Serum Phosphorus and Albumin in Patients Undergoing Peritoneal Dialysis: Interaction and Association With Mortality

Hyperphosphatemia and hypoalbuminemia confer worse clinical outcomes, whether these risk factors interact to predispose to mortality is unclear. In this prospective cohort study, 2,118 patients undergoing incident continuous ambulatory peritoneal dialysis (CAPD) were enrolled and categorized into four groups based on the changing point regarding mortality at 1.5 mmol/L for serum phosphorus and 35 g/L for serum albumin. Risks of all-cause and cardiovascular mortality were examined independently and interactively in overall and subgroups. There was no association between serum phosphorus with all-cause and cardiovascular mortality, but significant interactions (p = 0.02) between phosphorus and albumin existed in overall population. Patients in subgroup with high phosphorus and low albumin were at greater risk of all-cause (HR 1.95, 95%CI 1.27–2.98, p = 0.002) but not cardiovascular mortality (HR 0.37, 95%CI 0.10–1.33, p = 0.13), as compared to those with low phosphorus and high albumin. In contrast, patients with both low parameters had a higher risk of all-cause (HR 1.75, 95%CI 1.22–2.50, p = 0.002) and cardiovascular mortality (HR 1.92, 95%CI 1.07–3.45, p = 0.03). Notably, an elevated risk of both all-cause and cardiovascular mortality was observed in those with low serum albumin, irrespective of phosphorus levels, suggesting low albumin may be useful to identify a higher-risk subgroup of patients undergoing CAPD with different serum phosphorus levels.

The Effect of Phosphate Binders in Patients With End Stage Kidney Disease Undergoing Hemodialysis: a Prospective Observational Study

To compare the clinical efficacy of sevalamer carbonate and lanthanum carbonate in chronic hemodialysis patients. This prospective observational study included 80 patients randomly divided into two groups were followed from December 2019 to December 2020. After 12 months of maintenance hemodialysis treatment with sevalamer carbonate or lanthanum carbonate, serum phosphorus, serum calcium, alkaline phosphatase(ALP), parathyroid hormone (iPTH), low-density lipoprotein(LDL), hemoglobin(HGB), triglycerides(TG) and albumin(ALB) were evaluated. The adequacy of dialysis, the effective rate of treatment and the incidence of adverse reactions were compared as well. After treatment, In lanthanum carbonate group, serum phosphorus and iPTH decreased and albumin increased, the difference was significant(P < 0.05). In sevalamer carbonate group, serum phosphorus and LDL decreased and albumin increased after treatment, the difference was significant(P < 0.05). There was no significant difference in the dialysis adequacy and total effective rate between the two groups (P>0.05). However, the incidence of gastrointestinal adverse reactions in the sevalamer carbonate group was lower than in the lanthanum carbonate group and the difference was significant (P < 0.05). The two phosphate binders are safe and effective for the treatment of hyperphosphatemia in patients with ESKD undergoing maintenance hemodialysis. Nevertheless, sevalamer carbonate seems to be superior with lowering the incidence of gastrointestinal adverse reactions and improving lipid metabolism.

Higher Serum Phosphorus Is Not an Independent Risk Factor of Mortality in Heart Failure with Reduced Ejection Fraction

Higher serum phosphorus has detrimental health effects. Even high-normal rage sP is associated with worse outcomes. The relationship of serum phosphorus with prognostic markers in heart failure remains unclear. We investigated the association of serum phosphorus with heart failure prognostic factors and risk of mortality related to serum phosphorus. In 1029 stable heart failure patients, we investigated the distribution of markers of more advanced heart failure stage across quintiles of serum phosphorus and estimated the relative risk of mortality in comparison to reference. Higher serum phosphorus levels sP were associated with markers of a worse outcome. The best survival was observed in low-normal serum levels. The unadjusted hazard ratio for mortality increased toward higher phosphorus quintiles but not to lower levels of sP. The correction for age, sex, BMI, percent weight loss, inflammation, kidney function, and LVEF did not modify the risk profile substantially. The adjustment for NYHA, natriuretic peptides, serum sodium, and treatment characteristics broke down the risk relationship completely. A higher serum phosphorus is associated with markers of a more risky profile of heart failure. Elevated serum levels of phosphorus sP does not provide independent prognostic information beyond the strongest markers of the severity of the syndrome. The potential involvement of higher serum phosphorus as a mediator in the pathophysiology of heart failure warrants further study.

