Efecto de una dieta rica en calcio sobre el metabolismo mineral y óseo en ratas / Effect of a calcium-rich diet on bone and mineral metabolism in rats

Objetivo: Una dieta rica en calcio se ha recomendado generalmente para mantener una adecuada salud ósea; no obstante, estudios recientes han despertado la controversia sobre sus beneficios. En este sentido, la mayoría de los estudios existentes en modelos animales están realizados con dietas deficientes en vitamina D. En este estudio se evaluará el efecto de una dieta rica en calcio sobre el metabolismo mineral y la histomorfometría ósea en rata. Además, en células UMR-106 se evaluó el efecto directo del suplemento de calcio sobre la expresión de genes osteogénicos.Material y métodos: Un grupo de ratas wistar macho de aproximadamente 3 meses de edad fue alimentado con dieta de contenido normal de calcio (0,6%) mientras que otro grupo se alimentó con dieta de alto contenido en calcio (1,2%). Transcurridos 20 días se recogieron muestras de orina 24h, sangre para análisis bioquímicos y el fémur para estudio de histomorfometría ósea. In vitro, se estudió la expresión génica de Runx2, Osterix y Osteocalcina en células UMR-106 cultivadas en condiciones de alto contenido en calcio.Resultados: La ingesta de una dieta rica en calcio redujo la concentración de PTH y calcitriol en plasma, aumentó la calciuria y disminuyó la fosfaturia. A nivel óseo, se observó una drástica disminución de la actividad osteoblástica consistente con la bajada de PTH; sin embargo, el volumen trabecular permaneció similar en ambos grupos. In vitro, el suplemento de calcio no disminuyó la expresión de marcadores osteoblásticos en UMR-106, indicando que los efectos in vivo son mayormente indirectos y debidos a la bajada de PTH.Conclusiones: Una dieta de alto contenido en calcio reduce la concentración de PTH y calcitriol en plasma, resultando en una disminución de la actividad osteoblástica. (AU)

Cortical bone analysis in a predialysis population: a comparison with a dialysis population.

This study was designed to characterize cortical bone by histomorphometry in a predialysis population, to correlate turnover, mineralization, and volume between cortical and trabecular bone, and to compare the findings with those in patients treated with maintenance dialysis. We evaluated cortical bone by histomorphometry in 16 patients with stage 3 or stage 4 chronic kidney disease and in 16 dialysis patients. Dual-energy X-ray absorptiometry (DXA) of the distal end of the forearm was performed in seven predialysis patients, and the findings correlated with histologic parameters. Predialysis patients compared with dialysis patients showed increased cortical bone thickness (p = 0.027) and decreased osteonal bone formation rate (p = 0.020) and adjusted apposition rate (p = 0.018), mainly for external cortical bone. In this predialysis population, trabecular bone volume positively correlated with external cortical porosity (r = 0.723, p = 0.003), external cortical thickness (r = 0.569, p = 0.034), and external osteonal accumulation (osteonal osteoid thickness, r = 0.530, p = 0.05; osteonal osteoid volume to bone volume ratio, r = 0.921, p < 0.001; and osteonal osteoid surface to bone surface ratio, r = 0.631, p = 0.016). These correlations were not observed in the internal cortical bone. Cortical osteonal mineralization surface negatively correlated with DXA Z and T scores and bone mineral density for the distal end of the forearm. The osteonal bone formation rate of both internal cortical bone and external cortical bone correlated with Z score (r = -0.975, p = 0.005 and r = -0.880, p = 0.021 respectively). We found no significant correlations between cortical thickness or porosity and DXA parameters for either external cortical bone or internal cortical bone. Our results suggest that a greater degree of kidney disease is associated with thinner cortices, eventually contributing to the higher fracture rate observed in the chronic kidney disease population. In predialysis patients, parathyroid hormone seems to have a modulating effect on both trabecular bone and cortical bone, particularly in external cortical bone.

Cinacalcet reduces plasma intact parathyroid hormone, serum phosphate and calcium levels in patients with secondary hyperparathyroidism irrespective of its severity.

