Higher Serum Phosphate Research Articles

Molecular mechanisms of secondary hyperparathyroidism.

Secondary hyperparathyroidism is a frequent complication of chronic renal failure (CRF) and a major factor in the pathogenesis of renal osteodystrophy. A high serum phosphate, decreased levels of serum 1,25(OH) 2 D 3 and the subsequently low serum calcium are the major metabolic abnormalities in CRF, which lead to the secondary hyperparathyroidism. At the level of parathyroid hormone (PTH) secretion there is insensi- tivity to the ambient serum calcium. PTH mRNA levels are increased by a post-transcriptional mechanism that involves the binding of PT cytosolic proteins to the PTH mRNA 3'-untranslated region (UTR). In a dietary model of secondary hyperparathyroidism due to hypocalcemia there is increased binding of parathyroid proteins to the 3'-UTR and decreased degradation as determined by an in vitro degradation assay. Changes in serum phosphate also dramatically regulate PTH mRNA stability. There is also regulation at the level of PT cell proliferation. PT cell proliferation is increased by experimental hypocal- cemia or hyperphosphatemia and decreased by hypo- phosphatemia and administered 1,25(OH) 2 D 3 . The un- derstanding of the molecular mechanisms involved in the genesis of secondary hyperparathyroidism will allow the design of new effective strategies in the management of this troubling condition.

Hypocalcemia Due to Hypoparathyroidism in β-Thalassemia Major Patients

This is a retrospective analysis of case records of AA(2)-thalassemia major patients who developed hypoparathyroidism (HPT). The objective of this study was to assess the prevalence of hypocalcemia and hypoparathyroidism in AA(2)-thalassemia major patients being followed at King Khalid University Hospital (KKUH), Riyadh, Saudi Arabia. Diagnosis was based on low serum calcium (S/Ca), high serum phosphate (Po4), normal serum magnesium and alkaline phosphatase, and low serum parathyroid hormone levels. Other parameters analyzed included age, sex, serum ferritin levels, age of onset of HPT, any symptoms of hypocalcemia, and presence of other complications in these patients. Out of 40 patients, eight (20%) were diagnosed to have HPT. The mean age at diagnosis was 13.6 years (range 11-16 years), mean serum calcium was 1.88 mmol/L (range 1.58-2.04), mean serum ferritin was 7490 AA(1/4)g/L (range 2000-23,064) and mean serum phosphate was 1.88 mmol/L (range 1.50-2.73). Serum parathyroid hormone (PTH) levels were low in most of the patients. Only two patients (25%) had mild symptoms of hypocalcemia. Growth retardation was present in all patients, while four patients had liver dysfunction, two had diabetes mellitus and two had cardiac dysfunction. HPT due to iron overload may develop in a significant number of thalassemia major patients, especially when chelation therapy is not optimal, therefore, all thalassemics should be carefully watched for this complication from early in their second decade.

Molecular mechanisms of secondary hyperparathyroidism.

Secondary hyperparathyroidism is a frequent complication of chronic renal failure (CRF) and a major factor in the pathogenesis of renal osteodystrophy. A high serum phosphate, decreased levels of serum 1,25(OH)2D3 and the subsequently low serum calcium are the major metabolic abnormalities in CRF, which lead to the secondary hyperparathyroidism. At the level of parathyroid hormone (PTH) secretion there is insensitivity to the ambient serum calcium. PTH mRNA levels are increased by a post-transcriptional mechanism that involves the binding of PT cytosolic proteins to the PTH mRNA 3'-untranslated region (UTR). In a dietary model of secondary hyperparathyroidism due to hypocalcemia there is increased binding of parathyroid proteins to the 3'-UTR and decreased degradation as determined by an in vitro degradation assay. Changes in serum phosphate also dramatically regulate PTH mRNA stability. There is also regulation at the level of PT cell proliferation. PT cell proliferation is increased by experimental hypocalcemia or hyperphosphatemia and decreased by hypophosphatemia and administered 1,25(OH)2D3. The understanding of the molecular mechanisms involved in the genesis of secondary hyperparathyroidism will allow the design of new effective strategies in the management of this troubling condition.

