Renal Phosphate Handling Research Articles

Impact of lymphangiogenesis on renal phosphate handling following kidney injury

Overconsumption of inorganic phosphate (Pi) causes tubular cell damage and kidney dysfunction, and hyperphosphatemia can lead to Ca2+ retention, vascular calcification, and cardiovascular disease. Conversely, kidney injury and chronic kidney disease (CKD) cause hyperphosphatemia and Pi retention. We hypothesized that the damage caused by chronic Pi consumption likely induces kidney lymphangiogenesis and that changes to renal lymphatic density may alter kidney mineral handling. We identified significant lymphangiogenesis and increased expression of the lymphatic growth factors VEGF-C/D in kidneys of mice fed a 2% Pi diet for 2 months and as early as three weeks of diet. We then utilized “KidVD” mice, a mouse model of kidney-specific inducible expression of VEGF-D, to expand renal lymphatic density and test Pi handling. Mineral handling was largely normal in male and female KidVD mice compared to littermates on Pi diet. In a Pi-driven CKD model mice were injured with 10 mg/kg cisplatin dose, allowed to recover for 2 weeks, then challenged with chow or 2% Pi diet for 3 weeks with VEGF-D induction. This resulted in Pi retention in all mice. Pi handling in both male and female KidVD mice were normal to controls. Female KidVD, however, demonstrated significantly increased Ca2+ excretion compared to controls. Circulating FGF23 levels were significantly elevated in male and female with VEGF-D overexpression. Gene expression of Fgfr1 was also significantly increased in male and female KidVD mice. Renal lymphangiogenesis thus appears to specifically impact Ca2+ retention through the FGF23-Fgfr1 axis. National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01 DK119497). 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.

Serum total testosterone is associated with phosphate and calcium excretion in response to oral phosphate loading in healthy middle-aged males.

Androgen receptors are expressed in the kidney and serum testosterone is negatively associated with serum phosphate in males, suggesting a role of testosterone in renal phosphate handling. In this cross-sectional study, we examined the association of serum total and free testosterone with acute phosphate and calcium excretion in males in response to an oral phosphate challenge. Thirty-five healthy adult males with normal baseline testosterone levels consumed a 500mg phosphorus drink and the urinary excretion of minerals, as well as levels of relevant circulating parameters, were assessed at baseline and hourly for 4 h. Serum total testosterone was positively associated with overall phosphate excretion (r=0.35, p=0.04) and calcium excretion (r=0.44, p=0.00) in response to the challenge. Serum free testosterone was positively associated with post-challenge calcium excretion (r=0.34, p=0.048), but significance was not reached for phosphate excretion (r=0.31, p=0.07). Serum total and free testosterone were not associated with parathyroid hormone, fibroblast growth factor-23, or vitamin D-key factors implicated in phosphate and calcium regulation. Overall, higher serum total testosterone levels in healthy middle-aged males are associated with a greater capacity to acutely excrete phosphate and calcium after a single oral phosphate challenge, suggesting potential ramifications of testosterone deficiency related to mineral homeostasis.

The Effects of Acid on Calcium and Phosphate Metabolism.

A variety of changes in mineral metabolism aiming to restore acid-base balance occur in acid loading and metabolic acidosis. Phosphate plays a key role in defense against metabolic acidosis, both as an intracellular and extracellular buffer, as well as in the renal excretion of excess acid in the form of urinary titratable acid. The skeleton acts as an extracellular buffer in states of metabolic acidosis, as the bone matrix demineralizes, leading to bone apatite dissolution and the release of phosphate, calcium, carbonate, and citrate into the circulation. The renal handling of calcium, phosphate and citrate is also affected, with resultant hypercalciuria, hyperphosphaturia and hypocitraturia.

Fibroblast Growth Factor 23 Neutralizing Antibody Ameliorates Abnormal Renal Phosphate Handling in Sickle Cell Disease Mice.

