Effects Of Hyperphosphatemia Research Articles

Skeletal Muscle Injury in Chronic Kidney Disease-From Histologic Changes to Molecular Mechanisms and to Novel Therapies.

Chronic kidney disease (CKD) is associated with significant reductions in lean body mass and in the mass of various tissues, including skeletal muscle, which causes fatigue and contributes to high mortality rates. In CKD, the cellular protein turnover is imbalanced, with protein degradation outweighing protein synthesis, leading to a loss of protein and cell mass, which impairs tissue function. As CKD itself, skeletal muscle wasting, or sarcopenia, can have various origins and causes, and both CKD and sarcopenia share common risk factors, such as diabetes, obesity, and age. While these pathologies together with reduced physical performance and malnutrition contribute to muscle loss, they cannot explain all features of CKD-associated sarcopenia. Metabolic acidosis, systemic inflammation, insulin resistance and the accumulation of uremic toxins have been identified as additional factors that occur in CKD and that can contribute to sarcopenia. Here, we discuss the elevation of systemic phosphate levels, also called hyperphosphatemia, and the imbalance in the endocrine regulators of phosphate metabolism as another CKD-associated pathology that can directly and indirectly harm skeletal muscle tissue. To identify causes, affected cell types, and the mechanisms of sarcopenia and thereby novel targets for therapeutic interventions, it is important to first characterize the precise pathologic changes on molecular, cellular, and histologic levels, and to do so in CKD patients as well as in animal models of CKD, which we describe here in detail. We also discuss the currently known pathomechanisms and therapeutic approaches of CKD-associated sarcopenia, as well as the effects of hyperphosphatemia and the novel drug targets it could provide to protect skeletal muscle in CKD.

Contribution of phosphorus and PTH to the development of cardiac hypertrophy and fibrosis in an experimental model of chronic renal failure

Background and objectiveAdequate serum phosphorus levels in patients with chronic kidney disease is essential for their clinical management. However, the control of hyperphosphatemia is difficult because is normally associated with increases in serum PTH. In the present study, the effects of hyperphosphatemia, in the presence of elevated and normal PTH, on cardiac inflammation, hypertrophy and fibrosis in an experimental renal failure model were analyzed. Materials and methods4 groups of rats were formed. Two groups underwent total parathyroidectomy (PTx). Rats with Ca <7.5 mg/dL and PTH < 50 pg/mL underwent 7/8 nephrectomy (CRF) and a subcutaneous pellet was placed that releases PTH 1-34 (5 µg/kg/day). One group received a diet with normal P (NP) (CRF + PTx + rPTH + NP group) and another with a high P diet (0.9% - HP) (CRF + PTx + rPTH + HP group). Other 2 groups that only had CRF received NP (CRF + NP) and HP (CRF + HP) diet. A SHAM group for nephrectomy and parathyroidectomy was also added. After 14 weeks the rats were sacrificed. ResultsThe groups with a diet high in phosphorus (CRF + H A and CRF + PTx + rPTH + HP) had a significant reduction in creatinine clearance and also in body weight with an increase in serum phosphorus regardless of parathyroidectomy, but not serum levels of calcium, FGF23 and calcitriol that were 2–3 times higher in the group with secondary hyperparathyroidism (CRF + HP).The diameter of the cardiomyocytes was greater in the CRF + HP group, while parathyroidectomy (CRF + PTx + rPTH + HP) significantly reduced them, despite the high and similar serum phosphorus values. TNF-α, Adam17 and cardiac fibrosis at the histological and molecular level showed a similar pattern with increases in the group with severe secondary hyperparathyroidism (CRF + HP). ConclusionsHyperphosphatemia confirmed its importance in the genesis of secondary hyperparathyroidism, but also of kidney damage that was independent of PTH levels. However, inflammation, fibrosis, and cardiomyocyte growth were more closely related to PTH levels, since in the presence of similar severe hyperphosphatemia, parathyroidectomy reduced the values ​​of inflammatory parameters, cardiac hypertrophy, and fibrosis.

Effect of MgCl2 and GdCl3 on ORAI1 Expression and Store-Operated Ca2+ Entry in Megakaryocytes.

