Tubular Reabsorption Of Phosphate Research Articles

Burosumab Efficacy and Safety in Patients with X-Linked Hypophosphatemia: Systematic Review and Meta-analysis of Real-World Data.

To assess the efficacy and safety of burosumab in children and adults with X-linked hypophosphatemia based on real-world evidence. MEDLINE (via PubMed) and Cochrane Library were searched until 18 October 2023 for single-arm (before-after) studies. Registries including Clinicaltrials.gov, EU Clinical Trials, WHO International Clinical Trials Registry Platform, and conference abstracts. The outcomes were a change in serum phosphorus concentrations and change in RSS, a change in serum ALP, bone-specific ALP, a change in the ratio of Tubular maximum reabsorption of Phosphate to Glomerular Filtrate rate, a change in serum 1,25(OH)2D and 25(OH)2D concentrations, change in height Z-score, McMaster Universities Osteoarthritis Index (WOMAC) and safety outcomes. An inverse variance random-effects meta-analysis was applied for data synthesis. Fifteen studies (289 participants) were included. Burosumab treatment improved serum phosphate concentrations [mean difference 0.88mg/dl, 95% confidence interval 0.70 to 1.07, I2 = 92%), Rickets Severity score (mean difference -1.86, 95% confidence interval -2.5 to -1.21, I2 = 71%), serum alkaline phosphate concentrations (mean difference -1.86, 95% confidence interval -2.5 to -1.21, I2 = 71%), serum 1,25(OH)2D concentrations (mean difference 18.91pg/ml, 95% confidence interval 6.39 to 31.43, I2 = 96%) and renal phosphate reabsorption (mean difference 1.22 mg/dl, 95% confidence interval 0.70 to 1.74, I2 93%). Burosumab treatment improved overall clinical and laboratory findings in patients with X-linked hypophosphatemia.

Safety and efficacy of burosumab in improving phosphate metabolism, bone health, and quality of life in adolescents with X-linked hypophosphatemic rickets

Background and objectiveX-linked hypophosphatemic rickets (XLH) is due to loss-of-function mutations in the phosphate-regulating endopeptidase homologue on the X chromosome (PHEX) that lead to increased fibroblast growth factor 23 (FGF23) production. FGF23 excess causes renal phosphate wasting and insufficient 1,25-dihydroxyvitamin D (1,25(OH)2D) synthesis with reduced intestinal phosphate absorption, ultimately resulting in chronic hypophosphatemia.Children with XLH show typical skeletal lesions of rickets, deformities of the lower limbs, stunted growth with disproportionate short stature, bone pain, and physical dysfunctions.Burosumab, a fully human IgG1 monoclonal antibody that binds to FGF23 to inhibit its activity, is more effective to improve the biochemical and clinical signs of XLH than conventional treatment with phosphate supplements and vitamin D active metabolites. Data on adolescents with XLH during the transition period to young adulthood are few.In this prospective case series, we aimed to assess safety and efficacy of burosumab in adolescents with XLH who discontinued long-term conventional therapy. MethodsFive Caucasian adolescents (4 males, 1 female; mean age 15.4 ± 1.5 years) with XLH were recruited and switched from conventional treatment to burosumab (0.8–1.2 mg/kg, s. c. QW2). Burosumab was continued for 12–48 months and, once discontinued, patients were followed-up for 6–12 months. In all patients, serum calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and 1,25(OH)2D levels, and renal tubular reabsorption of phosphate (TmP/GFR) values were assessed at entry and during burosumab. Intact FGF23 plasma levels were measured at entry. Patient-reported outcomes (PROs) were assessed at entry and every 3–6 months to evaluate the impact of low extremity pain, stiffness, and difficulties performing daily activities. ResultsAt entry, all patients showed hypophosphatemia, increased intact FGF23 levels, reduced TmP/GFR, insufficient 1,25(OH)2D levels, and in four out of five increased ALP levels. Two patients had radiological signs of rickets. During burosumab, all patients showed a significant increase in serum phosphate and 1,25(OH)2D levels, and in TmP/GFR values (P < 0.05 - P < 0.0001). Serum ALP levels significantly declined (P < 0.05) to normal values. No changes of serum calcium and PTH levels (PNS) were found during burosumab. PROs significantly improved (P < 0.02 - P < 0.0001) in all patients. Four patients discontinued burosumab when they turned 18 or 19, whereas one continued the treatment since he was still younger than 18 during the study period. Four patients who suspended burosumab showed a rapid decline in serum phosphate and 1,25(OH)2D levels and in TmP/GFR values; serum ALP levels increased, and PROs progressively worsened with a significant reduction in quality of life. These consequences were not observed in the patient who continued burosumab treatment. DiscussionOur data showed that conventional treatment improved only in part the signs and symptoms of XLH. Burosumab was well tolerated and was effective in improving phosphate metabolism, bone health, and PROs. All the benefits of burosumab were lost after its discontinuation. These results suggested that continuing burosumab is required to achieve and maintain the clinical benefits of the treatment during the transition to young adulthood in patients with XLH.

