Monoclonal Gammopathy of Renal Significance: A Molecular Middle Earth between Oncology, Nephrology, and Pathology

L’Imperio, Vincenzo; Cazzaniga, Giorgio; Vergani, Barbara; Smith, Andrew; Alberici, Federico; Pagni, Fabio

doi:10.1159/000527056

Cited by 4 publications

(4 citation statements)

References 92 publications

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“…Type I (10-15%): monoclonal immunoglobulins, usually IgG or IgM, found in lymphoproliferative disorders (Waldenstrom’s macroglobulinemia, multiple myeloma, and monoclonal gammopathy of unknown significance, MGUS) 43 .…”

Section: Diagnostic Approach and Pathology Of Renal Vasculitismentioning

confidence: 99%

Systemic vasculitis involving the kidney: the nephropathologist’s point of view

L’Imperio,

Ceola,

Cerbelli

et al. 2024

Pathologica

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Summary Kidneys are often targets of systemic vasculitis (SVs), being affected in many different forms and representing a possible sentinel of an underlying multi-organ condition. Renal biopsy still remains the gold standard for the identification, characterization and classification of these diseases, solving complex differential diagnosis thanks to the combined application of light microscopy (LM), immunofluorescence (IF) and electron microscopy (EM). Due to the progressively increasing complexity of renal vasculitis classification systems (e.g. pauci-immune vs immune complex related forms), a clinico-pathological approach is mandatory and adequate technical and interpretative expertise in nephropathology is required to ensure the best standard of care for our patients. In this complex background, the present review aims at summarising the current knowledge and challenges in the world of renal vasculitis, unveiling the potential role of the introduction of digital pathology in this setting, from the creation of hub-spoke networks to the future application of artificial intelligence (AI) tools to aid in the diagnostic and scoring/classification process.

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Section: Diagnostic Approach and Pathology Of Renal Vasculitismentioning

confidence: 99%

Systemic vasculitis involving the kidney: the nephropathologist’s point of view

L’Imperio,

Ceola,

Cerbelli

et al. 2024

Pathologica

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“…Meanwhile, the presence of abnormal biosynthesis of Ig fragments and/or post-translational proteolysis suggests that the absence of known peptides from previous data leads to false negative identification of fibril precursor proteins, particularly in the localized forms. LMD/PRM-MS is not the only solution to this issue, because relatively new in situ proteomics techniques, MALDI-MSI can also detect and type even small amount of amyloid deposits directly on one single tissue slide without the need of LMD [13,40,41].…”

Section: Table 4 Examples From Two Early-stage Renal Amyloidosis Pati...mentioning

confidence: 99%

“…The renal biopsy plays a central role for the diagnosis of different forms of monoclonal gammopathy of renal significance (MGRS), helping in identifying patients with sub-detectable neoplastic clones. In this setting, proteomic techniques can play a crucial role in identifying early pathological glomerular modifications and shedding light on the pathobiology of these diseases [13]. Proteomics has been proposed the gold standard technique, with much higher sensitivity and specificity as compared to the "routine" immuno-based methods, which makes this tool necessary for the correct classification of amyloid deposits.…”

Section: Introductionmentioning

confidence: 99%

Precise diagnosis and typing of early-stage renal immunoglobulin-derived amyloidosis by label-free quantification of parallel reaction monitoring-based targeted proteomics

Zhang

Zhou

et al. 2023

BMC Nephrol

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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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“…Amyloidosis can affect the kidneys, and characterisation of the precursor protein is of paramount importance for therapeutic reasons, as cases related to monoclonal components (AL/AH) should be treated with aggressive chemotherapy 1. Amyloidosis falls under the definition of ‘monoclonal gammopathy of renal significance’ (MGRS),2 which is conventionally detected by light microscopy (LM), immunofluorescence/immunohistochemistry (IF/IHC) and transmission electron microscopy (TEM) 3. In challenging cases, amyloid precursor identification (typing) may be compromised by the inherent limitations of IF,4 leading to a paradigm shift towards more sensitive/specific techniques such as mass spectrometry (MS) 5.…”

Section: Introductionmentioning

confidence: 99%

Spatial resolution of renal amyloid deposits through MALDI-MSI: a combined digital and molecular approach to monoclonal gammopathies

et al. 2023

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AimsIdentification and characterisation of monoclonal gammopathies of renal significance (MGRS) is critical for therapeutic purposes. Amyloidosis represents one of the most common forms of MGRS, and renal biopsy remains the gold standard for their classification, although mass spectrometry has shown greater sensitivity in this area.MethodsIn the present study, a new in situ proteomic technique, matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI), is investigated as an alternative to conventional laser capture microdissection MS for the characterisation of amyloids. MALDI-MSI was performed on 16 cases (3 lambda light chain amyloidosis (AL), 3 AL kappa, 3 serum amyloid A amyloidosis (SAA), 2 lambda light chain deposition disease (LCDD), 2 challenging amyloid cases and 3 controls). Analysis began with regions of interest labelled by the pathologist, and then automatic segmentation was performed.ResultsMALDI-MSI correctly identified and typed cases with known amyloid type (AL kappa, AL lambda and SAA). A ‘restricted fingerprint’ for amyloid detection composed of apolipoprotein E, serum amyloid protein and apolipoprotein A1 showed the best automatic segmentation performance (area under the curve >0.7).ConclusionsMALDI-MSI correctly assigned minimal/challenging cases of amyloidosis to the correct type (AL lambda) and identified lambda light chains in LCDD cases, highlighting the promising role of MALDI-MSI for amyloid typing.

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Monoclonal Gammopathy of Renal Significance: A Molecular Middle Earth between Oncology, Nephrology, and Pathology

Cited by 4 publications

References 92 publications

Systemic vasculitis involving the kidney: the nephropathologist’s point of view

Systemic vasculitis involving the kidney: the nephropathologist’s point of view

Precise diagnosis and typing of early-stage renal immunoglobulin-derived amyloidosis by label-free quantification of parallel reaction monitoring-based targeted proteomics

Spatial resolution of renal amyloid deposits through MALDI-MSI: a combined digital and molecular approach to monoclonal gammopathies

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