We assessed the involvement of fibroblast growth factor 23 (FGF23) in phosphaturia in sickle cell disease (SCD) mice. Control and SCD mice were treated with FGF23 neutralizing antibody (FGF23Ab) for 24 hours. Serum ferritin was significantly increased in SCD mice and was significantly reduced in female but not male SCD mice by FGF23Ab. FGF23Ab significantly reduced increased erythropoietin in SCD kidneys. Serum intact FGF23 was significantly increased in SCD female mice and was markedly increased in SCD male mice; however, FGF23Ab significantly reduced serum intact FGF23 in both genotypes and sexes. Serum carboxy-terminal-fragment FGF23 (cFGF23) was significantly reduced in SCD IgG male mice and was markedly but not significantly reduced in SCD IgG female mice. FGF23Ab significantly increased cFGF23 in both sexes and genotypes. Serum 1,25-dihydroxyvitamin D3 was significantly increased in SCD IgG and was further significantly increased by FGF23Ab in both sexes and genotypes. Significantly increased blood urea nitrogen in SCD was not reduced by FGF23Ab. The urine phosphate (Pi)/creatinine ratio was significantly increased in SCD in both sexes and was significantly reduced by FGF23Ab. Increased SCD kidney damage marker kidney injury molecule 1 was rescued, but sclerotic glomeruli, increased macrophages, and lymphocytes were not rescued by short-term FGF23Ab. FGF23Ab significantly reduced increased phospho-fibroblast growth factor receptor 1, αKlotho, phosphorylated extracellular signal-regulated kinase, phosphorylated serum/glucocorticoid-regulated kinase 1, phosphorylated sodium-hydrogen exchanger regulatory factor-1, phosphorylated janus kinase 3, and phosphorylated transducer and activator of transcription-3 in SCD kidneys. The type II sodium Pi cotransporter (NPT2a) and sodium-dependent Pi transporter PiT-2 proteins were significantly reduced in SCD kidneys and were increased by FGF23Ab. We conclude that increased FGF23/FGF receptor 1/αKlotho signaling promotes Pi wasting in SCD by downregulating NPT2a and PIT2 via modulation of multiple signaling pathways that could be rescued by FGF23Ab.

Effects of parathyroid hormone on renal tubular calcium and phosphate handling.

Central to the maintenance of calcium homeostasis is the regulated reabsorption of calcium along the nephron. To this end, parathyroid hormone (PTH) is released from the parathyroid gland in response to lowered plasma calcium levels. This hormone acts through the PTH 1 receptor along the nephron to increase urinary phosphate excretion and decrease urinary calcium excretion. In the proximal tubule, PTH inhibits phosphate reabsorption by reducing the abundance of sodium phosphate cotransporters in the apical membrane. PTH likely decreases calcium reabsorption from the proximal tubule, by reducing the reabsorption of sodium, an event necessary for the paracellular movement of calcium across this segment. In the thick ascending limb (TAL), PTH increases calcium permeability and may increase the electrical driving force thereby increasing calcium reabsorption in the TAL. Finally, in the distal convolution, PTH acts to increase transcellular calcium reabsorption by increasing the activity and abundance of the apically expressed calcium channel TRPV5.

PTH and FGF23 exert interdependent effects on renal phosphate handling: evidence from patients with hypoparathyroidism and hyperphosphatemic familial tumoral calcinosis treated with synthetic human PTH 1-34

PTH and FGF23 exert interdependent effects on renal phosphate handling: evidence from patients with hypoparathyroidism and hyperphosphatemic familial tumoral calcinosis treated with synthetic human PTH 1-34

Hypophosphatemia in acute liver failure of a broad range of etiologies is associated with phosphaturia without kidney damage or phosphatonin elevation

