Reduction In Calcium Excretion Research Articles

Inorganic phosphate additives in meals and adaptations to 5-days of dietary inorganic phosphate loading alter acute calcium homeostasis in two randomized cross-over studies in healthy adults.

Diets containing inorganic phosphate additives are unbalanced with respect to calcium and these diets have been linked to the development of altered bone metabolism. Using 2 randomized cross-over studies in healthy humans, we (1) characterized the hormonal and urinary response to 2 meals with the same reported phosphorus amount (562-572mg), where one was manufactured with inorganic phosphate additives and a comparatively lower Ca:P molar ratio (0.26 vs 0.48), and (2) assessed how acute homeostatic mechanisms adapt following 5-d exposure to recommended dietary phosphorus amount (~700mg P/d) compared to a diet enriched with inorganic phosphate additives (~1100mg P/d). Participants were then challenged with 500mg of oral phosphorus in the form of inorganic phosphate after an overnight fast following each diet condition. Measurements included serum calcium, phosphate, PTH, and fibroblast growth factor 23 , vitamin D metabolites, and urine calcium and phosphate excretion. Following the meal containing inorganic phosphate additives with a low Ca:P ratio, serum phosphate was higher and more phosphate was excreted in the urine compared to the low additive meal. Although the Ca:P and calcium content was lower in the high additive meal, the same amount of calcium was excreted into the urine. Subsequently, increasing only dietary phosphate through additives resulted in lower 24-h excretion of calcium. The oral phosphate challenge promoted urinary calcium excretion, despite no consumption of calcium, which was attenuated when pre-acclimated to a high phosphate diet. These data suggest that ingestion of inorganic phosphate promotes calcium excretion, but homeostatic mechanisms may exist to reduce calcium excretion that are responsive to dietary intake of phosphate. Future studies are required to evaluate potential implication of diets enriched with inorganic phosphate additives on bone health.

An unusual case of nutritional Secondary hyperparathyroidism in a Mare- A case report

A case of nutritional secondary hyperparathyroidism in a mare was diagnosed on the basis of history, clinical signs, radiography and reduced calcium excretion in urine.

Severe hypercalcemia and hypernatremia in a patient treated with canagliflozin.

SummaryDrugs that inhibit the sodium-glucose co-transporter-2 (SGLT2) are an exciting novel, insulin-independent treatment for diabetes that block glucose reabsorption from the proximal tubules of the kidney, leading to increased glucose excretion and lower blood glucose levels. Inhibition of SGLT2 activity also reduces sodium reabsorption, which together with glycosuria produces a mild diuretic effect with the potential for dehydration and hyperkalemia. We report on a 60-year-old man with uncontrolled type 2 diabetes treated with insulin, glimepiride, metformin and canagliflozin, who was admitted with altered mental status after a syncopal episode. He had a 1-week history of ingestion of Tums for heartburn followed by poor appetite and lethargy. Laboratory work-up showed acute kidney injury, diabetic ketoacidosis (DKA), and parathyroid hormone-independent severe hypercalcemia of 17.4 mg/dl. DKA resolved with insulin treatment, and saline hydration led to improvement in hypercalcemia and renal function over 48 h, but was accompanied by a rapid increase in the serum sodium concentration from 129 to 162 mmol/l despite changing fluids to 0.45% saline. Urine studies were consistent with osmotic diuresis. Hypernatremia was slowly corrected with hypotonic fluids, with improvement in his mental status over the next 2 days. This is the first report of hypercalcemia associated with the use of a SLGT2 inhibitor. Although the exact mechanism is unknown, canagliflozin may predispose to hypercalcemia in patients ingesting excessive calcium because of dehydration from osmotic diuresis, with reduced calcium excretion and possible increased intestinal calcium absorption. Saline therapy and osmotic diuresis may lead to hypernatremia from electrolyte-free water loss.Learning points Canagliflozin, an SGLT2 inhibitor, may cause hypercalcemia in susceptible patients.Although the exact mechanisms are unknown, dehydration from osmotic diuresis and increased intestinal calcium absorption play a role.Close monitoring of serum calcium levels is recommended in patients treated with SGLT2 inhibitors who are elderly, have established hypercalcemia, or take oral calcium supplements.Saline therapy and osmotic diuresis may lead to hypernatremia from electrolyte-free water loss in susceptible patients.

