Case-control Study of the PTH Homeostasis in Adolescents and Young Adults With Bartter Syndrome

The parathyroid glands play a pivotal physiological function by maintaining blood calcium levels, specifically blood ionized calcium concentrations, within a very narrow range. They do so by modulating the minute-to-minute release of parathyroid hormone (PTH) into the circulation. Such changes have almost immediate effects on calcium excretion in the urine and on calcium efflux from bone and, if sustained for hours or days, affect renal vitamin D metabolism and ultimately the efficiency of intestinal calcium absorption. The capacity of chief cells of the parathyroid to detect small changes in blood ionized calcium levels, modify PTH release accordingly, and initiate these adaptive responses is mediated by a calcium-sensing receptor (CaSR) located at the cell surface.

The importance of the CaSR in parathyroid tissue extends beyond its traditional role as a modifier of calcium-regulated PTH secretion to involve other key components of parathyroid gland function that are frequently abnormal in clinical disorders characterized by excess parathyroid gland activity such as hyperparathyroidism. These include disturbances in the control of PTH gene transcription and hormone synthesis and the development of parathyroid gland enlargement due to tissue hyperplasia.

PTH acts mainly on renal proximal tubule phosphorus (Pi) reabsorption and bone osteoclast calcium and Pi resorption. CASR is also expressed in nephron thick ascending limb (TAL), where it interacts with luminal potassium ROMK channel. Mutations in several TAL channels and proteins (including ROMK, NKCC2, ClCKb, Barttin and CASR) cause Bartter syndrome (BS), a normotensive hypokalemic tubulopathy. Whereas the effects of CASR mutations on ROMK function in the kidney have been described , it is unknown whether ROMK mutations exert any effects on CASR function or PTH regulation. We describe here a group of children and adolescents with type II BS (due to mutations in ROMK) with abnormal PTH homeostasis.

Preliminary Data:

We compared laboratory data of 12 children with type II BS (4M, 8F) and 17 children (7M, 10F) with type IV BS (d/t mutations in the Barttin gene, a beta subunit of the ClCKb basolateral chloride channel in the TAL ), followed in our center over the past 10 years. A total of 86 and 105 datasets of blood and urine analyses (average datasets/pt: 7.3±4.1 and 6.9±2.9), for type II and IV BS respectively, were analyzed.Potassium levels were normal in all BS-II children without additional salt supplementation, whereas BS-IV children were usually mildly hypokalemic. Estimated GFR remains normal in all children. There was no hypomagnesemia. Average PTH values were significantly higher in BS-II (102±39 Vs 46±24 pg/ml in BS-IV, p<0.001) and were above upper normal limit in 93% of cases Vs 13% in BS-IV (p<0.001). Levels of 25(OH) vitamin D were not different. Total serum calcium was mildly decreased (within the normal range) and serum Pi increased in BS-II, both in absolute values or when normalized for age (PiSDS). The threshold for phosphate excretion (TpGFR) was slightly higher in BS-II. There was no difference in the degree of hypercalciuria between groups. Based on these preliminary data we concluded that the elevated PTH levels only in type II BS are not related to a decrease in GFR or vitamin D levels or decreased serum calcium or hypercalciuria. The elevated Pi levels are associated with a decrease in phosphate excretion, but are not correlated with PTH levels. The possibility that a mutation in ROMK may cause a dysregulation of PTH secretion via possible interaction with CASR should now be investigated.