Fractional Excretion Of Phosphate Research Articles

Short and long-term effects of kidney donation on mineral and bone metabolism

BackgroundLiving kidney donors (LKD) experience an abrupt decline in glomerular filtration rate (GFR) resulting in abnormalities of mineral and bone metabolism (MBD), and this may have implications for skeletal health. We prospectively studied acute and long term MBD adaptation of LKD from two kidney transplant centers (São Paulo, Brazil and Miami, USA).MethodsRenal function and MBD parameters longitudinally after kidney donation (baseline – D0, day 1, 14, 180 and 360 post-operatively) were measured in 74 patients (40 y, 73% female, 54% Brazilian). A subset of 20 donors from Brazil were reassessed after 10 years of nephrectomy.ResultsAt baseline, Brazilian donors presented lower intact FGF23 (20.8 vs. 80.1 pg/mL, P < 0.01) and higher PTH (47.4 vs. 40.1, P = 0.04) than their US counterparts. GFR decreased to 63% of its baseline levels just after donation but improved 10% during the first year. PTH levels increased on D1, returning to baseline levels on D14, while FGF23 remained higher than baseline over the first year. LKD had a significant reduction of serum phosphate on D1, which returned to baseline levels on D180. A higher fractional excretion of phosphate (FEP) was noted since D14. After 10 years of donation, 20 LKD presented a sustained reduction in GFR (74.8 ± 14mL/min). There was a return to baseline in serum FGF23 [21.8 (18–30) pg/mL] and FEP, accompanied by an increase in serum calcium. PTH remained elevated (57.9 ± 18 pg/mL), whereas serum calcitriol and Klotho were lower than before the donation.ConclusionsThe abrupt decline in kidney mass is associated with an increase in PTH and FGF23 that is not explained by phosphate retention. In a long-term evaluation, LKD showed a sustained drop in GFR, with lower serum calcitriol and Klotho, and higher PTH. The effects of these changes should be investigated in further studies.

7999 Tumor Induced Osteomalacia Caused By Glomangiopericytoma

Abstract Disclosure: N. Kabir: None. E. Campbell: None. S. Singh: None. Introduction: Tumor induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused primarily by FGF-23 secreting tumors. Excessive production of FGF23 causes hypophosphatemia, decreased phosphate resorption in the gut, increased renal phosphate wasting, and decreased activation of Vitamin D. This leads to decreased bone density, bone pain, proximal muscle weakness, impaired gait, and recurrent fractures. Case Presentation: 44 year old male with a history of recurrent insufficiency fractures and weakness. At the time of evaluation, he reported fracture of tibial growth plate, sacral fracture, and metatarsal stress fracture. Other symptoms included bone pain, fatigue, muscle weakness, and intercostal muscle spasms with exertion. His pain was debilitating, requiring crutches to ambulate. Available labs at that time were significant for hypophosphatemia (1.3 mg/dL), elevated ALP (160 U/L), low 25OH-vitamin D (26 ng/mL), and normal calcium (8.7 mg/dL). Urine studies demonstrated phosphaturia (fractional excretion of phosphate, 62.4%). FGF23 level resulted at the upper limit of normal (210 RU/mL). Pending further evaluation, burosumab was started. Further work up included a 68Ga-PET-DOTATATE scan revealing a somatostatin receptor expressing soft tissue mass in the left sphenoid sinus and posterior left ethmoid sinus. The scan also demonstrated impending bilateral femur fractures, prior rib fractures, and sacral insufficiency fractures. Based on these findings, he was admitted to the hospital and underwent prophylactic, intramedullary nail fixation of his bilateral femur fractures. He underwent resection of skull base tumor with the final pathology revealing a sinonasal glomangiopericytoma. Immunohistochemical stain was positive for CD99 and cyclin D1, and focally positive for SMA, consistent with histopathologic diagnosis. Patient required prolonged inpatient rehabilitation to recover independent ambulation. Discussion: Sinonasal glomangiopericytoma (SNGP) is a mesenchymal tumor that accounts for &amp;lt;0.5% of all nasal and sinus tumors. TIO due to SNGP is extremely rare, with only a few cases reported since the 1990s. As seen with our patient, TIO from SNGP rarely presents with sinonasal symptoms, and can often be overlooked. Our patient hadb significant progression of disease and disability due to numerous delays in diagnosis and management. Definitive cure for TIO can be achieved with complete surgical resection of the tumor, but failure to diagnose in a timely manner can result in decline in quality of life. Our takeaway from this case is that providers should obtain FGF23 levels, especially in the setting of hypophosphatemia and phosphaturia, to complete the work up for osteomalacia. Presentation: 6/1/2024