The 8th American Urological Association and the Japanese Urological Association International Affiliate Society Meeting

The 8th American Urological Association and the Japanese Urological Association International Affiliate Society Meeting

Importance of citrate and the calcium : citrate ratio in patients with calcium renal lithiasis and severe lithogenesis

Stone disease and osteopaenia are both common conditions, and reduced bone mineral density (BMD) is an increasingly recognized complication in stone formers; indeed, in a previous paper in BJUI, Arrabal-Polo et al. 1 reported that patients with recurrent stones have lower BMD compared with controls or patients with just a single episode of urolithiasis. Although the exact pathogenesis of bone loss in stone disease is yet to be determined, the conceptually obvious relationship with hypercalciuria is well documented 2. In the present study, Arrabal-Polo et al. emphasise that hypocitraturia is also associated with reduced BMD. Furthermore, they found a higher calcium : citrate ratio in patients with a cumulative maximum stone diameter >20 mm, or in those with frequent recurrences than in controls, and found that this correlated with higher levels of β-crosslaps, consistent with increased bone resorption in these patients. We commented in our previous editorial that metabolic abnormalities should be sought in recurrent stone formers, and managed in a multi-disciplinary setting 3. In addition to dietary advice, options for treatment include bisphosphonates (which inhibit bone resorption, and are commonly used in osteoporosis), thiazide diuretics (which reduce calcium excretion and can increase BMD) and potassium citrate (which acts as an alkalinizing agent mitigating the bone restorative effect of acidosis) 2. This approach is supported by recent data in medullary sponge kidneys, in which hypercalciuria and hypocitraturia were commonly detected in association with reduced BMD. Patients who were treated with potassium citrate were found to have increased urinary pH citrate levels, and an improvement in their BMD 4. In the present article, Arrabal-Polo et al. suggest using a calcium : citrate ratio of 0.25 for predicting the risk of future recurrent stone formation, but this value could equally be used to predict the risk of patients having reduced BMD and the complications that may follow. Either way, their findings strengthen the argument for metabolic screening of recurrent stone formers, and for an assessment of these patients' BMD. Patients can then be appropriately treated with a thiazide diuretic, potassium citrate, or a bisphosphonate, either singly or in combination, according to the abnormalities detected and their progress on treatment.

Sustained increase in bone mineral density with alendronate in combination with indapamide in postmenopausal women with idiopathic hypercalciuria associated to osteoporosis: A 1-year randomized trial followed by a 2-year extension

Sustained increase in bone mineral density with alendronate in combination with indapamide in postmenopausal women with idiopathic hypercalciuria associated to osteoporosis: A 1-year randomized trial followed by a 2-year extension

Calcium Homeostasis and Skeletal Integrity in Individuals with Familial Hypercholesterolemia and Aortic Calcification

Familial hypercholesterolemia (FH) due to mutations in the low-density lipoprotein receptor (LDLR) gene exhibit severe, premature aortic calcification in a gene-dosage, age-dependent fashion. We sought to determine potential associations with mineral and skeletal indices. We obtained computed tomography (CT) scan aortic calcium scores (AoCSs) in 19 (age 49 [SD 14] years) FH patients heterozygous for the 15-kb deletion at the LDLR gene and examined associations with various indices of mineral and skeletal homeostasis. We found that mean bone mineral density (BMD) at the femoral neck in these patients did not differ from age-, sex-, and province-matched mean BMD, and we observed no association of AoCS with any marker of bone resorption. However, there were negative correlations between AoCS and serum concentrations of osteocalcin, a marker of bone formation (r = -0.64, P = 0.0034), urinary calcium (r = -0.59, P = 0.0085), and estimated glomerular filtration rate (r = -0.67, P = 0.0019). We found that LDLR-deficient FH was not associated with obvious bone loss or a major disturbance in calcium homeostasis. The lack of LDLR, however, may modify osteoblast function or extracellular calcium distribution, manifesting as lower bone formation, and reduced calcium excretion, resulting in increased deposition in calcifying vascular tissue.