Activation of the Calcium Receptor by Calcimimetic Agents is Preserved Despite Modest Attenuating Effects of Hyperphosphatemia

Background Some reports indicate that serum phosphorus levels in the range seen clinically among patients undergoing dialysis attenuate calcium receptor activation and modify parathyroid hormone (PTH) release from isolated parathyroid glands in vitro. Some clinicians and providers of dialysis thus have suggested that calcimimetic agents are ineffective and should not be used to manage secondary hyperparathyroidism among those undergoing dialysis when serum phosphorus concentrations exceed certain threshold levels. Methods To determine whether hyperphosphatemia diminishes the therapeutic response to calcimimetic agents, we used data from large clinical trials to analyze the effects of etelcalcetide and cinacalcet to lower plasma PTH levels in individuals on hemodialysis who had secondary hyperparathyroidism and varying degrees of hyperphosphatemia. Results Plasma PTH levels declined progressively during 26 weeks of treatment with either etelcalcetide or cinacalcet without regard to the degree of hyperphosphatemia at baseline. However, with each calcimimetic agent, the decreases in PTH from baseline were less at each interval of follow-up during the trials among participants with serum phosphorus levels above one of three prespecified threshold values compared with those with serum phosphorus levels below these thresholds. Conclusions These in vivo findings are the first in humans to support the idea that hyperphosphatemia attenuates calcium receptor activation by calcium ions and by calcimimetic agents. The effect of hyperphosphatemia on the responsiveness to calcimimetic agents appears relatively modest, however, and unlikely to be significant therapeutically. The efficacy of treatment with calcimimetic agents for lowering plasma PTH levels among those with secondary hyperparathyroidism remains robust despite substantial elevations in serum phosphorus.

Multicenter Prospective Cohort on Aortic Valve Stenosis in Japanese Patients With End Stage Kidney Disease in Tokai Region (ASKIT)

Background:The prevalence of aortic valve stenosis (AS) in patients on maintenance dialysis is high and the prognosis is poor. Because only few large cohort studies have analyzed patients with AS on dialysis, the factors that cause AS in such patients remain unclear.Methods:This multicenter, prospective cohort study included 2,786 patients on dialysis who underwent transthoracic echocardiography between July 1, 2017 and June 30, 2018. Patients with a maximum aortic jet velocity (Vmax) ≥2.0 m/s, pressure gradient (PG) between the left ventricle and ascending aorta (mean PG) ≥20 mmHg, or aortic valve area (AVA) ≤1.0 cm2 were categorized into the AS group. Of these, patients with Vmax ≥3.0 m/s, mean PG ≥20 mmHg, or AVA ≤1.0 cm2 were categorized into the severe AS group. The AS and severe AS groups were then compared with the non-AS group to identify the risk factors for AS using multivariate logistic analysis. We also compared the risk factors for AS with and without aortic valve calcification, which is the stage prior to age-related AS.Results:Of the 2,786 patients analyzed, 555 (20.0%) and 139 (6.9%) were categorized into the AS and severe AS groups, respectively. Multivariate logistic analysis revealed that aging, long-term dialysis, and elevated serum phosphorus levels were associated with AS in the AS and severe AS groups (p <0.05). Additional investigation using stratified multivariate analysis revealed that groups with serum phosphorus levels of 5.0–5.9 mg/dL and >6.0 mg/dL had a higher risk of AS than those with serum phosphorus levels of <4.0 mg/dL (odds ratio: 2.24; p = 0.01 and odds ratio: 2.66, p = 0.005, respectively). Aortic valve calcification was associated with aging, long-term dialysis, diabetes mellitus, administration of vitamin D receptor activators, elevated serum calcium levels, and anemia (p <0.05 for all).Conclusions:Dialysis patients had a high prevalence of AS, and AS was associated with aging, long dialysis duration, and elevated serum phosphorus levels.Trial registration: UMIN000026756, Registered on March 29, 2017.

