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

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.

Dietary restriction and medical therapy drives PPARα-regulated improvements in early diabetic kidney disease in male rats

“…The post-DMT urinary metabolome was characterised by increased abundance of PPARα-responsive metabolites involved in nicotinamide metabolism (1-methylnicotinamide, nicotinamide N-oxide, and nicotinurate). Notably, changes in the urinary excretion of metabolites reflective of host-gut bacterial co-metabolism, which are well described following RYGB and associated with beneficial metabolic and renal effects of the procedure [ 102 – 104 ], were not pronounced following DMT.…”

Exploring the causal role of multiple metabolites on ovarian cancer: a two sample Mendelian randomization study

“…It's reported that in patients with acute kidney injury (AKI), 4-acetamidobutanoate increased 12-fold [ 37 ], and its levels significantly increased in patients with morbid hypertension [ 38 ]. Similarly, alpha-hydroxyisovalerate, an organic acid related to branched-chain amino acid metabolism, has been linked with liver injury [ 39 ], diabetic nephropathy [ 40 ], and Maple Syrup Urine Disease [ 41 ]. These findings might help in predicting the prognostic features of OC patients.…”

Metabolic remission precedes possible weight regain after gastric bypass surgery

“…Moreover, increased levels of the Krebs cycle intermediates citrate and malate further support a high activity in oxidative mitochondrial metabolism [31]. However, we cannot rule out that changes in these intermediates reflect RYGB‐associated changes in renal function [32].…”