The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group

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Abstract

The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly, the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally, bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently, this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS.

Abstract

This Expert Consensus Document from the International Kidney and Monoclonal Gammopathy Research Group includes an updated definition of monoclonal gammopathy of renal significance (MGRS) and recommendations for the use of kidney biopsy and other modalities for evaluating suspected MGRS

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MYD88 L265P somatic mutation in Waldenström's macroglobulinemia.

Steven P Treon, Lian Xu, Guang Yang … (2012)

Waldenström's macroglobulinemia is an incurable, IgM-secreting lymphoplasmacytic lymphoma (LPL). The underlying mutation in this disorder has not been delineated. We performed whole-genome sequencing of bone marrow LPL cells in 30 patients with Waldenström's macroglobulinemia, with paired normal-tissue and tumor-tissue sequencing in 10 patients. Sanger sequencing was used to validate the findings in samples from an expanded cohort of patients with LPL, those with other B-cell disorders that have some of the same features as LPL, and healthy donors. Among the patients with Waldenström's macroglobulinemia, a somatic variant (T→C) in LPL cells was identified at position 38182641 at 3p22.2 in the samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This variant predicted an amino acid change (L265P) in MYD88, a mutation that triggers IRAK-mediated NF-κB signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenström's macroglobulinemia and in 3 of 3 patients with non-IgM-secreting LPL (91% of all patients with LPL). MYD88 L265P was absent in paired normal tissue samples from patients with Waldenström's macroglobulinemia or non-IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance. Inhibition of MYD88 signaling reduced IκBα and NF-κB p65 phosphorylation, as well as NF-κB nuclear staining, in Waldenström's macroglobulinemia cells expressing MYD88 L265P. Somatic variants in ARID1A in 5 of 30 patients (17%), leading to a premature stop or frameshift, were also identified and were associated with an increased disease burden. In addition, 2 of 3 patients with Waldenström's macroglobulinemia who had wild-type MYD88 had somatic variants in MLL2. MYD88 L265P is a commonly recurring mutation in patients with Waldenström's macroglobulinemia that can be useful in differentiating Waldenström's macroglobulinemia and non-IgM LPL from B-cell disorders that have some of the same features. (Funded by the Peter and Helen Bing Foundation and others.).

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Proliferative glomerulonephritis with monoclonal IgG deposits.

G. Markowitz, D A Valeri, Anjali Satoskar … (2009)

Dysproteinemias that result in monoclonal glomerular deposits of IgG are relatively uncommon. Here, we report the largest series of proliferative glomerulonephritis with monoclonal IgG deposits, a form of renal involvement by monoclonal gammopathy that mimics immune-complex glomerulonephritis. We retrospectively identified 37 patients, most of whom were white (81%), female (62%), or older than 50 yr (65%). At presentation, 49% had nephrotic syndrome, 68% had renal insufficiency, and 77% had hematuria. In 30% of the patients, we identified a monoclonal serum protein with the same heavy- and light-chain isotypes as the glomerular deposits (mostly IgG1 or IgG2), but only one patient had myeloma. Histologic patterns were predominantly membranoproliferative (57%) or endocapillary proliferative (35%) with membranous features. Electron microscopy revealed granular, nonorganized deposits, and immunofluorescence demonstrated glomerular deposits that stained for a single light-chain isotype and a single heavy-chain subtype, most commonly IgG3kappa (53%). During an average of 30.3 mo of follow-up for 32 patients with available data, 38% had complete or partial recovery, 38% had persistent renal dysfunction, and 22% progressed to ESRD. Correlates of ESRD on univariate analysis were higher creatinine at biopsy, percentage of glomerulosclerosis, and degree of interstitial fibrosis but not immunomodulatory treatment or presence of a monoclonal spike. On multivariate analysis, higher percentage of glomerulosclerosis was the only independent predictor of ESRD. Only one patient lacking a monoclonal spike at presentation subsequently developed a monoclonal spike and no patient with a monoclonal spike at presentation subsequently developed a hematologic malignancy. We conclude that proliferative glomerulonephritis with monoclonal IgG deposits does not seem to be a precursor of myeloma in the vast majority of patients.

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Primary systemic amyloidosis: clinical and laboratory features in 474 cases.

R A Kyle, M A Gertz (1995)

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Author and article information

Contributors

Nelson Leung:

ORCID: http://orcid.org/0000-0002-5651-1411

leung.nelson@mayo.edu

Journal

Journal ID (nlm-ta): Nat Rev Nephrol

Journal ID (iso-abbrev): Nat Rev Nephrol

Title: Nature Reviews. Nephrology

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1759-5061

ISSN (Electronic): 1759-507X

Publication date (Electronic): 3 December 2018

Publication date PMC-release: 3 December 2018

Publication date (Print): 2019

Volume: 15

Issue: 1

Pages: 45-59

Affiliations

[1 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Division of Nephrology, Hematology, Department of Laboratory Medicine and Pathology, Mayo Clinic, ; Rochester, MN USA

