Exogenous BMP7 in aortae of rats with chronic uremia ameliorates expression of profibrotic genes, but does not reverse established vascular calcification

<div><p>Hyperphosphatemia and vascular calcification are frequent complications of chronic renal failure and bone morphogenetic protein 7 (BMP7) has been shown to protect against development of vascular calcification in uremia. The present investigation examined the potential reversibility of established uremic vascular calcification by treatment of uremic rats with BMP7. A control model of isogenic transplantation of a calcified aorta from uremic rats into healthy littermates examined whether normalization of the uremic environment reversed vascular calcification. Uremia and vascular calcification were induced in rats by 5/6 nephrectomy, high phosphate diet and alfacalcidol treatment. After 14 weeks severe vascular calcification was present and rats were allocated to BMP7, vehicle or aorta transplantation. BMP7 treatment caused a significant decrease of plasma phosphate to 1.56 ± 0.17 mmol/L vs 2.06 ± 0.34 mmol/L in the vehicle group even in the setting of uremia and high phosphate diet. Uremia and alfacalcidol resulted in an increase in aortic expression of genes related to fibrosis, osteogenic transformation and extracellular matrix calcification, and the BMP7 treatment resulted in a decrease in the expression of profibrotic genes. The total Ca-content of the aorta was however unchanged both in the abdominal aorta: 1.9 ± 0.6 μg/mg tissue in the vehicle group vs 2.2 ± 0.6 μg/mg tissue in the BMP7 group and in the thoracic aorta: 71 ± 27 μg/mg tissue in the vehicle group vs 54 ± 18 μg/mg tissue in the BMP7 group. Likewise, normalization of the uremic environment by aorta transplantation had no effect on the Ca-content of the calcified aorta: 16.3 ± 0.6 μg/mg tissue pre-transplantation vs 15.9 ± 2.3 μg/mg tissue post-transplantation. Aortic expression of genes directly linked to extracellular matrix calcification was not affected by BMP7 treatment, which hypothetically might explain persistent high Ca-content in established vascular calcification. The present results highlight the importance of preventing the development of vascular calcification in chronic kidney disease. Once established, vascular calcification persists even in the setting when hyperphosphatemia or the uremic milieu is abolished.</p></div

Effect of NAD(+) boosting on kidney ischemia-reperfusion injury

Acute kidney injury (AKI) is associated with a very high mortality and an increased risk for progression to chronic kidney disease (CKD). Ischemia-reperfusion injury (IRI) is a model for AKI, which results in tubular damage, dysfunction of the mitochondria and autophagy, and in decreased cellular nicotinamide adenine dinucleotide (NAD(+)) with progressing fibrosis resulting in CKD. NAD(+) is a co-enzyme for several proteins, including the NAD(+) dependent sirtuins. NAD(+) augmentation, e.g. by use of its precursor nicotinamide riboside (NR), improves mitochondrial homeostasis and organismal metabolism in many species. In the present investigation the effects of prophylactic administration of NR on IRI-induced AKI were studied in the rat. Bilateral IRI reduced kidney tissue NAD(+), caused tubular damage, reduced α-Klotho (klotho), and altered autophagy flux. AKI initiated progression to CKD, as shown by induced profibrotic Periostin (postn) and Inhibin subunit beta-A, (activin A / Inhba), both 24 hours and 14 days after surgery. NR restored tissue NAD(+) to that of the sham group, increased autophagy (reduced p62) and sirtuin1 (Sirt1) but did not ameliorate renal tubular damage and profibrotic genes in the 24 hours and 14 days IRI models. AKI induced NAD(+) depletion and impaired autophagy, while augmentation of NAD(+) by NR restored tissue NAD(+) and increased autophagy, possibly serving as a protective response. However, prophylactic administration of NR did not ameliorate tubular damage of the IRI rats nor rescued the initiation of fibrosis in the long-term AKI to CKD model, which is a pivotal event in CKD pathogenesis

Diurnal variation of magnesium and the mineral metabolism in patients with chronic kidney disease

Increasing levels of magnesium in blood are associated with reduced risk of cardiovascular disease in chronic kidney disease (CKD). Magnesium supplementation may reduce the progression of vascular calcification in CKD. The diurnal pattern and effect of fasting on magnesium in blood and urine in CKD is unknown, and knowledge of this may influence management of magnesium supplementation. We included ten patients with CKD stage four without diabetes mellitus and ten healthy controls. Participants were admitted to our hospital ward for a 24-h study period. Blood and urine samples were collected in a non-fasting state at 8 o'clock in the morning and every third hour hereafter until the final samples in a fasting state at 8 o'clock the following morning. We found no diurnal variation in plasma magnesium (p = 0.097) in either group, but a significant diurnal variation in urinary excretion of magnesium (p = 0.044) in both CKD and healthy controls with no significant interaction between the two groups, and thus no suggestion that CKD affects diurnal variation of plasma magnesium or urinary magnesium excretion. The levels of plasma magnesium were not significantly different in fasting and non-fasting conditions. Magnesium in plasma does not display a significant diurnal variation and can be measured at any time of day and in both fasting and non-fasting conditions. Urinary magnesium excretion displays diurnal variation, which is likely related to increased uptake of magnesium during meals and helps maintain a stable concentration of magnesium in blood