8400 An Unusual Case of Brittle Bone Disease

Abstract Disclosure: S.M. Middleton: None. M. Mogri: None. Introduction: We present the case of a now 21-month-old F with prenatally suspected skeletal dysplasia; subsequent evaluation revealed concern for a form of brittle bone disease that has not been previously described. Clinical Case: The patient was delivered at 37.0 weeks gestational age via C-section. There had been prior prenatal concerns for a possible skeletal dysplasia. A skeletal survey done on day-of-life 2 noted generalized demineralization of her bones, shortening/bowing of the long bones, an acute right proximal ulnar fracture, and evidence of multiple discontinuous healed rib fractures. A repeat skeletal survey done at day-of-life 19 demonstrated worsening skeletal findings with a very poorly mineralized skull, shortening of the clavicles and extremities, progressive fractures in all extremities and further bowing of the limbs, progressive rib fractures with callus formation, and multiple vertebral bodies with stature loss concerning for compression fractures. Directed genetic testing for osteogenesis imperfecta was negative, so whole exome sequencing was pursued and identified variants of unknown significance in the KAT6B and WDR35 genes not previously described, noting that the patient was heterozygous for both. She was suspected to be a carrier for the WDR35 mutation as it is inherited in an autosomal recessive fashion, and parental genetic testing revealed that the patient’s father carried the same KAT6B mutation and was phenotypically normal. Mutations in these genes have been described in disorders associated with bone abnormalities (such as genitopatellar syndrome and cranioectodermal dysplasia 2), but with different clinical presentations. During the course of her care, she was also identified to have hypophosphatemia shortly after birth and concerns for phosphate wasting; she was noted to have a high fractional excretion of phosphate in the setting of low serum phosphorus despite enteral phosphorus supplementation. She additionally was found to have an elevated FGF23 level at the same time the suspected renal phosphate wasting was identified. Her total calcium has remained normal with normal PTH values; her 25-OH vitamin D has also been normal. She has subsequently been successfully managed on sodium phosphate and calcitriol supplementation, as well as regular zolendronate infusions, without recurrence of fractures, and is clinically doing well with improvements in her respiratory status and overall development. Conclusion: This patient illustrates a severe case of brittle bone disease that presently does not have a clear etiology, though could represent a novel genetic mutation that has not been described and could subsequently be identified with continued review of her genetic testing in the future. Reporting her case could be beneficial to other patients with similar skeletal disease in helping to identify an underlying cause. Presentation: 6/3/2024

Safety of tenofovir alafenamide in people with HIV who experienced proximal renal tubulopathy on tenofovir disoproxil.

Twenty-eight individuals who experienced proximal renal tubulopathy (PRT, Fanconi syndrome) while receiving tenofovir disoproxil initiated tenofovir alafenamide (TAF) and were followed for 5 years. None developed recurrent PRT or experienced significant changes in estimated glomerular filtration rate (by creatinine or cystatin-C), albuminuria, proteinuria, retinol-binding proteinuria, fractional excretion of phosphate, alkaline phosphatase, or bone mineral density at the lumbar spine. These data suggest that TAF is a well tolerated treatment option for individuals vulnerable to developing PRT.

Unveiling the heightened susceptibility: Exploring early hypophosphatemia in critically ill trauma patients

BackgroundPhosphorus is a vital mineral crucial for various physiological functions. Critically ill trauma patients frequently experience hypophosphatemia during the immediate post-traumatic phase, potentially impacting outcomes. This study aims to investigate the incidence of early hypophosphatemia in critically major trauma patients. MethodsIn this prospective observational study, trauma patients admitted to the intensive care unit (ICU) within one day were enrolled. These patients were categorized into Hypo-P groups and Non-hypo groups based on the development of new-onset hypophosphatemia within 72 h after feeding. The primary outcome assessed was the incidence of new-onset hypophosphatemia. The secondary outcomes included ICU and hospital stay, ventilation duration, and mortality. Results76.1% of patients developed a new onset of hypophosphatemia within 72 h after feeding. The Hypo-P group had significantly longer ICU stays (8.1 days ± 5.5 vs. 4.4 days ± 3.1; p = 0.0251) and trends towards extended hospital stay, ventilation duration, and higher mortality. Additionally, they demonstrated significantly higher urine fractional excretion of phosphate (FEPO4) on the first ICU day (29.2% ± 14.23 vs. 19.5% ± 8.39; p = 0.0242). ConclusionCritically ill trauma patients exhibited a significantly higher incidence of early hypophosphatemia than typical ICU rates, indicating their heightened vulnerability. The significantly high urine FEPO4 underscores the crucial role of renal loss in disrupting phosphate metabolism in this early acute phase after trauma. A significant correlation was observed between hypophosphatemia and longer ICU stays. Monitoring and managing phosphate levels may influence outcomes, warranting further investigation.