Proteinuria and hematuria as early signs of renal involvement in juvenile idiopathic arthritis.

To evaluate glomerular and tubular renal functions and analyze blood pressure in a cohort of pediatric patients with juvenile idiopathic arthritis (JIA). A total of 40 pediatric patients, 20 (50%) with JIA and 20 (50%) healthy control subjects, were studied, and performed the renal function on 24-h collection and the 24-h ambulatory blood pressure monitoring (ABPM). Moreover, we compared renal function and blood pressure trends between the groups of JIA patients with different disease activities. No statistically significant differences were observed between patients with JIA and healthy children in terms of glomerular filtration rate (GFR), fractional excretion of sodium (FENa), tubular reabsorption of phosphate (TRP), and calcium-creatinine urine ratio (CaU/CrU). In contrast, we observed significantly higher values in JIA patients than in controls for the presence of hematuria (p < 0.0001) and proteinuria (p < 0.0001). Compared to the control group there were significantly higher values of hematuria and proteinuria/day in both groups of JIA patients with low disease activity (respectively, p = 0.0001 and p = 0.0002) and moderate disease activity (respectively p = 0.0001 and p = 0.0012). Systolic and diastolic dipping were significantly reduced in patients with JIA compared with healthy controls (p < 0.0001 and p < 0.0001, respectively). Our study showed that children with JIA, already in the early stages of the disease, have higher values of hematuria and proteinuria, which are early warning signs of nephropathy. Therefore, detailed screening of renal function and pressure monitoring in patients are necessary to monitor their evolution over time.

#2015 Burosumab therapy in adult patients with X-linked hypophosphatemia: a three-year follow-up study

