Whether vascular calcification can be prevented or reversed with strategies INK-128 aimed at maintaining phosphate homeostasis is as yet unknown. One recent study also determined an association between serum phosphate within the normal range and vascular and valvular calcification.21 This study of 439 young and middle-age participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with both normal renal function and CKD, and no known CVD, reported that after adjustment for eGFR, each 1 mg/dL increase in serum phosphate concentration was significantly associated with a 21%, 33%,
25% and 62% greater prevalence of coronary artery, thoracic, aortic valve and mitral valve calcification respectively. The CARDIA study, described earlier, also showed that phosphate levels within the reference range were significantly associated with coronary artery calcium levels in a young healthy adult population.19 Elevations in serum phosphate have been associated with structural changes and renal decline in animal models.68 In human observational studies, hyperphosphataemia is associated with progression of established CKD and the development of ESKD (end-stage Copanlisib in vivo kidney
disease)23,69–71 and studies of renal transplant recipients describe an association between higher serum phosphate and renal allograft loss.27,28 Serum phosphate levels in the upper-normal range have also recently been reported to be associated with an increased risk of developing incident CKD and ESKD.6,24 One study involving 2269 participants from the Framingham Heart Study showed that those in the highest phosphate category had an increased risk of CKD with OR 2.14 (95% CI 1.07–4.28) 4��8C when compared with the reference group with serum phosphate 2.5–3.49 mg/dL.6 The same study also analysed 13 372 participants
from the Third National Health and Nutrition Examination Survey (NHANES III) and reported that phosphate ≥4 mg/dL was associated with an increased risk of incident ESKD (RR 1.90 (95% CI 1.03–3.53)). Zoccali et al. recently evaluated the relationship between baseline serum phosphate, disease progression and response to angiotensin-converting enzyme (ACE) inhibition in 331 patients with proteinuric CKD in the prospective Ramipril Efficacy In Nephropathy (REIN) trial.72 Phosphate levels in the highest two quartiles were significantly associated with faster progression to both ESKD and to a composite end-point of doubling of serum creatinine or ESKD compared with patients with phosphate levels below the median. Therefore, with higher serum phosphate levels the renoprotective effect of ramipril decreased, despite adjustment for potential confounders such as GFR and urinary protein. This suggests that phosphate may potentially modify the protective effect of the only real therapeutic class of agents used in CKD. FGF-23 is the most potent hormone regulating phosphate homeostasis.73 In health, FGF-23 is secreted by osteocytes and osteoblasts in response to dietary phosphate intake.