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receptors. Reabsorption of calcium filtered calcium is reabsorbed along much of the nephron.
PTH acts at both cortical thick ascending limb of the loop of Henle and distal convoluted tubule to stimulate calcium reabsorption.54 Thus if PTH secretion falls appropriately after an increase in serum ionized calcium, the ensuing fall in tubular calcium reabsorption and increase in calcium excretion will tend to restore normocalcaemia. The high serum calcium itself also contributes to calciuresis acting via calcium sensing receptor.55, 56 Reabsorption of phosphate; PTH is the major determinate of serum phosphate concentrations. It inhibits mostly proximal but also distal tubular reabsorption of phosphorus. This effect is primarily mediated by decrease activity, internalisation and degradation of the sodium-phosphate co transporter in the luminal membrane of the proximal tubule.57, 58 Synthesis of calcitriol; PTH stimulates the synthesis of 1-alpha hydroxylase in the proximal tubules and thus conversion of calcidiol to calcitriol. It also decreases the activity of 24 hydroxylase that inactivates calcitriol; a particular important action of PTH in maintaining calcium homeostasis in stores of vitamin D deficiency.
Other actions of PTH include chronic excess of PTH which has been implicated in the pathogenesis of vascular calcification and hypertension in patients with CKD.57, 58 These non-classical effects of PTH may be mediated by differing PTH moieties and/or differing PTH receptors.59
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(eGFR) drops below 60mls/min /1.73m2.At that time serum calcium and phosphate levels are normal and remain within normal ranges until eGFR decrease to approximately 20ml/min /1.732.61 However low levels of calcitriol are common at higher levels of eGFR. In one study low levels of calcitriol occurred earlier in the course of eGFR decline than did elevations in iPTH levels.61 These suggested that low calcitriol levels may be the initial trigger for the increased in PTH production.
The control of three of the most important factors calcium, calcitriol and phosphate is very critical in preventing the development of secondary hyperparathyroidism and hyperplasia of the parathyroid gland. Figure 2.2 describe features involved in the pathogenesis of secondary hyperparathyroidism.
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Chronic Renal failure
Phosphate retention Low level of 1, 25 (OH)2D3
Resistance of bone to PTH
Hypocalcaemia
Hyperparathyroidism
Decreased Decreased
Ca Sensor 1, 25 (OH) 2 D3
Receptors
Fig. 2.2 Schematic representation of factors involved in the pathogenesis of secondary hyperparathyroidism.62
44 2.5.1 Role of Calcium
Calcium is a major regulator of PTH secretion acting through a specific membrane receptor, the calcium – sensing receptor, which is located on the surface of the chief cells of the parathyroid glands. Total serum calcium usually decreases during the course of CKD due to phosphate retention, decreased calcitriol level and resistance to the calcaemic actions of PTH on bone. PTH secretion varies inversely with serum calcium.62, 63
In CKD the number of calcium sensing receptors may be reduced in hypertrophied glands.
This change in receptor number can lead to inadequate suppression of PTH secretion by calcium, resulting in inappropriately high PTH levels in the setting of normal or high calcium levels.
2.5.2 Role of Phosphate
A tendency to phosphate retention, beginning early in the disease which occurs as the fall in glomerular filtration rate (GFR) decreases the filtered phosphate load. This plays a central role in the development of secondary hyperparathyroidism.2, 63, 64
Three major but not mutually exclusive theories have been proposed to explain how phosphate retention initially promotes PTH release. 62,65,66
The induction of hypocalcaemia
Decreased formation or activity of calcitriol
A direct effect of hyperphosphataemia to increase PTH gene expression.
Phosphate retention contributes to secondary hyperparathyroidism in early CKD at least in part by decreasing serum free calcium level and calcitriol synthesis.
In addition to its indirect effect, there is increasing evidence in both animals and humans for a direct effect of hyperphosphataemia (independent of the plasma concentration of calcium and calcitriol) on PTH synthesis and secretion in advanced renal failure.67,68,69,70 A study in experimental animals with ESRD demonstrated that dietary phosphate restriction normalize the plasma phosphate concentration and lowered plasma PTH levels from 130 to 35pg/ml.68 This occurred without change in plasma calcium or calcitriol concentrations. Parathyroid size also decreases suggesting that hyperphosphataemia stimulates parathyroid growth in renal failure.
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These assumptions appear to be applicable to humans as illustrated by the following finding;
One report evaluated 15 patients on maintenance haemodialysis.69 phosphate added to the dialysate for 12weeks raise the plasma phosphate concentration by 2.4mg/dl (0.7mmol/l) above the previous baseline of 4.7 to 5.9mg/dl [1.5-1.9 mmol/l]. Seven of the patients showed significant elevation in plasma PTH levels without change in plasma concentrations of ionised calcium or calcitriol (the latter was initially low and remained low throughout the study).
2.5.3 Role of Calcitriol
Plasma calcitriol fall below normal when the GFR is less than 30ml/min. low calcitriol levels have also been found in most studies of patients with mild to moderate CKD (GFR of 40-80ml/min).61,62In addition to reduction in renal mass, several other factors contribute to the low calcitriol levels in CKD. Phosphate retention can directly suppress the renal synthesis of calcitriol.62 Also; experimental studies suggest that the conversion of calcidiol to calcitriol can be diminished by substances retained in renal failure including uraemic toxins and uric acid.71 a similar phenomenon appears to occur in humans.71
High levels of the phosphaturic hormone FGF23 (fibroblast growth factor) whose activation is by Klotho a transmembrane protein also contributes to the low calcitriol in CKD. In the kidney FGF23 inhibits phosphate reabsorption and decreases the synthesis of calcitriol by suppressing activity of 1alpha hydroxylase enzyme. Calcitriol level can lead to increased PTH secretion by indirect as well as by direct mechanisms. Indirect effects on PTH are achieved through decreased intestinal absorption of calcium, which leads to hypocalcaemia which in turn stimulates PTH secretion.
There is also evidence that decreased responsiveness to calcitriol contributes to the development of hyperparathyroidism. In particular, physiologic concentrations of calcitriol may be unable to normally suppress PTH secretion, perhaps due to a reduction in the number of calcitriol receptors in the parathyroid gland.
2.6 CLINICAL SIGNIFICANCE OF PARATHYROID HORMONE, CALCIUM AND