Phosphorus metabolism disorders in erythrocytes and lymphocytes among patients with inflammatory breast cancer, infiltrative stomach and colorectal cancer.

Energy and plastic potential dysfunction of erythrocytes and lymphocytes among people with inflammatory breast cancer, infiltrative stomach cancer, and infiltrative colon cancer is characterized by a more aggressive clinical course and poor prognosis. We explored the features of energy metabolism and phosphorus metabolism disorders in the erythrocytes and lymphocytes of patients with inflammatory breast cancer, infiltrative stomach cancer, and infiltrative colon cancer as a predicting factor in the course of the disease. 49 people were examined; the 1st group had infiltrative stomach cancer (n=17); the 2nd group had infiltrative colon cancer (n=11); the 3rd group had inflammatory breast cancer (n=21). Glycerol-3-phosphate dehydrogenase activity was 1.8 times reduced (p≤0.005), and the activity of glyceraldehyde-3-phosphate dehydrogenase in erythrocytes of patients with cancer at the main localization increased 2.5 times, compared with normal. Inflammatory breast cancer patients had a statistically significant decrease (p<0.005) in erythrocytes adenosine triphosphate content by an average of 56.5% compared with the normal ratio, and in cases of patients with gastric and colorectal cancer, a decrease of 67%. Excessive use of phosphorus for energy metabolism and adenosine triphosphate production destroys the balance of energetic and plastic potentials of erythrocytes and lymphocytes in inflammatory breast cancer, infiltrative stomach, and infiltrative colorectal cancers patients.

The Molecular Basis of Calcium and Phosphorus Inherited Metabolic Disorders.

Calcium (Ca) and Phosphorus (P) hold a leading part in many skeletal and extra-skeletal biological processes. Their tight normal range in serum mirrors their critical role in human well-being. The signalling "voyage" starts at Calcium Sensing Receptor (CaSR) localized on the surface of the parathyroid glands, which captures the "oscillations" of extracellular ionized Ca and transfers the signal downstream. Parathyroid hormone (PTH), Vitamin D, Fibroblast Growth Factor (FGF23) and other receptors or ion-transporters, work synergistically and establish a highly regulated signalling circuit between the bone, kidneys, and intestine to ensure the maintenance of Ca and P homeostasis. Any deviation from this well-orchestrated scheme may result in mild or severe pathologies expressed by biochemical and/or clinical features. Inherited disorders of Ca and P metabolism are rare. However, delayed diagnosis or misdiagnosis may cost patient's quality of life or even life expectancy. Unravelling the thread of the molecular pathways involving Ca and P signaling, we can better understand the link between genetic alterations and biochemical and/or clinical phenotypes and help in diagnosis and early therapeutic intervention.

PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development.

Recessive mutations in Post-GPI attachment to proteins 3 (PGAP3) cause the rare neurological disorder hyperphosphatasia with mental retardation syndrome 4 type (HPMRS4). Here, we report a novel homozygous nonsense mutation in PGAP3 (c.265C>T-p.Gln89*), in a 3-year-old boy with unique novel clinical features. These include decreased intrauterine fetal movements, dysgenesis of the corpus callosum, olfactory bulb agenesis, dysmorphic features, cleft palate, left ear constriction, global developmental delay, and hypotonia. The zebrafish functional modeling of PGAP3 loss resulted in HPMRS4-like features, including structural brain abnormalities, dysmorphic cranial and facial features, hypotonia, and seizure-like behavior. Remarkably, morphants displayed defective neural tube formation during the early stages of nervous system development, affecting brain morphogenesis. The significant aberrant midbrain and hindbrain formation demonstrated by separation of the left and right tectal ventricles, defects in the cerebellar corpus, and caudal hindbrain formation disrupted oligodendrocytes expression leading to shorter motor neurons axons. Assessment of zebrafish neuromuscular responses revealed epileptic-like movements at early development, followed by seizure-like behavior, loss of touch response, and hypotonia, mimicking the clinical phenotype human patients. Altogether, we report a novel pathogenic PGAP3 variant associated with unique phenotypic hallmarks, which may be related to the gene's novel role in brain morphogenesis and neuronal wiring.

