Eicosanoids as Biomarkers of Hyperfiltration-Mediated Injury in CKD.

INTRODUCTION

Early biomarkers of hyperfiltration-induced injury are not known. We previously reported elevated urinary prostaglandin E2 (PGE2) preceding albuminuria in children with solitary kidney, and upregulated cyclooxygenase-2 (COX2)-PGE2-EP2 axis in unilaterally nephrectomized mice. To determine chronic kidney disease (CKD) stage-associated changes in urinary eicosanoids, baseline urine samples from the CKD in children (CKiD) biorepository (n = 318) and a comparator group of children with enuresis (n = 72) were analyzed.

METHODS

Liquid or gas chromatography-mass spectrometry was used to measure metabolites of arachidonic acid and linoleic acid (ng/mg creatinine, P ≤ 0.05).

RESULTS

The CKiD cohort included children with congenital anomalies of the kidney and urinary tract (CAKUT) (71%, n = 226) and glomerular disease (29%, n = 92). Glomerular filtration rate (GFR) measurement (Iohexol) showed 27% and 73% of CAKUT subjects at CKD stages 2 and 3, respectively. Among those with glomerular disease, 42% and 58% were at CKD stages 2 and 3, respectively. Comparisons across CKD stages identified increase in urinary PGE2, thromboxane, and dihydroxy eicosatrienoic acids (DHETs), with a decrease in prostacyclin, F2-isoprostane, and 9,10-dihydroxy-octadecenoic acids (DiHOMEs) from CKD stage 2 to 3 indicating perturbed metabolism through COX and cytochrome P-450 (CYP450) pathways. In unadjusted mixed models quantifying the associations of a 2-times higher baseline eicosanoid with initial GFR found prostacyclin, PGE2/prostacyclin ratio, thromboxane/prostacyclin ratio, LTE4, 9,10-DiHOME, and F2-Isoprostane were significantly associated with higher initial GFR and remained significant after adjusting for CAKUT diagnosis, sex and baseline age, proteinuria, and hypertension. However, none of the eicosanoids were associated with change in GFR over time or time to kidney replacement therapy.

CONCLUSION

We report for the first time linoleic acid-derived metabolites in children with CKD. A longitudinal study is needed to validate selected urinary eicosanoids as early biomarkers of hyperfiltration.