#2086 Dickkopf-3 (DKK3) and the progression of diabetic kidney disease in primary health care

Abstract Background and Aims In type 2 diabetes mellitus (T2DM), progressive CKD is a global public health problem and associated with significant co-morbidity and reduced life expectancy [1–3]. However, it is challenging to predict the individual course of diabetic kidney disease as patterns of progression in patients with T2DM include linear and nonlinear trajectories of eGFR decline. Moreover, in a substantial portion of patients with T2DM, loss of kidney function occurs in the absence of gross albuminuria [4]. Thus, novel biomarkers are needed to improve the detection of incipient kidney injury and the prediction of the individual course of CKD in patients with diabetes. Dickkopf-3 (DKK3) is a tubular protein which is released under stress conditions and promotes the development of kidney fibrosis via the Wnt/β-catenin signalling pathway [5]. Urinary DKK3 (uDKK3) is a promising biomarker for detecting early kidney injury and predicting the progression of CKD [5]. We explored the clinical utility of uDKK3 as a biomarker of kidney function decline and adverse cardiovascular outcomes in patients with T2DM in a primary healthcare setting. Method We analysed 3232 patients from the PROVALID study, a prospective study of patients with T2DM followed at the primary care level. The primary endpoint was a kidney composite outcome, including a sustained eGFR decline of ≥40%, a sustained increase in the urine albumin-creatinine ratio (UACR) of ≥30% (with a transition in albuminuria class), progression to end-stage kidney disease, or death due to kidney failure. The secondary endpoint encompassed a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Additionally, we evaluated all-cause mortality. Results The median age was 64 (58–70) years and 43% of participants were female. 20% of the participants had an eGFR <60 ml/min/1.73 m², 20% had an UACR >30 mg/g creatinine, and 34% met the diagnostic criteria of CKD according to KDIGO. The median follow-up time was 4.26 (2.91–5.56) years. When adjusted for age, gender, eGFR and UACR, uDKK3 values >200 pg/g creatinine were associated with a significantly higher risk of reaching the composite kidney endpoint (HR 1.52 [95% CI 1.13–2.04, p-value = 0.006]). In addition, individuals with higher uDKK3 concentrations had an increased risk for the cardiovascular composite endpoint (HR 1.52 [95% CI 1.07–2.16, p-value = 0.018]) as well as all-cause mortality (HR 1.44 [95% CI 1.03–1.99, p-value = 0.031]). uDKK3 levels >200 pg/mg creatinine, when used on top of established kidney risk factors such as eGFR <60 ml/min/1.73 m2, UACR >30 mg/g creatinine or the presence of CKD according to the KDIGO criteria, significantly increased the risk prediction for the composite kidney endpoint compared to the respective reference groups (i.e. eGFR >60 ml/min/1.73 m2, normoalbuminuria or no CKD) (Fig. 1). Further, uDKK3 at baseline helped predict the eGFR decline within the first observational year. This was particularly clear in patients with moderately and severely increased UACR (Fig. 2). Conclusion Increased uDKK3 identifies patients with type 2 diabetes mellitus at high risk for kidney function decline and adverse cardiovascular events, in addition with but also independent of UACR. uDKK3 may represent a novel tool for personalized management in these patients.