Hypophosphatemia after Start of Medical Nutrition Therapy Indicates Early Refeeding Syndrome and Increased Electrolyte Requirements in Critically Ill Patients but Has No Impact on Short-Term Survival.

Refeeding syndrome (RFS) is a potentially life-threatening complication in malnourished (critically ill) patients. The presence of various accepted RFS definitions and the inclusion of heterogeneous patient populations in the literature has led to discrepancies in reported incidence rates in patients requiring treatment at an intensive care unit (ICU). We conducted a prospective observational study from 2010 to 2013 to assess the RFS incidence and clinical characteristics among medical ICU patients at a large tertiary center. RFS was defined as a decrease of more than 0.16 mmol/L serum phosphate to values below 0.65 mmol/L within seven days after the start of medical nutrition therapy or pre-existing serum phosphate levels below 0.65 mmol/L. Overall, 195 medical patients admitted to the ICU were included. RFS was recorded in 92 patients (47.18%). The presence of RFS indicated significantly altered phosphate and potassium levels and was accompanied by significantly more electrolyte substitutions (phosphate, potassium, and magnesium). No differences in fluid balance, energy delivery, and insulin requirements were detected. The presence of RFS had no impact on ICU length of stay and ICU mortality. Screening for RFS using simple diagnostic criteria based on serum phosphate levels identified critically ill patients with an increased demand for electrolyte substitutions. Therefore, stringent monitoring of electrolyte levels is indicated to prevent life-threatening complications.

Nomogram for predicting early hypophosphatemia in term infants.

BACKGROUND: Physiological processes rely on phosphate, which is an essential component of adenosine triphosphate (ATP). Hypophosphatasia can affect nearly every organ system in the body. It is crucial to monitor newborns with risk factors for hypophosphatemia and provide them with the proper supplements. We aimed to evaluate the risk factors and develop a nomogram for early hypophosphatemia in term infants. METHODS: We conducted a retrospective study involving 416 term infants measured serum phosphorus within three days of birth. The study included 82 term infants with hypophosphatemia (HP group) and 334 term infants without hypophosphatemia (NHP group). We collected data on the characteristics of mothers, newborn babies, and childbirth. Furthermore, univariate and multivariate logistic regression analyses were performed to identify independent risk factors for hypophosphatemia in term infants, and a nomogram was developed and validated based on the final independent risk factors. RESULTS: According to our analysis, the multivariate logistic regression analysis showed that male, maternal diabetes, cesarean delivery, lower serum magnesium, and lower birth weight were independent risk factors for early hypophosphatemia in term infants. In addition, the C-index of the developed nomogram was 0.732 (95% CI = 0.668-0.796). Moreover, the calibration curve indicated good consistency between the hypophosphatemia diagnosis and the predicted probability, and a decision curve analysis (DCA) confirmed the clinical utility of the nomogram. CONCLUSIONS: The analysis revealed that we successfully developed and validated a nomogram for predicting early hypophosphatemia in term infants.

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.

Refeeding syndrome and psychopharmacological interventions in children and adolescents with Anorexia Nervosa: a focus on olanzapine-related modifications of electrolyte balance.