AIMS: To evaluate the relationship between the severity of secondary hyperparathyroidism (SHPT) - defined in terms of baseline plasma intact parathyroid hormone (iPTH) level - and the magnitude of response to cinacalcet. MATERIALS AND METHODS: In this post hoc analysis, data were pooled from three randomized, placebo-controlled trials in which dialysis patients with iPTH ≥ 300 pg/ml were dose-titrated with cinacalcet or placebo in addition to conventional treatment to achieve iPTH ≤ 250 pg/ml. In 953 patients analyzed (cinacalcet, 545; placebo, 408), baseline iPTH levels were categorized in 100 pg/ml intervals (300 - ≥ 1,000 pg/ml), and the impact of baseline iPTH on changes in iPTH, phosphate (P), calcium (Ca) and calcium- phosphate product (Ca × P) was evaluated. RESULTS: Cinacalcet reduced iPTH (47% reduction), P (9%), Ca (7%), and Ca × P (15%) across all subgroups. For patients receiving cinacalcet, the mean percentage reduction from baseline in iPTH varied from 35 to 55%, being consistently decreased across the severity subgroups. The mean absolute change in iPTH was more pronounced in patients with higher baseline iPTH levels, particularly in the ≥ 1,000 pg/ml subgroup vs. the other subgroups. However, as baseline iPTH levels increased, iPTH ≤ 250 pg/ml was achieved in fewer patients. A trend towards greater absolute change from baseline was observed for P in patients with more severe disease (iPTH ≥ 800 pg/ml) treated with cinacalcet compared with patients with less severe disease (iPTH 300 - < 800 pg/ml). CONCLUSIONS: Cinacalcet lowers plasma iPTH and serum P, Ca and Ca × P levels in dialysis patients with SHPT, regardless of disease severity. Patients with more severe disease experienced greater reductions in PTH and P, but fewer achieved iPTH ≤ 250 pg/ml by the efficacy assessment phase. Use of cinacalcet when baseline PTH is lower may result in more stable control of SHPT and help to control bone and mineral alterations.

Femoral bone mineral density reflects histologically determined cortical bone volume in hemodialysis patients.

UNLABELLED: We evaluated the associations between dual energy X-ray absorptiometry (DXA) and histologically determined cancellous and cortical bone volume by controlling for vascular calcifications and demographic variables in hemodialysis (HD) patients. Femoral bone mineral density (f-BMD) was associated with cortical porosity. INTRODUCTION: Assessment of bone mass in chronic kidney disease patients is of clinical importance because of the association between low bone volume, fractures, and vascular calcifications. DXA is used for noninvasive assessment of bone mass whereby vertebral results reflect mainly cancellous bone and femoral results reflect mainly cortical bone. Bone histology allows direct measurements of cancellous and cortical bone volume. The present study evaluates the association between DXA and histologically determined cancellous and cortical bone volumes in HD patients. METHODS: In 38 HD patients, DXA was performed for assessment of bone mass, anterior iliac crest bone biopsies for bone volume, and multislice computed tomography for vascular calcifications. RESULTS: While lumbar bone mineral density (l-BMD) by DXA was not associated with histologically measured cancellous bone volume, coronary Agatson score showed a borderline statistically significant association (P = 0.055). When controlled for age and dialysis duration, f-BMD by DXA was associated with cortical porosity determined by histology (P = 0.005). CONCLUSIONS: The usefulness of l-BMD for predicting bone volume is limited most probably because of interference by soft tissue calcifications. In contrast, f-BMD shows significant association with cortical porosity.

Efficacy and side effects of intermittent intravenous and oral doxercalciferol (1alpha-hydroxyvitamin D(2)) in dialysis patients with secondary hyperparathyroidism: a sequential comparison.

Most reports on the effectiveness and side effects of oral versus parenteral calcitriol or alfacalcidol in hemodialysis patients with secondary hyperparathyroidism show no advantage of parenteral treatment. The efficacy and safety of intravenous doxercalciferol (1alphaD(2)) were studied in hemodialysis patients with secondary hyperparathyroidism (plasma intact parathyroid hormone [iPTH]: range, 266 to 3,644 pg/mL; median, 707 pg/mL). These results were compared with those of a previous trial using intermittent oral 1alphaD(2); the same 70 patients were entered onto both trials, and 64 patients completed both trials per protocol. Twelve weeks of open-label treatment in both trials were preceded by identical 8-week washout periods. Degrees of iPTH suppression from baseline were similar in the two trials, with iPTH level reductions less than 50% in 89% and 78% of patients during oral and intravenous treatment, respectively. Grouping patients according to entry iPTH levels (<750 and >/=750 pg/mL) showed similar but more rapid iPTH suppression in the low-iPTH groups, whereas longer treatment and larger doses were required by the high-iPTH groups. Highest serum calcium levels averaged 9.82 +/- 0.14 and 9.67 +/- 0.11 mg/dL during oral and intravenous 1alphaD(2) treatment, respectively (P: = not significant [NS]). Prevalences of serum calcium levels greater than 11.2 mg/dL during oral and intravenous treatment were 3.62% and 0.86% of calcium measurements, respectively (P: < 0.001). Highest serum phosphorus levels during oral and intravenous treatment averaged 5.82 +/- 0.21 and 5.60 +/- 0.21 mg/dL, respectively (P: = NS). The percentage of increments in serum phosphorus levels during oral treatment exceeded that during intravenous treatment during 5 of 12 treatment weeks. Thus, intermittent oral and intravenous therapy with 1alphaD(2) reduced iPTH levels effectively and similarly, hypercalcemia was less frequent, and serum phosphorus levels increased less during intravenous than oral 1alphaD(2) therapy, suggesting that intravenous 1alphaD(2) therapy may be advantageous in patients prone to hypercalcemia or hyperphosphatemia.

