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Kono K, Sawa N, Oba Y, Kikuchi K, Mizuno H, Yamanouchi M, Hasegawa E, Suwabe T, Wake A, Shintani-Domoto Y, Ohashi K, Kametani F, Yazaki M, Wada T, Ubara Y. A case of IgG-type heavy chain amyloidosis with membranous nephropathy-like changes with long-term survival. CEN Case Rep 2025; 14:434-441. [PMID: 40021557 DOI: 10.1007/s13730-025-00982-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 02/14/2025] [Indexed: 03/03/2025] Open
Abstract
We performed a kidney biopsy on a 68-year-old man with 2.6 g/day proteinuria. Immunofluorescence (IF) study showed a positive finding of IgG (IgG1) along the glomerular capillary wall, suggesting membranous nephropathy. However, electron microscopy showed no subepithelial electron dense deposits and amorphous deposits of 8-12 nm fibrillar structure, and positive DFS/Congo red staining confirmed the diagnosis of amyloidosis. Amyloid deposits were localized only in the glomeruli. No overt extrarenal amyloid lesions were identified. Serum and urine were positive for monoclonal IgG-lambda, but IF was negative for kappa and lambda, ruling out AL-amyloidosis. At 75 years of age, he underwent a second kidney biopsy, and the IgG-positive findings at IF became more pronounced, with progressive glomerular sclerosing lesions. A proteomic analysis was performed focusing on the positive IgG finding in IF. The amyloid was proven to be composed of fragments of a heavy chain variable region sequence. AH-amyloidosis was the final diagnosis. He was treated according to the treatment for AL-amyloidosis, but hemodialysis was started at the age of 81, and died at the age of 86. We report a valuable case of AH-amyloidosis with an observed long-term prognosis.
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Affiliation(s)
- Kei Kono
- Department of Pathology, Toranomon Hospital, 2-2-2 Toranomon, Minato-Ku, Tokyo, 105-8470, Japan.
- Department of Human Pathology, Graduate School of Medicine, Tokyo Medical & Dental University, Bunkyo-ku, Tokyo, Japan.
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Minato-Ku, Tokyo, Japan.
| | - Naoki Sawa
- Department of Nephrology, Toranomon Hospital, Minato-Ku, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Minato-Ku, Tokyo, Japan
| | - Yuki Oba
- Department of Nephrology, Toranomon Hospital, Minato-Ku, Tokyo, Japan
| | - Koichi Kikuchi
- Department of Nephrology, Toranomon Hospital, Minato-Ku, Tokyo, Japan
| | - Hiroki Mizuno
- Department of Nephrology, Toranomon Hospital, Minato-Ku, Tokyo, Japan
| | | | - Eiko Hasegawa
- Department of Nephrology, Toranomon Hospital, Minato-Ku, Tokyo, Japan
| | - Tatsuya Suwabe
- Department of Nephrology, Toranomon Hospital, Minato-Ku, Tokyo, Japan
| | - Atsushi Wake
- Department of Hematology, Toranomon Hospital, Minato-Ku, Tokyo, Japan
| | - Yukako Shintani-Domoto
- Department of Diagnostic Pathology, Nippon Medical School Hospital, Bunkyo-ku, Tokyo, Japan
| | - Kenichi Ohashi
- Department of Pathology, Toranomon Hospital, 2-2-2 Toranomon, Minato-Ku, Tokyo, 105-8470, Japan
- Department of Human Pathology, Graduate School of Medicine, Tokyo Medical & Dental University, Bunkyo-ku, Tokyo, Japan
| | - Fuyuki Kametani
- Institute for Biomedical Sciences, Shinshu University, Nagano, Japan
- Tokyo Metropolitan Institute for Medical Science, Setagya-ku, Japan
| | - Masahide Yazaki
- Institute for Biomedical Sciences, Shinshu University, Nagano, Japan
| | - Takehiko Wada
- Department of Nephrology, Toranomon Hospital, Minato-Ku, Tokyo, Japan
| | - Yoshifumi Ubara
- Department of Nephrology, Toranomon Hospital, Minato-Ku, Tokyo, Japan.
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Minato-Ku, Tokyo, Japan.
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Chen B, Wang J, Zang W, Wang C, Li J, Yang R. Renal heavy and light chain amyloidosis: A rare case report. Medicine (Baltimore) 2025; 104:e42325. [PMID: 40295256 PMCID: PMC12039972 DOI: 10.1097/md.0000000000042325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Accepted: 04/15/2025] [Indexed: 04/30/2025] Open
Abstract
RATIONALE Renal heavy and light chain amyloidosis (AHL) is a rare disease primarily diagnosed through renal biopsy. Here, we report a patient with renal AHL. The decision to report this case stems from its rarity. This case provides a reference for the diagnosis and management of this disease. PATIENT CONCERNS A 58-year-old man was admitted to the nephrology department in May 2024 with the chief complaint of lower limb edema over the past year, which had worsened in the preceding 3 months. The clinical presentation included nephrotic syndrome and renal insufficiency. DIAGNOSIS The definitive diagnosis was established after comprehensive laboratory tests, bone marrow biopsy, renal pathology, and mass spectrometry analysis. INTERVENTIONS After a definitive diagnosis, the patient was treated with chemotherapy using a combination of bortezomib, dexamethasone, and cyclophosphamide. OUTCOMES The patient's renal function continued to deteriorate, ultimately leading to hemodialysis treatment. LESSONS Renal AHL, even though rare, needs to be considered strongly in elderly patients presenting with nephrotic syndrome and renal insufficiency. Cardiac involvement is uncommon. After active treatment, the prognosis is better than that of light chain amyloidosis.
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Affiliation(s)
- Binbin Chen
- Department of Nephrology, Liaocheng People’s Hospital, Liaocheng, Shandong, China
| | - Jie Wang
- Department of Nephrology, Liaocheng People’s Hospital, Liaocheng, Shandong, China
| | - Wenwen Zang
- Department of Nephrology, Liaocheng People’s Hospital, Liaocheng, Shandong, China
| | - Cong Wang
- Department of Pediatric Nephrology, Shandong Provincial Hospital, Jinan, Shandong, China
| | - Jie Li
- Department of Nephrology, Liaocheng People’s Hospital, Liaocheng, Shandong, China
| | - Ruiheng Yang
- Department of Nephrology, Liaocheng People’s Hospital, Liaocheng, Shandong, China
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Sheehan K, Jeon H, Corr SC, Hayes JM, Mok KH. Antibody Aggregation: A Problem Within the Biopharmaceutical Industry and Its Role in AL Amyloidosis Disease. Protein J 2025; 44:1-20. [PMID: 39527351 DOI: 10.1007/s10930-024-10237-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
Due to the large size and rapid growth of the global therapeutic antibody market, there is major interest in understanding the aggregation of protein products as it can compromise efficacy, concentration, and safety. Various production and storage conditions have been identified as capable of inducing aggregation of polyclonal and monoclonal antibody (mAb) therapies such as low pH, freezing, light exposure, lyophilisation and increased ionic strength. The addition of stabilising excipients to these therapeutics helps to combat the formation of aggregates with future aggregation inhibition mechanisms involving the introduction of point mutations and glycoengineering within aggregation prone regions (APRs). Antibody aggregation also plays an integral role in the pathogenesis of a condition known as amyloid light chain (AL) amyloidosis which is characterised by the production of improperly folded and amyloidogenic immunoglobulin light chains (LCs). Current diagnostic tools rely heavily on histological staining with their future moving towards amyloid component identification and proteomic analysis. For many years, treatment options designed for multiple myeloma (MM) have been applied to AL amyloidosis patients by depleting plasma cell numbers. More recently, treatment strategies more specific to this condition have been developed with many designed to recognize amyloid fibrils and trigger their degradation without causing systemic plasma cell cytotoxicity. Amyloid fibrils in AL disease and aggregates in antibody therapeutics are both formed through the oligomerisation of misfolded / modified proteins attempting to reach a thermodynamically stable, free energy minimum that is lower than the respective monomers themselves. Although the final morphologies are different, by understanding the principles underlying such aggregation, we expect to find common insights that may contribute to the development of new and effective methods of antibody aggregation and/or amyloidosis management. We envision that this area of research will continue to be very relevant in both industry and clinical settings.
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Affiliation(s)
- Kate Sheehan
- Trinity Biomedical Sciences Institute (TBSI), School of Biochemistry & Immunology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
- School of Genetics & Microbiology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
| | - Hyesoo Jeon
- Trinity Biomedical Sciences Institute (TBSI), School of Biochemistry & Immunology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
- Lonza Biologics Tuas Pte. Ltd., 35 Tuas South Ave 6, Singapore, 637377, Republic of Singapore
| | - Sinéad C Corr
- School of Genetics & Microbiology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
- School of Microbiology and APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Jerrard M Hayes
- Trinity Biomedical Sciences Institute (TBSI), School of Biochemistry & Immunology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
| | - K H Mok
- Trinity Biomedical Sciences Institute (TBSI), School of Biochemistry & Immunology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland.
- Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN), Trinity College Dublin, The University of Dublin, Dublin 2, Ireland.
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Netti GS, Troise D, Rossini M, Catalano V, De Luca F, Khalid J, Camporeale V, Ritrovato F, Infante B, Sanguedolce F, Stallone G, Ranieri E. Diagnostic and Therapeutic Aspects of Monoclonal Gammopathies of Renal Significance (MGRS): An Update. Diagnostics (Basel) 2024; 14:2892. [PMID: 39767252 PMCID: PMC11675341 DOI: 10.3390/diagnostics14242892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 12/16/2024] [Accepted: 12/18/2024] [Indexed: 01/11/2025] Open
Abstract
Monoclonal gammopathy of renal significance (MGRS) refers to a group of renal disorders caused by a monoclonal immunoglobulin (MIg), secreted by a non-malignant B-cell clone. Unlike overt multiple myeloma or B-cell proliferation, MGRS does not meet those diagnostic criteria. However, it is associated with significant morbidity, due to severe renal, and sometimes systemic, lesions induced by the MIg. Early recognition is crucial, as chemotherapy to suppress MIg secretion often improves outcomes. The spectrum of renal diseases in MGRS is broad, including both well-known conditions like AL amyloidosis and newly described lesions. Kidney biopsy is essential to determine the specific lesion associated with MGRS and assess its severity. Diagnosis involves integrating morphologic alterations using techniques such as light microscopy, immunofluorescence (IF), electron microscopy, and, in some cases, IF staining for Ig isotypes, immunoelectron microscopy, and proteomic analysis. Additionally, a complete hematologic evaluation, including serum and urine protein electrophoresis, immunofixation, and a serum-free light-chain assay, is necessary.
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Affiliation(s)
- Giuseppe Stefano Netti
- Unit of Clinical Pathology, Department of Medical and Surgical Sciences, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy; (V.C.); (F.D.L.); (J.K.); (V.C.); (F.R.); (E.R.)
- Center for Research and Innovation in Medicine (CREATE), Department of Medical and Surgical Sciences, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy; (D.T.); (G.S.)
| | - Dario Troise
- Center for Research and Innovation in Medicine (CREATE), Department of Medical and Surgical Sciences, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy; (D.T.); (G.S.)
- Unit of Nephrology, Dialysis and Transplantation, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy;
| | - Michele Rossini
- Unit of Nephrology, Dialysis and Transplantation, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy;
| | - Valeria Catalano
- Unit of Clinical Pathology, Department of Medical and Surgical Sciences, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy; (V.C.); (F.D.L.); (J.K.); (V.C.); (F.R.); (E.R.)
- Center for Research and Innovation in Medicine (CREATE), Department of Medical and Surgical Sciences, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy; (D.T.); (G.S.)
| | - Federica De Luca
- Unit of Clinical Pathology, Department of Medical and Surgical Sciences, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy; (V.C.); (F.D.L.); (J.K.); (V.C.); (F.R.); (E.R.)
