Serum Phosphate Concentrations Research Articles

High Serum Phosphate Is Associated with Cardiovascular Mortality and Subclinical Coronary Atherosclerosis: Systematic Review and Meta-Analysis

(1) Background: Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. The aim of the study was to examine the existing published results of the association between elevated serum phosphate concentrations and cardiovascular mortality, along with the CVD incidence and subclinical coronary atherosclerosis, in primary prevention among non-selected samples of the general population. (2) Methods: A systematic review and meta-analysis were carried out using literature obtained from PubMed, SCOPUS, and the Web Of Science until March 2024 and following the PRISMA guidelines. Relevant information was extracted and presented. Random and fixed effects models were used to estimate the pooled odds ratio (OR) and hazard ratio (HR) with their 95% coefficient interval (CI), and I2 was used to assess heterogeneity. (3) Results: Twenty-five studies met our inclusion criteria and were included in the meta-analysis (11 cross-sectional and 14 cohort studies). For cardiovascular mortality, which included 7 cohort studies and 41,764 adults, the pooled HR was 1.44 (95% CIs 1.28, 1.61; I2 0%) when the highest versus the reference level of serum phosphate concentrations were compared. For CVDs, which included 8 cohort studies and 61,723 adults, the pooled HR was 1.12 (95% CIs 0.99, 1.27; I2 51%). For subclinical coronary atherosclerosis, which included 11 cross-sectional studies and 24,820 adults, the pooled OR was 1.44 (95% CIs 1.15, 1.79; I2 88%). (4) Conclusions: The highest serum phosphate concentrations were positively associated with a 44% increased risk of cardiovascular mortality and subclinical coronary atherosclerosis.

A Randomized Noninferiority Trial to Compare Enteral to Parenteral Phosphate Replacement on Biochemistry, Waste, and Environmental Impact and Healthcare Cost in Critically Ill Patients With Mild to Moderate Hypophosphatemia.

Hypophosphatemia occurs frequently. Enteral, rather than IV, phosphate replacement may reduce fluid replacement, cost, and waste. Prospective, randomized, parallel group, noninferiority clinical trial. Single center, 42-bed state trauma, medical and surgical ICUs, from April 20, 2022, to July 1, 2022. Patients with serum phosphate concentration between 0.3 and 0.75 mmol/L. We randomized patients to either enteral or IV phosphate replacement using electronic medical record-embedded program. Our primary outcome was serum phosphate at 24 hours with a noninferiority margin of 0.2 mmol/L. Secondary outcomes included cost savings and environmental waste reduction and additional IV fluid administered. The modified intention-to-treat cohort comprised 131 patients. Baseline phosphate concentrations were similar between the two groups. At 24 hours, mean (sd) serum phosphate concentration were enteral 0.89 mmol/L (0.24 mmol/L) and IV 0.82 mmol/L (0.28 mmol/L). This difference was noninferior at the margin of 0.2 mmol/L (difference, 0.07 mmol/L; 95% CI, -0.02 to 0.17 mmol/L). When assigned IV replacement, patients received 408 mL (372 mL) of solvent IV fluid. Compared with IV replacement, the mean cost per patient was ten-fold less with enteral replacement ($3.7 [$4.0] vs. IV: $37.7 [$31.4]; difference = $34.0 [95% CI, $26.3-$41.7]) and weight of waste was less (7.7 g [8.3 g] vs. 217 g [169 g]; difference = 209 g [95% CI, 168-250 g]). CO2 emissions were 60-fold less for comparable phosphate replacement (enteral: 2 g producing 14.2 g and 20 mmol of potassium dihydrogen phosphate producing 843 g of CO2 equivalents). Enteral phosphate replacement in ICU is noninferior to IV replacement at a margin of 0.2 mmol/L but leads to a substantial reduction in cost and waste.

Does large parathyroid adenomas increase risk of severe hypercalcemia?

