic Igs and some recent in vitro studies have allowed two different monoclonal light chain (LC) types to be distinguished. Glomerulopathic LCs (G-LCs) in the mesangium recognize their target structure and induce two distinct mesangiopathies, monoclonal Ig deposition disease (MIDD) and AL-amyloidosis (AL). Tubulopathic LCs (T-LCs) act on the proximal or on the distal tubule and cause, respectively, Fanconi syndrome (FS) and cast nephropathy. Pathogenic monoclonal Igs have the propensity to deposit in different renal parenchymal structures in extracellular sites, because of the transformation of soluble precursors in insoluble products. Evidence suggests that somatic mutations can destabilize the normal LCs globular soluble structure and this could be the major driving force for precipitation. Based on these features, MG can be classified as conformational and depositional diseases. Electronmicroscopy (EM) analysis of renal biopsies in MG patients with glomerular diseases distinguishes two morphological aspects. MIDD and a recently identified entity named proliferative glomerulonephritis (GN) with monoclonal IgG deposits are both characterized by non-organized granular electrondense deposits. AL, immunotactoid (IT) glomerulopathy and monoclonal cryoglobulinemia are, instead, characterized by organized deposits such as fibrils or microtubules. Tubular diseases in MG patients produce two different histological patterns. In FS, monoclonal Igs form crystals in the renal interstitium able to induce a local intense flogosis, while in cast nephropathy monoclonal Igs precipitate with Tamm-Horsfall protein (THP) in the proximal tubular lumen and induce tubular obstruction. The different morphological aspects are unrelated to specific clinical manifestations, while renal biopsy can diagnose different entities that can respond to different therapeutical schedules. This reveals the importance of the renal biopsy in the clinical management of the renal pathology in plasma cells dyscrasias, mainly when supported by the most advanced techniques of immunoelectronmicroscopy and polymerase chain reaction (PCR)-mediated analysis. Further elucidation of the molecular events involved in the pathogenesis of the different forms of renal damage is needed to design new and more effective therapeutical strategies. In particular, urinary proteomics seem to be promising in this setting.     

Multiple myeloma-associated cast nephropathy with crystal structure: case report and review of the literature

The causes of renal failure are diverse. Among them, monoclonal gammopathy is one important but easily-missed cause in aged people. Monoclonal gammopathy may produce a large number of abnormal immunoglobulins and/or fragments and produce different kinds of deposition in tissues, including cast, crystal, fibril and granules. Cast nephropathy is considered the hallmark of the renal disease in patients with multiple myeloma. Crystaglobulinemia syndrome and crystal nephropathy, on the other hand, have been rarely reported. Herein, we report a case of multiple myeloma presented with irreversible renal failure. The biopsy showed massive crystal deposition in bone marrow and kidneys.     

Early initiation of dialysis fails to prolong survival in patients with end-stage renal failure

Sir, We write to express our concern about a letter recently publishedin NDT by Van Biesen et al. [1]. In this letter regarding initiationof dialysis, attention was drawn to our recent paper on thissubject [2]. In our study, we concluded that starting dialysisfor end-stage renal failure based on patients’ symptomsrather than level of renal function did not disadvantage thesepatients in terms of survival. Van Biesen et al. made two specific     

Long-term follow-up and response to chemotherapy in patients with light-chain deposition disease.

Nineteen patients with light-chain deposition disease (LCDD) were studied retrospectively. This report presents data on long-term patient and renal survival and the response to intermittent administration of melphalan and prednisone. Immunoelectrophoresis or immunofixation demonstrated a monoclonal protein in the serum of 78% and in the urine of 84% of the patients; 16% had no demonstrable monoclonal protein in serum or urine. The median age at presentation was 51 years (range, 37 to 77 years). Twelve (63%) of the patients had a monoclonal protein of undetermined significance without evidence of myeloma. The typical glomerular lesion was a diffuse mesangial nodular lesion that was positive for periodic acid-Schiff (PAS) stain with acute and chronic tubulointerstitial changes. Fifteen patients had kappa light-chain deposition and four had lambda light-chain deposition. Five-year actuarial patient survival and survival free of end-stage renal disease were 70% and 37%, respectively. Seventeen patients received melphalan and prednisone, and one patient received chlorambucil and prednisone. All of the patients had some impairment of renal function at presentation, and 58% had a serum creatinine concentration greater than 354 mumol/L (4.0 mg/dL). There was either stabilization or improvement in renal function after chemotherapy in five of eight patients who had a serum creatinine concentration less than 354 mumol/L (4.0 mg/dL) at the initiation of therapy. Of the 11 patients with a high serum creatinine concentration (greater than 354 mumol/dL [4.0 mg/dL]), 82% progressed to end-stage renal disease despite therapy. Follow-up urine protein studies demonstrated at least a 50% decrease in urine protein excretion in five of 15 patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Living Donor Kidney and Autologous Stem Cell Transplantation for Primary Systemic Amyloidosis (AL) with Predominant Renal Involvement

Primary systemic amyloidosis (AL) is characterized by multiorgan deposition of monoclonal immunoglobulin light chain. Renal involvement is common and impaired kidney function is associated with reduced median survival. Autologous stem cell transplantation (SCT) for AL achieves superior response rates compared to chemotherapy alone but patients with end-stage renal disease (ESRD) may be excluded from consideration. A treatment approach consisting of living donor kidney transplantation (LDKTx) followed by autologous SCT was developed for AL with ESRD. Eight patients underwent LDKTx with immediate graft function. Two suffered unanticipated complications post-KTx and died 10 and 3 months later. Two cases of subclinical acute cellular rejection (ACR) and one case of clinical ACR occurred--all reversible with corticosteroid. Six patients had successful stem cell harvests performed and five of these underwent SCT with satisfactory trilineage engraftment. Renal function remained stable following SCT in four and was reduced in one due to infectious and bleeding complications. One patient, who has thus far elected not to undergo SCT, has proteinuria and histologic evidence of recurrent renal amyloidosis. This experience supports the feasibility of sequential living donor KTx and autologous SCT for carefully selected patients with ESRD due to AL.     

Resolution of mesangial light chain deposits 3 years after high-dose melphalan with autologous peripheral blood stem cell transplantation

A 52-year-old woman was admitted to our hospital for treatment of nephrotic syndrome. Funduscopic findings showed fundal hemorrhage and soft exudates, and serologic analysis showed a monoclonal serum component that was identified as Bence Jones protein-k type. A bone marrow biopsy showed diffuse proliferation of atypical plasma cells, while a renal biopsy showed diffuse and nodular mesangial proliferation. Immunohistochemical staining confirmed the presence of k chains along the glomerular basement membrane and in mesangial areas. The patient was diagnosed as multiple myeloma (Bence Jones k type) with light chain deposition disease (LCDD). After high-dose melphalan and autologous peripheral blood stem cell transplantation (PBSCT), the multiple myeloma and nephrotic syndrome were in complete remission; her renal function was improved, but a renal biopsy performed 6 months after PBSCT showed the persistence of diffuse and nodular lesions. By contrast, a renal biopsy performed 3 years later showed complete resolution of the diffuse and nodular mesangial proliferation.