Low Serum Phosphate Research Articles

The impact of severe depression on the survival of older patients with end-stage kidney disease.

Incidence of depression increases in patients with end-stage kidney disease (ESKD). We evaluated the association between depression and mortality among older patients with ESKD, which has not been studied previously. This nationwide prospective cohort study included 487 patients with ESKD aged >65 years, who were categorized into minimal, mild-to-moderate, and severe depression groups based on their Beck Depression Inventory-II (BDI-II) scores. Predisposing factors for high BDI-II scores and the association between the scores and survival were analyzed. The severe depression group showed a higher modified Charlson comorbidity index value and lower serum albumin, phosphate, and uric acid levels than the other depression groups. The Kaplan-Meier curve revealed a significantly lower survival in the severe depression group than in the minimal and mild-to-moderate depression groups (p = 0.011). Multivariate Cox regression analysis confirmed that severe depression was an independent risk factor for mortality in the study cohort (hazard ratio, 1.39; 95% confidence interval, 1.01-1.91; p = 0.041). Additionally, BDI-II scores were associated with modified Charlson comorbidity index (p = 0.009) and serum albumin level (p = 0.004) in multivariate linear regression. Among the three depressive symptoms, higher somatic symptom scores were associated with increased mortality. Severe depression among older patients with ESKD increases mortality compared with minimal or mild-to-moderate depression, and patients with concomitant somatic symptoms require careful management of their comorbidities and nutritional status.

Constipation and clinical outcomes in peritoneal dialysis: Results from Thailand PDOPPS.

Patient-reported outcome measures (PROMs) are widely recognized as valuable predictors of clinical outcomes in peritoneal dialysis (PD). Our study aimed to explore the connections between patient-reported constipation and clinical outcomes. We assessed constipation in patients across 22 facilities participating in the Thailand Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) from 2014 to 2017. Constipation diagnosis utilized objective assessment tools such as the Bristol stool form scale (BSFS) and a self-reported questionnaire known as the constipation severity score (CSS). The BSFS is a 7-level scale that visually inspects feces based on texture and morphology, while the CSS measures constipation duration and severity using a 5-point Likert scale for various factors. We employed Cox proportional hazards model regression to determine the associations between constipation and clinical outcomes, including mortality, hemodialysis (HD) transfer and peritonitis. Among 975 randomly selected PD patients from 22 facilities, 845 provided written informed consent, and 729 completed CSS questionnaire. Constipation was prevalent in the PD population (13%), particularly among older patients, those who were caregiver dependent, had diabetes and poorer nutritional status (indicated by lower time-averaged serum albumin, potassium, creatinine and phosphate concentrations). Twenty-seven percent of which experiencing symptoms of constipation for over a year. Notably, self-reported constipation at baseline was significantly associated with a shorter time to first peritonitis and higher rates of peritonitis and death. However, no significant association was found between constipation and HD transfer after adjusting for various factors, including age, gender, PD vintage, comorbidities, shared frailty by study sites and serum albumin. Patient-reported constipation independently correlated with increased risks of peritonitis and all-cause mortality, though no such correlation was observed with HD transfer. These findings underscore the need for further investigation to identify effective interventions for constipation in PD patients.

Cystic Parathyroid Adenomas as a Risk Factor for Severe Hypercalcemia.

(1) Background: Parathyroid cystic adenomas (PCA) are rare entities representing only 0.5-1% of parathyroid adenomas, accounting for 1-2% of cases of primary hyperparathyroidism (PHPT). The purpose of this study was to compare classical and functional/secreting cystic parathyroid lesions and identify risk factors for severe hypercalcemia; (2) Methods: A total of 17 patients with PHPT and parathyroid cysts (study group) were compared with the group of 100 patients with hyperparathyroidism caused by adenoma or hyperplasia (control group). In both groups the majority were women (88% vs. 12%, with gender ratio 7, 3:1). The patients were examined preoperatively and postoperatively: PTH, creatine, calcium and phosphate serum and urine concentrations and calcidiol serum levels were assessed; (3) Results: Patients with parathyroid cyst had statistically higher PTH and calcium serum concentration, higher calciuria and lower serum phosphate concentration. There were no statistically significant differences in the concentration of creatine in serum and urine and tubular reabsorption of phosphorus (TRP); (4) Conclusions: Due to higher PTH and calcium levels, cystic parathyroid adenomas could be one of the rare risk factors for severe hypercalcemia and hypercalcemic crisis which can be life threatening.

The altered composition of gut microbiota and biochemical features as well as dietary patterns in a southern Chinese population with recurrent renal calcium oxalate stones.

The correlation among gut microbiota, biochemical features, and dietary patterns in recurrent stone formers has been inadequately investigated in the Chinese population. Forty-two patients with calcium oxalate stones (CaOxS group), including 34 recurrent stone formers (RS group), and 40 nonstone healthy subjects (NS group) from Changshu Hospital Affiliated with Soochow University, were prospectively recruited. Food frequency questionnaires were completed by participants, fasting vein blood was extracted, 24-h urine was collected for biochemical detection, and fecal samples were gathered for 16S ribosomal RNA (rRNA) gene sequencing. BMI; serum levels of triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), magnesium, and creatinine; and urine levels of magnesium in stone formers were significantly different from those of controls, and RS patients showed significantly low serum phosphate and high urine phosphate levels. Celery, bamboo shoots, and pickled food were the favored foods of local stone formers. Patients with recurrent stones had altered microbiota composition, with Escherichia, Fusobacterium, and Epulopiscium being the predominant pathogenic genera. The gut microbiota in RS patients had stronger functions in fatty acid and amino acid degradation but weaker functions in their biosynthesis. The pathogenic genera were positively correlated with BMI; serum levels of TGs and creatinine; urine levels of calcium, phosphate, and uric acid (UA); and celery, bamboo shoots, and pickled food intake. The abundance of Escherichia and Fusobacterium and the levels of serum magnesium and creatinine were the most relevant factors associated with stone recurrence and could be validated as biomarkers of recurrence. Our research provides a novel prevention strategy for the recurrence of renal calcium oxalate stones in the Han Chinese population of southern China.