(1) Background: Primary hyperparathyroidism (PHPT) is mainly caused by parathyroid adenoma (PA). Rare variants of PA, weighing >2,0-3,5g are called “large” or “giant” adenomas and account for about 1,5% of all PA. The purpose of this study was to compare normal sized and large parathyroid lesions identifying risk factors for severe hypercalcemia; (2) Methods: 27 patients with PHPT and parathyroid lesion ≥2,0cm3 (study group) were compared with 73 patients with PHPT and lesion <2,0cm3 (control group). In both groups majority were women (81,5%-study group, 90,5%-control group, gender ratios 9,4:1 and 4,4:1 respectively). The patients were examined preoperatively and postoperatively: PTH, creatine, calcium and phosphate serum and urine concentrations and calcidiol serum levels were assessed. Preoperatively ultrasonography (US) was performed. (3) Results: Patients with larger parathyroid lesions had signifficantly higher PTH and calcium serum concentration and lower serum phosphate and calcidiol concentration. There were no statistically significant differences in the concentration of creatine in serum and urine, calciuria and tubular reabsorption of phosphorus (TRP). US relatively underestimated the parathyroid volume of about 0,3-0,4ml (10% in larger lesions and 43% in smaller ones); (4) Conclusions: Due to higher PTH and calcium levels, larger parathyroid adenomas may be the higher risk of severe hypercalcemia. US underestimated in general parathyroid volume.

The Effect of Niacinamide Supplementation on Phosphate Concentrations in Dutch Dialysis Patients: a randomised, crossover trial

ObjectiveHyperphosphatemia is a common complication in patients with kidney failure, despite the use of phosphate binders (PBs). Vitamin B3, either in the form of niacin or niacinamide (NAM), shows potential as “add-on” treatment to reduce serum phosphate concentrations in this population. NAM seems to lack many of the side-effects that are observed with niacin. The aim of this study was to investigate whether NAM is an effective and acceptable treatment in reducing serum phosphate concentrations in patients with kidney failure. MethodsDiaNia was a double-blind placebo-controlled randomised crossover trial, comparing NAM (250-500 mg/day) to placebo as “add-on” treatment to an individual treatment with approved PBs for 12 weeks in patients receiving hemodialysis. The primary outcome was serum phosphate concentrations, and the secondary outcomes were platelet counts as well as drop-outs due to side-effects. Data was analysed using both per-protocol (PP) and intention-to-treat (ITT) analyses. ResultsMean age of the PP population (n=26) was 63.6 ± 17.2 years and 53.8% were men. NAM treatment significantly reduced serum phosphate with 0.59 mg/dL (p=0.03). Linear mixed models (LMMs) demonstrated superiority of 12 weeks NAM over 12 weeks placebo with a between-treatment difference of 0.77 mg/dL (95% CI 0.010, 1.43; p=0.03). Similar results, although not significant, were found in the ITT population. We found no between-treatment differences in platelet counts and during the NAM treatment we observed three drop-outs due to side effects (8.6%). ConclusionNAM is effective in reducing serum phosphate concentrations in patients with kidney failure receiving hemodialysis. In addition, NAM is well-tolerated and seems not to increase the risk of thrombocytopenia. Thus, NAM can be valuable as “add-on” treatment to combat hyperphosphatemia in patients with kidney failure. However, more research in larger populations is needed to confirm this.

Determinants of the serum phosphate concentration in chronic kidney disease.