[2 ]ISNI 0000 0000 9336 4276, GRID grid.411162.1, Department of Nephrology, , Centre Hospitalier Universitaire et Université de Poitiers, Poitiers, France; CNRS UMR7276, Limoges, France; and Centre de Référence Amylose AL et Autres Maladies par Dépôt d’Immunoglobulines Monoclonales, ; Poitiers, France

[3 ]ISNI 0000 0001 2217 8588, GRID grid.265219.b, Veterans Administration Medical Center, New Orleans, LA, , USA and Tulane University Medical School, ; Tulane, LA USA

[4 ]ISNI 0000 0001 0705 4923, GRID grid.413629.b, Centre for Haematology, Department of Medicine, , Imperial College London and Imperial College Healthcare NHS Trust, Hammersmith Hospital, ; London, UK

[5 ]ISNI 0000 0001 2177 007X, GRID grid.415490.d, Department of Nephrology, Renal Medicine — University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, ; Birmingham, UK

[6 ]ISNI 0000000419368729, GRID grid.21729.3f, Department of Pathology, Renal Pathology Laboratory, , Columbia University, College of Physicians and Surgeons, ; New York, NY USA

[7 ]ISNI 0000 0001 2300 6614, GRID grid.413328.f, Department of Haematology and Immunology, , University Hospital St Louis, ; Paris, France

[8 ]ISNI 0000 0004 1936 7857, GRID grid.1002.3, The Victorian and Tasmanian Amyloidosis Service, Department of Haematology, Monash Univerity Easter Health Clinical School, ; Melbourne, Victoria Australia

[9 ]ISNI 0000000121901201, GRID grid.83440.3b, National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, , University College London, ; London, UK

[10 ]ISNI 0000 0004 0443 6864, GRID grid.411417.6, Department of Pathology and Translational Pathobiology, , Louisiana State University Health Sciences Center, ; Shreveport, LA USA

[11 ]ISNI 0000 0001 1486 4131, GRID grid.411178.a, Service d’Hématologie et de Thérapie Cellulaire, Centre de Référence des Amyloses Primitives et des Autres Maladies par Dépôts d’Immunoglobuline, CHU Limoges, ; Limoges, France

[12 ]ISNI 0000 0001 2155 0800, GRID grid.5216.0, Department of Clinical Therapeutics, , School of Medicine National and Kapodistrian University of Athens Alexandra Hospital, ; Athens, Greece

[13 ]ISNI 0000 0001 2150 066X, GRID grid.415224.4, University Health Network, Princess Margaret Cancer Centre, ; Toronto, Canada

[14 ]Arkana Laboratories, Little Rock, AR USA

[15 ]ISNI 0000 0004 0524 3028, GRID grid.417109.a, Wilhelminen Cancer Research Institute, Wilhelminenspital, ; Vienna, Austria

[16 ]ISNI 0000 0004 1762 5736, GRID grid.8982.b, Amyloidosis Research and Treatment Center, IRCCS Policlinico San Matteo, , University of Pavia, ; Pavia, Italy

[17 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, Haematology Department, Princess Alexandra Hospital and School of Medicine, , University of Queensland, ; Brisbane, Australia

[18 ]ISNI 0000 0001 2215 0876, GRID grid.411451.4, Department of Pathology, , Loyola University Medical Center, ; Maywood, IL USA

[19 ]ISNI 0000 0001 2292 3357, GRID grid.14848.31, Department of Pathology, Hôpital Maisonneuve-Rosemont, , Université de Montreal, Montreal, ; Quebec, Canada

[20 ]ISNI 0000000106344187, GRID grid.265892.2, Department of Medicine, , University of Alabama at Birmingham and Department of Veterans Affairs Medical Center, ; Birmingham, AL USA

[21 ]GRID grid.17089.37, Cross Cancer Institute, , University of Alberta, ; Edmonton, Alberta Canada

[22 ]GRID grid.468189.a, Department of Hematologic Oncology and Blood Disorders, , Levine Cancer Institute, Atrium System, ; Charlotte, NC USA

[23 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Abramson Cancer Center, , University of Pennsylvania, Perelman School of Medicine, ; Philadelphia, PA USA

Author information

Nelson Leung http://orcid.org/0000-0002-5651-1411

Paul W. Sanders http://orcid.org/0000-0002-2915-5714

Sanjeev Sethi http://orcid.org/0000-0002-4536-7709

Article

Publisher ID: 77

DOI: 10.1038/s41581-018-0077-4

PMC ID: 7136169

PubMed ID: 30510265

SO-VID: 41ebafb5-72d2-483f-b2ab-cebbabe66f50

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Keywords: renal cancer,oncogenesis,nephritis,kidney,pathology

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Keywords: renal cancer, oncogenesis, nephritis, kidney, pathology

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The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group

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Most cited references 117

MYD88 L265P somatic mutation in Waldenström's macroglobulinemia.

Proliferative glomerulonephritis with monoclonal IgG deposits.

Primary systemic amyloidosis: clinical and laboratory features in 474 cases.

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Cited by 203

Most referenced authors 1,735