This study aims to investigate the potential correlation between the use of olanzapine, a psychopharmacological intervention commonly prescribed in Anorexia Nervosa treatment, and the occurrence of Refeeding Syndrome. Despite the acknowledged nutritional and biochemical impacts of olanzapine, the literature lacks information regarding its specific association with Refeeding Syndrome onset in individuals with Anorexia Nervosa. This is a naturalistic, retrospective, observational study, reporting the occurrence of Refeeding Syndrome in children and adolescents with Anorexia Nervosa, treated or untreated with olanzapine. Dosages and serum levels of olanzapine were assessed for potential associations with the occurrence of Refeeding Syndrome and specific variations in Refeeding Syndrome-related electrolytes. Overall, 113 patients were enrolled, including 46 (41%) who developed a Refeeding Syndrome. Mild (87%), moderate (6.5%), and severe (6.5%) Refeeding Syndrome was described, at a current average intake of 1378 ± 289 kcal/day (39 ± 7.7 kcal/kg/die), frequently associated with nasogastric tube (39%) or parenteral (2.2%) nutrition. Individuals receiving olanzapine experienced a more positive phosphorus balance than those who did not (F(1,110) = 4.835, p = 0.030), but no difference in the occurrence of Refeeding Syndrome was documented. The mean prescribed doses and serum concentrations of olanzapine were comparable between Refeeding Syndrome and no-Refeeding Syndrome patients.    Conclusion: The present paper describes the occurrence of Refeeding Syndrome and its association with olanzapine prescriptions in children and adolescents with Anorexia Nervosa. Olanzapine was associated with a more positive phosphorus balance, but not with a different occurrence of Refeeding Syndrome. Further, longitudinal studies are required. What is Known: • Refeeding Syndrome (RS) is a critical complication during refeeding in malnourished patients, marked by electrolyte (phosphorus, magnesium, potassium) imbalances. • Olanzapine, an atypical antipsychotic with nutritional and biochemical impacts, is used in Anorexia Nervosa (AN) treatment, however data concerning its association with RS are lacking. What is New: • The study observed RS in 46/113 (41%) young patients with AN. • Olanzapine-treated individuals showed a higher improvement in serum phosphate levels than untreated ones, although no impact on the occurrence of Refeeding Syndrome was observed.

Family analysis and literature study of hereditary hypophosphatemic rickets with hypercalciuria.

BACKGROUND: Hereditary hypophosphatemia rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder characterised by reduced renal phosphate reabsorption leading to hypophosphataemia, rickets and bone pain. Here, we present a case of HHRH in a Chinese boy. CASE PRESENTATION: We report a 11-year-old female proband, who was admitted to our hospital with bilateral genuvarum deformity and short stature. Computed Tomography (CT) showed kidney stones, blood tests showed hypophosphatemia, For a clear diagnosis, we employed high-throughput sequencing technology to screen for variants. Our gene sequencing approach encompassed whole exome sequencing, detection of exon and intron junction regions, and examination of a 20 bp region of adjacent introns. Flanking sequences are defined as ±50 bp upstream and downstream of the 5' and 3' ends of the coding region.The raw sequence data were compared to the known gene sequence data in publicly available sequence data bases using Burrows-Wheeler Aligner software (BWA, 0.7.12-r1039), and the pathogenic variant sites were annotated using Annovar. Subsequently, the suspected pathogenic variants were classified according to ACMG's gene variation classification system. Simultaneously, unreported or clinically ambiguous pathogenic variants were predicted and annotated based on population databases. Any suspected pathogenic variants identified through this analysis were then validated using Sanger sequencing technology. At last, the proband and her affected sister carried pathogenic homozygous variant in the geneSLC34A3(exon 13, c.1402C > T; p.R468W). Their parents were both heterozygous carriers of the variant. Genetic testing revealed that the patient has anLRP5(exon 18, c.3917C > T; p.A1306V) variant of Uncertain significance, which is a rare homozygous variant. CONCLUSION: This case report aims to raise awareness of the presenting characteristics of HHRH. The paper describes a unique case involving variants in both theSLC34A3andLRP5genes, which are inherited in an autosomal recessive manner. This combination of gene variants has not been previously reported in the literature. It is uncertain whether the presence of these two mutated genes in the same individual will result in more severe clinical symptoms. This report shows that an accurate diagnosis is critical, and with early diagnosis and correct treatment, patients will have a better prognosis.

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 and Genomics 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.

Complex intrinsic abnormalities in osteoblast lineage cells of X-linked hypophosphatemia: Analysis of human iPS cell models generated by CRISPR/Cas9-mediated gene ablation.