Effects of a low-salt diet on idiopathic hypercalciuria in calcium-oxalate stone formers: a 3-mo randomized controlled trial

A direct relation exists between sodium and calcium excretion, but randomized studies evaluating the sustained effect of a low-salt diet on idiopathic hypercalciuria, one of the main risk factors for calcium-oxalate stone formation, are still lacking. Our goal was to evaluate the effect of a low-salt diet on urinary calcium excretion in patients affected by idiopathic calcium nephrolithiasis. Patients affected by idiopathic calcium stone disease and hypercalciuria (>300 mg Ca/d in men and >250 mg Ca/d in women) were randomly assigned to receive either water therapy alone (control diet) or water therapy and a low-salt diet (low-sodium diet) for 3 mo. Twenty-four-hour urine samples were obtained twice from all patients: one sample at baseline on a free diet and one sample after 3 mo of treatment. A total of 210 patients were randomly assigned to receive a control diet (n = 102) or a low-sodium diet (n = 108); 13 patients (2 on the control diet, 11 on the low-sodium diet) withdrew from the trial. At the follow-up visit, patients on the low-sodium diet had lower urinary sodium (mean +/- SD: 68 +/- 43 mmol/d at 3 mo compared with 228 +/- 57 mmol/d at baseline; P < 0.001). Concomitant with this change, they showed lower urinary calcium (271 +/- 86 mg/d at 3 mo compared with 361 +/- 129 mg/d on the control diet, P < 0.001) and lower oxalate excretion (28 +/- 8 mg/d at 3 mo compared with 32 +/- 10 mg/d on the control diet, P = 0.001). Urinary calcium was within the normal range in 61.9% of the patients on the low-salt diet and in 34.0% of those on the control diet (difference: +27.9%; 95% CI: +14.4%, +41.3%; P < 0.001). A low-salt diet can reduce calcium excretion in hypercalciuric stone formers. This trial was registered at clinicaltrials.gov as NCT01005082.

