Renal Calcium Handling Research Articles

High fibroblast growth factor 23 is associated with coronary calcification in patients with high adiponectin: analysis from the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD) study.

The association between fibroblast growth factor 23 (FGF23) and coronary artery calcification (CAC) was inconclusive. Recently it was shown that adiponectin modulates renal handling of calcium and phosphorus. We hypothesized that adiponectin plays a role in the effect of FGF23 on CAC and explored whether the association between FGF23 and CAC is modified by serum adiponectin level in chronic kidney disease (CKD) patients. This cross-sectional study analyzed 1435 predialysis CKD patients from the Korean Cohort Study for Outcome in Patients with CKD cohort. Participants were divided into two groups according to their serum adiponectin (upper half and lower half). Each group was further divided into three groups according to their FGF23 levels as follows: low (<5.0RU/mL), middle (5.0-29.9RU/mL) and high (≥30.0RU/mL). The coronary artery calcium score (CACS) was assessed using cardiac computed tomography and CAC was defined as a CACS >100. The median CACS did not differ between the low and high adiponectin groups {3.2 [interquartile range (IQR) 0.0-98.1] versus 0.5 [0.0-99.5], P = 0.988}. The CACS ratio comparing high FGF23 to low FGF23 was significantly increased in the high adiponectin group, but not in the low adiponectin group [2.35 (IQR 1.14-4.85) versus 1.10 (0.60-2.03)]. The odds ratio for CAC in the high FGF23 group compared with the low group was 1.97 (IQR 1.10-3.53). The association between FGF23 and CAC was modified significantly by adiponectin level (P for interaction = 0.023). High serum FGF23 was associated with CAC in CKD patients with high adiponectin, but not in those with low adiponectin. Further studies are warranted to verify the role of adiponectin in FGF23-related CAC.

Role of NHE3 in renal calcium handling

In the renal proximal tubule (PT) and the intestine, passive paracellular Ca2+ reabsorption has been linked to active Na+ reabsorption via the Na+‐H+ exchanger type 3 (NHE3). Whole body NHE3 knockout mice show reduced intestinal Ca2+ absorption and significantly higher urinary Ca2+ excretion. To isolate the kidney‐specific role of NHE3 in this process, we examined Ca2+ handling in our recently generated kidney tubule‐specific NHE3 knockout mice [NHE3loxloxPax8Cre; Am J Physiol Renal Physiol. 2015;308(12):F1409‐20]. Twenty‐four‐hour metabolic cage experiments did not show significant differences in urinary Ca2+ excretion between genotypes on standard diet (control: 10.5 ± 1.4 μmol; NHE3loxloxPax8Cre: 11.3 ± 1.7 μmol, NS) in conjunction with normal plasma Ca2+ concentrations (control: 1.27 mM ± 0.01 mM; NHE3loxloxPax8Cre: 1.28 ± 0.01 μmol, NS). A high (4%) NaCl diet increased urinary Ca2+ excretion to a similar degree in both genotypes (control: 29.8 ± 6.3; NHE3loxloxPax8Cre: 28.9± 5.5, NS). Analysis of whole kidney samples for proteins involved in renal Ca2+ handling by RT‐qPCR indicated increased expression of transient receptor potential cation channel subfamily V member 5, TRPV5, and Na+‐Cl− cotransporter, NCC (1.34‐fold and 1.44‐fold, respectively, P &lt; 0.05) in NHE3loxloxPax8Cre vs control mice. Similar changes were detected by immunoblotting (TRPV5: 1.57‐fold; NCC: 1.27‐fold; P &lt; 0.05). Our results indicate intact Ca2+ homeostasis in kidney‐specific NHE3 knockout mice. We speculate that compensatory mechanisms exist; however, our results also suggest that PT Ca2+ reabsorption for long‐term Ca2+ homeostasis plays a less important role than previously assumed.Support or Funding InformationFunding to R.A.F. is provided by the Novo Nordisk Foundation, the Lundbeck Foundation and Danish Medical Research Council. T.R. is supported by NIDDK 1R01DK110621.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of a high-sodium/low-potassium diet on renal calcium, magnesium, and phosphate handling

