Urinary Dickkopf-3 Predicts GFR Loss in the General Population

Chronic kidney disease (CKD) affects > 800 million people globally, with prevalence expected to increase, emphasizing the need for effective early detection and management strategies. Urinary Dickkopf-3 (uDKK3), a profibrotic glycoprotein from renal tubular cells, has been linked to acute kidney injury (AKI) and CKD progression. This study assesses uDKK3 as a biomarker for predicting glomerular filtration rate (GFR) decline in the general population.

We conducted a prospective cohort study with 1316 participants aged 55 to 69 years from the Renal Iohexol Clearance Survey (RENIS) (2014-2015), undergoing 1 to 3 GFR measurements using iohexol clearance over 5.3 years. uDKK3 levels were normalized to creatinine (Cr), categorizing participants by uDKK3/Cr levels: undetectable, low (detectable < 400 pg/mg), and high (≥ 400 pg/mg). Linear mixed models were used to evaluate the relationship between uDKK3/Cr levels and GFR decline rate. Logistic regression was used to examine the association between uDKK3/Cr groups and accelerated GFR decline, defined as the top 10% steepest declines.

The mean annual GFR decline rate was -1.33 ml/min per 1.73 m². A total of 1112 individuals had undetectable uDKK3/Cr levels, 167 had low levels, and 37 had high levels. The high uDKK3/Cr level group comprised 63% men and had higher systolic and diastolic blood pressure (BP) levels, despite comparable use of antihypertensive medications. Higher baseline uDKK3/Cr levels significantly correlated with faster GFR decline, independent of traditional CKD risk factors. Participants with high uDKK3/Cr levels had an annual GFR reduction 0.63 ml/min per 1.73 m² faster than those with undetectable levels (P = 0.049). High uDKK3/Cr levels had an odds ratio of 2.68 for accelerated GFR decline, compared with those with undetectable levels (P = 0.03).

Elevated uDKK3 levels were linked to steeper GFR decline, independent of conventional CKD risk factors, confirming uDKK3 as a promising biomarker for early identification of individuals at risk for rapid GFR loss.