Renal Reabsorption of Phosphate in Children with Sickle Cell Anemia

It has previously been reported that in adult patients with sickle-cell anemia the serum phosphate value and the maximum tubular reabsorption of phosphate per liter of glomerular filtrate (TmP/GFR) were significantly higher than in normal controls. This does not appear to have been studied in children with sickle cell anemia (young sicklers) and this prompted us to assess renal phosphate reabsorption in this group of patients. We looked at serum phosphate level and calculated renal phosphate reabsorption (TP/GFR) in children taking random urine and blood samples at the same time and using the formula TP/GFR = Sp – Up × SCr: UCr, in 30 young sicklers all of whom had normal renal function (mean age 7.3 years) and 40 normal matching controls (mean age 6.5 years). The mean serum phosphate value in young sicklers was significantly lower than in controls (4.3 against 5.3 mg/dl) while the mean value of TP/GFR was 4.09 ± 0.74 mg/dl in young sicklers compared to 4.65 ± 0.75 mg/dl in the control group (p = 0.0026). Therefore, the TP/GFR in young sicklers was also significantly lower (p = 0.0026) than in the control group. This may be explained by the high serum level of parathyroid hormone reported previously in patients with sickle cell anemia which is expected to lower phosphate reabsorption (TmP/GFR and TP/GFR are identical in children). The lower serum phosphate value and TP/GFR in younger sicklers seems to be in contrast with the relatively high serum phosphate value and TP/GFR previously reported in adults with sickle cell anemia.

Effect of serum phosphate on parathyroid hormone secretion during hemodialysis

Recent studies have demonstrated that a high concentration of phosphate directly stimulates parathyroid hormone (PTH) secretion. High serum levels of phosphate are usually observed in patients with end-stage renal disease. The aim of the present study was to evaluate whether serum phosphate concentration had an acute effect on PTH secretion in hemodialysis patients. The levels of serum phosphate were manipulated during the hemodialysis session by using a phosphate free dialysate or a dialysate with a high content of phosphate. Ten stable hemodialysis patients with PTH values above 300 pg/ml were included in the study. A PTH-calcium curve was obtained during both high phosphate and phosphate free hemodialysis. The serum phosphate concentration remained high (2.17 +/- 0.18 mM) throughout the high phosphate hemodialysis and decreased progressively to normal levels (1.02 +/- 0.06 mM) during the phosphate free hemodialysis. The serum PTH levels at maximal inhibition by hypercalcemia (minimal PTH) were greater during the high phosphate than the phosphate free hemodialysis (413 +/- 79 vs. 318 +/- 76 pg/ml, P < 0.003). In all patients the values of minimum PTH were greater during the high phosphorus than the phosphorus free hemodialysis. The values of maximally stimulated PTH during hypocalcemia and the set point of the PTH-calcium curve were similar during the high phosphate and the phosphate free hemodialysis. The maintenance of high serum phosphorus levels during hemodialysis prevented, in part, the inhibition of PTH secretion by calcium, which strongly suggests that in hemodialysis patients high serum phosphate contributes directly to the elevation of PTH levels despite normal or high serum calcium concentration.

Regulation of parathyroid cell proliferation.

The parathyroid normally has very few cells in mitosis but it retains the potential to proliferate. In-vivo studies in rats have demonstrated that hypocalcaemia and high serum phosphate both lead to an increase in the number of proliferating cells, which is relevant to the increased parathyroid cell proliferation in chronic renal failure. Hypophosphataemia and 1,25(OH)2D3 decrease parathyroid cell proliferation. Genetic factors have been defined for multiple endocrine neoplasia which includes parathyroid cell hyperplasia, and in some parathyroid adenomas there are genetic rearrangements.

