LONGITUDINAL ANALYSIS OF THE ASSOCIATION BETWEEN URINARY DICKKOPF-RELATED PROTEIN 3 AND KIDNEY ALLOGRAFT FUNCTION IN KIDNEY TRANSPLANT RECIPIENTS

Urinary Dickkopf-related protein 3 (uDKK3), a stress-induced tubular cell-derived profibrotic glycoprotein, has been shown to be associated with tubulointerstitial fibrosis and loss of kidney function in patients with chronic kidney disease. However, its value in kidney transplant recipients (KTRs) is debated, potentially because of a disturbing influence of uDKK3 that is also excreted by native kidneys. Therefore, this study aimed to investigate the association between uDKK3 and kidney allograft function in KTR without urine production prior to transplantation.

Data from KTRs enrolled in the TransplantLines Biobank and Cohort Study were used. To eliminate the influence of uDKK3 from the recipients’ native kidneys, we only selected a subset of KTRs that were anuric prior to transplantation. uDKK3 was measured using a commercially available ELISA kit in the 24-hour urine samples that were taken at 3, 6, 12, and 24 months after transplantation. Estimated glomerular filtration rate (eGFR) was used to assess the kidney allograft function. Associations between uDKK3 and eGFR during the observed period were analyzed using linear mixed models. The influence of within-individual changes in uDKK3 on eGFR levels over time was evaluated using a within–between random effects model. uDKK3 were scaled when assessing the association with eGFR, as it gives the best model fit based on the Akaike Information Criterion values.

We included 88 KTRs (66% male, 34% received a kidney from a living donor, 30% with delayed graft function) in the analyses. At baseline, mean±SD age was 56±15 years, mean±SD eGFR was 45±17 ml/min/1.73m², median [Q1-Q3] 24h urinary protein excretion was 0.19 [0.12-0.26] g/24h, and median [Q1-Q3] 24h uDKK3 excretion was 1658 [469-5434] ng/24h. For the association of 24h uDKK3 excretion with eGFR, linear mixed-model analysis showed that eGFR decreased by -2.99 mL/min/1.73m2 per 1 SD increase in 24h uDKK3 excretion, regardless of the time of measurement(Table). There was no evidence that the association between 24h uDKK3 excretion and eGFR differed between different time points of measurement (pinteraction = 0.2) or depended on 24h urinary protein excretion (pinteraction = 0.1). The association remained robust when the uDKK3/Creatinine ratio or the uDKK3 concentration was used instead of 24h uDKK3 excretion. Findings from the within–between random effects model showed that within-individual increases in 24h uDKK3 excretion over time were significantly associated with decreases in eGFR over time (a decrease of 3.13 mL/min/1.73m2 in eGFR per SD increase of 24h uDKK3 excretion, p < 0.001), independent of 24h urinary protein excretion.

uDKK3 is independently associated with worse eGFR, regardless of the time measurement. Furthermore, the increases in uDKK3 over time are associated with decreases in eGFR changes over time. Both associations are independent of urinary protein excretion. This suggests that uDKK3 is a potential non-invasive biomarker for monitoring the kidney allograft function of KTRs without urine production prior to transplantation. Further studies using larger sample sizes and longer follow-up durations are warranted to confirm the study findings and to investigate whether findings can be extended to recipients with urine production prior to transplantation.