The case of oncogenic hypophosphatemic osteomalacia

Osteomalacia is a systemic bone disease, characterized by an excessive accumulation of non-mineralized osteoid and an imbalance in the organic matrix formation and mineralization. A rare cause of disease is tumor-induced osteomalacia, most often due to phosphaturic mesenchymal tumors (PMT). Usually there are benign small tumors, affecting the soft tissues and bones of any location. The basic pathogenesis of underlying oncogenic osteomalacia is a decreased renal tubular reabsorption of phosphate consequent to hyperproduction of fibroblast growth factor 23 in PMT. Clinical features are nonspecific, the average period from the symptoms onset to diagnosis reaches 3 years and at least 5 years before surgical treatment. Finding the tumour is crucial, as complete removal is curative. We present a clinical case of tumor-induced osteomalacia due to PMT required the complex differential diagnosis with other rare diseases.

Hypercalcemia in children

Hypercalcemia is a result of a wide range of hereditary and acquired conditions encountered by general physicians and pediatricians. Calcium participates in several key physiological functions, control of blood coagulation, bone calcification. Calcium homeostasis is tightly regulated by the interplay between absorption from the small intestine and renal tubular reabsorption, bone remodeling, and disposal through the gut and the kidney. These processes are regulated by local and circulating factors. The two main hormones influencing the homeostasis of calcium are PTH and calcitriol. Cancer-associated hypercalcemia and primary hyperparathyroidism are the most frequent causes of hypercalcemia in adults. In neonates and infants, one should look first at genetic and iatrogenic etiologies. The clinical manifestations of hypercalcemia in children are nonspecific due to damage to various organs and systems and depend on the degree of blood calcium level. Mild hypercalcemia is asymptomatic and often discovered during routine blood work. Moderate and severe hypercalcemia may cause cardiac arrhythmias, affect the nervous system. The differential diagnosis of the possible etiologies of hypercalcemia should start with the assessment of serum parathyroid hormone (PTH) concentration. The causes of hypercalcemia can be divided between PTH-mediated and non-PTH-mediated. Identification of the main causes of hypercalcemia contributes to the timely elimination of trigger factors, beginning of treatment, correction of nutrition and lifestyle. The article highlights physiological mechanisms of calcium homeostasis, clinical manifestations, diagnostic algorithms and treatment of hypercalcemia in children.

Disorders of phosphate metabolism

Phosphate in both inorganic and organic form is essential for several functions in the body. Plasma phosphate level is maintained by a complex interaction between intestinal absorption, renal tubular reabsorption, and the transcellular movement of phosphate between intracellular fluid and bone storage pools. This homeostasis is regulated by several hormones, principally the parathyroid hormone, 1,25-dihydroxyvitamin D and fibroblast growth factor 23. Abnormalities in phosphate regulation can lead to serious and fatal complications. In this review phosphate homeostasis and the aetiology, pathophysiology, clinical features, investigation and management of hypophosphataemia and hyperphosphataemia will be discussed.

Calcium and phosphorus metabolism and nutrition of poultry: are current diets formulated in excess?

Calcium (Ca) and phosphorus (P) are important nutrients in poultry diet formulations. In the present review, we discuss recent advances in our understanding of the metabolism of Ca and P in poultry. Recent data are provided in support of the proposition that current poultry diets are formulated in excess for Ca and P. The quantities of Ca and P available for metabolism reflect rates of intestinal absorption, bone accretion and resorption, glomerular filtration, renal tubular reabsorption, and intestinal endogenous losses. Ca and P homeostasis is largely under endocrine control. Parathyroid hormone and the hormonal form of vitamin D3 are the two hormones credited with this role. However, a novel hormonal axis involving Fibroblast Growth Factor 23 and Klotho has been recently delineated, which, in conjunction with parathyroid hormone and vitamin D3, tightly regulates Ca and P homeostasis. Recent studies have suggested that current commercial diets for both broilers and layers contain excess Ca and P, the content of which could be reduced without affecting production or bird welfare. The challenge in reducing Ca and P concentrations in poultry diets is the uncertainty about what concentrations of Ca and P can be fed without compromising bird welfare. This is because there are limited data on the available P and Ca concentrations in poultry feedstuffs determined biologically. This is further complicated by the need for agreement on evaluation systems for evaluation of Ca and P bioavailability. We conclude that direct ileal or pre-caecal digestible Ca and P values are preferred.