#2925 PI3K/AKT/mTOR pathway regulates renal expression of Klotho

Abstract Background and Aims Renal Klotho expression decreases early in chronic kidney disease (CKD), increasing circulating FGF23 and phosphate levels. This negatively affects renal disease progression and cardiovascular complications. Preserving renal Klotho expression is of interest, but the underlying mechanisms are unclear. During early stages of CKD, kidneys activate mechanisms of hypertrophy, in which the PI3K/Akt/mTOR pathway plays a role. The main negative regulator of this pathway is PTEN, which reduces the activation of canonical insulin signaling. Kidney transplantation is the treatment of choice for patients with end-stage kidney disease. However, complications may appear after transplantation, such as allograft reaction, compromising the function and the integrity of the transplanted kidney. Different immunosuppressants are currently administered to prevent this response, such as mTOR inhibitors or calcineurin antagonists. We aimed to investigate the role of PTEN and the PI3K/AKT/mTOR pathway in kidney Klotho levels and their possible implication in CKD. Method We measured renal Klotho levels, circulating FGF23, and phosphate in mice lacking PTEN in renal proximal tubular cells (PTEC) and in HK2 cells in vitro. We also examined normal mice with models of decreased renal mass caused by uninephrectomy (UNX) and 5/6 nephrectomy (SNX). Additionally, we tested the effect of mTOR inhibition. We analyzed PTEN and Klotho expression in kidney samples from CKD patients. Furthermore, we stablished whether there are improvements in Klotho expression in patients treated with an mTOR inhibitor versus other treatments. Results We found that PTEC with downregulated PTEN exhibited decreased Klotho expression both in vitro and in vivo, accompanied by increased mTOR activity. Animals with PTEN elimination in PTEC also showed increased circulating phosphate and FGF23 levels, as well as a decrease in the fractional excretion of phosphate. These alterations were normalized by treatment with rapamycin. Normal mice with UNX or SNX exhibited increased renal IGF-1 expression and activation of the PI3K/AKT/mTOR pathway. Furthermore, these mice showed a reduction in renal Klotho expression and an increase in circulating FGF23 and phosphate. Both of these alterations were restored with rapamycin administration. In renal samples from CKD patients, we observed a positive correlation between the expression of PTEN and KLOTHO. Finally, kidney transplanted patients treated during 9 months with mTOR have an increase of 22.8% Klotho levels and patients with other treatments a 14%. Conclusion The overactivation of the PI3K/AKT/mTOR pathway in PTEC modulates Klotho levels in the kidney. Our findings represent a significant advancement in the search for new therapeutic targets to maintain and prevent reductions in renal Klotho levels, potentially benefiting kidney disease patients.

#1333 SGLT2 inhibitors as a treatment for Fanconi-Bickel syndrome: a case report

Abstract Background and Aims Fanconi-Bickel syndrome is an ultra-rare genetic disease characterized by SLC2A2 mutation encoding for the basolateral glucose transporter (GLUT2) in the proximal tubule of the nephron. This defective transport ultimately leads to accumulation of glycogen and dysfunction of proximal tubule cells. This manifests clinically as the renal Fanconi syndrome and eventually kidney failure. Systemic complications of proximal tubule injury include metabolic acidosis, bone demineralization and, for some not completely elucidated reasons, dysglycemia. Method We present the case of a 43-year-old man who was diagnosed with Fanconi-Bickel syndrome (homozygous splice site mutation in SLC2A2). He had a history of infantile-onset renal Fanconi syndrome, hypercalciuria and bilateral nephrolithiasis, osteoporosis, bilateral sensorineural deafness and non-insulin dependent type 2 diabetes. At referral the patient presented with CKD G2, non-anion gap metabolic acidosis, slightly elevated serum calcium, decreased serum phosphate, suppressed PTH and hypercalciuria (Table 1), despite oral supplementation of phosphate, bicarbonate and vitamin D. We hypothesized that SGLT2i in this patient may halt the progressive proximal tubule injury by preventive glucose uptake and help the management of diabetes. Results Fractional excretion of phosphate (FEPO4) and urinary retinol-binding protein (RBP)-creatinine ratio, two markers of proximal tubular injury, were stable after 2 months of SGLT2i therapy (Fig. 1). Conclusion To date, Fanconi-Bickel syndrome does not have a specific treatment. Standard of care includes supplements of fluids and electrolytes to counterbalance proximal tubular injury and management of complications such as diabetes. SGLT2i use has been described in a mouse model of another glycogen storage disease (GSD1b), whose underlying defect is different from that of Fanconi-Bickel but presents with a similar phenotype [2]. Data showed that gliflozins prevents glycogen accumulation and restores proximal tubule cells’ function. Using the same rationale, the administration of SGLT2i in adult patients with Fanconi-Bickel syndrome may prevent further proximal damage and slow the progression towards end-stage kidney disease. In conclusion, we hypothesize a potential benefit of SGLT2i in adult patients affected by Fanconi-Bickel syndrome.