Hypophosphatemia is a common and dangerous complication of acute liver failure (ALF) of various etiologies. While various mechanisms for ALF-associated hypophosphatemia have been proposed including high phosphate uptake into regenerating hepatocytes, acetaminophen (APAP)-associated hypophosphatemia was linked to renal phosphate wasting, and APAP-induced renal tubular injury was proposed as underlying mechanism. We studied 30 normophosphatemic and 46 hypophosphatemic (serum phosphate < 2.5 mg/dL) patients from the Acute Liver Failure Study Group registry with APAP- or non-APAP-induced ALF. Since kidney injury affects phosphate excretion, patients with elevated serum creatinine (>1.2 mg/dL) were excluded. Maximal amount of renal tubular phosphate reabsorption per filtered volume (TmP/GFR) was calculated from simultaneous serum and urine phosphate and creatinine levels to assess renal phosphate handling. Instead of enhanced renal phosphate reabsorption as would be expected during hypophosphatemia of non-renal causes, serum phosphate was positively correlated with TmP/GFR in both APAP- and non-APAP-induced ALF patients (R2=0.66 and 0.46, respectively; both P < 0.0001), indicating renal phosphate wasting. Surprisingly, there was no evidence of kidney damage based on urinary markers including neutrophil gelatinase-associated lipocalin and cystatin C even in the APAP group. Additionally, there was no evidence that the known serum phosphatonins parathyroid hormone, fibroblast growth factor 23, and α-Klotho contribute to the observed hypophosphatemia. We conclude that the observed hypophosphatemia with renal phosphate wasting in both APAP- and non-APAP-mediated ALF is likely the result of renal tubular phosphate leak from yet-to-be identified factor(s) with no evidence for proximal tubular damage or contribution of known phosphatonins.

The Tmprss6-/- Mouse Model of Iron Refractory Iron Deficiency Anemia (IRIDA) Exhibits Disrupted Phosphate Homeostasis, Elevated Circulating FGF23 Levels, and Increased Fgf23 Expression in Bone Marrow

While the effects of chronic iron deficiency on erythropoiesis are well documented, the effects of iron deficiency on metabolism remain poorly understood. Recent studies suggest that iron deficiency anemia may impact systemic phosphate regulation (Farrow et al ., PNAS, 2011; Clinkenbeard et al ., J Bone Miner Res, 2014; David et al ., Kidney Int, 2016; Hanudel et al ., Am J Physiol Renal Physiol, 2016). Here we used Tmprss6-/- mice, a model of iron refractory iron deficiency anemia (IRIDA) characterized by hepcidin elevation, to explore the relationship between systemic iron deficiency and phosphate homeostasis. By intercrossing Tmprss6+/- mice, we generated Tmprss6-/- mice and littermate controls, which were raised on a standard rodent diet (Teklad 2018S containing 200 ppm iron and 0.7% phosphorus) prior to study at 8 weeks of age. Tmprss6-/- mice displayed a trend toward lower serum phosphate concentration, as well as a significant elevation in the urinary phosphate/creatinine ratio. Because of the role of phosphate in bone mineralization, we also analyzed the tibiae of Tmprss6-/- mice and found that they showed alterations in bone histology and biomechanical properties.To determine if fibroblast growth factor 23 (FGF23), a key phosphate-regulating hormone, may contribute to these changes in phosphate balance, we compared plasma FGF23 levels of 8-week-old Tmprss6-/- mice to littermate controls using enzyme-linked immunosorbant assays (ELISAs). Tmprss6-/- mice showed significantly higher levels of the biologically-active (“intact”) form of FGF23 as well as “total” FGF23 (a measure of both the intact form and the C-terminal cleavage product of FGF23). This FGF23 elevation was also observed in 3-week-old Tmprss6-/- pups (i.e. prior to weaning). Because osteocytes in bone have been described as a major site of FGF23 production, we measured Fgf23 mRNA levels by qRT-PCR in RNA that was prepared from femur bones of Tmprss6-/- mice or littermate controls after marrow removal by flushing. We observed a four-fold increase in Fgf23 expression in the femurs of Tmprss6-/- mice as compared to littermate controls. Because Fgf23 expression has previously been reported in Ter119+ erythroid cells from wild type mice (Coe et al ., J Biol Chem, 2014), and because our RNA preparations from femur bones showed evidence of residual bone marrow contamination (as assessed by alpha hemoglobin expression), we also measured Fgf23 mRNA expression in RNA prepared from total bone marrow. Tmprss6-/- mice exhibited significantly higher bone marrow Fgf23 mRNA levels than littermate controls. Notably, when RNA was prepared from bones that had been more effectively depleted of marrow by mechanical disruption and hypotonic lysis, Tmprss6-/- mice no longer showed an increase in Fgf23 mRNA levels in the femur RNA as compared to littermate controls. Collectively, these results suggest that increased Fgf23 production by one or more bone marrow cell populations contributes to elevated circulating FGF23 in Tmprss6-/- mice.FGF23 has been proposed as the basis for a bone-kidney axis that coordinates bone health with renal handling of phosphate. Our findings suggest that altered phosphate homeostasis in Tmprss6-/- mice may result from increased Fgf23 expression in the bone marrow and a corresponding elevation in circulating FGF23. These results may have relevance to the skeletal health of patients with IRIDA due to TMPRSS6 mutation and those with other forms of iron-restricted anemia resulting from hepcidin elevation. Additionally, as Tmprss6-/- mice are known to exhibit growth retardation, our results raise the possibility that disrupted phosphate homeostasis may contribute to the commonly observed association of childhood iron deficiency with growth impairment. Future studies will characterize the source of Fgf23 production in the bone marrow of Tmprss6-/- mice as well as the mechanism by which iron deficiency elevates Fgf23 expression. DisclosuresNo relevant conflicts of interest to declare.

