Monoclonal Ig Deposition Disease Research Articles

Proteomic Analysis of Complement Proteins in Glomerular Diseases

Complement plays an important role in the pathogenesis of glomerulonephritis (GN). Even though the underlying etiology of GN might be different, complement activation with subsequent glomerular deposition of complement proteins result in glomerular injury and progression of the lesions. Routine immunofluorescence microscopy (IF) includes staining for only complement factors C3c and C1q. Therefore, with regard to evaluation of the complement pathways, routine kidney biopsy provides only limited information. In this study, using laser microdissection of glomeruli followed by mass spectrometry, complement proteins and pathways involved in GN were analyzed. We found that C3 followed by C9 are the most abundant complement proteins in GN, indicating activation of classical or lectin or alternative, and terminal pathways, either exclusively or in a combination of pathways. Furthermore, depending on the type of GN, C4A and/or C4B were also present. Therefore, membranous nephropathy (MN), fibrillary GN, and infection-related GN showed C4A dominant pathways, whereas lupus nephritis (LN), proliferative GN with monoclonal Ig deposits, monoclonal Ig deposition disease (MIDD), and immunotactoid glomerulopathy showed C4B dominant pathways. Significant deposition of complement regulatory proteins, factor H-related protein-1 (FHR-1) and factor H-related protein-5 (FHR-5), were also detected in most GN. This study shows accumulation of specific complement proteins in GN. The complement pathways, complement proteins, and the amount of complement protein deposition are variable in different types of GN. Selective targeting of complement pathways may be a novel option in the treatment of GN.

Paraproteinämien und Nierenbeteiligung

Renal manifestations in patients with monoclonal paraproteinemia are frequent. Cast nephropathy is a disease that only occurs in manifest multiple myeloma with a high tumor burden. In contrast, monoclonal gammopathy of renal significance (MGRS) is defined as renal involvement due to a nephrotoxic clone that from a hematological standpoint would per se not require treatment. The diagnosis of MGRS can only be made by renal biopsy. Here monotypic immunoglobulin (Ig) deposits can be found in either organized (amyloidosis, fibrillary glomerulonephritis, GN, immunotactoid GN, cryoglobulinemic GN) or nonorganized forms (monoclonal Ig deposition disease, proliferative GN with monoclonal Ig deposits). There are two forms of MGRS that can occur without the deposition of Ig, namely C3 glomerulopathy and thrombotic microangiopathy. For cast nephropathy there is always a fundamental indication for chemotherapy. The data on mechanical elimination of light chains by plasmapheresis or high cut-off dialysis are inconsistent. In patients with MGRS the indications for treatment must be made based on the renal prognosis in a cooperation between nephrologists and hematologists. Only a clone-directed treatment can lead to an improvement of renal function.

Kidney Histopathologic Spectrum and Clinical Indicators Associated with MGRS.

Patients with monoclonal gammopathy and concomitant kidney diseases are frequently found in clinical practice. Some of them are diagnosed with monoclonal gammopathy of renal significance (MGRS) due to the presence of monoclonal Ig-related kidney injuries. This study aimed to investigate the histopathologic spectrum and clinical characteristics associated with MGRS in a large cohort of patients with monoclonal gammopathy and biopsy-proven kidney diseases from a single Chinese nephrology referral center. Patients who presented with monoclonal gammopathy (monoclonal spike on serum and/or urine immunofixation tests) and underwent kidney biopsy in the Peking University First Hospital from January 1, 1999 to December 31, 2020 were enrolled in this retrospective study. Patients with malignant hematologic diseases were excluded. Clinical and laboratory data were collected from the electronic medical record system. Comparisons of patients with and without MGRS and with and without amyloidosis were performed. The clinical characteristics associated with MGRS were identified using multivariable logistic regression. A total of 700 patients with monoclonal gammopathy and kidney biopsy were identified. Thirteen patients with repeat kidney biopsies were analyzed separately. For the remaining 687 patients with one kidney biopsy, 261 patients (38%) had MGRS lesions, and the rest (426 patients, 62%) had non-MGRS kidney diseases. Ig-related amyloidosis accounted for the most MGRS cases (n=164, 63%), followed by monoclonal Ig deposition disease (n=23, 9%) and thrombotic microangiopathy (n=22, 8%). In the non-MGRS group, membranous nephropathy was the most common diagnosis (n=171, 40%). In the multivariable logistic regression model, the presence of abnormal serum free light chain ratio, older age, and greater proteinuria were independently associated with MGRS. Monoclonal Ig amyloidosis is the leading cause of MGRS in Chinese patients with monoclonal gammopathy. The presence of abnormal free light chain ratio, older age, and greater proteinuria were associated with MGRS.

