Phosphorus is a macroelement found in the body, mostly in the bones as crystals of hydroxyapatite. Higher levels are found in patients affected by chronic kidney disease (CKD). Since the early stage of CKD phosphorous excretion is impaired, but the increase of PTH and FGF23 maintains its level in the normal range. In the last decades, the role of FGF23 in erythropoiesis was studied, and now it is well known for its role in anemia genesis in patients affected by conservative CKD. Both Hyperphosphatemia and anemia are two manifestations of CKD, but many studies showed a direct association between serum phosphorous and anemia. Phosphorus can be considered as the common point of more pathogenetic ways, independent of renal function: the overproduction of FGF23, the worsening of vascular disease, and the toxic impairment of erythropoiesis, including the induction of hemolysis.

OBJECTIVE: This review is a critical analysis of treatment results obtained in clinical trials conducted in patients with chronic kidney disease (CKD) and secondary hyperparathyroidism (SHPT), hyperphosphatemia, or both.
RESULTS: Patients with CKD have a high mortality rate. The disorder of mineral and bone metabolism (CKD-MBD), which is commonly present in these patients, is associated with adverse outcomes, including cardiovascular events and mortality. Clinical trials aimed at improving these outcomes by modifying CKD-MBD associated factors have most often resulted in disappointing results. The complexity of CKD-MBD, where many players are closely interconnected, might explain these negative findings. We first present an historical perspective of current knowledge in the field of CKD-MBD and then examine potential flaws of past and ongoing clinical trials targeting SHPT and hyperphosphatemia respectively in patients with CKD.

BACKGROUND: With age, lungs undergo typical changes that lead to a deterioration of respiratory function. Our aim was to assess the role of age-associated hyperphosphatemia in these changes.
METHODS: We used C57BL6 mice to study an ageing model in vivo and human lung fibroblasts were treated with a phosphate donor, beta-glycerophosphate (BGP), to explore mechanisms involved. Respiratory function was registered with a double chamber plethysmograph. Lung structure was analysed by different staining, phosphate and cytokines levels by colorimeric kits, expression of fibrosis, inflammation and ET-1 system by western blot or RT-PCR.
RESULTS: Old mice showed hyperphosphatemia, along with lung fibrosis, loss of elastin, increased expression of pro-inflammatory cytokines and impaired respiratory function. BGP induced inflammation and fibrosis in fibroblasts through the activation and binding of NFkB to the MCP-1 or FN promoters. BGP increased ECE-1 expression by inducing NFkB binding to the ECE-1 promoter. QNZ, an NFkB inhibitor, blocked these effects. When ECE-1 was inhibited with phosphoramidon, BGP-induced inflammation and fibrosis were significantly reduced, suggesting a role for ET-1 in BGP-mediated effects.ET-1 produced effects similar to those of BGP, which were also dependent on NFkB. To study the pathophysiological relevance of hyperphosphatemia in vivo, a low-P diet was administered to a group of old animals, showing an improvement in fibrosis, inflammation and respiratory function compared to old mice on a standard diet.
CONCLUSIONS: These results suggest that age-related hyperphosphatemia induces inflammation, fibrosis, and impaired respiratory function in old mice; these effects appear to be mediated by ET-1 and NFkB activation.

暂无摘要。

UNASSIGNED: Sarcopenia, commonly observed in patients treated with hemodialysis, correlates with low serum phosphate levels. Although normophosphatemia is desired, dietary phosphate restriction is difficult to achieve and may result in undesirable protein restriction.
UNASSIGNED: We aimed to evaluate whether hyperphosphatemia is associated with higher muscle strength in patients receiving hemodialysis treatment.
UNASSIGNED: A single-center prospective observational study.
UNASSIGNED: Ambulatory prevalent patients undergoing hemodialysis treatments in a dialysis unit of a tertiary hospital.
UNASSIGNED: Participants included prevalent patients treated with hemodialysis. All patients were above 18 years. Only patients with residual kidney function below 200 mL/24 hours were included to avoid bias.