Phosphate homeostasis disorders.

Our understanding of the regulation of phosphate balance has benefited tremendously from the molecular identification and characterization of genetic defects leading to a number of rare inherited or acquired disorders affecting phosphate homeostasis. The identification of the key phosphate-regulating hormone, fibroblast growth factor 23 (FGF23), as well as other molecules that control its production, such as the glycosyltransferase GALNT3, the endopeptidase PHEX, and the matrix protein DMP1, and molecules that function as downstream effectors of FGF23 such as the longevity factor Klotho and the phosphate transporters NPT2a and NPT2c, has permitted us to understand the complex interplay that exists between the kidneys, bone, parathyroid, and gut. Such insights from genetic disorders have allowed not only the design of potent targeted treatment of FGF23-dependent hypophosphatemic conditions, but also provide clinically relevant observations related to the dysregulation of mineral ion homeostasis in health and disease.

Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis.

BACKGROUND: Glycosylphosphatidylinositol biosynthesis defects (GPIBDs) cause a group of phenotypically overlapping recessive syndromes with intellectual disability, for which pathogenic mutations have been described in 16 genes of the corresponding molecular pathway. An elevated serum activity of alkaline phosphatase (AP), a GPI-linked enzyme, has been used to assign GPIBDs to the phenotypic series of hyperphosphatasia with mental retardation syndrome (HPMRS) and to distinguish them from another subset of GPIBDs, termed multiple congenital anomalies hypotonia seizures syndrome (MCAHS). However, the increasing number of individuals with a GPIBD shows that hyperphosphatasia is a variable feature that is not ideal for a clinical classification. METHODS: We studied the discriminatory power of multiple GPI-linked substrates that were assessed by flow cytometry in blood cells and fibroblasts of 39 and 14 individuals with a GPIBD, respectively. On the phenotypic level, we evaluated the frequency of occurrence of clinical symptoms and analyzed the performance of computer-assisted image analysis of the facial gestalt in 91 individuals. RESULTS: We found that certain malformations such as Morbus Hirschsprung and diaphragmatic defects are more likely to be associated with particular gene defects (PIGV, PGAP3, PIGN). However, especially at the severe end of the clinical spectrum of HPMRS, there is a high phenotypic overlap with MCAHS. Elevation of AP has also been documented in some of the individuals with MCAHS, namely those with PIGA mutations. Although the impairment of GPI-linked substrates is supposed to play the key role in the pathophysiology of GPIBDs, we could not observe gene-specific profiles for flow cytometric markers or a correlation between their cell surface levels and the severity of the phenotype. In contrast, it was facial recognition software that achieved the highest accuracy in predicting the disease-causing gene in a GPIBD. CONCLUSIONS: Due to the overlapping clinical spectrum of both HPMRS and MCAHS in the majority of affected individuals, the elevation of AP and the reduced surface levels of GPI-linked markers in both groups, a common classification as GPIBDs is recommended. The effectiveness of computer-assisted gestalt analysis for the correct gene inference in a GPIBD and probably beyond is remarkable and illustrates how the information contained in human faces is pivotal in the delineation of genetic entities.

Trafficking and Membrane Organization of GPI-Anchored Proteins in Health and Diseases.

Glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs) are a class of lipid-anchored proteins attached to the membranes by a glycolipid anchor that is added, as posttranslation modification, in the endoplasmic reticulum. GPI-APs are expressed at the cell surface of eukaryotes where they play diverse vital functions. Like all plasma membrane proteins, GPI-APs must be correctly sorted along the different steps of the secretory pathway to their final destination. The presence of both a glycolipid anchor and a protein portion confers special trafficking features to GPI-APs. Here, we discuss the recent advances in the field of GPI-AP trafficking, focusing on the mechanisms regulating their biosynthetic pathway and plasma membrane organization. We also discuss how alterations of these mechanisms can result in different diseases. Finally, we will examine the strict relationship between the trafficking and function of GPI-APs in epithelial cells.

[Inherited GPI deficiencies:a new disease with intellectual disability and epilepsy].

