Renal matrix Gla protein expression increases progressively with CKD and predicts renal outcome

Abstract

Background: Matrix Gla Protein (MGP) is a potent inhibitor of ectopic calcification and modulates bone morphogenesis. Little is known about MGP expression or function in kidney. Methods: We investigated renal MGP expression in Sprague-Dawley rats after 5/6 nephrectomy (5/6 Nx) and in human kidney biopsies in the Nephrotic Syndrome Study Network (NEPTUNE) cohort. We analyzed associations between glomerular (n = 182) and tubulointerstitial (TI) (n = 219) MGP mRNA levels and the disease activity/histologic features in NEPTUNE patients. Additionally, uncarboxylated and carboxylated MGP (ucMGP and cMGP, respectively) were localized by immunohistochemistry and quantitated in kidney tissues of patients at different stages of CKD (n = 18). Results: Renal MGP expression was increased in rats after 5/6 Nx. In NEPTUNE data, baseline estimated glomerular filtration rate (eGFR) negatively correlated with glomerular and TI MGP expression (p < 0.001). TI MGP expression strongly correlated with interstitial fibrosis, tubular atrophy, acute tubular injury, and inter-stitial inflammation, independent of eGFR. Kaplan-Meier analysis and multivariable Cox regression showed that higher levels of TI MGP expression were associated with an increased risk for the composite of 40% decline in eGFR and end-stage renal disease (ESRD) (HR, 3.31; 95% CI, 1.31 to 6.32; p =0.02). Glomerular and tubulointerstitial cells demonstrated nuclear and cytoplasmic cMGP and ucMGP staining, and eGFR inversely correlated with quantified glomerular cMGP staining (p < 0.05). Conclusions: Our data demonstrate that renal MGP expression is increased in human and experimental CKD, and is associated with renal outcome. Additional studies are needed to determine its mechanism of action.

The Association of dp-ucMGP with Cardiovascular Morbidity and Decreased Renal Function in Diabetic Chronic Kidney Disease

“…In rats, after 5/6 nephrectomy, renal expression of MGP was upregulated, and in human kidney tissues obtained from biopsies due to nephrotic syndrome, eGFR was inversely associated with glomerular and tubulointerstitial MGP expression. Similar to our findings, increased MGP expression in the renal tubules and the interstitium was associated with a 3.3-fold higher risk for the composite endpoint of a 40% decline in eGFR and progression to ESRD [ 41 ].…”

“…One of the main reasons for that is that in CKD settings, frequently used endpoints include the initiation of renal replacement therapy and/or doubling of serum creatinine (which corresponds to a 57–60% decline in eGFR), which are late events and may not be reached during the study period. Having these in mind, the endpoint that we adopted (a 30% reduction of eGFR) has been recently established as a validated early surrogate endpoint for the progression of CKD [ 40 , 41 ]. In our study, at baseline, plasma dp-ucMGP was significantly correlated with eGFR and proteinuria, a well-known risk factor for CKD progression and mortality [ 42 ].…”

Vascular Calcification—New Insights into Its Mechanism

“…Released active MGP acts as a local inhibitor of calcification [233,234]. MGP is also ubiquitously expressed in multiple organs, and it is likely that this widespread expression of MGP has considerably more functions than are known for local inhibitor of calcification [235][236][237][238][239]. Recently, plasma dephospho-uncarboxylated MGP (dp-ucMGP) is used as a biomarker reflecting pool vitamin K status.…”

Current Therapy in CKD Patients Can Affect Vitamin K Status

“…Moreover, high dp-ucMGP represents an independent predictor of mortality in renal transplant recipients [66] but not in other groups of CKD patients [38,43]. Interestingly, dp-ucMGP levels in blood [67] and kidney tissue [68] also predict the impairment of renal function both in the general population and in CKD patients, suggesting that vitamin K deficiency may increase the risk of progression towards end-stage renal disease. Even though vitamin K2 supplementation can lower dp-ucMGP levels in patients with CKD [43,[69][70][71], the effects of this treatment on clinical outcomes still need to be fully clarified.…”