Chest configuration in children and adolescents with infantile nephropathic cystinosis compared with other chronic kidney disease entities and its clinical determinants.

Infantile nephropathic cystinosis (INC) is a systemic lysosomal storage disease causing intracellular cystine accumulation, resulting in renal Fanconi syndrome, progressive kidney disease (CKD), rickets, malnutrition, and myopathy. An INC-specific disproportionately diminished trunk length compared to leg length poses questions regarding the functionality of the trunk. Thus, we prospectively investigated thoracic dimensions and proportions, as well as their clinical determinants in 44 pediatric patients with INC with CKD stages 1-5 and 97 age-matched patients with CKD of other etiology between the ages of 2-17years. A total of 92 and 221 annual measurements of patients with INC and CKD, respectively, were performed, and associations between anthropometric and clinical parameters were assessed using linear mixed-effects models. Patients with INC exhibited altered chest dimensions that were distinct from CKD controls, characterized by markedly increased chest depth to height and chest depth to chest width ratio z-scores (> 1.0), while those of patients with CKD were only mildly affected (z-score within ± 1.0). Ratio z-scores differed significantly between both patient groups from 2-6years of age onward. The degree of chest disproportion in INC patients was significantly associated with both the degree of CKD and tubular dysfunction (e.g., low serum phosphate and bicarbonate) across three different age groups (2-6, 7-12, and 13-17years). Our data show an INC-specific alteration in thoracic shape from early childhood onward, which is distinct from CKD of other etiologies, suggesting early childhood subclinical changes of the musculoskeletal unit of the thoracic cage, which are associated with kidney function. A higher resolution version of the Graphical abstract is available as Supplementary information.

#6652 ACUTE KIDNEY INJURY IN PATIENTS WITH MULTIPLE MYELOMA SUBMITTED TO AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANT: A COHORT ANALYSIS

Abstract Background and Aims The incidence of most haematological neoplasms has been increasing and with them hematopoietic cell transplantation (HCT) as it provides better survival rates to several of these malignancies. There is a wide range of acute kidney injury (AKI) reported incidence in HCT patients, mostly due to the heterogeneity of AKI definitions and study populations that include different underlying illnesses. We aimed to evaluate incidence, severity and risk factors of AKI by KDIGO classification considering creatinine and urinary output (UO) criteria in patients with multiple myeloma (MM) submitted to autologous HCT. Method We conducted a retrospective cohort study including patients with MM submitted to autologous HCT admitted in a tertiary hospital between Jan./2005-Dec./2015 with a 3 year follow-up period. To evaluate AKI cumulative incidence, risk factors and impact on relapse, survival analysis methods considering death as competing were used. Multivariate stepwise analysis using logistic regression was used to evaluate risk factors associated with AKI. Results 143 patients were included [median age was 50.5 (59.2-63.6) years, 61.5% male and 90.9% Caucasian]. 37.1% had hypertension, 12.6% diabetes mellitus and 10.5% chronic kidney disease (CKD) [median overall baseline eGFR 100.4 (89.5-110.8) mL/min/1.73 m2]. Median percentage of plasma cells on bone marrow aspirate was 30 (17-67) %, serum M-protein 3.3 (2.2-6.6) g/dL and serum titre of the affected light chain 3560 (890-7800) mg/dL. 49 patients had cytogenetic abnormalities. 49% of patients had R-ISS stage I at diagnosis. Median number of previous lines of therapy was 1 (1-2) and the median number of cycles 4 (3-4). 34.5% were previously submitted to radiotherapy. At admission, mean haemoglobin was 11.7 (10.8-12.4) g/dL, neutrophils 3375 (2330-4765) /mm3, serum urea 33 (28-44) mg/dL, uric acid 5 (4.1-6) mg/dL, phosphate 3.4 (3-2.9) mg/dL, LDH 333 (297-390) U/L, albumin 3.9 (3.7-4.2) mg/dL and alanine transaminase 18 (14-27) U/L. Fever (77.6%), exposure to nephrotoxins (74.1%), low grade mucositis (55.9%) and sepsis (26.6%) were common during hospital admission. Cumulative incidence of AKI at 100 days was 49.7% (71 patients) with median time to event of 8 (5-13) days. 85.9% of patients had stage 1 AKI at diagnosis, although 16.4% of these (10 patients) degraded to worse stages. On univariable analysis, the predictor variables with impact on AKI were higher age (p=0.057), higher body mass index (BMI) (p=0.048), HCT-comorbidity index ≥2 (p=0.005), lower baseline eGFR (p<0.001), previous CKD (p=0.001), presence of amyloidosis (p=0.078), higher R-ISS (p=0.002), presence of cytogenetic abnormalities (p=0.055), development of sepsis (p=0.016), fever (p=0.044) and higher grade mucositis (p<0.001), exposure to nephrotoxins (p=0.007), higher neutrophils count (p=0.021), serum urea (p<0.001) and LDH (p=0.002) and lower phosphate (p=0.049), and alanine transaminase (p=0.077). Multivariable analysis showed an independent association of AKI with BMI [HR 1.08 (1.03-1.14), p=0.004], CKD [HR 3.00 (1.55-5.78), p=0.001], amyloidosis [HR 2.73 (1.40-5.33), p=0.003], high grade mucositis [HR 2.35 (1.37-4.02), p=0.002], exposure to nephrotoxins [HR 2.20 (1.08-4.47), p=0.029], leukocyte count [HR 1.01 (1.01-1.01), p<0.001] and serum phosphate [HR 0.57 (0.39-0.84), p=0.004] maintained an independent association with AKI. Conclusion Our results show that AKI occurs in almost half of the patients with MM submitted to HCT and reinforce the need for prevention, monitoring and early approach to AKI in these patients particularly in those with higher BMI, CKD, secondary amyloidosis, higher leukocyte count and lower serum phosphate at admission, as well as in those that develop mucositis and are exposed to nephrotoxins. We also believe considering both SCr and UO KDIGO criteria for AKI may have increased the reliability of our data, this being the first study to include both criteria in this population of patients.