UNASSIGNED: Muscle strength was measured by handgrip strength (HGS). Each patient repeated 3 measurements, and the highest value was recorded. Handgrip strength cutoffs for low muscle strength were defined as <27 kg in men and <16 kg in women. Biochemical parameters, including serum phosphate level, were driven from routine monthly blood tests. Hyperphosphatemia was defined as serum phosphate above 4.5 mg/dL.
UNASSIGNED: Handgrip strength results were compared to nutritional, anthropometric, and biochemical parameters-in particular phosphate level. Long-term mortality was recorded.
UNASSIGNED: Seventy-four patients were included in the final analysis. Handgrip strength was abnormally low in 33 patients (44.5%). Patients with abnormal HGS were older and more likely to have diabetes mellitus and lower albumin and creatinine levels. There was no correlation between HGS and phosphate level (r = 0.008, P = .945). On multivariable analysis, predictors of higher HGS were body mass index and creatinine. Diabetes mellitus and female sex predicted lower HGS. Hyperphosphatemia correlated with protein catabolic rate, blood urea nitrogen, and creatinine. On multivariable analysis, predictors of hyperphosphatemia were higher creatinine level, normal albumin level, and heart failure. During mean follow-up time of 7.66 ± 3.9 months, 11 patients died. Mortality was significantly higher in patients with abnormally low HGS compared with normal HGS (odds ratio = 9.32, P = .02).
UNASSIGNED: A single-center study. All measurements were performed at one time point without repeated assessments. Direct dietary intake, degree of physical activity, and medication compliance were not assessed.
UNASSIGNED: Hyperphosphatemia correlated with increased protein intake as assessed by protein catabolic rate in patients treated with hemodialysis; however, neither correlated with higher muscle strength as measured by HGS.Trial registration: MOH 202125213.
UNASSIGNED: La sarcopénie, qui est fréquemment observée chez les patients traités par hémodialyse, est corrélée à de faibles taux sériques de phosphate. Dans ce contexte, la normophosphatémie est souhaitée, mais la restriction alimentaire en phosphate est difficile à réaliser et peut entraîner une restriction indésirable en protéines.
UNASSIGNED: Notre objectif était de déterminer si l’hyperphosphatémie est associée à une plus grande force musculaire chez les patients qui reçoivent un traitement par hémodialyse.
UNASSIGNED: Étude observationnelle prospective monocentrique.
UNASSIGNED: Le service de dialyse d’un hôpital de soins tertiaires.
UNASSIGNED: Des patients prévalents âgés de plus de 18 ans qui recevaient des traitements d’hémodialyse en ambulatoire dans le service de dialyse de l’hôpital. Afin de limiter les biais, seuls les patients avec une fonction rénale résiduelle inférieure à 200 ml/24 heures ont été inclus.
UNASSIGNED: La force musculaire a été mesurée par le test de force de préhension (HGS - handgrip strength). Trois mesures ont été faites pour chaque patient et la valeur la plus élevée a été enregistrée. Les seuils de faible force musculaire à l’HGS ont été établis à < 27 kg pour les hommes et à < 16 kg pour les femmes. Les paramètres biochimiques, notamment le taux de phosphate sérique, ont été déterminés à partir des analyses sanguines mensuelles des patients. L’hyperphosphatémie a été définie par une concentration sérique en phosphate supérieure à 4,5 mg/dl.
UNASSIGNED: Les résultats de l’HGS ont été comparés aux paramètres nutritionnels, anthropométriques et biochimiques — plus particulièrement au taux de phosphate. La mortalité à long terme a été enregistrée.