If Ccr is creatinine clearance and EP and TRP are rates of phosphate excretion and reabsorption, the serum phosphate concentration (Ps) is the sum of EP/Ccr and TRP/Ccr, i.e., the amounts of phosphate excreted and reabsorbed per volume of filtrate. At equilibrium, influx of phosphate into plasma determines EP, and EP/Ccr quantifies the contribution of phosphate influx to Ps. We used data obtained at 688 clinic visits of 387 patients to analyze the evolution of Ps in chronic kidney disease (CKD) stages G1 - 5 (dialysis excluded). EP/Ccr was calculated as (Pu×crs)/cru and TRP/Ccr as Ps-EP/Ccr (where u is urine, s is serum, and cr is creatinine). Means of these parameters were plotted against CKD stages, and correlations among variables were determined with regression analyses. In comparison to values in CKD stages G1 - 2, EP/Ccr rose and TRP/Ccr fell by the same amount in CKD G3a and G3b, and Ps did not change. In stages G4 and G5, EP/Ccr increased sharply, TRP/Ccr fell minimally, and Ps rose significantly. At estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73m2, TRP/Ccr was the principal determinant of Ps at eGFR < 45 mL/min/1.73m2, contributions of EP/Ccr and TRP/Ccr to Ps were comparable. Taken together, our results show that in CKD stages G4 and G5, the effect of phosphate reabsorption on Ps changes negligibly while that of phosphate influx increases dramatically. Because the tubular response to rising EP/Ccr is limited, maintenance of stable Ps in advanced CKD requires extreme reduction of phosphate influx into plasma. TRP/Ccr may define the lowest attainable Ps.

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

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

The Magnitude of Change in Serum Phosphate Concentration Is Associated with Mortality in Patients with Severe Trauma.

Previous studies have suggested that serum phosphate concentration is a prognostic factor in critically ill patients. However, the association between changes in serum phosphate levels and prognosis of patients with trauma remains unclear. This study included patients with severe trauma who were treated at the emergency department. Delta phosphate (Δ phosphate) was defined as the difference between serum phosphate concentrations measured at baseline and after 24 hours from the initial measurement. Patients were divided into five groups according to their Δ phosphate levels: group I (Δ phosphate <-2 mg/dL), group II (Δ phosphate -2 to -0.5 mg/dL), group III (Δ phosphate -0.5 to 0.5 mg/dL), group IV (Δ phosphate 0.5 to 2 mg/dL), and group V (Δ phosphate ≥2 mg/dL). Overall, 1905 patients with severe trauma were included in the analysis. The 30-day mortality was the lowest in group III and tended to increase in groups with a larger Δ phosphate in both the positive and negative directions (group I: 13.7%, group II: 6.8%, group III: 4.6%, group IV: 6.6%, and group V: 26.8%). In multivariable analysis with group III as the reference group, the odds ratios (ORs) of mortality were statistically significant in group IV [OR, 1.92; 95% confidence interval (CI), 1.05-3.56] and group V (OR, 5.28; 95% CI, 2.47-11.24). An increase in serum phosphate concentrations 24 hours after the initial measurement could be considered as an independent prognostic factor in patients with severe trauma.

Bilateral or Unilateral Aldosterone Hypersecretion and Responsiveness to Therapy are Associated with Differences in Calcium/Phosphate Homeostasis in Patients with Primary Aldosteronism.

Introduction Primary aldosteronism is characterized by the autonomous excretion of aldosterone, which may induce bone mineral disorders. Patients and methods A total of 96 patients with primary aldosteronism were analyzed to identify differences in the regulation of serum calcium/phosphate balance between patients with unilateral and bilateral aldosterone hypersecretion and to determine whether or not adrenalectomy or mineralocorticoid receptor blockers affected such differences. Results Serum phosphate concentrations were significantly lower in patients with unilateral aldosterone hypersecretion than in patients with bilateral aldosterone hypersecretion (2.96±0.45 vs. 3.36±0.55 mg/dL, P<0.05), and recovered after adrenalectomy (2.96±0.45 vs. 3.49±0.32 mg/dL, P<0.01). In patients with bilateral aldosterone hypersecretion, the baseline serum phosphate levels were significantly lower in responders to mineralocorticoid receptor blocker treatment, defined as post-treatment plasma renin activity ≥1 ng/mL/h, than in non-responders. In responders, these levels tended to recover after treatment. A weak negative correlation between the plasma aldosterone concentration (PAC) and serum phosphate was observed, but there were no associations between the PAC and serum calcium concentration or between the aldosterone renin ratio and serum calcium and phosphate concentrations. Conclusions The effects on calcium/phosphate homeostasis may differ according to the primary aldosteronism subtype.