Glycosylphosphatidylinositol (GPI) is a glycolipid, which anchors 150 or more types of proteins to the cell surface. There are at least 26 genes involved in the biosynthesis and transport of GPI-anchored proteins (GPI-APs). Many inherited GPI deficiencies (IGDs) have been recently found using whole-exome sequencing. Patients with IGD have only a partial deficiency because complete GPI deficiency causes embryonic death. The major symptoms of IGDs include intellectual disability, epilepsy, coarse facial features, and multiple organ anomalies. These symptoms vary in severity depending upon the degree of the defect and/or position in the pathway of the affected gene. We clarified a mechanism of hyperphosphatasia, which is characterized by elevated release of tissue-nonspecific alkaline phosphatase. Hyperphosphatasia is observed in some patients with IGDs, such as hyperphosphatasia mental retardation syndrome or Mabry syndrome, caused by mutations in genes in the later stage of GPI biosynthesis. The possibility of IGD should be considered in patients with seizures and intellectual disability. The presence of hyperphosphatasia is strong evidence of IGD. Flow cytometric analysis of GPI-APs on granulocytes is also useful for the detection of IGD.

Treatment of phosphorus balance disorders.

Phosphorus (P) homeostasis in ruminants has received increased attention over the past decades. Although environmental concerns associated with excessive P excretion in cattle manure have led to incentives to lower dietary P intake, hypophosphatemia-particularly in the periparturient dairy cow-has been associated with conditions, such as the downer cow syndrome or postparturient hemoglobinuria. The objective of this article is to revisit current understanding of P homeostasis in ruminants, to discuss the pathophysiology and clinical presentation of P balance disorders, and to review different treatment approaches to correct imbalances of the body's P equilibrium.

Phosphorus metabolic disorder of Guizhou semi-fine wool sheep.

Guizhou semi-fine wool sheep are affected by a disease, characterized by emaciation, lameness, stiffness in the gait, enlargement of the costochondral junctions, and abnormal curvature in the long bones. The objective of this study was to determine possible relationships between the disease and mineral deficiencies. Samples of tissue and blood were collected from affected and unaffected sheep. Samples of soil and forage were collected from affected and unaffected areas. The samples were used for biochemical analyses and mineral nutrient measurements. Results showed that phosphorus (P) concentrations in forage samples from affected areas were significantly lower than those from unaffected areas (P < 0.01) and the mean ratio of calcium (Ca) to P in the affected forage was 12:1. Meanwhile, P concentrations of blood, bone, tooth, and wool from the affected sheep were also significantly lower than those from the unaffected group (P < 0.01). Serum P levels of the affected animals were much lower than those of the unaffected ones, whereas serum alkaline phosphatase levels from the affected were significantly higher than those from the unaffected (P < 0.01). Inorganic P levels of the affected sheep were about half of those in the control group. Oral administration of disodium hydrogen phosphate prevented and cured the disease. The study clearly demonstrated that the disease of Guizhou semi-fine wool sheep was mainly caused by the P deficiency in forage, as a result of fenced pasture and animal habitat fragmentation.

Clinical assessment of phosphorus status, balance and renal handling in normal individuals and in patients with chronic kidney disease.

PURPOSE OF REVIEW: The concepts of steady state, external balance, total body status and internal distribution are not always appreciated or even considered in clinical practice. The current tests available for clinical assessment of phosphorus physiology and pathophysiology are valid in some aspects, but also have many limitations. The purpose of this review is to clarify the above concepts and discuss the utility of the currently available tests to assess phosphorus disorders. RECENT FINDINGS: Both epidemiologic and preclinical data have shown that disturbances in mineral metabolism contribute significantly to the morbidity and mortality in chronic kidney disease. There are also emerging data supporting the notion that phosphotoxicity may exist even in individuals with normal renal function. In chronic kidney disease (CKD), hyperphosphatemia is a relative late event and is a suboptimal indicator of phosphorus balance and status. The judicious use of plasma and urine chemistry and hormonal biomarkers such as fibroblast growth factor 23 should be considered. SUMMARY: There is a dire need to increase awareness of what physiologic parameters should be monitored in terms of phosphorus pathophysiology. Although the current available tests in the clinical armamentarium are not ideal, understanding their implications and limitations will improve patient care and motivate practitioners and investigators to develop better tests.