The Effect of Phosphate Binders in Patients With End Stage Kidney Disease Undergoing Hemodialysis: a Prospective Cohort Study

Background: To compare the clinical efficacy of sevalamer carbonate and lanthanum carbonate in chronic hemodialysis patients. Methods: This prospective observational study included 76 patients with follow-up from September 2019 to December 2020. After 15 months of maintenance hemodialysis treatment with sevalamer carbonate or lanthanum carbonate, serum phosphorus, serum calcium, alkaline phosphatase(ALP), parathyroid hormone (iPTH), low-density lipoprotein(LDL), hemoglobin(HGB), triglycerides(TG) and albumin(ALB) were evaluated. The adequacy of dialysis, the effective rate of treatment and the incidence of adverse reactions were compared as well. Results: After treatment, In lanthanum carbonate group, serum phosphorus and iPTH decreased and albumin increased, the difference was significant(P < 0.05). In sevalamer carbonate group, serum phosphorus and LDL decreased and albumin increased after treatment, the difference was significant(P < 0.05). There was no significant difference in the dialysis adequacy and total effective rate between the two groups (P>0.05). However, the incidence of adverse reactions in the sevalamer carbonate group was lower than in the lanthanum carbonate group and the difference was significant (P < 0.05). Conclusion: The two phosphate binders are safe and effective for the treatment of hyperphosphatemia in patients with ESKD undergoing maintenance hemodialysis. Nevertheless, sevalamer carbonate seems to be superior with lowering the incidence of gastrointestinal adverse reactions and improving lipid metabolism.

Sustained efficacy and safety of burosumab, a monoclonal antibody to FGF23, in children with X-linked hypophosphatemia

Purpose In X-linked hypophosphatemia (XLH), excess FGF23 causes hypophosphatemia and low calcitriol, leading to musculoskeletal disease with clinical consequences. XLH treatment options include conventional oral phosphate with active vitamin D, or monotherapy with burosumab, a monoclonal antibody approved to treat children and adults with XLH. We have previously reported outcomes up to 64 weeks, and here, we report safety and efficacy follow-up results up to 160 weeks from an open-label, multicenter, randomized, dose-finding trial of burosumab for 5 to 12 year-old children with XLH. Methods After one week of conventional therapy washout, patients were randomized 1:1 to burosumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for 64 weeks, with dosing titrated based on fasting serum phosphorus levels between baseline and Week 16. From Week 66 to Week 160, all patients received Q2W burosumab. Results Twenty-six children were randomized initially into each Q2W and Q4W group and all completed treatment to Week 160. In 41 children with open distal femoral and proximal tibial growth plates (from both treatment groups), total Rickets Severity Score significantly decreased by 0.9±0.1 (least squares mean±SE; p&lt;0.0001) from baseline to Week 160. Fasting serum phosphorus increases were sustained by burosumab therapy throughout the study, with an overall population mean (SD) of 3.35 (0.39) mg/dL, within the pediatric normal range (3.2 to 6.1 mg/dL) at Week 160 (mean change from baseline p&lt;0.0001). Most adverse events were mild to moderate in severity. Main conclusions In children with XLH, burosumab administration for 160 weeks improved phosphate homeostasis and rickets and was welltolerated. Long-term safety was consistent with the reported safety profile of burosumab.

