Urinary Phosphate Excretion Research Articles

8810 Improvement in bone mineral density in tertiary hyperparathyroidism after renal transplant treated with parathyroidectomy

Abstract Disclosure: M. Zakher: None. 55 year old man with past medical history of end-stage renal disease (ESRD) and alcoholic cirrhosis who underwent simultaneous liver-kidney transplant (SLKT) seven months prior to presentation to endocrinology who was referred for management of hypophosphatemia as low as 1.0 mg/dl. Prior to the transplant, he had hyperphosphatemia and hyperparathyroidism with phosphate and parathyroid hormone (PTH) levels as high as 8.2 mg/dL and 682 pg/mL, respectively. PTH remained elevated at 244 pg/mL and vitamin D was 35 ng/mL the week of the initial endocrinology visit. Initial DXA scan six months after SLKT showed osteoporosis of the lumbar spine, total left proximal femur, and left femoral neck with T-scores of -3.4, -4.9, -5.6, respectively. Alendronate was started three weeks prior to the initial visit. Urine studies confirmed phosphate wasting with urinary phosphate excretion significantly higher than 100 mg/24h, FEPO4 greater than 70%, and TmP/GFR less than 2 mg/dL. Increased urinary excretion of phosphate was consistent with hyperparathyroidism. The extremely low urinary calcium in the setting of normocalcemia and the history of renal transplant suggested a tertiary hyperparathyroidism. Alendronate was discontinued eight months after the initial visit to reduce the risk of post-parathyroidectomy hypocalcemia and post-parathyroidectomy bone remodeling inhibition.One year after the initial visit, the patient had a bilateral neck exploration with total parathyroidectomy and auto transplantation of the parathyroid. Pathology showed hypercellular parathyroid tissue. He was hospitalized one week after surgery for symptomatic hypolcalcemia (calcium 5.8 mg/dL). He was taking one tablet of calcium carbonate three times daily at home instead of three tablets three times daily as prescribed. He was discharged on calcitriol 0.5 mcg once daily, magnesium oxide 800 mg twice daily, calcium carbonate 1 g three times daily, and cholecalciferol 5000 units once daily. He remained on these for eleven months as well as calcitriol for fifteen months with dose adjustments during visits. Calcitriol was discontinued when calcium was found to be 8.9 mg/dL and the patient was asymptomatic. Repeat DXA scan two years after the baseline DXA showed osteoporosis of the left femoral neck with a T score of -2.5. There was a tremendous improvement from the baseline DXA scan from +20% in the total lumbar spine to +170% in the left femoral neck. DXA scan four years after the baseline DXA scan showed osteopenia of the lumbar spine, total left proximal femur, and left femoral neck with T-scores of -1.7, -2.4, -1.9.This is a 55 year old man who underwent SLKT seven months prior to presentation to endocrinology who was referred for management of hypophosphatemia as low as 1.0 mg/dL found with tertiary hyperparathyroidism who underwent a parathyroidectomy that resulted in significant improvement in bone mineral density test. Presentation: 6/2/2024

7984 A Challenging Case Of Hyperphosphatemic Familial Tumoral Calcinosis

Abstract Disclosure: T.G. de Souza: None. T.J. Weber: None. Introduction: Hyperphosphatemic Familial Tumoral Calcinosis (hFTC) is a rare, autosomal recessive metabolic disorder characterized by elevated serum phosphate levels and the accumulation of calcium phosphate deposits in soft tissues. There are fewer that 150 genetically confirmed cases in the literature. There are no consensus guidelines; therapeutic approaches are guided by case reports or series. This case serves to heighten awareness of therapeutic strategies including global health considerations for the disabled adult with a rare bone disorder. Case: A 32-year-old African-American woman presented to establish care for hFTC, for which she takes ibuprofen for disabling bilateral hip pain. hFTC was diagnosed in early childhood and managed at a large children’s hospital. Therapeutic modalities relied on operative resection of skin lesions on eruption. She describes cosanguinous parentage, consignment to foster care as a child and homelessness as an adult. She has not had adult endocrine care for her hFTC. Her medical comorbidities include major depressive disorder, PTSD and suicide attempt. She reports one uncle with hFTC noting that his phenotype was not significantly disabling and apparent recession of his lesions with age. Her parents did not have symptoms of hFTC. Radiographically, she had amorphous calcium deposits over both hips (her primary sites of severe pain), upper back (site of painless spontaneous eruptions), and left elbow without pain or skin penetration, as well as hyperostosis of the ilium bilaterally. She noticed waxing and waning of her eruptions with her menstrual cycle, such that lesions worsen in the luteal phase. Megestrol acetate also induced new eruptions. Examination shows brown staining to all teeth with several missing teeth. She had a marked lower extremity limb length discrepancy with severe restriction of hip abduction. Blood chemistries were grossly normal, including renal function, calcium, uric acid and PTH. Serum phosphorous was elevated at 5.2 (2.3 - 4.5 mg/dL). CT showed bilateral nephrocalcinosis. We instituted treatment with a low phosphorous diet, sevelamer to reduce intestinal phosphate absorption and acetazolamide to increase urinary phosphate excretion. For her pain and functional disability, we recommended continued NSAIDs, physical therapy and social work consultation to facilitate continued access to care. Conclusions: This case uniquely describes hFTC symptom fluctuation with the menstrual cycle, worsening with increased progesterone, suggesting a possible role of gonadal hormones on FGF-23 biology. It also highlights the socioeconomic burdens that can accompany rare bone disease, which become more pronounced as the patient achieves adulthood. Successful transition of care from pediatric to adult endocrinologist, in addition to engaging multi-disciplinary support, is essential in optimizing life-long care in hFTC. Presentation: 6/1/2024