X-linked hypophosphatemia (XLH) is caused by inactivating variants of the phosphate regulating endopeptidase homolog X-linked (PHEX) gene. Although the overproduction of fibroblast growth factor 23 (FGF23) is responsible for hypophosphatemia and impaired vitamin D metabolism, the pathogenesis of XLH remains unclear. We herein generated PHEX-knockout (KO) human induced pluripotent stem (iPS) cells by applying CRISPR/Cas9-mediated gene ablation to an iPS clone derived from a healthy male, and analyzed PHEX-KO iPS cells with deletions extending from exons 1 to 3 and frameshifts by inducing them to differentiate into the osteoblast lineage. We confirmed the increased production of FGF23 in osteoblast lineage cells differentiated from PHEX-KO iPS cells. In vitro mineralization was enhanced in osteoblast lineage cells from PHEX-KO iPS cells than in those from isogenic control iPS cells, which reminded us of high bone mineral density and enthesopathy in patients with XLH. The extracellular level of pyrophosphate (PPi), an inhibitor of mineralization, was elevated, and this increase appeared to be partly due to the reduced activity of tissue non-specific alkaline phosphatase (TNSALP). Osteoblast lineage cells derived from PHEX-KO iPS cells also showed the increased expression of multiple molecules such as dentine matrix protein 1, osteopontin, RUNX2, FGF receptor 1 and early growth response 1. This gene dysregulation was similar to that in the osteoblasts/osteocytes of Phex-deficient Hyp mice, suggesting that common pathogenic mechanisms are shared between human XLH and Hyp mice. Moreover, we found that the phosphorylation of CREB was markedly enhanced in osteoblast lineage cells derived from PHEX-KO iPS cells, which appeared to be associated with the up-regulation of the parathyroid hormone related protein gene. PHEX deficiency also affected the response of the ALPL gene encoding TNSALP to extracellular Pi. Collectively, these results indicate that complex intrinsic abnormalities in osteoblasts/osteocytes underlie the pathogenesis of human XLH.

Sustained hypophosphatemia after denosumab in a patient on hemodialysis.

An 81-year-old Caucasian man who had commenced thrice weekly hemodialysis (HD) three months earlier, presented with a hip fracture, two vertebral fractures and a bone mineral density T-score of -3.6. He had received weekly iron sucrose infusions for 6 weeks and alphacalcidol on dialysis days. Although he suffered from coeliac disease and cirrhosis, he was fully ambulatory and well-nourished. He was normocalcaemic with a marginally low plasma phosphate and the PTH was 11.8 pmol/L (<2-times the upper range of the assay). In view of his severe osteoporosis, it was decided to treat him with denosumab (dmab). Laboratory assessment 2 weeks post dmab showed severe hypophosphatemia and hypocalcemia; phosphate 0.11 mmol/L and ionized calcium 0.83 mmol/L, and he was admitted for intravenous phosphate infusion. Three months later he remained on a phosphate supplement. The case illustrates that, in addition to the risks of hypocalcemia in patients with kidney failure and high bone turnover, kidney failure patients without evidence of high bone turnover, can also be at risk of hypocalcemia and severe hypophosphatemia requiring acute hospitalization and phosphate infusion. The potential role of compromised phosphate absorption versus increased deposition will be discussed. We recommend a cautious approach to dmab therapy in patients on dialysis, with evaluation of bone turnover and serum phosphate levels prior to initiation of treatment.

An infant developing hypercalcemia and hypophosphatemia due to the use of exclusively almond milk.

OBJECTIVES: Plant-based milk alternatives are increasingly utilized in children with cow milk allergy, lactose intolerance, and personal preference. However, notable differences exist in mineral content between cow milk and plant-based alternatives. Almond milk, in particular, varies in mineral and caloric content across different brands. This case report highlights a toddler who developed hypercalcemia and hypophosphatemia attributed to almond milk consumption. CASE PRESENTATION: A fourteen-month-old girl with a history of biliary atresia underwent liver transplant at seven months of age. She was exclusively consuming almond milk for two months prior to presentation. She was admitted to the hospital for severe hypercalcemia (14.6 mg/dL) and hypophosphatemia (1.6 mg/dL). She had elevated random urine calcium to creatinine ratio (2.56 mg/g) and low urine phosphorus to creatinine ratio (<0.44 mg/g) were noted. Parathyroid hormone (PTH) level was appropriately suppressed (<6 pg/mL), while 1,25 dihydroxyvitamin D level was slightly elevated at 88 pg/mL. Initial management included intravenous fluids, followed by a switch to a formula with higher phosphorus and lower calcium concentrations. The patient was discharged after six days with normalized calcium and phosphorus levels, which remained within the normal range. CONCLUSIONS: Although plant-derived milk serves as a viable alternative to cow milk, careful consideration of mineral content, particularly in infants and toddlers, is imperative. Sole reliance on almond milk for nutritional needs in this population is not recommended. Caregivers should be informed about the potential risks associated with almond milk consumption in infants and toddlers.