Multiple Myeloma as a rare cause of membranoproliferative glomerular nephritis

Multiple myeloma (MM) is a relatively uncommon cancer characterized by the neoplastic proliferation of plasma cells producing a monoclonal immunoglobulin(Ig). Renal failure in multiple myeloma is around 48% and it may be the presenting manifestation of MM.[1] Renal involvement is multifactorial including light chain cast nephropathy amyloidosis, monoclonal Ig deposition disease and less frequently cryoglobulinaemic glomerulonephritis and proliferative glomerulonephritis.[2-5] Hence membrano proliferative glomerulonephritis (MPGN) is a rare form in MM. Here we report a case of multiple myeloma with MPGN in a 60-year-old male who succumbed to death while on chemotherapy.

The histopathological spectrum of kidney biopsies in patients with thymoma and myasthenia gravis: a report of 24 biopsies from a single institution.

BackgroundNephropathy in patients with thymic diseases such as thymoma and myasthenia gravis (MG) is rare and has been described mostly as isolated case reports. Here we evaluate a series of kidney biopsies from patients with thymoma and/or MG from a single institution in order to better define the spectrum and relative frequencies of thymic disease–associated nephropathies.MethodsWe conducted a retrospective case series study of 32 462 native kidney biopsies from January 2005 through December 2019 at Cedars-Sinai Medical Center, Los Angeles, CA, USA.ResultsTwenty-four biopsy specimens (0.07%) from patients with a history of thymoma and/or MG were identified. Two patients had repeat biopsies. The most common pathologic diagnosis that could be immunologically attributed to thymic disease was minimal change disease (MCD; 45%), followed by tubulointerstitial nephritis (TIN; 14%), immune complex (IC)-mediated glomerulonephritis (9%), membranous nephropathy (5%) and immunoglobulin A (IgA) nephropathy (5%). Interestingly, 50% of the MCD and 67% of TIN cases concomitantly showed mild IgG-dominant IC deposition in mesangial areas and/or in tubular basement membranes. In the two patients with repeat biopsies, mild mesangial IC deposition developed in the MCD patient but disappeared in the TIN patient with the second biopsy. Pathologic diagnoses unlikely related to the underlying thymic disease were diabetic glomerulosclerosis (9%), acute tubular necrosis (9%) and monoclonal Ig deposition disease (5%).ConclusionsThymic disease is associated with a wide spectrum of kidney diseases affecting the glomerular and tubulointerstitial compartments, often with low-grade IC deposition. These findings suggest a role of immunologic dysregulation in the pathogenesis of thymic disease–associated nephropathy.

The Role of Kidney Transplantation in Monoclonal Ig Deposition Disease

IntroductionMonoclonal Ig deposition disease (MIDD) frequently leads to kidney failure, and a large proportion of these patients would greatly benefit from kidney transplantation. However, data on kidney transplantation outcomes in MIDD are limited.MethodsThis was a retrospective analysis of long-term renal outcomes of 23 patients with MIDD, including 6 patients who underwent kidney transplantation.ResultsThe 1-, 5-, and 10-year overall survival (OS) from diagnosis were 95%, 78%, and 65%, respectively. Approximately half of the patients (n = 12) progressed to end-stage renal disease (ESRD) with a median time from diagnosis to ESRD of 3.4 years. The 1-, 5-, and 10-year renal survival from diagnosis were 77%, 48%, and 29% respectively. Renal response was observed only in 5 patients (22%), all of them after achieving hematologic complete response. Median OS from diagnosis was significantly better for those who underwent kidney transplantation versus those who remained on dialysis (19.8 years vs. 8.3 years, P = 0.016). Among patients who underwent kidney transplantation, the shortest survival from MIDD diagnosis was 13.7 years and the longest was 27.8 years. Of the 3 patients with kidney transplants who died, the time from the first kidney transplantation to death was 7.4, 18.8, and 20.4 years. Graft loss due to disease recurrence occurred at 4 months and 3.8 years after kidney transplantation in 2 patients who either were not treated or did not respond to treatment.ConclusionAs treatments for MIDD have dramatically improved, more patients are achieving sustained hematologic responses with longer patient and graft survival after kidney transplantation.

