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Abstract
Evaluation of renal dysfunction includes estimation of glomerular filtration rate (eGFR) as the initial step and subsequent laboratory testing. We hypothesized that combined analysis of serum creatinine, myo-inositol, dimethyl sulfone, and valine would allow both assessment of renal dysfunction and precise GFR estimation. Bio-banked sera were analyzed using nuclear magnetic resonance spectroscopy (NMR). The metabolites were combined into a metabolite constellation (GFRNMR) using n = 95 training samples and tested in n = 189 independent samples. Tracer-measured GFR (mGFR) served as a reference. GFRNMR was compared to eGFR based on serum creatinine (eGFRCrea and eGFREKFC), cystatin C (eGFRCys-C), and their combination (eGFRCrea-Cys-C) when available. The renal biomarkers provided insights into individual renal and metabolic dysfunction profiles in selected mGFR-matched patients with otherwise homogenous clinical etiology. GFRNMR correlated better with mGFR (Pearson correlation coefficient r = 0.84 vs. 0.79 and 0.80). Overall percentages of eGFR values within 30% of mGFR for GFRNMR matched or exceeded those for eGFRCrea and eGFREKFC (81% vs. 64% and 74%), eGFRCys-C (81% vs. 72%), and eGFRCrea-Cys-C (81% vs. 81%). GFRNMR was independent of patients’ age and sex. The metabolite-based NMR approach combined metabolic characterization of renal dysfunction with precise GFR estimation in pediatric and adult patients in a single analytical step.
Highlights
In use for decades, the methods available for estimating glomerular filtration rate with endogenous markers still present important drawbacks [1,2] and were described to be a weak link in renal diagnostics [3]
It was concluded that a single filtration marker is unlikely to successfully overcome the limitations of endogenous metabolites, because of variables affecting the pathophysiology of chronic kidney disease (CKD) other than
The persistence of these limitations prompted Porrini et al to suggests that the problem perse might be associated with the biochemical natureof creatinine and cystatin C as markers of renal function, rather than with the mathematical methods used for GFR estimation [8]
Summary
In use for decades, the methods available for estimating glomerular filtration rate (eGFR) with endogenous markers still present important drawbacks [1,2] and were described to be a weak link in renal diagnostics [3]. We aimed at a more complex approach that interprets multiple biomarkers reflecting both the glomerular filtration rate and CKD-associated renal dysfunction Such an approach requires the quantification of several renal biomarkers with high precision and accuracy. We hypothesized that NMR-based analysis of myo-inositol as a marker of uremia, dimethyl sulfone as a marker of oxidative stress, and valine as an indicator of acid-base metabolism in combination with creatinine would provide a ‘metabolite constellation’ that describes the complex renal and metabolic dysfunction in CKD. We tested whether this framework would allow a precise estimation of glomerular filtration
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