UNASSIGNED: Soixante-quatorze patients ont été inclus dans l’analyse finale. Les résultats de l’HGS étaient anormalement faibles chez 33 patients (44,5 % des sujets). Les patients qui avaient obtenu un résultat anormal à l’HGS étaient plus âgés, plus susceptibles de souffrir de diabète, et présentaient des taux d’albumine et de créatinine plus faibles. Aucune corrélation n’a été observée entre le résultat à l’HGS et le taux sérique de phosphate (r=0.008; p=0.945). Dans l’analyse multivariée, l’indice de masse corporelle et le taux de créatinine étaient des prédicteurs d’un résultat plus élevé à l’HGS, alors que le diabète et le fait d’être une femme étaient prédictifs d’un résultat inférieur à l’HGS. L’hyperphosphatémie a été corrélée au taux de catabolisme des protéines, à l’urée et au taux de créatinine. Dans l’analyse multivariée, un taux de créatinine plus élevé, un taux d’albumine normal et une insuffisance cardiaque étaient des facteurs prédictifs d’une hyperphosphatémie. Au cours de la période moyenne de suivi (7,66 ± 3,9 mois), 11 patients sont décédés. La mortalité était significativement plus élevée chez les patients qui présentaient un résultat anormalement faible à l’HGS par rapport à la normale (RC: 9,32; p = 0,02).
UNASSIGNED: L’étude a été menée dans un seul centre. Toutes les mesures ont été effectuées à un moment donné sans évaluations répétées. L’apport alimentaire direct, le degré d’activité physique et l’observance des médicaments n’ont pas été évalués.
UNASSIGNED: Chez des patients traités par hémodialyse, l’hyperphosphatémie est corrélée à une augmentation de l’apport en protéines évalué par le taux de catabolisme des protéines, mais ni l’une ni l’autre n’est corrélée à une plus grande force musculaire mesurée par HGS.

BACKGROUND: Aberrations in blood phosphate (Pi) levels, whether presenting as hypo- or hyperphosphatemia, appear to be associated with clinical complications and adverse outcomes in patients admitted to an intensive care unit (ICU). However, the prevalence of Pi disorders and the association with subsequent factors and organ failures leading to death in ICU patients are poorly described. Despite endeavors to understand the etiology and treatment of low Pi levels from systematic reviews and meta-analyses, the literature lacks comprehensive guidance for managing hypophosphatemia. Hyperphosphatemia, on the other hand, appears to be associated with higher mortality among critically ill patients, yet its prevalence among ICU patients, particularly following phosphate repletion, remains unknown. The present study aims to investigate the prevalence of Pi abnormalities upon ICU admission and their incidence during the first week of ICU stay, the factors associated with Pi alterations, and the effect of phosphate repletion on the normalization of Pi levels, and its associations with clinical outcomes.
METHODS: This multicentre, prospective, non-interventional cohort study will include at least 1000 consecutive adult ICU patients (≥18 years) as part B of the GUTPHOS study. Sites are eligible if an anticipated minimal inclusion of 50 eligible patients during eight weeks from January 2024 until June 2024 and daily phosphate measurements during the first seven days of ICU stay are expected. All consecutive adult patients admitted to a participating ICU during the recruitment period, lasting up to eight weeks, or up to 120 patients if enrollment reaches that limit earlier, will be included. Study parameters include study site characteristics, patient demographics, daily assessment of Pi levels, Pi-related treatment, feeding details, renal replacement therapy details, the incidence of refeeding-associated hypophosphatemia and administered medication (during the first seven calendar days of ICU stay). There will be a follow-up period of a maximum of 90 days to document 28- and 90-day all-cause mortality as the primary outcome. Multiple logistic regression will be used to assess independent associations with mortality in addition to Receiver Operating Characteristics curves to identify cut-off Pi values associated with mortality and overcorrection. Linear mixed models will be conducted to assess Pi treatment effects. Subgroup analyses will be performed based on Pi abnormalities observed during ICU admission, categorized as normo-, hypo-, hyper-, or mixed, along with its severity (mild, moderate, or severe).
CONCLUSIONS: The GUTPHOS study will be the first multicentre, prospective observational cohort study to investigate the prevalence, management practices, and consequent outcomes associated with Pi abnormalities during the first week of ICU admission. Its results may bridge the current evidence gap in repletion protocols while establishing the groundwork for a subsequent randomized controlled trial.
BACKGROUND: NCT05909722.

UNASSIGNED: COPD patients frequently have abnormal serum phosphorus levels. The objective of this study was to examine the correlation between serum phosphorus levels with hospital and 90-day mortality in critically ill patients with COPD.