Rapidly progressive immunoglobulin M monoclonal gammopathy presenting with nephrotic syndrome and hepatic failure

We report a 73-year-old male with no relevant past medical history who presented with nephrotic syndrome and jaundice. Subsequent studies revealed immunoglobulinM (IgM) monoclonal gammopathy. Kidney biopsy revealed monoclonal Ig deposition disease and amyloidosis. Bone marrow biopsy demonstrated <10% infiltration by lymphoplasmacytic cells. However, rapidly progressive hypergammaglobulinemia of IgM and hyperbilirubinemia were noted. Despite aggressive treatment, the patient developed acute kidney injury and complications of hepatic failure. He eventually died of pneumonia, just two months after diagnosis.

Standardized classification and reporting of glomerulonephritis

A kidney biopsy is done to determine the etiology of the glomerulonephritis (GN) and the severity of the lesion, to identify whether other lesions, related to or not related to the GN, are present on the kidney biopsy and finally to ascertain the extent of chronicity of the GN. The etiology of GN is based on the classification of GN into five groups: immune complex-mediated GN, antineutrophil cytoplasmic antibody (ANCA)-associated GN, anti-glomerular basement membrane (GBM) GN, monoclonal immunoglobulin-mediated GN and C3 glomerulopathy. Immune complex GN includes multiple specific diseases such as lupus nephritis, IgA nephropathy, infection-related GN and fibrillary GN. ANCA GN, anti-GBM GN and C3 glomerulopathy are specific diseases in themselves, while monoclonal Ig GN includes proliferative GN with monoclonal Ig deposits and monoclonal Ig deposition disease. Thus identification of the class of GN and within it the specific disease determines the etiology of GN. Ancillary studies may be required to confirm the etiology of GN. The severity of the GN is revealed by the pattern of injury, such as crescentic, necrotizing, diffuse proliferative, exudative, membranoproliferative, mesangial proliferative or a sclerosing GN. Secondary diagnosis either related or unrelated to the GN, such as diabetic glomerulosclerosis, acute tubular necrosis or thrombotic microangiopathy, may also be present. The secondary diagnosis may sometimes be the reason for the kidney biopsy. The chronicity of GN is determined by evaluating the extent of glomerulosclerosis, tubular atrophy and interstitial fibrosis and vascular sclerosis present on the biopsy. This review summarizes the approach to standardizing a kidney biopsy report that includes these components in a logical and sequential manner. Translation by D.A. Mayer, T.O. Muzhetckaya, A.O. Mukhametdinova, M.S. Khrabrova.

Standardized classification and reporting of glomerulonephritis.

A kidney biopsy is done to determine the etiology of the glomerulonephritis (GN) and the severity of the lesion, to identify whether other lesions, related to or not related to the GN, are present on the kidney biopsy and finally to ascertain the extent of chronicity of the GN. The etiology of GN is based on the classification of GN into five groups: immune complex-mediated GN, antineutrophil cytoplasmic antibody (ANCA)-associated GN, anti-glomerular basement membrane (GBM) GN, monoclonal immunoglobulin-mediated GN and C3 glomerulopathy. Immune complex GN includes multiple specific diseases such as lupus nephritis, IgA nephropathy, infection-related GN and fibrillary GN. ANCA GN, anti-GBM GN and C3 glomerulopathy are specific diseases in themselves, while monoclonal Ig GN includes proliferative GN with monoclonal Ig deposits and monoclonal Ig deposition disease. Thus identification of the class of GN and within it the specific disease determines the etiology of GN. Ancillary studies may be required to confirm the etiology of GN. The severity of the GN is revealed by the pattern of injury, such as crescentic, necrotizing, diffuse proliferative, exudative, membranoproliferative, mesangial proliferative or a sclerosing GN. Secondary diagnosis either related or unrelated to the GN, such as diabetic glomerulosclerosis, acute tubular necrosis or thrombotic microangiopathy, may also be present. The secondary diagnosis may sometimes be the reason for the kidney biopsy. The chronicity of GN is determined by evaluating the extent of glomerulosclerosis, tubular atrophy and interstitial fibrosis and vascular sclerosis present on the biopsy. This review summarizes the approach to standardizing a kidney biopsy report that includes these components in a logical and sequential manner.

