Clinical application of calcium modeling in patients with chronic kidney disease

Metabolic balance studies have a long and important history in medical research [1]. On the most fundamental level balance studies are used to quantitate whether the amount of a substance (mass) has been added, retained or lost from the body. Over a fixed period of time, input and output are measured, the latter is subtracted from the former, and if there is no internal production or degradation, the results indicate either a positive (gain of mass) or a negative (loss of mass) balance. The demands of the balance technique require that the organism be in a ‘steady state’; during these measurements, the ionic and hormonal milieu must be constant or, if not, at least accounted for by this now more complex model. During growth, one would expect a positive mass balance of most ions, including calcium, and with osteoporosis a negative calcium balance. However, while balance studies have value, they are not designed nor are they sufficient to understand how an ion, such as calcium, is redistributed within the body. For that more complex understanding, which can be termed kinetic modeling, one would need to know not only if the patient was in positive, neutral or negative mass balance but if an ion was moving from one body compartment to another. During growth, one would expect not only a positive mass balance for calcium but movement of this ion from the intestine into the blood and then into bone. This complex ionic choreography is controlled by a number of ions in addition to calcium and several hormones and growth factors. With respect to calcium, as far as we know, humans do not have a mechanism to measure mass nor balance; our bodies sense only blood-ionized calcium concentration ([Ca]), a measure of mass/volume of a liquid phase. The calcium-sensing receptor (CaR) precisely measures [Ca] but does not detect the total calcium content nor whether it has changed [2]. While bone can respond to stress by altering its mass and architecture, calcium balance is not being detected. The clinical examples of primary hyperparathyroidism and adolescent bone growth teach us that blood calcium concentration and mass balance are not necessarily linked. Patients with primary hyperparathyroidism have an elevated [Ca] but have a reduction in bone mineral density indicating a negative mass balance [3, 4]. In adolescents, [Ca] is in the normal range while the growing bone incorporates calcium into the mineral, indicating a positive mass balance [5]. Humans and other mammals not only sense [Ca] but have robust passive and active transport mechanisms to maintain it within a very narrow range [6, 7]. Alterations in [Ca] set into play physiological measures aimed at restoring the [Ca] toward normal, with no regard to the body or bone calcium content. A low [Ca] induces rapid physicochemical mineral dissolution—a rapidly exchangeable pool of mineral on the bone surface releases calcium in an attempt to restore [Ca] toward normal. The low [Ca] also induces a marked increase in parathyroid hormone (PTH) and increases the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (1,25(OH)2D). PTH stimulates cell-mediated bone resorption and renal tubular calcium reabsorption and 1,25(OH)2D increases intestinal calcium absorption and bone resorption, all resulting in increased [Ca]. Through this process, [Ca] is restored toward normal, often at the expense of diminished bone calcium content. The reduced calcium content weakens the bone and predisposes to fractures. In the short term, a normal [Ca] is far more important than a normal bone mass as failure to maintain a physiologically normal [Ca] leads to neurological dysfunction, seizures and cardiac arrhythmias and, in the extreme, death [7, 8]. With increases in dietary calcium, a decreasing percentage of that calcium is absorbed; however, absolute absorption continues to rise as intake increases [9]. In patients with intact kidney function, any absorbed calcium, in excess of body needs, is excreted in the urine. However, in patients with chronic kidney disease (CKD), the kidney does not and cannot perform this vital function [10]. Other than losses in sweat, any net absorbed intestinal calcium must be deposited either in bone or in soft tissues or lost during dialysis [11]. In patients with CKD, a number of factors induce the movement of calcium out of bone and into the extracellular fluid (ECF) [12]. Secondary