Circulating Levels of Dickkopf-Related Protein 1 Decrease as Measured GFR Declines and Are Associated with PTH Levels

Abstract

<b><i>Background:</i></b> The Wnt/β-catenin pathway has been implicated in the development of adynamic bone disease in early-stage chronic kidney disease (CKD). Dickkopf-related protein 1 (DKK1) and sclerostin are antagonists of the Wnt/β-catenin pathway yet have not been widely used as clinical indicators of bone disease. This study characterized levels of DKK1, sclerostin, and other biomarkers of mineral metabolism in participants across a spectrum of inulin-measured glomerular filtration rate (GFR). <b><i>Methods:</i></b> GFR was measured by urinary inulin clearance (mGFR) in 90 participants. Blood samples were obtained for measurement of circulating DKK1, sclerostin, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), calcium, phosphate, α-klotho, and vitamin D metabolites including 25-hydroxyvitamin D<sub>3</sub> and 1,25-dihydroxyvitamin D<sub>3</sub>. Spearman correlations and linear regressions were used where appropriate to examine the associations between measured values. <b><i>Results:</i></b> The median [IQR] age was 64 years [53.0–71.0], and the median [IQR] mGFR was 32.6 [21.7–60.6] mL/min. DKK1 decreased (<i>r</i> = 0.6, <i>p</i> < 0.001) and sclerostin increased (<i>r</i> = −0.4, <i>p</i> < 0.001) as kidney function declined, and both were associated with phosphate, PTH, FGF-23, and 1,25-dihydroxyvitamin D<sub>3</sub> in the unadjusted analysis. After adjustment for age and mGFR, DKK1 remained significantly associated with PTH. <b><i>Conclusion:</i></b> The results of this study demonstrate opposing trends in Wnt/β-catenin pathway inhibitors, DKK1 and sclerostin, as mGFR declines. Unlike sclerostin, DKK1 levels decreased significantly as mGFR declined and was independently associated with PTH. Future studies should determine whether measurement of Wnt signaling inhibitors may be useful in predicting bone histomorphometric findings and important clinical outcomes in patients with CKD.

Osteocytic Sclerostin Expression as an Indicator of Altered Bone Turnover

“…This is in line with the loss of correlation between serum and osseous sclerostin in corticosteroid-treated patients in our previous report [ 44 ]. Moreover, since it has been reported that serum sclerostin levels highly depend on renal function [ 25 , 45 ], our lack of correlation could, at least to a certain extent, be explained by the fact that eGFR levels in the high turnover group were considerably higher than in low and normal turnover patients. Hence, the expected lower serum sclerostin levels in the high turnover group could be confounded by more pronounced renal retention.…”

The Molecular Mechanisms Underlying the Systemic Effects Mediated by Parathormone in the Context of Chronic Kidney Disease

“…Alongside Dkk1, sclerostin displays increased circulating levels in CKD patients, although there is vast variance across the analyzed groups [83,[87][88][89][90]. Contrasting with Dkk1, sclerostin shows an increasing trend with a decline of eGFR, independent of PTH levels [83]. However, assessment of the effect bared by PTH alone on sclerostin returned dissimilar results to the ones observed in CKD.…”

“…Dkk1 levels increase early in the course of the disease, mainly under the stimulus of tubular epithelial proliferation. With advancing disease, as measured through eGFR, Dkk1 circulating levels progressively decline but never return to the normal range [82,83]. More importantly, the extent of Dkk1 concentration decline is independently and inversely associated with PTH levels in CKD subjects.…”

“…Sclerostin is another inhibitor of the Wnt pathway, a powerful antagonist of Wnt and bone morphogenetic proteins, more selective than Dkk1 [86]. Alongside Dkk1, sclerostin displays increased circulating levels in CKD patients, although there is vast variance across the analyzed groups [83,[87][88][89][90]. Contrasting with Dkk1, sclerostin shows an increasing trend with a decline of eGFR, independent of PTH levels [83].…”

Correlation between DKK-1 Level and Bone Density Status in Children on Maintenance Haemodialysis

“…The Wnt/β-catenin pathway has been implicated in developing adynamic bone disease in early-stage chronic kidney disease (CKD). Dickkopf-related protein 1 (DKK1) and sclerostin are antagonists of the Wnt/β-catenin pathway yet have not been widely used as clinical indicators of bone disease [3].…”