- Center for Research and Innovation in Medicine (CREATE), Department of Medical and Surgical Sciences, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy; (D.T.); (G.S.)
| | - Javeria Khalid
- Unit of Clinical Pathology, Department of Medical and Surgical Sciences, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy; (V.C.); (F.D.L.); (J.K.); (V.C.); (F.R.); (E.R.)
- Center for Research and Innovation in Medicine (CREATE), Department of Medical and Surgical Sciences, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy; (D.T.); (G.S.)
| | - Valentina Camporeale
- Unit of Clinical Pathology, Department of Medical and Surgical Sciences, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy; (V.C.); (F.D.L.); (J.K.); (V.C.); (F.R.); (E.R.)
- Center for Research and Innovation in Medicine (CREATE), Department of Medical and Surgical Sciences, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy; (D.T.); (G.S.)
| | - Fabiana Ritrovato
- Unit of Clinical Pathology, Department of Medical and Surgical Sciences, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy; (V.C.); (F.D.L.); (J.K.); (V.C.); (F.R.); (E.R.)
| | - Barbara Infante
- Unit of Nephrology, Dialysis and Transplantation, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy;
| | - Francesca Sanguedolce
- Unit of Pathology, Department of Clinical and Experimental Medicine, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy;
| | - Giovanni Stallone
- Center for Research and Innovation in Medicine (CREATE), Department of Medical and Surgical Sciences, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy; (D.T.); (G.S.)
- Unit of Nephrology, Dialysis and Transplantation, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy;
| | - Elena Ranieri
- Unit of Clinical Pathology, Department of Medical and Surgical Sciences, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy; (V.C.); (F.D.L.); (J.K.); (V.C.); (F.R.); (E.R.)
- Center for Research and Innovation in Medicine (CREATE), Department of Medical and Surgical Sciences, University of Foggia, University Hospital “Policlinico Riuniti”, Viale Luigi Pinto, 71122 Foggia, Italy; (D.T.); (G.S.)
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Sarosiek S, Doughty CT, Castillo JJ. Monoclonal Gammopathy-Associated Neuropathy. Curr Hematol Malig Rep 2024; 20:2. [PMID: 39680359 DOI: 10.1007/s11899-024-00745-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2024] [Indexed: 12/17/2024]
Abstract
PURPOSE OF REVIEW Peripheral neuropathy (PN) is more commonly seen in individuals with monoclonal gammopathies, especially in patients with an IgM monoclonal gammopathy or Waldenström macroglobulinemia. RECENT FINDINGS There are multiple potential ways that the paraprotein may result in peripheral neuropathy. The diagnosis and management of monoclonal gammopathy-associated PN are challenging and necessitate a concerted effort between the hematologist/oncologist and the neurologist. This review describes the most common PN syndromes associated with monoclonal gammopathy, such as anti-myelin-associated glycoprotein neuropathy, light chain amyloidosis, cryoglobulinemia, POEMS, CANOMAD, and others. We also review the therapies used to treat these conditions.
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Affiliation(s)
- Shayna Sarosiek
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute450 Brookline Ave, Mayer 223, Boston, MA, 02215, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
| | - Christopher T Doughty
- Department of Neurology, Brigham & Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Jorge J Castillo
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute450 Brookline Ave, Mayer 223, Boston, MA, 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
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Lu J, Zhu Y, Huang H, Yang Q, Qi S. Warning values of serum total kappa/lambda ratio for M-proteinemia. BMC Immunol 2024; 25:73. [PMID: 39478462 PMCID: PMC11523637 DOI: 10.1186/s12865-024-00664-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 10/24/2024] [Indexed: 11/03/2024] Open
Abstract
BACKGROUND To introduce the serum total kappa/lambda ratio (K/L) in humoral immunity testing reports to improve the detection rate of M-proteinemia. METHODS 156 M protein-positive and 5464 M protein-negative samples confirmed by serum immunofixation electrophoresis(sIFE) were accumulated from January 2021 to December 2023 in the First Affiliated Hospital of Soochow University and the contents of immunoglobulins (IgG, IgA, IgM, kappa and lambda) were tested by Beckman IMMAGE800. All the samples were divided into two groups by time: the modeling group and the validation group. The K/L values in the modeling group were analyzed by SPSS 27.0 to get the receiver operating characteristic curve (ROC). Furthermore, a more in-depth analysis was conducted to verify the reliability of the optimal cutoff values in the validation group. In addition, the levels of immunoglobulins of another group including 106 patients with definite diagnosis of monoclonal gammopathy ranging from January 2021 to June 2024 were traced back to improve the diagnostic efficiency. RESULTS The optimal cutoff values of K/L were 2.31 and 1.43 corresponding to K-type and L-type M-proteinemia respectively by ROC analysis. The sensitivity and specificity were validated as 76.14% and 77.42%. False positives were mainly found in samples with systemic sclerosis (36.84%), hypohepatia (28.71%) and sicca syndrome (27.27%). While false negatives were mainly found in IgA monoclonal gammopathy (38.39%) and IgM monoclonal gammopathy (28.57%). Combining with the detection rules of IgG, IgA and IgM, the sensitivities for the diagnosis of immunoglobulin light chain amyloidosis(AL) and monoclonal gammopathy of undetermined significance(MGUS) can be increased to 83.33% and 85%. CONCLUSIONS K/L > 2.31 and K/L < 1.43 can be used as warning values for M-proteinemia. In addition, the content of the heavy chain in IgA- or IgM-type M-proteinemia may be considered to improve the detection rate.
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Affiliation(s)
- Jie Lu
- Department of Clinical Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China
| | - Ying Zhu
- Department of Clinical Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China
| | - Huifang Huang
- Department of Clinical Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China
| | - Qian Yang
- Department of Clinical Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China
| | - Songnan Qi
- Department of Clinical Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China.
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Leung N, Nasr SH. 2024 Update on Classification, Etiology, and Typing of Renal Amyloidosis: A Review. Am J Kidney Dis 2024; 84:361-373. [PMID: 38514011 DOI: 10.1053/j.ajkd.2024.01.530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 12/20/2023] [Accepted: 01/29/2024] [Indexed: 03/23/2024]
Abstract
Amyloidosis is a protein folding disease that causes organ injuries and even death. In humans, 42 proteins are now known to cause amyloidosis. Some proteins become amyloidogenic as a result of a pathogenic variant as seen in hereditary amyloidoses. In acquired forms of amyloidosis, the proteins form amyloid in their wild-type state. Four types (serum amyloid A, transthyretin, apolipoprotein A-IV, and β2-macroglobulin) of amyloid can occur either as acquired or as a mutant. Iatrogenic amyloid from injected protein medications have also been reported and AIL1RAP (anakinra) has been recently found to involve the kidney. Finally, the mechanism of how leukocyte cell-derived chemotaxin 2 (ALECT2) forms amyloid remains unknown. This article reviews the amyloids that involve the kidney and how they are typed.
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Affiliation(s)
- Nelson Leung
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota; Division of Hematology, Mayo Clinic, Rochester, Minnesota.
| | - Samih H Nasr
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
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Sanchorawala V. Systemic Light Chain Amyloidosis. N Engl J Med 2024; 390:2295-2307. [PMID: 38924733 DOI: 10.1056/nejmra2304088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/28/2024]
Affiliation(s)
- Vaishali Sanchorawala
- From the Amyloidosis Center, Boston University Chobanian and Avedisian School of Medicine, Boston Medical Center, Boston
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Chow MBCY, Bushrow L, Siddiqui I, Chiu A, Hamirani M, Satoskar AA. Congophilic fibrils in the glomeruli with polyclonal immunoglobulin gamma staining - another cause for diagnostic overlap: A case report. World J Clin Cases 2024; 12:3200-3205. [PMID: 38898862 PMCID: PMC11185376 DOI: 10.12998/wjcc.v12.i17.3200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 03/15/2024] [Accepted: 04/23/2024] [Indexed: 06/04/2024] Open
Abstract
BACKGROUND Glomerulopathy with fibrillary deposits is not uncommon in routine nephropathology practice, with amyloidosis and fibrillary glomerulonephritis being the two most frequently encountered entities. Renal amyloid heavy and light chain (AHL) is relatively uncommon and its biopsy diagnosis is usually limited to cases that show strong equivalent staining for a single immunoglobulin (Ig) heavy chain and a single light chain, further supported by mass spectrometry (MS) and serum studies for monoclonal protein. But polyclonal light chain staining can pose a challenge. CASE SUMMARY Herein we present a challenging case of renal AHL with polyclonal and polytypic Ig gamma (IgG) staining pattern by immunofluorescence. The patient is a 62-year-old Caucasian male who presented to an outside institution with a serum creatinine of up to 8.1 mg/dL and nephrotic range proteinuria. Despite the finding of a polyclonal and polytypic staining pattern on immunofluorescence, ultrastructural study of the renal biopsy demonstrated the presence of fibrils with a mean diameter of 10 nm. Congo red was positive while DNAJB9 was negative. MS suggested a diagnosis of amyloid AHL type with IgG and lambda, but kappa light chains were also present supporting the immunofluorescence staining results. Serum immunofixation studies demonstrated IgG lambda monoclonal spike. The patient was started on chemotherapy. The chronic renal injury however was quite advanced and he ended up needing dialysis shortly after. CONCLUSION Tissue diagnosis of AHL amyloid can be tricky. Thorough confirmation using other available diagnostic techniques is recommended in such cases.
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Affiliation(s)
- Maria Bernadette Che-Ying Chow
- Department of Pathology, The Ohio State University Medical Center, Columbus, OH 43210, United States
- Department of Pathology, North District Hospital, Sheung Shui, Hong Kong, China
| | - Lucas Bushrow
- Department of Pathology, The Ohio State University Medical Center, Columbus, OH 43210, United States
| | - Irmeen Siddiqui
- Department of Pathology, The Ohio State University Medical Center, Columbus, OH 43210, United States
| | - April Chiu
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, United States
| | - Mirza Hamirani
- Department of Internal Medicine, S. Joseph's Hospital, Parkersburg, WV 26101, United States
| | - Anjali A Satoskar
- Department of Pathology, The Ohio State University Medical Center, Columbus, OH 43210, United States
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Liu W, Wang Q, Yeerlan J, Yan Y, Xu L, Jia C, Liu X, Zhang L. Global research trends and hotspots for leukocyte cell-derived chemotaxin-2 from the past to 2023: a combined bibliometric review. Front Immunol 2024; 15:1413466. [PMID: 38881894 PMCID: PMC11176436 DOI: 10.3389/fimmu.2024.1413466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 05/15/2024] [Indexed: 06/18/2024] Open
Abstract
Leukocyte cell-derived chemotaxin-2 (LECT2) is an important cytokine synthesized by liver. Significant research interest is stimulated by its crucial involvement in inflammatory response, immune regulation, disease occurrence and development. However, bibliometric study on LECT2 is lacking. In order to comprehend the function and operation of LECT2 in human illnesses, we examined pertinent studies on LECT2 investigation in the Web of Science database, followed by utilizing CiteSpace, VOSview, and Scimago Graphica for assessing the yearly quantity of papers, countries/regions involved, establishments, authors, publications, citations, and key terms. Then we summarized the current research hotspots in this field. Our study found that the literature related to LECT2 has a fluctuating upward trend. "Angiogenesis", "ALECT2", "diagnosis", and "biliary atresia" are the current investigative frontiers. Our findings indicated that liver diseases (e.g. liver fibrosis and hepatic cell carcinoma), systemic inflammatory disease, and amyloidosis are the current research focus of LECT2. The current LECT2 research outcomes are not exceptional. We hope to promote the scientific research of LECT2 and exploit its potential for clinical diagnosis and treatment of related diseases through a comprehensive bibliometric review.
