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-to-creatinine 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.

Keywords: IgA nephropathy; chronic kidney disease; clinical nephrology; interstitial fibrosis; progression of chronic renal failure; tubule cells.

Copyright © 2018 by the American Society of Nephrology.

Figures

Graphical abstract

Figure 1.

Overview of studies and cohorts. (A) CARE FOR HOMe study (CKD patients) comprising 575 participants with annual follow-up (2,035 patient years). (B) STOP IgAN study, randomized-controlled study comprising 96 patients with IgA nephropathy. (C) Cross-sectional cohorts, Kidney Biopsies study comprising 76 patients and I LIKE HOMe study comprising 481 participants of the general population.

Figure 2.

Urinary Dickkopf-3 (DKK3) is elevated in patients with CKD. Distribution of urinary Dickkopf-3 (DKK3)-to-creatinine levels (on logarithmic scale) in the participants of the I LIKE HOMe Study cohort representing the general population (n=481) compared with patients with CKD from the CARE FOR HOMe Study cohort (n=575), with no relevant overlap between subjects from the general population and patients with CKD. Urinary DKK3-to-creatinine levels were comparable in hypertensive patients with CKD with (n=184) and without (n=202) diabetes and patients with CKD of other etiology (n=189).

Figure 3.

DKK3 predicts risk of short-term eGFR loss in patients with CKD. (A and B) Restricted cubic spline plots of the association between annual change of eGFR in (A) percentage and (B) milliliters per minute per 1.73 m2 and urinary Dickkopf-3 (DKK3)-to-creatinine concentrations in participants of the CARE FOR HOMe Study in 1-year blocks with a total of 2035 patient-years available. The red line indicates the estimated change of eGFR with the respective 95% confidence interval (gray area). Dashed vertical lines indicate DKK3-to-creatinine levels used as cutoffs in subsequent analyses. Blue spikes show the distribution of urinary DKK3-to-creatinine concentrations. All plots are adjusted for age, sex, body mass index, systolic BP, diabetes, smoking status, eGFR, and log albuminuria. (C) Annual change of eGFR according to categories of DKK3 to creatinine in patients with albuminuria <30, 30–300, and >300 mg/g. All analyses were adjusted for age, sex, body mass index, systolic BP, diabetes, smoking status, eGFR, and log albuminuria.

Figure 4.

DKK3 associates with higher tubulointerstitial fibrosis. (A) Tubulointerstitial fibrosis in patients who underwent diagnostic kidney biopsies according to urinary Dickkopf-3 (DKK3)-to-creatinine concentrations. (B) Representative kidney biopsy specimens from three patients with membranous nephropathy (upper panels) and three patients with focal segmental sclerosis (lower panels) according to urinary DKK3-to-creatinine concentrations.

Figure 5.

DKK3 predicts eGFR loss in patients with IgA nephropathy. (A) Restricted cubic spline plot of the association between change of eGFR and urinary Dickkopf-3 (DKK3)-to-creatinine concentrations during the run-in phase in participants of the STOP IgAN Trial adjusted for age, sex, body mass index, systolic BP, smoking status, eGFR, and log albuminuria. (B) Restricted cubic spline plot of the association between change of eGFR (percentage) and change of urinary DKK3 to creatinine during early treatment phase in participants of the STOP IgAN Trial adjusted for age, sex, body mass index, systolic BP, smoking status, eGFR, and log albuminuria.

Figure 6.

Summarizing figure. Main concept of the work. DKK3, Dickkopf-3; ECM; WNT.