#5293 THE IMPACT OF SEVERE DEPRESSION ON THE SURVIVAL OF OLDER PATIENTS WITH END-STAGE KIDNEY DISEASE

Abstract Background and Aims Incidence of depression increases in patients with end-stage kidney disease (ESKD). We evaluated the association between depression and mortality among older patients with ESKD, which has not been studied previously. Method This nationwide prospective cohort study included 487 patients with ESKD aged > 65 years, who were categorized into minimal, mild-to-moderate, and severe depression groups based on their Beck Depression Inventory-II (BDI-II) scores. BDI-II scores were separated into three symptom domains: affective, cognitive, and somatic depressive symptoms. The association between the depression groups and survival were analyzed using multivariate Cox proportional hazard regression models. Predisposing factors for high BDI-II scores were evaluated using logistic regression analysis. The associations among the three depressive-symptom domains and survival were also analyzed. Results The severe depression group showed a higher modified Charlson comorbidity index value and lower serum albumin, phosphate, and uric acid levels than the other depression groups. The Kaplan–Meier curve revealed a significantly lower survival in the severe depression group than in the minimal and mild-to-moderate depression groups (P = 0.011). Multivariate Cox regression analysis confirmed that severe depression was an independent risk factor for mortality in the study cohort [hazard ratio (HR), 1.39; 95% confidence interval (CI), 1.01–1.91; P = 0.041). BDI-II scores were associated with modified Charlson comorbidity index (P = 0.009) and serum albumin level (P = 0.004) in multivariate linear regression. Among the three depressive symptoms, higher somatic symptom scores were associated with increased mortality (HR, 2.45; 95% CI, 1.25–4.79; P = 0.009). Conclusion Among older patients with ESKD, severe depression increases mortality compared with minimal or mild-to-moderate depression. And patients with concomitant somatic symptoms require careful management of their comorbidities and nutritional status.

Sexual dimorphisms in serum calcium and phosphate concentrations in the Rotterdam Study

Sex differences in serum phosphate and calcium have been reported but the exact nature and underlying regulatory mechanisms remain unclear. We aimed to compare calcium and phosphate concentrations between sexes, and explore potential covariates to elucidate underlying mechanisms of sex differences in a prospective, population-based cohort study. Pooled data of subjects > 45 years from three independent cohorts of the Rotterdam Study (RS) were used: RS-I-3 (n = 3623), RS-II-1 (n = 2394), RS-III-1 (n = 3241), with separate analyses from an additional time point of the first cohort RS-I-1 (n = 2688). Compared to men, women had significantly higher total serum calcium and phosphate concentrations which was not explained by BMI, kidney function nor smoking. Adjustment for serum estradiol diminished sex differences in serum calcium while adjustment for serum testosterone diminished sex differences in serum phosphate. Adjustment for vitamin D and alkaline phosphatase did not change the association between sex and calcium or phosphate in RS-I-1. In the sex-combined group, both serum calcium and phosphate decreased with age with a significant interaction for sex differences for serum calcium but not phosphate. In sex-stratified analyses, serum estradiol but not testosterone was inversely associated with serum calcium in both sexes. Serum estradiol was inversely associated with serum phosphate in both sexes to a similar degree, while serum testosterone was inversely associated with serum phosphate in both sexes with an apparent stronger effect in men than in women. Premenopausal women had lower serum phosphate compared to postmenopausal women. Serum testosterone was inversely associated with serum phosphate in postmenopausal women only. In conclusion, women > 45 years have higher serum calcium and phosphate concentrations compared to men of similar age, not explained by vitamin D or alkaline phosphatase concentrations. Serum estradiol but not testosterone was inversely associated with serum calcium while serum testosterone was inversely associated with serum phosphate in both sexes. Serum testosterone may in part explain sex differences in serum phosphate while estradiol could partly explain sex differences in serum calcium.

Intact FGF23 predicts serum phosphate improvement after combined nicotinamide and phosphate binder treatment in hemodialysis patients.

