Urinary Dickkopf-3 as a Potential Marker for Estimated Glomerular Filtration Rate Decline in Patients With Heart Failure

Abstract

Background: Patients with chronic heart failure (HF) show an increased risk for the occurrence of chronic kidney disease and cardiorenal syndrome. Urinary Dickkopf-3 (uDKK3), a stress-induced, tubular profibrotic glycoprotein, may be elevated in HF as early as in New York Heart Association class I HF and may indicate subsequent decline in estimated glomerular filtration rate (eGFR).

Methods and results: uDKK3 levels in patients with HF and controls were measured by enzyme-linked immunosorbent assay. eGFR was determined up to 5 years in HF. Change in eGFR was assessed with respect to baseline uDKK3 using (mixed-effect) linear and logistic regression models. A total of 488 patients with chronic HF and 45 control patients were included. Patients with HF showed higher median uDKK3 levels than controls (259.6 pg/mg creatinine [interquartile range (IQR), 119.2-509.4 pg/mg creatinine] versus 107.5 pg/mg creatinine [IQR, 60.5-181.2 pg/mg creatinine], P<0.001). Regression models demonstrated a significant association between log uDKK3 and the decline in eGFR during a median of 13 months (IQR, 12-59 months) (estimated higher eGFR loss, 0.8039 mL/min per 1.73 m²/year [95% CI, 0.002-1.606 mL/min per 1.73 m²/year], P=0.049; odds ratio, 1.345 [95% CI, 1.049-1.741], P=0.021). uDKK3 levels ≥354 pg/mg creatinine were associated with a significantly higher risk for eGFR decline at 1-year follow-up (estimated higher eGFR loss, 4.538 mL/min per 1.73 m² [95% CI, 1.482-9.593 mL/min per 1.73 m²]), P=0.004). Even patients with HF without chronic kidney disease (n=334) had higher uDKK3 levels compared with controls (233.4 [IQR, 109.0-436.9 pg/mg creatinine] versus 107.5 [IQR, 60.5-181.2 pg/mg creatinine], P<0.001).

Conclusions: The present findings indicate that uDKK3 is a promising prognostic biomarker for subsequent eGFR decline in patients with HF, irrespective of the presence of chronic kidney disease and even in the early stages of HF. This potential allows for early intervention to mitigate the deterioration of kidney function. Further investigation is warranted to validate its clinical utility.

Keywords: Dickkopf‐3; cardiorenal syndrome; estimated glomerular filtration rate; heart failure.

Figure 1. Flow diagram of the study.

eGFR indicates estimated glomerular filtration rate; HF, heart failure; ICM, ischemic cardiomyopathy; NICM, nonischemic cardiomyopathy; and uDKK3, urinary Dickkopf‐3.

Figure 2. eGFR slope during follow‐up in patients with HF.

The gray dots are the measurements with their distribution per time point additionally visualized as overlayed violin plots. The black bars show the 95% CIs around the expected marginal means estimated from a linear mixed‐effect regression model using time point as fixed effects and patient as random effect. The annotated P values comparing the follow‐up time points to baseline are also results from that model. eGFR indicates estimated glomerular filtration rate; and HF, heart failure.

Figure 3. Log uDKK3 in patients with different causes of HF and the control group.

P values were adjusted for age, sex, and body mass index. HF indicates heart failure; ICM, ischemic cardiomyopathy; NICM, nonischemic cardiomyopathy; and uDKK3, urinary Dickkopf‐3.

Figure 4. uDKK3 predicts eGFR decrease in patients with HF.

Linear trend of the association between ΔeGFR in mL/min per 1.73 m² to the earliest follow‐up and uDKK3 in patients with HF resulting from a linear model for earliest eGFR follow‐up. The blue line indicates the estimated change in eGFR with the respective 95% CI (gray area). Analyses and plots were adjusted for age, sex, body mass index, cause of HF, diabetes, log UACR, and baseline eGFR. ΔeGFR indicates change in estimated glomerular filtration rate; eGFR, estimated glomerular filtration rate; HF, heart failure; UACR, urinary albumin creatinine ratio; and uDKK3, urinary Dickkopf‐3.

Figure 5. Short‐term eGFR loss according to uDKK3 category in patients with HF.

Change in eGFR from baseline to 1‐year follow‐up in mL/min per 1.73 m² according to uDKK3/mg creatinine in patients with HF. Testing for significance was adjusted for age, sex, and body mass index. eGFR indicates estimated glomerular filtration rate; HF, heart failure; and uDKK3, urinary Dickkopf‐3.