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RAS inhibition modulates kynurenine levels in a CKD population with and without type 2 diabetes mellitus

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Abstract

Kynurenine pathway of tryptophan metabolism is involved in the pathophysiology of chronic kidney disease (CKD) and diabetes mellitus, mainly through the inflammation-induced activity of indoleamine 2,3-dioxygenase (IDO), and few studies have investigated its potential link with proteinuria. Renin–angiotensin system inhibitors (RASis) are recommended in these patients to decrease proteinuria, slow CKD progression and reduce cardiovascular risk, but whether these drugs influence kynurenine levels in humans is unknown. We evaluated serum tryptophan and kynurenine in patients suffering from CKD with or without type 2 diabetes mellitus, their correlations with markers of reduced kidney function, and their relationship with RAS-inhibiting therapy. Of 72 adult patients enrolled, 55 were receiving RASis, whereas 17 were not. Tryptophan was assessed by HPLC (high-performance liquid chromatography); kynurenine was measured using an enzyme-linked immunosorbent assay kit; IDO activity (%) was calculated with the formula (kynurenine/tryptophan) × 100. Kynurenine levels were significantly lower in the group under RASis compared to the untreated group (1.56 ± 0.79 vs 2.16 ± 1.51 µmol/l; P = 0.0378). In patients not receiving RASis, kynurenine was inversely related to estimated glomerular filtration rate (eGFR) (r = − 0.4862; P = 0.0478) and directly related to both proteinuria (ρ = 0.493; P = 0.0444) and albuminuria (ρ = 0.542; P = 0.0247). IDO activity was higher in patients with history of cardiovascular disease compared to patients with no such history, and it negatively correlated with eGFR (ρ = − 0.554; P = 0.0210) in the same group. These findings may contribute to explain the well-known beneficial effects of RAS inhibition in CKD population, especially considering that kynurenine is emerging as a potential new biomarker of CKD.

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Authors and Affiliations

  1. Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria n. 1, 98124, Messina, Italy

    Valeria Cernaro, Antonina Rita Rosalia Genovese, Guido Gembillo, Domenico Santoro & Michele Buemi

  2. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

    Saverio Loddo, Vincenzo Macaione & Valentina Teresa Ferlazzo

  3. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy

    Rosalia Maria Cigala, Francesco Crea & Concetta De Stefano

  4. Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy

    Davide Bolignano

  5. Endocrinology, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

    Roberto Vita & Salvatore Benvenga

  6. Master Program on Childhood, Adolescent and Women’s Endocrine Health, University of Messina, Messina, Italy

    Salvatore Benvenga

  7. Interdepartmental Program of Molecular and Clinical Endocrinology, and Women’s Endocrine Health, University Hospital, Policlinico Universitario G. Martino, Messina, Italy

    Salvatore Benvenga

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  1. Valeria Cernaro
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  2. Saverio Loddo
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  3. Vincenzo Macaione
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  4. Valentina Teresa Ferlazzo
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  8. Antonina Rita Rosalia Genovese
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  14. Salvatore Benvenga
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Correspondence to Valeria Cernaro.

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Cernaro, V., Loddo, S., Macaione, V. et al. RAS inhibition modulates kynurenine levels in a CKD population with and without type 2 diabetes mellitus. Int Urol Nephrol 52, 1125–1133 (2020). https://doi.org/10.1007/s11255-020-02469-z

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