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Alkali therapy protects renal function, suppresses inflammation, and improves cellular metabolism in kidney disease


Pastor Arroyo, Eva Maria; Yassini, Nima; Sakiri, Elif; Russo, Giancarlo; Bourgeois, Soline; Mohebbi, Nilufar; Amann, Kerstin; Joller, Nicole; Wagner, Carsten A; Imenez Silva, Pedro Henrique (2022). Alkali therapy protects renal function, suppresses inflammation, and improves cellular metabolism in kidney disease. Clinical Science, 136(8):557-577.

Abstract

Chronic kidney disease (CKD) affects approximately 10–13% of the population worldwide and halting its progression is a major clinical challenge. Metabolic acidosis is both a consequence and a possible driver of CKD progression. Alkali therapy counteracts these effects in CKD patients, but underlying mechanisms remain incompletely understood. Here we show that bicarbonate supplementation protected renal function in a murine CKD model induced by an oxalate-rich diet. Alkali therapy had no effect on the aldosterone–endothelin axis but promoted levels of the anti-aging protein klotho; moreover, it suppressed adhesion molecules required for immune cell invasion along with reducing T-helper cell and inflammatory monocyte invasion. Comparing transcriptomes from the murine crystallopathy model and from human biopsies of kidney transplant recipients (KTRs) suffering from acidosis with or without alkali therapy unveils parallel transcriptome responses mainly associated with lipid metabolism and oxidoreductase activity. Our data reveal novel pathways associated with acidosis in kidney disease and sensitive to alkali therapy and identifies potential targets through which alkali therapy may act on CKD and that may be amenable for more targeted therapies.

Abstract

Chronic kidney disease (CKD) affects approximately 10–13% of the population worldwide and halting its progression is a major clinical challenge. Metabolic acidosis is both a consequence and a possible driver of CKD progression. Alkali therapy counteracts these effects in CKD patients, but underlying mechanisms remain incompletely understood. Here we show that bicarbonate supplementation protected renal function in a murine CKD model induced by an oxalate-rich diet. Alkali therapy had no effect on the aldosterone–endothelin axis but promoted levels of the anti-aging protein klotho; moreover, it suppressed adhesion molecules required for immune cell invasion along with reducing T-helper cell and inflammatory monocyte invasion. Comparing transcriptomes from the murine crystallopathy model and from human biopsies of kidney transplant recipients (KTRs) suffering from acidosis with or without alkali therapy unveils parallel transcriptome responses mainly associated with lipid metabolism and oxidoreductase activity. Our data reveal novel pathways associated with acidosis in kidney disease and sensitive to alkali therapy and identifies potential targets through which alkali therapy may act on CKD and that may be amenable for more targeted therapies.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Nephrology
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Functional Genomics Center Zurich
04 Faculty of Medicine > Institute of Laboratory Animal Science
05 Vetsuisse Faculty > Veterinärwissenschaftliches Institut > Institute of Laboratory Animal Science

04 Faculty of Medicine > Institute of Experimental Immunology
07 Faculty of Science > Department of Quantitative Biomedicine
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > General Medicine
Uncontrolled Keywords:General Medicine
Language:English
Date:29 April 2022
Deposited On:05 May 2022 12:57
Last Modified:28 Mar 2024 02:36
Publisher:Portland Press
ISSN:0143-5221
OA Status:Hybrid
Publisher DOI:https://doi.org/10.1042/cs20220095
PubMed ID:35389462
Project Information:
  • : FunderSNSF
  • : Grant IDN-403-07-25
  • : Project TitleNCCR Kidney.CH
  • : FunderHartman Müller Stiftung
  • : Grant ID2382
  • : Project Title
  • : FunderSNSF
  • : Grant IDPP00P3_181037
  • : Project TitleImmune Regulation through Infection History
  • : FunderH2020
  • : Grant ID677200
  • : Project TitleHow Infection History Shapes the Immune System: Pathogen-induced Changes in Regulatory T Cells
  • : FunderSNSF
  • : Grant ID31003A_176125
  • : Project TitleMolecular mechanisms of mammalian phosphate sensing and homeostatic control
  • : FunderSNSF
  • : Grant ID33IC30_166811
  • : Project TitlePreservation of kidney function in kidney transplant recipients by alkali therapy (Preserv-Transplant Study)
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)