A PAI-1 antagonist ameliorates hypophosphatemia in the Hyp vitamin D-resistant rickets model mouse.

Congenital fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets/osteomalacia is a rare bone metabolism disorder characterized by hypophosphatemia and caused by genetic abnormalities that result in excessive secretion of FGF23. Hyp mice are a model of X-linked hypophosphatemia (XLH) caused by deletion of the PHEX gene and excessive production of FGF23. The purpose of this study was to investigate the potential of TM5614 as a therapeutic agent for the treatment of congenital FGF23-related hypophosphatemic rickets and osteomalacia in humans by administering TM5614 to Hyp mice and examining its curative effect on hypophosphatemia. After a single oral administration of TM5614 10 mg·kg-1 to female Hyp mice starting at 17 weeks of age, the serum phosphate concentration increased with a peak at 6 h after administration. ELISA confirmed that TM5614 administration decreased the intact FGF23 concentration in the blood. Expression of 25-hydroxyvitamin D-1α-hydroxylase protein encoded by Cyp27b1 mRNA in the kidney was suppressed in Hyp mice, and treatment with 10 mg·kg-1 of TM5614 normalized the expression of 25-hydroxyvitamin D-1α-hydroxylase protein and Cyp27b1 mRNA in the kidneys of these mice. Our data indicate that oral administration of TM5614 ameliorates hypophosphatemia in Hyp mice, suggesting that TM5614 may be an effective treatment for congenital FGF23-related hypophosphatemic rickets and osteomalacia.

Intact FGF23 concentration in healthy infants, children, and adolescents, and diagnostic usefulness in patients with X-linked hypophosphatemic rickets.

FGF23 measurement may have a diagnostic role to investigate patients with phosphate disorders. However, normal values for infants, children, and adolescents have not been defined. In a total of 282 (males 145, females 137) healthy infants (n = 30), prepubertal (n = 147), pubertal (n = 59), and postpubertal (n = 46), and in twenty patients with X-linked hypophosphatemic rickets (XLH, age 10.2 ± 5.6years) serum phosphate (automated analyzer), and plasma intact FGF23 (immunochemiluminescent sandwich assay, DiaSorin) concentrations were measured. Intact FGF23 concentrations were higher in healthy infants than in prepubertal (P < 0.01) and postpubertal subjects (P < 0.05); pubertal subjects showed higher values (P < 0.05) than postpubertal subjects. Serum phosphate concentrations were higher (P < 0.001) in healthy infants than in prepubertal, pubertal, and postpubertal subjects. Pubertal subjects had higher (P < 0.001) serum phosphate concentrations than postpubertal subjects. Intact FGF23 and serum phosphate concentrations did not differ (P = NS) by sex, age of menarche, and time after menarche. In healthy subjects, there was no correlation between intact FGF23 and serum phosphate concentrations. Intact FGF23 concentrations were higher (P < 0.0001) in patients with XLH than in healthy subjects according to chronological age and pubertal development. In all patients, intact FGF23 concentrations were above 40pg/mL; intact FGF23 concentrations were inversely correlated with serum phosphate concentrations (r = -0.65; P < 0.01). In healthy subjects, chronological age and puberty were main determinants of intact FGF23 concentrations. Intact FGF23 concentrations may be a useful marker for the early diagnosis of XLH in pediatric patients.

Effect of 2 dosages of prepartum cholecalciferol injection on blood minerals, vitamin D metabolites, and milk production in multiparous dairy cows: A randomized clinical trial