In chronic kidney disease, hyperphosphatemia upregulates the Ca2+ channel ORAI and its activating Ca2+ sensor STIM in megakaryocytes and platelets. ORAI1 and STIM1 accomplish store-operated Ca2+ entry (SOCE) and play a key role in platelet activation. Signaling linking phosphate to upregulation of ORAI1 and STIM1 includes transcription factor NFAT5 and serum and glucocorticoid-inducible kinase SGK1. In vascular smooth muscle cells, the effect of hyperphosphatemia on ORAI1/STIM1 expression and SOCE is suppressed by Mg2+ and the calcium-sensing receptor (CaSR) agonist Gd3+. The present study explored whether sustained exposure to Mg2+ or Gd3+ interferes with the phosphate-induced upregulation of NFAT5, SGK1, ORAI1,2,3, STIM1,2 and SOCE in megakaryocytes. To this end, human megakaryocytic Meg-01 cells were treated with 2 mM ß-glycerophosphate for 24 h in the absence and presence of either 1.5 mM MgCl2 or 50 µM GdCl3. Transcript levels were estimated utilizing q-RT-PCR, protein abundance by Western blotting, cytosolic Ca2+ concentration ([Ca2+]i) by Fura-2 fluorescence and SOCE from the increase in [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 µM). As a result, Mg2+ and Gd3+ upregulated CaSR and blunted or virtually abolished the phosphate-induced upregulation of NFAT5, SGK1, ORAI1,2,3, STIM1,2 and SOCE in megakaryocytes. In conclusion, Mg2+ and the CaSR agonist Gd3+ interfere with phosphate-induced dysregulation of [Ca2+]i in megakaryocytes.

Contribución de fósforo y PTH al desarrollo de hipertrofia y fibrosis cardíaca en un modelo experimental de insuficiencia renal crónica

Background and objectiveAdequate serum phosphorus levels in patients with chronic kidney disease is essential for their clinical management. However, the control of hyperphosphatemia is difficult because is normally associated with increases in serum PTH. In the present study, the effects of hyperphosphatemia, in the presence of elevated and normal PTH, on cardiac inflammation, hypertrophy and fibrosis in an experimental renal failure model were analyzed. Materials and methodsFour groups of rats were formed. Two groups underwent total parathyroidectomy (PTx). Rats with Ca < 7.5 mg/dL and PTH < 50 pg/mL underwent 7/8 nephrectomy (CRF) and a subcutaneous pellet was placed that releases PTH 1-34 (5 μg/kg/day). One group received a diet with normal P (NP) (CRF + PTx + rPTH + NP group) and another with a high P diet (0.9% HP) (CRF + PTx + rPTH + HP group). Other two groups that only had CRF received NP (CRF + NP) and HP (CRF + HP) diet. A SHAM group for nephrectomy and parathyroidectomy was also added. After 14 weeks the rats were sacrificed. ResultsThe groups with a diet high in phosphorus (CRF + H A and CRF + PTx + rPTH + HP) had a significant reduction in creatinine clearance and also in body weight with an increase in serum phosphorus regardless of parathyroidectomy, but not serum levels of calcium, FGF23 and calcitriol that were 2-3 times higher in the group with secondary hyperparathyroidism (CRF + HP).The diameter of the cardiomyocytes was greater in the CRF + HP group, while parathyroidectomy (CRF + PTx + rPTH + HP) significantly reduced them, despite the high and similar serum phosphorus values. TNF-α, Adam17 and cardiac fibrosis at the histological and molecular level showed a similar pattern with increases in the group with severe secondary hyperparathyroidism (CRF + HP). ConclusionsHyperphosphatemia confirmed its importance in the genesis of secondary hyperparathyroidism, but also of kidney damage that was independent of PTH levels. However, inflammation, fibrosis, and cardiomyocyte growth were more closely related to PTH levels, since in the presence of similar severe hyperphosphatemia, parathyroidectomy reduced the values of inflammatory parameters, cardiac hypertrophy, and fibrosis.

Effect of hyperphosphatemia on gene expression of the Na-Pi cotransporter in rats.