Renal Dnase1 expression is regulated by FGF23 but loss of Dnase1 does not alter renal phosphate handling

Fibroblast growth factor 23 (FGF23) is a bone-derived endocrine hormone that regulates phosphate and vitamin D metabolism. In models of FGF23 excess, renal deoxyribonuclease 1 (Dnase1) mRNA expression is downregulated. Dnase-1 is an endonuclease which binds monomeric actin. We investigated whether FGF23 suppresses renal Dnase-1 expression to facilitate endocytic retrieval of renal sodium dependent phosphate co-transporters (NaPi-IIa/c) from the brush border membrane by promoting actin polymerization. We showed that wild type mice on low phosphate diet and Fgf23−/− mice with hyperphosphatemia have increased renal Dnase1 mRNA expression while in Hyp mice with FGF23 excess and hypophosphatemia, Dnase1 mRNA expression is decreased. Administration of FGF23 in wild type and Fgf23−/− mice lowered Dnase1 expression. Taken together, our data shows that Dnase1 is regulated by FGF23. In 6-week-old Dnase1−/− mice, plasma phosphate and renal NaPi-IIa protein were significantly lower compared to wild-type mice. However, these changes were transient, normalized by 12 weeks of age and had no impact on bone morphology. Adaptation to low and high phosphate diet were similar in Dnase1−/− and Dnase1+/+ mice, and loss of Dnase1 gene expression did not rescue hyperphosphatemia in Fgf23−/− mice. We conclude that Dnase-1 does not mediate FGF23-induced inhibition of renal tubular phosphate reabsorption.

Renal Phosphate Handling: Independent Effects of Circulating FGF23, PTH, and Calcium.

ABSTRACTExcess fibroblast growth factor 23 (FGF23), excess PTH, and an increase in extracellular calcium cause hypophosphatemia by lowering the maximum renal phosphate reabsorption threshold (TmP/GFR). We recently reported two cases of X‐linked hypophosphatemia (XLH) with severe tertiary hyperparathyroidism who had normalization of TmP/GFR upon being rendered hypoparathyroid following total parathyroidectomy, despite marked excess in both C‐terminal FGF23 (cFGF23) and intact FGF23 (iFGF23). We explored the effects of FGF23, PTH, and calcium on TmP/GFR in a cross‐sectional study (n = 74) across a spectrum of clinical cases with abnormalities in TmP/GFR, PTH, and FGF23. This comprised three groups: FGF23‐dependent hypophosphatemia (n = 27), hypoparathyroidism (HOPT; n = 17), and chronic kidney disease (n = 30). Measurements included TmP/GFR, cFGF23, PTH, ionized calcium, vitamin D metabolites, and bone turnover markers. The combined effect of cFGF23, PTH, and ionized calcium on TmP/GFR was modeled using hierarchical multiple regression and was probed by moderation analysis with PROCESS. Modeling analysis showed independent effects on TmP/GFR by cFGF23, PTH, and ionized calcium in conjunction with a weak but significant effect of the interaction term for PTH and FGF23; probing showed that the effect was most prominent during PTH deficiency. Teriparatide 20 μg daily was self‐administered for 28 days by one case of X‐linked hypophosphatemia with hypoparathyroidism (XLH‐HOPT) to assess the response of TmP/GFR, cFGF23, iFGF23, nephrogenous cyclic adenosine monophosphate (NcAMP), vitamin D metabolites, and bone turnover markers. After 28 days, TmP/GFR was lowered from 1.10 mmol/L to 0.48 mmol/L; this was accompanied by increases in NcAMP, ionized calcium, and bone turnover markers. In conclusion, the effect of FGF23 excess on TmP/GFR is altered by PTH such that the effect is ameliorated by hypoparathyroidism and the effect is augmented by hyperparathyroidism. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