Hyperphosphatemia is associated with increased mortality and cardiovascular morbidity of end-stage kidney failure (ESKF) patients. Managing serum phosphate in ESKF patients is challenging and mostly based on limiting intestinal phosphate absorption with low phosphate diets and phosphate binders (PB). In a multi-centric, double-blinded, placebo-controlled study cohort of maintenance hemodialysis patients with hyperphosphatemia, we demonstrated the efficacy of nicotinamide modified release (NAMR) formulation treatment in addition to standard PB therapy in decreasing serum phosphate. Here we aimed to assess the relationship between phosphate, FGF23, inflammation and iron metabolism in this cohort. We measured the plasma concentrations of intact fibroblast growth factor 23 (iFGF23) and selected proinflammatory cytokines at baseline and Week 12 after initiating treatment. We observed a strong correlation between iFGF23 and cFGF23 (C-terminal fragment plus iFGF23). We identified iFGF23 as a better predictor of changes in serum phosphate induced by NAMR and PB treatment compared with cFGF23. Recursive partitioning revealed at baseline and Week 12, that iFGF23 and cFGF23 together with T50 propensity were the most important predictors of serum phosphate, whereas intact parathyroid hormone (iPTH) played a minor role in this model. Furthermore, we found serum phosphate and iPTH as the best predictors of iFGF23 and cFGF23. Sex, age, body mass index, and markers of inflammation and iron metabolism had only a minor impact in predicting FGF23. Lowering serum phosphate in ESKF patients may depend highly on iFGF23 which is correlated to cFGF23 levels. Serum phosphate was the most important predictor of plasma FGF23 in this ESKF cohort.

Variability of Serum Phosphate in Incident Hemodialysis Patients: Association with All-Cause Mortality.

Key Points An increase in serum phosphate variability is an independent risk factor of mortality.The effects of a positive directional range (DR) is most pronounced in patients with high serum phosphate levels whereas the effects of a negative DR is most pronounced in patients with low serum phosphate and/or serum albumin. Background In maintenance hemodialysis (HD) patients, previous studies have shown that serum phosphate levels have a bidirectional relation to outcome. Less is known about the relation between temporal dynamics of serum phosphate in relation to outcome. We aimed to further explore the relation between serum phosphate variability and all-cause mortality. Methods All adult incident HD patients treated in US Fresenius Kidney Care clinics between January 2010 and October 2018 were included. Baseline period was defined as 6 months after initiation of HD and months 7–18 as follow-up period. All-cause mortality was recorded during the follow-up period. The primary metric of variability used was directional range (DR) that is the difference between the largest and smallest values within a time period; DR was positive when the smallest value preceded the largest and negative otherwise. Cox proportional hazards models with spline terms were applied to explore the association between phosphate, DR, and all-cause mortality. In addition, tensor product smoothing splines were computed to further elucidate the interactions of phosphate, DR, and all-cause mortality. Results We included 302,613 patients. Baseline phosphate was 5.1±1.2 mg/dl, and mean DR was +0.6±3.3 mg/dl. Across different levels of phosphate, higher levels of DR of phosphate were associated with higher risk of all-cause mortality. In patients with lower levels of phosphate and serum albumin, the effect of a negative DR was most pronounced, whereas in patients with higher phosphate levels, a positive DR was related to increased mortality. Conclusions Higher variability of serum phosphate is related to mortality at all levels of phosphate, especially in lower levels with a negative DR and in low serum albumin levels. This could possibly reflect dietary intake in patients who are already inflamed or malnourished, where a further reduction in serum phosphate should prompt for nutritional evaluation.

Efficacy of Lanthanum Carbonate and Sevelamer Carbonate as Phosphate Binders in Chronic Kidney Disease—A Comparative Clinical Study

(1) Background: Hyperphosphatemia is correlated with an increased rate of mortality and morbidity due to cardiovascular diseases in chronic kidney disease (CKD) patients. It can be improved by restricting dietary intake of phosphate and oral phosphate binders, such as lanthanum carbonate and sevelamer carbonate. (2) Objective: To evaluate the clinical efficacy of sevelamer carbonate in comparison to lanthanum carbonate as phosphate binders for the treatment of hyperphosphatemia in CKD patients. (3) Methods: A randomized control comparative clinical study was conducted for one year on 150 CKD patients associated with hyperphosphatemia, divided into two groups, i.e., Group 1 (n = 75) treated with sevelamer carbonate 800 mg thrice daily and Group 2 (n = 75) treated with lanthanum carbonate 500 mg thrice daily. The patients were assessed at the time of enrollment in the study, after three months and after six months from baseline for different parameters, i.e., complete blood count, liver function tests, renal function tests, electrolytes, and serum phosphate level. (4) Results: 150 CKD patients aged 51-60 participated in the study. The mean age of patients was 54 ± 4.6 years, and males (55.71%) were more common than females (44.29%). Hypertension was the common comorbidity in both groups with chronic kidney disease. After six months of treatment, the mean serum phosphate level was significantly decreased from 8.31 ± 0.09 mg/dL to 5.11 ± 0.18 (38%) in Group 1 and from 8.79 ± 0.28 mg/dl to 4.02 ± 0.12 (54%; p < 0.05) in Group 2, respectively. In both groups, no significant difference was found in other parameters such as parathyroid hormone, calcium, uric acid, LFT, RFT, CBC, etc. (5) Conclusion: Lanthanum carbonate is more efficacious in lowering serum phosphate concentrations and effectively managing hyperphosphatemia as compared to sevelamer carbonate.