Dysproteinemias and Glomerular Disease.

Dysproteinemia is characterized by the overproduction of an Ig by clonal expansion of cells from the B cell lineage. The resultant monoclonal protein can be composed of the entire Ig or its components. Monoclonal proteins are increasingly recognized as a contributor to kidney disease. They can cause injury in all areas of the kidney, including the glomerular, tubular, and vascular compartments. In the glomerulus, the major mechanism of injury is deposition. Examples of this include Ig amyloidosis, monoclonal Ig deposition disease, immunotactoid glomerulopathy, and cryoglobulinemic GN specifically from types 1 and 2 cryoglobulins. Mechanisms that do not involve Ig deposition include the activation of the complement system, which causes complement deposition in C3 glomerulopathy, and cytokines/growth factors as seen in thrombotic microangiopathy and precipitation, which is involved with cryoglobulinemia. It is important to recognize that nephrotoxic monoclonal proteins can be produced by clones from any of the B cell lineages and that a malignant state is not required for the development of kidney disease. The nephrotoxic clones that do not meet requirement for a malignant condition are now called monoclonal gammopathy of renal significance. Whether it is a malignancy or monoclonal gammopathy of renal significance, preservation of renal function requires substantial reduction of the monoclonal protein. With better understanding of the pathogenesis, clone-directed strategies, such as rituximab against CD20 expressing B cell and bortezomib against plasma cell clones, have been used in the treatment of these diseases. These clone-directed therapies been found to be more effective than immunosuppressive regimens used in nonmonoclonal protein-related kidney diseases.

Paraprotein-Related Kidney Disease: Glomerular Diseases Associated with Paraproteinemias.

Paraproteins are monoclonal Igs that accumulate in blood as a result of abnormal excess production. These circulating proteins cause a diversity of kidney disorders that are increasingly being comanaged by nephrologists. In this review, we discuss paraprotein-related diseases that affect the glomerulus. We provide a broad overview of diseases characterized by nonorganized deposits, such as monoclonal Ig deposition disease (MIDD), proliferative GN with monoclonal Ig deposits (PGNMID), and C3 glomerulopathy, as well as those characterized by organized deposits, such as amyloidosis, immunotactoid glomerulopathy, fibrillary GN, and cryoglobulinemic GN, and rarer disorders, such as monoclonal crystalline glomerulopathies, paraprotein-related thrombotic microangiopathies, and membranous-like glomerulopathy with masked IgGκ deposits. This review will provide the nephrologist with an up to date understanding of these entities and highlight the areas of deficit in evidence and future lines of research.

Paraprotein-Related Kidney Disease: Kidney Injury from Paraproteins-What Determines the Site of Injury?

Disorders of plasma and B cells leading to paraproteinemias are associated with a variety of renal diseases. Understanding the mechanisms of injury and associated nephropathies provides a framework that aids clinicians in prompt diagnosis and appropriate adjunctive treatment of these disorders. Glomerular diseases that may be associated with paraproteinemias include amyloid deposition, monoclonal Ig deposition disease, proliferative GN with monoclonal Ig deposits, C3 glomerulopathy caused by alterations in the complement pathway, immunotactoid glomerulopathy, fibrillary GN, and cryoglobulinemia. Tubular lesions include the classic Fanconi syndrome, light-chain proximal tubulopathy, interstitial fibrosis, and cast nephropathy. These paraproteinemic renal diseases are distinct in their pathogenesis as well as their urinary and kidney biopsy findings. Renal pathology is usually initiated by deposition and direct involvement of the intact monoclonal Ig or Ig fragments with resident cells of the nephron. Our review summarizes current insights into the underlying molecular pathogenesis of these interesting kidney lesions.