Rare but Relevant Kidney Disorders

These two groups of investigators identified simultaneously the same disease, named SeSame and EAST syndrome, respectively, acronyms based on the clinical abnormalities found in this disease (seizures or epilepsy, sensorineural deafness, ataxia, mental retardation and tubulopathy). This new autosomal recessive disorder was described from the study of six kindreds. In four of them, parental consanguinity was documented. All affected patients initially presented with generalized seizures in infancy. Later, they developed speech and motor delay and marked ataxia. Brain magnetic resonance imaging did not show significant lesions, except volume loss of cerebellum in rare patients. Sensorineural hearing loss was noted from the ages of 1 to 18 yr. All affected patients had hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. Renin-angiotensin-aldosterone system was stimulated. BP was normal. By ultrasonography, kidneys were normal. Electrolyte imbalance mimics Gitelman syndrome; however, neurologic involvement makes the difference. Genome-wide linkage analysis was performed on four informative families and identified a single significant locus on chromosome 1q23.2 with a logarithm of odds score of 3.00 and 4.98, respectively. The linked interval contains 70 well-defined and at least six hypothetical genes. Attention was focused on KCNJ10, which encodes the inwardly rectifying K+ channel Kir4.1, which consists of two transmembrane segments and one pore. KCNJ10 had been shown to be expressed in the central nervous system, cochlea, and distal nephron. A mouse knockout has a neurologic phenotype similar to that seen in the patients. Various homozygous or compound heterozygous mutations were identified in KCNJ10 in affected patients. Heterologous expression of wild-type KCJN10 in Xenopus oocytes resulted in robust currents. In contrast, currents from KCNJ10 mutants were reduced in the study by Bockenhauer et al. In normal mice, the presence of Kcnj10 was demonstrated on the basolateral membrane of the distal convoluted tubule, the connecting tubule, and the early cortical collecting duct. No signal was detected in Kcnj10 knockout mice. These mice die very early as a consequence of central nervous system symptoms. They also had diminished growth, renal salt wasting, and decreased calcium urinary excretion. Conditional knockout in glial cells resulted in death later in life, suggesting that renal salt loss is an aggravating factor in the mice with complete knockout. Kir4.1/5.1 heteromultimers are located in the basolateral membrane of the distal nephron (more specific, in the distal convoluted tubule, the only tubular site at which inhibition of NaCl reabsorption produces hypomagnesemia and reduced calcium excretion). These multimers recycle potassium that enters the cell via the Na+-K+-ATPase back into the interstitial space and contribute to the negative membrane potential that promotes basolateral Cl exit. Loss of Kir4.1 activity inhibits the function of Na+-K+-ATPase via loss of K recycling, reduces basolateral Cl reabsorption by rendering the membrane potential less negative, and thereby inhibits both apical sodium and Cl reabsorption by NCCT and Mg2+ reabsorption by TRPM6 because of a less negative membrane potential. The resulting renal salt loss activates the renin-angiotensin-aldosterone system. In the brain, KCNJ10 seems to be primarily expressed in glial cells. Some Mendelian seizure disorders have already been described, involving K+ or Na+ channels. Kir4.1 is expressed in intermediate cells of the stria vascularis, where it is believed to contribute to the generation of the endocochlear potential. As emphasized by Claude Amiel several decades ago, there are many analogies between cochlear and renal physiology and pathology. Single-gene mutations may produce effects on both systems. For example, loss-of-function mutations in ATP6B1, which encodes a subunit of the H+-ATPase, result in distal tubular acidosis and sensorineural hearing loss. Similarly, mutations in Barttin, which encodes a subunit of some Cl channels, result in both Bartter syndrome and deafness. Not surprising, inherited channel or transporter disorders bridge the gap between medical disciplines and open new avenues for further research (1).

Not just calcium and vitamin D: Other nutritional considerations in osteoporosis

Calcium and vitamin D are the mainstays of nutritional intervention for the prevention and treatment of osteoporosis. However, conditions that alter nutritional status as well as other nutrients should be considered when diagnosing and treating osteoporosis and osteopenia. Current research supports the early diagnosis and treatment of anorexia nervosa to prevent associated bone loss and increased risk of fracture. Weight restoration in patients with anorexia nervosa is central to bone mass stabilization. Other nutritional considerations include nutrients such as vitamin B-12 and vitamin K that may reduce fracture risk by increasing bone mineral density as well as the improvement of bone microarchitecture. Diets high in fruits and vegetables contribute nutrients such as magnesium associated with bone health and may also produce an alkaline environment, reducing calcium excretion and thus improving bone density.

Influence of organic salts of potassium on bone health: Possible mechanisms of action for the role of fruit and vegetables

There is evidence that fruit and vegetables may be beneficial for bone health. Protein-containing foods such as meats, fish and cereals are acid-generating because of the sulphur and phosphorous they contain. It has been suggested that fruit and vegetables may be important for bone health because of the alkaline salts they provide (for example potassium citrate or potassium malate), which can balance the acidity produced by eating a Westernized diet. There have been a number of intervention studies investigating the effect of potassium bicarbonate or potassium citrate on markers of bone turnover. This chapter reviews the evidence from these studies and concludes that although short-term studies show that alkaline salts of potassium reduce calcium excretion and affect bone turnover, the body may adapt so that the benefit on bone metabolism is not continued long-term. Fruit and vegetable consumption may be advantageous to bone health, not because of balancing dietary acidity but because of the nutrients they contain (e.g. certain minerals, vitamins, or bioactive compounds such as flavonoids and phytoestrogens).