Management of natural and added dietary phosphorus burden in kidney disease.

Phosphorus retention occurs from higher dietary phosphorus intake relative to its renal excretion or dialysis removal. In the gastrointestinal tract the naturally existing organic phosphorus is only partially (∼60%) absorbable; however, this absorption varies widely and is lower for plant-based phosphorus including phytate (<40%) and higher for foods enhanced with inorganic phosphorus-containing preservatives (>80%). The latter phosphorus often remains unrecognized by patients and health care professionals, even though it is widely used in contemporary diets, in particular, low-cost foods. In a nonenhanced mixed diet, digestible phosphorus correlates closely with total protein content, making protein-rich foods a main source of natural phosphorus. Phosphorus burden is limited more appropriately in predialysis patients who are on a low-protein diet (∼0.6 g/kg/d), whereas dialysis patients who require higher protein intake (∼1.2 g/kg/d) are subject to a higher dietary phosphorus load. An effective and patient-friendly approach to reduce phosphorus intake without depriving patients of adequate proteins is to educate patients to avoid foods with high phosphorus relative to protein such as egg yolk and those with high amounts of phosphorus-based preservatives such as certain soft drinks and enhanced cheese and meat. Phosphorus rich foods should be prepared by boiling, which reduces phosphorus as well as sodium and potassium content, or by other types of cooking-induced demineralization. The dose of phosphorus-binding therapy should be adjusted separately for the amount and absorbability of phosphorus in each meal. Dietician counseling to address the emerging aspects of dietary phosphorus management is instrumental for achieving a reduction of phosphorus load.

FGF-23: the rise of a novel cardiovascular risk marker in CKD.

Elevated plasma levels of the phosphaturic hormone fibroblast growth factor 23 (FGF-23) are a hallmark of chronic kidney disease (CKD)-mineral and bone disorder. FGF-23 allows serum phosphate levels within physiological limits to be maintained in progressive CKD until end-stage renal disease is reached. Despite its seemingly beneficial role in phosphate homeostasis, several prospective studies in dialysis patients and in patients with less advanced CKD associated elevated FGF-23 with poor cardiovascular and renal outcome. Moreover, very recent evidence suggests an adverse prognostic impact of elevated FGF-23 even in subjects without manifest CKD. These epidemiological data are supplemented by laboratory findings that reveal a pathophysiological role of FGF-23 in the pathogenesis of myocardial injury. In aggregate, these clinical and experimental data identify FGF-23 as a promising target of novel therapeutic interventions in CKD and beyond, which should be tested in future clinical trials.

Clinical practice. Fibroblast growth factor (FGF)23: a new hormone.

Until a decade ago, two main hormones were recognized as directly affecting phosphate homeostasis and, with that, bone metabolism: parathyroid hormone and 1,25(OH)(2) vitamin D (calcitriol). It was only a decade ago that the third major player hormone was found, linking gut, bone, and kidney. The physiologic role of fibrinogen growth factor (FGF)23 is to maintain serum phosphate concentration within a narrow range. Secreted from osteocytes, it modulates kidney handling of phosphate reabsorption and calcitriol production. Genetic and acquired abnormalities in FGF23 structure and metabolism cause conditions of either hyper-FGF23-manifested by hypophosphatemia, low serum calcitriol, and rickets/osteomalacia-or hypo-FGF23, expressed by hyperphosphatemia, high serum calcitriol, and extra-skeletal calcifications. In patients with chronic renal failure, FGF23 levels increase as kidney functions deteriorate and are under investigation to learn if the hormone actually participates in the pathophysiology of the deranged bone and mineral metabolism typical for these patients and, if so, whether it might serve as a therapeutic target. This review addresses the physiology and pathophysiology of FGF23 and its clinical applications.

Disturbance of inorganic phosphate metabolism in diabetes mellitus: its impact on the development of diabetic late complications.