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Affiliation(s)
- Wei Liu
- Department of Neurology, Nanbu People’s Hospital, Nanbu, China
| | - Qin Wang
- School of Laboratory Medicine, Chengdu Medical College, Chengdu, China
| | | | - Yirui Yan
- School of Laboratory Medicine, Chengdu Medical College, Chengdu, China
| | - Luke Xu
- School of Laboratory Medicine, Chengdu Medical College, Chengdu, China
| | - Cui Jia
- Development and Regeneration Key Laboratory of Sichuan Province, Institute of Neuroscience, Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu, China
| | - Xinlian Liu
- Development and Regeneration Key Laboratory of Sichuan Province, Institute of Neuroscience, Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu, China
| | - Lushun Zhang
- Development and Regeneration Key Laboratory of Sichuan Province, Institute of Neuroscience, Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu, China
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11
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Delrue C, Dendooven A, Vandendriessche A, Speeckaert R, De Bruyne S, Speeckaert MM. Advancing Renal Amyloidosis Care: The Role of Modern Diagnostic Techniques with the Potential of Enhancing Patient Outcomes. Int J Mol Sci 2024; 25:5875. [PMID: 38892061 PMCID: PMC11172584 DOI: 10.3390/ijms25115875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/24/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
Renal amyloidosis is a set of complex disorders characterized by the deposition of amyloid proteins in the kidneys, which causes gradual organ damage and potential kidney failure. Recent developments in diagnostic methods, particularly mass spectrometry and proteome profiling, have greatly improved the accuracy of amyloid typing, which is critical for disease management. These technologies provide extensive insights into the specific proteins involved, allowing for more targeted treatment approaches and better patient results. Despite these advances, problems remain, owing to the heterogeneous composition of amyloid proteins and the varying efficacy of treatments based on amyloid type. Access to sophisticated diagnostics and therapy varies greatly, highlighting the global difference in renal amyloidosis management. Future research is needed to investigate next-generation sequencing and gene-editing technologies, like clustered regularly interspaced short palindromic repeats (CRISPR), which promise more profound insights into the genetic basis of amyloidosis.
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Affiliation(s)
- Charlotte Delrue
- Department of Nephrology, Ghent University Hospital, 9000 Ghent, Belgium;
| | - Amélie Dendooven
- Department of Pathology, Ghent University Hospital, 9000 Ghent, Belgium; (A.D.); (A.V.)
- Faculty of Medicine, University of Antwerp, 2610 Wilrijk, Belgium
| | | | | | - Sander De Bruyne
- Department of Laboratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium;
| | - Marijn M. Speeckaert
- Department of Nephrology, Ghent University Hospital, 9000 Ghent, Belgium;
- Research Foundation-Flanders (FWO), 1000 Brussels, Belgium
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12
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Fontana F, Alfano G, Verga L, Magistroni R, Donati G. Silver-positive kidney AL amyloidosis. J Nephrol 2024; 37:1175-1176. [PMID: 38252262 DOI: 10.1007/s40620-023-01827-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 11/08/2023] [Indexed: 01/23/2024]
Affiliation(s)
- Francesco Fontana
- Nephrology, Dialysis and Kidney Transplant Unit, Azienda Ospedaliero Universitaria di Modena, Modena, Italy.
| | - Gaetano Alfano
- Nephrology, Dialysis and Kidney Transplant Unit, Azienda Ospedaliero Universitaria di Modena, Modena, Italy
| | - Laura Verga
- Pathology Unit, Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo e Università di Pavia, Pavia, Italy
| | - Riccardo Magistroni
- Nephrology, Dialysis and Kidney Transplant Unit, Azienda Ospedaliero Universitaria di Modena, Modena, Italy
- Surgical Medical and Dental Department of Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Gabriele Donati
- Nephrology, Dialysis and Kidney Transplant Unit, Azienda Ospedaliero Universitaria di Modena, Modena, Italy
- Surgical Medical and Dental Department of Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy
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13
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Dhaliwal A, Tripathi A, Ravi S. A Case of μ Heavy and λ Light Chain Amyloidosis in a Patient With Bi-Clonal (IgM κ and λ) Gammopathy Treated With Daratumumab. Cureus 2024; 16:e56994. [PMID: 38681439 PMCID: PMC11045342 DOI: 10.7759/cureus.56994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/19/2024] [Indexed: 05/01/2024] Open
Abstract
Our case report is of an elderly male with a history of IgM κ lymphoplasmacytic lymphoma (LPL) presenting with generalized neuropathy and weakness. Due to his LPL history and worsening renal function, he underwent a renal biopsy revealing the presence of μ heavy and λ light chains, revealing a diagnosis of amyloidosis with unbound heavy & light chains (AHL), a rare type of amyloidosis. His bone marrow biopsy demonstrated κ light chain restriction by flow cytometry and amyloid deposition. The patient's serum had elevated free κ and λ light chains with a free light chain (FLC) ratio of 3.17. Serum immunofixation was positive for IgM κ and λ light chain clones. He completed six cycles of cyclophosphamide, bortezomib, dexamethasone, and rituximab (CyBorD+R), normalizing the FLC ratio. Still, he continued to present with persistently elevated M protein, IgM κ, and λ light chains on immunofixation. Thereafter, daratumumab, a human monoclonal antibody directed against CD38 expressed on myeloma cells was initiated, which led to a negative immunofixation study after two cycles accompanied by a reduction in protein excretion in the urine. The patient achieved a complete hematological response with daratumumab. To date, our case is the only reported μ heavy and λ light chain amyloidosis patient with bi-clonal (IgM κ and λ) gammopathy to be successfully treated with daratumumab.
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Affiliation(s)
- Armaan Dhaliwal
- Internal Medicine, University of Arizona College of Medicine, Tucson, USA
| | - Ashish Tripathi
- Internal Medicine, Dayanand Medical College and Hospital, Ludhiana, IND
| | - Soumiya Ravi
- Internal Medicine, University of Arizona College of Medicine, Tucson, USA
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14
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Shimamoto Y, Takahashi N, Katoh N, Matsui Y, Mochizuki Y, Ito M, Yazaki M, Kametani F, Kasuno K, Sekijima Y, Naiki H, Iwano M. Light and heavy chain deposition disease with focal amyloid deposition diagnosed with mass spectrometry: a case report. BMC Nephrol 2023; 24:187. [PMID: 37365566 DOI: 10.1186/s12882-023-03207-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 05/18/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND Light and heavy chain deposition disease (LHCDD) is a rare condition characterised by the deposition of immunoglobulin components in the kidneys. Similarly, Amyloidosis is also caused by the deposition of light chain and/or heavy chain components of immunoglobulins which are folded into amyloid fibrils characterised by Congophilic deposits that exhibit apple-green birefringence under polarised light. Only a handful of reports describing LHCDD with amyloid fibril deposition have been previously published, however, none have characterized the composition of the deposited immunoglobulin components via mass spectrometry. CASE PRESENTATION We report a case of a 79-year-old Japanese woman with nephrotic syndrome. Bone marrow aspiration revealed a slight proliferation of plasma cells (under 10%). Immunofluorescence assessment of renal biopsy showed amyloid-like deposits in the glomerulus that were positive for IgA and kappa. Further, the Congo red staining of the deposits was faintly positive, and only a slight birefringence was detected. Electron microscopy confirmed fine fibrillar structures and non-amyloid deposits. Finally, mass spectrometry revealed that the deposits were composed of abundant amounts of light chain with small amounts of heavy chain. Therefore, the patient was diagnosed with LHCDD and focal amyloid deposition. Chemotherapy was subsequently initiated, which resulted in haematological and renal response. Under polarised light, faint birefringence with Congo red staining and periodic acid-methenamine silver positivity indicated that the deposits were mostly non-amyloid fibrils with a small component of amyloid fibrils. Generally, the diagnosis of heavy- and light-chain amyloidosis is defined by greater heavy chain deposition compared to the light chain. However, in our case, contrary to the definition, the light-chain deposition was far greater than that of the heavy-chain. CONCLUSIONS This is the first case of LHCDD with focal amyloid deposition diagnosed by analysing the glomerular deposits by mass spectrometry.
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Affiliation(s)
- Yuki Shimamoto
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuokashimoaizuki Eiheiji-Cho, Yoshida-Gun, Fukui, Japan.
| | - Naoki Takahashi
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuokashimoaizuki Eiheiji-Cho, Yoshida-Gun, Fukui, Japan
| | - Nagaaki Katoh
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Yuki Matsui
- Department of Nephrology and Urology, Japanese Red Cross Fukui Hospital, Fukui, Japan
| | - Yusuke Mochizuki
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Masanori Ito
- Department of Nephrology and Urology, Japanese Red Cross Fukui Hospital, Fukui, Japan
| | - Masahide Yazaki
- Institute for Biomedical Sciences, Shinshu University, Matsumoto, Nagano, Japan
- Clinical Laboratory Sciences Division, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan
| | - Fuyuki Kametani
- Tokyo Metropolitan Institute of Medical Science, Setagaya-Ku, Tokyo, Japan
| | - Kenji Kasuno
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuokashimoaizuki Eiheiji-Cho, Yoshida-Gun, Fukui, Japan
| | - Yoshiki Sekijima
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Nagano, Japan
- Institute for Biomedical Sciences, Shinshu University, Matsumoto, Nagano, Japan
| | - Hironobu Naiki
- Department of Pathology, University of Fukui, Fukui, Japan
| | - Masayuki Iwano
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuokashimoaizuki Eiheiji-Cho, Yoshida-Gun, Fukui, Japan
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15
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Abstract
Various types of systemic amyloidosis can wreak havoc on the architecture and functioning of the kidneys. Amyloidosis should be suspected in patients with worsening kidney function, proteinuria, and multisystem involvement, but isolated kidney involvement also is possible. Confirming the amyloidosis type and specific organ dysfunction is of paramount importance to select the appropriately tailored treatment and aim for better survival while avoiding treatment-associated toxicities. Amyloid renal staging in light chain amyloidosis amyloidosis helps inform prognosis and risk for end-stage kidney disease. Biomarker-based staging systems and response assessment guide the therapeutic strategy and allow the timely identification of refractory or relapsing disease so that patients can be switched to salvage therapy. Kidney transplantation is a viable option for selected patients with amyloidosis. Because of the complex nature of the pathophysiology and treatment of amyloidosis, a multidisciplinary team-based approach should be used in the care of these patients.
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Affiliation(s)
- Ralph Nader
- Renal, Electrolyte and Hypertension Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Avital Angel-Korman
- Nephrology and Hypertension Institute, Samson Assuta University Hospital, Ashdod, Israel; Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheba, Israel
| | - Andrea Havasi
- Amyloidosis Center, Boston University School of Medicine, Boston, MA; Clinical Research, Alnylam Pharmaceuticals, Cambridge, MA.
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16
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Li Y, Zhang Y, Zhou X, Xue X, Wang M, Kang D, Zhou Y, Hu R, Quan S, Xing G, Yang J. Precise diagnosis and typing of early-stage renal immunoglobulin-derived amyloidosis by label-free quantification of parallel reaction monitoring-based targeted proteomics. BMC Nephrol 2023; 24:50. [PMID: 36894904 PMCID: PMC9999574 DOI: 10.1186/s12882-023-03105-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 03/03/2023] [Indexed: 03/11/2023] Open
Abstract
BACKGROUND Early diagnosis and typing are crucial for improving the prognosis of patients with renal amyloidosis. Currently, Untargeted proteomics based precise diagnosis and typing of amyloid deposits are crucial for guiding patient management. Although untargeted proteomics achieve ultra-high-throughput by selecting the most abundant eluting cationic peptide precursors in series for tandem MS events, it lacks in sensitivity and reproducibility, which may not be suitable for early-stage renal amyloidosis with minor damages. Here, we aimed to develop parallel reaction monitoring (PRM)-based targeted proteomics to achieve high sensitivity and specificity by determining absolute abundances and codetecting all transitions of highly repeatable peptides of preselected amyloid signature and typing proteins in identifying early-stage renal immunoglobulin-derived amyloidosis. METHODS AND RESULTS In 10 discovery cohort cases, Congo red-stained FFPE slices were micro-dissected and analyzed by data-dependent acquisition-based untargeted proteomics for preselection of typing specific proteins and peptides. Further, a list of proteolytic peptides from amyloidogenic proteins and internal standard proteins were quantified by PRM-based targeted proteomics to validate performance for diagnosis and typing in 26 validation cohort cases. The diagnosis and typing effectiveness of PRM-based targeted proteomics in 10 early-stage renal amyloid cases was assessed via a comparison with untargeted proteomics. A peptide panel of amyloid signature proteins, immunoglobulin light chain and heave chain in PRM-based targeted proteomics showed significantly distinguishing ability and amyloid typing performance in patients. The diagnostic algorithm of targeted proteomics with a low amount of amyloid deposits in early-stage renal immunoglobulin-derived amyloidosis showed better performance than untargeted proteomics in amyloidosis typing. CONCLUSIONS This study demonstrates that the utility of these prioritized peptides in PRM-based targeted proteomics ensure high sensitivity and reliability for identifying early-stage renal amyloidosis. Owing to the development and clinical application of this method, rapid acceleration of the early diagnosis, and typing of renal amyloidosis is expected.