Intermittent doxercalciferol (1alpha-hydroxyvitamin D(2)) therapy for secondary hyperparathyroidism.

Hypercalcemia and hyperphosphatemia frequently necessitate vitamin D withdrawal in hemodialysis patients with secondary hyperparathyroidism. In short-term trials, doxercalciferol (1alpha-hydroxyvitamin D(2) [1alphaD(2)]) suppressed intact parathyroid hormone (iPTH) effectively with minimal increases in serum calcium and phosphorus (P) levels. This modified, double-blinded, controlled trial examined the efficacy and safety of 1alphaD(2) use in 138 hemodialysis patients with moderate to severe secondary hyperparathyroidism by using novel dose titration; 99 patients completed the study. Hemodialysis patients with secondary hyperparathyroidism were enrolled onto this study, consisting of washout (8 weeks), open-label 1alphaD(2) treatment (16 weeks), and randomized, double-blinded treatment with 1alphaD(2) or placebo (8 weeks). Oral 1alphaD(2) was administered at each hemodialysis session, with doses titrated to achieve target iPTH levels of 150 to 300 pg/mL. Baseline iPTH levels (897 +/- 52 [SE] pg/mL) decreased by 20% +/- 3.4% by week 1 (P: < 0.001) and by 55% +/- 2.9% at week 16; iPTH levels returned to baseline during placebo treatment but remained suppressed with 1alphaD(2) treatment. In 80% of the patients, iPTH level decreased by 70%, reaching the target level in 83% of the patients. Grouping patients by entry iPTH level (<600, 600 to 1,200, and >1,200 pg/mL) showed rapid iPTH suppression in the group with the lowest level; greater doses and longer treatment were required in the group with the highest level. During open-label treatment, serum calcium and P levels were 9.2 +/- 0.84 (SD) to 9.7 +/- 1.05 mg/dL and 5.4 +/- 1.10 to 5.9 +/- 1.55 mg/dL, respectively. During double-blinded treatment, serum calcium levels were slightly greater with 1alphaD(2) than placebo, but P levels did not differ. During double-blinded treatment, 3.26% and 0.46% of serum calcium measurements exceeded 11.2 mg/dL with 1alphaD(2) and placebo, respectively (P: < 0.01); median level was 11.6 mg/dL during hypercalcemia. Intermittent oral 1alphaD(2) therapy effectively suppresses iPTH in hemodialysis patients with secondary hyperparathyroidism, with acceptable mild hypercalcemia and hyperphosphatemia.

A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism.

BACKGROUND: The calcimimetic agent R-568 lowers plasma parathyroid hormone (PTH) levels in hemodialysis patients with mild secondary hyperparathyroidism, but its efficacy in those with more severe secondary hyperparathyroidism has not been studied. METHODS: Twenty-one patients undergoing hemodialysis three times per week with plasma PTH levels between 300 and 1200 pg/mL were randomly assigned to 15 days of treatment with either 100 mg of R-568 (N = 16) or placebo (N = 5). Plasma PTH and blood ionized calcium levels were measured at intervals of up to 24 hours after oral doses on days 1, 2, 3, 5, 8, 11, 12, and 15. RESULTS: Pretreatment PTH levels were 599 +/- 105 (mean +/- SE) and 600 +/- 90 pg/mL in subjects given R-568 or placebo, respectively, and values on the first day of treatment did not change in those given placebo. In contrast, PTH levels fell by 66 +/- 5%, 78 +/- 3%, and 70 +/- 3% at one, two, and four hours, respectively, after initial doses of R-568, remaining below pretreatment values for 24 hours. Blood ionized calcium levels also decreased after the first dose of R-568 but did not change in patients given placebo. Despite lower ionized calcium concentrations on both the second and third days of treatment, predose PTH levels were 422 +/- 70 and 443 +/- 105 pg/mL, respectively, in patients given R-568, and values fell each day by more than 50% two hours after drug administration. Predose PTH levels declined progressively over the first nine days of treatment with R-568 and remained below pretreatment levels for the duration of study. Serum total and blood ionized calcium concentrations decreased from pretreatment levels in patients given R-568, whereas values were unchanged in those given placebo. Blood ionized calcium levels fell below 1.0 mmol/L in 7 of 16 patients receiving R-568; five patients withdrew from study after developing symptoms of hypocalcemia, whereas three completed treatment after the dose of R-568 was reduced. CONCLUSIONS: The calcimimetic R-568 rapidly and markedly lowers plasma PTH levels in patients with secondary hyperparathyroidism caused by end-stage renal disease.