Increase of calcitriol during treatment with protein-reduced diet in patients with renal failure.

Vitamin D metabolites 25-OH-D3 (calcifediol) and 1,25-(OH)2-D3 (calcitriol) were measured in plasma in 16 patients with advanced chronic renal failure during treatment with a protein-restricted diet for 6 months. The glomerular filtration rate (GFR) decreased only marginally, from 8.3 to 7.9 ml/min, during the study while there was a significant decrease of serum urea levels after the initiation of the protein-reduced diet. Calcitriol levels rose significantly (p < 0.05) after 3 months from 17.1 to 27.7 pg/ml but fell after another 3 months to nearly their initial values, 15.3 pg/ml. The serum phosphate levels changed during the same periods from 1.99 to 1.67 to 1.93 mmol/l. There were significant inverse correlations between the calcitriol and phosphate levels at the start and after 3 months but not after 6 months. There was also a significant correlation between the changes in calcitriol and initial GFR. A subgroup of patients with decreased or unchanged calcitriol concentrations during dietary treatment had significantly higher serum phosphate and creatinine and significantly lower standard bicarbonate concentrations. Multivariate regression analysis for the pooled set of data with calcitriol as the dependent variable showed significant values for GFR (p < 0.02), body mass index (p < 0.02), and serum phosphate concentrations (p < 0.04). These results show the importance of phosphate control and renal function for the regulation of calcitriol synthesis.

Heritable syndrome of pseudoxanthoma elasticum with abnormal phosphorus and vitamin D metabolism

A patient with pseudoxanthoma elasticum was documented to be hyperphosphatemic and mildly hypercalcemic for six years. Complications included metastatic calcification, absorptive hypercalciuria, and renal insufficiency. The 1,25-dihydroxyvitamin D value was elevated, despite normal serum parathyroid hormone values, high serum phosphate levels, and renal insufficiency. Either increased dietary calcium or prednisone seemed to suppress the 1,25-dihydroxyvitamin D value. Nephrolithiasis or abnormalities suggestive of pseudoxanthoma elasticum occurred in the patient's father, daughter, and several siblings, suggesting a distinct familial syndrome in which connective tissue changes are accompanied by abnormalities of phosphorus and vitamin D metabolism that may resemble those in the syndrome of familial tumoral calcinosis. Nine similar cases were described before 1970.

