Urinary Dickkopf-3 Predicts GFR Loss in the General Population

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Introduction Chronic kidney disease affects over 800 million people globally, with prevalence expected to rise, 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 and chronic kidney disease progression. This study assesses uDKK3 as a biomarker for predicting GFR decline in the general population. Methods We conducted a prospective cohort study with 1 316 participants aged 55-69 from the Renal Iohexol Clearance Survey (RENIS) (2014-2015), undergoing one to three GFR measurements via iohexol clearance over 5.3 years. uDKK3 levels were normalized to creatinine, categorizing participants by uDKK3/Cr levels: undetectable, low (detectable <400 pg/mg), and high (≥400 pg/mg). Linear mixed models evaluated the relationship between uDKK3/Cr levels and GFR decline rate. Logistic regression examined the association between uDKK3/Cr groups and accelerated GFR decline, defined as the top 10% steepest declines. Results The mean annual GFR decline rate was -1.33 ml/min/1.73m 2 . 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 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/1.73 m 2 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 to those with undetectable levels (p=0.03). Conclusion Elevated uDKK3 levels were linked to steeper GFR decline, independent of conventional chronic kidney disease risk factors, confirming uDKK3 as a promising biomarker for early identification of individuals at risk for rapid GFR loss.

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