Antenatal presentation and early postnatal treatment of infantile hypercalcemia type 2.

Infantile hypercalcemia (IH) is a rare genetic disorder characterized by hypercalcemia, hypercalciuria, low parathyroid hormone, and nephrocalcinosis during the first months of life. Biallelic variants in the genes CYP24A1 and SCL34A1 cause IH1 and 2, respectively. We present the case of a newborn with an antenatal diagnosis of IH2 due to the identification of echogenic, yet normal-sized kidneys at 23 weeks gestation. Trio whole-exome sequencing initially identified only a heterozygous pathogenic variant in SLC34A1. Re-analysis of the exome data because of the clinical suspicion of IH2 revealed a 21-basepair deletion in trans that had initially been filtered out because of its high allele frequency. The diagnosis of IH2 enabled postnatal screening for hypercalcemia, present already at week 1, resulting in early treatment with phosphate supplementation and vitamin D avoidance. In the subsequent course, biochemical parameters were normalized, and the patient showed no obvious clinical complications of IH2, apart from the nephrocalcinosis.

The Intricacies of Renal Phosphate Reabsorption-An Overview.

To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This amazing feat is accomplished through synchronised phosphate transport by myriads of ciliated cells lining the renal proximal tubules. These respond in real time to changes in phosphate and composition of the renal filtrate and to hormonal instructions. How they do this has stimulated decades of research. New analytical techniques, coupled with incredible advances in computer technology, have opened new avenues for investigation at a sub-cellular level. There has been a surge of research into different aspects of the process. These have verified long-held beliefs and are also dramatically extending our vision of the intense, integrated, intracellular activity which mediates phosphate absorption. Already, some have indicated new approaches for pharmacological intervention to regulate phosphate in common conditions, including chronic renal failure and osteoporosis, as well as rare inherited biochemical disorders. It is a rapidly evolving field. The aim here is to provide an overview of our current knowledge, to show where it is leading, and where there are uncertainties. Hopefully, this will raise questions and stimulate new ideas for further research.

Vitamin B12 deficiency-induced increase of osteoclastic bone resorption caused by abnormal renal resorption of inorganic phosphorus via Napi2a.

Vitamin B12 deficiency is a risk factor for bone disorders via mechanisms not fully understood. In this study, an increase in serum inorganic phosphorus (Pi) concentrations was associated with a vitamin B12 deficiency. Napi2a, a renal cotransporter for Pi reabsorption, accumulated on plasma membranes in a vitamin B12 deficiency suggests that vitamin B12 plays an important role in Pi homeostasis.

Corrigendum: Fucoidan ameliorates renal injury-related calcium-phosphorus metabolic disorder and bone abnormality in the CKD-MBD model rats by targeting FGF23-Klotho signaling axis.

[This corrects the article DOI: 10.3389/fphar.2020.586725.].

Clinical and Functional Assessment of Digenicity in Renal Phosphate Wasting.

Apart from increased fluid intake, patients with kidney stone disease (KSD) due to renal phosphate wasting require specific metaphylaxis. NaPi2a, NaPi2c, and NHERF1 regulate plasma phosphate concentration by reabsorbing phosphate in proximal kidney tubules and have been found altered in monogenic hypophosphatemia with a risk of KSD. In this study, we aimed at assessing the combined genetic alterations impacting NaPi2a, NaPi2c, and NHERF1. Therefore, we screened our hereditary KSD registry for cases of oligo- and digenicity, conducted reverse phenotyping, and undertook functional studies. As a result, we identified three patients from two families with digenic alterations in NaPi2a, NaPi2c, and NHERF1. In family 1, the index patient, who presented with severe renal calcifications and a bone mineralization disorder, carried digenic alterations affecting both NaPi transporter 2a and 2c. Functional analysis confirmed an additive genetic effect. In family 2, the index patient presented with kidney function decline, distinct musculature-related symptoms, and intracellular ATP depletion. Genetically, this individual was found to harbor variants in both NaPi2c and NHERF1 pointing towards genetic interaction. In summary, digenicity and gene dosage are likely to impact the severity of renal phosphate wasting and should be taken into account in terms of metaphylaxis through phosphate substitution.

Unusual presentation of a five-month-old boy with NaPi2a homozygous mutation without hyperphosphaturia: Case report and review of the literature.

Deletions of the NaPi2a gene and mutations in the SLC34A gene should be considered in patients with atypical presentation, without phosphaturia, with mild hypo to normal phosphatemia, and nephrocalcinosis.