Diagnosis of a case of Gitelman’s syndrome based on renal clearance studies and gene analysis of a novel mutation of the thiazide-sensitive Na-Cl cotransporter

Gitelman's syndrome is a recessively inherited renal tubular disorder characterized by low plasma potassium and magnesium levels, reduced calcium excretion, metabolic alkalosis, and increased plasma renin activity and plasma aldosterone concentration with normal blood pressure levels. A 23-yr-old man was referred to our department for further evaluation of hypokalemia. The patient also had hypomagnesemia and markedly reduced urinary calcium excretion. Renal clearance studies and gene analysis of the thiazide-sensitive Na-Cl cotransporter (TSC) were performed in the patient. In response to an iv injection of furosemide, chloride clearance (CCl) increased markedly, while distal fractional chloride reabsorption CH2O/(CH2O+CCl) was considerably reduced. In contrast, thiazide ingestion had no significant effects on these parameters. The patient had compound heterozygous mutations in the alleles encoding the TSC gene, one of which has not been formerly reported. Renal clearance studies and TSC gene analysis by amplification and direct sequencing are useful diagnostic tools for confirming a diagnosis of Gitelman's syndrome.

Hypocalcemia and Parathyroid Function in Metastatic Prostate Cancer

To report the occurrence of hypocalcemia in a patient with metastatic prostate cancer, discuss its pathogenesis, and review the related medical literature. An 82-year-old man with a known history of prostate cancer was found to have a serum calcium level of 5.4 mg/dL during an admission to the hospital for small bowel obstruction. A thorough review of his medical history revealed a temporal relationship between the diagnosis of malignant disease and progressive hypocalcemia. A complete evaluation was performed, including laboratory and imaging studies, to ascertain the cause of the hypocalcemia. The patient had no history of hypocalcemia before the diagnosis of, and initiation of antiandrogen therapy for, advanced prostate cancer. Serum magnesium and phosphorus levels were within normal limits. The serum calcium level responded to therapy in the hospital but remained between 5.8 and 7.1 mg/dL. The parathyroid hormone level was normal, and the 25-hydroxyvitamin D value was low. A 24-hour urine collection showed substantially reduced calcium excretion, and a whole-body bone scan revealed widespread metastatic deposits. These findings were compatible with hypocalcemia related to prostate cancer and bone metastatic lesions. This case serves as a reminder that hypocalcemia can be a manifestation of prostate cancer metastatic to bone. In contrast to the occurrence of secondary hyperparathyroidism in this setting, however, this patient had normal levels of parathyroid hormone. Review of similar previous reports and the causes and implications of a possible functional hypoparathyroid state are discussed.

The DASH Diet and Sodium Reduction Improve Markers of Bone Turnover and Calcium Metabolism in Adults

Dietary strategies to prevent and treat osteoporosis focus on increased intake of calcium and vitamin D. Modification of whole dietary patterns and sodium reduction may also be effective. We examined the effects of two dietary patterns and three sodium levels on bone and calcium metabolism in a randomized feeding study. A total of 186 adults, aged 23-76 y, participated. After a 2-wk run-in period, participants were assigned randomly to diets containing three levels of sodium (50, 100 and 150 mmol/d) to be consumed for 30 d in random order. Serum osteocalcin (OC), C-terminal telopeptide of type I collagen (CTX), fasting serum parathyroid hormone (PTH), urinary sodium, potassium, calcium and cAMP were measured at baseline and at the end of each sodium period. The Dietary Approaches to Stop Hypertension (DASH) diet reduced serum OC by 8-11% and CTX by 16-18% (both P < 0.001). Urinary calcium excretion did not differ between subjects that consumed the DASH and control diets. Reducing sodium from the high to the low level significantly decreased serum OC 0.6 microg/L in subjects that consumed the DASH diet, fasting serum PTH 2.66 ng/L in control subjects and urinary calcium 0.5 mmol/24 h in both groups. There were no consistent effects of the diets or sodium levels on urinary cAMP. In conclusion, the DASH diet significantly reduced bone turnover, which if sustained may improve bone mineral status. A reduced sodium intake reduced calcium excretion in both diet groups and serum OC in the DASH group. The DASH diet and reduced sodium intake may have complementary, beneficial effects on bone health.