Circulating phosphorus level and risk of prostate cancer: a Mendelian randomization study

Background Recent observational studies have suggested that circulating phosphorus levels are positively associated with risk of prostate cancer. However, little is known about the causal direction of the association. Objective To explore the potential causal relationship between circulating phosphorus and risk of prostate cancer, we conducted a Mendelian randomization (MR) study. Design Summary statistics of prostate cancer were obtained from a meta-analysis of genome-wide association studies (GWAS) consisting of 79,148 cases and 61,106 controls. Single nucleotide polymorphisms (SNP) associated with serum phosphorus level were selected from a GWAS of 291,408 individuals from the UK Biobank. MR analysis was performed using the inverse-variance weighted (IVW) method, supplemented with simple-median, weighted-median, maximum likelihood-based, MR-Egger regression and MR-PRESSO test. We also performed a meta-analysis of observational studies to assess the associations of dietary phosphorus intake and serum phosphorus level with risk of prostate cancer. Results In the MR analysis, a total of 125 independent SNPs associated with serum phosphorus levels were used as instrumental variables. Genetically predicted serum phosphorus levels were associated with a 19% increased risk of prostate cancer (95% confidence interval (CI): 9%, 31%) per one SD increment of serum phosphorus by IVW (P = 1.82 × 10–4). Sensitivity analyses using alternative MR methods produced similar positive associations, and no evidence of pleiotropy was detected by MR-Egger regression (P = 0.422). For meta-analysis, eight studies for dietary phosphorus intake and four for serum phosphorus levels were included involving a total of 669,080 participants. Consistently, high dietary phosphorus intake and serum phosphorus levels were associated with an 8% (95% CI: 4%, 12%) and 7% (95% CI: 1%, 14%) increase in prostate cancer risk, respectively. Conclusions Our study suggested a potential causal relationship between circulating phosphorus and risk of prostate cancer. Further studies are warranted to elucidate the underlying mechanism of phosphorus in the development of prostate cancer.

Higher levels of serum phosphorus are associated with coronary calcification post heart transplantation

Background A higher serum phosphorus level, although within the normal range has been linked to coronary artery and aortic calcification in the non-transplant population. Coronary calcification is mostly associated with donor-derived lesions, and is uncommon within the first years after heart transplantation. Purpose We aimed to investigate the association of phosphorus levels with plaque calcification after heart transplantation. Methods A total of 156 patients who underwent virtual histology intravascular ultrasound (VH-IVUS) studies for cardiac allograft vasculopathy (CAV) surveillance and had fasting serum phosphorus levels &lt;4.5 mg/dL, were included in the analyses. IVUS analyses were performed in the proximal left anterior descending artery, and plaque composition of dense calcium (DC) was evaluated using VH-IVUS, and presented as percent DC of total plaque volume. The patients were separated into 3 groups according to tertiles of serum phosphorus levels. Results Mean recipient and donor ages were 54±13 and 31±14 years, respectively. Mean serum phosphorus in recipients was 3.5±0.6 mg/dL, with median time after transplantation at the IVUS studies of 6 (3,10) years. There were no significant differences in %DC between phosphorus tertiles in patients who underwent IVUS within 6 years after transplantation (p=0.11, Fig. 1A). However, beyond 6 years after transplantation, we observed an incremental association between phosphorus levels and the extent of calcification (p=0.02, Fig. 1B). In this group, serum phosphorus levels significantly correlated with %DC (standardized β=0.29, P=0.008), and this correlation remained significant after adjustment for donor age, recipient age, and eGFR (standardized β=0.26, P=0.001). Conclusion Higher serum phosphorus levels were associated with a level-dependent increase in calcified coronary artery plaque in patients starting 6 years post heart transplant. Long-term exposure to higher serum phosphorus, even within the normal range, might promote plaque calcification after heart transplantation. FUNDunding Acknowledgement Type of funding sources: None.