Cost-utility analysis of ferric derisomaltose versus ferric carboxymaltose in patients with inflammatory bowel disease and iron deficiency anemia in England.

AIMS: Anemia is the most common extraintestinal complication of inflammatory bowel disease (IBD), with approximately half of cases caused by iron deficiency (ID). Intravenous iron is the preferred ID anemia (IDA) treatment where oral iron is contraindicated, ineffective or not tolerated, or where ID correction is urgent. The objective was to evaluate the cost-utility of ferric derisomaltose (FDI) versus ferric carboxymaltose (FCM) in patients with IBD and IDA in England, in whom IV iron treatment is preferred. MATERIALS AND METHODS: A patient-level simulation model was developed, capturing quality of life (QoL) differences based on SF-36v2 data from the PHOSPHARE-IBD randomized controlled trial, monitoring and incidence of post-infusion hypophosphatemia, and number of iron infusions required. Analyses were conducted over a five-year time horizon from the Department of Health and Social Care (DHSC) perspective, with healthcare provider and societal perspectives adopted in separate analyses. Future costs and effects were discounted at 3.5% per annum and one-way and probabilistic sensitivity analyses were performed. RESULTS: FDI increased quality-adjusted life expectancy by 0.075 QALYs versus FCM from 2.57 QALYs to 2.65 QALYs per patient. Patients receiving FDI required 1.63 fewer iron infusions over the five-year time horizon, driving infusion-related cost savings of GBP 496 per patient (GBP 2,188 versus GBP 1,692) from the DHSC perspective. Costs of monitoring and treating hypophosphatemia after FCM were GBP 226, yielding total savings of GBP 722 per patient (GBP 2,414 versus GBP 1,692) over the five-year time horizon. FDI also led to reduced costs versus FCM in the societal and provider analyses and was therefore the dominant intervention across all three perspectives. LIMITATIONS: The analysis did not capture patient adherence, hypophosphatemic osteomalacia, or fractures. CONCLUSIONS: Results showed that FDI improved patient QoL and reduced direct healthcare expenditure versus FCM in patients with IBD and IDA in England.

Ferric derisomaltose (FDI) is an intravenous iron approved for the treatment of clinically diagnosed iron deficiency in the United Kingdom (UK), and can be an important therapeutic option for patients with inflammatory bowel disease (IBD), who require regular and rapid iron replenishment. Ferric carboxymaltose (FCM) is the sole alternative intravenous iron formulation available in the UK, but is associated with reduced blood phosphate levels, potentially causing fatigue and weakening of the bones. We conducted an economic analysis to weigh the costs and clinical outcomes associated with FDI and FCM in the UK, for patients with IBD and iron deficiency anemia (IDA). The main clinical difference we investigated was reduced blood phosphate levels, which occurred more often after FCM than FDI. We also incorporated recent quality of life data from a clinical study, and calculated the number of infusions (and associated costs) of each iron formulation, that patients would require over five years. Clinical data were obtained from published medical literature, while cost data came from UK sources including the 2022/2023 National Tariff Payment System and the British National Formulary. Our model showed that FDI was associated with quality of life improvements, fewer overall infusions per treatment course, and reduced costs compared to FCM, from the English Department of Health and Social Care perspective, the societal perspective, and the perspective of individual healthcare providers (namely NHS Trusts) within NHS England. FDI is therefore likely to represent the best value intravenous iron for the treatment of IDA with IBD in the UK.