PTH and FGF23 Exert Interdependent Effects on Renal Phosphate Handling: Evidence From Patients With Hypoparathyroidism and Hyperphosphatemic Familial Tumoral Calcinosis Treated With Synthetic Human PTH 1-34.

Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) both influence blood phosphate levels by regulating urinary phosphate reabsorption. Clinical data suggest that adequate renal phosphate handling requires the presence of both FGF23 and PTH, but robust evidence is lacking. To investigate whether the phosphaturic effects of PTH and FGF23 are interdependent, 11 patients with hypoparathyroidism, which features high blood phosphate in spite of concomitant FGF23 elevation, and 1 patient with hyperphosphatemic familial tumoral calcinosis (HFTC), characterized by deficient intact FGF23 action and resulting hyperphosphatemia, were treated with synthetic human PTH 1-34 (hPTH 1-34). Biochemical parameters, including blood phosphate, calcium, intact FGF23 (iFGF23), nephrogenic cAMP, 1,25(OH)2 vitamin D (1,25D), and tubular reabsorption of phosphate (TRP), were measured at baseline and after hPTH 1-34 treatment. In patients with hypoparathyroidism, administration of hPTH 1-34 increased nephrogenic cAMP, which resulted in serum phosphate normalization followed by a significant decrease in iFGF23. TRP initially decreased and returned to baseline. In the patient with HFTC, hPTH 1-34 administration also increased nephrogenic cAMP, but this did not produce changes in phosphate or TRP. No changes in calcium were observed in any of the studied patients, although prolonged hPTH 1-34 treatment did induce supraphysiologic 1,25D levels in the patient with HFTC. Our results indicate that PTH and FGF23 effects on phosphate regulation are interdependent and both are required to adequately regulate renal phosphate handling. Published 2021. This article is a U.S. Government work and is in the public domain in the USA.

Renal Phosphate Handling in Antiretroviral-naive HIV-Infected Patients.

Human immunodeficiency virus (HIV) infection impairs renal function, thereby affecting renal phosphate metabolism. We prospectively estimated the prevalence of phosphate abnormalities (mild, moderate to life-threatening hypophosphataemia, and hyperphosphataemia) before initiating antiretroviral therapy (ART). A cross-sectional analysis was performed on 170 consecutive newly diagnosed ARTnaive, HIV-infected patients attending our HIV/AIDS clinics over a period of one year. Fifty (50) screened HIV-negative blood donors were used for comparison (controls). Blood and urine were collected simultaneously for phosphate and creatinine assay to estimate fractional phosphate excretion (FEPi %) and glomerular filtration rate (eGFR). eGFR showed significant difference between patients' and controls' medians (47.89ml/ min/1.73m2 versus 60ml/min/1.73m2, p <0.001); which denotes a moderate chronic kidney disease in the patients. Of the 170 patients, 78 (45.9%) had normal plasma phosphate (0.6-1.4 mmol/L); 85 (50%) had hyperphosphataemia. Grades 1, 2 and 3 hypophosphataemia was observed in 3 (1.8%), 3 (1.8%), and 1(0.5%) patient(s) respectively. None had grade 4 hypophosphataemia. Overall, the patients had significantly higher median of plasma phosphate than the controls, 1.4 mmol/L (IQR: 1.0 - 2.2) versus 1.1 mmol/L (IQR: 0.3 - 1.6), p <0.001, implying hyperphosphataemia in the patients; significantly lower median urine phosphate than the controls, 1.5 mmol/L (IQR: 0.7 -2.1) versus 8.4 mmol/L (IQR: 3.4 - 16), p <0.001), justifying the hyperphosphataemia is from phosphate retention; but a non-significantly lower median FEPi% than the controls, 0.96% (IQR: 0.3 -2.2) versus 1.4% (IQR: 1.2 -1.6), p > 0.05. Predictors of FEPi% were age (Odds ratio, OR 0.9, p = 0.009); weight (OR 2.0, p < 0.001); CD4+ cells count predicted urine phosphate among males (p = 0.029). HIV infection likely induces renal insufficiency with reduced renal phosphate clearance. Thus, hyperphosphataemia is highly prevalent, and there is mild to moderate hypophosphataemia but its life-threatening form (grade 4) is rare among ART-naive HIV patients.

