Dickkopf-3 (DKK3) in Urine Identifies Patients with Short-Term Risk of eGFR Loss

Abstract

Background The individual course of CKD may vary, and improved methods for identifying which patients will experience short-term eGFR loss are needed. Assessing urinary Dickkopf-3 (DKK3), a stress-induced tubular epithelia-derived profibrotic glycoprotein, may provide information about ongoing tubulointerstitial fibrosis and short-term eGFR loss.Methods To investigate urinary DKK3's potential as a biomarker of short-term eGFR loss (over 12 months), we prospectively assessed eGFR and urinary DKK3 levels in patients with CKD of various etiologies at baseline and annual follow-ups. We also measured urinary DKK3 in a general population sample and patients with diagnostic kidney biopsies or IgA nephropathy under treatment.Results Median urinary DKK3-to-creatinine concentration at baseline was significantly higher in patients with CKD than the general population sample (431 versus 33 pg/mg). In the CKD cohort, having a urinary DKK3-to-creatinine level .4000 pg/mg was independently and significantly associated after multiple adjustments with mean annual decline in eGFR of 7.6% over 12 months. Urinary DKK3 significantly improved prediction of kidney function decline compared with eGFR or albuminuria alone. Urinary DKK3-tocreatinine levels were related to the extent of tubulointerstitial fibrosis in kidney biopsies. In patients with IgA nephropathy, a rise in urinary DKK3 was associated with significant eGFR decline within 6 months, whereas stable or decreasing urinary DKK3 indicated a more favorable course.Conclusions Urinary DKK3 levels identify patients at high risk for eGFR decline over the next 12 months regardless of the cause of kidney injury and beyond established biomarkers, potentially providing a tool to monitor CKD progression and assess effects of interventions.

Intra-individual variability of eGFR trajectories in early diabetic kidney disease and lack of performance of prognostic biomarkers

“…It will also mandate a critical appraisal of the current clinical practise of caring for patients with DKD as re-assessment of prognosis as well as efficacy of therapy will be needed in regular intervals. This conclusion is supported by a publication of Zewinger et al Measurements of urinary Dickkopf-3 levels, a stress-induced www.nature.com/scientificreports/ tubular epithelia-derived pro-fibrotic glycoprotein, in patients with IgA nephropathy predicted eGFR decline for the next a maximum of 6 months but, if repeated, also over a prolonged period of time 28 . It could be argued that our results are caused by fluctuations of serum creatinine levels that are not due to changes in renal function.…”

Dickkopf-3 in the prediction of contrast media induced acute kidney injury

“…Thus, it was speculated that increased urinary DKK3 concentrations could indicate a higher risk of progression of chronic kidney disease (CKD). This association has indeed been demonstrated in the participants of the STOP-IgAN trial [2]. Beyond CKD, there is a first investigation on DKK3 in the context of acute kidney injury (AKI).…”

Dickkopf-3: Current Knowledge in Kidney Diseases

“…In addition to Wnt signaling, DKK3 contributes to renal injury in multiple ways (Lipphardt et al, 2019). DKK3, whether in urine or tissue, may be a potential biomarker to monitor kidney disease progression and assess the effects of interventions (Zewinger et al, 2018;Schunk et al, 2019). Here, we summarize recent novel findings regarding the implications for DKK3 in kidney diseases.…”