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

Abstract

Introduction: Phenotypic 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 DKK3 (uDKK3) levels in 195 pediatric patients with renal ciliopathy to assess its potential as a discriminative and prediction marker. Methods: uDKK3 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). The results were correlated with chronic kidney disease (CKD) stage and annual estimated glomerular filtration rate (eGFR) decline. Results: Median uDKK3-to-creatinine ratios (uDKK3/crea) in all disease entities were significantly higher compared with healthy controls (11pg/mg uDKK3/crea, P 4.700 pg/mg were associated with a significantly greater annual eGFR loss independently of diagnosis and eGFR (P = 0.0029). Although we observed a trend toward lower uDKK3 levels in glomerulopathies compared to renal ciliopathies, there was no discriminative difference between individual ciliopathy entities (P = 0.2637). Conclusion: In renal ciliopathies, uDKK3 is a marker to assess disease severity and estimate short-term kidney function decline.

Keywords

• DKK3
• kidney fibrosis
• kidney function decline
• pediatric kidney disease
• predictive biomarker
• renal ciliopathies