An examination of adults with atypical anorexia nervosa at admission to treatment at higher levels of care: An attempt to increase diagnostic clarity.

OBJECTIVE: Anorexia nervosa (AN) is a serious illness with a high mortality rate and multiple physiological complications. The vague definition of atypical AN allows for subjective interpretation. This retrospective study aimed to focus future research on the operational definition of atypical AN by examining four factors associated with atypical AN at admission to higher level of care treatment. METHODS: Adults with atypical AN (n = 69) were examined within sample analyses among four groups: (1) >10% versus ≤10% weight loss; (2) weight loss within the previous 3 months versus >3 months; (3) engaging in purging behaviors versus absence of purging behaviors; and (4) endorsing versus not endorsing significant cognitive aspects of AN. RESULTS: Patients with atypical AN endorsed elevated ED cognitions on the Eating Disorder Examination-Questionnaire and depressive symptoms; a lack of association was found between weight loss severity and weight loss time frame with depressive symptoms, eating concern, and restraint. Purging behavior was associated with a higher expected body weight percentage (%EBW) and dietary restraint, while greater AN cognitions were associated with a higher EBW and weight loss percentage. Few patients demonstrated bradycardia, hypophosphatemia, or amenorrhea. DISCUSSION: This study demonstrated the severity of ED cognitions and depressive symptoms in this atypical AN sample and provided directions for future studies in the nosology of atypical AN. It may be important to distinguish between individuals with atypical AN who are purging and those who are not. Atypical AN was associated with a low frequency of physiological disturbances. PUBLIC SIGNIFICANCE: This study provides further clarification regarding the operational definition of atypical AN; currently, a constellation of symptoms under Other Specified Feeding or Eating Disorders. This study was consistent with previous research in reporting severe eating disorder cognitions in adults with atypical AN, and noted the potential importance of distinguishing a purging distinction. A minority of patients in this study had physiological impairments.

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

BACKGROUND: Inflammatory 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. CASE: An 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. CONCLUSION: Vitamin D deficiency in entero-Behçet's disease leads to severe hypocalcemia and hypophosphatemia, highlighting the importance of awareness in management.

Rare renal proximal tubular dysfunctions in primary biliary cholangitis.

INTRODUCTION: Renal involvement of primary biliary cholangitis (PBC) usually presents as distal renal tubular acidosis. Proximal tubular (PT) dysfunctions in PBC were rarely reported with unclear clinicopathological characteristics and renal prognosis. METHODS: We identified 11 cases of PBC with PT dysfunctions (PBC-PT). Their medical document, kidney pathology, and follow-up data were retrospectively reviewed and analyzed. RESULTS: The 11 PBC-PT patients were mainly middle-aged (57.8 ± 5.2 years) females (81.8%). Most of them were asymptomatic PBC (7, 63.6%) with a high prevalence of elevated serum immunoglobulin M (IgM, 81.8%) and G (IgG, 54.5%) levels. In the kidney, they had a mean estimated glomerular filtration rate (eGFR) level of 46.54 ± 23.03 ml/min/1.73m2, and 81.8% of them had eGFR below 60 ml/min/1.73m2. They showed different degrees of PT dysfunctions, including hyperuricosuria, hypouricemia, normoglycemic glycosuria, generalized aminoaciduria, hyperphosphaturia, and hypophosphatemia. Their kidney pathology showed tubulointerstitial nephritis with lymphoplasmacytic infiltrates, brush border defects, and proximal tubulitis. After glucocorticoids treatment, the PT dysfunctions manifesting as hypophosphatemia, hypouricemia, and renal glycosuria all recovered, and the eGFR levels were improved from 43.24 ± 19.60 ml/min/1.73m2 to 55.02 ± 21.14 ml/min/1.73m2 (p = 0.028), accompanied by significant improvements of serum IgM levels (from 5.97 ± 4.55 g/L to 2.09 ± 1.48 g/L, p = 0.019). CONCLUSIONS: The PT dysfunctions were rare in PBC patients, and glucocorticoids treatment could benefit the improvements of eGFR and tubular functions.

