Urinary 3-hydroxyisovaleryl carnitine excretion, protein energy malnutrition and risk of all-cause mortality in kidney transplant recipients: Results from the TransplantLines cohort studies

Adrian Post,M Yusof Said,Antonio W Gomes-Neto,Isidor Minović,Dion Groothof,J Casper Swarte,Theo Boer,Ido P Kema,M Rebecca Heiner-Fokkema,Casper F.M Franssen,Stephan J.L Bakker

doi:10.1016/j.clnu.2020.09.035

Adrian Post, M Yusof Said + Show 9 more

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https://doi.org/10.1016/j.clnu.2020.09.035

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Journal: Clinical Nutrition	Publication Date: Oct 1, 2020
Citations: 2	License type: cc-by

Affiliation: University of Groningen

Abstract

Leucine is an essential amino acid and a potent stimulator of muscle protein synthesis. Since muscle wasting is a major risk factor for mortality in kidney transplant recipients (KTR), dietary leucine intake might be linked to long-term mortality. Urinary 3-hydroxyisovaleryl carnitine (3-HIC) excretion, a functional marker of marginal biotin deficiency, may also serve as a marker for dietary leucine intake. In this study we aimed to investigate the cross-sectional determinants of urinary 3-HIC excretion and to prospectively investigate the association of urinary 3-HIC excretion with all-cause mortality in KTR. Urinary 3-HIC excretion and plasma biotin were measured in a longitudinal cohort of 694 stable KTR. Cross-sectional and prospective analyses were performed using ordinary least squares linear regression analyses and Cox regression analyses, respectively. In KTR (57% male, 53±13 years, estimated glomerular filtration rate 45±19mL/min/1.73m2), urinary 3-HIC excretion (0.80 [0.57-1.16] μmol/24 h) was significantly associated with plasma biotin (std. β=-0.17; P<0.001). Subsequent adjustment for potential covariates revealed urinary creatinine excretion (std. β=0.24; P<0.001) and urinary urea excretion (std. β=0.53; P<0.001) as the primary determinant of urinary 3-HIC excretion. Whereas plasma biotin explained only 1% of the variance in urinary 3-HIC excretion, urinary urea excretion explained >45%. During median follow-up for 5.4 [4.8-6.1] years, 150 (22%) patients died. Log2-transformed urinary 3-HIC excretion was inversely associated with all-cause mortality (HR: 0.52 [0.43-0.63]; P<0.001). This association was independent of potential confounders. Urinary 3-HIC excretion more strongly serves as a marker of leucine intake than of biotin status. A higher urinary 3-HIC excretion is associated with a lower risk of all-cause mortality. Future studies are warranted to explore the underlying mechanism. NCT02811835. TRIAL REGISTRATION URL: https://clinicaltrials.gov/ct2/show/NCT02811835.

Highlights

Amongst the amino acids deriving from protein intake, leucine may be of special interest as it is considered the most potent stimulator of muscle protein synthesis [12]
In a large cohort of stable kidney transplant recipients (KTR), we demonstrated that urinary 3HIC excretion is lower and plasma biotin concentration is higher in KTR compared to healthy controls
Subsequent analyses demonstrated that renal function, urinary creatinine excretion and, most notably, urinary urea excretion are the primary determinants of 3HIC excretion in KTR

Summary

Introduction

A higher dietary leucine intake, alone or along with an increased protein intake, could potentially improve long-term survival in KTR. Since muscle wasting is a major risk factor for mortality in kidney transplant recipients (KTR), dietary leucine intake might be linked to long-term mortality. Objective: In this study we aimed to investigate the cross-sectional determinants of urinary 3-HIC excretion and to prospectively investigate the association of urinary 3-HIC excretion with all-cause mortality in KTR. Log2-transformed urinary 3-HIC excretion was inversely associated with all-cause mortality (HR: 0.52 [0.43e0.63]; P < 0.001). This association was independent of potential confounders. A higher urinary 3-HIC excretion is associated with a lower risk of all-cause mortality.

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