The distal convoluted tubule (DCT) of the kidney plays an important role in blood pressure regulation by modulating Na+ reabsorption via the Na+-Cl- cotransporter (NCC). A diet containing high salt (NaCl) and low K+ activates NCC, thereby causing Na+ retention and a rise in blood pressure. Since high blood pressure, hypertension, is associated with changes in serum calcium (Ca2+) and magnesium (Mg2+) levels, we hypothesized that dietary Na+ and K+ intake affects Ca2+ and Mg2+ transport in the DCT. Therefore, the present study aimed to investigate the effect of a high-Na+/low-K+ diet on renal Ca2+ and Mg2+ handling. Mice were divided in four groups and fed a normal-Na+/normal-K+, normal-Na+/low-K+, high-Na+/normal-K+, or high-Na+/low-K+ diet for 4 days. Serum and urine were collected for electrolyte and hormone analysis. Gene and protein expression of electrolyte transporters were assessed in kidney and intestine by qPCR and immunoblotting. Whereas Mg2+ homeostasis was not affected, the mice had elevated urinary Ca2+ and phosphate (Pi) excretion upon high Na+ intake, as well as significantly lower serum Ca2+ levels in the high-Na+/low-K+ group. Alterations in the gene and protein expression of players involved in Ca2+ and Pi transport indicate that reabsorption in the proximal tubular and TAL is affected, while inducing a compensatory response in the DCT. These effects may contribute to the negative health impact of a high-salt diet, including kidney stone formation, chronic kidney disease, and loss of bone mineral density.

Effects of phospho- and calciotropic hormones on electrolyte transport in the proximal tubule.

Calcium and phosphate are critical for a myriad of physiological and cellular processes within the organism. Consequently, plasma levels of calcium and phosphate are tightly regulated. This occurs through the combined effects of the phospho- and calciotropic hormones, parathyroid hormone (PTH), active vitamin D 3, and fibroblast growth factor 23 (FGF23). The organs central to this are the kidneys, intestine, and bone. In the kidney, the proximal tubule reabsorbs the majority of filtered calcium and phosphate, which amounts to more than 60% and 90%, respectively. The basic molecular mechanisms responsible for phosphate reclamation are well described, and emerging work is delineating the molecular identity of the paracellular shunt wherein calcium permeates the proximal tubular epithelium. Significant experimental work has delineated the molecular effects of PTH and FGF23 on these processes as well as their regulation of active vitamin D 3 synthesis in this nephron segment. The integrative effects of both phospho- and calciotropic hormones on proximal tubular solute transport and subsequently whole body calcium-phosphate balance thus have been further complicated. Here, we first review the molecular mechanisms of calcium and phosphate reabsorption from the proximal tubule and how they are influenced by the phospho- and calciotropic hormones acting on this segment and then consider the implications on both renal calcium and phosphate handling as well as whole body mineral balance.

Mathematical rationalization for the renal tubular transport: revised concepts

The current emphasis on kinetics and in situ control of molecular exchanges, across the tubular membrane, has not been paralleled by corresponding improvements in our understanding of tubular behaviour at the macroscopic level of classical physiology. In this paper, we propose a mathematical rationalization of macroscopic tubular transport by means of a principal transport equation, originating from the law of mass action between substrate and carrier. The other equations, derived from the main one, demonstrate the possibility of distinguishing between transporters with low affinity and high capacity and transporters with high affinity and low capacity. Moreover, our model formalizes both tubular reabsorption and tubular secretion. Regarding the renal calcium handling, our model confirms the two-compartment system proposed by Mioni in 1971, with some important variants, which are in agreement with the fractional reabsorptions of this cation along the tubule, as verified by micro-puncture technique. To obtain the frequency distribution of saturated tubules, we have utilized the infinitesimal analysis method, starting from the equations proposed by Smith in 1943, concluding that all titration curves result from the combined effect of enzymatic approach and anatomical heterogeneity of the nephrons. The theoretical equations included in our manuscript reflect substantial and palpable physiological mechanisms able to suggest diagnosis and therapy of some electrolyte and hormonal disorders. At the end of this paper, we highlight advantages and disadvantages detectable by comparing our mathematical approach with Marshall’s and Bijvoet’s methods, proposed, respectively, in 1976 and 1984.

Ways of calcium reabsorption in the kidney.