#1905 Sex differences in primary distal renal tubular acidosis: a single-centre retrospective study

Abstract Background and Aims The kidney has been described as one of the most estrogen-responsive organs after reproductive ones. Many non-X-linked renal diseases present with sex differences. Although not completely elucidated, an influence of estrogens has been described in several transporters along the renal tubule such as the Na+/phosphate cotransporter (NaPi-IIa) in the proximal tubule, the Na+/K+/2Cl⁻ cotransporter (NKCC) in the thick ascending limb of the loop of Henle, the thiazide-sensitive Na+/Cl⁻ cotransporter (NCC) in the distal convoluted tubule and the epithelial sodium channel (ENaC) expressed by the principal cells of the collecting duct. Our study aimed to investigate possible phenotypic sex differences over the natural history of primary distal renal tubular acidosis (dRTA), a rare genetic condition characterized by impaired urinary acidification in the collecting duct that results in non-anion gap metabolic acidosis, hypokalemia, hypercalciuria, nephrolithiasis and nephrocalcinosis, which can lead to chronic kidney disease (CKD). Method We included a cohort of 31 genetically confirmed dRTA patients (19 women and 12 men) followed at the London Tubular Centre. We retrospectively collected data from 2012 to 2023. Estimated glomerular filtration rate (eGFR) was calculated with the CKD-EPIcr formula. Hypokalemia was defined as serum potassium &amp;lt; 3.5 mmol/L, hypercalciuria was defined as urinary calcium/creatinine (uCa/Cr) &amp;gt; 0.7 mmol/mmol and acidosis was defined as HCO3− ≤ 22 mmol/L. Data were analyzed using non-parametric Mann-Whitney as appropriate (Prism GraphPad 8.0.2). A p value &amp;lt; 0.05 was considered as statistically significant. Results Baseline characteristics and prevalence of different mutations are shown in Table 1. At baseline, both cohorts were young, with preserved kidney function. 60% of women were acidotic compared to 50% of men, and 30% of men were hypokalemic compared to 8% of women. The majority of patients in both cohorts presented with overt hypercalciuria (60% of women vs 90% of men). Prevalence of nephrolithiasis and nephrocalcinosis was similar among women and men. At baseline, no statistically significant difference between sexes was found for serum or urinary parameters. Interestingly, men exhibited a tendency towards higher annual mean slope of eGFR (−3.3 ± 2.5 mL/min/1.73 m2) compared to women (−0.5 ± 1.5 mL/min/1.73 m2) in a statistically significant fashion (Fig. 1a). Although not statically significant, we noticed a tendency towards higher fractional excretion of phosphate (FEPO4) (Fig. 1b) and dyslipidemia in men (Fig. 1c). There was no difference in PTH between the two groups (Fig. 1c). Conclusion Men affected by primary dRTA are at increased risk of CKD progression, tend to have a more severe phenotype at baseline and appear to be more dyslipidemic than women. This is consistent with findings in the literature that report accelerated CKD progression and higher cardiovascular morbidity and mortality in men. To our knowledge, this is the first study reporting sex differences in primary dRTA.

#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.

P-17 Hypophosphatemia related to intravenous iron therapy: A case report

Abstract Introduction Intravenous iron supplementation is a good alternative to oral iron replacement in iron deficiency anaemia. Intravenous iron formulations such as ferric carboxymaltose allow administration of high doses of elemental iron and enable correction of total iron deficit in one or two infusions. An important complication of ferric carboxymaltose is hypophosphatemia caused by increased secretion of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). In this case, we aimed to present our patient with this rare side effect of intravenous iron replacement. Clinical Case A 40-year-old female patient who has no chronic systemic disease was admitted to our endocrinology service for fatigue and weakness. In the patient's history, it was learned that she had been treated with 2500 mg intravenous iron replacement (ferric carboxymaltose) for iron deficiency anaemia in the last month. In the laboratory tests; serum phosphorus 1.05 mg/dl (normal 2.5-4.5 mg/dl), corrected calcium 8.45 mg/dl (normal 8.4-10.2 mg/dl), 25-OH vitamin D 31.4 µg/L (normal &amp;gt;30 µg/L), parathormone 83.2 pg/ml (normal 15-65 ng/ml), alkaline phosphatase 63 U/L (normal 35-105 U/L). Fractional excretion of phosphate (FePO4) confirmed renal phosphate wasting (FePO4: 28.6%; normal &amp;lt;5%). Urinary protein and glucose were negative. FGF23 measured 71 pg/ml (normal &amp;lt;59 pg/mL). Intravenous iron-induced hypophosphataemia was suspected. After initiation of oral phosphate and 1,25-dihydroxyvitamin D3 supplementation, serum phosphate rose to reference range (Figure 1). The patient was taken to outpatient follow-up. Conclusion Physicians should be aware of hypophosphatemia as a common complication of intravenous iron therapy and monitor serum phosphate concentrations in patients receiving repeated doses.Figure 1.Patient phosphorus data during follow-up