Effects of growth hormone replacement on parathyroid hormone sensitivity and bone mineral metabolism.

Adult GH deficiency (AGHD) is associated with reduced bone mineral density, and decreased end-organ sensitivity to the effects of PTH has been suggested as a possible underlying mechanism. We investigated the effects of GH replacement (GHR) on PTH circulating activity and its association with phosphocalcium metabolism and bone turnover in 16 (8 men and 8 women) AGHD patients. Half-hourly blood and 3 hourly urine sampling was performed on each patient over a 24-h period before GHR and then after 1, 3, 6, and 12 months of GHR. GH was commenced at a dose of 0.5 IU/d and was titrated to achieve and maintain an IGF-I SD score within 2 SD of the age-related reference range. The target IGF-I SD score was achieved within 3 months and was maintained at 12 months after GHR in all patients. Our results demonstrated a significant decrease in serum PTH at all visits after GHR compared with baseline values (P < 0.001), with a concomitant increase in nephrogenous cAMP excretion at 1 (P < 0.001) and 3 (P < 0.05) months and increases in serum calcium (P < 0.001), serum phosphate (P < 0.001), 1,25-dihydroxyvitamin D(3) (P < 0.001), type I collagen C-telopeptide (a bone resorption marker; P < 0.001), and procollagen type I amino-terminal propeptide (a bone formation marker; P < 0.001). Simultaneously, we observed a significant decrease in urinary calcium excretion (P < 0.001) and an increase in maximum tubular phosphate reabsorption (P < 0.001). Together these results suggest increased end-organ responsiveness to the effects of circulating PTH resulting in increased bone turnover and reduced calcium excretion. Significant circadian rhythms were observed for serum PTH, phosphate, type I collagen C-telopeptide, and procollagen type I amino-terminal propeptide before and after GHR. However, sustained PTH secretion was observed between 1400-2200 h, with a reduced nocturnal rise in untreated AGHD patients, whereas PTH secretion decreased significantly between 1400-2200 h (P < 0.001), with a significant increase in nocturnal PTH secretion (P < 0.001) after 12 months of GHR. Our results demonstrate that GH may have a regulatory role in bone mineral metabolism, and our data provide a possible underlying mechanism for the development of osteoporosis in AGHD patients. The changes observed after GHR may further explain the beneficial effects of GHR on bone mineral density that have consistently been reported.

Avaliação do Desempenho e Excreção de Cálcio em Duas Linhagens de Frangos de Corte, na Fase Inicial, Alimentados com Diferentes Níveis de Aminoácidos e de Cálcio

Dois experimentos foram realizados com o objetivo de avaliar os efeitos de diferentes níveis de aminoácidos e de cálcio sobre o desempenho e excreção de cálcio de duas linhagens de frangos de corte (Cobb e Avian Farms) na fase inicial de criação. Foram avaliados os dados de desempenho (consumo de ração, ganho de peso e conversão alimentar) e excreção de cálcio. Foram utilizadas 540 aves, em cada experimento, distribuídas em delineamento inteiramente casualizado, em esquema fatorial 3x2, ou seja, 3 perfis de aminoácidos (metionina, metionina+cistina, lisina e treonina - 100%, 125% e 150% dos níveis do NRC,1994) e 2 níveis de cálcio (75% e 100% dos níveis do NRC,1994), com 30 aves por repetição. Analisou-se o cálcio excretado das aves, e para tanto, utilizou-se 72 aves, em cada experimento, alojadas em gaiolas, seguindo o mesmo delineamento descrito anteriormente. Não houve interação entre os tratamentos estudados. Para a linhagem Avian Farms, o ganho de peso diminuiu com a elevação dos níveis de aminoácidos e ocorreu menor excreção de cálcio com menor nível de cálcio da dieta. A linhagem Cobb não foi influenciada pelos tratamentos em nenhum dos parâmetros estudados.