The role of the kidney in calcium homeostasis has been reshaped from a classic view in which the kidney was regulated by systemic calcitropic hormones such as vitamin D3 or parathyroid hormone to an organ actively taking part in the regulation of calcium handling. With the identification of the intrinsic renal calcium-sensing receptor feedback system, the regulation of paracellular calcium transport involving claudins, and new paracrine regulators such as klotho, the kidney has emerged as a crucial modulator not only of calciuria but also of calcium homeostasis. This review summarizes recent molecular and endocrine contributors to renal calcium handling and highlights the tight link between calcium and sodium reabsorption in the kidney.

Physiological and Clinical Implications of Adrenergic Pathways at High Altitude.

The adrenergic system is part of a full array of mechanisms allowing the human body to adapt to the hypoxic environment. Triggered by the stimulation of peripheral chemoreceptors, the adrenergic centers in the medulla are activated in acute hypoxia and augment the adrenergic drive to the organs, especially to the heart, leading to tachycardia. With prolonged exposure to altitude hypoxia, the adrenergic drive persists, as witnessed by elevated blood concentrations of catecholamines and nerve activity in adrenergic fibers. In response to this persistent stimulation, the pathways leading to the activation of adenylate cyclase are modified. A downregulation of β-adrenergic and adenosinergic receptors is observed, while muscarinic receptors are upregulated. The expression and activity of Gi and Gs proteins are modified, leading to a decreased response of adenylate cyclase activity to adrenergic stimulation. The clinical consequences of these cellular and molecular changes are of importance, especially for exercise performance and protection of heart function. The decrease in maximal exercise heart rate in prolonged hypoxia is fully accounted for the observed changes in adrenergic and muscarinic pathways. The decreased heart rate response to isoproterenol infusion is another marker of the desensitization of adrenergic pathways. These changes can be considered as mechanisms protecting the heart from a too high oxygen consumption in conditions where the oxygen availability is severely reduced. Similarly, intermittent exposure to hypoxia has been shown to protect the heart from an ischemic insult with similar mechanisms involving G proteins and downregulation of β receptors. Other pathways with G proteins are concerned in adaptation to hypoxia, such as lactate release by the muscles and renal handling of calcium. Altogether, the activation of the adrenergic system is useful for the acute physiological response to hypoxia. With prolonged exposure to hypoxia, the autonomous nervous system adapts to protect vital organs, especially the heart, against a too high energetic state, via a purely local autoregulation mechanism necessary for the preservation of overall homeostasis.

The role of calbindin-D28k on renal calcium and magnesium handling during treatment with loop and thiazide diuretics.

Calbindin-D28k (CBD-28k) is a calcium binding protein located in the distal convoluted tubule (DCT) and plays an important role in active calcium transport in the kidney. Loop and thiazide diuretics affect renal Ca and Mg handling: both cause Mg wasting, but have opposite effects on Ca excretion as loop diuretics increase, but thiazides decrease, Ca excretion. To understand the role of CBD-28k in renal Ca and Mg handling in response to diuretics treatment, we investigated renal Ca and Mg excretion and gene expression of DCT Ca and Mg transport molecules in wild-type (WT) and CBD-28k knockout (KO) mice. Mice were treated with chlorothiazide (CTZ; 50 mg · kg(-1) · day(-1)) or furosemide (FSM; 30 mg · kg(-1) · day(-1)) for 3 days. To avoid volume depletion, salt was supplemented in the drinking water. Urine Ca excretion was reduced in WT, but not in KO mice, by CTZ. FSM induced similar hypercalciuria in both groups. DCT Ca transport molecules, including transient receptor potential vanilloid 5 (TRPV5), TRPV6, and CBD-9k, were upregulated by CTZ and FSM in WT, but not in KO mice. Urine Mg excretion was increased and transient receptor potential subfamily M, member 6 (TRPM6) was upregulated by both CTZ and FSM in WT and KO mice. In conclusion, CBD-28k plays an important role in gene expression of DCT Ca, but not Mg, transport molecules, which may be related to its being a Ca, but not a Mg, intracellular sensor. The lack of upregulation of DCT Ca transport molecules by thiazides in the KO mice indicates that the DCT Ca transport system is critical for Ca conservation by thiazides.