Abstract Background and Aims X-linked hypophosphatemic rickets (XLH) arises from mutations in the PHEX gene, resulting in elevated FGF23 levels, renal phosphate loss, hypophosphatemia, low vitamin D, heightened alkaline phosphatase (AP), and associated bone disorders. In challenging the conventional therapy of vitamin D and phosphate supplements, Burosumab, a monoclonal antibody against FGF23, has shown promise in normalizing phosphate and vitamin D levels in pediatric patients. However, its effectiveness in adult patients with established bone lesions remains an area of investigation. This study aims to present the three-year outcomes of Burosumab therapy on both biochemical and clinical aspects in adult XLH patients. Method The study assessed the efficacy of Burosumab in adult XLH patients (age &amp;gt;18, drug-naïve) before and continuously over three years post-therapy. Monthly assessments of biochemical parameters (phosphatemia, alkaline phosphatase, Tubular Maximum Reabsorption of Phosphate per Glomerular Filtration Rate, TMP/GFR) were conducted before the monthly administration of Burosumab, while clinical improvements were monitored every six months using established tests, including the six-minute walk test, UP and go timed test, and WOMAC Index. Burosumab was administered monthly at a consistent dosage of 1 mg/kg throughout the entire follow-up period. Results In a cohort of five genetically diagnosed XLH patients (average age 45 ± 10 years, average weight 60 ± 10 kg), the average monthly Burosumab dose was 60 ± 10 mg. Baseline values and subsequent changes in Ps, TMP/GFR, WOMAC Index, six-minute walk, and UP and go test are presented in Table 1 and Fig. 1. Importantly, no significant adverse events were reported during the initial year of treatment. Conclusion Burosumab therapy demonstrated excellent tolerability and yielded substantial improvements in biochemical parameters (Ps and TMP/GFR), maintaining stability over the entire three-year follow-up. Alkaline phosphatase levels, initially elevated, exhibited a progressive reduction in the second and third years, eventually reaching values within the normal range. Functional indices, reflective of enhanced strength (improved walk test and UP and go timed test) and diminished pain (optimal WOMAC test score), showcased notable improvements in the first year, persisting with stability during the follow-up period, with the exception of the walk test, which demonstrated a gradual and sustained enhancement. The findings suggest that Burosumab is a well-tolerated and effective therapeutic option for adult XLH patients. The observed reduction in alkaline phosphatase after a year of treatment implies a normalization of bone turnover, while the progressive improvement in the walk test indicates a sustained clinical enhancement likely associated with the chronic positive effects of maintaining biochemical stability.

#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.

Dynamics of Urine Electrolytes in Term Neonates during the 1st Week of Life

Abstract Background: Urine electrolyte assessment is vital for diagnosing and managing neonatal conditions. However, the challenge of urine collection in neonates has resulted in a lack of standardized urine electrolyte reference values. Aim: This study seeks to explore the reference levels and potential trends in serum and urine electrolytes to better understand how the kidneys handle these substances. Methods: Healthy neonates were prospectively enrolled following normal births. Using biochemical methods, blood and urine samples were collected and analyzed on the 1st and 5th postnatal days. Statistical analysis was performed using descriptive statistics and the Wilcoxon matched-pairs signed-rank test. Results: This prospective study enrolled 55 healthy neonates. Significant changes in serum electrolyte concentrations were observed between the 1st and 5th days after birth. Notably, sodium, creatinine, urea nitrogen, and uric acid levels decreased, whereas potassium, calcium, and phosphate levels increased. Urine analysis revealed significant increases in the tubular maximum phosphate reabsorption per glomerular filtration rate and decreases in the fractional excretion of potassium and uric acid by Day 5. Conclusion: This study challenges prevailing assumptions about the stability of neonatal urine electrolytes and highlights dynamic changes in the first postnatal week. These insights lay the groundwork for further research into electrolyte disorders in newborns and have potential implications for improving neonatal care practices.

Multiparametric renal function assessment in cirrhotic patients shows high prevalence of medically actionable changes in multiple modules.

Renal dysfunction is a common complication of cirrhosis, occurring either as part of multiorgan involvement in acute illness or secondary to advanced liver disease. To date, no study has comprehensively assessed multiple renal function parameters in hospitalized patients with cirrhosis through a multiparametric analysis of renal biochemistry markers. We conducted a retrospective, observational study including all consecutive patients hospitalized with cirrhosis who underwent a 43-multiparametric renal function assessment between January 1, 2021, and June 30, 2023. All patients showed at least one of the following renal abnormalities: Kidney Disease: Improving Global Outcomes stage G2 or higher, sodium and/or chloride excretion fraction <1%, electrolyte-free water clearance <0.4mL/min, or tubular maximum phosphate reabsorption capacity <0.8mmol/L. The estimated glomerular filtration rate equations significantly overestimated the measured creatinine clearance with median differences of +14mL/min/1.73m2 (95% CI 6-29) and +9mL/min/1.73m2 (95% CI 2-15) for European Kidney Function Consortium equations, respectively. Notably, 54% and 39% of patients demonstrated estimated glomerular filtration rates exceeding 30% of the measured creatinine clearance when the Chronic Kidney Disease - Epidemiology Collaboration and European Kidney Function Consortium formulas were employed, respectively. Substantial discrepancies in Kidney Disease: Improving Global Outcomes stage assignments were observed between the estimated glomerular filtration rate- and measured creatinine clearance-based assessments. This study underscores the value of a multiparametric renal function assessment as a routine tool for evaluating renal function in patients with cirrhosis. A high prevalence of medically actionable renal abnormalities spanning multiple renal function modules, including alterations in glomerular function, salt and solute-free water excretion, and proximal tubule phosphate reabsorption, has been demonstrated in hospitalized patients with cirrhosis.