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Affiliation(s)
- Yuan Li
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Ying Zhang
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Xinjin Zhou
- Renal Path Diagnostics at Pathologists BioMedical Laboratories, Lewisville, TX, 75067, USA
| | - Xinli Xue
- Clinical Systems Biology Key Laboratories of Henan, Translational Medicine Center, the First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Muxi Wang
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, 61801, USA
| | - Dedong Kang
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, 1428555, Japan
| | - Yali Zhou
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Ruimin Hu
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Songxia Quan
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Guolan Xing
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, Henan, China.
| | - Jinghua Yang
- Clinical Systems Biology Key Laboratories of Henan, Translational Medicine Center, the First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, Henan, China.
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17
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Zanwar S, Gertz MA, Muchtar E. Immunoglobulin Light Chain Amyloidosis: Diagnosis and Risk Assessment. J Natl Compr Canc Netw 2023; 21:83-90. [PMID: 36630897 PMCID: PMC10164359 DOI: 10.6004/jnccn.2022.7077] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 09/22/2022] [Indexed: 01/13/2023]
Abstract
Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder with multiple clinical presentations. The diagnosis of AL amyloidosis requires a high index of suspicion, making a delay in diagnosis common, which contributes to the high early mortality seen in this disease. Establishing the diagnosis of AL amyloidosis requires the demonstration of tissue deposition of amyloid fibrils. A bone marrow biopsy and fat pad aspirate performed concurrently have a high sensitivity for the diagnosis of AL amyloidosis and negate the need for organ biopsies in most patients. An accurate diagnosis requires amyloid typing via additional testing, including tissue mass spectrometry. Prognostication for AL amyloidosis is largely driven by the organs impacted. Cardiac involvement represents the single most important prognostic marker, and the existing staging systems are driven by cardiac biomarkers. Apart from organ involvement, plasma cell percentage on the bone marrow biopsy, specific fluorescence in situ hybridization findings, age at diagnosis, and performance status are important prognostic markers. This review elaborates on the diagnostic testing and prognostication for patients with newly diagnosed AL amyloidosis.
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Affiliation(s)
- Saurabh Zanwar
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
| | - Morie A Gertz
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
| | - Eli Muchtar
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
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18
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Al‐Kuraishy HM, Al‐Gareeb AI, Mohammed AA, Alexiou A, Papadakis M, Batiha GE. The potential link between Covid-19 and multiple myeloma: A new saga. Immun Inflamm Dis 2022; 10:e701. [PMID: 36444620 PMCID: PMC9673426 DOI: 10.1002/iid3.701] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Covid-19 is considered a primary respiratory disease-causing viral pneumonia and, in severe cases, leads to acute lung injury and acute respiratory distress syndrome (ARDS). In addition, though, extra-pulmonary manifestations of Covid-19 have been shown. Furthermore, severe acute respiratory distress syndrome coronavirus type 2 (SARS-CoV-2) infection may coexist with several malignancies, including multiple myeloma (MM). METHODS This critical literature review aimed to find the potential association between SARS-CoV-2 infection and MM in Covid-19 patients with underlying MM. Narrative literature and databases search revealed that ARDS is developed in both MM and Covid-19 due to hypercalcemia and proteasome dysfunction. RESULTS Notably, the expression of angiogenic factors and glutamine deficiency could link Covid-19 severity and MM in the pathogenesis of cardiovascular complications. MM and Covid-19 share thrombosis as a typical complication; unlike thrombosis in Covid-19, which reflects disease severity, thrombosis does not reflect disease severity in MM. In both conditions, thromboprophylaxis is essential to prevent pulmonary thrombosis and other thromboembolic disorders. Moreover, Covid-19 may exacerbate the development of acute kidney injury and neurological complications in MM patients. CONCLUSION These findings highlighted that MM patients might be a risk group for Covid-19 severity due to underlying immunosuppression and most of those patients need specific management in the Covid-19 era.
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Affiliation(s)
- Hayder M. Al‐Kuraishy
- Department of Clinical Pharmacology and Medicine, College of MedicineALmustansiriyia UniversityBaghdadIraq
| | - Ali I. Al‐Gareeb
- Department of Clinical Pharmacology and Medicine, College of MedicineALmustansiriyia UniversityBaghdadIraq
| | - Ali A Mohammed
- The Chest Clinic, Barts Health NHS TrustWhipps Cross University HospitalLondonUK
| | - Athanasios Alexiou
- Department of Science and EngineeringNovel Global Community Educational FoundationHebershamAustralia
- AFNP MedWienAustria
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten‐HerdeckeUniversity of Witten‐HerdeckeWuppertalGermany
| | - Gaber El‐Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary MedicineDamanhour UniversityDamanhourEgypt
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19
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IgM-Related Immunoglobulin Light Chain (AL) Amyloidosis. HEMATO 2022. [DOI: 10.3390/hemato3040049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Waldenström macroglobulinemia (WM) is a rare lymphoplasmacytic disorder characterized by an IgM paraprotein. The clinical presentation of WM varies and can include common manifestations such as anemia and hyperviscosity, in addition to less common features such as cryoglobulinemia, IgM-related neuropathy, and immunoglobulin light chain (AL) amyloidosis. Amyloidosis is a protein-folding disorder in which vital organ damage occurs due to the accumulation of misfolded protein aggregates. The most common type of amyloidosis in patients with an IgM paraprotein is AL amyloidosis, although other types of amyloidosis may occur. IgM-related amyloidosis has distinct clinical features when compared with other subtypes of AL amyloidosis. This review highlights the diagnostic criteria of IgM-related AL amyloidosis, as well as the clinical characteristics and treatment options for this disorder.
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20
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Fedotov SA, Khrabrova MS, Anpilova AO, Dobronravov VA, Rubel AA. Noninvasive Diagnostics of Renal Amyloidosis: Current State and Perspectives. Int J Mol Sci 2022; 23:ijms232012662. [PMID: 36293523 PMCID: PMC9604123 DOI: 10.3390/ijms232012662] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 10/17/2022] [Accepted: 10/18/2022] [Indexed: 11/05/2022] Open
Abstract
Amyloidoses is a group of diseases characterized by the accumulation of abnormal proteins (called amyloids) in different organs and tissues. For systemic amyloidoses, the disease is related to increased levels and/or abnormal synthesis of certain proteins in the organism due to pathological processes, e.g., monoclonal gammopathy and chronic inflammation in rheumatic arthritis. Treatment of amyloidoses is focused on reducing amyloidogenic protein production and inhibition of its aggregation. Therapeutic approaches critically depend on the type of amyloidosis, which underlines the importance of early differential diagnostics. In fact, the most accurate diagnostics of amyloidosis and its type requires analysis of a biopsy specimen from the disease-affected organ. However, absence of specific symptoms of amyloidosis and the invasive nature of biomaterial sampling causes the late diagnostics of these diseases, which leads to a delayed treatment, and significantly reduces its efficacy and patient survival. The establishment of noninvasive diagnostic methods and discovery of specific amyloidosis markers are essential for disease detection and identification of its type at earlier stages, which enables timely and targeted treatment. This review focuses on current approaches to the diagnostics of amyloidoses, primarily with renal involvement, and research perspectives in order to design new specific tests for early diagnosis.
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Affiliation(s)
- Sergei A. Fedotov
- Laboratory of Amyloid Biology, St. Petersburg State University, St. Petersburg 199034, Russia
- Pavlov Institute of Physiology, Russian Academy of Sciences, St. Petersburg 199034, Russia
| | - Maria S. Khrabrova
- Laboratory of Amyloid Biology, St. Petersburg State University, St. Petersburg 199034, Russia
- Research Institute of Nephrology, Pavlov University, St. Petersburg 197101, Russia
| | - Anastasia O. Anpilova
- Laboratory of Amyloid Biology, St. Petersburg State University, St. Petersburg 199034, Russia
- Research Institute of Nephrology, Pavlov University, St. Petersburg 197101, Russia
| | | | - Aleksandr A. Rubel
- Laboratory of Amyloid Biology, St. Petersburg State University, St. Petersburg 199034, Russia
- Department of Genetics and Biotechnology, St. Petersburg State University, St. Petersburg 199034, Russia
- Correspondence: ; Tel.: +7-812-428-40-09
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21
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Renal Amyloidosis: Epidemiological, Clinical, and Laboratory Profile in Adults from One Nephrology Center. Int J Nephrol 2022; 2022:8493479. [PMID: 35898389 PMCID: PMC9314002 DOI: 10.1155/2022/8493479] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 06/13/2022] [Accepted: 06/29/2022] [Indexed: 11/18/2022] Open
Abstract
Background Renal amyloidosis is one of the main differential diagnoses of nephrotic proteinuria in adults and the elderly. The aim of this study with the most important series in our country is to contribute to the epidemiological, clinical, and etiological study of the renal amyloidosis. Methods In a retrospective study carried out between 1975 and 2019, 310 cases of histologically proven and typed renal amyloidosis were selected for this study. Results There were 209 men and 101 women with a mean age of 53.8 ± 15.4 years (range, 17–84 years). Of the 310 cases, 255 (82.3%) were diagnosed with AA renal amyloidosis and 55 (17.7%) with non-AA amyloidosis. Infections were the main cause of AA amyloidosis, and tuberculosis was the most frequent etiology. The period from the onset of the underlying disease to diagnosis of the renal amyloidosis was an average of 177 months. The most frequent manifestations at the time of diagnosis were nephrotic syndrome (84%), chronic renal failure (30.3%), and end-stage renal disease (37.8%). After a medium follow-up of 16 months (range, 0–68 months), mortality occurred in 60 cases. Conclusions Given the high frequency of AA amyloidosis in our country, awareness of the proper management of infectious and chronic inflammatory diseases remains a priority in reducing the occurrence of this serious disease.
