Orphanic hereditary hypophosphatemic rachit with hypercalciuria, nephrocalcinosis on account of mutation gene SLC34A3(Review and case report)

Orphan Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) (OMIM: 241530; ORPHA: 157215) with an autosomal recessive mode of inheritance occurs with an estimated prevalence of 1: 250,000 in the child population. HHRH was first described by M. Tieder, et al. (1985). The syndrome is caused by heterozygous or homozygous mutations in the SLC34A3 gene mapped to chromosome 9q34.3, which encodes a type II sodium phosphate cotransporter (NaPiIIc). Mutations result in loss of NaPi-IIc function and impairment of phosphate reabsorption in the proximal renal nephron. HHRH is characterized by a decrease in phosphate reabsorption in the proximal nephron tubules, manifested by hyperphosphaturia, hypercalciuria, hypophosphatemia, an increase in the concentration of 1,25(OH) 2D3, a decrease in parathyroid hormone (PTH) circulating in the blood, osteomalacia, inhibition of growth, low corrosiveness, low corrosiveness. The article presents the characteristics of the phenotype and genotype of HHRH, diagnostic criteria and treatment strategy. A description of a clinical case of HHRH with hypercalciuria, nephrocalcinosis and urolithiasis due to mutation of the SLC34A3gene is presented.

Contribution of Bone Tissue to Regulation of Calcium and Phosphate Metabolism. Role of FGF23 and Klotho Protein

Bone tissue actively contributes to the regulation of systemic homoeostasis, and particularly the maintenance of calcium-phosphate balance. The parathyroid hormone-vitamin D feedback axis is balanced by the recently discovered bone-FGF23-kidney hormonal axis. An active complex consisting of FGF23, a receptor and Klotho protein blocks phosphate reabsorption in the proximal tubules, increasing urine phosphate levels and decreasing blood phosphate levels. Mutations of the gene mediating FGF23 transcription lead to a number of diseases, examples including autosomal dominant hypophosphataemic rickets. Klotho protein is a cofactor for FGF23 displaying cardio-, vaso- and nephroprotective activity. It increases calcium reabsorption in the kidneys and inhibits phosphate reabsorption. It also exerts antioxidative and anti-insulin effects and inhibits tissue calcification and apoptosis. As an inhibitor of bone resorption, osteoprotegerin becomes an important contributor to bone remodelling, while RANK/RANKL signalling inhibition is used in the treatment of postmenopausal osteoporosis. Osteocalcin plays an important role in energy metabolism in the human body. Sclerostin exerts a strong catabolic effect on bone tissue. Newly identified contributors to the regulation of calcium and phosphate homoeostasis suggest that bone tissue plays a complex role in the systemic metabolism.

P41 Searching high and low for a cause of transient migratory bone oedema: fibroblast growth factor-23 secreting mesenchymal tumour