Role of claudins in renal calcium handling

Paracellular channels occurring in tight junctions play a major role in transepithelial ionic flows. This pathway includes a high number of proteins, such as claudins. Within renal epithelium, claudins result in an ionic selectivity in tight junctions. Ascending thick limb of loop of Henle (ATLH) is the most important segment for calcium reabsorption in renal tubules. Its cells create a water-proof barrier, actively transport sodium and chlorine through a transcellular pathway, and provide a paracellular pathway for selective calcium reabsorption. Several studies have led to a model of paracellular channel consisting of various claudins, particularly claudin-16 and 19. Claudin-16 mediates cationic paracellular permeability in ATLH, whereas claudin-19 increases cationic selectivity of claudin-16 by blocking anionic permeability. Recent studies have shown that claudin-14 promoting activity is only located in ATLH. When co-expressed with claudin-16, claudin-14 inhibits the permeability of claudin-16 and reduces paracellular permeability to calcium. Calcium reabsorption process in ATLH is closely regulated by calcium sensor receptor (CaSR), which monitors circulating Ca levels and adjusts renal excretion rate accordingly. Two microRNA, miR-9 and miR-374, are directly regulated by CaSR. Thus, miR-9 and miR-374 suppress mRNA translation for claudin-14 and induce claudin-14 decline.

Epigenetic regulation of microRNAs controlling CLDN14 expression as a mechanism for renal calcium handling.

The kidney has a major role in extracellular calcium homeostasis. Multiple genetic linkage and association studies identified three tight junction genes from the kidney--claudin-14, -16, and -19--as critical for calcium imbalance diseases. Despite the compelling biologic evidence that the claudin-14/16/19 proteins form a regulated paracellular pathway for calcium reabsorption, approaches to regulate this transport pathway are largely unavailable, hindering the development of therapies to correct calcium transport abnormalities. Here, we report that treatment with histone deacetylase (HDAC) inhibitors downregulates renal CLDN14 mRNA and dramatically reduces urinary calcium excretion in mice. Furthermore, treatment of mice with HDAC inhibitors stimulated the transcription of renal microRNA-9 (miR-9) and miR-374 genes, which have been shown to repress the expression of claudin-14, the negative regulator of the paracellular pathway. With renal clearance and tubule perfusion techniques, we showed that HDAC inhibitors transiently increase the paracellular cation conductance in the thick ascending limb. Genetic ablation of claudin-14 or the use of a loop diuretic in mice abrogated HDAC inhibitor-induced hypocalciuria. The genetic mutations in the calcium-sensing receptor from patients with autosomal dominant hypocalcemia (ADH) repressed the transcription of miR-9 and miR-374 genes, and treatment with an HDAC inhibitor rescued the phenotypes of cell and animal models of ADH. Furthermore, systemic treatment of mice with antagomiRs against these miRs relieved claudin-14 gene silencing and caused an ADH-like phenotype. Together, our findings provide proof of concept for a novel therapeutic principle on the basis of epigenetic regulation of renal miRs to treat hypercalciuric diseases.

Disorders of mineral metabolism in the newborn.

Disorders of calcium and phosphorus homeostasis present both acute and chronic clinical consequences for newborns. The etiologies responsible range from iatrogenic, idiopathic, and inherited metabolic abnormalities. Maintenance of physiologically normal serum calcium and phosphorus requires complex interactions between the kidneys, gastrointestinal tract, and bone. Calciotropic hormones such as vitamin D and parathyroid hormone, as well as hormones controlling phosphorus homeostasis, such as fibroblast growth factor-23 (FGF-23), are essential in controlling these interactions. In newborns, calcium and phosphorus balance must necessarily be positive in order to provide the requisite building blocks for growth and maturation. Renal tubular handling of these minerals is a key control point in regulating the overall body balance in calcium and phosphorus. Adaptive changes in renal calcium and phosphorus reabsorption in newborns explain how a net positive total body balance of these minerals is achieved. Monogenetic disorders leading to abnormal renal handling of calcium and/or phosphorus have immediate clinical consequences in terms of complications associated with high or low levels of these minerals. Perhaps more importantly, chronic abnormalities of calcium and/or phosphorus, without treatment, may have serious consequences for growth and development of the growing skeleton. This article serves to review calcium and phosphorus regulation in the human body, describe differences in handling of these minerals by the newborn, and review the conditions, both acquired and congenital, that may present with abnormalities in calcium and/or phosphorus in the newborn period.