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22
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Ohashi N, Katoh N, Kasuga K, Yoshinaga T, Kametani F, Yazaki M, Sekijima Y. AH amyloid neuropathy: a novel clinical phenotype confirmed by histopathology and mass spectrometry. Amyloid 2022; 29:141-142. [PMID: 35285361 DOI: 10.1080/13506129.2022.2049745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Affiliation(s)
- Nobuhiko Ohashi
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan
| | - Nagaaki Katoh
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan
| | - Kazuki Kasuga
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan
| | - Tsuneaki Yoshinaga
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan
| | - Fuyuki Kametani
- Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Masahide Yazaki
- Clinical Laboratory Sciences Division, Shinshu University Graduate of School of Medicine, Matsumoto, Japan.,Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan
| | - Yoshiki Sekijima
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan.,Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan
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23
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Ke M, Li X, Wang L, Yue S, Zhao B. A stepwise data interpretation process for renal amyloidosis typing by LMD-MS. BMC Nephrol 2022; 23:144. [PMID: 35418036 PMCID: PMC9008935 DOI: 10.1186/s12882-022-02785-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 04/07/2022] [Indexed: 11/25/2022] Open
Abstract
Backgrounds Systemic amyloidosis is classified according to the deposited amyloid fibril protein (AFP), which determines its best therapeutic scheme. The most common type of AFP found are immunoglobulin light chains. The laser microdissection combined with mass spectrometry (LMD-MS) technique is a promising approach for precise typing of amyloidosis, however, the major difficulty in interpreting the MS data is how to accurately identify the precipitated AFP from background. Objectives The objective of the present study is to establish a complete data interpretation procedure for LMD-MS based amyloidosis typing. Methods Formalin-fixed paraffin-embedded specimens from patients with renal amyloidosis and non-amyloid nephropathies (including diabetic nephropathy, fibrillary glomerulonephritis, IgA nephropathy, lupus nephritis, membranous nephropathy, and normal tissue adjacent to tumors) were analyzed by LMD-MS. Forty-two specimens were used to train the data interpretation procedure, which was validated by another 50 validation specimens. Area under receiver operating curve (AUROC) analysis of amyloid accompanying proteins (AAPs, including apolipoprotein A-IV, apolipoprotein E and serum amyloid P-component) for discriminating amyloidosis from non-amyloid nephropathies was performed. Results A stepwise data interpretation procedure that includes or excludes the types of amyloidosis group by group was established. The involvement of AFPs other than immunoglobulin was determined by P-score, as well as immunoglobulin light chain by variable of λ-κ, and immunoglobulin heavy chain by H-score. This achieved a total of 88% accuracy in 50 validation specimens. The AAPs showed significantly different expression levels between amyloidosis specimens and non-amyloid nephropathies. Each of the single AAP had a AUROC value more than 0.9 for diagnosis of amyloidosis from non-amyloid control, and the averaged level of the three AAPs showed the highest AUROC (0.966), which might be an alternative indicator for amyloidosis diagnosis. Conclusions The proteomic data interpretation procedure for LMD-MS based amyloidosis typing was established successfully that has a high practicability in clinical application. Supplementary Information The online version contains supplementary material available at 10.1186/s12882-022-02785-9.
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Affiliation(s)
- Ming Ke
- Guangzhou KingMed Center for Clinical Laboratory Co.,Ltd, Guangzhou, 510005, China
| | - Xin Li
- Guangzhou KingMed Center for Clinical Laboratory Co.,Ltd, Guangzhou, 510005, China
| | - Lin Wang
- Guangzhou KingMed Center for Clinical Laboratory Co.,Ltd, Guangzhou, 510005, China
| | - Shuling Yue
- Guangzhou KingMed Center for Clinical Laboratory Co.,Ltd, Guangzhou, 510005, China
| | - Beibei Zhao
- Guangzhou KingMed Center for Clinical Laboratory Co.,Ltd, Guangzhou, 510005, China.
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24
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Shiao JC, Wolf AB, Rabinovitch RA, Smith C, Kleinschmidt-DeMasters B, Ney DE. Long-Term Control of Primary Cerebral ALH Amyloidoma With Focal Radiation Therapy. Adv Radiat Oncol 2022; 7:100831. [PMID: 34934868 PMCID: PMC8654634 DOI: 10.1016/j.adro.2021.100831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 09/13/2021] [Accepted: 09/30/2021] [Indexed: 11/24/2022] Open
Affiliation(s)
- Jay C. Shiao
- Department of Radiation Oncology, Aurora, Colorado
- University of Colorado Cancer Center, Aurora, Colorado
- Corresponding author: Jay Shiao, MD, MPH
| | | | - Rachel A. Rabinovitch
- Department of Radiation Oncology, Aurora, Colorado
- University of Colorado Cancer Center, Aurora, Colorado
| | - Clay Smith
- University of Colorado Cancer Center, Aurora, Colorado
- Division of Hematology, Department of Medicine, Aurora, Colorado
| | - B.K. Kleinschmidt-DeMasters
- University of Colorado Cancer Center, Aurora, Colorado
- Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado
| | - Douglas E. Ney
- University of Colorado Cancer Center, Aurora, Colorado
- Department of Neurology, Aurora, Colorado
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25
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Schürmann J, Gottwald J, Rottenaicher G, Tholey A, Röcken C. MALDI mass spectrometry imaging unravels organ and amyloid-type specific peptide signatures in pulmonary and gastrointestinal amyloidosis. Proteomics Clin Appl 2021; 15:e2000079. [PMID: 34061454 DOI: 10.1002/prca.202000079] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 05/26/2021] [Accepted: 05/31/2021] [Indexed: 12/12/2022]
Abstract
PURPOSE Amyloidosis is a disease group caused by pathological aggregation and deposition of peptides in diverse tissue sites. Recently, matrix-assisted laser desorption/ionization mass spectrometry imaging coupled with ion mobility separation (MALDI-IMS MSI) was introduced as a novel tool to identify and classify amyloidosis using single sections from formalin-fixed and paraffin-embedded cardiac biopsies. Here, we tested the hypothesis that MALDI-IMS MSI can be applied to lung and gastrointestinal specimens. EXPERIMENTAL DESIGN Forty six lung and 65 gastrointestinal biopsy and resection specimens with different types of amyloid were subjected to MALDI-IMS MSI. Ninety three specimens included tissue areas without amyloid as internal negative controls. Nine cases without amyloid served as additional negative controls. RESULTS Utilizing a peptide filter method and 21 known amyloid specific tryptic peptides we confirmed the applicability of a universal peptide signature with a sensitivity of 100% and a specificity of 100% for the detection of amyloid deposits in the lung and gastrointestinal tract. Additionally, the frequencies of individual m/z-values of the 21 tryptic marker peptides showed organ- and tissue-type specific differences. CONCLUSIONS AND CLINICAL RELEVANCE MALDI-IMS MSI adds a valuable analytical approach to diagnose and classify amyloid and the detection frequency of individual tryptic peptides is organ-/tissue-type specific.
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Affiliation(s)
- Jan Schürmann
- Department of Pathology, Christian-Albrechts-University, Kiel, Germany
| | - Juliane Gottwald
- Department of Pathology, Christian-Albrechts-University, Kiel, Germany
| | - Georg Rottenaicher
- Center for Integrated Protein Science Munich at the Department of Chemistry, Technical University of Munich, Garching, Germany
| | - Andreas Tholey
- Systematic Proteome Research & Bioanalytics, Institute of Experimental Medicine, Christian-Albrechts-University, Kiel, Germany
| | - Christoph Röcken
- Department of Pathology, Christian-Albrechts-University, Kiel, Germany
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26
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The Clone Wars: Diagnosing and Treating Dysproteinemic Kidney Disease in the Modern Era. J Clin Med 2021; 10:jcm10081633. [PMID: 33921394 PMCID: PMC8069250 DOI: 10.3390/jcm10081633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 03/23/2021] [Accepted: 03/25/2021] [Indexed: 11/17/2022] Open
Abstract
Dysproteinemic kidney diseases are disorders that occur as the result of lymphoproliferative (B cell or plasma cell) disorders that cause kidney damage via production of nephrotoxic monoclonal immunoglobulins or their components. These monoclonal immunoglobulins have individual physiochemical characteristics that confer specific nephrotoxic properties. There has been increased recognition and revised characterization of these disorders in the last decade, and in some cases, there have been substantial advances in disease understanding and treatments, which has translated to improved patient outcomes. These disorders still present challenges to nephrologists and patients, since they are rare, and the field of hematology is rapidly changing with the introduction of novel testing and treatment strategies. In this review, we will discuss the clinical presentation, kidney biopsy features, hematologic characteristics and treatment of dysproteinemic kidney diseases.
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27
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Nakagawa M, Yazaki M, Kametani F, Katoh N, Yoshinaga T, Higuchi K, Sekijima Y. Development of diagnostic antibodies against immunoglobulin heavy chain variable region for heavy chain amyloidosis (AH amyloidosis). Pathol Int 2021; 71:245-254. [PMID: 33713540 DOI: 10.1111/pin.13081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 01/27/2021] [Indexed: 12/01/2022]
Abstract
It is difficult to diagnose immunoglobulin heavy chain amyloidosis (AH amyloidosis) without proteomic analysis due to no useful diagnostic antibodies. The aim of this study was to develop diagnostic antibodies available to immunohistochemistry and immunoblotting. Two rabbit anti-heavy chain variable region antibodies were generated and evaluated in immunohistochemical studies performed on 11 AH amyloidosis patients and 64 patients with other systemic amyloidoses. Additionally, immunoblotting was performed using extracted amyloid protein from one patient and serum samples from two patients with AH amyloidosis. Immunohistochemical analysis generated a positive outcome in 10 of 11 AH amyloidosis patients (sensitivity 90.9%). While positive staining was also observed in 9 of 64 non-AH amyloidosis patients (specificity 85.9%), substitution of the blocking agent reversed the positive reactivity in 5 of 9 patients. Amyloid protein band was clearly detected via immunoblotting analysis, and protein bands with similar molecular weights of amyloid protein were observed in serum samples from patients with AH amyloidosis. The two antibodies may represent a powerful diagnostic tool for AH amyloidosis. In addition, our data revealed the existence of amyloidogenic variable region fragments in the serum of patients, suggesting their potential as diagnostic markers for AH amyloidosis.
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Affiliation(s)
- Mayuko Nakagawa
- Institute for Biomedical Sciences, Shinshu University, Nagano, Japan
- Clinical Laboratory Sciences Division, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Masahide Yazaki
- Institute for Biomedical Sciences, Shinshu University, Nagano, Japan
- Clinical Laboratory Sciences Division, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Fuyuki Kametani
- Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Nagaaki Katoh
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan
| | - Tsuneaki Yoshinaga
- Institute for Biomedical Sciences, Shinshu University, Nagano, Japan
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan
| | - Keiichi Higuchi
- Institute for Biomedical Sciences, Shinshu University, Nagano, Japan
- Department of Aging Biology, Shinshu University School of Medicine, Nagano, Japan
| | - Yoshiki Sekijima
- Institute for Biomedical Sciences, Shinshu University, Nagano, Japan
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan
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28
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Matiiv AB, Trubitsina NP, Matveenko AG, Barbitoff YA, Zhouravleva GA, Bondarev SA. Amyloid and Amyloid-Like Aggregates: Diversity and the Term Crisis. BIOCHEMISTRY (MOSCOW) 2021; 85:1011-1034. [PMID: 33050849 DOI: 10.1134/s0006297920090035] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Active accumulation of the data on new amyloids continuing nowadays dissolves boundaries of the term "amyloid". Currently, it is most often used to designate aggregates with cross-β structure. At the same time, amyloids also exhibit a number of other unusual properties, such as: detergent and protease resistance, interaction with specific dyes, and ability to induce transition of some proteins from a soluble form to an aggregated one. The same features have been also demonstrated for the aggregates lacking cross-β structure, which are commonly called "amyloid-like" and combined into one group, although they are very diverse. We have collected and systematized information on the properties of more than two hundred known amyloids and amyloid-like proteins with emphasis on conflicting examples. In particular, a number of proteins in membraneless organelles form aggregates with cross-β structure that are morphologically indistinguishable from the other amyloids, but they can be dissolved in the presence of detergents, which is not typical for amyloids. Such paradoxes signify the need to clarify the existing definition of the term amyloid. On the other hand, the demonstrated structural diversity of the amyloid-like aggregates shows the necessity of their classification.