Use of Stable Calcium Isotopes (42Ca &amp; 44Ca) in Evaluation of Calcium Absorption in Beijing Adolescents with Low Vitamin D Status

Female adolescent populations with low calcium intakes and sub-optimal vitamin D status are found in northern China. Whether these individuals are able to adapt by enhancing calcium absorption and reducing calcium excretion for maximizing calcium retention is unknown. This study examined the association between true-fractional-calcium-absorption (TFCA), plasma 25-hydroxy-vitamin-D, and urinary calcium excretion among adolescents in Northern China. Twelve healthy girls 9 to 17 years old were recruited from Beijing during a winter. Calcium intake, anthropometry, pubertal status, plasma 25-hydroxyvitamin-Ds (25-OHD), serum calcium, and urinary calcium were determined. TFCA was evaluated by dual stable calcium isotopes. The mean +/- SD calcium intake, 24-hour urinary calcium excretion, plasma 25-OHD and TFCA were 591 +/- 164 mg/day, 79.9 +/- 49.6 mg/day, 30.5 +/- 9.8 nmol/L, and 60.4 +/- 14.4%, respectively. TFCA was inversely correlated with 25-OHD (r = -0.73, p = .008). Urinary calcium was correlated with the onset of menarche (r = 0.63, p = .027). Post-menarcheal girls had a higher urinary calcium output than premenarcheal girls (p = .03). Adolescents from north China with sub-optimal vitamin-D status are able to adapt by enhancing TFCA and reducing urinary calcium excretion to retain calcium for bone development. TFCA was inversely correlated with plasma 25-OHD. Whether a higher efficiency of calcium absorption is sustainable if the shortfall of vitamin D persisting remains to be studied.

Cure of lifelong fatigue by calcium supplementation

A 56-year-old woman was referred to our department of gynaecology in December, 1999, for operation on an ovarian cyst. A low preoperative calcium (1·40 mmol/L, [normal range 1·90–2·70] and ionised calcium (0·69 mmol/L [1·15–1·30]) and a raised creatinine (239 mol/L [40-100] troubled the anaesthestist. He referred her to a nephrologist before the operation. In her past medical history she had had life-long fatigue and depression. A dentist had diagnosed rickets and another doctor had diagnosed impaired kidney function with renal dysplasia on the right side. The patient had no history of thyroidectomy. On physical examination, the patient had no teeth, was deaf (apparently since birth), and had micrognathia. Further investigations showed a parathyroid hormone in the lower normal range (1·1 pmol/L [1·1–6·9]. Vitamin D and metabolites were in the normal range, as were thyroid stimulating hormone and phosphate. A 24-h urine collection showed a reduced calcium excretion (0·5 mmol/24 h [normal range 2·5–10]); the phosphate excretion was normal. The creatinine-clearance was reduced (31 mL/min). Adominal ultrasound showed a small right kidney (73 mm) and dilatation of the ureter on the right (10 mm). The left kidney size was in the lower normal range.

