Current and potential therapeutic strategies for the management of vascular calcification in patients with chronic kidney disease including those on dialysis

Abstract

Patients with CKD have accelerated vascular stiffening contributing significantly to excess cardiovascular morbidity and mortality. Much of the arterial stiffening is thought to involve vascular calcification (VC), but the pathogenesis of this phenomenon is complex, resulting from a disruption of the balance between promoters and inhibitors of calcification in a uremic milieu, along with derangements in calcium and phosphate metabolic pathways. Management of traditional cardiovascular risk factors to reduce VC may be influential but has not been shown to significantly improve mortality. Control of mineral metabolism may potentially reduce the burden of VC, although using conventional approaches of restricting dietary phosphate, administering phosphate binders, and use of active vitamin D and calcimimetics, remains controversial because recommended biochemical targets are hard to achieve and clinical relevance hard to define. Increasing time on dialysis is perhaps another therapy with potential effectiveness in this area. Despite current treatments, cardiovascular morbidity and mortality remain high in this group. Novel therapies for addressing VC include magnesium and vitamin K supplementation, which are currently being investigated in large randomized control trials. Other therapeutic targets include crystallization inhibitors, ligand trap for activin receptors and BMP-7. This review summarizes current treatment strategies and therapeutic targets for the future management of VC in patients with CKD.

Pathogenesis and management of vascular calcification in CKD and dialysis patients

“…Vitamin k is a cofactor for this γ‐carboxylation; hence, warfarin interferes with activation of MGP and favors calcification . Due to promising preliminary results of vitamin K therapy in the CKD population, trials looking at the therapeutic application of vitamin K to prevent vascular calcification in CKD patients are underway . Of note, alkalemia occurring after hemodialysis, not uncommon with high bicarbonate dialysate, can favor both reactions in the above two‐step process of calcification.…”

“…In serum, amorphous primary CPP particles transform into larger crystalline secondary CPP (CPP‐2) particles when there is dysregulated mineral metabolism such as that occurring in CKD due to all the above factors. Uptake by cells of this CPP‐2 (rather than primary CPP) is known to induce vascular calcification . The propensity of the serum to resist calcification can be measured using the T‐50 time.…”

“…Magnesium has been recently found to inhibit calcification by reducing the precipitation of CPP and thus prolonging the T‐50 time. Magnesium up‐regulates inhibitors of vascular calcification including MGP, osteogenic transcription factors in VSMCs (runt‐related transcription factor‐2 [RUNX2] and bone morphogenetic protein 2 [BMP‐2]) . Recently, a trial found that increasing dialysate magnesium from 1 to 2 mEq/L for 28 days improved the T‐50 time …”

“…A positive calcium balance from increased calcium load, activated vitamin D, vitamin D receptor agonists, and use of calcium based phosphate binders can occur in CKD and ESRD patients. VSMCs, when exposed to a medium rich in calcium, undergo osteogenic differentiation and synthesize proteins such as collagen type 1, osteocalcin, osteopontin, alkaline phosphatase, RUNX2, BMP‐2 and cause matrix mineralization . Hyperphosphatemia induces VSMCs and endothelial cells to undergo apoptosis and to release matrix vesicles containing procalcific substances, increase in reactive oxygen species production and ultimately leading to calcification …”

Contemporary Trends in Clinical Outcomes among Dialysis Patients with Medicare Coverage

“…Mean predialysis systolic blood pressure varies between 145 and 150 mm Hg, with nearly 30% of HD patients presenting systolic blood pressure ≥160 mm Hg [26]. Almost 35% of HD patients present serum phosphorus > 5.5 mg/dL [26], despite extensive use of phosphate binders [27], and in turn, almost 25% of HD patients present serum parathyroid hormone > 600 pg/mL [26]; hyperphosphatemia and secondary hyperparathyroidism are risk factors for vascular calcification [28]. Finally, although more patients have received care from a nephrologist before dialysis initiation, use of central venous catheters at dialysis initiation still exceeds 80% [1].…”