Aluminum and Phosphate: The Double Bind

THE recognition that aluminum contaminated dialyzate was responsible for dementia and osteomalacic bone disease led to the expectation that with suitable water treatment, aluminum storage, and, on occasion, intoxication, would be eliminated. I -5 Instead the epidemiology has changed so that sporadic cases are occurring rather than the clusters seen previously. 5-8 This represents an indication of the more gradual, insidious exposure to aluminum by the oral rather than by the dialyzate route. In areas such as our own where dialyzate has always been essentially aluminum free, 26 out of 47 patients or 55 % on dialysis for at least one year have stainable bone aluminum. All except three had taken oral aluminum compounds and these had negative staining. The prescription of oral aluminum salts, usually the hydroxide (AI(OHh), has been widely employed once it was shown that hyperphosphatemia was pivotal in the progression of the secondary hyperparathyroidism of end-stage renal disease (ESRD). It is necessary then to examine the major determinants of serum phosphorus in patients on renal replacement therapy. These would include residual renal function, bone resorption, dietary phosphorus, dialysis prescription, and, finally, dose of Al(OHh. Residual renal function, urine volume, and, hence, solute excretion are generally insignificant in patients on dialysis. The few with creatinine clearances of 4 to 6 mLimin will see these decline following the initiation of dialysis. The subjects own excretory function for phosphate (although not necessarily for water and other solutes) can therefore usually be ignored. Increased rates for bone resorption are characteristic of secondary hyperparathyroidism and would lead to increased flux of calcium and phosphate into extracellular fluid. Hypercalcemia, while it does occur, is uncommon and because calcium and phosphorus are found in a fixed ratio in apatite, hyperphosphatemia also would be infrequent. The reason for this anomaly is the coupling of formation to resorption so that although more bone is removed more is also formed at roughly equal rates. A further consideration is that if hyperphosphatemia is in fact responsible for secondary hyperparathyroidism then the finding of high serum phosphate levels are not necessarily the result of the parathyroid hyperactivity leading to augmented bone turnover but rather the cause. This is probably the reason for the previous report of higher serum phosphorus levels in patients with overt hyperparathyroidism when compared to those without, although several in the former group were hypercalcemic. 9 In our data, 39 patients were divided on the basis of their bone histology into either absent or minimal hyperparathyroidism (17 patients) or active disease (22 patients). Predialysis serum phosphorus was 6.2 ± 0.3 in both groups. Agreement with these propositions means that dietary phosphorus intake and the dialysis prescription for most patients are the only important parameters determining the predialysis serum phosphorus levels, in addition to oral AI(OHh intake. Any attempt to decrease AI(OH)3 intake will necessitate changes in either dietary phosphorus and/ or the amount of phosphorus removed by dialysis. Dietary phosphorus intake in the usual European and North American diet is quite high and the decreased incidence of renal osteodystrophy in Israel was reported to be associated with lower protein and phosphorus intakes and lower serum phosphorus values. lo In the National Cooperative Dialysis Study (NCDS) mean dietary phosphorus during the control phase for the 162 subjects was 879 mg/d with a standard deviation of 248 mg. II This indicates that a proportion of these selected compliant patients were ingesting more than 1,000

Immunoreactive parathyroid hormone in early and advanced renal failure.

Immunoreactive parathyroid hormone (iPTH) was measured in the serum of 20 patients with early renal failure (ERF) using three assays with different specificity. Half of these patients had elevated iPTH in one or more assays, up to twice the upper limit of normal. In contrast, 36 patients with a creatinine clearance below less than 20 ml/min had an 80% elevated iPTH, up to 5 times the upper limit of normal. The patients with ERF and elevated iPTH had a lower serum calcium but no higher serum phosphate than those with normal iPTH. The differences in iPTH in early and end-stage renal failure can be explained by known differences in metabolism of different PTH forms in uremia.

Urinary excretion of phosphate in normal children.

In 55 normal children on a normal diet, the phosphate and creatinine were estimated in a fasting 2-hour urine collection and in a simultaneous blood sample. In comparison with adults, a high serum phosphate and relatively decreased phosphaturia were found, both of which tended to adult values with the advent of puberty. A correlation between the serum phosphate and the urine phosphate/creatinine ratio (r = + 0·42, p &lt;0·002) was found. The phosphate excretion index was lower in mid-childhood than in adulthood. The interpretation of any expression of phosphaturia in childhood requires its own age-specific normal range.

Hyperphosphatemia and tumoral calcinosis.

Two teenage negro brothers with chronic hyperphosphatemia, one of whom exhibited heterotopic calcifications around large joints, underwent studies of phosphate metabolism. Both patients demonstrated normal inulin clearance and increased phosphate clearance in response to exogenous parathyroid hormone. Increased phosphaturia after ethylene-diaminetetraacetic acid infusion suggested normal endogenous parathormone (PTH) secretory reserve. Immunoassays of serum PTH concentration revealed values within the normal range. Serum growth hormone after arginine infusion rose appropriately in one patient studied. Karyotype analyses of leukocyte cultures yielded 46 XY patterns. It is postulated that hyperphosphatemia was due to inherited reduction in renal tubular responsiveness to the phosphaturic action of PTH, and that chronic high serum phosphate was a contributing factor to the development of extraskeletal calcifications.

Selected features of the clinical course of hypoparathyroidism.