The pathogenesis of diabetic late complications (DLC) is multifactorial. Studies of mechanisms leading to early functional microvascular changes in retina and kidneys point towards a disturbance in the metabolism of inorganic phosphate (Pi) in diabetes. Since tissue hypoxia and reduced high energy phosphates may be important factors in the development of DLC, the influence of Pi concentration on the metabolism and function of the erythrocytes and renal tubular cells, as well as the relationship of the concentration of Pi to total oxygen consumption, have been reviewed. While extensive research data in non-diabetic conditions support the suggestion, that the Pi concentration is a determining factor in regulation of metabolism and rate of oxygen consumption, diabetes shows the opposite behavior. In diabetes, the highest oxygen consumption is associated with the lowest concentration of Pi. Many conventionally-treated juvenile diabetic patients respond as if their tissues were in a state of chronic hypoxia. A disturbance in phosphate handling occurs in the kidney tubules, where the excessive sodium-dependent glucose entry in diabetics depolarizes the electrochemical sodium gradient and consequently impairs inorganic phosphate reabsorption. Similar changes may occur in other cells and tissues in which glucose entry is not controlled by insulin, and particularly in poorly-regulated diabetic patients in whom long-term vascular complications are more likely.

Phosphate binders in chronic kidney disease and end-stage renal disease: a patient-centered approach.

Disorders of calcium and phosphorus metabolism are associated with significant morbidity and mortality in patients with advanced chronic kidney disease. These patients typically require oral phosphate binders to maintain phosphorus homeostasis, but the choice of which among several agents to use has been actively investigated and debated. Recent debate has been polarized between those who favor calcium-based binders for their proven efficacy and relatively low cost and those who favor sevelamer for its putative beneficial effects on inflammatory biomarkers and vascular calcification. This review summarizes the current state of the art of prescribing phosphate binders, ranging from large-scale clinical trials to focused mechanistic studies, and proposes that the available evidence does not conclusively prove the relative superiority of any one binder.

Calcium and phosphate homeostasis: concerted interplay of new regulators.

Calcium (Ca(2+)) and phosphate (P(i)) are essential to many vital physiological processes. Consequently the maintenance of Ca(2+) and P(i) homeostasis is essential to a healthy existence. This occurs through the concerted action of intestinal, renal, and skeletal regulatory mechanisms. Ca(2+) and P(i) handling by these organs is under tight hormonal control. Disturbances in their homeostasis have been linked to pathophysiological disorders including chronic renal insufficiency, kidney stone formation, and bone abnormalities. Importantly, the kidneys fine-tune the amount of Ca(2+) and P(i) retained in the body by altering their (re)absorption from the glomerular filtrate. The ion transport proteins involved in this process have been studied extensively. Recently, new key players have been identified in the regulation of the Ca(2+) and P(i) balance. Novel regulatory mechanisms and their implications were introduced for the antiaging hormone klotho and fibroblast growth factor member 23 (FGF23). Importantly, transgenic mouse models, exhibiting disturbances in Ca(2+) and P(i) balance, have been of great value in the elucidation of klotho and FGF23 functioning. This review highlights the current knowledge and ongoing research into Ca(2+) and P(i) homeostasis, emphasizing findings from several relevant knockout mouse models.

Lanthanum carbonate--a first line phosphate binder?

Hyperphosphatemia is associated with increased morbidity and mortality in dialysis patients. Oral phosphate binders are necessary to control serum phosphate in patients eating a normal diet and undergoing peritoneal dialysis or thrice weekly hemodialysis. Until recently, none of the available drugs came close to the model of an ideal oral binder, which would demonstrate high affinity, rapid binding regardless of pH, low solubility and absorption, lack of toxicity, palatability, and reasonable cost. Lanthanum carbonate is a safe and effective binder with data demonstrating no toxic effects after continuous exposure up to 6 years. Suggestions that absorption and accumulation of lanthanum is significant and of clinical importance do not stand up to close scrutiny and recommended it as a first line treatment for dialysis patients, particularly if they have evidence of vascular calcification.