UNASSIGNED: The MIMIC IV database was used for this retrospective cohort analysis. We extracted demographics, vital signs, laboratory tests, comorbidity, antibiotic usage, ventilation and scoring systems within the first 24 hours of ICU admission. Restricted cubic splines and multivariate cox regression analysis models were used to evaluate the connection between serum phosphorus with hospital and 90-day mortality. We assessed and classified various factors including gender, age, renal disease, severe liver disease, the utilization of antibiotics and congestive heart failure.
UNASSIGNED: We included a total of 3611 patients with COPD, with a median age of 70.7 years. After adjusting for all other factors, we observed a significant positive association between serum phosphate levels with both hospital mortality (HR 1.19, 95% CI: 1.07-1.31, p<0.001) and 90-day mortality (HR 1.15, 95% CI: 1.06-1.24, p<0.001). Compared to the medium group (Q2 ≥3.15, <4.0), the adjusted hazard ratios for hospital mortality were 1.47 (95% CI: 1.08-2, p=0.013), and 1.31 (95% CI: 1.06-1.61, p=0.013) for 90-day mortality in the high group (Q3≥4.0). Hospital mortality decreased at serum phosphate levels below 3.8 mg/dl (HR 0.664, 95% CI: 0.468-0.943, p=0.022), but increased for both hospital (HR 1.312, 95% CI: 1.141-1.509, p<0.001) and 90-day mortality (HR 1.236, 95% CI: 1.102-1.386, p<0.001) when levels were above 3.8 mg/dl. Subgroup and sensitivity analyses yielded consistent results.
UNASSIGNED: In critical ill COPD patients, this study demonstrated a non-linear association between serum phosphate levels and both hospital and 90-day mortality. Notably, there was an inflection point at 3.8 mg/dl, indicating a significant shift in outcomes. Future prospective research is necessary to validate this correlation.

BACKGROUND: There was limited research on the epidemiology of hyperphosphatemia in early-stage chronic kidney disease (CKD) patients. We aimed to explore the clinical characteristics and prognostic value of hyperphosphatemia in patients with CKD stages 1-2.
METHODS: We enrolled adult patients with CKD stages 1-2 from 24 regional central hospitals across China. Hyperphosphatemia was defined as a serum phosphate level exceeding 1.45 mmol/L. The study outcomes included all-cause and cardiovascular (CV) mortality. Cox proportional hazard models were used to investigate the association of hyperphosphatemia with all-cause and CV mortality.
RESULTS: Among 99,266 patients with CKD stages 1-2 across China, the prevalence of hyperphosphatemia was 8.3%. The prevalence of hyperphosphatemia was increased with the level of urinary protein and was higher in younger and female patients. Among 63,121 patients with survival information, during a median of 5.2 years follow-up period, there were 436 (8.0%) and 4,695 (8.1%) deaths in those with and without hyperphosphatemia, respectively. After adjusting for potential confounders, compared with patients without hyperphosphatemia, patients with hyperphosphatemia were associated with a higher risk of all-cause mortality (hazard ratio: 1.28, 95% CI: 1.16-1.41). Although nearly 60.3% of hyperphosphatemia could be relieved without phosphate-lowering drug therapy among patients with CKD stages 1-2, transient hyperphosphatemia was also associated with an increased risk of all-cause mortality (p = 0.048).