We investigated the effect of high phosphorus content on the sodium-phosphate cotransporter (NaPi-IIa and NaPi-IIl). Forty-eight Sprague-Dawley rats were divided into 3 groups: high-phosphorus group (HP) with fructose diphosphate sodium injection; self-manufactured low-phosphorus diet group (LP); and normal diet group (NP). At the 1st, 2nd, 4th, and 6th weeks, 4 rats from each group were sacrificed for detecting serum levels of calcium, phosphorus, and intact parathyroid hormone. Semi-quantitative retrovirus-polymerase chain reaction was used to detect the expression of NaPi-IIa and NaPi-III mRNA in kidney. At the 1st, 2nd, 4th, and 6th weeks, serum phosphorus and parathyroid hormone levels in HP group were significantly higher than those in LP and NP groups (P < 0.05). Serum calcium levels in the 3 groups showed no difference (P > 0.05). Comparing the expression of NaPi-IIa mRNA in HP group with LP and NP groups, NaPi-IIa mRNA expression was significantly reduced in HP group (P < 0.05), while NaPi-IIa mRNA expression in LP group began increasing at the 4th week (P < 0.05). At the 1st, 2nd, and 4th weeks, the expression of NaPi-III mRNA in HP, LP, and NP groups showed no clear differences (P > 0.05), while at the 6th week in HP group, NaPi-III mRNA expression was slightly increased compared to in LP and NP groups (P < 0.05). Hyperphosphatemia significantly affected NaPi-IIa and NaPi-III mRNA expression, and a factor promote an increase in intact parathyroid hormone independently of calcium.

Phosphates and Behavioral Abnormalities

In their review article, Ritz et al. described the consequences of hyperphosphatemia caused by phosphate additives in food with regard to increased renal and cardiovascular morbidity and mortality (1). I want to add that phosphates for some time have been suspected of being associated with behavioral abnormalities. The doctor and children’s book author Heinrich Hoffmann described in his character of Fidgety Philip not only a child in whom nowadays attention deficit hyperactivity disorder (ADHD) would be diagnosed, but he also adds that “a normal human being has only 1.5/1000 phosphorus in their brain”, and wonders if it should be investigated whether “any fellow who was happy as a lark did not carry two or three times of that amount in his head” (2). The association of phosphorus and behavioral abnormalities has been the subject of a controversial discussion ever since, and in ADHD, a low-phosphate diet has been recommended. However, only recently, several clinical studies have suggested an association between (organo-)phosphates and ADHD (3, 4). Bearing in mind the rising incidence of ADHD and increasing numbers of prescriptions for methylphenidate, it would be interesting to study the association between dietary components such as in fast food and processed food with a high phosphate content and a causal association with the development of ADHD.

What Can a Keto Acid/Amino Acid-Supplemented Protein-Restricted Diet Do for the “Butterfly Effect” in Chronic Kidney Disease Patients?

ACCORDING TO THE “butterfly effect” theory, a change in something apparently harmless, such as the flapping of a butterfly's wings, may cause unexpected larger changes in the future, such as a tornado. The transfer of this “butterfly effect” to chronic kidney disease (CKD) may be reasonable regarding the consequences of hyperphosphatemia on bone disease, cardiovascular disease, and mortality.

Hepatocellular transport and gastrointestinal absorption of lanthanum in chronic renal failure

Lanthanum carbonate is a new phosphate binder that is poorly absorbed from the gastrointestinal tract and eliminated largely by the liver. After oral treatment, we and others had noticed 2-3 fold higher lanthanum levels in the livers of rats with chronic renal failure compared to rats with normal renal function. Here we studied the kinetics and tissue distribution, absorption, and subcellular localization of lanthanum in the liver using transmission electron microscopy, electron energy loss spectrometry, and X-ray fluorescence. We found that in the liver lanthanum was located in lysosomes and in the biliary canal but not in any other cellular organelles. This suggests that lanthanum is transported and eliminated by the liver via a transcellular, endosomal-lysosomal-biliary canicular transport route. Feeding rats with chronic renal failure orally with lanthanum resulted in a doubling of the liver levels compared to rats with normal renal function, but the serum levels were similar in both animal groups. These levels plateaued after 6 weeks at a concentration below 3 microg/g in both groups. When lanthanum was administered intravenously, thereby bypassing the gastrointestinal tract-portal vein pathway, no difference in liver levels was found between rats with and without renal failure. This suggests that there is an increased gastrointestinal permeability or absorption of oral lanthanum in uremia. Lanthanum levels in the brain and heart fluctuated near its detection limit with long-term treatment (20 weeks) having no effect on organ weight, liver enzyme activities, or liver histology. We suggest that the kinetics of lanthanum in the liver are consistent with a transcellular transport pathway, with higher levels in the liver of uremic rats due to higher intestinal absorption.