Background Fibroblast Ggrowth factor-23 (FGF-23) is a phosphate regulator primarily expressed by osteocytes. Excess FGF-23 leads to decreased hydroxylation of 25-hydroxyvitamin D and poor renal phosphate reabsorption. This leads to hypophosphataemia and represents a rare cause of osteomalacia, resulting in bone oedema and stress fractures. Methods A 57-year-old man with known skin psoriasis presented with a two-year history of left foot and ankle pain. On examination, he had chronic dactylitis of the left, big toe associated with skin psoriasis and nail pitting. Serum inflammatory markers were normal, and autoimmune screens for RF, anti-CCP and HLA-B27 were negative. Bilateral foot and ankle X-rays showed no bony abnormality. This was diagnosed as likely psoriatic arthritis and MRI showed talar bone oedema, felt to be related to the inflammatory arthritis. Symptoms settled well on non-steroidal anti-inflammatories. However, he presented two months later with focal distal tibial pain and swelling. There was no history of trauma. Repeat MRI showed proximal migration of bone oedema with stress fractures of the left posterior talus and distal tibial metaphysis. Results Blood tests showed low phosphate, elevated PTH, normal adjusted calcium, raised ALP and low 25-hydroxyvitamin D. DEXA scan confirmed osteoporosis of the hip. The patient was commenced on intravenous three-monthly pamidronate and colecalciferol (vitamin D3) supplements. Despite this, the patient continued to have migratory joint pain affecting the ankle, hip and sacroiliac joints. Methotrexate was prescribed to improve his psoriasis, but whilst his skin improved his legs remained painful. A repeat MRI showed new insufficiency fractures to the left talus and right neck of femur. Although taking colecalciferol supplementation, his serum phosphate remained low (0.5mmol/L). On further investigation, Myeloma screen and FDG PET were normal but he was noted to have an increased fractional urinary phosphate excretion indicating poor renal phosphate reabsorption. Serum FGF-23 assay was elevated at 131 mIU/L (normal <100mIU/L). The patient underwent 68-Gallium DOTATATE PET imaging, utilising a tracer specific for somatostatin receptors found on neuroendocrine tumours, which showed a T9 pedicle lesion. CT-guided biopsy confirmed a mesenchymal tumour as the cause of FGF-23 secretion, resulting in transient bone marrow oedema and insufficiency fractures. The patient has become asymptomatic on calcitriol (1,25-dihydroxyvitamin D) and phosphate supplementation, and is being considered for radiofrequency ablation therapy. Conclusion This case illustrates the need for thorough investigation of symptomatic, treatment-refractory hypophosphataemia. Although mild hypophosphatemia could indicate adult onset rickets, rarer causes such as FGF-23 secreting tumours should be considered. These tumours are notoriously difficult to locate; 68-Gallium DOTATATE PET may offer superior specificity to other imaging modalities, including FDG-PET, in detecting these mesenchymal tumours. FGF-23 decreases hydroxylation of vitamin D3 and renal phosphate reabsorption, and calcitriol alongside phosphate supplementation is advisable for symptomatic management until definitive treatment. Disclosures K. Fisher None. S. Melath None. S. Patel None.

1,25-Dihydroxyvitamin D Maintains Brush Border Membrane NaPi2a and Attenuates Phosphaturia in Hyp Mice

Phosphate homeostasis is critical for many cellular processes and is tightly regulated. The sodium-dependent phosphate cotransporter, NaPi2a, is the major regulator of urinary phosphate reabsorption in the renal proximal tubule. Its activity is dependent upon its brush border localization that is regulated by fibroblast growth factor 23 (FGF23) and PTH. High levels of FGF23, as are seen in the Hyp mouse model of human X-linked hypophosphatemia, lead to renal phosphate wasting. Long-term treatment of Hyp mice with 1,25-dihydroxyvitamin D (1,25D) or 1,25D analogues has been shown to improve renal phosphate wasting in the setting of increased FGF23 mRNA expression. Studies were undertaken to define the cellular and molecular basis for this apparent FGF23 resistance. 1,25D increased FGF23 protein levels in the cortical bone and circulation of Hyp mice but did not impair FGF23 cleavage. 1,25D attenuated urinary phosphate wasting as early as one hour postadministration, without suppressing FGF23 receptor/coreceptor expression. Although 1,25D treatment induced expression of early growth response 1, an early FGF23 responsive gene required for its phosphaturic effects, it paradoxically enhanced renal phosphate reabsorption and NaPi2a protein expression in renal brush border membranes (BBMs) within one hour. The Na-H+ exchange regulatory factor 1 (NHERF1) is a scaffolding protein thought to anchor NaPi2a to the BBM. Although 1,25D did not alter NHERF1 protein levels acutely, it enhanced NHERF1-NaPi2a interactions in Hyp mice. 1,25D also prevented the decrease in NHERF1/NaPi2a interactions in PTH-treated wild-type mice. Thus, these investigations identify a novel role for 1,25D in the hormonal regulation of renal phosphate handling.