6970 Severe Symptomatic Hypophosphatemia After Intravenous Iron Therapy: An Under-recognized Adverse Reaction

Abstract Disclosure: A. Morvant: None. O. Olajide: None. Introduction: Iron deficiency is a common condition that is often treated with intravenous preparations of iron supplementation. It has been documented in the literature that ferric carboxymaltose is the form of intravenous iron supplementation that is associated with the highest incidence of hypophosphatemia, when compared to other formulations of intravenous iron therapy. This case highlights a severe case of hypophosphatemia after ferric carboxymaltose therapy that led to multiple hospitalizations and required several months of oral and intravenous phosphorus repletion. Clinical Case A 36-year-old woman presented to the ED with severe diffuse arthralgias, generalized muscle weakness, and fatigue. Laboratory analysis revealed the following: phosphorus 1.2 mg/dL (2.3-4.7 mg/dL), 25-hydroxyvitamin D 13 ng/mL (25-80 ng/mL), parathyroid hormone 220 pg/mL (16-77 pg/mL), and calcium 8.5 mg/dL (8.4-10.5 mg/dL). She was admitted and started on intravenous and oral phosphorus repletion as well as oral ergocalciferol. She was subsequently discharged home on oral phosphorus and ergocalciferol supplementation, with a phosphorus level of 1.8 mg/dL. She was readmitted one day later with persistent arthralgias, myalgias, and severe fatigue, and found to have a phosphorus level of 1.1 mg/dL. Additional laboratory studies revealed the following: FGF23 41 pg/mL (<59 pg/mL) and 24-hour urine phosphorus 2191 mg/24hr (400-1300 mg/24hr). The patient notably had a history of chronic severe iron deficiency anemia due to menorrhagia and had been treated with intravenous iron sucrose infusions 7 months prior to her presentation. Due to adverse reactions to iron sucrose, this was switched to ferric carboxymaltose, and she had received two doses; one month and two weeks prior to her initial presentation. She was treated again with intravenous and oral phosphorus repletion and ergocalciferol and discharged after two weeks on oral phosphorus and ergocalciferol as well as thrice-weekly intravenous phosphorus infusions in the outpatient setting. She continued intravenous phosphorus infusions for about three months, and this was subsequently discontinued without recurrent hypophosphatemia. She is currently on low doses of oral phosphorus with normophosphatemia. Conclusion: Intravenous ferric carboxymaltose therapy can lead to severe and long-lasting, treatment-resistant hypophosphatemia due to increased urinary phosphate excretion. An increased awareness about this is needed by clinicians in treating patients who receive ferric carboxymaltose and monitoring phosphorous levels is crucial.

Combination Oxylanthanum Carbonate and Tenapanor Lowers Urinary Phosphate Excretion in Rats

Combination Oxylanthanum Carbonate and Tenapanor Lowers Urinary Phosphate Excretion in Rats

Association of Urinary Phosphate Excretion and Osteoporosis in Patients with CKD: Result from KNOW-CKD

Association of Urinary Phosphate Excretion and Osteoporosis in Patients with CKD: Result from KNOW-CKD

Biology of bone mineralization and ectopic calcifications: the same actors for different plays