Calcium-sensing receptor and calcimimetic agents.

Recognizing the role of the extracellular calcium-sensing receptor (CaR) in mineral metabolism greatly improves our understanding of calcium homeostasis. The biology of the low affinity, G-protein-coupled CaR and the effects of its activation in various tissues are reviewed. Physiological roles include regulation of parathyroid hormone (PTH) secretion by small changes in ionized calcium (Ca2+) and control of urinary calcium excretion with small changes in blood Ca2+. The CaR also affects the renal handling of sodium, magnesium and water. Mutations affecting the CaR that make it either less or more sensitive to Ca2+ cause various clinical disorders; heterozygotes of mutations causing the CaR to be less sensitive to extracellular Ca2+ cause familial hypocalciuric hypercalcemia, while the homozygous form results in severe infantile hyperparathyroidism. Mutations causing increased sensitivity of the CaR to extracellular Ca2+ produce hereditary forms of hypoparathyroidism. Disorders, such as primary and secondary hyperparathyroidism, may exhibit acquired abnormalities of the CaR. Calcimimetic drugs, which amplify the sensitivity of the CaR to Ca2+, can suppress PTH levels, leading to a fall in blood Ca2+. Experiences with this agent in patients with secondary and primary hyperparathyroidism and parathyroid carcinoma are summarized. In animals and humans with hyperparathyroidism, this agent produces a dose-dependent fall in PTH and blood Ca2+, with larger doses causing more sustained effects. The treatment has been short-term except for one patient followed for more than 600 days for parathyroid carcinoma; nonetheless the drug did not cause major side-effects and appears to be safe. Further long-term controlled studies are needed with calcimimetic agents of this type.

Intermittent oral 1alpha-hydroxyvitamin D2 is effective and safe for the suppression of secondary hyperparathyroidism in haemodialysis patients. 1alphaD2 Study Group.

Calcitriol and alfacalcidol are useful in suppressing parathyroid hormone (PTH) in haemodialysis patients, but hypercalcaemia and hyperphosphataemia are frequent. The vitamin D analogue, 1alpha-hydroxyvitamin D2 (1alphaD2), has a higher therapeutic index in animal models. Previously, 1alphaD2, 4 microg/day or 4 microg/haemodialysis, lowered iPTH to the target range in 87.5% of 24 haemodialysis patients with moderate to severe secondary hyperparathyroidism (plasma iPTH, 359-1521 pg/ml). The incidences of hypercalcaemia (serum Ca>2.8 mM) or hyperphosphataemia (serum P>2.23 mM) were low. Later, 10 of these patients were re-treated with 1alphaD2, initial dose, 10 microg, thrice weekly with haemodialysis. The iPTH was suppressed as readily, and there was no greater incidence of hypercalcaemia and hyperphosphataemia. Based on these data, a large, multicentre study is ongoing in California and Tennessee/Mississippi, using 1alphaD2 in haemodialysis patients with iPTH >400 pg/ml. In this and the earlier studies, only calcium-based phosphate binders were used to control serum phosphorus. The initial dose, 10 microg thrice weekly with haemodialysis, is adjusted to maintain a target iPTH within the range of 150-300 microg/ml; the final dose range is 2.5-20 microg per haemodialysis. The protocol includes 8 weeks of wash-out with no vitamin D, 16 weeks of open label treatment period with 1alphaD2, and finally 8 weeks of randomized double blinded treatment with either continued 1alphaD2 or placebo. Forty two patients from California and 38 from Tennessee/Mississippi have completed 16 weeks of open label treatment. In California, iPTH declined from 832+/-95 pg/ml at baseline to 222+/-71 pg/ml at the nadir and to 477+/-117 pg/ml at week 16 of the treatment. In Tennessee/Mississippi, the iPTH declined from 977+/-65 pg/ml to 286+/-42 pg/ml at the lowest point and to 493+/-79 at the end of the treatment. Plasma iPTH reached or fell below the target range in 84% of the 80 patients completing open treatment. Asymptomatic hypercalcaemia (serum Ca>2.8 mM) increased from 0.3 episodes/100 weeks during wash-out to 3.6 episodes/100 treated weeks in California and from 0 to 3.7 episodes in Tennessee/Mississippi. In California and Tennessee, the episodes of hyperphosphataemia (serum P>2.2 mM) increased from 5.0 and 5.0 episodes per 100 patient/week during wash-out to 10.1 and 10.9 episodes/100 treatment weeks, respectively, with 1alphaD2 treatment. There were no adverse events in association with 1alphaD2 treatment. Thus, oral 1alphaD2 is safe and highly effective for the treatment of secondary hyperparathyroidism.