#5799 COMPENSATORY HYPERTROPHY OF THE KIDNEY CONTRIBUTES TO LOSS OF KLOTHO KIDNEY THROUGH PAKT SIGNALING

Abstract Background and Aims Chronic kidney disease (CKD) represents a significant public health burden worldwide, mainly driven by the increase of the incidence of associated risk factors like diabetes. Decreased renal Klotho expression is an early feature of CKD, driving an increase on circulating FGF23 and phosphate. These alterations in mineral metabolism have a direct negative impact on the progression of renal dysfunction and can cause bone alterations, vascular calcification and heart failure. In parallel, during the early stages of CKD, kidneys activate molecular mechanisms of hypertrophy in an attempt to counteract the loss of renal function. The PI3K/Akt/mTOR pathway, activated by growing factors like insulin-like growing factor-1 (IGF-1) participates in compensatory renal growth. The aim of the present study is to investigate the possible role of PI3K/Akt activation on renal Klotho levels during renal compensatory hypertrophy. Method We generated a mice model of kidney compensatory hypertrophy (UNX mice) in which kidney klotho levels and circulating mineral metabolism parameters were analyzed. Furthermore, some of the mice were treated with inhibitors of the PI3K/Akt/mTOR pathway. In vitro, proximal tubular epithelial human cells (PTEC) were stimulated with IGF-1 in order to activate the PI3K/Akt pathway, and the effects on Klotho expression were determined. Results UNX mice present with an activation of the PI3K/Akt/mTOR pathway in kidney, which correlates with the loss on renal Klotho expression. Moreover, UNX mice showed an increase on both, plasma phosphate and FGF23, and a decrease in the fractional excretion of phosphate (% FEPi). Renal function, estimated by BUN plasma levels, was unaltered. Pharmacological inhibition of the pathway restored Klotho and decreased FGF23 levels, normalizing renal phosphate excretion and blood levels. In vitro, IGF-1 stimulated PI3K/Akt activation in PTEC and induced a decline on Klotho expression, which was restored with PI3K/AKT inhibitors. Conclusion The overactivation of PI3K/Akt/mTOR pathway in renal hypertrophy modulates Klotho expression and has direct effects on FGF23 and phosphate. Our findings constitute an important breakthrough in the research of new therapeutic targets in order to maintain renal Klotho levels, and it may be useful in the treatment of kidney disease patients.

Calcification Propensity (T50) Predicts a Rapid Decline of Renal Function in Kidney Transplant Recipients.

Serum creatinine level, proteinuria, and interstitial fibrosis are predictive of renal prognosis. Fractional excretion of phosphate (FEP)/FGF23 ratio, tubular reabsorption of phosphate (TRP), serum calcification propensity (T50), and Klotho's serum level are emerging as determinants of poor kidney outcomes in CKD patients. We aimed at analysing the use of FGF23, FEP/FGF23, TRP, T50, and Klotho in predicting the rapid decline of renal function in kidney allograft recipients. We included 103 kidney allograft recipients in a retrospective study with a prospective follow-up of 4 years. We analysed the predictive values of FGF23, FEP/FGF23, TRP, T50, and Klotho for a rapid decline of renal function defined as a drop of eGFR > 30%. During a follow-up of 4 years, 23 patients displayed a rapid decline of renal function. Tertile of FGF23 (p value = 0.17), FEP/FGF23 (p value = 0.78), TRP (p value = 0.62) and Klotho (p value = 0.31) were not associated with an increased risk of rapid decline of renal function in kidney transplant recipients. The lower tertile of T50 was significantly associated with eGFR decline >30% with a hazard ratio of 3.86 (p = 0.048) and remained significant in multivariable analysis. T50 showed a strong association with a rapid decline of renal function in kidney allograft patients. This study underlines its role as an independent biomarker of loss of kidney function. We found no association between other phosphocalcic markers, such as FGF23, FEP/FGF23, TRP and Klotho, with a rapid decline of renal function in kidney allograft recipients.

Hepatic phosphate uptake and subsequent nerve-mediated phosphaturia are crucial for phosphate homeostasis following portal vein passage of phosphate in rats

Fibroblast growth factor 23, parathyroid hormone, and 1,25-dihydroxyvitamin D are critical in phosphate homeostasis. Despite these factors’ importance, regulators of phosphaturia in the acute postprandial phase remain largely unknown. This study investigated the mechanism of acute phosphate regulation in the postprandial phase in rats. Duodenal administration of radiolabeled phosphate (32P) showed that 32P levels in the inferior vena cava (IVC) blood were lower than those in the portal vein (PV) blood. Serum phosphate concentration transiently increased 5 min after phosphate solution administration through IVC, while it was maintained after the administration through PV. Phosphate administration through both IVC and PV resulted in increased fractional excretion of phosphate (FEPi) at 10 min without elevation of the known circulating factors, but urinary phosphate excretion during the period was 8% of the dose. Experiments using 32P or partial hepatectomy showed that the liver was one of the phosphate reservoirs. The elevation of FEPi and suppression of sodium-phosphate cotransporter 2a in the kidney at 10 min was attenuated in rats with SCH23390, hepatic denervation, or renal denervation, thus indicating that the liver communicated with the kidney via the nervous system to promote phosphaturia. These results revealed previously unknown mechanisms for serum phosphate maintenance.