Tumor-induced Osteomalacia Secondary to Phosphaturic Mesenchymal Tumor.

HomeRadiology: Imaging CancerVol. 5, No. 2 PreviousNext Images in CancerFree AccessTumor-induced Osteomalacia Secondary to Phosphaturic Mesenchymal TumorAmit Agarwal , Girish Bathla, Vivek GuptaAmit Agarwal , Girish Bathla, Vivek GuptaAuthor AffiliationsFrom the Departments of Radiology (A.A.) and Neuroradiology (V.G.), Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224; and Department of Radiology, Mayo Clinic, Rochester, Minn (G.B.).Address correspondence to A.A. (email: [email protected]).Amit Agarwal Girish BathlaVivek GuptaPublished Online:Mar 10 2023https://doi.org/10.1148/rycan.220170MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In Tumor-induced osteomalacia (TIO), or oncogenic osteomalacia, is an uncommon paraneoplastic syndrome characterized by urinary phosphate wasting due to an increased production of fibroblast growth factor 23 (FGF23), secondary to an underlying phosphaturic mesenchymal tumor (PMT). Patients usually present with bone pain and pathologic fractures caused by hypophosphatemic hyperphosphaturic osteomalacia (Fig 1), characterized by high serum FGF23 levels (Fig 2) and low serum calcitriol levels. Given the rarity of this entity and nonspecific clinical and imaging features, these tumors are challenging to diagnose and can go undetected for many years (1). Tumors can be found in any osseous or soft-tissue location, however, and are typically observed in the extremities, most commonly the femur, of middle-aged adults. TIO is also associated with other mesenchymal tumors, including solitary fibrous tumors and giant cell tumors, primarily due to FGF23 secretion. A combination of nuclear scans using somatostatin analogs, such as gallium-68 tetraazacyclododecane tetraacetic acid octreotate (68Ga-DOTATATE) and indium-111 (111In)-pentetreotide (OctreoScan), provides the highest sensitivity for detecting tumors, which are usually small in size and not evident at clinical examination. These lesions appear to be moderately fluorodeoxyglucose avid, potentially aiding in diagnosis, but have wide variability in uptake and limited specificity. CT and MRI are noncontributory for initial location but are usually needed later to evaluate anatomic extent. Surgical resection of PMTs is typically curative, resulting in complete resolution of the syndrome (2,3). While few cases of PMT have been reported, it is important to consider this diagnosis in all patients with hypophosphatemic osteomalacia.Figure 1: (A) Methylene diphosphonate bone scan in a 65-year-old female patient with bone pain reveals multiple foci of increased uptake (arrowheads) over bilateral femur and sternum, along with prominent costochondral beadings (rosary), suggesting metabolic bone disease (osteomalacia). Serologic workup revealed a high serum fibroblast growth factor 23 (FGF23) level of 1155 reference unit (RU)/mL (reference range, ≤180 RU/mL) with low serum phosphate level and elevated alkaline phosphatase level. (B) Coronal noncontrast CT image of the lumbar spine reveals a lytic lesion in the right transverse process of L3 (arrow) with (C) increased fluorodeoxyglucose uptake (standardized uptake value, 9.8) (arrow) on the axial PET/CT image.Figure 1:Download as PowerPointOpen in Image Viewer Figure 2: Histopathologic features of phosphaturic mesenchymal tumors, with predominantly spindled cells on hematoxylin-eosin (H&E) stains and strong expression of fibroblast growth factor 23 (FGF-23) mRNA on in situ hybridization (ISH).Figure 2:Download as PowerPointOpen in Image Viewer Disclosures of conflicts of interest: A.A. Consulted for and expert testimony for Authnetic4D in 2020; institutional CME fund (attending meetings/travel); stocks in Gilead Pharma. G.B. Grant from Foundation of Sarcoidosis Research, unrelated to current work. V.G. No relevant relationships.Keywords: Osteomalacia, Phosphaturic, Spine, Tumor MicroenvironmentAuthors declared no funding for this work.

Relationship between clinical phenotype and in vitro analysis of 13 NPT2c/SCL34A3 mutants

Biallelic pathogenic variants in the SLC34A3 gene, encoding for the NPT2c cotransporter, cause Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH). However, the associated phenotype is highly variable. In addition, mice deleted for Slc34a3 exhibit a different phenotype compared to humans, without urinary phosphate leakage. The mechanisms by which SLC34A3 variants disrupt phosphate/calcium metabolism are un-completely understood. In this study we explored these mechanisms in vitro using SLC34A3 variants identified in patients with urinary phosphate leakage. We analyzed the consequences of these variants on NPT2c function and the link with the phenotype of the patients. We studied 20 patients with recurrent nephrolithiasis and low serum phosphate concentration harboring variants in the SLC34A3 gene. Half of the patients carried homozygous or composite heterozygous variants. Three patients had in addition variants in SLC34A1 and SLC9A3R1 genes. All these patients benefited from a precise analysis of their phenotype. We generated 13 of these mutants by site-directed mutagenesis. Then we carried out transient transfections of these mutants in HEK cells and measured their phosphate uptake capacity under different conditions. Among the 20 patients included, 3 had not only mutations in NPT2c but also in NPT2a or NHERF1 genes. Phosphate uptake was decreased in 8 NPT2c mutants studied and normal for 5. Four variants were initially categorized as variants of uncertain significance. Expression of the corresponding mutants showed that one did not modify phosphate transport, two reduced it moderately and one abolished it. Co-transfection of the NPT2c mutants with the wild-type plasmid of NPT2c or NPT2a did not reveal dominant negative effect of the mutants on NPT2c-mediated phosphate transport. A detailed analysis of patient phenotypes did not find a link between the severity of the disorder and the level of phosphate transport impairment. NPT2c mutations classified as ACMG3 identified in patients with renal phosphate leak should be characterized by in vitro study to check if they alter NPT2c-mediated phosphate transport since phosphate uptake capacity may not be affected. In addition, research for mutations in NHERF1 and NPT2a genes should always be associated to NPT2c sequencing.