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Affiliation(s)
- A B Matiiv
- Department of Genetics and Biotechnology, Faculty of Biology, St. Petersburg State University, St. Petersburg, 199034, Russia
| | - N P Trubitsina
- Department of Genetics and Biotechnology, Faculty of Biology, St. Petersburg State University, St. Petersburg, 199034, Russia
| | - A G Matveenko
- Department of Genetics and Biotechnology, Faculty of Biology, St. Petersburg State University, St. Petersburg, 199034, Russia
| | - Y A Barbitoff
- Department of Genetics and Biotechnology, Faculty of Biology, St. Petersburg State University, St. Petersburg, 199034, Russia.,Bioinformatics Institute, St. Petersburg, 197342, Russia
| | - G A Zhouravleva
- Department of Genetics and Biotechnology, Faculty of Biology, St. Petersburg State University, St. Petersburg, 199034, Russia.,Laboratory of Amyloid Biology, St. Petersburg State University, St. Petersburg, 199034, Russia
| | - S A Bondarev
- Department of Genetics and Biotechnology, Faculty of Biology, St. Petersburg State University, St. Petersburg, 199034, Russia. .,Laboratory of Amyloid Biology, St. Petersburg State University, St. Petersburg, 199034, Russia
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29
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Kim C, Brealey J, Jobert A, Nolan J. A case of monoclonal gammopathy of renal significance presenting as atypical amyloidosis with IgA lambda paraproteinemia. J Pathol Transl Med 2020; 54:504-507. [PMID: 33153243 PMCID: PMC7674760 DOI: 10.4132/jptm.2020.09.18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 09/18/2020] [Indexed: 11/29/2022] Open
Abstract
Monoclonal gammopathy of renal significance is defined as any B cell or plasma cell clonal lymphoproliferation which neither causes tumor complications nor meets any current hematological criteria for specific therapy, with one or more kidney lesions related to the produced monoclonal immunoglobulin, such as amyloidosis. A 50-year-old male presented with heavy proteinuria and blood tests showing IgA and Lambda paraproteinemia. Light microscopy showed mesangial eosinophilic ground substance extending into the capillary loops, and positive staining within the glomeruli and vessel walls for amyloid P immunohistochemistry was also noted. Immunofluorescence showed positive staining for IgA and Lambda in the mesangia and capillary loops. Electron microscopy exhibited organized fibrils measuring 4–5 nm in diameter in the mesangia, glomerular basement membranes and vessel walls. We interpreted the overall findings as atypical renal amyloidosis with IgA and Lambda deposition on immunofluorescence. Further amyloid typing using laser microdissection-liquid chromatography and mass spectrometry will be useful.
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Affiliation(s)
- Chankyung Kim
- Department of Anatomical Pathology, SA Pathology, Adelaide, Australia
| | - John Brealey
- Department of Anatomical Pathology, SA Pathology, Adelaide, Australia
| | - Anjelo Jobert
- Central and Northern Adelaide Renal Transplantation Services, Royal Adelaide Hospital, Adelaide, Australia
| | - James Nolan
- Department of Anatomical Pathology, SA Pathology, Adelaide, Australia
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30
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Abe R, Katoh N, Takahashi Y, Takasone K, Yoshinaga T, Yazaki M, Kametani F, Sekijima Y. Distribution of amyloidosis subtypes based on tissue biopsy site - Consecutive analysis of 729 patients at a single amyloidosis center in Japan. Pathol Int 2020; 71:70-79. [PMID: 33112446 DOI: 10.1111/pin.13041] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 10/06/2020] [Indexed: 01/30/2023]
Abstract
This study was performed to elucidate the distribution of amyloidosis subtypes based on tissue biopsy site. Samples obtained from 729 consecutive patients with amyloidosis were analyzed by immunohistochemical staining (IHC) and supplemental mass spectrometry (MS). The correlations between the type of organs from which samples were obtained and amyloidosis subtypes were investigated retrospectively. Among the patients, 95.1% were diagnosed by IHC and 4.9% were diagnosed by MS. The distribution of amyloidosis subtypes was as follows: AL, 59.1%; ATTR, 32.9%; AA, 4.0%; AH, 1.4%; Aβ2M, 0.8%; and others, 0.9%. AL was the most common subtype in most organs, including the liver, lung, kidney, lower urinary tract, bone marrow, gastrointestinal tract, and skin/subcutaneous tissue. ATTR was the most common subtype in the heart, carpal tunnel, and peripheral nerves. AH was the second most common subtype in renal biopsy. Three or more amyloidosis subtypes were detected in each organ. In conclusion, AL was the most common subtype in most biopsy sites except the heart, carpal tunnel, and peripheral nerve, in which ATTR was more common. Because several types of amyloidogenic protein were detected in each organ, amyloid typing must be pursued, no matter the site from where biopsy was obtained.
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Affiliation(s)
- Ryuta Abe
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan
| | - Nagaaki Katoh
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan
| | - Yusuke Takahashi
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan
| | - Ken Takasone
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan
| | - Tsuneaki Yoshinaga
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan
| | - Masahide Yazaki
- Clinical Laboratory Science Division, Shinshu University Graduate School of Medicine, Nagano, Japan.,Institute for Biomedical Sciences, Shinshu University, Nagano, Japan
| | - Fuyuki Kametani
- Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Yoshiki Sekijima
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan.,Institute for Biomedical Sciences, Shinshu University, Nagano, Japan
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31
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Karam S, Leung N. Renal Involvement in Systemic Amyloidosis Caused by Monoclonal Immunoglobulins. Hematol Oncol Clin North Am 2020; 34:1069-1079. [PMID: 33099424 DOI: 10.1016/j.hoc.2020.08.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Kidney involvement in immunoglobulin-related amyloidosis (AIg) is common. Although patients with renal-limited AIg tend not to have the high mortality that patients with cardiac amyloidosis have, they do experience significant morbidity and impact on quality of life. The complexity of the pathogenesis remains incompletely understood. Models have been established to prognosticate and assess for the response to therapy. Patients with advanced renal impairment from immunoglobulin light chain amyloidosis still have poor renal prognosis, and better therapy is needed in order to preserve kidney function. Patients who develop end-stage renal disease can undergo renal replacement therapy with kidney transplantation.
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Affiliation(s)
- Sabine Karam
- Division of Nephrology and Hypertension, Saint George Hospital University Medical Center, PO Box 166 378 Achrafieh, Beirut 11 00 2807, Lebanon. https://twitter.com/sabinekaram6
| | - Nelson Leung
- Division of Nephrology and Hypertension, Division of Hematology, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55905, USA.
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32
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Morgan GJ, Wall JS. The Process of Amyloid Formation due to Monoclonal Immunoglobulins. Hematol Oncol Clin North Am 2020; 34:1041-1054. [PMID: 33099422 DOI: 10.1016/j.hoc.2020.07.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Monoclonal antibodies secreted by clonally expanded plasma cells can form a range of pathologic aggregates including amyloid fibrils. The enormous diversity in the sequences of the involved light chains may be responsible for complexity of the disease. Nevertheless, important common features have been recognized. Two recent high-resolution structures of light chain fibrils show related but distinct conformations. The native structure of the light chains is lost when they are incorporated into the amyloid fibrils. The authors discuss the processes that lead to aggregation and describe how existing and emerging therapies aim to prevent aggregation or remove amyloid fibrils from tissues.
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Affiliation(s)
- Gareth J Morgan
- Amyloidosis Center and Section of Hematology and Medical Oncology, Department of Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA.
| | - Jonathan S Wall
- Amyloidosis and Cancer Theranostics Program, Preclinical and Diagnostic Molecular Imaging Laboratory, The University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37920, USA
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33
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Dasari S, Theis JD, Vrana JA, Rech KL, Dao LN, Howard MT, Dispenzieri A, Gertz MA, Hasadsri L, Highsmith WE, Kurtin PJ, McPhail ED. Amyloid Typing by Mass Spectrometry in Clinical Practice: a Comprehensive Review of 16,175 Samples. Mayo Clin Proc 2020; 95:1852-1864. [PMID: 32861330 DOI: 10.1016/j.mayocp.2020.06.029] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 05/11/2020] [Accepted: 06/03/2020] [Indexed: 12/29/2022]
Abstract
OBJECTIVE To map the occurrence of amyloid types in a large clinical cohort using mass spectrometry-based shotgun proteomics, an unbiased method that unambiguously identifies all amyloid types in a single assay. METHODS A mass spectrometry-based shotgun proteomics assay was implemented in a central reference laboratory. We documented our experience of typing 16,175 amyloidosis specimens over an 11-year period from January 1, 2008, to December 31, 2018. RESULTS We identified 21 established amyloid types, including AL (n=9542; 59.0%), ATTR (n=4600; 28.4%), ALECT2 (n=511; 3.2%), AA (n=463; 2.9%), AH (n=367; 2.3%), AIns (n=182; 1.2%), KRT5-14 (n=94; <1%), AFib (n=71; <1%), AApoAIV (n=57; <1%), AApoA1 (n=56; <1%), AANF (n=47; <1%), Aβ2M (n=38; <1%), ASem1 (n=34; <1%), AGel (n=29; <1%), TGFB1 (n=29; <1%), ALys (n=15; <1%), AIAPP (n=13; <1%), AApoCII (n=11; <1%), APro (n=8; <1%), AEnf (n=6; <1%), and ACal (n=2; <1%). We developed the first comprehensive organ-by-type map showing the relative frequency of 21 amyloid types in 31 different organs, and the first type-by-organ map showing organ tropism of 18 rare types. Using a modified bioinformatics pipeline, we detected amino acid substitutions in cases of hereditary amyloidosis with 100% specificity. CONCLUSION Amyloid typing by proteomics, which effectively recognizes all amyloid types in a single assay, optimally supports the diagnosis and treatment of amyloidosis patients in routine clinical practice.
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Affiliation(s)
- Surendra Dasari
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN
| | - Jason D Theis
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Julie A Vrana
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Karen L Rech
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Linda N Dao
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Matthew T Howard
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Angela Dispenzieri
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; Department of Medicine, Mayo Clinic, Rochester, MN
| | | | - Linda Hasadsri
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - W Edward Highsmith
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Paul J Kurtin
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Ellen D McPhail
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
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34
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Chaulagain CP, Herlitz LC, Fu J, Bilani N, Lucitt C, Comenzo RL. How We Manage Systemic Immunoglobulin Heavy Chain Amyloidosis (AH Amyloidosis) and Immunoglobulin Heavy-and-Light-Chain Amyloidosis (AH/AL Amyloidosis). CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2020; 20:e826-e831. [PMID: 32703752 DOI: 10.1016/j.clml.2020.06.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 06/17/2020] [Accepted: 06/22/2020] [Indexed: 11/29/2022]
Affiliation(s)
- Chakra P Chaulagain
- Department of Hematology and Oncology, Maroone Cancer Center, Myeloma and Amyloidosis Program, Cleveland Clinic Florida, Weston, FL.
| | - Leal C Herlitz
- Department of Anatomic Pathology, Section of Medical Kidney Pathology, Cleveland Clinic, Cleveland, OH
| | - Julie Fu
- Division of Hematology and Oncology, Tufts Medical Center Cancer Center, Stoneham, MA; Tufts Medical Center, Boston, MA
| | - Nadeem Bilani
- Department of Hematology and Oncology, Maroone Cancer Center, Myeloma and Amyloidosis Program, Cleveland Clinic Florida, Weston, FL
| | - Camerun Lucitt
- Arizona College of Osteopathic Medicine at Midwestern University, Glendale, AZ
| | - Raymond L Comenzo
- The John Conant Davis Myeloma and Amyloid Program, Division of Hematology-Oncology, Tufts Medical Center, Boston, MA
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35
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Canetti D, Rendell NB, Gilbertson JA, Botcher N, Nocerino P, Blanco A, Di Vagno L, Rowczenio D, Verona G, Mangione PP, Bellotti V, Hawkins PN, Gillmore JD, Taylor GW. Diagnostic amyloid proteomics: experience of the UK National Amyloidosis Centre. Clin Chem Lab Med 2020; 58:948-957. [PMID: 32069225 DOI: 10.1515/cclm-2019-1007] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 01/16/2020] [Indexed: 11/15/2022]
Abstract
Systemic amyloidosis is a serious disease which is caused when normal circulating proteins misfold and aggregate extracellularly as insoluble fibrillary deposits throughout the body. This commonly results in cardiac, renal and neurological damage. The tissue target, progression and outcome of the disease depends on the type of protein forming the fibril deposit, and its correct identification is central to determining therapy. Proteomics is now used routinely in our centre to type amyloid; over the past 7 years we have examined over 2000 clinical samples. Proteomics results are linked directly to our patient database using a simple algorithm to automatically highlight the most likely amyloidogenic protein. Whilst the approach has proved very successful, we have encountered a number of challenges, including poor sample recovery, limited enzymatic digestion, the presence of multiple amyloidogenic proteins and the identification of pathogenic variants. Our proteomics procedures and approaches to resolving difficult issues are outlined.