Of Mice and Men, Recapitulation of Blomstrand's Chondrodysplasia

When PTH-related protein (PTHrP) was discovered it was looked on as a hormone, secreted as it was by several cancers and causing hypercalcemia by its actions on bone to promote resorption and the kidney to reduce calcium excretion. It soon became apparent that PTHrP was produced in many tissues in the body, including skin, bone, blood vessels, and the uterus, where it exerts local biological actions that vary according to the location. Once sensitive assays for PTHrP were applied, it became clear that any PTHrP in the circulation postnatally was there at exceedingly low levels. Thus, the concept has developed that PTHrP is a paracrine and/or autocrine factor in many tissues of the body, functioning as a hormone when produced in excess by many cancers, but otherwise as a hormone only in the fetus, where it promotes calcium transfer across the placenta from mother to fetus. Genetic studies in mice have revealed much more of the physiological roles of PTHrP. Mice rendered null for the PTHrP gene die very soon after birth, most likely from respiratory failure resulting from widespread abnormalities of endochondral bone development. Nonskeletal tissues and organs appear normal. Only when genetic “rescue” of the bone/cartilage phenotype was achieved in PTHrP2/2 mice by using transgenes expressing either PTHrP under the control of a cartilage-specific promoter or constitutively active PTH/PTHrP receptor (PTHR1) did it become clear that PTHrP deficiency resulted in major defects in breast, skin, and tooth development. The insights provided by these models obtained through mouse genetics provided the guidelines used by Wysolmerski et al. (1) in their morphological study of fetuses with Blomstrand’s chondrodysplasia, a rare syndrome resulting from loss-of-function mutations in the PTHR1 gene. Blomstrand’s chondrodysplasia is typified by short limbs, hypoplasia of the mandibles, advancement of skeletal maturation accompanied with ossification of the thyroid, and hyoid cartilages. Mice rendered null for the PTHrP gene and rescued by transgenic expression of PTHrP in cartilage fail to develop mammary glands. This is the result of failure of branching morphogenesis, even though the first step in embryonic mammary gland development and formation of the mammary bud take place. The fetuses with Blomstrand’s chondrodysplasia lacked identifiable breast or nipple tissue. Thus, just as the evidence from mouse genetics has shown that PTHrP is essential to the formation of the embryonic mammary gland, this seems likely to be the case also in human embryonic breast development. In both mouse and human breast, PTHrP is expressed in epithelial cells and PTHR1 in mesenchymal cells, with the functional data suggesting strongly that PTHrP plays a crucial role in epithelialmesenchymal signaling. The finding in the Blomstrand fetuses of developing teeth severely impacted within the alveolar bone seems also to recapitulate the abnormalities in tooth development detected in PTHrP null mice. Careful analysis of the PTHrP2/2 mice rescued by cartilage-directed PTHrP established that PTHrP is necessary for normal tooth eruption (2) and that this is due to failure of PTHrP-dependent osteoclast formation, the process necessary to form an eruption pathway (3). Indeed, the mouse studies revealed a special role for

Failure of short-term gamma-linolenic acid treatment to reduce urinary calcium loss of diabetic rats.

Calcium re-absorption in the kidney is impaired in streptozotocin (STZ) diabetic rats, thereby causing hypercalciuria. Increased calcium loss starts within 1-2 days after induction of diabetes and reaches a plateau after 2 weeks. The excessive calcium excretion was previously shown to be reduced by treatment with gamma-linolenic acid (GLA) or evening primrose oil rich in GLA. However, in these studies, the animals were pre-treated for several weeks before injection of STZ. In the present study we investigated whether GLA can reduce calcium excretion when treatment starts at the same time as induction of diabetes. Rats were made diabetic with 60 mg/kg STZ and at the same time food was fortified with 0.4% GLA for the treatment group. A control group was treated with vehicle alone and given standard feed only. Urine was collected from animals in metabolism cages every 3rd day for a period of 26 days. The diabetic group increased their food and water consumption, and urine and faeces production as compared to the control group. The urinary loss of Ca, Mg, Zn, Na, K and creatinine was markedly increased in the diabetic group as compared to the control. GLA treatment, however, did not affect any of these variables. Analysis of fatty acids in kidneys of the rats showed an increased concentration of GLA in the treated group as compared to the two non-treated groups. We conclude that GLA treatment must commence before STZ injection in order to attenuate diabetes-induced hypercalciuria.