The risk of nephrolithiasis is causally related to inactive matrix Gla protein, a marker of vitamin K status: a Mendelian randomization study in a Flemish population.

Abstract

Background:

Vitamin K (VK)-dependent γ-glutamate carboxylation and serine phosphorylation activate matrix Gla protein (MGP) to a potent locally acting inhibitor of calcification. Nephrolithiasis represents a process of unwanted calcification associated with substantial mortality and high recurrence rates. We hypothesized that the risk of nephrolithiasis increases with VK shortage, as exemplified by higher plasma levels of desphospho-uncarboxylated MGP (dp-ucMGP).

Methods:

In 1748 randomly recruited Flemish individuals (51.1% women; mean age 46.8 years), we determined dp-ucMGP and the prevalence of nephrolithiasis at baseline (April 1996-February 2015) and its incidence during follow-up until March 2016. We estimated the multivariable-adjusted relative risk associated with the doubling of dp-ucMGP, using logistic or Cox regression. We did a Mendelian randomization analysis using four MGP genotypes as instrumental variables.

Results:

With adjustments applied for sex, age and 24-h urinary volume and calcium excretion, the odds of having prevalent nephrolithiasis [n = 144 (8.2%)] associated with dp-ucMGP was 1.31 [95% confidence interval (CI) 1.04-1.64; P = 0.022]. dp-ucMGP levels were associated (P ≤ 0.001) with MGP variants rs2098435, rs4236 and rs2430692. In the Mendelian analysis, the causal odds ratio was 3.82 (95% CI 1.15-12.7; P = 0.029). The incidence of nephrolithiasis over 12.0 years (median) was 37 cases (0.2%). With similar adjustments as before, the hazard ratio in relation to dp-ucMGP was 2.48 (95% CI 1.71-3.61; P < 0.001). Additional adjustment for a nephrolithiasis propensity score produced consistent results.

Conclusion:

Higher levels of inactive dp-ucMGP may be causally associated with the risk of nephrolithiasis. Whether or not VK deficiency plays a role in these observations remains to be firmly established.

• Authors: Fang-Fei Wei, Lutgarde Thijs, Zhen-Yu Zhang, Lotte Jacobs, Wen-Yi Yang, Erika Salvi, Lorena Citterio, Nicholas Cauwenberghs, Tatiana Kuznetsova, Nadja E A Drummen, Azusa Hara, Paolo Manunta, Yan Li, Peter Verhamme, Karel Allegaert, Daniele Cusi, Cees Vermeer, Jan A Staessen
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 33 Issue 3 Pg. 514-522 (03 01 2018) ISSN: 1460-2385 [Electronic] England
• PMID: 28340119 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Chemical References

• Biomarkers
• Calcium-Binding Proteins
• Extracellular Matrix Proteins
• Vitamin K

Topics

• Adult
• Belgium (epidemiology)
• Biomarkers (blood)
• Calcium-Binding Proteins (blood, genetics)
• Extracellular Matrix Proteins (blood, genetics)
• Female
• Genotype
• Humans
• Incidence
• Male
• Mendelian Randomization Analysis
• Middle Aged
• Nephrolithiasis (blood, epidemiology, etiology)
• Phosphorylation
• Prognosis
• Vitamin K (metabolism)
• Vitamin K Deficiency (complications)
• Young Adult
• Matrix Gla Protein