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Affiliation(s)
- Diana Canetti
- Wolfson Drug Discovery Unit and National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK
| | - Nigel B Rendell
- Wolfson Drug Discovery Unit and National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK
| | - Janet A Gilbertson
- Wolfson Drug Discovery Unit and National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK
| | - Nicola Botcher
- Wolfson Drug Discovery Unit and National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK
| | - Paola Nocerino
- Wolfson Drug Discovery Unit and National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK
| | - Angel Blanco
- Wolfson Drug Discovery Unit and National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK
| | - Lucia Di Vagno
- Wolfson Drug Discovery Unit and National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK
| | - Dorota Rowczenio
- Wolfson Drug Discovery Unit and National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK
| | - Guglielmo Verona
- Wolfson Drug Discovery Unit and National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK
| | - P Patrizia Mangione
- Wolfson Drug Discovery Unit and National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK.,Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, Pavia, Italy
| | - Vittorio Bellotti
- Wolfson Drug Discovery Unit and National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK.,Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, Pavia, Italy
| | - Philip N Hawkins
- Wolfson Drug Discovery Unit and National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK
| | - Julian D Gillmore
- Wolfson Drug Discovery Unit and National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK
| | - Graham W Taylor
- Wolfson Drug Discovery Unit and National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK
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36
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Adachi M, Kitamura M, Muta K, Maekawa A, Uramatsu T, Tadokoro M, Funakoshi S, Hisano S, Kuwahara N, Shimizu A, Mukae H, Nishino T. IgM monoclonal gammopathy with heavy-and-light-chain amyloidosis resembling fibrillary glomerulonephritis determined by tandem mass spectrometry: a case report. BMC Nephrol 2020; 21:195. [PMID: 32448180 PMCID: PMC7245905 DOI: 10.1186/s12882-020-01851-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 05/11/2020] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Fibrillary glomerulonephritis (FGN) is distinguished from amyloidosis by thicker fibrils and the lack of staining with histochemical dyes typically reactive with amyloid. However, congophilic FGN has been proposed recently and adding laser microdissection followed by mass spectrometry (LMD/MS) to conventional pathological methods would be helpful to diagnose FGN. Here, we report a patient initially diagnosed with FGN whose final pathological diagnosis was changed to immunoglobulin heavy-and-light-chain amyloidosis (AHL) after LMD/MS. CASE PRESENTATION A 75-year-old male developed nephrotic syndrome. Protein electrophoresis showed IgM κ type M proteinemia and he was diagnosed with IgM monoclonal gammopathy. A renal biopsy was performed and pathological examination showed marked periodic acid-Schiff-positive enlargement of the mesangial region and silver stain positivity, but weak direct fast scarlet staining. Immunofluorescence analysis showed monoclonal deposition of IgM-κ chain in the glomerulus. Under electron microscopy, the fibrils were about 20 nm in diameter, which was thicker than typical amyloid fibrils. Based on these findings, the patient was diagnosed with FGN. Although cyclophosphamide and prednisolone were administered, his renal function deteriorated and progressed to end stage renal disease requiring maintenance hemodialysis. As congophilic FGN has been recognized since 2018, Congo red staining and LMD/MS were performed. The Congo red staining was positive and LMD/MS results indicated that this was a case of AHL. CONCLUSIONS We reported a case of μ and κ chain AHL resembling FGN requiring LMD/MS for definitive diagnosis. Since FGN and amyloidosis exhibit pathological findings, even if Congo red staining is positive, LMD/MS needs to be considered in cases atypical pathological findings, such as silver stain positivity or thicker fibrils.
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Affiliation(s)
- Misa Adachi
- Department of Nephrology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Mineaki Kitamura
- Department of Nephrology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. .,Department of Nephrology, Nagasaki Renal Center, Nagasaki, Japan.
| | - Kumiko Muta
- Department of Nephrology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Akihiro Maekawa
- Department of Nephrology, Nagasaki Medical Center, Omura, Japan
| | - Tadashi Uramatsu
- Department of Nephrology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masato Tadokoro
- Department of Nephrology, Koritsu Shin-Obama Hospital, Nagasaki, Japan
| | | | - Satoshi Hisano
- Department of Pathology, University of Occupational and Environmental Health School of Medicine, Kitakyushu, Japan
| | - Naomi Kuwahara
- Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan
| | - Akira Shimizu
- Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan
| | - Hiroshi Mukae
- Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tomoya Nishino
- Department of Nephrology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Sekulic M, Pichler Sekulic S, Weins A. Heavy and light chain (AHL)-type cardiac amyloidosis: first histopathologic-proven case illustrating involvement of the heart. Virchows Arch 2020; 477:733-738. [PMID: 32388718 DOI: 10.1007/s00428-020-02837-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 04/23/2020] [Accepted: 04/28/2020] [Indexed: 10/24/2022]
Abstract
Cardiac amyloidosis is most commonly comprised of either a monoclonal immunoglobulin or transthyretin; however, in practice, detailing of the former beyond light chain restriction is not typically performed. We present briefly the case of an 80-year-old man with concern for cardiac amyloidosis and a subsequent endomyocardial biopsy revealing significant deposition of amorphous Congo red-positive material. By immunofluorescence microscopy, the amyloidogenic material showed positive expression for IgG heavy chain and kappa light chain, with negative staining for IgM and IgA heavy chains and lambda light chain supporting a diagnosis of heavy and light chain (AHL)-type amyloidosis. Immunofluorescence staining for the IgG heavy chain subclasses supported and further classified the patient's AHL-type cardiac amyloidosis as being IgG4/kappa restricted. The presented case is the first to illustrate AHL-type cardiac amyloidosis via sampling of heart tissue.
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Affiliation(s)
- Miroslav Sekulic
- Department of Pathology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
| | - Simona Pichler Sekulic
- Department of Pathology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Astrid Weins
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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Ville S, Kandel C, Delaunay J, Cantarovich D. IgGκ light and heavy chain amyloidosis secondary to a B-cell lymphoproliferative disorder, whole picture on a renal biopsy. Nephrology (Carlton) 2019; 25:429-430. [PMID: 31726478 DOI: 10.1111/nep.13673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 09/23/2019] [Accepted: 10/13/2019] [Indexed: 11/27/2022]
Affiliation(s)
- Simon Ville
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France
| | | | | | - Diego Cantarovich
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France
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40
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Fung AWS, Sugumar V, Ren AH, Kulasingam V. Emerging role of clinical mass spectrometry in pathology. J Clin Pathol 2019; 73:61-69. [PMID: 31690564 DOI: 10.1136/jclinpath-2019-206269] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 10/14/2019] [Indexed: 12/20/2022]
Abstract
Mass spectrometry-based assays have been increasingly implemented in various disciplines in clinical diagnostic laboratories for their combined advantages in multiplexing capacity and high analytical specificity and sensitivity. It is now routinely used in areas including reference methods development, therapeutic drug monitoring, toxicology, endocrinology, paediatrics, immunology and microbiology to identify and quantify biomolecules in a variety of biological specimens. As new ionisation methods, instrumentation and techniques are continuously being improved and developed, novel mass spectrometry-based clinical applications will emerge for areas such as proteomics, metabolomics, haematology and anatomical pathology. This review will summarise the general principles of mass spectrometry and specifically highlight current and future clinical applications in anatomical pathology.
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Affiliation(s)
- Angela W S Fung
- Department of Pathology and Laboratory Medicine, St Paul's Hospital, Vancouver, British Columbia, Canada.,Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Vijithan Sugumar
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Annie He Ren
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Vathany Kulasingam
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada .,Clinical Biochemistry, University Health Network, Toronto, Ontario, Canada
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41
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Otaka Y, Nakazato Y, Tsutsui T, Tamura J. Cardiac involvement in heavy and light chain amyloidosis: A case report and literature review. Medicine (Baltimore) 2019; 98:e17999. [PMID: 31725668 PMCID: PMC6867769 DOI: 10.1097/md.0000000000017999] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
INTRODUCTION Heavy and light chain amyloidosis is an extremely rare condition. There are few reports referring to the clinical impact of cardiac involvement in heavy and light chain amyloidosis, and the significance of myocardial impairment has not yet been completely explained. PATIENT CONCERNS A 66-year-old Japanese man was admitted to our hospital presenting with nephrotic syndrome and congestive heart failure. DIAGNOSIS Kidney and endoscopic gastric mucosal biopsy demonstrated congophilic hyalinization in most of the glomeruli and surrounding vessel walls, which were highly positive for immunoglobulin A and lambda. Finally, the patient was diagnosed as an atypical multiple myeloma with systemic heavy and light chain amyloidosis. INTERVENTIONS The patient was referred to hematology for further treatment and was moved to another hospital for the administration of chemotherapy using melphalan and dexamethasone. OUTCOMES The patient was still alive after 15-month follow-up from the initial diagnosis. CONCLUSION Initial screening and follow-up for cardiac involvement are important for heavy and light chain amyloidosis. Further investigation for the prognosis of heavy and light chain amyloidosis is required to improve the strategies of diagnosis and treatment options for patients with this disease.
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Affiliation(s)
- Yukihiro Otaka
- Department of General Medicine, Gunma University Graduate School of Medicine, Maebashi
- Kidney Disease and Dialysis Center
| | - Yoichi Nakazato
- Department of Pathology, Hidaka-kai Hidaka Hospital, Takasaki, Gunma, Japan
| | | | - Jun’ichi Tamura
- Department of General Medicine, Gunma University Graduate School of Medicine, Maebashi
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42
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Wu HT, Wen YB, Ye W, Liu BY, Shen KN, Gao RT, Li MX. Underlying IgM heavy chain amyloidosis in treatment-refractory IgA nephropathy: A case report. World J Clin Cases 2019; 7:3055-3061. [PMID: 31624754 PMCID: PMC6795715 DOI: 10.12998/wjcc.v7.i19.3055] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 08/14/2019] [Accepted: 08/26/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Monoclonal immunoglobulin can cause renal damage, with a wide spectrum of pathological changes and clinical manifestations without hematological evidence of malignancy. These disorders can be missed, especially when combined with other kidney diseases.
CASE SUMMARY A 61-year-old woman presented with moderate proteinuria with normal renal function. She was diagnosed with IgA nephropathy combined with monoclonal gammopathy of undetermined significance after the first renal biopsy. Although having received immunosuppressive treatment for 3 years, the patient developed nephrotic syndrome. Repeated renal biopsy and laser microdissection/mass spectrometry analysis confirmed heavy chain amyloidosis. After nine cycles of bortezomib, cyclophosphamide and dexamethasone, she achieved very good partial hematological and kidney responses.
CONCLUSION Renal injury should be monitored closely in monoclonal gammopathy patients without obvious hematological malignancy, especially in patients with other pre-existing renal diseases.