Serum 25-Hydroxyvitamin D Level Is Negatively Associated with Fatigue in Elderly Maintenance Hemodialysis Patients

Introduction: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is frequently observed in maintenance hemodialysis (MHD) patients and is associated with fracture, muscle weakness, malnutrition, etc.; however, relationships of CKD-MBD markers and fatigue are not well established. Methods: This was a cross-sectional study including 244 MHD patients (89 elders) from July to September 2021 in the First Affiliated Hospital of Shandong First Medical University. CKD-MBD markers and other clinical data were collected from medical records. Fatigue in the past week was measured by Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) fatigue measure; fatigue at the end of hemodialysis was measured by numeric rating scale (NRS). Spearman correlation, linear regression, and robust linear regression were. Results: In all MHD patients, lg[25(OH)D] (nmol/L) was negatively correlated with SONG-HD score (β = −1.503, 95% CI: −2.826 to 0.18, p = 0.026) and NRS score (β = −1.532, p = 0.04) in multiple regression models adjusting for sex, age, and all CKD-MBD characters; but no correlations were found on univariate regression or in other multiple regression models. Interaction effects between age ≥65 years and lg(25[OH]D [nmol/L]) in terms of fatigue scores were significant based on multiple linear regressions (SONG-HD score β = −3.613, p for interaction = 0.006; NRS score β = −3.943, p for interaction = 0.008). Compared with non-elderly patients, elderly patients were with higher ACCI scores (7 [6, 8] vs. 4 [3, 5], p < 0.001), higher SONG-HD scores (3 [2, 6] vs. 2 [1, 3], p < 0.001), higher NRS score (4 [2, 7] vs. 3 [1, 5], p < 0.001), lower serum phosphate levels (1.65 [1.29, 2.10] vs. 1.87 [1.55, 2.26] mmol/L, p = 0.002), and lower serum iPTH levels (160.6 [90.46, 306.45] vs. 282.2 [139, 445.7] pg/mL, p < 0.001). There were no differences in serum calcium, alkaline serum, or 25(OH)D levels between the two groups. In elderly patients, lg[25(OH)D] was negatively correlated with SONG-HD score (β = −3.323, p = 0.010) and NRS score (β = −3.521, p = 0.006) on univariate linear regressions. Following adjustment for sex, age, and all CKD-MBD characters, lg[25(OH)D] was negatively correlated with SONG-HD scores (multiple linear regression β = −4.012, p = 0.004; multiple robust regression β = −4.012, p = 0.003) or NRS scores (multiple linear regression β = −4.104, p = 0.002; multiple robust regression β = −4.104, p = 0.001). There were no significant correlations between fatigue scores and other CKD-MBD markers (calcium, phosphate, lgiPTH, alkaline phosphatase) in elderly MHD patients, on either univariate linear regressions or multiple regressions. Conclusion: Serum 25(OH)D level is negatively associated with fatigue in elderly MHD patients.

Mild Hypophosphatemia-Associated Conditions in Children: The Need for a Comprehensive Approach.

To better understand the causes of hypophosphatemia in children, we evaluated all serum phosphate tests performed in a tertiary hospital with unexpected but persistent temporary or isolated hypophosphatemia over an 18 year period. We collected 29,279 phosphate tests from 21,398 patients, of which 268 (1.2%) had at least one result showing hypophosphatemia. We found that endocrinopathies (n = 60), tumors (n = 10), and vitamin D deficiency (n = 3) were the medical conditions most commonly associated with mild hypophosphatemia, but in many patients the cause was unclear. Among patients with endocrinopathies, those with diabetes mellitus were found to have lower mean serum phosphate levels (mean 3.4 mg/dL) than those with short stature (3.7 mg/dL) or thyroid disorders (3.7 mg/dL). In addition, we found a correlation between glycemia and phosphatemia in patients with diabetes. However, despite the potential relevance of monitoring phosphate homeostasis and the underlying etiologic mechanisms, renal phosphate losses were estimated in less than 5% of patients with hypophosphatemia. In the pediatric age group, malignancies, hypovitaminosis D, and endocrine disorders, mostly diabetes, were the most common causes of hypophosphatemia. This real-world study also shows that hypophosphatemia is frequently neglected and inadequately evaluated by pediatricians, which emphasizes the need for more education and awareness about this condition to prevent its potentially deleterious consequences.

Effect of residual kidney function and dialysis adequacy on chronic pruritus in dialysis patients.

