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

Abstract

Background: Understanding 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-Ca(2+) (p-Ca(2+)) takes place via an exchange mechanism of Ca(2+) 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-Ca(2+) 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-Ca(2+) from a brief induction of acute hypocalcemia.

Methods: The rapid regulation of p-Ca(2+) was examined in sham-operated rats, acute nephrectomized rats (NX), acute thyroparathyrectomized(TPTX) rats and NX-TPTX rats.

Results: The results clearly showed that p-Ca(2+) 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-Ca(2+) 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-Ca(2+) 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-Ca(2+) independent of PTH, C-PTH and CT.

Conclusions: P-Ca(2+) on a minute-to-minute basis is influenced by presence of kidneys. Hypocalcemia developed rapidly in acute uremia. Levels of p-Ca(2+), 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-Ca(2+) 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-Ca(2+).

Figure 1

Rapid development of hypocalcemia in total nephrectomized (NX) rats. Plasma Ca²⁺ concentrations in sham, NX, TPTX, and NX-TPTX rats. Plasma Ca²⁺ in the NX rats declined rapidly with development of significant hypocalcemia already within 60 minutes, as compared to sham rats (p < 0.01). TPTX resulted as expected in significant hypercalcemia (p < 0.05) within 60 minutes. The increase in plasma Ca²⁺ was significantly lower in NX-TPTX rats, than in TPTX rats, (p <0.05).

Figure 2

Impact of the kidney on recovery of plasma Ca ²⁺ from acute hypocalcemia. NX rats had a significant lower nadir of EGTA induced hypocalcemia than EGTA infused sham rats (p < 0.01). During the recovery from hypocalcemia the concentration of plasma Ca²⁺ remained at all time points significantly lower in the NX group compared to the sham group (p < 0.01).

Figure 3

Impact of the kidney on recovery of plasma Ca ²⁺ from acute hypocalcemia in thyroparathyroidectomized (TPTX) rats. NX-TPTX rats had significantly lower nadir of EGTA induced hypocalcemia than that of EGTA infused TPTX rats (p < 0.01). Plasma Ca²⁺ concentration remained significantly lower in the NX-TPTX rats at all time points during recovery from hypocalcemia, (p < 0.01).

Figure 4

Plasma-phosphate concentrations in NX, TPTX, NX-TPTX and sham rats. Despite large deviations in plasma Ca²⁺ induced by NX, TPTX, NX-TPTX and EGTA infusion plasma P levels remained stable within the groups. The exception was in the NX-EGTA group, where a significant increase of plasma phosphate (p < 0.01) developed late in the experiment (please, see text).