Difference in Profiles of the Gut-Derived Tryptophan Metabolite Indole Acetic Acid between Transplanted and Non-Transplanted Patients with Chronic Kidney Disease.

Sophie Liabeuf,Lynda Cheddani,Ziad A Massy,Griet Glorieux,François Brazier,Gabriel Choukroun,Raymond Vanholder,Dimitri Titeca Beauport,Solène M Laville

doi:10.3390/ijms21062031

Abstract

Background: Uremic toxins have emerged as potential mediators of morbidity and mortality in patients with chronic kidney disease (CKD). Indole-3-acetic acid (IAA, a tryptophan-derived uremic toxin) might be a useful biomarker in patients with CKD. The objectives of the present study were to (i) describe IAA concentrations in a cohort of non-transplanted patients with CKD and a cohort of transplanted patients with CKD, and (ii) investigate the possible relationship between IAA levels and adverse outcomes in the two cohorts. Methods: Levels of free and total IAA were assayed in the two prospective CKD cohorts (140 non-transplanted patients and 311 transplanted patients). Cox multivariate analyses were used to evaluate the association between IAA levels and outcomes (mortality, cardiovascular events, and graft loss). Results: In the non-transplanted CKD cohort, free and total IAA increased progressively with the CKD stage. In the transplanted CKD cohort, free and total IAA levels were elevated at the time of transplantation but had fallen substantially at one-month post-transplantation. Indole acetic acid concentrations were lower in transplanted patients than non-dialysis non-transplanted patients matched for estimated glomerular filtration rate (eGFR), age, and sex. After adjustment for multiple confounders, the free IAA level predicted overall mortality and cardiovascular events in the non-transplanted CKD cohort (hazard ratio [95% confidence interval]: 2.5 [1.2–5.1] and 2.5 [1.3–4.8], respectively). In the transplanted CKD cohort, however, no associations were found between free or total IAA on one hand, and mortality, CV event, or graft survival on the other. Conclusion: We demonstrated that levels of IAA increase with the CKD stage, and fall substantially, even normalizing, after kidney transplantation. Free IAA appears to be a valuable outcome-associated biomarker in non-transplanted patients, but—at least in our study setting—not in transplanted patients.

Highlights

Patients with chronic kidney disease (CKD) suffer from several metabolic and enzymatic impairments, which result in high morbidity and mortality rates [1]
After matching 45 patients in the transplanted cohort and 45 non-dialysis patients in the non-transplanted cohort for estimated glomerular filtration rate and age, we found that mean levels of free and total indole-3-acetic acid (IAA) were significantly lower in transplanted patients than in non-transplanted patients (respectively, 0.028 ± 0.007 mg/dL vs. 0.009 ± 0.006 mg/dL for free IAA (p < 0.0001) and 0.092 ± 0.042 mg/dL vs. 0.067 ± 0.056 mg/dL for total IAA (p = 0.020)) (Figure 3A,B)
We measured IAA concentrations, a protein-bound uremic toxin that originates from microbiota metabolism of amino acids and activates the aryl hydrocarbon receptor (AhR) complex, in non-transplanted and transplanted patients with CKD

Summary

Introduction

Patients with chronic kidney disease (CKD) suffer from several metabolic and enzymatic impairments, which result in high morbidity and mortality rates [1]. The gut microbiota has an important role in the generation of precursors of specific uremic toxins associated with poor outcomes in patients with CKD [3] Both indoxyl sulfate (IS) and indole-3-acetic acid (IAA) originate in the colon, where tryptophan is metabolized by gut bacteria into indole and IAA. Methods: Levels of free and total IAA were assayed in the two prospective CKD cohorts (140 non-transplanted patients and 311 transplanted patients). Results: In the non-transplanted CKD cohort, free and total IAA increased progressively with the CKD stage. In the transplanted CKD cohort, no associations were found between free or total IAA on one hand, and mortality, CV event, or graft survival on the other. Free IAA appears to be a valuable outcome-associated biomarker in non-transplanted patients, but—at least in our study setting—not in transplanted patients

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Conclusion