Pediatric early-phase anorexia nervosa without hypokalemia exhibiting acute tubular injury: a case report.

Anorexia nervosa can lead to kidney complications. Few studies reported kidney biopsy results in young adults, most of whom had chronic anorexia nervosa, and kidney biopsy findings in pediatric patients with early-phase anorexia nervosa are rarely reported. A 14-year-old girl who lost weight due to excessive exercise and reduced diet was admitted for kidney dysfunction. She was 147cm tall and weighed 32.9kg, with a body mass index of 15.2kg/m2. She was 39kg about a year earlier. Her heart rate and blood pressure were 30-40 beats/min and 108/68mmHg, respectively. She had kidney dysfunction (estimated glomerular filtration rate, 56.6mL/min/1.73 m2). Urine β2-microglobulin was slightly elevated (393μg/L), and percent tubular phosphate reabsorption was low (75.2%), suggesting tubular damage; however, hypokalemia was absent. Kidney dysfunction did not improve with fluid loading. Kidney biopsy revealed that all glomeruli were intact, with no vasculitis, interstitial inflammation or fibrosis on light microscopy. However, proximal tubular epithelial walls were flattened and the brush border was absent, suggesting acute tubular injury. Immunofluorescent staining was negative for immunoglobulins and complement proteins, and electron microscopy showed no significant electron-dense deposition. The patient's serum creatinine gradually declined, normalizing on the 17th day of admission. Unlike previous reports in young adults, kidney dysfunction was observed even in the absence of hypokalemia in the current pediatric patient with early-phase anorexia nervosa. Proximal tubular injury in early-phase anorexia nervosa may be caused by bradycardia without hypokalemia, leading to subsequent kidney dysfunction.

Experience of X-linked hypophosphatemic rickets in the Gulf Cooperation Council countries: case series.

X-linked hypophosphatemic rickets (XLH), the most prevalent form of inherited hypophosphatemic rickets, is caused by loss-of-function mutations in the gene encoding phosphate-regulating endopeptidase homolog, X-linked (PHEX). This case series presents 14 cases of XLH from Gulf Cooperation Council (GCC) countries. The patients' medical history, biochemical and radiological investigative findings, as well as treatment responses and side effects from both conventional and burosumab therapy, are described. Cases were aged 2-40 years at diagnosis. There were two male cases and 12 female cases. All cases were treated with conventional therapy which resulted in a lack of improvement in or worsening of the clinical signs and symptoms of rickets or biochemical parameters. Side effects of conventional therapy included nausea, diarrhea, abdominal pain, nephrocalcinosis, and hyperparathyroidism, which affected the patients' quality of life and adherence to treatment. In the 10 patients treated with burosumab, there was a marked improvement in the biochemical markers of rickets, with a mean increase in serum phosphate of +0.56 mmol/L and tubular maximum phosphate reabsorption (TmP) to glomerular filtration rate (GFR) ratio (TmP/GFR) of +0.39 mmol/L at 12 months compared to baseline. Furthermore, a mean decrease in serum alkaline phosphatase (ALP) of -80.80 IU/L and parathyroid hormone (PTH) of -63.61 pmol/L at 12 months compared to baseline was observed in these patients. Additionally, patients treated with burosumab reported reduced pain, muscle weakness, and fatigue as well as the ability to lead more physically active lives with no significant side effects of treatment. Conventional therapy resulted in a suboptimal response, with a lack of improvement of clinical signs and symptoms. Side effects of conventional therapy included nausea, diarrhea, abdominal pain, nephrocalcinosis, and hyperparathyroidism, which affected the patients' quality of life and adherence to treatment. Burosumab demonstrated marked improvements in the biochemical markers of rickets, in addition to reducing pain, muscle weakness, and fatigue. There were no significant side effects associated with burosumab therapy.

