Kidney bone disease and mortality in CKD: revisiting the role of vitamin D, calcimimetics, alkaline phosphatase, and minerals

Abstract

Recent evidence indicates that the traditional syndromes known as renal osteodystrophy, secondary hyperparathyroidism and vitamin D deficiency are related to mortality in persons with chronic kidney disease (CKD). The so-called “Kidney Bone Disease”, also know as “Mineral-and-Bone-Disorders”, is defined to include 3 interrelated entities: bone disorders, mineral disarrays, and vascular calcification. These disorders are common in individuals with moderate to advanced CKD and may be related to cardiovascular disease and risk. We have identified 13 common and clinically relevant conditions of contemporary nature that are related to the Kidney Bone Disease, including: calcitriol (active vitamin D) deficiency, 25(OH)-vitamin D deficiency, biochemical hyperparathyroidism, relatively low parathyroid hormone level, increased serum alkaline phosphatase (hyperphosphatasemia), elevated fibroblast growth factor-23, high turnover bone disease, adynamic bone disease, vascular calcification, hyper- and hypophosphatemia, and hyper- and hypocalcemia. We present a critical review of these 13 conditions with emphasis on CKD patient survival and other pertinent clinical outcomes. We also review unresolved controversies surrounding the administration of nutritional vitamin D, activate vitamin D analogs, calcimimetics and recombinant parathyroid hormone teriparatide; compare mortality predictability of parathyroid hormone and alkaline phosphatase; and examine potential risks of mineral disarrays and abnormally high and low levels of calcium and phosphorus in CKD patients.

PTH—A Particularly Tricky Hormone

“…There was no confirmation of major adverse cardiac events by electrocardiographic or echocardiographic readings or clinical record confirmation of myocardial infarction, stroke, or abnormal heart rhythm, which obviously brings accuracy limitations to the definition of endpoints in this report. Alternatively, Kalantar-Zadeh and colleagues suggest that there is a U-shaped relationship between PTH and overall adverse endpoints in CKD (higher mortality with low and high PTH concentrations) (27). However, data to support this interpretation mainly come from dialysis chains where we believe that many residual undetected or unmeasured confounders are likely to still be operating.…”

Antilipolytic effect of calcimimetics depends on the allelic variant of calcium-sensing receptor gene polymorphism rs1042636 (Arg990Gly)

“…12 Recent registry data 15 support the idea that cinacalcet therapy target levels of PTH should depend on the patients' rs1042636 status: survival of Japanese end-stage kidney disease patients (95% carry the glycine allele) is best at PTH levels between 80-160 pg/ml, whereas Blacks and Whites (glycine allele 5-10%) need levels between 150-300 pg/ml. Our present in-vitro evidence is consistent with the clinical observations, showing a genotype-phenotype relationship where this polymorphism influences the antilipolytic response of CASR stimulation in adipocytes.…”

Comparative Mortality–Predictability Using Alkaline Phosphatase and Parathyroid Hormone in Patients on Peritoneal Dialysis and Hemodialysis

“…The bone isoform of ALP is produced by osteoblasts and may be a more specific indicator of bone turnover than is PTH, which originates from the parathyroid glands and is influenced by age, race, suboptimal assays, inflammation, and nutrition and anthropometric status (19)(20)(21)(22)(23). Experimental data suggest that ALP may be causally associated with vascular calcification via hydrolysis of pyrophosphate, a potent calcification inhibitor (18,24,25).…”