Effect of anti-retroviral regimen on proximal tubular function in Zambian adolescents and young adults living with HIV: A cross sectional study

Background: Tenofovir regimens remain the preferred formulations in the HIV guidelines for adolescents and young adults in Zambia and globally. However, some adolescents and young adults are maintained on abacavir by clinicians because of anxiety about possible proximal tubular dysfunction from tenofovir. We assessed the effect of two regimens on proximal tubular function in adolescents and young adults living with HIV. Methods: This was a cross-sectional study involving 180 participants with HIV receiving either tenofovir or abacavir for ≥12 months at the largest tertiary teaching hospital. Two first-morning urine and blood specimens were collected and analyzed for proximal tubular markers, glomerular function, electrolytes, and routine monitoring tests. Proximal tubular function was determined by measuring the fractional excretion of phosphate (FePO4). Proximal tubular dysfunction was defined by FePO4 ≥20% regardless of serum phosphate and FePO4 ≥10-20% when serum phosphate was below 0.81mmol/L. Results: The prevalence of proximal tubular dysfunction was 6% and was higher in the tenofovir group than the abacavir (10% vs. 2%, p&lt;0.058). However, after adjusting for potential confounders, tenofovir was not associated with worse proximal tubular function. Age, urine b2-microglobulin: creatinine ratio, C-reactive protein, and urine protein: creatinine ratio was all associated with worsening proximal tubular dysfunction. Reduced estimated glomelurar filtration rate (eGFR) was found in four (2.2%) participants; three of which were on tenofovir. Conclusions: Proximal tubular dysfunction defined by FePO4 was more prevalent in the tenofovir group than the abacavir group, but not after adjusting for age. Our findings should be interpreted with caution as age differences between the two groups confounded the results.

Mineral bone disorder in children with chronic kidney disease: Data from the KNOW-Ped CKD (Korean cohort study for outcome in patients with pediatric chronic kidney disease) study.

Children with chronic kidney disease (CKD) are at high risk of mineral bone disorder (MBD), which leads to fractures, growth retardation, and cardiovascular disease. We aimed to comprehensively understand the relationship between renal function and factors related to MBD and evaluate the prevalence and distribution characteristics of MBD, specifically among Korean patients from the KNOW-PedCKD cohort. From the baseline data of the KNOW-PedCKD cohort, we examined the prevalence and distribution of MBD in 431 Korean pediatric CKD patients, including the level of corrected total calcium, serum phosphate, serum alkaline phosphatase, serum intact parathyroid hormone (iPTH), fibroblast growth factor 23 (FGF-23), serum vitamin D, fractional excretion of phosphate (FEP), and bone densitometry Z-scores. The median serum calcium level remained relatively normal regardless of the CKD stage. The levels of 1,25-dihydroxy vitamin D, urine calcium-to-creatinine ratio, and bone densitometry Z-score significantly decreased with advancing CKD stage, while those of serum phosphate, FGF-23, and FEP significantly increased with CKD stage. The prevalence of hyperphosphatemia (17.4%, 23.7%, and 41.2% from CKD stages 3b, 4, and 5, respectively) and hyperparathyroidism (37.3%, 57.4%, 55.3%, and 52.9% from CKD stages 3a, 3b, 4, and 5, respectively) significantly increased with the CKD stage. Prescriptions of medications, such as calcium supplements (39.1%, 42.1%, 82.4%), phosphate binders (39.1%, 43.4%, 82.4%), and active vitamin D (21.7%, 44.7%, and 64.7%) significantly increased with CKD stage 3b, 4, and 5, respectively. The results demonstrated the prevalence and relationship of abnormal mineral metabolism and bone growth according to CKD stage in Korean pediatric CKD patients for the first time.