Familial cases with adult-onset FGF23-related hypophosphatemic osteomalacia -A PHEX 3’-UTR change as a possible cause-

Excessive actions of FGF23 cause several kinds of hypophosphatemic rickets/osteomalacia. It is possible that there still remain unknown causes or mechanisms for FGF23-related hypophosphatemic diseases. We report two male cousins who had been suffering form FGF23-related hypophosphatemic osteomalacia. Sequencing of exons and exon-intron junctions of known causative genes for FGF23-related hypophosphatemic diseases and whole genome sequencing were conducted. Luciferase assay was used to evaluate the effect of a detected nucleotide change on mRNA stability. Two cousins showed hypophosphatemia with impaired proximal tubular phosphate reabsorption and high FGF23. Serum phosphate of their mothers was within the reference range. Exome sequencing of the proband detected no mutations. Whole genome sequencing of the patients and their mothers identified a nucleotide change in the 3’-UTR of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) gene (c.*1280_*1287dupGTGTGTGT) which is heterozygous in the mothers and hemizygous in the patients. While sixteen is the most prevalent number of GT repeats, this family had twenty repeats. Luciferase assay indicated that mRNA with 3’-UTR of PHEX with 20 GT repeats was more unstable than that with 16 repeats. Sequencing of exons and exon-intron junctions of known causative genes for FGF23-related hypophosphatemic diseases cannot identify all the genetic causes. Our results strongly suggest that changes of PHEX expression by a nucleotide change in the 3’-UTR is a novel mechanism of FGF23-related hypophosphatemic osteomalacia.

An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH)

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.

Influence of hydroxyurea on tubular phosphate handling in sickle cell nephropathy

ObjectiveThis study aims to evaluate the markers of tubular phosphate handling in adults with sickle cell anemia (SCA) and the influence of hydroxyurea (HU), the degree of anemia and Hb F concentration on these markers. MethodsEighty-eight steady state SCA patients in outpatient follow-up in Fortaleza, Ceara, Brazil and 31 healthy individuals were included in this study. Vitamin D (25OHD) was measured by enzyme-bound fluorescence assay, intact parathyroid hormone (iPTH) by electrochemiluminescence, and serum and urinary phosphate and creatinine by colorimetric methods. Details of Hb F and HU use were obtained from clinical records. Tubular reabsorption of phosphate (TRP) and maximum tubular reabsorption of phosphate (MTRP) were calculated. SCA patients were stratified according to the use of HU, degree of anemia and percentage of Hb F. The significance level was set for p-values <0.05. ResultsCompared to controls the 25OHD level (25 ± 11 vs. 30 ± 9 pg/mL) was lower in SCA, while serum phosphate and MTRP were higher (3.86 ± 0.94 vs. 3.46 ± 0.72 and 3.6 ± 1.21 vs. 3.21 ± 0.53, respectively). There was no significant difference in iPTH, TRP and phosphaturia. Serum phosphate showed correlation with TRP (r = 0.32; p-value = 0.008) and MTRP (r = 0.9; p-value <0.001) in SCA. Patients taking HU, especially those with Hb F >10 % presented reduced serum phosphate levels, and TRP and MTRP rates. Those with mild anemia presented reduced serum phosphate levels and MTRP rates. ConclusionSerum phosphate levels and renal phosphate reabsorption rate were increased in SCA. HU use, high Hb F concentration and total Hb were associated with better control of tubular phosphate handling markers.