Bone has several crucial functions. It is essential for locomotion and allows our body to stand erect against gravity. A mismatch between the mechanical stresses applied to it and its mechanical resistance leads to fractures. Bone also has numerous endocrine functions. It acts as a reservoir for minerals such as calcium and phosphorus, making it the target of calciotropic hormones that mobilize these minerals, particularly calcium, according to the body's needs. Additionally, bone secretes hormones, notably fibroblast growth factor 23 (FGF23), which regulates urinary excretion of phosphate and the bioavailability of active vitamin D. Bone mineralization is the process that facilitates the organized deposition of minerals in the bone matrix, providing rigidity and appropriate mechanical resistance. This process is compromised in genetically related bone mineralization disorders, such as those causing hypophosphatemia or hypophosphatasia. Conversely, calcification can be pathological, affecting soft tissues like the blood vessels, as seen in generalized arterial calcification of infancy (GACI) or arterial calcification due to CD73 deficiency (ACDC). The aim of this article is to first present the composition and structure of the mineralized bone matrix, to review the current understanding of the molecular mechanisms of mineralization, and finally to discuss the conditions associated with ectopic calcification and the underlying mechanisms.

Absence of claudin-3 does not alter intestinal absorption of phosphate in mice

Intestinal absorption of phosphate is bimodal, consisting of a transcellular pathway and a poorly characterized paracellular mode, even though the latter one contributes to the bulk of absorption under normal dietary conditions. Claudin-3 (Cldn3), a tight junction protein present along the whole intestine in mice, has been proposed to tighten the paracellular pathway for phosphate. The aim of this work was to characterize the phosphate-related phenotype of Cldn3-deficient mice. Cldn3-deficient mice and wildtype littermates were fed standard diet or challenged for 3 days with high dietary phosphate. Feces, urine, blood, intestinal segments and kidneys were collected. Measurements included fecal, urinary, and plasma concentrations of phosphate and calcium, plasma levels of phosphate-regulating hormones, evaluation of trans- and paracellular phosphate transport across jejunum and ileum, and analysis of intestinal phosphate and calcium permeabilities. Fecal and urinary excretion of phosphate as well as its plasma concentration was similar in both genotypes, under standard and high-phosphate diet. However, Cldn3-deficient mice challenged with high dietary phosphate had a reduced urinary calcium excretion and increased plasma levels of calcitriol. Intact FGF23 concentration was also similar in both groups, regardless of the dietary conditions. We found no differences either in intestinal phosphate transport (trans- or paracellular) and phosphate and calcium permeabilities between genotypes. The intestinal expression of claudin-7 remained unaltered in Cldn3-deficient mice. Our data do not provide evidence for a decisive role of Cldn3 for intestinal phosphate absorption and phosphate homeostasis. In addition, our data suggest a novel role of Cldn3 in regulating calcitriol levels.

Phosphate as an adjunct to calcium in promoting coronary vascular calcification in chronic inflammatory states.

Bone releases calcium and phosphate in response to pro-inflammatory cytokine-mediated inflammation. The body develops impaired urinary excretion of phosphate with age and chronic inflammation given the reduction of the kidney protein Klotho, which is essential to phosphate excretion. Phosphate may also play a role in the development of the resistance of the parathyroid calcium-sensing receptor (CaSR) to circulating calcium thus contributing to calcium retention in the circulation. Phosphate can contribute to vascular smooth muscle dedifferentiation with manifestation of osteoblastogenesis and ultimately endovascular calcium phosphate precipitation. Thus phosphate, along with calcium, contributes to the calcification and inflammation of atherosclerotic plaques and the origin of these elements is likely the bone, which serves as storage for the majority of the body's supply of extracellular calcium and phosphate. Early cardiac evaluation of patients with chronic inflammation and attempts at up-regulating the parathyroid CaSR with calcimimetics or introducing earlier anti-resorptive treatment with bone active pharmacologic agents may serve to delay onset or reduce the quantity of atherosclerotic plaque calcification in these patients.

