Review Article | Published:

Animal models of monoclonal immunoglobulin-related renal diseases

Nature Reviews Nephrology volume 14, pages 246264 (2018) | Download Citation

Abstract

The renal deposition of monoclonal immunoglobulins can cause severe renal complications in patients with B cell and plasma cell lymphoproliferative disorders. The overproduction of a structurally unique immunoglobulin can contribute to the abnormal propensity of monoclonal immunoglobulins to aggregate and deposit in specific organs. A wide range of renal diseases can occur in multiple myeloma or monoclonal gammopathy of renal significance, including tubular and glomerular disorders with organized or unorganized immunoglobulin deposits. The development of reliable experimental models is challenging owing to the inherent variability of immunoglobulins and the heterogeneity of the pathologies they produce. However, although imperfect, animal models are invaluable tools to understand the molecular pathogenesis of these diseases, and advances in creating genetically modified animals might provide novel approaches to evaluate innovative therapeutic interventions. We discuss the strategies employed to reproduce human monoclonal immunoglobulin-induced kidney lesions in animal models, and we highlight their advantages and shortcomings. We also discuss how these models have affected the management of these deposition diseases and might do so in the future. Finally, we discuss hypotheses that explain some limitations of the various models, and how these models might improve our understanding of other nephropathies without immunoglobulin involvement that have similar pathogenic mechanisms.

Key points

  • Numerous renal diseases occur owing to the deposition of a monoclonal immunoglobulin, including multiple myeloma and monoclonal gammopathy of renal significance

  • Understanding the molecular pathogenesis of human immunoglobulin deposition diseases and testing new therapeutic strategies requires relevant animal models, which is a challenge owing to the heterogeneity of these diseases

  • Models based on the injection of purified human immunoglobulins and on tumour grafts that produce the monoclonal immunoglobulin have revealed several early pathogenic events in immunoglobulin deposition and demonstrated the efficacy of innovative therapeutic agents

  • Advances in transgenic techniques have allowed the creation of mouse models that faithfully reproduce the human diseases and have aided in unravelling the pathogenic mechanisms of monoclonal immunoglobulin deposition

  • Animal models are invaluable tools to study the process of deposition and to explore the direct toxicity of monoclonal immunoglobulins in tissues and immunoglobulin-producing plasma cells

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Acknowledgements

The authors thank the members of the International Kidney and Monoclonal Gammopathy Research Group for their intellectual support in this project. C.S. thanks C. Carrion, A. Rinsant, S. Kaaki, N. Quellard, J.M. Goujon, A. Jaccard and D. Lavergne for their technical and intellectual support. C.S. is supported by a grant from Fondation Française pour le Recheche contre le Myelome et les Gammapathies Monoclonales. G.A.H. is supported by a grant from the Amyloidosis Foundation. P.W.S. is supported by grants from the Office of Research and Development, Medical Research Service, US Department of Veterans Affairs (I01 CX001326) and the US National Institutes of Health George M. O'Brien Kidney and Urological Research Centers Program (P30 DK079337). M.V.A. is funded by a fellowship from region Nouvelle Aquitaine. S.B. is supported by the French Ministry of Research 'Plan maladies rares'.

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Affiliations

  1. CNRS UMR 7276-CRIBL, University of Limoges, Limoges, France, and French National Reference Centre for “AL Amyloidosis and Other Monoclonal Immunoglobulin Deposition Diseases”, University Hospital Dupuytren, Limoges, France.

    • Christophe Sirac
    • , Sebastien Bender
    • , Maria V. Ayala
    • , Vincent Javaugue
    • , Michel Cogné
    •  & Frank Bridoux
  2. Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.

    • Guillermo A. Herrera
    • , Jiamin Teng
    •  & Elba A. Turbat-Herrera
  3. Division of Nephrology, Department of Medicine, University of Alabama at Birmingham and Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA.

    • Paul W. Sanders
  4. Department of Medicine, Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA, and Department of Medicine, Nephrology Section-SL45, Tulane University Medical School, New Orleans, LA, USA.

    • Vecihi Batuman
  5. Department of Nephrology and Transplantation, University Hospital of Poitiers, Poitiers, France.

    • Vincent Javaugue
    • , Guy Touchard
    •  & Frank Bridoux
  6. Division of Nephrology and Hypertension and Division of Hematology, Mayo Clinic, Rochester, MN, USA.

    • Nelson Leung

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All authors contributed to researching data for the article and writing, reviewing and editing the article before submission.

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Correspondence to Christophe Sirac.

Glossary

Immunoglobulin-related amyloidosis

Accumulation of abnormal immunoglobulin fragments that form fibrils and deposit in organs and tissues, causing their dysfunction.

Monoclonal immunoglobulin deposition disease

(MIDD). Accumulation of abnormal immunoglobulin fragments that form granular deposits in organs and tissues, mainly the kidneys, causing their dysfunction.

Myeloma cast nephropathy

(MCN). Acute kidney disease that occurs in multiple myeloma and is characterized by the obstruction of distal tubules by casts composed of a monoclonal immunoglobulin light chain.

Light chain-induced Fanconi syndrome

Generalized dysfunction of reabsorption in proximal tubules due to the intracellular accumulation of a monoclonal immunoglobulin light chain.

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https://doi.org/10.1038/nrneph.2018.8