Androgen action on renal calcium and phosphate handling: Effects of bisphosphonate treatment and low calcium diet

Renal calcium and phosphate handling is an important contributor to mineral homeostasis and bone health and the androgen receptor (AR) is highly expressed in the kidney. We investigated the short term effects of androgen deprivation on renal calcium and phosphate reabsorption, independent of their effects on bone. Two weeks following orchidectomy (ORX) of adult mice, bone loss occurred along with hypercalciuria, which was similarly prevented by testosterone and dihydrotestosterone supplementation. Treatment with bisphosphonates prior to ORX also inhibited hypercalciuria, indicating that the calcium flux originated from the bone. Renal calcium and phosphate transporter expression was increased post-ORX, independent of bisphosphonates. Furthermore, androgen deprivation appeared to stimulate local synthesis of 1,25(OH)2D3. When bisphosphonate-treated mice were fed a low calcium diet, bone resorption was no longer blocked and secondary hyperparathyroidism developed, which was more pronounced in ORX mice than sham-operated mice. In conclusion, this study shows that androgen deprivation increased renal calcium and phosphate transporter expression, independent of bone, and underlines the importance of adequate intestinal calcium supply in circumstances of androgen deprivation and bisphosphonate treatment.

Bone Mineral Density, Body Composition, and Mineral Homeostasis Over 24 Months in Urban South African Women With HIV Exposed to Antiretroviral Therapy.

ABSTRACTHuman immunodeficiency virus‐ (HIV‐) infection and antiretroviral therapy (ART) exposure are associated with bone loss. African data are limited despite the region's HIV burden. Of 247 ART‐naïve, premenopausal, urban, black African women aged 33.9 ± 6.6 years from Soweto, South Africa, measured at baseline, 110 underwent anthropometry, DXA, and blood and urine collections at 12 and 24 months; 39 were HIV‐negative (Nref), 28 were people with HIV (PWH) not ART‐exposed for the duration of the study (ART‐N), and 43 were PWH who were ART‐exposed within the first 12 months (ART‐Y). At baseline, the ART‐Y group had lower BMI and fat mass than the Nref group. Within 12 months of ART initiation, areal bone mineral density (aBMD) had decreased at the lumbar spine and at the whole body less head, despite increased weight, and hip aBMD had not increased in line with the Nref group. There was no evidence of further bone changes between 12 and 24 months. By 24 months, the ART‐Y women had gained weight and fat mass, but remained lighter with less fat than the Nref women. ART initiation normalized the low serum albumin of the ART‐Y group at baseline, but was associated with elevated bone turnover markers at 12 and 24 months. Vitamin D status and renal phosphate handling were normal. ART‐N had similar aBMD and other characteristics to the Nref group throughout, except unlike the Nref group, weight and fat mass did not increase and serum albumin decreased. This study in African women of childbearing age demonstrated that the bone loss that had occurred in these PWH after ART initiation did not continue after 12 months and that bone loss did not occur in ART‐unexposed PWH over 2 years. At 24 months, despite gains in weight and fat mass, ART‐exposed women remained lighter, with lower aBMD, fat mass, and higher bone turnover than women without HIV. More studies are required to establish if the bone loss and fat gain reverse, stabilize, or continue with further ART exposure, particularly during and after menopause. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Developmental Changes in Phosphate Homeostasis.