The objective of the present study was to evaluate the effect of 2 dosages of prepartum cholecalciferol injection on blood minerals, vitamin D metabolites, and milk production. Cows entering their second or greater lactation (n = 158) were randomly assigned to a control group (CON) or one of 2 treatment groups receiving either 6 × 106 IU (6VitD) or 12 × 106 IU (12VitD) cholecalciferol intramuscularly on d 275 ± 1.2 (SD) of gestation. Concentrations of serum total Ca (tCa), phosphate, and Mg were determined on 1, 2, 3, 5, 7, and 10 d in milk (DIM). For a subsample of 30 cows entering the third lactation (n = 10/group), these samples were analyzed for cholecalciferol, 25-hydroxycholecalciferol (25-OHD3), and 24,25-dihydroxycholecalciferol (24,25-[OH]2D3). In these cows, we also determined 1,25-dihydroxycholecalciferol (1,25-[OH]2D3), the biologically most active metabolite, on 1, 2, 3, and 5 DIM. Repeated measures ANOVA was performed to evaluate the effect of different dosages of cholecalciferol on blood minerals, vitamin D metabolites, and milk yield over the first 5 test days after calving. Binary outcomes such as retained placenta and metritis were analyzed using a chi-squared test. Although the 12VitD treatment increased tCa concentrations on 1, 2, and 3 DIM compared with CON, administration of 6VitD increased tCa concentrations only on 1 DIM. Compared with CON cows and 6VitD cows, 12VitD cows had greater serum phosphate concentration during the first 10 DIM. Furthermore, 6VitD cows had greater serum phosphate concentrations compared with CON cows. On the contrary, 12VitD cows had lower serum Mg concentrations during the first 10 DIM compared with CON and 6VitD cows. Cholecalciferol was increased by the treatment and decreased quickly until 10 DIM. In respect to 25-OHD3, the 6VitD treatment resulted in a 4.1-fold increase in comparison to the CON group, while a 6.5-fold increase was observed in 12VitD animals. The vitamin D metabolite 24,25-(OH)2D3 increased linearly with 25-OHD3 serum levels, resulting in the highest concentrations in the 12VitD group. An increase of 1,25-(OH)2D3 until 3 DIM was observed in all cows. However, this rise was most pronounced in the CON group. The incidence of retained placenta was 1.9%, 11.5%, and 29.6%, and that of metritis was 11.5%, 15.4%, and 31.5% for CON, 6VitD, and 12VitD cows, respectively. Although none of the treated cows exerted clinical signs of hypocalcemia, one cow in CON incurred clinical hypocalcemia. Cows of the 12VitD group had a lower milk yield over the first 5 monthly test days compared with the control and 6VitD group (42.2 ± 0.5, 42.0, ± 0.5 and 40.7 ± 0.5 kg for control cows, 6VitD cows and 12VitD cows, respectively). Although no negative side effects were observed in 6VitD cows, we do not recommend the general application of 6 × 106 IU cholecalciferol before calving as positive effects on calcium homeostasis were marginal and restricted to the first DIM. The present findings confirm that the application of 12 × 106 IU cholecalciferol negatively affected milk production on this farm.

Predictions of Serum Phosphate Concentration during Continuous Renal Replacement Therapy Using a Steady-State Mass Balance Model

Introduction: Hypophosphatemia is common during continuous renal replacement therapy (CRRT), but serum phosphate levels can potentially be maintained during treatment by either intravenous phosphate supplementation or addition of phosphate to renal replacement therapy (RRT) solutions. Methods: We developed a steady-state phosphate mass balance model to assess the effects of CRRT dose on serum phosphate concentration when using both phosphate-free and phosphate-containing RRT solutions, with emphasis on low CRRT doses. Results: The model predicted that measurements of serum phosphate concentration prior to (initial) and during CRRT (final) together with clinical data on CRRT dose, treatment duration, and phosphate supplementation can determine model patient parameters, that is, both the initial generation rate and clearance of phosphate prior to CRRT. Model parameters were then calculated from average patient data reported in several previous publications with a standard or high CRRT dose. Using representative model parameters for typical patients, predictions were then made of the effect of low CRRT dose on the change in serum phosphate levels after implementation of CRRT. The model predicted that CRRT at a low dose using phosphate-free RRT solutions will limit, but not eliminate, the incidence of hypophosphatemia. Further, the model predicted that CRRT at a low dose will have virtually no influence on the incidence of hyperphosphatemia when using phosphate-containing RRT solutions. Conclusions: This report identifies the clinical measurements to be used with the proposed model for individualizing the CRRT dose and RRT phosphate concentration to maintain serum phosphate concentrations in a desired range.

