Metabalomic Signatures and Nitric Oxide Pathway Perturbations in Patients With End Stage Renal Disease
Authors: Staton Kyle Mitchell , Berceli Scott , Jiang Zhihua , Rozowsky Jared , Quinlivan Eoin , Garrett Timothy , Kuppler Christopher 
Published: June 2021

Introduction

The systemic deleterious effects of End Stage Renal Disease (ESRD) are numerous and well established, however, advances in our understanding of the fundamental biology within the local small‐molecule environment has been limited. This study utilizes high‐throughput techniques to quantify global and targeted metabolomics of ESRD in comparison to healthy counterparts. We hypothesize that ESRD patients exhibit critical deviations in their metabolome, particularly within those elements surrounding nitric oxide (NO) production. These changes may provide a mechanistic explanation of previously established functional and structural vascular abnormalities associated with ESRD.

Methods

Following Institutional Review Board approval, human plasma samples were obtained from 5 patients with normal renal function and 5 patients with ESRD currently on hemodialysis. Global metabolomic analysis was performed by LC‐MS, and metabolites identified by their retention time and exact mass analysis using an in‐house library. Targeted metabolite analysis was performed by stable isotope dilution LC‐MS/MS on 31 NO‐associated metabolites of specific interest. Descriptive statistical analysis was performed to compare the respective metabolomes of ESRD to those with normal renal function. The discussion and inference of downstream effects was aided with the use of BioCyc™ pathway analysis tools.

Results

Targeted Metabolomics

Patients with ESRD in comparison to control patients had significant differences p‐value <0.05 in 6 of the targeted 31 (19%) metabolites. Of those metabolites 5 of 6 (83%) were increased significantly in the ESRD population, with 1 of 6 (17%) significantly decreased (FIGURE).

Global Metabolomics

3788 metabolite signatures were detected, of which 1099 (29%) were mapped to specific compounds. 523 of the identified 1099 metabolites (47.6%) were found to be different (p<0.05) in the ESRD population, with 212 (41%) significantly increased vs 311 (59%) significantly decreased.

Discussion

With the loss of glomerular filtration and replacement with 3×/week hemodialysis, we see significant alterations within the small‐molecule environment of those with ESRD. Targeted metabolomics provide insight into how these differences alter key regulators of vascular and cardiovascular homeostasis. Our data would suggest patients with ESRD have decreased production of NO. This is supported by our findings of ESRD patients exhibiting significant increases in both competitive NO inhibitors (SDMA, Methyl Arginine, and ADMA) and end products of alternative NO‐related pathways (Citrulline, and Ornithine). Expanding our understanding of the small‐molecule environment and its effects will provide important insights into the etiology of altered vascular pathophysiology observed in the ESRD population and offer potential novel targets of intervention to re‐establish normal homeostasis within the cardiovascular system.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.