Phosphate is a multivalent ion critical for a variety of physiological functions including bone formation, which occurs rapidly in the developing infant. In order to ensure maximal bone mineralization, young animals must maintain a positive phosphate balance. To accomplish this, intestinal absorption and renal phosphate reabsorption are greater in suckling and young animals relative to adults. This review discusses the known intestinal and renal adaptations that occur in young animals in order to achieve a positive phosphate balance. Additionally, we discuss the ontogenic changes in phosphotropic endocrine signalling as it pertains to intestinal and renal phosphate handling, including several endocrine factors not always considered in the traditional dogma of phosphotropic endocrine signalling, such as growth hormone, triiodothyronine, and glucocorticoids. Finally, a proposed model of how these factors may contribute to achieving a positive phosphate balance during development is proposed.

Rare cause of pathological fracture in adults as hypophosphatemic rickets

Hypophosphatemic rickets is a disorder of defective bone minerlization due to defect in renal phosphate handling process. It is characterised by increased phosphate excretion accompanied by increased phosphatonins like fibroblast growth factor 23. It can be hereditary form of X linked, autosomal dominant, autosomal recessive type of hypophosphatemic rickets. It is associated with low serum phosphorus, normal serum calcium, inappropriately low to normal vitamin D level. Correct identification of these disorders is important for determining therapy. Early diagnosis and management prevent subsequent complication of the disease.

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.

Kynurenine Induces Renal Fibrosis which May Contribute to Bone Loss in Aging

Aging results in both bone loss and renal dysfunction, and the two conditions are interrelated. Low‐protein diets are recommended to increase longevity in the elderly but may occur at the expense of bone density. Tryptophan, an essential amino acid, is at greatest risk of depletion. Aging is marked by low tryptophan levels and higher levels of its oxidized metabolite, kynurenine (KYN). Feeding a low‐protein diet supplemented with KYN results in bone loss in younger mice; however, the renal effects of KYN have not been evaluated in this model. We hypothesized that KYN feeding induces bone loss and renal dysfunction through the fibroblast growth factor‐23 (FGF23)/α‐Klotho pathway involved in renal handling of calcium and phosphate and production of 1,25‐dihydroxyvitamin D. Male C57BL/6 mice (13 months old) were fed either a low‐protein (LP, 8%) or normal‐protein (NP, 18%) diet with or without KYN for 8 weeks. LP induced significant diuresis (2.16 ± 0.08 mL/day) that was attenuated with KYN (1.28 ± 0.10 mL/day). Glomerular filtration rate (GFR) was not different among the groups. Albuminuria was increased with age in the NP‐ or NP+KYN‐fed mice but not in the LP or LP+KYN groups. Tubulo‐interstitial fibrosis was present in LP‐ and LP+KYN‐fed mice and was not different from 24‐month‐old mice. Serum levels of FGF23 were elevated in LP‐fed mice but did not reach significance. Kidney protein levels of α‐Klotho declined with age. Our preliminary data suggest that KYN feeding may induce renal fibrosis that may contribute to bone loss, and FGF23/α‐Klotho may be involved. Further studies are needed to define a role for KYN in renal aging.Support or Funding InformationPO1 AG036675 and AG036675S1This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of Highly Active Antiretroviral Therapy on Renal Function and Renal Phosphate Handling in African Adults with Advanced HIV and CKD.

