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Oxalate homeostasis

Nature Reviews Nephrology volume 19, pages 123–138 (2023)Cite this article

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Abstract

Oxalate homeostasis is maintained through a delicate balance between endogenous sources, exogenous supply and excretion from the body. Novel studies have shed light on the essential roles of metabolic pathways, the microbiome, epithelial oxalate transporters, and adequate oxalate excretion to maintain oxalate homeostasis. In patients with primary or secondary hyperoxaluria, nephrolithiasis, acute or chronic oxalate nephropathy, or chronic kidney disease irrespective of aetiology, one or more of these elements are disrupted. The consequent impairment in oxalate homeostasis can trigger localized and systemic inflammation, progressive kidney disease and cardiovascular complications, including sudden cardiac death. Although kidney replacement therapy is the standard method for controlling elevated plasma oxalate concentrations in patients with kidney failure requiring dialysis, more research is needed to define effective elimination strategies at earlier stages of kidney disease. Beyond well-known interventions (such as dietary modifications), novel therapeutics (such as small interfering RNA gene silencers, recombinant oxalate-degrading enzymes and oxalate-degrading bacterial strains) hold promise to improve the outlook of patients with oxalate-related diseases. In addition, experimental evidence suggests that anti-inflammatory medications might represent another approach to mitigating or resolving oxalate-induced conditions.

Key points

  • Oxalate homeostasis is maintained through a combination of endogenous biosynthesis, exogenous supply, and renal and faecal excretion. Disruptions to these mechanisms caused by genetic mutations (primary hyperoxaluria) or increased oxalate absorption (secondary hyperoxaluria) result in oxalate nephropathy.

  • Solute carrier family 26 member 6 anion transporter has an important role in the maintenance of oxalate homeostasis by facilitating transcellular oxalate secretion in the intestine (in contrast to paracellular absorption).

  • Among several oxalate-degrading bacteria in the human gut microbiota, Oxalobacter formigenes represents a major reservoir of oxalate-metabolizing genes.

  • Oxalate inhibits kidney epithelial cell proliferation, promotes fibrotic transformation, calcification and atherosclerosis, and induces cell death. These pathological pathways are probably mediated, at least in part, through NLRP3 inflammasome stimulation and mitochondrial disruption.

  • Urinary oxalate excretion is independently associated with the progression of chronic kidney disease and kidney failure. Elevated blood oxalate is also associated with increased risk of cardiovascular events, in particular sudden cardiac death.

  • Oxalate-balancing treatment options include O. formigenes analogues and oxalate decarboxylase supplements, small interfering RNA therapeutics that target oxalate-producing hepatic enzymes, and experimental CRISPR–Cas9 approaches and anti-inflammatory strategies.

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Fig. 1: Oxalate homeostasis.
Fig. 2: Model of endogenous oxalate synthesis pathways.
Fig. 3: Oxalate transport in the small intestine.
Fig. 4: Microbial modulation of oxalate homeostasis.

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Acknowledgements

The work of F.K. was supported by the German Research Foundation (DFG) — KN1148/4-1 and Project-ID 394046635, SFB 1365.

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Authors and Affiliations

  1. Department of Surgery, Division of Thoracic Surgery, Yale School of Medicine, New Haven, CT, USA

    Theresa Ermer

  2. Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA

    Lama Nazzal

  3. Division of Nephrology, University of Mississippi Medical Center, Jackson, MS, USA

    Maria Clarissa Tio

  4. Department of Medicine, Section of Nephrology, Boston University, Boston, MA, USA

    Sushrut Waikar

  5. Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, CT, USA

    Peter S. Aronson & Felix Knauf

  6. Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Felix Knauf

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F.K. reports personal fees from Allena, Oxthera, Sanofi, Fresenius Medical Care, Alnylam Pharmaceuticals, Advicenne, Medice and Zai, and grant support from Alnylam and Dicerna Pharmaceuticals. S.W. reports personal fees from Public Health Advocacy Institute, CVS, Roth Capital Partners, Kantum Pharma, Mallinckrodt, Wolters Kluewer, GE Health Care, GSK, Allena Pharmaceuticals, Mass Medical International, Barron and Budd (versus Fresenius), JNJ, Venbio, Strataca, Takeda, Cerus, Pfizer, Bunch and James, Harvard Clinical Research Institute (also known as Baim Institute for Clinical Research), Oxidien, Sironax, Metro Biotechnology, Biomarin, Bain and Regeneron. L.N. reports personal fees from Oxthera, Dicerna, Federation Bio, Allena, Novome and Synlogic. All other authors declare no competing interests.

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Ermer, T., Nazzal, L., Tio, M.C. et al. Oxalate homeostasis. Nat Rev Nephrol 19, 123–138 (2023). https://doi.org/10.1038/s41581-022-00643-3

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