Introduction

Introduction

Consequences of hyperphosphatemia in patients with end-stage renal disease (ESRD)

Hyperphosphatemia is invariably present among patients with end-stage renal disease (ESRD) and is becoming an increasingly important clinical entity. Despite concerted efforts by patients, dietitians, and nephrologists to control serum phosphorus, a recent study by Block et al found that more than 60% of patients on hemodialysis in the United States have serum phosphorus levels above the recommended goal of 5.5 mg/dL. Historically, nephrologists have been concerned about the central role of elevated serum phosphorus in the pathogenesis of secondary hyperparathyroidism and extraosseous calcification. However, the consequences of untreated hyperphosphatemia have assumed more importance in the last few years, largely due to recent clinical studies that revealed a more sinister role of elevated serum phosphorus in increasing the mortality risk among patients with ESRD. Hemodialysis patients with serum phosphorus greater than 6.5 mg/dL were reported to have a 27% higher mortality risk than patients with serum phosphorus between 2.4 and 6.5 mg/dL. The pathophysiologic mechanisms by which persistent hyperphosphatemia enhances the mortality risk in dialysis patients are not yet completely understood. However, given that inadequate control of serum phosphorus contributes to elevated calcium-phosphorus product (Ca x P), untreated hyperphosphatemia may play a key role in cardiovascular calcification. In response to these findings, the National Kidney Foundation Kidney Disease Outcome Quality Initiative (K/DOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease have recently recommended more stringent levels for controlling serum phosphorus and Ca x P product in order to improve patients' quality of life and longevity.

Patient Education and Its Effects on Calcium-Phosphate Balance in Hemodialysis Patients

Calcium-phosphate imbalance is common in hemodialysis patients and is an important cause of increased morbidity and mortality. The objective of this study is to determine the effectiveness of patient education in improving calcium-phosphate balance. This is a cross-sectional cohort study with a control group. Hemodialysis patients at 2 centers with serum phosphate levels ≥ 4.5 mg/dL and a Ca × P product > 55 mg2/dl2 were enrolled into the study. The patients were interviewed to determine their knowledge of phosphate binders, compliance and dietary restrictions. Formal counseling was provided to ensure that the patients were aware of the importance of taking their phosphate binders regularly and the adverse consequences of hyperphosphatemia. At the end of 3 months, the patients’ serum calcium and phosphate levels and CaxP product were measured. In the control arm, no formal counseling was done. 31 patients were enrolled in the study arm and 30 patients were controls. At the start of the study, 39% of patients in the study group were incompliant with their phosphate binders. After counseling, there was a significant decrease in the serum phosphate level (8.6 ± 0.4 vs 7.4 ± 0.6 mg/dl, p < 0.05) and Ca × P product (83.6 ± 4.9 vs 68.9 ± 5.6 mg2/dl2, p < 0.01) of the patients at one month. At 3 months, the mean serum phosphate level and Ca × P product had returned to baseline levels. No significant changes were noted in the control arm. This study suggests that patient education on the use phosphate binders had a positive impact on hyperphosphatemia. However, the effect was lost after one month and continuing patient education may be needed to achieve a long-term result.

Hyperphosphatemia Modestly Retards Parathyroid Hormone Suppression during Calcitriol-Induced Hypercalcemia in Normal and Azotemic Rats

Background/Aims: In in vitro studies, a high phosphate concentration has been shown to directly stimulate parathyroid hormone (PTH) secretion in a normal calcium concentration and to reduce PTH suppression in a high calcium concentration. In hemodialysis patients during dialysis-induced hypercalcemia, the effect of hyperphosphatemia on PTH secretion was less than in vitro studies. Our goal was to determine whether hyperphosphatemia retards PTH suppression during calcitriol-induced hypercalcemia in azotemic rats with hyperparathyroidism. Methods: Rats underwent a two-stage 5/6 nephrectomy or sham operations. After surgery, rats received a high phosphate diet (P 1.2%, Ca 0.6%) for 4 weeks to induce hyperparathyroidism and then were placed on a normal diet (P 0.6%, Ca 0.6%) for two additional weeks to normalize serum calcium values in azotemic rats. At week 7, rats were divided into five groups and before sacrifice received at 24-hour intervals, three doses of calcitriol (CTR) or its vehicle. The five groups and dietary phosphate content were: group 1 – normal renal function (NRF) + 0.6% P + vehicle; group 2 – NRF + 0.6% P + CTR; group 3 – renal failure (RF) + 0.6% P + vehicle; group 4 – RF + 1.2% P + CTR; and group 5 – RF + 0.6% P + CTR. Results: In the two CTR-treated groups with marked hypercalcemia (groups 2 and 5), 15.52 ± 0.26 and 15.12 ± 0.13 mg/dl, respectively, stepwise regression showed that hyperphosphatemia retarded PTH suppression. When the two azotemic groups treated with CTR (groups 4 and 5) were combined to expand the range of serum calcium values, stepwise regression showed that hypercalcemia suppressed and hyperphosphatemia modestly retarded PTH suppression. Similarly, in groups 4 and 5 combined, correlations were present between PTH and both serum calcium (r = –0.70, p < 0.001) and serum phosphate (r = 0.64, p = 0.001). Conclusions: Hypercalcemia and high doses of calcitriol markedly reduced PTH secretion in azotemic rats despite severe hyperphosphatemia. Even though hyperphosphatemia did retard PTH suppression during hypercalcemia, its effect was small.