#1448 Regulation of renal phosphate excretion independent of FGF23 and PTH

Abstract Background and Aims The phosphaturic hormones fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) promote renal phosphate excretion through FGFR1/Klotho and PTH1R-mediated ERK1/2 activation, respectively, leading to inhibition of the sodium-phosphate cotransporters NPT2a (SLC34A1) and NPT2c (SLC34A3) in proximal tubule (PT) cells. In bone cells, high extracellular phosphate can directly activate ERK1/2 via the sodium-phosphate cotransporters PiT-1 (SLC20A1) and PiT-2 (SLC20A2). To date, it is unclear to what extent phosphate can also regulate its own excretion in the kidney independently of FGF23 and PTH. Method To further investigate the role of phosphate in the regulation of renal phosphate homeostasis, male C57BL/6 mice were placed on a 0.8% control phosphate diet (CPD) or a 2% high phosphate diet (HPD) for 6 months. After four months, one HPD group was additionally treated with a calcimimetic (etelcalcetide) to lower FGF23 and PTH. In vitro, PT cells were stimulated with phosphate, FGF23 or PTH ± the phosphate transporter inhibitor foscarnet. Results HPD resulted in increased plasma concentrations of FGF23 and PTH, which were associated with reduced tubular phosphate reabsorption and increased fractional phosphate excretion. RNAseq analyses from isolated PT cells showed a reduction of Fgfr1, Kl, Slc34a1 and Slc34a3 and an induction of Slc20a2 in the HPD group compared to CPD. qPCR and immunoblot analyses of whole kidney tissue confirmed the reduction of the FGF23 co-receptor Klotho in the HPD group, while Fgfr1 was not significantly altered. Protein expression of NPT2a was decreased in isolated brush border membrane vesicles from HPD-fed mice, and immunofluorescence staining showed internalization of NPT2a from the apical brush border membrane. Treatment with etelcalcetide resulted in a reduction of circulating FGF23 and PTH, whereas urinary phosphate excretion in HPD mice remained elevated. In cultured PT cells, high phosphate induced phosphorylation of ERK1/2 and mRNA expression of Slc20a2, while Slc34a1 was suppressed. Phosphate-mediated PiT-2/ERK1/2 activation could be blocked by simultaneous treatment with foscarnet. Conclusion Our data suggest that high phosphate leads to internalization of NPT2a via direct activation of the PiT-2/ERK1/2 signaling cascade, independent of FGF23 and PTH, resulting in increased renal phosphate excretion.

Phosphocalcic metabolism and its potential association with biomarkers of kidney disease in dogs with spontaneous hyperadrenocorticism

The pathogenesis of increased serum phosphate concentration and proteinuria in dogs with spontaneous hyperadrenocorticism (HAC) is unclear. A potential link between proteinuria and calcium/phosphate metabolism has never been studied in dogs with HAC. The aims of the study were: (1) To evaluate calcium/phosphate metabolism in dogs with spontaneous HAC and compare to healthy dogs as well as to dogs with non-HAC illness; (2) to look for associations between markers of calcium/phosphate metabolism and biomarkers of kidney disease in dogs with HAC. Fifty-four dogs were included in the study, classified as HAC (n=27), non-HAC disease (n=17), and healthy (n=10). Serum calcium, phosphate, 25(OH)Vitamin D, 1,25(OH)2Vitamin D, plasma intact parathyroid hormone concentration (iPTH), FGF23, and urinary fractional excretion of calcium and phosphate were evaluated in all dogs at diagnosis and compared between each group. The correlation between these variables and urine protein-to-creatinine ratio (UPC) and urinary N-acetylglucosaminidase-to-creatinine ratio (uNAG/C) was evaluated in the HAC group. Medians [range] of serum phosphate concentration, urinary fractional excretion of calcium (FE(Ca)), and iPTH were significantly higher in dogs with HAC than in dogs with non-HAC illness (P<0.01) and healthy dogs (P<0.01). Increased 1,25(OH)2Vitamin D/25(OH)Vitamin D was also observed (P<0.001). In HAC group, UPC was significantly negatively correlated with 25(OH)Vitamin D (r(s): -0.54; P<0.01). Urinary NAG/C was significantly positively correlated with serum phosphate (r(s): 0.46; P=0.019). Increased serum phosphate, urinary excretion of calcium, and hyperparathyroidism were observed in dogs with HAC. Vitamin D metabolism may be shifted towards increased 1-alpha hydroxylation.