A rare case of concomitant hypophosphatemic osteomalacia and neurofibromatosis type 1

Abstract Introduction Neurofibromatosis type 1 is a rare genetic disorder with an increased susceptibility to develop skeletal abnormalities. However, the association of hypophosphatemic osteomalacia and neurofibromatosis type 1 is extremely rare. Herein, we report a case of hypophosphatemic osteomalacia in concomitant with neurofibromatosis type 1. Clinical Case A 45-year-old Turkish female patient, who was followed up in another hospital due to osteoporosis and kyphoscoliosis, applied to us with the complaints of persistent bone pain and inability to walk. She had no chronic diseases other than osteoporosis. The physical examination revealed widespread freckling over her trunk and proximal parts of upper and lower extremities and multiple neurofibromas and cafe au lait spots all over her body (figure 1). It was learned that her 2 brothers, mother and daughter also had the widespread freckling. They have no known chronic diseases. She had a severe degree of kyphoscoliosis. She had not have any complaints up to 24 years of age, and low back pain started after delivery. She was diagnosed with osteoporosis at the age of 29. In about 15 years, her height decreased from 167 cm to 135 cm. She had a severe degree of kyphoscoliosis and severe bone pain and was unable to walk on her own because of pain. Bilateral ophthalmic examination revealed no Lisch nodules. Audiometer revealed no abnormalities. Laboratory findings were as follows: Ca: 9.4 (8.4–10.6 mg/dl), phosphorus: 1.8 (2.3–4.7 mg/dl), albumin: 4.2 g/dl, parathormone: 88.3 (11–80 pg/ml), 25 hydroxy vitamin D: 26.1 ug/L, creatinine: 0.4 mg/dl, alkaline phosphatase: 79 (35–105 U/L), the 24-hour urinary excretion of calcium: 187.5 mg/24 h, the 24-hour urinary excretion of phosphorus: 253 mg/24 h, fractional excretion of phosphate: %8.5 and maximum transport of phosphorus in the renal proximal tubules (TmP/GFR): 0.74 (0.88–1.42 mmol/L). According to laboratory data there was a hyperphosphaturia. On the basis of the physical examination, laboratory and radiological findings, she was diagnosed with neurofibromatosis type 1 and hypophosphatemic osteomalacia. Oral phosphate solution (1.5 gram as elemantary phosphorus per day in 3 divided doses) and calcitriol (1 microgram per day in 2 divided doses) were started. After 6 months of therapy, bone pain was significantly decreased and her serum phosphorus level increased. The results of genetic analysis are awaited. Conclusion The coexistence of hypophosphatemic osteomalacia and neurofibromatosis type 1 have been reported in less than 50 cases in the literature. The underlying mechanism is not clarified. The diagnosis of hypophosphatemic osteomalacia should be kept in mind in patients with neurofibromatosis type 1, as they will benefit greatly from oral phosphorus solution and active vitamin D.

Klotho Supplementation Reverses Renal Dysfunction and Interstitial Fibrosis in Remnant Kidney

Introduction: While recent investigations show that klotho exerts renoprotective actions, it has not been fully addressed whether klotho protein supplementation reverses renal damage. Methods: The impacts of subcutaneous klotho supplementation on rats with subtotal nephrectomy were examined. Animals were divided into 3 groups: group 1 (short remnant [SR]): remnant kidney for 4 weeks, group 2 (long remnant [LR]): remnant kidney for 12 weeks, and group 3 (klotho supplementation [KL]): klotho protein (20 μg/kg/day) supplementation on the remnant kidney. Blood pressure, blood and urine compositions with conventional methods such as enzyme-linked immunosorbent assay and radioimmunoassay, kidney histology, and renal expressions of various genes were analyzed. In vitro studies were also performed to support in vivo findings. Results: Klotho protein supplementation decreased albuminuria (−43%), systolic blood pressure (−16%), fibroblast growth factor (FGF) 23 (−51%) and serum phosphate levels (−19%), renal angiotensin II concentration (−43%), fibrosis index (−70%), renal expressions of collagen I (−55%), and transforming growth factor β (−59%) (p < 0.05 for all). Klotho supplementation enhanced fractional excretion of phosphate (+45%), glomerular filtration rate (+76%), renal expressions of klotho (+148%), superoxide dismutase (+124%), and bone morphogenetic protein (BMP) 7 (+174%) (p < 0.05 for all). Conclusion: Our data indicated that klotho protein supplementation inactivated renal renin-angiotensin system, reducing blood pressure and albuminuria in remnant kidney. Furthermore, exogenous klotho protein supplementation elevated endogenous klotho expression to increase phosphate excretion with resultant reductions in FGF23 and serum phosphate. Finally, klotho supplementation reversed renal dysfunction and fibrosis in association with improved BMP7 in remnant kidney.