Prevalence of FGF23 elevation in patients with hypophosphatemia.

BACKGROUND AND AIMS: To investigate the contribution of FGF23 in explaining the cases of hypophosphatemia observed in clinical practice, we aimed to determine for the first time the prevalence of FGF23 elevation in patients with hypophosphatemia and to describe the different mechanisms of FGF23-related hypophosphatemic disorders. MATERIALS AND METHODS: We performed a prospective, observational, multicenter, cohort study of 260 patients with hypophosphatemia. Blood measurements (PTH, 1,25-dihydroxyvitamin D, bone alkaline phosphatase, 25-hydroxyvitamin D, and FGF23) were performed on a Liaison XL® (DiaSorin) analyzer. RESULTS: Primary elevation of FGF23 (>95.4 pg/mL) was reported in 10.4% (95CI: 7.0-14.7) of patients (n = 27) with hypophosphatemia, suggesting that at least 1 in 10 cases of hypophosphatemia was erroneously attributed to an etiology other than FGF23 elevation. Patients with elevated blood FGF23 were grouped according to the etiology of the FGF23 elevation. Thus, 10 patients had a renal pathology, chronic kidney disease or post-renal transplantation condition. The remaining patients (n = 17) had the following etiologies: malignancies (n = 9), benign pancreatic tumor (n = 1), post-cardiac surgery (n = 4), cirrhosis (n = 2), and chronic obstructive pulmonary disease (n = 1). CONCLUSION: In order to improve patient management, it seems essential to better integrate plasma FGF23 measurement into the routine evaluation of hypophosphatemia.

Successful Burosumab Treatment in an Adult Patient with X-Linked Hypophosphatemia and Chronic Kidney Disease Stage 3b.

X-linked hypophosphatemic rickets (XLH) is a genetic cause of renal hypophosphatemia due to inactivation of the PHEX gene, with an inappropriate concentration of fibroblast growth factor 23 (FGF23). Burosumab, an anti-FGF23 monoclonal antibody, is a validated treatment for XLH, but its use in patients with chronic kidney disease (CKD) has not been validated. A 61-year-old man with XLH developed CKD during follow-up. Conventional treatment (phosphate salts and active vitamin D analogs) was poorly tolerated. Treatment with burosumab was decided at a multi-professional meeting. Before burosumab initiation, his measured glomerular filtration rate was 44 mL/min/1.73 m2 defining CKD stage 3b and intact FGF23 concentration was very high (4496.0 ng/mL, N: 22.7-93.1) due to both XLH and CKD. Severe hypophosphatemia was observed after the two first injections of burosumab at usual doses (1 mg/kg monthly) and concomitant discontinuation of the conventional treatment. After increasing the dose and reducing the interval between doses (1.3 mg/kg every three weeks) from the third injection, serum phosphate concentration normalized and remained around the lower limit of the normal range. A local cutaneous reaction was observed just after the second injection, but did not recur. We report for the first time the efficacy and good short-term tolerance of burosumab in a patient with XLH and CKD, subject to a higher dosage aimed at achieving a phosphatemia at the lower limit of the normal range.

Disease Manifestations and Complications in Dutch X-Linked Hypophosphatemia Patients.