Pathology after Eculizumab in Dense Deposit Disease and C3 GN

Eculizumab might benefit C3 glomerulopathies mediated by dysregulation of the alternative complement pathway. Here, we report renal biopsy findings before and after eculizumab therapy in three patients with dense deposit disease and two with C3 GN. All pretreatment biopsies had glomerular and tubular basement membrane deposits that stained exclusively for C3 without significant Ig. After 1 year of therapy, there was reduction in active glomerular proliferation and neutrophil infiltration in three of five patients, consistent with effective C5 blockade, which prevents production of chemotactin C5a. One individual with mild mesangial disease had no significant change in activity or chronicity. One patient exhibited persistent activity and worsening chronicity despite therapy. Immunofluorescence showed no significant reduction in C3 or C5b-9, and electron microscopy revealed persistent deposits in all cases, suggesting a long t(1/2) of C5b-9 in extracellular matrix. Normal renal biopsies stained positive for C5b-9 in glomeruli, tubular basement membranes, and vessel walls, albeit at lower intensity than in C3 glomerulopathy. This indication of physiologic levels of C5b-9 activation in normal kidney potentially explains the localization of deposits in patients with dysregulation of the alternative complement pathway. All post-treatment biopsies showed de novo monoclonal staining for IgG-κ in the same distribution as C3 and C5b-9, mimicking monoclonal Ig deposition disease (MIDD). Staining of the γ heavy chain was restricted to the IgG2 and IgG4 subclasses, suggesting the binding of monoclonal eculizumab to C5 in renal tissues. The long-term effects of this apparent drug-tissue interaction are unknown.

Atteintes rénales des dysglobulinémies : avancées diagnostiques et thérapeutiques

Various renal disorders are associated with monoclonal gammopathies, secondary to tissue deposition or precipitation of a monoclonal immunoglobulin (Ig) or a fragment thereof (isolated Ig light chain or heavy chain). They are classified according to the localization of renal lesions, either glomerular or tubular and to the pattern of ultrastructural organization of Ig deposits. Renal disease in monoclonal gammopathies may be isolated, or associated with various systemic symptoms particularly in AL amyloidosis, Randall-type monoclonal Ig deposition disease and monoclonal cryoglobulinemias. Except for myeloma cast nephropathy, which occurs in the setting of high-mass myeloma and is recognized after electrophoretic analysis of proteinuria and AL amyloidosis, which diagnosis is usually made after pathological examination of non-invasive tissue specimens (i.e. abdominal fat or minor salivary glands), a kidney biopsy is required to identify the other types of renal disorders associated with monoclonal gammopathies and to estimate renal prognosis. Renal pathological diagnosis is difficult and relies on careful examination of kidney biopsy samples, by light microscopy, immunofluorescence studies using conjugates specific for Ig light and heavy chains, IgG sub-classes and heavy chain constant domains and by electron microscopy. In some cases, additional studies are required to identify the nature of deposits, such as immuno-electron microscopy or mass spectrometric-based proteomic analysis after laser dissection. In patients with renal disorders related to Ig light chain precipitation or deposition (myeloma cast nephropathy, AL amyloidosis, Randall-type light chain deposition disease), measurement of serum free light chains at baseline and throughout follow-up is mandatory to evaluate clonal response to chemotherapy. A more than or equal to 50% decrease in serum free light chain levels is associated with increased renal and patient survival. In AL amyloidosis, serum levels of markers of cardiac disease (NT-proBNP and troponin) are also closely associated with prognosis. Efficient chemotherapy, tailored to the underlying plasma cell or lymphoproliferative disorder and adapted to renal function, should be promptly introduced, even in the absence of overt malignant haematological disease. Renal prognosis and patient survival (particularly in AL amyloidosis and cast nephropathy) are closely associated with the rapid achievement of an haematological response. The combination of melphalan plus dexamethasone (MDex) is currently used as first-line chemotherapy in systemic AL amyloidosis. Bortezomib-based regimens are commonly employed as first-line treatment in myeloma cast nephropathy and Randall-type monoclonal Ig deposition disease and as second line therapy in AL amyloidosis patients with advanced cardiomyopathy or refractory to previous chemotherapy. Solid organ transplantation (heart and kidney) should be considered in patients with AL amyloidosis or Randall-type monoclonal Ig deposition disease and advanced cardiac or renal failure. Prolonged graft and patient survival may be obtained, providing that recipients do not have other severe organ involvement or symptomatic myeloma and that haematological remission has been achieved with chemotherapy before or after organ transplantation.