PSAT189 Severe Hypocalcemia and Hypophosphatemia Associated with Denosumab use in a Chronic Myeloid Leukemia Patient on Imatinib

Abstract Background Hypocalcemia and hypophosphatemia are known side effects of Denosumab, especially in presence of risk factors including underlying chronic kidney disease, osteoblastic metastasis, high bone turnover states, vitamin D deficiency and preexisting hypocalcemia. We report a unique case of prolonged severe hypocalcemia and hypophosphatemia in a patient with CML on Imatinib, treated with Denosumab for osteoporosis. Clinical case A 73-year-old lady with history of CML, on Imatinib for 4 years and osteoporosis with a chronic L1 compression fracture treated with her second dose of Denosumab 3-months back, presented with complaints of numbness and tingling involving the entire body. Labs revealed severe hypocalcemia (calcium 5.6 mg/dL, ionized calcium 2.93 mg/dL), severe hypophosphatemia, (phosphorus of 0.5mg/dL) and a low normal magnesium level of 1.5mg/dL, with normal ALP, liver and kidney function parameters. Of note she had normal calcium, phosphorus and vitamin D levels before receiving denosumab. Further work-up revealed an elevated PTH level of 241 pg/mL, normal 25 hydroxy vitamin D level of 26.0 ng/ml, slightly low 1,25 (OH) vitamin D of 16pg/ml and an elevated FGF 23 of 299RU/mL (normal &amp;lt;180RU/mL). Her calcium and phosphorus levels remained suboptimal despite treatment with up to 24 grams of calcium carbonate supplementation daily, K-phos 1 packet QID and calcitriol 0.25 mcg TID. 24-hour urine calcium and phosphorus levels were low at 4mg/day and 0.2mg/day respectively. Fractional excretion of phosphate was 13.63%, suggesting renal phosphorus wasting, likely from an elevated FGF23. Bone scan showed no metastatic lesion. After discussion with oncology, Imatinib was held inpatient and she was started on intravenous calcium gluconate infusion, and continued on Calcitriol, vitamin D3 and K-phos supplementation. After receiving almost 18gm of calcium gluconate intravenously over 2 days, her hypocalcemia and hypophosphatemia resolved with improvement in symptoms. Conclusion Hypocalcemia is a recognized adverse effect of Denosumab that is seen in patients with underlying risk factors. Emerging data now suggests the deregulatory effect of long term Imatinib therapy on bone formation by inhibition of osteoclastic activity along with transient increase in osteoblastic activity leading to retention and sequestration of calcium and phosphate in bone, resulting in hypocalcemia and hypophosphatemia. Ours is the first reported case of severe hypocalcemia and hypophosphatemia observed in a CML patient on Imatinib after receiving Denosumab, with resistance to high dose oral calcium and phosphate supplementation, requiring intravenous supplementation and transient discontinuation Imatinib. The elevated FGF 23 likely played a key role in severe hypophosphatemia. This unique case addresses the prospect of occurrence of severe hypocalcemia and hypophosphatemia in patients on Imatinib receiving Denosumab, while questioning the possibility of potentiation of the osteoclast inhibitory effect of this medication when used in patients on long term Imatinib therapy. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Proximal tubular renal dysfunction among HIV infected patients on Tenofovir versus Tenofovir sparing regimen in western Kenya.

Tenofovir Disoproxil Fumarate (TDF) is the most widely used Anti-Retroviral Therapy (ART) drug due to its potency, safety profile and World Health Organization (WHO) recommendation. TDF causes proximal tubular renal dysfunction (PTRD) leading to Fanconi syndrome, acute kidney injury and chronic kidney disease. Modest rates (2-4%) of TDF related toxicity based on estimated Glomerular Filtration Rate (GFR) have been described, while TDF-induced PTRD has been reported to be 22%. TDF toxicity is more likely among African patients, it is reversible and TDF may be renal dosed in patients with dysfunction. The objective of this study was to assess proximal tubular renal dysfunction, global renal function, and their determinants among patients on TDF versus TDF-sparing regimen. This was a cross-sectional study among people living with HIV/AIDS (PLWHA) attending the Academic Model Providing Access to Healthcare (AMPATH) program. The primary outcome of interest in this study was PTRD while the secondary outcome of interest was estimated GFR. PTRD was defined as any two of beta-2 microglobulin in urine, metabolic acidosis, normoglycemic glucosuria and fractional excretion of phosphate. Student's t-test, chi-square and their non-parametric equivalents were used to test for statistical significance. Univariate and multivariate logistic regression analysis was carried out. A total of 516 participants were included in the final analysis, 261 on TDF while 255 were on TDF-sparing regimens. The mean (SD) age of all participants was 41.5 (12.6) years with majority being female (60.3%). The proportion of PTRD was 10.0% versus 3.1% in the TDF compared to TDF-sparing group (P<0.001). Mean estimated GFR was 112.8 (21.5) vs 109.7 (21.9) ml/min/1.73mm3 (P = 0.20) for the TDF compared to TDF-sparing group. TDF users were more likely to have PTRD compared to non-TDF users, adjusted Odds Ratio (AOR) 3.0, 95% CI 1.12 to 7.75. There was significant PTRD in the TDF compared to TDF-sparing group without significant difference in estimated GFR. The clinical significance of these findings may not be clear in the short term.