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Affiliation(s)
- Hai-Ting Wu
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yu-Bing Wen
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Wei Ye
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Bing-Yan Liu
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Kai-Ni Shen
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Rui-Tong Gao
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Ming-Xi Li
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Gonzalez Suarez ML, Zhang P, Nasr SH, Sathick IJ, Kittanamongkolchai W, Kurtin PJ, Alexander MP, Cornell LD, Fidler ME, Grande JP, Herrera Hernandez LP, Said SM, Sethi S, Dispenzieri A, Gertz MA, Leung N. The sensitivity and specificity of the routine kidney biopsy immunofluorescence panel are inferior to diagnosing renal immunoglobulin-derived amyloidosis by mass spectrometry. Kidney Int 2019; 96:1005-1009. [DOI: 10.1016/j.kint.2019.05.027] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 03/27/2019] [Accepted: 05/02/2019] [Indexed: 10/26/2022]
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Regression of renal amyloid deposits by VAD therapy plus autologous stem cell transplantation in a patient with primary AL amyloidosis. CEN Case Rep 2019; 9:6-10. [PMID: 31522370 DOI: 10.1007/s13730-019-00416-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 09/03/2019] [Indexed: 10/26/2022] Open
Abstract
We report a 58-year-old Japanese woman who presented with nephrotic syndrome. Steroid therapy and cyclosporine A administration were initiated, but hematological remission and renal response were not achieved. Renal biopsy revealed amyloid deposits in the mesangial region and the small arteries. Proteomic analysis based on laser microdissection and mass spectrometry showed that the amyloid deposits were composed of the constant region of the lambda light chain. She received vincristine, adriamycin, and dexamethasone therapy followed by high-dose melphalan and autologous stem cell transplantation, resulting in hematological complete remission and renal response with negative urinary Bence-Jones protein and proteinuria. Renal biopsy was performed four times during follow-up, demonstrating that amyloid deposits decreased gradually, while glomeruli showing global sclerosis increased from 3 to 62%. This case suggests that glomerular amyloid deposits can be cleared via tissue remodeling, if stem cells producing amyloid precursors are completely replaced by unrelated cells after stem cell transplantation.
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45
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Nasr SH, Fogo AB. New developments in the diagnosis of fibrillary glomerulonephritis. Kidney Int 2019; 96:581-592. [PMID: 31227146 DOI: 10.1016/j.kint.2019.03.021] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 02/28/2019] [Accepted: 03/08/2019] [Indexed: 11/25/2022]
Abstract
Fibrillary glomerulonephritis is a glomerular disease historically defined by glomerular deposition of Congo red-negative, randomly oriented straight fibrils that lack a hollow center and stain with antisera to immunoglobulins. It was initially considered to be an idiopathic disease, but recent studies highlighted association in some cases with autoimmune disease, malignant neoplasm, or hepatitis C viral infection. Prognosis is poor with nearly half of patients progressing to end-stage renal disease within 4 years. There is currently no effective therapy, aside from kidney transplantation, which is associated with disease recurrence in a third of cases. The diagnosis has been hampered by the lack of biomarkers for the disease and the necessity of electron microscopy for diagnosis, which is not widely available. Recently, through the use of laser microdissection-assisted liquid chromatography-tandem mass spectrometry, a novel biomarker of fibrillary glomerulonephritis, DnaJ homolog subfamily B member 9, has been identified. Immunohistochemical studies confirmed the high sensitivity and specificity of DnaJ homolog subfamily B member 9 for this disease; dual immunofluorescence showed its colocalization with IgG in glomeruli; and immunoelectron microscopy revealed its localization to individual fibrils of fibrillary glomerulonephritis. The identification of this tissue biomarker has already entered clinical practice and undoubtingly will improve the diagnosis of this rare disease, particularly in developing countries where electron microscopy is less available. Future research is needed to determine whether DnaJ homolog subfamily B member 9 is an autoantigen or just an associated protein in fibrillary glomerulonephritis, whether it can serve as a noninvasive biomarker, and whether therapies that target this protein are effective in improving prognosis.
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Affiliation(s)
- Samih H Nasr
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
| | - Agnes B Fogo
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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46
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Nasr SH, Sirac C, Bridoux F, Javaugue V, Bender S, Rinsant A, Kaaki S, Pinault E, Dasari S, Alexander MP, Said SM, Hogan JJ, Dispenzieri A, Touchard G, McPhail ED, Leung N. Heavy Chain Fibrillary Glomerulonephritis: A Case Report. Am J Kidney Dis 2019; 74:276-280. [PMID: 30955945 DOI: 10.1053/j.ajkd.2019.01.032] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 01/21/2019] [Indexed: 11/11/2022]
Abstract
Heavy chain amyloidosis and heavy chain deposition disease are the only known kidney diseases caused by the deposition of truncated immunoglobulin heavy chains. Fibrillary glomerulonephritis typically results from deposition of DNAJB9 (DnaJ heat shock protein family [Hsp40] member B9) and polytypic immunoglobulin G (IgG). We describe a patient with monoclonal gammopathy (IgG with λ light chain) who developed DNAJB9-negative fibrillary glomerulonephritis leading to end-stage kidney disease, with recurrence in 2 kidney allografts. Pre- and postmortem examination showed glomerular deposition of Congo red-negative fibrillar material that was determined to be immunoglobulin heavy chain. We propose the term "heavy chain fibrillary glomerulonephritis" to describe this lesion, which appears to be a rare kidney complication of monoclonal gammopathy. The diagnosis should be suspected when the kidney biopsy shows fibrillary glomerulonephritis with negative staining for immunoglobulin light chains and DNAJB9; the diagnosis can be confirmed using immunochemical and molecular studies.
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Affiliation(s)
- Samih H Nasr
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
| | - Christophe Sirac
- Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Limoges, France.
| | - Frank Bridoux
- Department of Nephrology, Dialysis and Renal Transplantation, University Hospital of Poitiers, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Poitiers, France
| | - Vincent Javaugue
- Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Limoges, France; Department of Nephrology, Dialysis and Renal Transplantation, University Hospital of Poitiers, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Poitiers, France
| | - Sebastien Bender
- Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Limoges, France
| | - Alexia Rinsant
- Department of Pathology, University Hospital of Poitiers, Poitiers, France
| | - Sihem Kaaki
- Department of Pathology, University Hospital of Poitiers, Poitiers, France
| | - Emilie Pinault
- University of Limoges, BISCEm Mass Spectrometry Platform, F-87000 Limoges, France
| | - Surendra Dasari
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN
| | - Mariam P Alexander
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Samar M Said
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Jonathan J Hogan
- Division of Nephrology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | | | - Guy Touchard
- Department of Nephrology, Dialysis and Renal Transplantation, University Hospital of Poitiers, Centre de référence de l'amylose AL et des autres maladies par dépôts d'immunoglobuline monoclonale, Poitiers, France
| | - Ellen D McPhail
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Nelson Leung
- Division of Hematology, Mayo Clinic, Rochester, MN
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47
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Cao Q, Qi H, Yao L, Liu Q. Monoclonal gammopathy of renal significance: clinical manifestation, pathogenic characteristic and treatment. Panminerva Med 2019; 62:38-53. [PMID: 30848114 DOI: 10.23736/s0031-0808.19.03609-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Monoclonal gammopathy of renal significance (MGRS) is a group of renal disorders caused by a monoclonal immunoglobulin (MIg) secreted by a dangerous plasmatic/B-cell clone hyperplasia through MIg deposition or dysfunction of complement pathway, with increasing risk of progress to end stage renal disease (ESRD) and the underlying hematologic malignancy. The combination of renal biopsy, complete laboratory examination and bone marrow biopsy is an indispensable diagnostic tool for MGRS to identify accurately and unequivocally the pathogenic monoclonal MIg and provide guidance to treatment. Treatment of MGRS is composed of conventional therapy, chemotherapy, and stem cell transplantation to target the underlying clone and eliminate the noxious MIg on the basis of clinical data of some retrospective studies and a small amount of prospective trial. In addition, it is worthwhile point out assessment of therapeutic effect is significantly relevant for renal and overall prognosis. Thus, by comprehensively analyzing the clinical manifestations and pathogenic characteristic of MGRS, early recognition and prompt treatment can improve the prognosis and prevent post-translation recurrence with multidisciplinary cooperation.
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Affiliation(s)
- Qin Cao
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, China
| | - Huimeng Qi
- Department of General Practice, The First Hospital of China Medical University, Shenyang, China
| | - Li Yao
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, China
| | - Qiang Liu
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, China -
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48
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Fu J, Lee LX, Zhou P, Fogaren T, Varga C, Comenzo RL. A Case of T-Cell Large Granular Lymphocytic Leukemia and Renal Immunoglobulin Heavy Chain Amyloidosis. AMERICAN JOURNAL OF CASE REPORTS 2019; 20:43-47. [PMID: 30631033 PMCID: PMC6345110 DOI: 10.12659/ajcr.912282] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Patient: Female, 57 Final Diagnosis: Renal heavy chain amyloidosis Symptoms: Fatigue • proteinuria Medication: — Clinical Procedure: Chemotherapy, consideration of autologous stem cell transplant Specialty: Hematology
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Affiliation(s)
- Julie Fu
- Division of Hematology Oncology, Tufts Medical Center, Boston, MA, USA.,School of Medicine, Tufts University, Boston, MA, USA.,Cancer Center in Stoneham, Tufts Medical Center, Stoneham, MA, USA
| | - Lisa X Lee
- Division of Hematology Oncology, Tufts Medical Center, Boston, MA, USA.,John C Davis Myeloma and Amyloid Program, Tufts Medical Center, Boston, MA, USA
| | - Ping Zhou
- John C Davis Myeloma and Amyloid Program, Tufts Medical Center, Boston, MA, USA
| | - Teresa Fogaren
- Division of Hematology Oncology, Tufts Medical Center, Boston, MA, USA
| | - Cindy Varga
- Division of Hematology Oncology, Tufts Medical Center, Boston, MA, USA.,School of Medicine, Tufts University, Boston, MA, USA.,John C Davis Myeloma and Amyloid Program, Tufts Medical Center, Boston, MA, USA
| | - Raymond L Comenzo
- Division of Hematology Oncology, Tufts Medical Center, Boston, MA, USA.,School of Medicine, Tufts University, Boston, MA, USA.,John C Davis Myeloma and Amyloid Program, Tufts Medical Center, Boston, MA, USA
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49
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Otaka Y, Goda F, Nakazato Y, Tsutsui T. Systemic heavy- and light-chain amyloidosis presenting nephrotic syndrome and congestive heart failure: a case presentation and literature review. Amyloid 2019; 26:95-96. [PMID: 31343287 DOI: 10.1080/13506129.2019.1582022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Yukihiro Otaka
- a Hidaka Hospital, Kidney Disease and Dialysis Center , Gunma , Japan
| | - Fumito Goda
- b Department of General Internal Medicine, Takasaki General Medical Center , Gunma , Japan
| | - Yoichi Nakazato
- c Hidaka Hospital, Hidaka Center for Pathologic Diagnosis and Research , Gunma , Japan
| | - Takaaki Tsutsui
- a Hidaka Hospital, Kidney Disease and Dialysis Center , Gunma , Japan
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50
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Fu J, Lee L, Zhou P, Fogaren T, Comenzo R. A case report - renal heavy chain amyloidosis and T-cell large granular lymphocytic leukaemia. Amyloid 2019; 26:130-131. [PMID: 31343367 DOI: 10.1080/13506129.2019.1583180] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Julie Fu
- a Division of Hematology Oncology, Tufts Medical Center , Boston , MA , USA.,b Tufts University School of Medicine , Boston , MA , USA.,c Tufts Medical Center Cancer Center , Stoneham , MA , USA
| | - Lisa Lee
- a Division of Hematology Oncology, Tufts Medical Center , Boston , MA , USA.,d John C Davis Myeloma and Amyloid Program, Tufts Medical Center Cancer Center , Boston , MA , USA
| | - Ping Zhou
- d John C Davis Myeloma and Amyloid Program, Tufts Medical Center Cancer Center , Boston , MA , USA
| | - Teresa Fogaren
- a Division of Hematology Oncology, Tufts Medical Center , Boston , MA , USA
| | - Raymond Comenzo
- a Division of Hematology Oncology, Tufts Medical Center , Boston , MA , USA.,b Tufts University School of Medicine , Boston , MA , USA.,d John C Davis Myeloma and Amyloid Program, Tufts Medical Center Cancer Center , Boston , MA , USA
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