Vascular calcification and secondary hyperparathyroidism of severe chronic kidney disease and its relation to serum phosphate and calcium levels

Abstract

Background and purpose:Various complications consequent on disordered calcium and phosphate homeostasis occur frequently in chronic kidney disease (CKD) patients. Particularly, vascular calcification has high morbidity and mortality rates. There is a clear need for a better CKD model to examine various aspects of this disordered homeostasis. Experimental approach: Oral dosing with adenine induced CKD in rats in only 10 days. Serum calcium, phosphate and parathyroid hormone were measured and calcification in aorta was assessed histologically. The effects of varying phosphorus content of diet or treatment with phosphate binders or active vitamin D3 on these parameters were examined. Key results: After adenine dosing, significant hyperphosphatemia, hypocalcemia and secondary hyperparathyroidism (2HPT) were observed during the experimental period of 15 weeks. Aortic calcification was detected in only some of the animals even at 15 weeks (~40%). Treatment with vitamin D3 for 18 days, even at a low dose (100 ng·kg -1 , 3-4 times week -1 , p.o), caused aortic calcification in all animals and increases in serum calcium levels up to the normal range. The vitamin D3-induced calcification was significantly inhibited by phosphate binders which lowered serum phosphate levels and the calcium ¥ phosphate product, although serum calcium levels were elevated. Conclusions: These data suggest that rats dosed orally with adenine provide a more useful model for analysing calcium/ phosphate homeostasis in severe CKD. Controlling serum calcium/phosphate levels with phosphate binders may be better than vitamin D3 treatment in hyperphosphatemia and 2HPT, to avoid vascular calcification.

Vascular Calcification in Chronic Renal Failure

“…Only few experimental studies made a direct comparison between calcium and noncalcium phosphate binders on the development of uremia-related arterial calcifications. Recently, Terai et al 93 nicely showed that when serum phosphate and PTH were equally controlled by sevelamer and calcium carbonate, both agents significantly reduced the development of medial calcifications, although a slightly better outcome was seen with sevelamer which was probably attributable to lower serum calcium levels. These experimental data suggest that the traditional calcium containing phosphate binders are not necessarily harmful in CKD patients, particularly not in those without vascular calcification at the start of treatment, provided the calcium balance is regularly monitored and no adynamic bone disease is diagnosed.…”

“…The consistent onset and progression of aortic medial calcification is most likely caused by the more severe hyperphosphatemia, 92 because in this synthetic diet, less protein-bound phosphate and more anorganic phosphate is present, with the latter being much more bioavailable. Another promising alternative was recently explored by Terai et al, 93 dosing rats orally through gavage with adenine for 10 days. Unfortunately, only about one third of the animals presented aortic calcification after 15 weeks.…”

Vascular Calcification in Animal Models of CKD: A Review

“…However, in a recent report of a modified version of the adenine model, weight loss was not an issue. Instead of using a chow-based adenine diet, Terai et al [39 ]orally dosed adenine at 600 mg/kg/day for 10 days as the initial acute insult to induce CKD in Wistar rats. On a normal diet with or without high phosphate (i.e.…”

Vitamin D deficiency and toxicity in chronic kidney disease: in search of the therapeutic window

“…Treatment with VDR activators, targeted at PTH levels, affects mineral metabolism, bone, and the arterial wall, but few clinical tools are currently available for monitoring the safety and efficacy of such a powerful therapy. Thus, although hypercalcemia is an indicator of vitamin D toxicity, it should be noted that in animals with CKD, vascular calcification can be induced not only by high [95], but also low doses of calcitriol [94,161] in the absence of hypercalcemia. Similarly, although the PTH level plays a central role in the therapeutic strategy, bone biopsy studies in children have shown that PTH levels are not a good indicator of bone morphology [43,162,163].…”