Multiple electrolytes imbalances in a patient with inflammatory bowel disease associated with vitamin D deficiency: a case report

BackgroundInflammatory bowel disease involves chronic inflammation and ulceration, primarily Crohn’s disease and ulcerative colitis. The prevalence of inflammatory bowel disease is rising in industrialized countries. We describe the case of a patient with inflammatory bowel disease and multiple electrolyte disturbances that emphasize the link between a vitamin D deficiency and electrolyte imbalances.CaseAn 86‐year‐old Japanese man with severe hypocalcemia, hypophosphatemia, hypokalemia, and hypomagnesemia was referred to the gastroenterology and hepatology department our university hospital for severe diarrhea and abdominal pain. Based on clinical symptoms and biochemical and endoscopic findings, Crohn’s disease, intestinal Behçet’s disease, and intestinal tuberculosis were considered as differential diagnoses, but a final diagnosis was not reached. Prednisolone, azathioprine, and metronidazole were administered, and no apparent electrolyte abnormality was observed at the patient’s admission to our hospital. On the 80th hospital day, marked hypocalcemia, hypophosphatemia, hypokalemia, and hypomagnesemia were noted and prolonged, despite daily supplementation with Ca and inorganic P. At his consultation with our department, we observed decreased fractional excretion of Ca, tubular reabsorption of phosphate, fractional excretion of K, and fractional excretion of Mg, suggesting the depletion of vitamin D and extrarenal wasting of K and Mg. The patient’s serum Ca and inorganic P were quickly elevated in response to treatment with an active form of vitamin D, and his serum levels of K and Mg were restored to the normal range by an intravenous administration of K and Mg. A vitamin D deficiency is not rare in inflammatory bowel disease and is caused primarily by the decreased intestinal absorption of vitamin D. In the management of electrolyte imbalances in patients with inflammatory bowel disease, clinicians must consider the possible development of vitamin D deficiency-related disorders.ConclusionVitamin D deficiency in entero-Behçet’s disease leads to severe hypocalcemia and hypophosphatemia, highlighting the importance of awareness in management.

LMS-Based Pediatric Reference Values for Parameters of Phosphate Homeostasis in the HARP Cohort.

The assessment of phosphate homeostasis in children is challenging due to the marked changes in laboratory parameters during growth and development, and the lack of adequate reference values. To develop Lambda-Mu-Sigma (LMS)-based continuous pediatric reference percentiles for 7 key laboratory parameters of phosphate homeostasis. This cross-sectional, single-center study, the HAnnover Reference values for Pediatrics (HARP) study, included 455 children aged 0.1-18 years (254 boys) from outpatient hospital clinics and a secondary school program. Main outcome measures were LMS-based continuous reference percentiles for serum phosphate, plasma intact fibroblast growth factor 23 (iFGF23), and its cofactor soluble Klotho (sKlotho), tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR), fractional tubular reabsorption of phosphate (TRP), and urinary calcium/creatinine (Ca/Crea) and phosphate/creatinine (Pi/Crea) ratios. LMS-based percentiles and z-scores were established for 7 key laboratory parameters of phosphate homeostasis, which were all found to be age-dependent. Serum phosphate, TmP/GFR, and sKlotho associated with sex. Serum phosphate, TmP/GFR, and urinary Ca/Crea and Pi/Crea levels were highest in infancy and declined until age 18 years, while phosphate and TmP/GFR values reached adult levels earlier in girls compared to boys. iFGF23 concentrations are highest in infancy and fall to a stable plateau by 4 years of age, while sKlotho peaks during adolescence. This is the first report of LMS-based continuous pediatric reference percentiles for key laboratory parameters of phosphate homeostasis that allow calculation of standardized patient z-scores to facilitate test result interpretation in children and adolescents.