X-linked hypophosphatemia (XLH) is the most common monogenetic cause of chronic hypophosphatemia, characterized by rickets and osteomalacia. Disease manifestations and treatment of XLH patients in the Netherlands are currently unknown. Characteristics of XLH patients participating in the Dutch observational registry for genetic hypophosphatemia and acquired renal phosphate wasting were analyzed. Eighty XLH patients, including 29 children, were included. Genetic testing, performed in 78.8% of patients, showed a PHEX mutation in 96.8%. Median (range) Z-score for height was - 2.5 (- 5.5; 1.0) in adults and - 1.4 (- 3.7; 1.0) in children. Many patients were overweight or obese: 64.3% of adults and 37.0% of children. All children received XLH-related medication e.g., active vitamin D, phosphate supplementation or burosumab, while 8 adults used no medication. Lower age at start of XLH-related treatment was associated with higher height at inclusion. Hearing loss was reported in 6.9% of children and 31.4% of adults. Knee deformities were observed in 75.0% of all patients and osteoarthritis in 51.0% of adult patients. Nephrocalcinosis was observed in 62.1% of children and 33.3% of adults. Earlier start of XLH-related treatment was associated with higher risk of nephrocalcinosis and detection at younger age. Hyperparathyroidism longer than six months was reported in 37.9% of children and 35.3% of adults. This nationwide study confirms the high prevalence of adiposity, hearing loss, bone deformities, osteoarthritis, nephrocalcinosis and hyperparathyroidism in Dutch XLH patients. Early start of XLH-related treatment appears to be beneficial for longitudinal growth but may increase development of nephrocalcinosis.

Biochemical Clusters as Substitutes of Bone Biopsies in Kidney Transplant Patients.

Bone and mineral metabolism abnormalities are frequent in kidney transplant recipients and have been associated with cardiovascular morbidity. The primary aim of this study was to analyse the association between routine clinically available biochemical evaluation, non-routine histomorphometric bone evaluation, and vascular disease in kidney transplanted patients. A cross-sectional analysis was performed on 69 patients, 1-year after kidney transplantation. Laboratory analysis, radiography of hands and pelvis, bone biopsy, bone densitometry, and coronary CT were performed. One-year post-transplantation, nearly one-third of the patients presented with hypercalcemia, 16% had hypophosphatemia, 39.3% had iPTH levels > 150 pg/mL, 20.3% had BALP levels > 40 U/L, and 26.1% had hypovitaminosis D. Evaluation of extraosseous calcifications revealed low Adragão and Agatston scores. We divided patients into three clusters, according to laboratory results routinely used in clinical practice: hypercalcemia and hyperparathyroidism (Cluster1); hypercalcemia and high BALP levels (Cluster2); hypophosphatemia and vitamin D deficiency (Cluster 3). Patients in clusters 1 and 2 had higher cortical porosity (p = 0.001) and osteoid measurements, although there was no difference in the presence of abnormal mineralization, or low volume. Patients in cluster 2 had a higher BFR/BS (half of the patients in cluster 2 had high bone turnover), and most patients in cluster 1 had low or normal bone turnover. Cluster 3 has no differences in volume, or turnover, but 60% of the patients presented with pre-osteomalacia. All three clusters were associated with high vascular calcifications scores. Vascular calcifications scores were not related to higher bone mineral density. Instead, an association was found between a higher Adragão score and the presence of osteoporosis at the femoral neck (p = 0.008). In conclusion, inferring bone TMV by daily clinical biochemical analysis can be misleading, and bone biopsy is important for assessing both bone turnover and mineralization after kidney transplantation, although hypophosphatemia combined with vitamin D deficiency is associated with abnormal mineralization. The presence of hypercalcemia with high levels of PTH or high levels of BALP, or hypophosphatemia and vitamin D deficiency should remind us to screen vascular calcification status of patients.Clinical Research: ClinicalTrials.gov ID NCT02751099.

Fibroblast growth factor 23 and its role in bone diseases.

Fibroblast growth factor 23 (FGF23) has been casually linked to numerous hypophosphatemic bone diseases, however connection with bone loss or fragility fractures is still a matter of debate. The purpose of this review is to explore and summarise the known actions of FGF23 in various pathological bone conditions. Besides implication in bone mineralisation, elevated FGF23 showed a pathological effecton bone remodelling, primarily by inhibiting osteoblast function. Unlike the weak association with bone mineral density, high values of FGF23 have been connected with fragility fracture prevalence. This review shows that its effects on bone are concomitantly present on multiple levels, affecting both qualitative and quantitative part of bone strength, eventually leading to impaired bone strength and increased tendency of fractures. Recognising FGF23 as a risk factor for the development of bone diseases and correcting its levels could lead to the reduction of morbidity and mortality in specific groups of patients.