Urinary Metabolomic Changes Accompanying Albuminuria Remission following Gastric Bypass Surgery for Type 2 Diabetic Kidney Disease.

William P Martin,Anders Pedersen,Carel W Le Roux,Lívia P Cunha Da Silveira,Ricardo V Cohen,Lars Fändriks,Cristina M Aboud,Tarissa B Zanata Petry,Ana C Calmon Da Costa Silva,Daniel Malmodin,Neil G Docherty,Martina Wallace

doi:10.3390/metabo12020139

Abstract

In the Microvascular Outcomes after Metabolic Surgery randomised clinical trial (MOMS RCT, NCT01821508), combined metabolic surgery (gastric bypass) plus medical therapy (CSM) was superior to medical therapy alone (MTA) as a means of achieving albuminuria remission at 2-year follow-up in patients with obesity and early diabetic kidney disease (DKD). In the present study, we assessed the urinary 1H-NMR metabolome in a subgroup of patients from both arms of the MOMS RCT at baseline and 6-month follow-up. Whilst CSM and MTA both reduced the urinary excretion of sugars, CSM generated a distinctive urinary metabolomic profile characterised by increases in host–microbial co-metabolites (N-phenylacetylglycine, trimethylamine N-oxide, and 4-aminobutyrate (GABA)) and amino acids (arginine and glutamine). Furthermore, reductions in aromatic amino acids (phenylalanine and tyrosine), as well as branched-chain amino acids (BCAAs) and related catabolites (valine, leucine, 3-hydroxyisobutyrate, 3-hydroxyisovalerate, and 3-methyl-2-oxovalerate), were observed following CSM but not MTA. Improvements in BMI did not correlate with improvements in metabolic and renal indices following CSM. Conversely, urinary metabolites changed by CSM at 6 months were moderately to strongly correlated with improvements in blood pressure, glycaemia, triglycerides, and albuminuria up to 24 months following treatment initiation, highlighting the potential involvement of these shifts in the urinary metabolomic profile in the metabolic and renoprotective effects of CSM.

Highlights

Diabetic kidney disease (DKD) affects up to 40% of people with longstanding type 2 diabetes mellitus and is the leading cause of end-stage renal disease [1,2]
We recently reported the 2-year outcomes of the Microvascular Outcomes after Metabolic Surgery (MOMS) randomised clinical trial (RCT), comparing the impact of combined metabolic surgery plus medical therapy (CSM) versus intensive medical therapy alone (MTA) on urinary albumin excretion in patients with DKD and a body-mass index (BMI) in the 30–35 kg/m2 range (NCT01821508)
We have shown in preclinical rat models of DKD that the impact of Roux-en-Y gastric bypass surgery (RYGB) on albuminuria is reflective of structural improvements in the glomerulus and the emergence of a reparative pattern of global changes in the renal cortical transcriptome [21,22,23,24]

Summary

Introduction

Diabetic kidney disease (DKD) affects up to 40% of people with longstanding type 2 diabetes mellitus and is the leading cause of end-stage renal disease [1,2]. Whilst renin– angiotensin–aldosterone system blockade has been the backbone of DKD treatment over the last two decades [3], a significant residual risk of progressive renal disease and accelerated cardiovascular disease has remained in people with DKD despite intensive treatment [4]. The evidence base for the endothelin-A receptor antagonist atrasentan [8] and the nonsteroidal, selective mineralocorticoid receptor antagonist finerenone [9] is following closely behind. Together, these medications promise to improve outcomes. As the most efficacious weight loss intervention, a growing body of research has focused on the renoprotective and cardioprotective effects of bariatric surgery in patients with DKD [16,17,18]

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