Cardiorenal Effects of Chronic High Phosphate Diet in Female Rats

Cardiorenal Syndrome Type 4 (CRS4) refers to the development of cardiovascular dysfunction as a result of chronic kidney disease. The accumulation of circulating phosphate in the later stages of chronic kidney disease (CKD) has been positively associated with cardiac hypertrophy and dysfunction. In our previous work, we found that male Sprague Dawley rats that underwent 5/6 nephrectomy (5/6Nx) to induce CKD phenotypes also developed cardiac pathology when serum phosphorus levels became elevated. Small RNA sequencing of left ventricle tissue revealed upregulated microRNA-21-5p and -3p expression in 5/6Nx rats, when compared to sham-operated controls, and suppression of miR-21-5p attenuated left ventricle pathology in male 5/6Nx rats. We hypothesize that hyperphosphatemia, independent of CKD, can impair cardiac function and that miR-21 may mediate these effects. It has been recently reported that females exhibit higher urinary phosphate excretion in response to high dietary phosphate intake than males. In this study, hyperphosphatemia was induced by placing 9-week old female wild-type (WT) Sprague Dawley and global miR-21 knockout (miR-21−/−; lacking both miR-21-5p and -3p rats) (n=4-9/group) on either high phosphate (2% Pi) or control diet (0.6% Pi) for 8 weeks. Echocardiography and renal ultrasound were performed under anesthesia to assess cardiac function and renal cross-sectional area, respectively, prior to tissue collection at endpoint. Rats of either genotype fed 2% Pi diet exhibited increased left kidney weight, left kidney/body weight, and left kidney cross-sectional area (2-way ANOVA, main effect of diet; p&lt;0.05). In animals fed 2% Pi, miR-21−/− rats had significantly higher left ventricle fractional shortening than WT rats (57.06 ± 3.32 vs. 43.96 ± 1.34; 2-way ANOVA with Tukey multiple comparisons; p&lt;0.05). This study allowed the cardiovascular effects of chronically elevated phosphate to be isolated from other uremic toxins elevated in CKD. We find that loss of miR-21 augments cardiac function, supporting a role for miR-21 in mediating phosphate-related pathology. Ongoing studies are focused on identifying specific molecular mechanisms driving these changes. This study was supported by T32HL007852 and R01HL128332. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Autosomal dominant hypercalciuric hypocalcaemia: the calcium-sensing receptor in renal calcium homeostasis and the impact of renal transplantation.

Calcium-sensing receptors (CaSRs) are G protein-coupled receptors that help maintain Ca2+ concentrations, modulating calciotropic hormone release (parathyroid hormone (PTH), calcitonin and 1,25-dihydroxyvitamin D) by direct actions in the kidneys, gastrointestinal tract and bone. Variability in population calcium levels has been attributed to single nucleotide polymorphisms in CaSR genes, and several conditions affecting calcium and phosphate homeostasis have been attributed to gain- or loss-of-function mutations. An example is autosomal dominant hypercalciuric hypocalcaemia, because of a missense mutation at codon 128 of chromosome 3, as reported in our specific case and her family. As a consequence of treating symptomatic hypocalcaemia as a child, this female subject slowly developed progressive end-stage kidney failure because of nephrocalcinosis and nephrolithiasis. After kidney transplantation, she remains asymptomatic, with decreased vitamin D and elemental calcium requirements, stable fluid and electrolyte homeostasis during intercurrent illnesses and has normalised urinary calcium and phosphate excretion, reducing the likelihood of hypercalciuria-induced graft impairment. We review the actions of the CaSR, its role in regulating renal Ca2+ homeostasis along with the impact of a proven gain-of-function mutation in the CaSR gene resulting in autosomal dominant hypercalciuric hypocalcaemia before and after kidney transplantation.

P075 What has parenteral iron got to do with rheumatology?

Abstract Background/Aims A 39 year-old female had been experiencing a six-month history of insidious onset migratory joint and bone pain, stiffness, malaise and over the last four months proximal muscle weakness. There had been partial relief with the use of non-steroidal anti-inflammatory medication. Past medical history included severe menorrhagia secondary to fibroids with a haemoglobin of 50g/dl on a handful of occasions, requiring x3 iron infusions (Ferric Carboxymaltose (FCM)1000mg) over a two year period. The last two infusions were provided three months apart. After each infusion, profound fatigue ensued. A blood test demonstrated an elevated ALP 301 (RR 30-130 U/L), reduced phosphate 0.48 (RR 0.8-1.5mmol/L) and mildly reduced 25OH vitamin D 44 (RR 50-140nmol/L). Corrected calcium was low-normal 2.29 (RR 2.2-2.6mmol/L) as was PTH 4.62 (RR 1.6-6.9pmol/L). A CTCAP excluded malignancy. Methods The patient had been treated with Cholecalciferol 1000iu and Dipyridamole 100mg daily with weekly blood test monitoring for six weeks prior to review in the metabolic bone clinic. Dipyridamole aided biochemical and symptomatic improvement. Further tests returned with an elevated FGF23 252 (RR 0-100 RU/ml), a normal Urine phosphate/Creatinine 1.6 and TmP/GFR ratio (suggesting the FGF23 effect on the kidney was not severe or its effects inhibited by Dipyridamole). ALP had reduced slightly to 269, PTH was elevated at 10.81 (RR 1.95-8.49micromol/L) and 1,25 Dihydroxy Vit D 182 (RR43-144 pmol/L). Results The patient was diagnosed with Parenteral iron triggered hypophosphatemia osteomalacia (6H-syndrome). A delayed diagnosis and referral resulted from unfamiliarity of side-effects of parenteral iron, especially Ferric Carboxymaltose, which has an alert on the GOV.UK website. The patient discontinued IV iron and was placed on oral Ferrous Gluconate 300mg daily. In retrospect, bone and joint pain was likely the result of enthesial pain and pseudofractures. In patients with diagnostic uncertainty, an isotope bone scan would be beneficial in assessing the extent of such pseudofractures. Hypophosphatemia is common following FCM (≥1/100 to &amp;lt; 1/10), and often self-limiting and asymptomatic. However, sustained hypophosphatemia (from recurrent infusions) can result in osteomalacia. Both anaemia and certain iron preparations can cause an elevation in FGF23 leading to increased urinary phosphate excretion. Dipyridamole has anti-phosphaturic effects by inhibiting FGF23. Conclusion It is advised in such patients to monitor serum phosphate levels at two- and five-weeks post infusion and to re-evaluate therapy with FCM in patients with persistent hypophosphatemia. It is common for symptoms, imaging, and biochemistry (FGF23 and ALP) to remain elevated/positive several months after diagnosis. This case highlights the need to ask about iron infusions in the drug history in patients presenting with hypophosphatemia and to be aware that musculoskeletal pain following iron infusions can be a sign of osteomalacia which will need investigating. Rarely, proximal muscle weakness can occur following the above iron preparation. Disclosure K.M. Achilleos: None. V. Rajagopal: None. C. Adams: None. G. Clunie: None.