Highly Active Antiretroviral Therapy (HAART) has been implicated in renal dysfunction with hypophosphataemia. We prospectively evaluated renal phosphate excretion during HAART use. Newly diagnosed human immunodeficiency virus (HIV)-infected individuals were treated with Tenofovir disoproxil fumarate/Emtricitabine/Efavirenz (TDF/FTC/EFV), n=33; Zidovudine/Lamivudine/Nevirapine (ZDV/3TC/NVP), n=53; and Zidovudine/Lamivudine/Efavirenz (ZDV/3TC/EFV), n=16. Creatinine and phosphate were assayed in blood and urine simultaneously at baseline, 1, 3, 6 and 9 months. Glomerular filtration rate (eGFR), fractional phosphate excretion and reabsorption (FEPi % and TRP), and the ratio of tubular maximum reabsorption of phosphate (TmP) to GFR (TmP/GFR) were estimated. At baseline, eGFR showed moderate chronic kidney disease (mean: 35.50 ± 2.02, 33.14 ± 1.63, and 39.97±1.84 ml/min/1.73m2 in the 3 groups respectively); 54 (52.9%) patients had hyperphosphataemia (>1.4mmo/L); 43 (42.2%) had normophosphataemia (0.6-1.4mmol/L); 5 (4.9%) had hypophosphataemia (<0.6mmol/L). eGFR improved significantly from 1 month (≥60, 58.65 ± 1.11, and 51.76 ±1.59 ml/min/1.73m2; p=0.04, <0.001, 0.67 respectively), with a relapse at 9 months in TDFtreated subjects (50.10 ± 1.89 ml/min/1.73m2). TDF/FTC/EFV resulted in significantly greater reduction in plasma phosphate than ZDV/3TC/NVP (p=0.031), but not significantly different from ZDV/3TC/EFV (p=0.968). Similarly, ZDV/3TC/EFV resulted in significantly greater reduction in plasma phosphate than ZDV/3TC/NVP (p=0.036). FEP% progressively increased with HAART duration, more in TDF-treated and ZDV/3TC/EFV-treated groups than ZDV/3TC/NVP (p=0.014); TRP was elevated (>0.86), implying non-maximal phosphate reabsorption. TmP/GFR values were elevated, (>1.35mmol/l). HIV causes kidney dysfunction with reduced phosphate excretion resulting in hyperphosphataemia but HAART improves renal function. Prolonged use of TDF can cause renal toxicity with hypophosphataemia as fractional excretion progressively increased with duration of therapy unlike ZDV/3TC/NVP. The use of different third agents (either NVP or EFV) in zidovudine-based therapy results in significantly different plasma phosphate levels; ZDV/3TC/EFV, like TDF/FTC/EFV, resulted in significantly greater decline in plasma phosphate than ZDV/3TC/NVP. Thus, Evafirenz (EVF) may have similar or synergistic adverse effects with tenofovir disoproxil fumarate (TDF).

Improvement of bone mineral density and markers of proximal renal tubular function in chronic hepatitis B patients switched from tenofovir disoproxil fumarate to tenofovir alafenamide.

Tenofovir alafenamide (TAF) is a novel prodrug that reduces tenofovir plasma levels by 90% compared to tenofovir disoproxil fumarate (TDF), resulting in decreased bone mineral density (BMD) loss and renal toxicity. We aimed to study changes in BMD and markers of renal function of chronic hepatitis B (CHB) patients previously treated with TDF who were switched to TAF in as early as 12weeks. This was a prospective single-arm open-label study of 75 CHB patients treated with TDF 300mg daily who were switched to TAF 25mg daily and followed for 24weeks. All patients had been treated with TDF for at least 12months and had HBV DNA <21IU/mL at the time of switch. BMD and markers of renal function were taken on the day of switch and repeated after 12 and 24weeks of TAF treatment. Hip and spine bone mineral density significantly increased from baseline to week 12 (+12.9% and +2.4%, respectively, P<0.01). There were significant decreases in urinary beta-2-microglobulin to creatinine and retinol-binding protein to creatinine ratios by week 12 (P<0.01 for both). Mean estimated glomerular filtration rate (GFR) did not change. Tubular reabsorption of phosphate was decreased at week 24 (P<0.05). In conclusion, CHB patients previously treated with TDF experienced significant improvement in bone density and some markers of renal tubular function and as early as 12weeks after switching to TAF. Bone density changes associated with TDF may not be entirely related to renal handling of phosphate.