Urinary Dickkopf-3 Reflects Disease Severity and Predicts Short-Term Kidney Function Decline in Renal Ciliopathies

Abstract

BackgroundPhenotypic heterogeneity and unpredictability of individual disease progression present enormous challenges in ultrarare renal ciliopathies. The tubular-derived glycoprotein Dickkopf-related protein 3 (DKK3) is a promising biomarker for kidney fibrosis and prediction of kidney function decline. Here, we measured urinary (u)DKK3 levels in 195 pediatric renal ciliopathy patients to assess its potential as a discriminative and prediction marker. MethodsUDKK3 concentration was measured in 357 spot urine samples from 247 individuals including 52 healthy age-matched controls. Disease entities comprised nephronophthisis (NPH) (n=37), autosomal recessive polycystic kidney disease (ARPKD) (n=61), Bardet Biedl syndrome (BBS) (n=57) and hepatocyte nuclear factor 1 beta (HNF1B)-nephropathy (n=40). Results were correlated with chronic kidney disease (CKD) stage and annual estimated glomerular filtration rate (eGFR) decline. ResultsMedian uDKK3/creatinine ratios in all disease entities were significantly higher compared with healthy controls (11pg/mg uDKK3/crea, p<0.001): NPH 1.219pg/mg, HNF1B 731pg/mg, BBS 541pg/mg and ARPKD 437pg/mg. A significant correlation of CKD stage with uDKK3 levels was observed for all disease entities (p<0.0001) with no other clinical parameter having a relevant impact. In our cohort, uDKK3 values >4.700 pg/mg were associated with a significantly greater annual eGFR loss independently of diagnosis and eGFR (p=0.0029). While we observed a trend towards lower uDKK3 levels in glomerulopathies compared to renal ciliopathies, there was no discriminative difference between individual ciliopathy entities (p=0.2637). ConclusionIn renal ciliopathies uDKK3 is a marker to assess disease severity and estimate short-term kidney function decline.