Carbamylated hemoglobin in prerenal azotemia.

UNLABELLED: Carbamylated hemoglobin (Carb Hb) levels were measured in 16 patients with a documented transient rise in BUN due to prerenal azotemia, in whom BUN levels before and after the episode were normal. They were compared with 13 controls. Carb Hb was expressed as carbamyl valine concentrations, which were significantly higher in the patients (166 micrograms/g Hb) than in controls (95.3 micrograms/g Hb, p < 0.01). The mean maximum BUN level in the patients was 51.8 +/- 23.9 mg/dl. There was a significant correlation between the product of mean BUN level times the number of days of BUN elevation, and the Carb Hb level (r = 0.5197; p < 0.05). There was no correlation between Carb Hb and either mean BUN level or maximum BUN level. Elevated Carb Hb was seen after a minimum of 4 days' BUN elevation. Four patients had no elevation of Carb Hb despite elevated BUN levels. CONCLUSION: Carb Hb may be elevated after a minimum of 4 days' transient BUN elevation; Carb Hb is not useful in differentiating between mild acute renal failure and prerenal azotemia.

Persistence of antibodies to hepatitis C virus in a chronic hemodialysis population.

In order to evaluate the persistence of antibodies against hepatitis C virus (HCV) in a chronic hemodialysis population, we studied 151 HBsAg-negative patients. Anti-HCV titers were evaluated every 3 months over 1 year, and the serum alanine aminotransferase/serum aspartate aminotransferase ratio monthly from the start of hemodialysis. The anti-HCV titers (ELISA C100-3) remained stable in 127 patients and fluctuated in 24, without an evident correlation with hepatic function. Using our criteria, we found 85 patients with non-A, non-B hepatitis, 57 of them with biochemical criteria of chronic hepatic disease. There was a strong correlation between antibodies to HCV and non-A, non-B hepatitis (chi 2; p < 0.05) which was more marked in those patients with biochemical criteria of chronic hepatic disease (chi 2; p < 0.001). We concluded that the anti-HCV titer is reliable as a long-term marker of hepatitis C virus infection.

[Significance of digestive hemorrhage in patients with chronic renal insufficiency in hemodialysis]. / Importância da hemorragia digestiva nos doentes com insuficiência renal crónica em hemodiálise.

Gastrointestinal Bleeding (GIB) is a complication in patients with Chronic Renal Failure (CRF) on regular hemodialysis (HD). To analyse the importance of GIB we studied, retrospectively, the causes of hospitalization in 301 patients, all on HD in the same Unit in January 1990. The average age was 57.4 +/- 14.2 years (17 to 87), time on HD 58.3 +/- 44.9 months, male = 166, female = 135. Of a total of 169 hospitalizations, the infectious disease were the most frequent cause with 37 admissions (21.9%), followed by gastrointestinal diseases with 34 admissions (21.1%). Of these, 23 (13.6%) were due to GIB (Upper GIB = 19, Lower GIB = 4). The etiologies of Upper GIB were: Peptic Ulcer = 9, erosive Gastritis/Duodenitis = 7. Angiodysplasia = 1, Mallory Weiss = 1 and unknown = 1. The etiologies of Lower GIB were: Angiodysplasia of the colon = 3, Cancer of the colon = 1. Non-steroid anti-inflammatory drugs (NSAID) had a positive correlation (p less than 0.01) with Upper GIB due to erosive Gastritis/Duodenitis. Surgery was necessary in a 8 cases of GIB, 7 of them due to Peptic Ulcer. GIB is an important cause of morbidity in patients with CRF on HD. Peptic Ulcer and erosive Gastritis/Duodenitis were the most frequent causes of GIB in the population studied. Angiodysplasia of the colon was the most important cause of Lower GIB. NSAID appear to be a risk factor for GIB from erosive Gastritis and or Duodenitis.