Long-term outcome of patients with monoclonal Ig deposition disease treated with high-dose melphalan and stem cell transplantation

Long-term outcome of patients with monoclonal Ig deposition disease treated with high-dose melphalan and stem cell transplantation

High-dose melphalan and auto-SCT in patients with monoclonal Ig deposition disease

The treatment of monoclonal Ig deposition disease (MIDD) is controversial and not standardized. We report our experience with high dose melphalan and auto-SCT (HDM/auto-SCT) in seven patients with MIDD associated with underlying Durie-Salmon stage IB multiple myeloma, including five with light chain deposition disease, one with light and heavy chain deposition disease and one with light chain crystal deposition disease. The median age of these patients was 50 years; six of them were male subjects. A monoclonal kappa-light chain was detected by Serum Free Light Chain Assay in all seven. The patients received melphalan 140 mg/m(2) followed by auto-SCT. All patients are alive and six remain in hematologic CR with a median follow up of 23.6 months (7.9-69.8 months). Renal function has improved compared to pre-HDSM/auto-SCT in five patients--two of whom had a renal transplant and became dialysis independent--remained stable in one and worsened in one leading to hemodialysis despite hematologic CR. Our results corroborate previous experience with HDM/auto-SCT in MIDD and argue in favor of kidney transplantation in patients who achieve hematologic CR after HDM/auto-SCT. Although this approach appears effective, multi-center studies are needed to define the optimal treatment for patients with MIDD.

Dysproteinemia and the kidney.

Dysproteinemia is a clinical state characterized by abnormal, often excessive, synthesis of immunoglobulin (Ig) molecules or subunits. Dysproteinemia results from clonal proliferation of plasma cells or B lymphocytes. The abnormal circulating Ig molecules or subunits (most commonly free light chains) reach the glomerulus via the systemic circulation and are associated with the development of a variety of pathologic lesions within the kidney. Free light chain molecules may pass through the glomerular basement membrane and form casts within distal tubular lumina (myeloma cast nephropathy) or form crystals within the cytoplasm of proximal tubules (light chain Fanconi syndrome). Alternatively, Ig molecules or subunits may form paraprotein tissue deposits and produce an array of pathologic lesions, most commonly amyloidosis and monoclonal Ig deposition disease. The pattern of renal parenchymal disease is determined by the unique properties of the Ig molecule or subunit. Each of the patterns of renal disease is in turn associated with unique, but frequently overlapping, clinical features and outcomes. This review emphasizes the pathologic, clinical, and prognostic differences among the patterns of renal parenchymal disease related to dysproteinemia.

V-domain deposition of lambda Bence Jones protein in the renal tubular epithelial cells in a patient with the adult Fanconi syndrome with myeloma

An extracted Bence Jones lambda protein from a Japanese patient with myeloma-associated Fanconi syndrome was found to contain 5 components, including the dimer and the monomer of the entire light-chain, the dimer and the monomer of the constant domain, and monomer of the variable domain. The entire amino acid sequence of this lambda chain was completed. The protein, containing 5 components, was injected intraperitoneally in C3H mice, 20 mg for 13 days and 200 mg for 3 days. Both groups of CJT mice showed a renal proximal tubular deposition of variable domain fragment of the Bence Jones protein by immunoperoxidase staining. Other control Bence Jones proteins of the lambda type and serum albumin were negative in terms of deposition in the epithelial tubular cells.It is also shown that the proximal tubules of the biopsied kidney from the patient had a deposition of variable domain fragment of Bence Jones protein. Thus, the myeloma-associated Fanconi syndrome could be included in the spectrum of light-chain associated disease or monoclonal Ig deposition disease. This is the first case of lambda type Bence Jones protein with a complete amino acid sequence analysis found in Fanconi syndrome with myeloma, demonstrating the deposition of the variable domain in the proximal tubules of the kidney.