Ignite Creation Date:
2024-05-05 @ 10:06 PM
Last Modification Date:
2024-10-26 @ 10:13 AM
Study NCT ID:
NCT01021280
Status:
UNKNOWN
Last Update Posted:
2012-06-14
First Post:
2009-11-25
Brief Title:
Parathyroid Hormone PTH Homeostasis in Bartter Syndrome
Sponsor:
Soroka University Medical Center
Organization:
Soroka University Medical Center
Study Overview
Official Title:
Case-control Study of the PTH Homeostasis in Adolescents and Young Adults With Bartter Syndrome
Status:
UNKNOWN
Status Verified Date:
2012-06
Last Known Status:
NOT_YET_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Parathyroid hormone PTH gland calcium sensing receptor CASR regulates PTH secretion CASR is also expressed in nephron thick ascending limb TAL Bartter syndrome BS a normotensive hypokalemic tubulopathy may be due to mutations in different TAL channels including the potassium channel ROMK Mutations in CASR may also cause BS through its effects on ROMK function However it is unknown whether ROMK mutations exert any effects on CASR function and PTH physiology Preliminary data from our center shows that PTH levels were specifically elevated in type II where ROMK is mutated and not in type IV where another gene Barttin is defective BS without a common explanation We assume that the mutation in ROMK may cause a dysregulation of PTH secretion via possible interaction with CASR
The purpose of this study is to investigate the PT-gland function and regulation in BS
Methods Patients with BS type II and IV and normal controls will undergo a standard protocol of controlled ionic hypo- and hypercalcemia during which PTH secretion phosphate balance and calcium excretion will be followed Calcium Vs PTH response curves will be generated and compared
Expected impact and benefit the results of this study will help understand the mechanisms of PTH regulation beyond CASR
The purpose of this study is to investigate the PT-gland function and regulation in BS
Methods Patients with BS type II and IV and normal controls will undergo a standard protocol of controlled ionic hypo- and hypercalcemia during which PTH secretion phosphate balance and calcium excretion will be followed Calcium Vs PTH response curves will be generated and compared
Expected impact and benefit the results of this study will help understand the mechanisms of PTH regulation beyond CASR
Detailed Description:
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 dt 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 datasetspt 7341 and 6929 for type II and IV BS respectively were analyzedPotassium 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 10239 Vs 4624 pgml in BS-IV p0001 and were above upper normal limit in 93 of cases Vs 13 in BS-IV p0001 Levels of 25OH 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
Methods
The investigative protocol has been submitted to the local Committee for Human Experimentation Informed consent will be obtained from affected children or young adults and their parents
We expect to recruit 5 patients from each BS subgroup In addition we will recruit 5 normal volunteers to serve as an additional control group
Subjects will be evaluated during 2-day admissions to the General Pediatric Ward as previously described On the first day of study 2-h IV infusions of sodium citrate will be done to gradually lower blood ionized calcium concentrations to a level of at least 02 mmolL below preinfusion values the dose of sodium citrate ranges usually from 28-118 mgkgh Blood samples for measurements of ionized calcium and PTH will be obtained 30 15 and 0 min before and every 10 min during sodium citrate infusions The following day 2-h IV infusions of 10 calcium gluconate will be done to gradually raise blood ionized calcium concentrations to a level at least 02 mmolL above preinfusion values The dose of calcium gluconate usually ranges from 2-8 mgkgh Blood samples for measurements of ionized calcium and PTH will be obtained as described previously for infusions of sodium citrate The average of measurements obtained 30 15 and 0 min before starting each infusion will be used to determine basal values for blood ionized calcium and serum PTH for each day of study
Blood ionized calcium levels will be monitored during calcium infusions using a calcium-specific electrode Radiometer ICA-II Copenhagen Denmark blood samples will be collected anaerobically and measurements will be obtained immediately thereafter Serum samples for PTH determinations will be separated by centrifugation immediately after collection snap frozen on solid CO2 and stored at -70 oC until assay Ionized calcium levels will be monitored after stopping calcium infusions until values returned to baseline levels
