Assessment of total parathyroidectomy with and without autoimplantation in prevalent hemodialysis patients

Abstract

Renal failure disrupts systemic calcium and phosphate homeostasis and affects the bone, gut, and parathyroid glands. This occurs because of decreased renal excretion of phosphate and diminished renal hydroxylation of 25-hydroxyvitamin D to calcitriol (1,25-dihydroxyvitamin D). Circulating calcitriol levels begin to fall when the glomerular filtration rate is less than 40 mL/min (occasionally even less than 80 mL/min) and are typically markedly reduced in subjects with end-stage renal failure (Levin et al., 2007). The calcium-sensing receptor (CaSR), which is highly expressed in the parathyroid glands, permits variations in the serum calcium concentration to be sensed by the parathyroid gland, leading to the desired changes in PTH secretion. The fall in serum calcium concentration with renal failure, as sensed by the CaSR, is a potent stimulus to the release of PTH. Extracellular calcium acting through the CaSR plays the predominant role in regulating parathyroid function, resulting in this receptor being the major therapeutic target for suppressing parathyroid gland function. This is best shown in mouse and human genetic studies in which extracellular calcium acting through CaSR was the major regulator of PTH transcription, secretion, and parathyroid gland hyperplasia (Panda et al., 2004). Since vitamin D stimulates intestinal phosphate absorption, the decrease in active vitamin D production may be viewed as an adaptive response to minimize hyperphosphatemia in the setting of reduced renal phosphate excretion in patients with kidney failure (Mazess and Elangovan., 2003). The absence of vitamin D also decreases calcium and phosphorus absorption in the gastrointestinal tract. The net effect of low vitamin D levels is to directly increase PTH production due to removal of the normal suppressive effect of calcitriol on the parathyroid glands, and indirectly increase secretion through the gastrointestinal mediated hypocalcemic stimulus. Hyperphosphatemia is also an important factor underlying hyperparathyroidism. Although the identity of the extracellular phosphate sensor is unknown and may not exist, a novel phosphaturic factor, FGF23, may be regulated by phosphate and vitamin D (Wetmore et al., 2010). Hyperphosphatemia also lowers the levels of ionized calcium and interferes with the production of 1,25-dihydroxyvitamin D, thereby resulting in increased PTH levels (Saito et al.,2005). The relationship between FGF23 and PTH is not completely understood. As an example, although FGF23 suppresses PTH via the activation of FGFR/Klotho complexes, elevated FGF23 concentrations do not prevent the development of hyperparathyroidism in patients with CKD. Rather FGF23 and PTH concentrations are directly correlated. Down regulation of FGFR and Klotho expression may cause parathyroid gland resistance to the suppressive effects of FGF23 (Martin et al., 2012). In patients with ESRD, secondary hyperparathyroidism (sHPT) is a common problem requiring surgical parathyroidectomy (PTX) if medical treatment with active vitamin D and calcimimetics fails.