Growth Hormone, Insulin-Like Growth Factor-1, and the Kidney: Pathophysiological and Clinical Implications

Besides their growth-promoting properties, GH and IGF-1 regulate a broad spectrum of biological functions in several organs, including the kidney. This review focuses on the renal actions of GH and IGF-1, taking into account major advances in renal physiology and hormone biology made over the last 20 years, allowing us to move our understanding of GH/IGF-1 regulation of renal functions from a cellular to a molecular level. The main purpose of this review was to analyze how GH and IGF-1 regulate renal development, glomerular functions, and tubular handling of sodium, calcium, phosphate, and glucose. Whenever possible, the relative contributions, the nephronic topology, and the underlying molecular mechanisms of GH and IGF-1 actions were addressed. Beyond the physiological aspects of GH/IGF-1 action on the kidney, the review describes the impact of GH excess and deficiency on renal architecture and functions. It reports in particular new insights into the pathophysiological mechanism of body fluid retention and of changes in phospho-calcium metabolism in acromegaly as well as of the reciprocal changes in sodium, calcium, and phosphate homeostasis observed in GH deficiency. The second aim of this review was to analyze how the GH/IGF-1 axis contributes to major renal diseases such as diabetic nephropathy, renal failure, renal carcinoma, and polycystic renal disease. It summarizes the consequences of chronic renal failure and glucocorticoid therapy after renal transplantation on GH secretion and action and questions the interest of GH therapy in these conditions.

The influence of lithium on calcium homeostasis in older patients in daily clinical practice

Lithium can influence calcium homeostasis resulting in changes in parathormone set point and renal calcium handling. The clinical significance of these changes in older patients is unknown. The objective of this study was to investigate the possible association between duration of lithium treatment and corrected calcium, parathormone and 24-h urinary calcium excretion in older psychiatric patients corrected for renal function and vitamin 25OH D and also to estimate the point prevalence of hypercalcemia and raised parathormone. A cross-sectional study of psychiatric outpatients visiting a specialized facility for older patients treated with lithium was performed. Patients underwent a comprehensive assessment and blood and urine testing. Potential confounders of calcium homeostasis were recorded. On the basis of the duration of lithium treatment, patients were divided into four groups. One hundred eleven patients were included, mean age 75.2 years. There was no significant association between the duration of lithium treatment and corrected calcium, parathormone and 24-h urinary calcium excretion. The point prevalence of hypercalcemia was 2.7% and 47.8% for raised parathormone. There was an unexpected but significant negative association between the duration of lithium treatment and vitamin 25OH D, with 76.9% vitamin 25OH D deficiency (<50 nmol/L) in the group using lithium for more than 10 years. No association was found between duration of lithium treatment and calcium parameters in older psychiatric outpatients, but there was a high prevalence of raised parathormone and an unexpected negative association between duration of lithium treatment and 25OH D.

Primary male osteoporosis is associated with enhanced glucocorticoid availability

While systemic glucocorticoids compromise bone metabolism, altered intracellular cortisol availability may also contribute to the pathogenesis of primary male osteoporosis (MO). The objective of this study was to assess whether intracellular cortisol availability is increased in MO due to a distorted local cortisol metabolism. Forty-one patients with MO were compared with age- and BMI-matched non-osteoporotic subjects after excluding overt systemic hypercortisolism (N = 41). Cortisol, cortisone and the respective tetrahydro-, 5α-tetrahydro- and total cortisol metabolites were analysed by GC-MS in 24 h urine. Apparent 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme activities, excretion of cortisol metabolites and calcium, and fractional urinary calcium excretion were assessed and related to BMD. Fractional and total urinary calcium excretion negatively correlated with BMD at all (P < 0.05) and at three of five (P < 0.05) measurement sites, respectively. While systemic cortisol was unchanged, apparent 11β-HSD enzyme activity in MO patients (P < 0.01) suggested increased intracellular cortisol availability. Total and fractional urinary calcium excretion was higher, with apparent 11β-HSD enzyme activities consistent with an enhanced intracellular cortisol availability (P < 0.05). Apparent 11β-HSD enzyme activities consistent with increased intracellular cortisol availability correlated with urinary calcium loss and reduced bone mineral density in MO. The changes in 11β-HSD activity were associated with both the fractional calcium excretion, suggesting altered renal calcium handling, and the absolute urinary calcium excretion. Both mechanisms could result in a marked bone calcium deficiency if insufficiently compensated for by intestinal calcium uptake.