The calcium-sensing receptor has only a parathyroid hormone-dependent role in the acute response of renal phosphate transporters to phosphate intake.

The kidney controls systemic inorganic phosphate (Pi) levels by adapting reabsorption to Pi intake. Renal Pi reabsorption is mostly mediated by sodium-phosphate cotransporters NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) that are tightly controlled by various hormones including parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). PTH and FGF23 rise in response to Pi intake and decrease NaPi-IIa and NaPi-IIc brush border membrane abundance enhancing phosphaturia. Phosphaturia and transporter regulation occurs even in the absence of PTH and FGF23 signaling. The calcium-sensing receptor (CaSR) regulates PTH and FGF23 secretion, and may also directly affect renal Pi handling. Here, we combined pharmacological and genetic approaches to examine the role of the CaSR in the acute phosphaturic response to Pi loading. Animals pretreated with the calcimimetic cinacalcet were hyperphosphatemic, had blunted PTH levels upon Pi administration, a reduced Pi-induced phosphaturia, and no Pi-induced NaPi-IIa downregulation. The calcilytic NPS-2143 exaggerated the PTH response to Pi loading but did not abolish Pi-induced downregulation of NaPi-IIa. In mice with a dominant inactivating mutation in the Casr (CasrBCH002), baseline NaPi-IIa expression was higher, whereas downregulation of transporter expression was blunted in double CasrBCH002/PTH knockout (KO) transgenic animals. Thus, in response to an acute Pi load, acute modulation of the CaSR affects the endocrine and renal response, whereas chronic genetic inactivation, displays only subtle differences in the downregulation of NaPi-IIa and NaPi-IIc renal expression. We did not find evidence that the CaSR impacts on the acute renal response to oral Pi loading beyond its role in regulating PTH secretion.NEW & NOTEWORTHY Consumption of phosphate-rich diets causes an adaptive response of the body leading to the urinary excretion of phosphate. The underlying mechanisms are still poorly understood. Here, we examined the role of the calcium-sensing receptor (CaSR) that senses both calcium and phosphate. We confirmed that the receptor increases the secretion of parathyroid hormone involved in stimulating urinary phosphate excretion. However, we did not find any evidence for a role of the receptor beyond this function.

Phosphorus Intake and Potential Dietary Influences Examined via 24-Hour Urinary Biomarker Measurements in German Children and Adolescents Over 3 Decades