Elderly-onset calcinosis of hyperphosphataemic familial tumoural calcinosis/hyperostosis-hyperphosphataemia syndrome: the role of comorbid scleroderma.

A 73-year-old woman with type 2 diabetes mellitus was referred to our department for glycaemic control. Physical examination revealed two subcutaneous hard masses around the left shoulder and the right hip joint. The patient could not fully extend her fingers because of skin sclerosis in both hands. Laboratory studies showed hyperphosphataemia and a high ratio of renal tubular maximum reabsorption of phosphate to glomerular filtration rate. There were no abnormalities in serum calcium, creatinine, alkaline phosphatase, and intact parathyroid hormone levels, whereas serum fibroblast growth factor 23 was low. Hyperphosphataemic familial tumoural calcinosis/hyperostosis-hyperphosphataemia syndrome (HFTC/HHS) was diagnosed using whole genome sequencing that revealed a novel frameshift beyond the 584th threonine located in the lectin domain of UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 associated with a duplication of the 1748th thymine in the coding region of the corresponding gene. Furthermore, anti-nuclear, anti-centromere, and anti-cardiolipin antibodies were positive, implying that comorbid limited type scleroderma might play a role in tumoural calcinosis (TC) development. A low phosphate diet was prescribed with phosphate-lowering medications, including aluminium hydroxide, acetazolamide, and sevelamer hydrochloride. The patient displayed a decrease in serum phosphate levels from 6.5 to 5.5 mg/dL 10 months after the initiation of treatment, but her TC had not improved during treatment for more than 1 year. This case was interesting because the patient with HFTC/HHS exhibited TC despite being over her 60s, and subsequent scleroderma might contribute to the specific clinical course. When HFTC/HHS presents with elderly-onset TC, the involvement of comorbidities in exacerbating TC should be considered. HFTC/HHS occurs on an autosomal recessive basis, but its clinical course and manifestations differ significantly throughout the cases. HFTC/HHS may be undiagnosed until later in life because of its rarity, unfamiliarity, and phenotype diversity; therefore, HFTC/HHS should be included in the differential diagnosis of elderly patients with unexplained hyperphosphataemia or ectopic calcinosis. Comorbidities, including rheumatologic disorders, may contribute to developing HFTC/HHS-associated calcinosis.

Uncertainty in measurement and the renal tubular reabsorption of phosphate.

The ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR) is used toevaluate renal phosphate transport. TmP/GFR is most probably calculated using the formula described by Kenny and Glen or obtained from the nomogram described by Walton and Bijvoet. Even though the calculation itself is well described, no attention has been given to its measurement uncertainty (MU). The aim of this study is to provide a procedure for evaluating the MU of the Kenny and Glen formula; a procedure which is based on the Evaluation of measurement data- Guide to the expression of uncertainty in measurement (GUM). TmP/GFR is a quantity value calculated from the input of measured values for serum (plasma) phosphate and creatinine, plus measured values of urine phosphate and creatinine. Given the measurement uncertainty associated with these input quantities, the GUM describes the mathematical procedures required to determine the uncertainty ofthe calculated TmP/GFR. From a medical laboratory perspective, these input uncertainties are the standard deviations of the respective internal quality control estimates for serum and urine phosphate, plus serum and urine creatinine. Based on representative measurements for the input quantities and their associated standard uncertainties, the expanded relative uncertainty for a calculated TmP/GFR is approximately 3.0-4.5 %. With the continued relevance of the TmP/GFR procedure and the use of creatinine clearance as an estimate of GFR, the addition of an uncertainty estimate is important as an adjunct to this diagnostic procedure.