Variations of Dietary Salt and Fluid Modulate Calcium and Magnesium Transport in the Renal Distal Tubule

Background: The renal distal tubule fine-tunes renal epithelial calcium transport. Dietary intake of salt and fluid varies day-to-day and the kidney adapts accordingly to maintain homeostasis. The alternations in salt and fluid balance affect calcium and magnesium transport in the distal tubule, but the mechanisms are not fully understood. Methods: Sprague-Dawley rats were grouped into high-salt, low-salt and dehydration treatment. Daily intake, water consumption and urine output were recorded. At the end of the experiment, blood and urine samples were collected for hormonal and biochemical tests. Genetic analysis, immunoblotting and immunofluorescence studies were then performed to assess the alterations of calcium and magnesium transport-related molecules. Results: High-salt treatment increased urinary sodium, calcium and magnesium excretion. Low-salt treatment and dehydration were associated with decreased urinary excretion of all electrolytes. High-salt treatment was associated with increased intact parathyroid hormone levels. A significant increase in gene expression of TRPV5, TRPV6, calbindin-D28k and TRPM6 was found during high-salt treatment, while low salt and dehydration diminished expression. These findings were confirmed with immunofluorescence studies. High-salt and low-salt intake or dehydration did not cause any significant changes in WNK1, WNK3 and WNK4. Conclusions: Alternations in salt and water intake affect renal calcium and magnesium handling. High-salt intake increases the distal delivery of the divalent cations which upregulates distal tubule calcium and magnesium transport molecules, while the opposite effects are associated with low-salt intake or dehydration.

Effects of Acute Sodium Fluoride Exposure on Kidney Function, Water Homeostasis, and Renal Handling of Calcium and Inorganic Phosphate

Fluoride compounds are abundant and widely distributed in the environment at a variety of concentrations. Further, fluoride induces toxic effects in target organs such as the liver and kidney. In this study, we performed an early analysis of renal function using a clearance technique in Wistar rats acutely exposed to fluoride at a plasma concentration of 0.625μg/ml. Our results revealed that fluoride, at a concentration close to the concentration present in the serum after environmental exposure, induced a significant tubular dysfunction, resulting in diluted urine, impaired protein reabsorption, and increased calcium and phosphate urinary excretion. Our work demonstrates that even acute exposures to low concentrations of NaF may induce renal damage and confirms that, after exposure, the kidney participates directly in the calcium and phosphate deficiencies observed in fluoride-exposed populations.

Renal calcium, phosphorus, magnesium and uric acid handling: comparison between stage III chronic kidney disease patients and healthy oldest old

It is known that chronic kidney disease (CKD) and senescence bring about a progressive reduction in glomerular filtration rate (GFR) and that in the former this is usually associated with an increase in the fractional excretion of calcium, phosphorus, magnesium, and uric acid. However, it has not yet been explained how these substances are excreted in the healthy oldest old. Thus, in the present study, we examined the renal handling of these substances in very aged people in comparison with CKD patients with similar GFR levels (stage III-CKD). Twenty volunteers were studied; 10 of them were healthy very old (VO) (≥ 75 years old) individuals and 10 were stage III CKD patients. Exclusion criteria were as follows: presence of altered (abnormally high or low) plasma calcium, phosphorus, magnesium and uric acid, as well as previous diagnoses of diabetes mellitus and obstructive uropathy and use of drugs that could alter plasma levels of the studied substances. All volunteers were on a diet with the same content of these elements (3-day dietary register). We measured calcium, phosphorus, magnesium, uric acid, creatinine in serum plasma and morning urine, as well as serum parathyroid hormone level, in each volunteer. From these data, fractional excretion (FE) of these substances was obtained. A statistical analysis was carried out using the Wilcoxon test. Serum creatinine: 1.8 ± 0.4 mg/dl (CKD) versus 0.8 ± 0.2 mg/dl (VO), p = 0.0002; serum calcium: 9.1 ± 0.3 mg/dl (CKD) versus 8.7 ± 0.4 (VO), p = 0.022; serum magnesium: 2.3 ± 0.2 mg/dl (CKD) versus 2.0 ± 0.1 (VO), p = 0.05; serum phosphorus: 3.9 ± 0.5 mg/dl (CKD) versus 3.0 ± 0.4 mg/dl (VO), p = 0.002; serum uric acid: 6.6 ± 1.5 (CKD) versus 5.2 ± 1.4 mg/dl (VO), p = 0.04; FE of calcium: 2.5 ± 1 % (CKD) versus 0.8 ± 0.3 % (VO), p = 0.04; FE of magnesium: 7.2 ± 4.1 % (CKD) versus 2.9 ± 0.9 % (VO), p = 0.02; FE of phosphorus: 25 ± 9 % (CKD) versus 9.1 ± 5.7(VO), p = 0.001; FE of uric acid: 10 ± 3 % (CKD) versus 8 ± 5 % (VO), p = 0.05. Serum levels and FE of calcium, phosphorus, magnesium and uric acid were significantly higher in CKD patients compared to healthy very old people with similar GFR, except for serum magnesium and FE of uric acid, which were similar in both groups.