BackgroundIncreases in phosphorus intake have been observed over the past years in adult populations. However, biomarker-based data are lacking on whether or not phosphorus intake also increased in children. ObjectiveThe aim of this study was to examine 24-hour urinary phosphate excretion (PO4-Ex) and diet-related biomarkers potentially influencing phosphorus status in German children and adolescents from 1985 to 2015. DesignThis longitudinal noninvasive biomarker-based cohort study examined 24-hour urine samples from children and adolescents of the Dortmund Nutritional and Anthropometric Longitudinally Designed Study, collected over 3 decades. Participants/settingExamined individuals (n = 1,057) were healthy participants of the Dortmund Nutritional and Anthropometric Longitudinally Designed Study, situated in Dortmund, Germany, who had been asked to collect one yearly 24-hour urine sample. Six thousand seven hundred thirty-seven samples collected from participants aged 3 to 17 years between 1985 (baseline) and 2015, were included. Main outcome measuresphosphorus intake was examined biomarker-based by analyzed PO4-Ex in 24-hour urine samples. Whether acid-base status and intakes of protein, salt, and fruits and vegetables, may have relevantly contributed to PO4-Ex levels was assessed by determining 24-hour excretions of net acid, urea-nitrogen, and sodium as well as specific standardized excretions of potassium plus oxalate. Statistical analyses performedTrend analysis over 30 years and potentially influencing diet factors were examined using linear mixed-effect regression models (PROC-MIXED). Adjustments for sex, age, and body surface area were performed. ResultsNo change was identifiable for PO4-Ex over the 3 decades; neither in 3 to 8, 9 to 13, nor in 14 to 17 year olds. However, sodium excretion increased (P = .001). PROC-MIXED analysis on intraindividual changes in PO4-Ex revealed direct relationships with net acid excretion, urea-nitrogen, and sodium excretion and an inverse relationship with a biomarker of fruit and vegetable intake. ConclusionsDespite a direct relationship between PO4-Ex and a biomarker of industrially processed food consumption; that is, sodium excretion, which showed an increasing time trend, phosphorus intake was found to remain stable over decades in children and adolescents.

Urinary excretion of calcium, phosphate, magnesium, and uric acid in healthy infants and young children. Influence of feeding practices in early infancy.

Reference values for urinary calcium (Ca) and other solutes/creatinine (Cr) ratios in infants and young children are scarce. Its variation with type of lactation administered, breastfed (BF) or formula (F), is incompletely known. A total of 511 spot urine samples from 136 children, aged 6days to < 5years, was collected. Urine was collected no fasting in infants < 18months and first morning fasting in children aged 2.5-4years. Urinary osmolality, Cr, urea, Ca, phosphate (P), magnesium (Mg), and uric acid (UA) were determined. Values are expressed as solute-to-Cr ratio. Urinary values were grouped according to the child's age: 6-17days (G1), 1-5months (G2), 6-12months (G3), 13-18months (G4), and 2.5-4years (G5). G1 was excluded; Ca/Cr and UA/Cr (95th percentile) decreased with age (G2 vs. G5) from 1.64 to 0.39 and 2.33 to 0.83mg/mg, respectively. The P/Cr median rises significantly with age from 0.31 (G2) to 1.66mg/mg (G5). Mg/Cr was similar in all groups (median 0.20, 95th percentile 0.37mg/mg). Ca/Cr (95th percentile) of BF infants was 1.80mg/mg (< 3months) and 1.63mg/mg (3-5months), much higher than F infants (0.93 and 0.90mg/mg, respectively). P/Cr and P/Ca were lower in BF infants. Values for urinary Ca/Cr, P/Cr, Mg/Cr, and UA/Cr in infants and children < 5years were updated. BF infants < 6months showed higher Ca/Cr and lower P/Cr than F infants. New cutoff values to diagnose hypercalciuria in infants < 6months, according to the type of lactation, are proposed.

Risk Profile of Patients with Brushite Stone Disease and the Impact of Diet.

This study examined the profile of patients and the impact of diet on the risk of brushite stone formation under controlled, standardized conditions. Sixty-five patients with brushite nephrolithiasis were enrolled in the study. Metabolic, dietary, and 24 h urinary parameters were collected under the habitual, self-selected diet of the patients and the balanced mixed, standardized diet. The [13C2]oxalate absorption, ammonium chloride, and calcium loading tests were conducted. All patients had at least one abnormality on the usual diet, with hypercalciuria (84.6%), increased urine pH (61.5%), and hyperphosphaturia (43.1%) being the most common. Absorptive hypercalciuria was present in 32.1% and hyperabsorption of oxalate in 41.2%, while distal renal tubular acidosis (dRTA) was noted in 50% of brushite stone formers. The relative supersaturation of brushite did not differ between patients with and without dRTA. Among all recent brushite-containing calculi, 61.5% were mixed with calcium oxalate and/or carbonate apatite. The relative supersaturation of brushite, apatite, and calcium oxalate decreased significantly under the balanced diet, mainly due to the significant decline in urinary calcium, phosphate, and oxalate excretion. Dietary intervention was shown to be effective and should be an integral part of the treatment of brushite stone disease. Further research on the role of dRTA in brushite stone formation is needed.