Occipital bone and tumor-induced osteomalacia: a rare tumor site for an uncommon paraneoplastic syndrome

IntroductionTumor-induced osteomalacia (TIO) is an uncommon paraneoplastic syndrome due to the overproduction of fibroblast growth factor 23 (FGF23). It is predominantly caused by mesenchymal tumors and cured upon their complete removal. Non-surgical treatment is an alternative option but limited to specific clinical conditions.MethodsWe report a challenging case of TIO caused by a tumor involving the occipital bone. We also performed a literature review of TIO caused by tumors localized at this site, focusing on clinical findings, treatment, and outcomes.ResultsThe patient, a 62-year-old male, presented with a long-lasting history of progressive weakness. Biochemical evaluation revealed severe hypophosphatemia due to low renal tubular reabsorption of phosphate with raised intact FGF23 values. A 68 Ga-DOTATATE PET/TC imaging showed a suspicious lesion located in the left occipital bone that MRI and selective venous catheterization confirmed to be the cause of TIO. Stereotactic gamma knife radiosurgery was carried out, but unfortunately, the patient died of acute respiratory failure.To date, only seven additional cases of TIO have been associated to tumors located in the occipital bone. Furthermore, the tumor involved the left side of the occipital bone in all these patients.ConclusionThe occipital region is a difficult area to access so a multidisciplinary approach for their treatment is required. If anatomical differences could be the basis for the predilection of the left side of the occipital bone, it remains to be clarified.

#4205 ESTIMATED PROXIMAL TUBULE FLUID PHOSPHATE (EPTFP) CONCENTRATION: AN EARLY MARKER OF CHRONIC KIDNEY DISEASE-MINERAL AND BONE DISORDER (CKD-MBD)?

Abstract Background and Aims MBD develops early in CKD and is associated with kidney damage progression, but CKD-MBD markers, of initial CKD-MBD like FGF23 and α-Klotho are not available in clinical practice. Recently ePTFp has been proposed as a new early marker of MBD. In fact, the progressive reduction of nephron number, with the proportional FGF23 increments, reduce renal tubular phosphate reabsorption to maintain phosphate balance. As a consequence, PTFp concentration per single nephron progressively increases, leading to progression of kidney tubular damage. For this reason, PTFp could represent an innovative early marker of CKD-MBD. We evaluated the relationship of ePTFp with FGF23, α-Klotho and kidney damage progression. Method In CKD stage G2-4, we assayed serum FGF23, α-Klotho and ePTFp [ePTFp = (Phosphaturia / creati-ninuria) x creatininemia x 3,33]. The progression of CKD was evaluated during 5 years and the patients were splitted in two groups according to the basal ePTFp median value. 30 healthy subject pro-vided the normal value of ePTFp. Results In 68 CKD patients (age 58,9 ± 15.6 y.o. eGFR 45 ± 21 mL/min), ePTFp averaged 2.4±1.3 mg/mg which was higher than the control group (ePTFp = 1.2±0.5; p&amp;lt;.01). ePTFp increased progressively along with the increasing CKD stages with values higher than the control group since stage 2 (Table 1). ePTFp showed a positive correlation with FGF23 (r: 0.69; p&amp;lt;.001) and a negative correlation with α-Klotho (r:-237; p&amp;lt;.05) and eGFR (r:-647; p&amp;lt;.001). Follow-up was available in 30 patients (Table 2) and showed a greater reduction of eGFR in the 15 patient with higher ePTFp (threshold 2 mg/dl) (Fig. 1). Conclusion Our data show early and progressive increments of ePTFp in CKD along with increments of FGF23 and PTH and reduction of α-Klotho, as per reciprocal pathophysiologic dependence. ePTFp values &amp;gt; than 2 mg/dl identified patients at highest risk of CKD progression. Accordingly, ePTFp, a surrogate of renal tubular cells phosphate overload, could represent a novel marker of CKD-MBD development and of increased risk of kidney damage potentially helpful to make therapeutic choice.

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.

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).