Abstract 050: mir-192-5p in the Kidney is Protective Against the Development of Hypertension

MicroRNAs (miRs) are short RNAs that primarily reduce protein abundance by base-paring with their target mRNA. The role of most miRs in the development of hypertension remains unknown. We performed a deep sequencing analysis of miR expression in human kidney biopsies with hypertensive nephrosclerosis or without any significant injury. miR-192-5p was one of the most abundant miRs detected and was down-regulated in hypertensive nephrosclerosis. Previous studies have shown that miR-192-5p targets the beta 1 subunit of Na/K-ATPase which drives renal tubular reabsorption. We hypothesized that miR-192-5p in the kidney protects against hypertension. We used the Dahl salt sensitive (SS) rat and a congenic rat SS.13BN26 (L26) with reduced salt sensitivity as well as Mir192 knockout mice (KO) to test this hypothesis. SS rats had a decreased level of abundance of miR-192-5p in the renal cortex compared to the L26 rats (n=9, p<0.05). The protein abundance of the beta 1 subunit of Na/K-ATPase was higher in the SS rat compared to the L26 rat (n= 3, p<0.05). Treatment with anti-miR-192-5p, delivered directly into the kidney through renal artery injection, in uninephrectomized L26 rats significantly exacerbated hypertension. Mean arterial blood pressure (MAP) of L26 rats treated with anti-miR-192-5p reached 151+/-5 mmHg at day 14 post anti-miR treatment and 4% NaCl (HS) diet, which was significantly higher than L26 rats treated with a control anti-miR and HS (135+/-5 mmHg, n=6 and 8, p<0.05). Tissues were collected in additional groups of rats at 9 days after anti-miR injection, which was just before MAP became significantly different between the two groups, for analysis of Na/K-ATPase activity. Na/K-ATPase activity was increased in the renal cortex of rats treated with anti-miR-192-5p compared to control anti-miR (9.8 +/-1.8μmole/min/μg vs 7.2+/-1.3μmole/min/μg, n=5 and 6, p<0.05). Furthermore, Mir192 KO mice treated with 1μg/Kg/min of Angiotensin II and HS for 14 days exhibited an increased MAP compared to wild-type (WT) mice (190+/-4 mmHg vs 167+/-12 mmHg; n= 3 WT and 5 KO, p<0.05). In conclusion, miR-192, particularly miR-192-5p in the kidney, confers significant protection against the development of hypertension.

Approach to the patient with hypo-/hyperphosphataemia

Phosphate is the most abundant anion in the human body and has an indispensable role in numerous biological functions, including energy metabolism, bone formation, signal transduction, and as a constituent of phospholipids and nucleic acids. Only 1% is in extracellular fluid, but serum phosphate (Pi) levels are subject to fine tuning involving several hormones modulating renal tubular reabsorption, intestinal absorption, and bone homeostasis to maintain a normal range from 0.81 to 1.45 mmol/L (2.5–4.5 mg/dL) in adulthood and higher levels during infancy and childhood. An approach to the diagnosis of low and high phosphate levels is described.

Paracellular calcium transport across renal and intestinal epithelia

Calcium (Ca2+) is a key constituent in a myriad of physiological processes from intracellular signalling to the mineralization of bone. As a consequence, Ca2+ is maintained within narrow limits when circulating in plasma. This is accomplished via regulated interplay between intestinal absorption, renal tubular reabsorption, and exchange with bone. Many studies have focused on the highly regulated active transcellular transport pathways for Ca2+ from the duodenum of the intestine and the distal nephron of the kidney. However, comparatively little work has examined the molecular constituents creating the paracellular shunt across intestinal and renal epithelium, the transport pathway responsible for the majority of transepithelial Ca2+ flux. More specifically, passive paracellular Ca2+ absorption occurs across the majority of the intestine in addition to the renal proximal tubule and thick ascending limb of Henle’s loop. Importantly, recent studies demonstrated that Ca2+ transport through the paracellular shunt is significantly regulated. Therefore, we have summarized the evidence for different modes of paracellular Ca2+ flux across renal and intestinal epithelia and highlighted recent molecular insights into both the mechanism of secondarily active paracellular Ca2+ movement and the identity of claudins that permit the passage of Ca2+ through the tight junction of these epithelia.

Successful Management of Repetitive Urinary Obstruction and Anuria Caused by Double J Stent Calculi Formation after Renal Transplantation

This report firstly describes an extremely rare case of repetitive double J stent calculi formation after renal transplantation caused by the antihyperparathyroidism (HPT) drug calcitriol. In 2012, a woman initially presented to our hospital for anuria with lower abdominal pain. She was diagnosed with allograft hydronephrosis and double J stents obstruction by calculi formation after transplantation and treated with triplicate stents replacements in another hospital without clinical manifestations improvements. Through detailed exploration of medical history, we conclude that the abnormal calculi formation is due to the calcitriol (1,25-dihydroxyvitamin D3) administration, a drug which can increase renal tubular reabsorption of calcium for treating posttransplant HPT bone disease. After discontinuing calcitriol, the patient was stone-free and had a good recovery without severe complications during the 9-month follow-up. Our novel findings may provide an important clue and approach to managing formidable repetitive double J stent calculi formation in the clinical trial.