A potential kidney - bone axis involved in the rapid minute-to-minute regulation of plasma Ca2+

Abstract

BackgroundUnderstanding the regulation of mineral homeostasis and function of the skeleton as buffer for Calcium and Phosphate has regained new interest with introduction of the syndrome “Chronic Kidney Disease-Mineral and Bone Disorder”(CKD-MBD). The very rapid minute-to-minute regulation of plasma-Ca2+ (p-Ca2+) takes place via an exchange mechanism of Ca2+ between plasma and bone. A labile Ca storage pool exists on bone surfaces storing excess or supplying Ca when blood Ca is lowered. Aim was to examine minute-to-minute regulation of p-Ca2+ in the very early phase of acute uremia, as induced by total bilateral nephrectomy and to study the effect of absence of kidneys on the rapid recovery of p-Ca2+ from a brief induction of acute hypocalcemia.MethodsThe rapid regulation of p-Ca2+ was examined in sham-operated rats, acute nephrectomized rats(NX), acute thyroparathyrectomized(TPTX) rats and NX-TPTX rats.ResultsThe results clearly showed that p-Ca2+ falls rapidly and significantly very early after acute NX, from 1.23 ± 0.02 to 1.06 ± 0.04 mM (p < 0.001). Further hypocalcemia was induced by a 30 min iv infusion of EGTA. Control groups had saline. After discontinuing EGTA a rapid increase in p-Ca2+ took place, but with a lower level in NX rats (p < 0.05). NX-TPTX model excluded potential effect of accumulation of Calcitonin and C-terminal PTH, both having potential hypocalcemic actions. Acute TPTX resulted in hypercalcemia, 1.44 ± 0.02 mM and less in NX-TPTX rats,1.41 ± 0.02 mM (p < 0.05). Recovery of p-Ca2+ from hypocalcemia resulted in lower levels in NX-TPTX than in TPTX rats, 1.20 ± 0.02 vs.1.30 ± 0.02 (p < 0.05) demonstrating that absence of kidneys significantly affected the rapid regulation of p-Ca2+ independent of PTH, C-PTH and CT.ConclusionsP-Ca2+ on a minute-to-minute basis is influenced by presence of kidneys. Hypocalcemia developed rapidly in acute uremia. Levels of p-Ca2+, obtained during recovery from hypocalcemia resulted in lower levels in acutely nephrectomized rats. This indicates that kidneys are of significant importance for the ‘set-point’ of p-Ca2+ on bone surface, independently of PTH and calcitonin. Our results point toward existence of an as yet unknown factor/mechanism, which mediates the axis between kidney and bone, and which is involved in the very rapid regulation of p-Ca2+.

Acute calcium kinetics in haemodialysis patients

“…However, we could not confirm a previously described association of OC with iCaMB . Interestingly, a recent study demonstrated that nephrectomy‐induced acute uraemia immediately leads to the onset of hypocalcemia in thyro parathyroidectomized rats independent of calcitropic hormones and phosphate levels . Thus, analog to the immediate increase in osteocytic FGF 23 levels following renal injury , a kidney–bone axis affecting acute Ca regulation has been postulated.…”

“…However, elegant animal studies demonstrated that acute Ca S regulation (i.e. on a minute-to-minute basis) is primarily independent of calcitropic hormones (PTH, active vitamin D or calcitonin), cell-mediated bone remodelling, gastrointestinal uptake as well as renal Ca handling as a rapid counter-regulatory response to acute hyper-and hypocalcemia has been observed in rats within several minutes that is still present after combined nephrectomy and thyro parathyroidectomy [2][3][4][5][6]. Moreover, inhibition of bone remodelling using bisphosphonates did not alter acute Ca S recovery after induction of hypocalcemia [7].…”

Key role of the kidney in the regulation of fibroblast growth factor 23

“…83 Our laboratory has previously demonstrated a rapid minute-to-minute regulation of p-Ca 2+ , where the set point for Ca 2+ on the bone surface was defined by the level of calciotropic hormones, activity of CaR, and the presence of kidneys. [84][85][86][87][88] The minute-to-minute regulation of P is not well understood. A rise in p-P resulted not only in an immediate dose-dependent drop in p-Ca 2+ but also in prolonged recovery in BNX rats.…”

Arterial Calcification in Diabetes Mellitus

“…Serum phosphate levels at any level of renal function convey cardiovascular risk, and exert pro-inflammatory actions upon VSM that promote vesicle-mediated vascular mineralization 118, 119 . It has been proposed that the skeleton represent an important “buffer” for phosphate in CKD 120 , and that orthotopic osteoblast –mediated calcium phosphate (as hydroxyapatite) deposition in bone may be responsible for the vascular benefits of normal bone formation. As compared to ApoE-null models, this model has relatively modest arterial calcium loads.…”