The sigmoidal curve that describes the relationship between blood ionized calcium and serum PTH levels will be determined for each study subject using the combined results obtained during sodium citrate and calcium gluconate infusions According to the four parameter model the set point for calcium-regulated PTH release represents the ionized calcium concentration at which serum PTH levels are midway between the maximum value achieved during hypocalcemia and the minimum value attained during hypercalcemia as reported previously
Results obtained during calcium gluconate infusions will be separately analyzed to assess the inhibitory effect of increasing blood ionized calcium concentrations on PTH release To improve the linear fit of the data serum PTH levels expressed as the natural logarithm ln of percent preinfusion values will be plotted against the corresponding blood ionized calcium concentration at each 10-min interval as previously described
Statistical Analysis
Linear regression analysis will be done using the method of least squares and slope and y-intercept values will be compared using the t statistic A mono-exponential curve fitting algorithm of the form y A e-2kt B will be also used to examine the curvilinear relationship between blood ionized calcium and serum PTH levels during IV calcium infusions these results will be presented as mean values with 95 confidence intervals
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 dt 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 datasetspt 7341 and 6929 for type II and IV BS respectively were analyzedPotassium 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 10239 Vs 4624 pgml in BS-IV p0001 and were above upper normal limit in 93 of cases Vs 13 in BS-IV p0001 Levels of 25OH 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
Methods
The investigative protocol has been submitted to the local Committee for Human Experimentation Informed consent will be obtained from affected children or young adults and their parents
We expect to recruit 5 patients from each BS subgroup In addition we will recruit 5 normal volunteers to serve as an additional control group
Subjects will be evaluated during 2-day admissions to the General Pediatric Ward as previously described On the first day of study 2-h IV infusions of sodium citrate will be done to gradually lower blood ionized calcium concentrations to a level of at least 02 mmolL below preinfusion values the dose of sodium citrate ranges usually from 28-118 mgkgh Blood samples for measurements of ionized calcium and PTH will be obtained 30 15 and 0 min before and every 10 min during sodium citrate infusions The following day 2-h IV infusions of 10 calcium gluconate will be done to gradually raise blood ionized calcium concentrations to a level at least 02 mmolL above preinfusion values The dose of calcium gluconate usually ranges from 2-8 mgkgh Blood samples for measurements of ionized calcium and PTH will be obtained as described previously for infusions of sodium citrate The average of measurements obtained 30 15 and 0 min before starting each infusion will be used to determine basal values for blood ionized calcium and serum PTH for each day of study
Blood ionized calcium levels will be monitored during calcium infusions using a calcium-specific electrode Radiometer ICA-II Copenhagen Denmark blood samples will be collected anaerobically and measurements will be obtained immediately thereafter Serum samples for PTH determinations will be separated by centrifugation immediately after collection snap frozen on solid CO2 and stored at -70 oC until assay Ionized calcium levels will be monitored after stopping calcium infusions until values returned to baseline levels
The sigmoidal curve that describes the relationship between blood ionized calcium and serum PTH levels will be determined for each study subject using the combined results obtained during sodium citrate and calcium gluconate infusions According to the four parameter model the set point for calcium-regulated PTH release represents the ionized calcium concentration at which serum PTH levels are midway between the maximum value achieved during hypocalcemia and the minimum value attained during hypercalcemia as reported previously
Results obtained during calcium gluconate infusions will be separately analyzed to assess the inhibitory effect of increasing blood ionized calcium concentrations on PTH release To improve the linear fit of the data serum PTH levels expressed as the natural logarithm ln of percent preinfusion values will be plotted against the corresponding blood ionized calcium concentration at each 10-min interval as previously described
Statistical Analysis
Linear regression analysis will be done using the method of least squares and slope and y-intercept values will be compared using the t statistic A mono-exponential curve fitting algorithm of the form y A e-2kt B will be also used to examine the curvilinear relationship between blood ionized calcium and serum PTH levels during IV calcium infusions these results will be presented as mean values with 95 confidence intervals
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None