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Drug repurposing for glomerular diseases: an underutilized resource

Nature Reviews Nephrology (2024)Cite this article

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Abstract

Drug repurposing in glomerular disease can deliver opportunities for steroid-free regimens, enable personalized multi-target options for resistant or relapsing disease and enhance treatment options for understudied populations (for example, children) and in resource-limited settings. Identification of drug-repurposing candidates can be data driven, which utilizes existing data on disease pathobiology, drug features and clinical outcomes, or experimental, which involves high-throughput drug screens. Information from databases of approved drugs, clinical trials and PubMed registries suggests that at least 96 drugs on the market cover 49 targets with immunosuppressive potential that could be candidates for drug repurposing in glomerular disease. Furthermore, evidence to support drug repurposing is available for 191 immune drug target–glomerular disease pairs. Non-immunological drug repurposing includes strategies to reduce haemodynamic overload, podocyte injury and kidney fibrosis. Recommended strategies to expand drug-repurposing capacity in glomerular disease include enriching drug databases with glomeruli-specific information, enhancing the accessibility of primary clinical trial data, biomarker discovery to improve participant selection into clinical trials and improve surrogate outcomes and initiatives to reduce patent, regulatory and organizational hurdles.

Key points

  • Drug repurposing can improve the treatment of glomerular disease by providing steroid-free regimens, enabling options for resistant or relapsing disease, enhancing treatment options for understudied populations and increasing therapy options in resource-limited settings.

  • Contemporary methods of identifying drug-repurposing candidates can be data driven or experimental.

  • At least 96 drugs on the market have targets with immunosuppressive potential that could be candidates for repurposing for glomerular disease treatment.

  • Non-immunological drug repurposing for glomerular disease involves strategies to reduce haemodynamic overload, podocyte injury and kidney fibrosis.

  • Strategies to expand drug-repurposing capacity need to enrich datasets with glomeruli-specific information, enhance the accessibility of clinical trial data, improve biomarker discovery and address patent, regulatory and organizational hurdles.

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Fig. 1: Methodologies for identifying candidate drugs for repurposing.
Fig. 2: Drug classes targeting innate immune system and complement cascade for repurposing in glomerular disease.
Fig. 3: Drug classes targeting adaptive immune system and downstream mechanisms for repurposing in glomerular disease.
Fig. 4: Current evidence supporting drug target–glomerular disease pairs for drug repurposing.

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Acknowledgements

M.S.Y.N. acknowledges support for the research of this work from the Royal Brisbane and Women’s Hospital Foundation (2020 Robert and Janelle Bird Postdoctoral Research Fellowship).

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Authors and Affiliations

  1. Kidney Health Service, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia

    Monica Suet Ying Ng

  2. Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Brisbane, Queensland, Australia

    Monica Suet Ying Ng

  3. Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia

    Monica Suet Ying Ng & Ross S. Francis

  4. Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia

    Monica Suet Ying Ng, Ross S. Francis, Carmel M. Hawley & David W. Johnson

  5. Department of Rheumatology, Saint Vincent’s Hospital, Sydney, New South Wales, Australia

    Gursimran Kaur

  6. Saint Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia

    Gursimran Kaur

  7. Rheumatology Department, Sunshine Coast University Hospital, Birtinya, Queensland, Australia

    Gursimran Kaur

  8. Translational Research Institute, Brisbane, Queensland, Australia

    Carmel M. Hawley & David W. Johnson

  9. Centre for Kidney Disease Research, University of Queensland, Brisbane, Queensland, Australia

    Carmel M. Hawley & David W. Johnson

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Contributions

M.S.Y.N., G.K. and R.S.F. researched data for the article. M.S.Y.N. wrote the article. All authors made substantial contributions to discussions of the content, and reviewed or edited the manuscript before submission.

Corresponding author

Correspondence to Monica Suet Ying Ng.

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Competing interests

M.S.Y.N. has received research grants and travel sponsorships from Avant Foundation and postdoctoral research fellowship from the Royal Brisbane and Women’s Hospital Foundation. G.K. has received research grants from the New Zealand Rheumatology Association. R.S.F. has received consultancy fees from Exelixis. C.M.H. has received research grants from Baxter Healthcare. D.W.J. has received consultancy fees, research grants, speaker’s honoraria and travel sponsorships from Baxter Healthcare and Fresenius Medical Care, consultancy fees from Astra Zeneca, Bayer, and AWAK, speaker’s honoraria from Ono and Boehringer Ingelheim & Lilly, and travel sponsorships from Ono and Amgen; D.W.J. is a current recipient of an Australian National Health and Medical Research Council Leadership Investigator Grant.

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Nature Reviews Nephrology thanks Gabriel Cara Fuentes, Duvuru Geetha, William Smoyer and Vladimir Tesar for their contribution to the peer review of this work.

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Related links

European Medicines Agency: https://www.ema.europa.eu/en/medicines

NIH clinical trials database: https://www.clinicaltrials.gov/

US Food and Drug Administration: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm

Supplementary information

Glossary

Adaptive trials

Clinical trials that allow modifications to trial protocol after trial initiation without undermining internal validity. Adaptive trials move away from traditional phase I–III categories and allows a single study to move between different phases of clinical trials.

Bags-of-words

A method of representing text data for natural language processing or machine-learning algorithms that converts text into an unordered collection of words; captures word frequency but not word order.

Basket trials

Clinical trials in which a drug is tested against multiple diseases with a shared disease mechanism (for example, testing an anti-complement drug against lupus nephritis, IgAN, membranous nephropathy, C3 glomerulopathy and dense deposit disease); also known as bucket trials.

First-pass metabolism

Pharmacological phenomenon whereby a drug undergoes metabolism prior to reaching systemic circulation or site of action. The first-pass effect is often associated with the liver, particularly for oral medications, but can also occur in the small intestine, lungs, vasculature or other metabolically active tissues.

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Ng, M.S.Y., Kaur, G., Francis, R.S. et al. Drug repurposing for glomerular diseases: an underutilized resource. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00864-8

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