Population pharmacokinetic and exposure-response analyses of pemigatinib in patients with advanced solid tumors including cholangiocarcinoma.

Pemigatinib is a selective, potent, oral inhibitor of fibroblast growth factor receptor (FGFR)1-3 with efficacy in patients with previously treated, advanced/metastatic cholangiocarcinoma (CCA) with FGFR2 alterations. A previously developed population pharmacokinetic (PK) model of pemigatinib was refined using an updated dataset with 467 participants from seven clinical studies, including patients with CCA. Updated PK model parameters were used to evaluate the association between pemigatinib exposure and efficacy and safety. Pemigatinib PK was adequately described by a two-compartment model with linear elimination and sequential zero- and first-order absorption. The final model successfully minimized, had a successful covariance step, and showed unbiased goodness-of-fit. Estimated first-order absorption rate constant and apparent clearance were 3.7/h and 10.7 L/h, respectively. Sex, baseline body weight, and concomitant use of phosphate binders, proton pump inhibitors, or histamine-2 antagonists significantly impacted PK parameters; however, the impact of covariates on PK exposure was not clinically significant. Steady-state pemigatinib exposure and mean change from baseline in serum phosphate concentration were associated with objective response rate in a bell-shaped relationship and were significantly associated with increased hyperphosphatemia. Pemigatinib exposure was associated with treatment-emergent adverse events, such as decreased appetite, nausea, and stomatitis, although the relationships were shallow. Overall, analyses indicate that 13.5 mg pemigatinib once daily in 21-day cycles (2 weeks on, 1 week off) offers a favorable benefit-risk profile in patients with advanced/metastatic or surgically unresectable CCA and is the optimal dose for clinical development.

The SGLT2 inhibitor dapagliflozin improves kidney function in glycogen storage disease XI.

Glycogen storage disease XI, also known as Fanconi-Bickel syndrome (FBS), is a rare autosomal recessive disorder caused by mutations in the SLC2A2 gene that encodes the glucose-facilitated transporter type 2 (GLUT2). Patients develop a life-threatening renal proximal tubule dysfunction for which no treatment is available apart from electrolyte replacement. To investigate the renal pathogenesis of FBS, SLC2A2 expression was ablated in mouse kidney and HK-2 proximal tubule cells. GLUT2Pax8Cre+ mice developed time-dependent glycogen accumulation in proximal tubule cells and recapitulated the renal Fanconi phenotype seen in patients. In vitro suppression of GLUT2 impaired lysosomal autophagy as shown by transcriptomic and biochemical analysis. However, this effect was reversed by exposure to a low glucose concentration, suggesting that GLUT2 facilitates the homeostasis of key cellular pathways in proximal tubule cells by preventing glucose toxicity. To investigate whether targeting proximal tubule glucose influx can limit glycogen accumulation and correct symptoms in vivo, we treated mice with the selective SGLT2 inhibitor dapagliflozin. Dapagliflozin reduced glycogen accumulation and improved metabolic acidosis and phosphaturia in the animals by normalizing the expression of Napi2a and NHE3 transporters. In addition, in a patient with FBS, dapagliflozin was safe, improved serum potassium and phosphate concentrations, and reduced glycogen content in urinary shed cells. Overall, this study provides proof of concept for dapagliflozin as a potentially suitable therapy for FBS.

Mendelian randomisation and colocalization analyses reveal novel drug targets for the prevention of kidney stone disease by modulating serum calcium and phosphate concentrations

Mendelian randomisation and colocalization analyses reveal novel drug targets for the prevention of kidney stone disease by modulating serum calcium and phosphate concentrations

Tenapanor Improves Long-Term Control of Hyperphosphatemia in Patients Receiving Maintenance Dialysis: the NORMALIZE Study.