Tubular maximum phosphate reabsorption capacity in living kidney donors is independently associated with one-year recipient GFR

The donor glomerular filtration rate (GFR) measured before kidney donation is a strong determinant of recipient graft outcome. No tubular function markers have been identified that can similarly be used in donors to predict recipient outcomes. In the present study we investigated whether the pre-donation tubular maximum reabsorption capacity of phosphate (TmP-GFR), which may be considered a functional tubular marker in healthy kidney donors, is associated with recipient GFR at 1 yr after transplantation, a key determinant of long-term outcome. We calculated the pre-donation TmP-GFR from serum and 24-h urine phosphate and creatinine levels in 165 kidney donors, and recipient 125I-iothalamate GFR and eGFR (CKD-EPI) at 12 mo after transplantation. Kidney donors were 51 ± 10 yr old, 47% were men, and mean GFR was 118 ± 26 ml/min. The donor TmP-GFR was associated with recipient GFR 12 mo after transplantation (GFR 6.0 ml/min lower per 1 mg/dl decrement of TmP-GFR), which persisted after multivariable adjustment for donor age, sex, pre-donation GFR, and blood pressure and other potential confounders. Results were highly similar when eGFR at 12 mo was taken as the outcome. Tubular damage markers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were low and not associated with recipient GFR. A lower donor TmP-GFR before donation, which may be considered to represent a functional measure of tubular phosphate reabsorption capacity, is independently associated with a lower recipient GFR 1 yr after transplantation. These data are the first to link donor tubular phosphate reabsorption with recipient GFR post-transplantation.

Differential Determinants of Tubular Phosphate Reabsorption: Insights on Renal Excretion of Phosphates in Kidney Disease

We assessed the tubular reabsorption of phosphate (TRP) and maximal renal threshold for phosphate reabsorption to glomerular filtration rate (TmPi/GFR) and their determinants in 64 stages 2–4 chronic kidney disease (CKD) patients in order to define the early changes in phosphate metabolism in CKD. In multivariable analysis, TmPi/GFR correlates were estimated GFR (eGFR), intact parathyroid hormone (iPTH), and hemoglobin (R2 = 0.417), while TRP correlates were eGFR, iPTH, 24-h phosphaturia, and calcitriol (R2 = 0.72). This suggests that TmPi/GFR and TRP, respectively, assess hemoglobin-phosphate and bowel-kidney phosphate regulation axis. Iron supplementation based on TmPi/GFR or earlier phosphate restriction based on TRP should be investigated in view of modifying clinical outcomes in CKD.

Parathyroid Hormone, Fibroblast Growth Factor 23, and Parameters of Phosphate Reabsorption

Background: The serum phosphorus concentration ([P]s) is the sum of EP/Ccr and TRP/Ccr, where Ccr is creatinine clearance and EP and TRP are rates of excretion and reabsorption of phosphate. In chronic kidney disease (CKD), parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) mediate reduction of TRP/Ccr, and [PTH] and [FGF23] are linear functions of EP/Ccr. If controls and patients with CKD are considered together, TRP/Ccr is a hyperbolic function of EP/Ccr. Given these observations, we hypothesized that hyperbolas would describe relationships of phosphate reabsorption to [PTH] and [FGF23]. Methods: We studied 30 patients and 28 controls with mean eGFR of 29.5 and 86.0 mL/min/1.73 m2, respectively. All analyses combined both subsets. We measured fasting [PTH] 1–84 and intact [FGF23], and determined contemporaneous EP/Ccr, TRP/Ccr, fractional excretion of phosphorus (FEP), and phosphate tubular maximum per volume of filtrate (TmP/GFR). We examined linear regressions of TRP/Ccr and TmP/GFR on 100/[PTH] and 100/[FGF23]; from linear equations we derived hyperbolic equations relating reabsorptive parameters to hormone concentrations. Results: TRP/Ccr and TmP/GFR were linear functions of 100/[PTH] and 100/[FGF23] and hyperbolic functions of [PTH] and [FGF23]. TRP/Ccr and TmP/GFR fell minimally over the ranges of EP/Ccr, [PTH], and [FGF23] seen in CKD. FEP rose with EP/Ccr despite stable phosphate reabsorption. Conclusions: Hyperbolas describe relationships of TRP/Ccr and TmP/GFR to [PTH] and [FGF23] if subjects with normal and reduced GFR are analyzed together. Although FEP rises with [PTH] and [FGF23] as GFR falls, the simultaneous increments do not signify hormonally mediated reductions in phosphate reabsorption.