Fucoidan Ameliorates Renal Injury-Related Calcium-Phosphorus Metabolic Disorder and Bone Abnormality in the CKD-MBD Model Rats by Targeting FGF23-Klotho Signaling Axis.

Background: Recently, chronic kidney disease (CKD)-mineral and bone disorder (MBD) has become one of common complications occurring in CKD patients. Therefore, development of a new treatment for CKD-MBD is very important in the clinic. In China, Fucoidan (FPS), a natural compound of Laminaria japonica has been frequently used to improve renal dysfunction in CKD. However, it remains elusive whether FPS can ameliorate CKD-MBD. FGF23-Klotho signaling axis is reported to be useful for regulating mineral and bone metabolic disorder in CKD-MBD. This study thereby aimed to clarify therapeutic effects of FPS in the CKD-MBD model rats and its underlying mechanisms in vivo and in vitro, compared to Calcitriol (CTR). Methods: All male rats were divided into four groups: Sham, CKD-MBD, FPS and CTR. The CKD-MBD rat models were induced by adenine administration and uninephrectomy, and received either FPS or CTR or vehicle after induction of renal injury for 21 days. The changes in parameters related to renal dysfunction and renal tubulointerstitial damage, calcium-phosphorus metabolic disorder and bone lesion were analyzed, respectively. Furthermore, at sacrifice, the kidneys and bone were isolated for histomorphometry, immunohistochemistry and Western blot. In vitro, the murine NRK-52E cells were used to investigate regulative actions of FPS or CTR on FGF23-Klotho signaling axis, ERK1/2-SGK1-NHERF-1-NaPi-2a pathway and Klotho deficiency. Results: Using the modified CKD-MBD rat model and the cultured NRK-52E cells, we indicated that FPS and CTR alleviated renal dysfunction and renal tubulointerstitial damage, improved calcium-phosphorus metabolic disorder and bone lesion, and regulated FGF23-Klotho signaling axis and ERK1/2-SGK1-NHERF-1-NaPi-2a pathway in the kidney. In addition, using the shRNA-Klotho plasmid-transfected cells, we also detected, FPS accurately activated ERK1/2-SGK1-NHERF-1-NaPi-2a pathway through Klotho loss reversal. Conclusion: In this study, we emphatically demonstrated that FPS, a natural anti-renal dysfunction drug, similar to CTR, improves renal injury-related calcium-phosphorus metabolic disorder and bone abnormality in the CKD-MBD model rats. More importantly, we firstly found that beneficial effects in vivo and in vitro of FPS on phosphorus reabsorption are closely associated with regulation of FGF23-Klotho signaling axis and ERK1/2-SGK1-NHERF-1-NaPi-2a pathway in the kidney. This study provided pharmacological evidences that FPS directly contributes to the treatment of CKD-MBD.

Phosphaturia in kidney stone formers: Still an enigma.

Calcium kidney stones are common worldwide. Most are idiopathic and composed of calcium oxalate. Calcium phosphate is present in around 80% and may initiate stone formation. Stone production is multifactorial with a polygenic genetic contribution. Phosphaturia is found frequently among stone formers but until recently received scant attention. This review examines possible mechanisms for the phosphaturia and its relevance to stone formation from a wide angle. There is a striking lack of clinical data. Phosphaturia is associated, but not correlated, with hypercalciuria, increased 1,25 dihydroxy-vitamin D [1,25 (OH)2D], and sometimes evidence of disturbances in proximal renal tubular function. Phosphate reabsorption in the proximal renal tubules requires tightly regulated interaction of many proteins. Paracellular flow through intercellular tight junctions is the major route of phosphate absorption from the intestine and can be reduced therapeutically in hyperphosphatemic patients. In monogenic defects stones develop when phosphaturia is associated with hypercalciuria, generally explained by increased 1,25 (OH)2D production in response to hypophosphatemia. Calcification does not occur in disorders with increased FGF23 when phosphaturia occurs in isolation and 1,25 (OH)2D is suppressed. Candidate gene studies have identified mutations in the phosphate transporters, but in few individuals. One genome-wide study identified a polymorphism of the phosphate transporter gene SLC34A4 associated with stones. Others did not find mutations obviously linked to phosphate reabsorption. Future genetic studies should have a wide trawl and should focus initially on groups of patients with clearly defined phenotypes. The global data should be pooled.