Chronic kidney disease-associated pruritus (CKD-aP) is common in dialysis patients, and is associated with lower quality of life and increased risk of death. We investigated the association between residual estimated glomerular filtration rate (eGFR), dialysis adequacy or serum phosphate level and CKD-aP in incident dialysis patients. A total of 1256 incident hemodialysis (HD) and 670 peritoneal dialysis (PD) patients (>18 years) from the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) study were included (1997-2007) and followed until death, transplantation or a maximum of 10 years. CKD-aP was measured using a single item of the Kidney Disease Quality of Life Instrument-36. The associations were studied by logistic and linear regression analyses, adjusted for potential baseline confounders. At baseline mean (standard deviation) age was 60 (16) years, 62% were men and median (interquartile range) residual eGFR was 3.4 (1.7; 5.3) mL/min/1.73 m2. The prevalence of CKD-aP (∼70%) was similar in HD and PD. It was observed that 12months after starting dialysis (after multivariable adjustment) each 1 mL/min/1.73 m2 higher residual eGFR, one unit higher total weekly Kt/V, or 1mmol/L lower serum phosphate level was associated with lower burden of CKD-aP in HD and PD patients of -0.05 (95% CI -0.09; -0.02) and -0.09 (95% CI -0.13; -0.05), -0.15 (95% CI -0.26; -0.05) and -0.35 (95% CI -0.54; -0.16), and of -0.34 (95%CI: -0.51; -0.17) and -0.45 (95%CI: -0.71; -0.19), respectively. We found no association between dialysis Kt/V and CKD-aP. Higher residual eGFR and lower serum phosphate level, but not the dialysis dose, were related with lower burden of CKD-aP in dialysis patients.

Impact of X-Linked Hypophosphatemia on Muscle Symptoms

X-linked hypophosphatemia (XLH) is the most common hereditary form of rickets and deficiency of renal tubular phosphate transport in humans. XLH is caused by the inactivation of mutations within the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene and follows an X-dominant transmission. It has an estimated frequency of 1 case per 20,000, and over 300 distinct pathogenic variations have been reported that result in an excess of fibroblast growth factor 23 (FGF23) in the serum. Increased levels of FGF23 lead to renal phosphate loss, decreased serum 1,25-dihydroxyvitamin D, and increased metabolism of 1,25-dihydoxyvitamin D, resulting in hypophosphatemia. Major clinical manifestations include rickets, bone deformities, and growth retardation that develop during childhood, and osteomalacia-related fractures or pseudo-fractures, degenerative osteoarthritis, enthesopathy, dental anomalies, and hearing loss during adulthood, which can affect quality of life. In addition, fatigue is also a common symptom in patients with XLH, who experience decreased motion, muscle weakness, and pain, contributing to altered quality of life. The clinical and biomedical characteristics of XLH are extensively defined in bone tissue since skeletal deformations and mineralization defects are the most evident effects of high FGF23 and low serum phosphate levels. However, despite the muscular symptoms that XLH causes, very few reports are available on the effects of FGF23 and phosphate in muscle tissue. Given the close relationship between bones and skeletal muscles, studying the effects of FGF23 and phosphate on muscle could provide additional opportunities to understand the interactions between these two important compartments of the body. By describing the current literature on XLH and skeletal muscle dysfunctions, the purpose of this review is to highlight future areas of research that could contribute to a better understanding of XLH muscular disability and its management.

ODP085 Denosumab Induced Severe Hypophosphatemia

Abstract Introduction Denosumab is a receptor activator of nuclear factor kappa-B (RANK) ligand inhibitor used for treatment of osteoporosis and bone metastases in patients with solid tumors. Denosumab induced hypophosphatemia has been reported in less than 1% of patients, and in most cases described as mild to moderate in severity. We present a case of severe hypophosphatemia after denosumab treatment for diffuse bone metastases due to prostate cancer. Case report A 78-year-old male patient with history of diffuse bone metastases due to prostate cancer, schizophrenia on treatment and intermittent alcohol use, presented to the hospital with suicidal ideation and worsening fatigue. Patient was found to have a phosphorus levels of &amp;lt;1. 0 mg/dL (2.5-4.6 mg/dL), corrected calcium of 8.2 mg/dL (8.4-10.5 mg/dl), vitamin D 25 OH of 36.34 ng/mL (30-100 ng/mL), magnesium of 2.3 mg/dL (1.7-2.5 mg/dL), parathyroid hormone (iPTH) level of 379 pg/mL (10-65pg/mL) and serum creatinine of 1.1 mg/dL (0.5-1.2 mg/dL). Urinary studies showed 24 hour urinary phosphate 1282 mg/24h (360-1600 mg/24h), urine creatinine 1570 mg/24h (500-2150 mg/24h). There was no evidence of acidosis, chronic kidney disease, preexisting osteomalacia or vitamin D deficiency. The patient had no recent alcohol consumption and his alcohol level was undetectable. After reviewing the outside medical records it was noted that the patient had received denosumab 120 mg, 11 days prior to the hospital admission, as part of the management of bone metastases due to prostate cancer. The patient's baseline phosphorus prior to denosumab was in the low normal range. The severe hypophosphatemia and secondary hyperparathyroidism were attributed to denosumab administration. Patient was initially treated with intravenous phosphate and then transitioned to oral phosphate along with elemental calcium and calcitriol during the course of his hospitalization. Patient's phosphorus improved to 2.3 mg/dL by the time of discharge. Discussion In patients treated with denosumab, the primary concern is potential post-treatment hypocalcemia, however, our case brings attention to severe hypophosphatemia as a serious side effect to treatment with denosumab. Multiple specialties are involved in the treatment of osteoporosis and metastatic bone lesions, and each should be aware that denosumab can lead to lower serum phosphate levels due to its effects on bone resorption and reduction of proximal tubular reabsorption of the phosphate resulting in clinical symptoms of muscle weakness, bone pain, fractures and even stupor, coma and death. We therefore conclude that monitoring phosphate levels should be part of the pre- and post-treatment evaluation in patients who are candidates for treatment with denosumab, particularly high-dose denosumab. Presentation: No date and time listed

Treating 'osteoporosis': a near miss in an unusual case of FGF-23-mediated hypophosphataemic osteomalacia.