CONCLUSIONS: Hyperphosphatemia was not rare in patients with CKD stages 1-2 and was associated with an increased risk of mortality. Clinicians should closely monitor serum phosphorus levels in patients with CKD, even in those with normal kidney function.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare disorder caused by deficient FGF23 signaling and resultant ectopic calcification. Here, we systematically characterized and quantified macro- and micro-calcification in a HFTC cohort using CT and 18F-sodium fluoride PET/CT (18F-NaF PET/CT). Fourier-transform infrared (FTIR) spectroscopy was performed on 4 phenotypically different calcifications from a patient with HFTC, showing the dominant component to be hydroxyapatite. Eleven patients with HFTC were studied with CT and/or 18F-NaF PET/CT. Qualitative review was done to describe the spectrum of imaging findings on both modalities. CT-based measures of volume (eg, total calcific burden and lesion volume) and density (Hounsfield units) were quantified and compared to PET-based measures of mineralization activity (eg, mean standardized uptake values-SUVs). Microcalcification scores were calculated for the vasculature of 6 patients using 18F-NaF PET/CT and visualized on a standardized vascular atlas. Ectopic calcifications were present in 82% of patients, predominantly near joints and the distal extremities. Considerable heterogeneity was observed in total calcific burden per patient (823.0 ± 670.1 cm3, n = 9) and lesion volume (282.5 ± 414.8 cm3, n = 27). The largest lesions were found at the hips and shoulders. 18F-NaF PET offered the ability to differentiate active vs quiescent calcifications. Calcifications were also noted in multiple anatomic locations, including brain parenchyma (50%). Vascular calcification was seen in the abdominal aorta, carotid, and coronaries in 50%, 73%, and 50%, respectively. 18F-NaF-avid, but CT-negative calcification was seen in a 17-year-old patient, implicating early onset vascular calcification. This first systematic assessment of calcifications in a cohort of patients with HFTC has identified the early onset, prevalence, and extent of calcification. It supports 18F-NaF PET/CT as a clinical tool for distinguishing between active and inactive calcification, informing disease progression, and quantification of ectopic and vascular disease burden.
Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare disorder in which patients develop sometimes large debilitating calcifications of soft tissues and blood vessels. It is caused by deficient fibroblast growth factor-23 that leads to high phosphate levels, which contributes to the calcifications. The calcifications and manifestations of this disorder have not been well characterized. We determined the mineral composition of the calcifications to be hydroxyapatite. Capitalizing on the fact fluoride can be integrated into hydroxyapatite, we used radiolabeled sodium fluoride PET/CT scans (18F-NaF PET/CT) to characterize and quantify the calcifications in 11 patients. Eighty-two percent of the patients had calcifications, with the largest located at the hips and shoulders. Micro-calcifications were found in the blood vessels of most patients, including children. The technique also enabled us to differentiate between active vs stable calcifications. This first systematic assessment of calcifications in patients with HFTC showed the utility of 18F-NaF PET/CT as a tool to identify and quantify calcifications, as well as distinguish between active and stable calcifications. This approach will inform disease progression and may prove useful for measuring response to treatment.

What is this summary about?This is a summary of an article that was published in the medical journal Kidney360 describing results from the NORMALIZE study. The NORMALIZE study looked at how well tenapanor tablets reduced higher-than-normal levels of phosphate in the blood of persons with kidney disease who are on maintenance dialysis. These persons are unable to keep their blood phosphate levels in a normal range, and high levels of phosphate can contribute to several serious health consequences.Tenapanor is approved as an add-on treatment for high levels of phosphate in the blood of adults with chronic kidney disease who are on maintenance dialysis and whose disease does not respond adequately to treatment with phosphate binders or who are not able to take phosphate binders. In earlier clinical studies, tenapanor was studied alone or studied together with phosphate binders. In a 1-year clinical study called PHREEDOM, researchers learned that when tenapanor was used alone, it lowered blood phosphate levels, and treated patients experienced acceptable safety and tolerability as determined by the doctors running the study. In the NORMALIZE study, adult patients took a 30-mg tenapanor tablet twice a day, either alone or with sevelamer, for up to 18 months after they completed the PHREEDOM study.What were the main conclusions reported by the researchers?The researchers found that one-third of patients taking tenapanor, either alone or with sevelamer, achieved normal blood phosphate levels. This is an improvement from the current standard of care with sevelamer alone to reduce blood phosphate levels. As seen in the earlier studies of tenapanor, the most common adverse event experienced by patients was softer or loose stools. No new safety concerns were reported in the NORMALIZE study.What are the key takeaways?The researchers concluded that tenapanor, used alone or combined with sevelamer, can be used long-term by adult patients receiving maintenance dialysis to reduce the phosphate levels in their blood to within the normal range. Patients who take tenapanor may experience softer or loose stools.This summary was developed by the authors to help adult patients with chronic kidney disease receiving dialysis, and their family members and/or caregivers, better understand the effects of taking tenapanor.[Box: see text]Link to original article here.