The role of hyperphosphatemia in the pathogenesis of secondary hyperparathyroidism

Renal phosphate handling plays key role in phosphate metabolism. Kidney dysfunction induced hyperphosphatemia. The phosphatemia with renal insufficiency, especially uremia, indirectly progresses into secondary hyperparathyroidism via suppression of vitamin D/Ca system. This indirect effect on parathyroid is called "Trade-off theory". Recently, the direct effect of hyperphosphatemia on parathyroid has been reported independent of vitamin D/Ca system in renal failure. The control of serum phosphate is certainly important by restriction of phosphate intake in renal failure patients.

Consequences of hyperphosphatemia and elevated levels of the calcium-phosphorus product in dialysis patients.

Control of serum phosphorus levels is a central goal in the management of patients with chronic renal failure. Inadequate control of serum phosphorus leads to elevated levels of the calcium-phosphorus product. This plays a pivotal role in vascular calcification, cardiovascular disease, calciphylaxis, and death. Elevated phosphorus and elevated levels of the calcium-phosphorus product are both significant predictors of cardiovascular mortality, at phosphorus and calcium-phosphorus product levels that were considered safe until recently. A lowering of levels such that phosphorus is maintained between 2.2 and 5.5 mg/dl, calcium-phosphorus product is below 55 mg(2)/dl(2), and serum calcium is at 9.2-9.6 mg/dl, respectively, might well be the goal of therapeutic management strategies.

Assessment of Hyperphosphatemia and Hypophosphatemia

Methodologic aspects including causes of factitious hyperphosphatemia and hypophosphatemia are summarized. The differential diagnosis of hyperphosphatemia is reviewed under its three broad causes: decreased glomerular filtration rate, increased exogenous or endogenous phosphate load, and increased renal tubular phosphate reabsorption. The differential diagnosis of hypophosphatemia is reviewed under its three broad causes: inadequate gastrointestinal input, excess phosphate losses, and transcellular shifts. The consequences of hyperphosphatemia and hypophosphatemia are outlined with a focus on pathophysiologic and clinicochemical sequelae. A laboratory perspective is emphasized in outlining management strategies.

Effects of hyperphosphatemia on diaphragmatic strength and endurance.

Effects of an infusion of Na2HPO4 on diaphragm strength, endurance, and magnitude of recovery were evaluated in in situ canine diaphragm strips. Results showed no effect on maximal isometric tetanic tension. Twitch tension and tension in the low- (10-Hz) frequency range were significantly increased (P less than 0.01). Time to fatigue (endurance) increased by 38 +/- 4.5% in the group that received phosphorus compared with its control and decreased by 18.5 +/- 2.5% in the group that received dextrose compared with its control (P less than 0.005). Recovery from fatigue was also significantly improved after the phosphorus infusion. Serum ATP and 2,3-diphosphoglycerate levels were unchanged throughout the experiment. The results of this study support the notion that hyperphosphatemia improves diaphragmatic endurance and recovery from fatigue. The mechanisms involved may in part be due to the phosphate-buffering effects, which limit the extent of the muscle intracellular acidosis produced with fatigue.

The interrelationship between phosphate and magnesium metabolism.

a) It appears that the interrelationship between phosphate and magnesium metabolism is complicated and the mechanisms involved are not fully understood, b) the interaction between the homeostasis of these two ions is species dependent and its full expression is most evident in the rat, c) body depletion of either of these ions may result in marked changes in the blood levels, intestinal absorption, renal handling and body content of the other, d) hypermagnesemia causes hyperphosphatemia and decreased urinary excretion of phosphate, and e) the effects of hyperphosphatemia on magnesium are not elucidated as yet.