Most patients with end-stage kidney disease and hyperphosphatemia have difficulty controlling serum phosphate concentrations (sP) despite maintenance dialysis, dietary restriction, and phosphate binder treatment. NORMALIZE evaluated the efficacy and safety of tenapanor 30 mg twice daily alone or in combination with phosphate binders to achieve sP within the adult population reference range (2.5-4.5 mg/dL). Patients who completed the phase 3 PHREEDOM study could enroll in NORMALIZE. Patients enrolled in NORMALIZE who had received tenapanor during the PHREEDOM study (n=111) added sevelamer carbonate if sP was >4.5 mg/dL. Patients who had received sevelamer carbonate during the PHREEDOM study (n=61) added tenapanor and decreased sevelamer carbonate if sP was ≤4.5 mg/dL, per protocol titration schedule. Patients were followed in NORMALIZE for up to 18 months. We assessed efficacy in the full analysis set (FAS), defined as patients who received ≥1 dose of study drug and had ≥1 posttreatment sP measurement (n=171). We assessed safety in all patients who received ≥1 dose of study drug (n=172). At the endpoint visit, 57 of 171 patients (33%) in the FAS achieved sP between 2.5 and 4.5 mg/dL. Eight of 23 patients (35%) who were on tenapanor alone at the endpoint visit achieved sP between 2.5 and 4.5 mg/dL. The mean reduction from PHREEDOM baseline to end of NORMALIZE in sP was 2.0 mg/dL. Serum iFGF23 was significantly reduced; serum iPTH was significantly reduced among patients with iPTH ≥300 pg/mL at PHREEDOM baseline. The most commonly reported treatment-emergent adverse event was diarrhea in 38 of 172 patients (22%), which led to tenapanor discontinuation in 4 patients (2%). Tenapanor alone or in combination with phosphate binders helped adult patients on maintenance dialysis achieve normal sP concentrations. Safety was consistent with previous studies of tenapanor. A Long-Term Study to Evaluate the Ability of Tenapanor Alone or in Combination With Sevelamer to Treat to Goal Serum Phosphorus in Patients With End-Stage Kidney Disease on Dialysis (NORMALIZE), NCT03988920.

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.

Hypophosphataemia definitions, incidence and associated outcomes in paediatric intensive care: A retrospective cohort study in post-cardiac surgical patients

Hypophosphataemia has been linked to higher morbidity and mortality in intensive care but there is inconsistency in the definition of hypophosphataemia for infants and children. We aimed to determine the incidence of hypophosphataemia in a group of at-risk children in paediatric intensive care unit (PICU) and associations with patient characteristics and clinical outcomes using three different hypophosphataemia thresholds. Retrospective cohort study of 205 post-cardiac surgical patients <2 years of age admitted to Starship Child Health PICU, Auckland, New Zealand. Patient demographics and routine daily biochemistry for 14 days after PICU admission were collected. Rates of sepsis, mortality and length of mechanical ventilation were compared between groups with different serum phosphate concentrations. Out of 205 children, 6 (3%), 50 (24%) and 159 (78%) had hypophosphataemia at thresholds of <0.7, <1.0 and <1.4 mmol/L, respectively. There were no differences in gestational age at birth, sex, ethnicity or mortality in those with and without hypophosphataemia at any threshold. Children with a serum phosphate <1.4 mmol/L had more mean (SD) total hours of mechanical ventilation (85.2 (79.6) vs. 54.9 (36.2) h, P = 0.02) and those with mean serum phosphate <1.0 mmol/L had more mean hours of mechanical ventilation (119.4 (102.8) vs. 65.2 (54.8) h, P < 0.0001), episodes of sepsis (14% vs. 5%, P = 0.03) and longer length of stay (6.4 (4.8-20.7) vs. 4.9 (3.9-6.8) days, P = 0.02). Hypophosphataemia is common in this PICU cohort and serum phosphate <1.0 mmol/L is associated with increased morbidity and length of stay.