Pathophysiology of Renal Calcium Handling in Acromegaly: What Lies behind Hypercalciuria?

Hypercalciuria is frequent in patients with acromegaly, but it is unclear how GH/IGF-I regulate renal calcium handling. Elevated fasting plasma calcium levels despite increased glomerular filtration suggest enhanced renal calcium reabsorption. The aim of this study was to investigate the impact of acromegaly on phosphocalcium metabolism. We conducted a prospective sequential study at a tertiary referral medical center and clinical investigation center (www.ClinicalTrials.gov Identifier: NCT00531908). Sixteen consecutive patients (five females/11 males) with acromegaly received a single iv infusion of 25 mg of furosemide to induce an acute increase in calcium and magnesium delivery to distal tubular segments during a high-sodium diet with stable dietary calcium, magnesium, and phosphate intake. Baseline plasma and urine electrolytes, plasma calciotropic hormones, and furosemide-induced changes in the fractional excretion and tubular reabsorption of Na, Ca, and Mg were measured before and 6 months (range, 1-12) after effective treatment of acromegaly. Serum IGF-I concentrations normalized in all the patients after acromegaly treatment. Compared with controlled acromegaly, active acromegaly was associated with higher fasting plasma (P = 0.0002) and urinary calcium (P = 0.0003) levels, lower PTH levels (P = 0.0075), higher calcitriol levels (P = 0.0137), higher phosphatemia (P<0.0001) and tubular phosphate reabsorption (P = 0.0002), and a lower calciuric (P = 0.0327) but not magnesiuric response to furosemide related to higher baseline and postfurosemide tubular calcium (P = 0.0034 and P = 0.0081, respectively), but not magnesium reabsorption. The IGF-I-mediated and PTH-independent increase in calcitriol synthesis in acromegaly is responsible for both absorptive hypercalciuria and increased fasting plasma calcium linked to enhanced distal tubular calcium reabsorption, as shown by the selectively diminished calciuric response to furosemide.

Responses of Urinary N-Telopeptide and Renal Calcium Handling to PTH Infusion after Treatment with Estrogen, Raloxifene, and Tamoxifen

This prospective, randomized, placebo-controlled study investigated whether estrogen, tamoxifen, and raloxifene protect the skeleton from the acute catabolic effects of continuous PTH(1-34) infusion. It was infused over 24h in 25 postmenopausal women both before and while on medication for 16-20weeks (estrogen n=7, raloxifene n=5, tamoxifen n=7, placebo n=6). Blood and urine samples were collected at baseline and every 4h during the PTH(1-34) infusion and analyzed for calcium homeostasis, bone remodeling, and specific cytokines. Data for the premedication PTH(1-34) infusions were pooled. During the premedication PTH(1-34) infusions, serum calcium and urine phosphorus increased, while serum phosphorus and urine calcium declined. Osteocalcin decreased (mean 18%), while urine NTX increased (mean 315%). Serum IL-6 increased 260%, but there were no other cytokine changes as a result of the PTH(1-34) infusion. On medication, the mean peak change in NTX with PTH(1-34) infusion was less (77, 59, and 31nM/mM with raloxifene, tamoxifen, and estrogen, respectively). The reduction in urine calcium excretion was prolonged with each agent but only significantly with estrogen. There was no reduction in the IL-6 elevation induced by PTH(1-34) with any medication. The differential skeletal resorption response to PTH(1-34) infusion after the treatments may reflect different potencies of these agents or variability in interaction with the estrogen receptor. Renal calcium conservation and the blunted response of bone resorption to PTH(1-34) infusion may be mechanisms by which estrogen and estrogen agonist/antagonist agents preserve bone mass.

Thyroid bone disease

Thyroid bone disease