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Acidosis and alkali therapy in patients with kidney transplant is associated with transcriptional changes and altered abundance of genes involved in cell metabolism and acid-base balance


Silva, Pedro H Imenez; Wiegand, Anna; Daryadel, Arezoo; Russo, Giancarlo; Ritter, Alexander; Gaspert, Ariana; Wüthrich, Rudolf P; Wagner, Carsten A; Mohebbi, Nilufar (2021). Acidosis and alkali therapy in patients with kidney transplant is associated with transcriptional changes and altered abundance of genes involved in cell metabolism and acid-base balance. Nephrology, Dialysis, Transplantation, 36(10):1806-1820.

Abstract

BACKGROUND: Metabolic acidosis occurs frequently in patients with kidney transplant and is associated with higher risk for and accelerated loss of graft function. To date, it is not known whether alkali therapy in these patients improves kidney function and whether acidosis and its therapy is associated with altered expression of proteins involved in renal acid-base metabolism.
METHODS: We collected retrospectively kidney biopsies from 22 patients. Of these patients, 9 had no acidosis, 9 had metabolic acidosis (plasma HCO3- < 22 mmol/l), and 4 had acidosis and received alkali therapy. We performed transcriptome analysis and immunohistochemistry for proteins involved in renal acid-base handling.
RESULTS: We found the expression of 40 transcripts significantly changed between kidneys from non-acidotic and acidotic patients. These genes are mostly involved in proximal tubule amino acid and lipid metabolism and energy homeostasis. Three transcripts were fully recovered by alkali therapy: the Kir4.2 K+-channel, an important regulator of proximal tubule HCO3--metabolism and transport, ACADSB and SHMT1, genes involved in beta-oxidation and methionine metabolism. Immunohistochemistry showed reduced staining for the proximal tubule NBCe1 HCO3- transporter in kidneys from acidotic patients that recovered with alkali therapy. In addition, the HCO3-exchanger pendrin was affected by acidosis and alkali therapy.
CONCLUSIONS: Metabolic acidosis in kidney transplant recipients is associated with alterations in the renal transcriptome that are partly restored by alkali therapy. Acid-base transport proteins mostly from proximal tubule were also affected by acidosis and alkali therapy suggesting that the downregulation of critical players contributes to metabolic acidosis in these patients.

Abstract

BACKGROUND: Metabolic acidosis occurs frequently in patients with kidney transplant and is associated with higher risk for and accelerated loss of graft function. To date, it is not known whether alkali therapy in these patients improves kidney function and whether acidosis and its therapy is associated with altered expression of proteins involved in renal acid-base metabolism.
METHODS: We collected retrospectively kidney biopsies from 22 patients. Of these patients, 9 had no acidosis, 9 had metabolic acidosis (plasma HCO3- < 22 mmol/l), and 4 had acidosis and received alkali therapy. We performed transcriptome analysis and immunohistochemistry for proteins involved in renal acid-base handling.
RESULTS: We found the expression of 40 transcripts significantly changed between kidneys from non-acidotic and acidotic patients. These genes are mostly involved in proximal tubule amino acid and lipid metabolism and energy homeostasis. Three transcripts were fully recovered by alkali therapy: the Kir4.2 K+-channel, an important regulator of proximal tubule HCO3--metabolism and transport, ACADSB and SHMT1, genes involved in beta-oxidation and methionine metabolism. Immunohistochemistry showed reduced staining for the proximal tubule NBCe1 HCO3- transporter in kidneys from acidotic patients that recovered with alkali therapy. In addition, the HCO3-exchanger pendrin was affected by acidosis and alkali therapy.
CONCLUSIONS: Metabolic acidosis in kidney transplant recipients is associated with alterations in the renal transcriptome that are partly restored by alkali therapy. Acid-base transport proteins mostly from proximal tubule were also affected by acidosis and alkali therapy suggesting that the downregulation of critical players contributes to metabolic acidosis in these patients.

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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 > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Functional Genomics Center Zurich
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:27 September 2021
Deposited On:27 Aug 2021 07:39
Last Modified:25 Jun 2024 01:42
Publisher:Oxford University Press
ISSN:0931-0509
Additional Information:This is a pre-copyedited, author-produced PDF of an article accepted for publication in NDT following peer review. The definitive publisher-authenticated version Nephrology Dialysis Transplantation, Volume 36, Issue 10, October 2021, Pages 1806–1820, is available online at: https://doi.org/10.1093/ndt/gfab210.
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/ndt/gfab210
PubMed ID:34240183
  • Content: Accepted Version
  • Language: English