#2918 SERUM 25(OH)-VITAMIN D AND 1,25(OH)2 VITAMIN D IN HEMODIALYSIS PATIENTS: FACTORS AFFECTING THEIR CONCENTRATIONS AND THEIR EFFECT ON SURVIVAL

Abstract Background and Aims In haemodialysis patients, serum levels of vitamin D metabolites, 25-hydroxy-vitamin D (25D), a nutritional status of vitamin D, and 1,25-dihydroxy-vitamin D (1,25D), an active form of vitamin D, are previously reported to be low. In recent years of new CKD-MBD guidelines utilizing calcimimetics, vitamin D receptor agonists (VDRA) and new phosphate binders, relationship between serum 25D, 1,25D concentrations and clinical parameters in haemodialysis patients are not well known. We measured both serum 25D and 1,25D concentrations in chronic haemodialysis patients, and examined their association with several clinical factors and also with survival, in both cross-sectional and longitudinal analyses. Method A total of 108 stable haemodialysis patients (72 ± 10 year-old, 64 males, haemodialysis duration 6.9 ± 7.5 years, 45 with type 2 diabetes) were examined. Serum 25D was measured by a ECRIA method, and 1,25D by a RIA2 antibody method, and serum PTH by a IRMA assay. In a cross-sectional analysis, association of these vitamin D metabolites with clinical parameters was examined. In a longitudinal study, patients were followed for 3 years and survival of the patients was examined in relation with these vitamin D metabolites. Results Serum 25D concentrations were 12.0 ± 4.0 ng/ml, being hypovitaminosis D (&amp;lt;30 ng/ml) in all patients. Serum 1,25D concentrations were 14.7 ± 8.7 pg/ml, being lower than normal ranges (60-120 pg/ml) in 93% of the patients. There was no significant differences in 25D or 1,25D between those with diabetes and without. Although there was no significant correlation between 25D and haemodialysis duration, there was a significant negative correlation between 1,25D and haemodialysis duration (r = -0.187, p = 0.042). Neither of 1,25D or 25D was significantly correlated with serum calcium or phosphate concentrations. There was a significant, positive correlation between 25D and serum albumin (r = 0.172, p = 0.0454), although there was no significant correlation between 1,25D and serum albumin. Although there was no significant correlation between 25D and serum PTH, there was a significant, negative correlation between 1,25D and serum PTH (r = -0.379, p&amp;lt;0.001). Similarly, although there was no significant correlation between 25D and serum alkaline phosphatase, there was a significant, negative correlation between 1,25D and serum alkaline phosphatase (r = -0.309, p = 0.001). There were no significant differences in serum two vitamin D metabolites between patients with (n = 65) and without VDRA treatment, nor between those with (n = 12) and without calcimimetics. In a multiple regression analysis after adjustment of age, gender, haemodialysis duration, and VDRA treatment, serum 25D concentrations were significantly, independently associated with serum albumin (β = -0.244, p = 0.0149) (R2 = 0.125, p = 0.007). In a multiple regression analysis after the same adjustment, serum 1,25D concentrations were significantly, independently associated with serum intact PTH (β = -0.310, p = 0.003) (R2 = 0.200, p = 0.002). In the follow-up of three year, 16 patients died. Kaplan Meier analysis revealed that there tended to be better survival in patients with higher 25D concentration (n = 52) than those with lower concentration (p = 0.1936), although no significant association was seen between 1,25D and survival. Conclusion These results indicate that hypovitaminosis D (low 25D&amp;lt;30 ng/ml) is seen in all haemodialysis patients, and in most of these patients, serum 1,25D concentrations are low. Lower serum 25D concentrations are significantly associated with lower serum albumin, i.e., poorer nutritional status. Higher serum 1,25D, even in low ranges, is significantly associated with lower intact PHT and alkaline phosphatase, i.e. lower bone metabolism status. The results suggest that, in the era of new CKD-MBD treatments with calcimimetics and new VDRA, serum 25D may represent a nutritional status, and that serum 1,25D concentrations with regard to bone metabolism may be re-considered for the assessment of CKD-MBD, particularly in regards to prevention of secondary hyperparathyroidism.