Special report: controversies in bone and mineral metabolism in chronic kidney disease

Vascular calcification in chronic kidney disease

Elevated levels of deoxycholic acid (DCA) are associated with adverse outcomes and may contribute to vascular calcification in patients with chronic kidney disease (CKD). We tested the hypothesis that elevated levels of DCA were associated with increased risks of cardiovascular disease, CKD progression, and death in patients with CKD.

Prospective observational cohort study.

We included 3,147 Chronic Renal Insufficiency Cohort study participants who had fasting DCA levels. The average age was 59 ± 11 years, 45.3% were women, 40.6% were African American, and the mean estimated glomerular filtration rate was 42.5 ± 16.0 mL/min/1.73 m².

Fasting DCA levels in Chronic Renal Insufficiency Cohort study participants.

Risks of atherosclerotic and heart failure events, end-stage kidney disease (ESKD), and all-cause mortality.

We used Tobit regression to identify predictors of DCA levels. We used Cox regression to examine the association between fasting DCA levels and clinical outcomes.

The strongest predictors of elevated DCA levels in adjusted models were increased age and nonuse of statins. The associations between log-transformed DCA levels and clinical outcomes were nonlinear. After adjustment, DCA levels above the median were independently associated with higher risks of ESKD (HR, 2.67; 95% CI, 1.51-4.74) and all-cause mortality (HR, 2.13; 95% CI, 1.25-3.64). DCA levels above the median were not associated with atherosclerotic and heart failure events, and DCA levels below the median were not associated with clinical outcomes.

We were unable to measure DCA longitudinally or in urinary or fecal samples, and we were unable to measure other bile acids. We also could not measure many factors that affect DCA levels.

In 3,147 participants with CKD stages 2-4, DCA levels above the median were independently associated with ESKD and all-cause mortality.

Vitamin K, well known for its role in coagulation, encompasses 2 major subgroups: vitamin K1 is exclusively synthesized by plants, whereas vitamin K2 mostly originates from bacterial synthesis. Vitamin K serves as a cofactor for the enzyme γ-glutamyl carboxylase, which carboxylates and thereby activates various vitamin K–dependent proteins. Several vitamin K–dependent proteins are synthesized in bone, but the role of vitamin K for bone health in chronic kidney disease patients, in particular the prevention of osteoporosis, is still not firmly established. Herein, we focus on another prominent action of vitamin K, in particular vitamin K2 (namely, the activation of matrix γ-carboxyglutamic acid protein, the most potent inhibitor of cardiovascular calcifications). Multiple observational studies link relative vitamin K deficiency or low intake to cardiovascular calcification progress, morbidity, and mortality. Patients with advanced chronic kidney disease are particularly vitamin K deficient, in part because of dietary restrictions but possibly also due to impaired endogenous recycling of vitamin K. At the same time, this population is characterized by markedly accelerated cardiovascular calcifications and mortality. High-dose dietary supplementation with vitamin K2, in particular the most potent form, menaquinone 7, can potently reduce circulating levels of dephosphorylated uncarboxylated (i.e., inactive matrix γ-carboxyglutamic acid protein) in patients with end-stage kidney disease. However, despite this compelling data basis, several randomized controlled trials with high-dose menaquinone 7 supplements in patients with advanced chronic kidney disease have failed to confirm cardiovascular benefits. Herein, we discuss potential reasons and solutions for this.

Patients with chronic kidney disease (CKD) are at high risk of cardiovascular morbidity and mortality. Subclinical cardiac structural alterations have prognostic value in these patients. The aim was to analyse the prevalence of valvular calcification, the evolution and the relationship with different risk factors.

Part of the sample of the NEFRONA study was randomly selected. Aortic and mitral valve calcification were analysed in echocardiograms performed at the baseline visit and at 24 months.

We included 397 patients, the estimated basal glomerular filtrate (eGFR) was 33 ml/min with significant decrease to 30.9 ml/min. There was an increase in the area of carotid and femoral plaque, as well as an increase in patients with aortic and mitral calcification at 24 months. A positive association of mitral calcification at 24 months with age, ankle-brachial index (ABI) and calcium-phosphorus product (CaxP) at baseline visit was observed, without association with eGFR. Aortic calcification at 24 months was positively associated with age, phosphorous and total carotid plaque area at baseline, with no relationship to eGFR.

A significant prevalence of valvular calcification was observed in patients with CKD without known cardiovascular disease.Two-year progression was observed independently of the eGFR. Patients with higher risk of mitral valve calcification were those with older age, higher ABI and CaxP product. Patients with a higher risk of aortic calcification were those with older age, higher phosphorous levels and larger area of carotid plaque. Identifying these higher risk patients would help to avoid future cardiovascular events intensifying follow-ups.

Los pacientes con enfermedad renal crónica (ERC) tiene alto riesgo de morbimortalidad cardiovascular. Las alteraciones estructurales cardiacas subclínicas tienen valor pronóstico en estos pacientes. El objetivo fue estudiar la calcificación valvular, su evolución y relación con diferentes factores de riesgo.

Se seleccionó aleatoriamente parte de la muestra del estudio NEFRONA analizando la calcificación valvular aórtica y mitral en ecocardiogramas de la visita basal y a los 24 meses.

Se estudiaron 397 pacientes con filtrado glomerular estimado (FGE) basal de 33 ml/min/1.73 m² con disminución significativa hasta 30.9 ml/min/1.73 m² Se produjo aumento del área de placa carotidea y femoral, así como aumento de los pacientes con calcificación valvular a los 24 meses. Se observó asociación positiva de la calcificación mitral a 24 meses con la edad, el índice tobillo brazo (ITB) y el producto calcio fósforo (CaxP) basal, sin asociación con el FGE. La calcificación aórtica a los 24 meses presentó asociación positiva con el área total de placa carotidea, el fósforo y la edad basal, sin relación con el FGE.

Se objetivó en pacientes con ERC, sin enfermedad cardiovascular conocida progresión de la calcificación valvular a dos años independientemente del FGE. Presentaron mayor calcificación valvular mitral aquellos de mayor edad, mayor ITB y producto CaxP. Presentaron mayor calcificación valvular aórtica aquellos de mayor edad, mayores niveles de fósforo y mayor área total de placa carotidea. La identificación de estos pacientes con mayor riesgo, podría ayudar a evitar eventos cardiovasculares futuros intensificando el seguimiento.

Chronic kidney disease (CKD) is associated with derangements in the metabolism of calcium, phosphorus, parathyroid hormone (PTH), fibroblast growth factor-23, vitamin D, and Klotho. These alterations start very early in the course of renal disease and lead to severe systemic complications, including secondary hyperparathyroidism, bone fragility and fracture risk, vascular calcifications, and an increase in morbidity and mortality due to cardiovascular disease These alterations have been collectively termed the CKD-bone and mineral disorder (CKD-MBD). In this review, we analyze the interrelationship between the physiology and pathophysiology of factors that lead to progressive alterations of mineral metabolism and their clinical consequences. With regard to management, we focus on the control of phosphorus metabolism by reducing phosphate intake and absorption with phosphate binders, the correction of hypocalcemia while minimizing the risk of hypercalcemia and calcium burden, and control of PTH levels with active vitamin D sterols and calcimimetics. While numerous studies have demonstrated significant progress in the management of CKD-MBD, studies demonstrating their impact on hard clinical outcomes are still relatively scarce.