INFORMATION concerning the function of every endocrine organ has been obtained by ablation experiments and study of the deficiency state. The parathyroids are no exception, since much of our knowledge of calcium and phosphorus metabolism has resulted from the study of patients with parathyroid deficiency. The purpose of this presentation is to review our clinical experience with hypoparathyroidism as it pertains to parathyroid function in man. Several excellent general reviews of hypoparathyroidism with detailed analysis of case reports have been published1-3since the major features were so concisely formulated by Dr. Fuller Albright and his associates.4 The criteria for the diagnosis of hypoparathyroidism are as follows: (1) low serum calcium and high serum phosphate levels usually associated with low urinary calcium excretion, (2) normal renal function, (3) no defect in intestinal absorption, (4) absence of rickets, and (5) chronic tetany.5However, these criteria are not absolute. For

Idiopathic hypoparathyroidism and chronic adrenal insufficiency: a case report.

THE clinical syndrome of idiopathic hypoparathyroidism has recently been reviewed by Steinberg and Waldron (1). They accept the criteria previously established by Drake and associates (2)—low serum calcium level, high serum phosphate level, normal renal function, normal bones by x-ray examination, and chronic tetany—but make several minor modifications. These include the requirement that the serum phosphorus level be above 5 mg. per 100 ml. in adults and above 7 mg. per 100 ml. in persons under the age of 16, and that the clinical course be not characterized by chronic diarrhea. The coincidence of idiopathic hypoparathyroidism and chronic adrenal insufficiency (Addison's disease) has been reported in 3 previous cases to our knowledge. Only 1 of these;, however, (that reported by Leonard (3) in 1946) would seem to have been sufficiently documented to make both diagnoses certain. The foregoing criteria for the diagnosis of idiopathic hypoparathyroidism were met in this case, and autopsy revealed complete fi...

THE PROGNOSIS IN POSTERIOR BASIC MENINGITIS

<h3>Summary</h3> <h3>Background and objectives</h3> IGF-1 deficiency links to malnutrition in CKD patients; however, it is not clear to what extent it associates with survival among these patients. <h3>Design, setting, participants, &amp; measurements</h3> Serum IGF-1 and other biochemical, clinical (subjective global assessment), and densitometric (dual energy x-ray absorptiometry) markers of nutritional status and mineral and bone metabolism were measured in a cohort of 365 Swedish clinically stable CKD stage 5 patients (median age of 53 years) initiating dialysis between 1994 and 2009; in 207 patients, measurements were also taken after 1 year of dialysis. Deaths were registered during a median follow-up of 5 years. Associations of mortality with baseline IGF-1 and changes of IGF-1 after 1 year of dialysis were evaluated by Cox models. <h3>Results</h3> At baseline, IGF-1 concentrations associated negatively with age, diabetes mellitus, cardiovascular disease, poor nutritional status, IL-6, and osteoprotegerin and positively with body fat mass, bone mineral density, serum phosphate, calcium, and fibroblast growth factor-23. At 1 year, IGF-1 had increased by 33%. In multivariate regression, low age, diabetes mellitus, and high serum phosphate and calcium associated with IGF-1 at baseline, and in a mixed model, these factors, together with high fat body mass, associated with changes of IGF-1 during the first 1 year of dialysis. Adjusting for calendar year of inclusion, age, sex, diabetes mellitus, cardiovascular disease, IL-6, and poor nutritional status, a 1 SD higher level of IGF-1 at baseline associated with lower mortality risk (hazard ratio, 0.57; 95% confidence interval, 0.32 to 0.98). Persistently low or decreasing IGF-1 levels during the first 1 year on dialysis predicted worse survival (adjusted hazard ratio, 2.19; 95% confidence interval, 1.06 to 4.50). <h3>Conclusion</h3> In incident dialysis patients, low serum IGF-1 associates with body composition and markers of mineral and bone metabolism, and it predicts increased mortality risk.