Antiaging hormone Klotho derived from renal distal-convolution regulates calcium but not phosphate homeostasis

Soluble-Klotho (sKl) is the shed ectodomain of the transmembrane protein-Klotho (mKl) that exhibits pleiotropic actions, including lifespan extension, mineral metabolism, slowing-down kidney diseases and cardioprotection. The sKl is derived from the kidneys, but what type/s of renal cells secrete it is unknown. Secondly the respective roles of mKl versus sKl in regulating mineral metabolism is unclear due to the lack of appropriate in vivo models. Here, using scRNA-seq of renal distal-convolution (DC) cells, we found an unexpected pattern revealing that Klotho transcripts ( Kl) are moderately expressed in overall distal convoluted tubule (DCT), but highly enriched in the end of DCT and in connecting tubule (CNT). Immunohistochemistry further confirmed this pattern for mKl protein as well. Next, Kl was knocked-out only in renal DC to check if it affects sKl production. Interestingly, deleting Kl in the DCT and late-DCT+CNT in mice showed ~20% and ~80% reduction in sKl levels, respectively. Expectedly, knocking-out Kl along the entire DC in mice (Kl-KO DC ) abolished sKl levels. Furthermore, we found that compared to control mice, Kl-KO DC mice exhibited reduced renal TRPV5-Ca 2+ channel expression, profound calciuria, and loss of bone mineral density. The RNA-seq of automated-sorted DC cells from Kl-KO DC mice revealed enhanced caveolae-mediated endocytosis of TRPV5. On the other hand, Kl-KO DC mice had normal phosphate metabolism as confirmed by unchanged serum FGF23, serum phosphate, urinary phosphate excretion, and renal NaPi-IIa expression. Our findings reveal that a small population of renal DC cells accounts for the sKl levels. The lack of sKl may leads to disturbed Ca 2+ homeostasis and bone loss without affecting phosphate balance in mice. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Commentary on Severe Hypophosphatemia: The Hidden Truth.

Abnormal phosphate results are common in daily practice, but often neglected by laboratorians and clinicians. This case of severe hypophosphatemia highlights the critical implications that a delayed diagnostic workup of the underlying cause can have. Early diagnosis and treatment could have prevented years of continuous bone loss and immobility. Therefore, severe hypophosphatemia should always trigger additional investigations to find the underlying cause. Determination of the tubular maximum reabsorption of phosphate for glomerular filtration rate was pivotal for establishing renal phosphate wasting and for guiding further diagnostic measures. This rarely used parameter can easily be determined in most laboratories, but pathologists are often unaware of its diagnostic value. Consequently, many laboratories limit themselves to the measurement of timed urinary phosphate excretion, despite the fact that a wide reference interval limits its diagnostic utility. In adult patients with renal phosphate wasting, measurement of fibroblast growth factor-23 (FGF-23) helps to further narrow the spectrum of potential causes. Elevated FGF-23 concentrations are typical in tumor-induced osteomalacia, but normal values can occur when the underlying tumor secretes other phosphatonins or in the presence of interfering heterophile antibodies or human antimouse antibodies that disturb the assay (1).

Nephron index rather than serum FGF 23 predicts endothelial dysfunction in early but not advanced chronic kidney disease patients

BackgroundEndothelial dysfunction is the primary step for the development of CKD-related cardiovascular disease. Early prediction and management can influence patient survival. Serum testing of FGF 23 hormone and urinary phosphate excretion were studied as predictors of all-cause cardiovascular morbidity in CKD patients; however, their relation to endothelial dysfunction is controversial. A combination of both in one index is hypothesized to increase their sensitivity in detecting endothelial dysfunction, especially in the early stages of CKD before the dominance of hyperphosphatemia, the original risk.MethodsA cross-sectional comparative analysis between thirty CKD stage 3 patients and sixty stage 4–5 CKD patients was conducted. All patients were tested for markers of mineral bone disorders including serum FGF 23 and 24-h urinary phosphate excretion. A combination of both in one index (nephron index) is calculated and hypothesized to correlate with nephron number. Endothelial dysfunction was assessed by measuring the post-occlusion brachial flow-mediated dilatation (FMD).ResultsIn univariate and multivariate regression analyses, the nephron index was the only predictor of endothelial dysfunction in individuals with stage 3 CKD (r = 0.74, P 0.01). This was not applied to stage 4–5 CKD patients where serum phosphorus (r = − 0.53, P 0.001), intact PTH (r = − 0.53, P 0.001), uric acid (r = − 0.5, P 0.001), and measured GFR (r = 0.59, P 0.001) were the highest correlates to FMD; the Nephron index had the weakest correlation (r = 0.28, P = 0.02) and is not predictive of endothelial dysfunction.ConclusionNephron index calculation showed better correlation with endothelial dysfunction than using any of its determinants alone in early stages of CKD when FGF 23 levels are just beginning to rise. In advanced CKD patients, hyperphosphatemia, hyperparathyroidism, hyperuricemia, and measured GFR are more reliable than nephron index.