Kidney Function-Dependence of Vitamin K-Status Parameters: Results from the TransplantLines Biobank and Cohort Studies

Abstract

High circulating dephosphorylated (dp) uncarboxylated (uc) matrix Gla protein (MGP) and uc osteocalcin (OC) concentrations are regarded as markers of vitamin K-deficiency. However, because MGP and OC are small molecules, they may potentially pass the glomerulus, and their blood concentrations may strongly depend on kidney function. However, many studies with vitamin K-status parameters do not structurally adjust for baseline kidney function, and detailed studies on kidney function-dependence of vitamin K-status markers are lacking. We therefore measured plasma dp-ucMGP using a chemiluminescent assay in 578 kidney transplant recipients (41% females, age 56 ± 13y, 7.5 (3.2 to 13.7)y after transplantation, eGFR 49 ± 17 mL/min/1.73 m²) participating in the prospective TransplantLines Cohort Studies. Additionally, dp-carboxylated MGP, ucOC and carboxylated OC were measured using ELISA in plasma of a subgroup of 60 participants. Finally, dp-ucMGP was measured in a separate cohort of 124 kidney transplant recipients before and three months after kidney transplantation. Dp-ucMGP positively correlated with creatinine, cystatin C, and negatively with eGFR (Spearman's ρ 0.54, 0.60, and -0.54, respectively, p < 0.001 for all), and each 10 mL/min/1.73 m² increase in eGFR was associated with a 14.0% lower dp-ucMGP. Additionally, dp-ucMGP strongly declined after kidney transplantation (pretransplantation: 1252 (868 to 1744) pmol/L to posttransplantation: 609 (451 to 914) pmol/L, p < 0.001). Proportions of dp-ucMGP over total MGP and ucOC over total OC were not associated with eGFR. This study highlights that dp-ucMGP is strongly associated with kidney function, and that levels strongly decrease after kidney transplantation. We therefore propose adequate adjustment for kidney function, or the use of kidney function-independent parameters such as proportion of uncarboxylated MGP or OC in the assessment of vitamin K-status in clinical practice and research.

Keywords: kidney function; kidney transplant; matrix Gla protein; osteocalcin; vascular calcification; vitamin K.

Figure 1

Scatter plot and linear association of dp-ucMGP with eGFR in 578 kidney transplant recipients with and without vitamin K-antagonist use. Dp-ucMGP was strongly associated with eGFR in both vitamin K-antagonist users (St. β −0.584, p < 0.001) and non-users (St. β −0.518, p < 0.001). Abbreviations: dp-ucMGP, dephosphorylated matrix Gla protein; eGFR, creatinine-based estimated glomerular filtration rate; Vit K, vitamin K.

Figure 2

Plasma dp-ucMGP before and three months after kidney transplantation in 124 kidney transplant recipients from cohort 2. Dp-ucMGP plasma concentrations were strongly decreased at three months after transplantation, compared to immediately prior to transplantation (median decrease 50% (29% to 63%)). Abbreviations: dp-ucMGP, dephosphorylated uncarboxylated matrix Gla protein.

Figure 3

Correlation heat map of vitamin K-associated and kidney function-associated parameters, in a subgroup of 60 kidney transplant recipients from cohort 1. Numbers indicate Spearman’s rank-based coefficients multiplied by 100. p-values were multiplied by 90 to adjust for multiple testing (following the Bonferroni method), and the tiles of insignificant correlations are blanked. Abbreviations: dp, dephosphorylated; eGFR, estimated glomerular filtration rate; MGP, matrix Gla protein; OC, osteocalcin; (u)c, (un)carboxylated.

Figure 4

Visual presentation of the univariable linear association of uncarboxylated, carboxylated and proportion uncarboxylated matrix Gla protein and osteocalcin with eGFR, in a subgroup of 60 kidney transplant recipients from cohort 1. In brief, both dp-ucMGP and dp-cMGP were strongly negatively associated with eGFR, whereas the negative association of ucOC with eGFR was less pronounced. No statistically significant associations of cOC, proportion of uncarboxylated dp-MGP and proportion of uncarboxylated OC were found with eGFR. Abbreviations: dp-ucMGP, dephosphorylated uncarboxylated matrix Gla protein; dp-cMGP, dephosphorylated carboxylated matrix Gla protein; eGFR, creatinine-based estimated glomerular filtration rate; ucOC, uncarboxylated osteocalcin; cOC, carboxylated osteocalcin.