We present the case of a 60-year-old female who developed repeated atraumatic stress fractures. She was initially diagnosed with osteoporosis based on her dual-energy X-ray absorptiometry (DXA) scan bone mineral density (BMD) T-scores and started on denosumab therapy. Secondary osteoporosis screen revealed abnormal myeloma screen and low serum phosphate levels. It was thought that the patient had multiple myeloma with associated Fanconi-related tubular dysfunction. However, fibroblast growth factor-23 (FGF-23) levels were grossly elevated, making Fanconi syndrome unlikely. The patient was subsequently diagnosed with two separate conditions, namely cardiac amyloid light-chain (AL) amyloidosis and FGF-23-related hypophosphataemia, likely due to tumour-induced osteomalacia. This case highlights the importance of excluding osteomalacia as a cause of low BMD and checking FGF-23 levels in the workup for hypophosphataemia. Tumour-induced osteomalacia is a difficult diagnosis as the tumour is often small and slow growing. Imaging may fail to identify a tumour, and treatment therefore consists of calcitriol and phosphate replacement. Tumour-induced osteomalacia should be suspected in the adult presenting with new-onset hypophosphataemia, elevated FGF-23 levels and isolated renal phosphate wasting. Serum phosphate is not part of the routine chemistry panels. Routinely checking phosphate levels prior to initiating antiresorptive therapy is warranted. DXA cannot distinguish low bone mineral density due to osteoporosis from osteomalacia. Antiresorptive therapy should be avoided in osteomalacia due to the risk of clinical and radiographic deterioration.

PSAT219 Renal Phosphate Wasting Caused by ENPP-1 mutation.

Abstract Background Increased renal phosphate loss can be Fibroblast Growth Factor-23 (FGF-23) dependent or independent. FGF-23 reduces expression of Sodium-Phosphate co-transporters, responsible for phosphate reabsorption; and by inhibition of 1-alpha hydroxylation of 25-OH-D3. Reduced serum concentration of 1, 25-OH2-D3 results in secondary hyperparathyroidism. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) mutation is one of the rarest causes of hypophosphatemia, which causes FGF-23 dependent hypophosphatemia. Case description 31-year-old female referred to endocrinology for evaluation of recurrent nephrolithiasis despite normalization of PTH and serum Calcium (Ca) after right inferior parathyroid adenoma resection. Repeated renal stone analysis revealed calcium phosphate as the major stone composition. Patient achieved mid parental height, denied history of calcium or phosphate metabolism disorders/ rickets in the family. Physical exam was not suggestive of rickets and skeletal survey showed normal bone mineralization. Initial labs following parathyroid adenoma resection showed normal Ca 9.7 mg/dl, PTH 47 pg/ml, Phosphorus (Ph) 2.3 mg/dl, 25-OH-D3 51 ng/ml, albumin 3.9 g/dl, Mg 1.8 mg/dl. Repeat fasting labs six months later revealed Ca 9 mg/dl, Ph 1.7 mg/dl, 25-OH-D3 52 ng/ml, PTH 67.5 pg/ml and albumin 3.7 g/dl. Persistent low serum phosphate was evaluated further by a 24-hour urine collection which revealed high urine phosphate of 828 mg/day, Ca 181 mg/day, Mg 23 mg/day and creatinine was 1485 mg/day. Tubular reabsorption of phosphorus was 77% (normal: &amp;gt;80%), indicating renal phosphate wasting. Serum FGF-23 on two different days was &amp;gt;180 RU/ml. Next-generation sequencing tested positive for heterozygous ENPP-1 gene mutation variant c1441C&amp;gt;T (p. Arg481Trp). Patient was started on oral Phosphorus supplementation &amp; calcitriol. Repeat labs showed normalization of Ph 2.4 mg/dl. Audiology evaluation suggested mild sensorineural hearing loss. Heart calcium score was zero. Discussion ENPP1 gene mutation's clinical presentations can vary from no symptoms, hypophosphatemic rickets to death in the first six months of life from generalized arterial calcification. ENPP1 is an enzyme, which degrades ATP into adenosine monophosphate (AMP) and pyrophosphate (PPi). PPI is an inhibitor of hydroxyapatite crystallization in vascular tissue and organs, while Ph is a pro-mineralization factor. ENPP1 gene mutation results in a low concentration of PPi, predisposing the patient to pathological calcification. It is speculated that ENPP-1 modulates FGF-23 secretion. FGF-23 elevation in these patients is a protective response, as hypophosphatemia prevents pathological calcification. Treatment target is to keep phosphate at low end of normal. In our patient, ENPP- 1 mutation likely contributed to recurrent renal stones and possible parathyroid adenoma. Evaluation of genetic mutations is necessary to decide for or against FGF-23 antibody/Burosumab treatment. In ENPP-1 mutation. Burosumab should be avoided as it can bind to FGF-23 resulting in pathological calcification. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.