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Diabetes, Metabolic Syndrome and... 2024Pseudohypoparathyroidism (PHP) is a rare genetic disease characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) in serum. Here, we...
Pseudohypoparathyroidism (PHP) is a rare genetic disease characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) in serum. Here, we report a case of a patient with pseudohypoparathyroidism type IB (PHPIB) and subclinical hypothyroidism, analyze the clinical and genetic data of his family members, review the relevant literature, and classify and discuss the pathogenesis and clinical characteristics of each subtype. Finally, we discuss the treatment approach to improve clinicians' understanding of the disease.
PubMed: 38765469
DOI: 10.2147/DMSO.S458405 -
Cureus May 2024We present the case of an elderly female who presented to the emergency department with dizziness. She was found to have an acute chronic kidney injury complicated by a...
We present the case of an elderly female who presented to the emergency department with dizziness. She was found to have an acute chronic kidney injury complicated by a complete heart block (CHB). She received a transvenous pacemaker and was taken for hemodialysis (HD) with complete resolution of her heart block. The following day, she was noted to be symptomatic and bradycardic. A repeat electrocardiogram showed a recurrence of the CHB. She was taken again for HD which led to the resolution of her conduction abnormalities. Electrophysiology was consulted and she had a permanent pacemaker implanted prior to being discharged.
PubMed: 38751404
DOI: 10.7759/cureus.60339 -
International Journal of Molecular... Apr 2024To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This... (Review)
Review
To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This amazing feat is accomplished through synchronised phosphate transport by myriads of ciliated cells lining the renal proximal tubules. These respond in real time to changes in phosphate and composition of the renal filtrate and to hormonal instructions. How they do this has stimulated decades of research. New analytical techniques, coupled with incredible advances in computer technology, have opened new avenues for investigation at a sub-cellular level. There has been a surge of research into different aspects of the process. These have verified long-held beliefs and are also dramatically extending our vision of the intense, integrated, intracellular activity which mediates phosphate absorption. Already, some have indicated new approaches for pharmacological intervention to regulate phosphate in common conditions, including chronic renal failure and osteoporosis, as well as rare inherited biochemical disorders. It is a rapidly evolving field. The aim here is to provide an overview of our current knowledge, to show where it is leading, and where there are uncertainties. Hopefully, this will raise questions and stimulate new ideas for further research.
Topics: Humans; Phosphates; Animals; Renal Reabsorption; Kidney; Kidney Tubules, Proximal
PubMed: 38731904
DOI: 10.3390/ijms25094684 -
JBMR Plus Jun 2024Hypoparathyroidism, a deficiency of parathyroid hormone (PTH), results in hypocalcemia, hyperphosphatemia, and hypercalciuria. The disease is poorly controlled by...
Hypoparathyroidism, a deficiency of parathyroid hormone (PTH), results in hypocalcemia, hyperphosphatemia, and hypercalciuria. The disease is poorly controlled by calcium and vitamin D supplements or native PTH(1-84) replacement therapy. A version of PTH is being developed using D-VITylation technology, whereby vitamin D is conjugated to a therapeutic peptide, which confers a long plasma half-life by virtue of binding to the abundant vitamin D binding protein (DBP). D-VITylation of PTH caused no reduction in activity at the PTHR1 receptor, and resulted in a plasma elimination half-life of 7-15 h in rats and 24-32 h in cynomolgus monkeys. Analysis of steady-state pharmacokinetics as a function of dose showed flat profiles with smaller peak:trough ratios at low doses, indicative of slower subcutaneous absorption. In thyroparathyroidectomized (TPTx) rats, PTH(1-34)-vitamin D conjugates restored serum calcium and phosphate levels into the normal range over the 24 h dosing period, and increased bone turnover markers and reduced bone mineral density. Urinary calcium was initially elevated, but normalized by the end of treatment on day 27. In healthy monkeys, a single dose of PTH(1-34)-vitamin D conjugates elevated serum calcium levels above the normal range for a period of 24-48 h while simultaneously reducing urinary calcium. Therefore, the lead compound, EXT608, is a promising candidate as a therapeutic that can truly mimic the endogenous activity of PTH and warrants further study in patients with hypoparathyroidism.
PubMed: 38721043
DOI: 10.1093/jbmrpl/ziae045 -
Nature Medicine Jun 2024Fibroblast growth factor receptor (FGFR) alterations drive oncogenesis in multiple tumor types. Here we studied pemigatinib, a selective, potent, oral FGFR1-FGFR3...
Fibroblast growth factor receptor (FGFR) alterations drive oncogenesis in multiple tumor types. Here we studied pemigatinib, a selective, potent, oral FGFR1-FGFR3 inhibitor, in the phase 2 FIGHT-207 basket study of FGFR-altered advanced solid tumors. Primary end points were objective response rate (ORR) in cohorts A (fusions/rearrangements, n = 49) and B (activating non-kinase domain mutations, n = 32). Secondary end points were progression-free survival, duration of response and overall survival in cohorts A and B, and safety. Exploratory end points included ORR of cohort C (kinase domain mutations, potentially pathogenic variants of unknown significance, n = 26) and analysis of co-alterations associated with resistance and response. ORRs for cohorts A, B and C were 26.5% (13/49), 9.4% (3/32) and 3.8% (1/26), respectively. Tumors with no approved FGFR inhibitors or those with alterations not previously confirmed to be sensitive to FGFR inhibition had objective responses. In cohorts A and B, the median progression-free survival was 4.5 and 3.7 months, median duration of response was 7.8 and 6.9 months and median overall survival was 17.5 and 11.4 months, respectively. Safety was consistent with previous reports. The most common any-grade treatment-emergent adverse events were hyperphosphatemia (84%) and stomatitis (53%). TP53 co-mutations were associated with lack of response and BAP1 alterations with higher response rates. FGFR1-FGFR3 gatekeeper and molecular brake mutations led to acquired resistance. New therapeutic areas for FGFR inhibition and drug failure mechanisms were identified across tumor types. ClinicalTrials.gov identifier: NCT03822117 .
Topics: Humans; Receptor, Fibroblast Growth Factor, Type 3; Female; Receptor, Fibroblast Growth Factor, Type 1; Pyrimidines; Male; Neoplasms; Middle Aged; Adult; Aged; Mutation; Protein Kinase Inhibitors; Progression-Free Survival; Drug Resistance, Neoplasm; Morpholines; Pyrroles
PubMed: 38710951
DOI: 10.1038/s41591-024-02934-7 -
Journal of Multidisciplinary Healthcare 2024Patients on maintenance hemodialysis have an increased risk of fracture. However, the relationship between fracture and poor prognosis is not clear.
BACKGROUND
Patients on maintenance hemodialysis have an increased risk of fracture. However, the relationship between fracture and poor prognosis is not clear.
METHODS
A total of 182 maintenance hemodialysis patients were enrolled in the study. The relationship between fracture and poor prognosis (cardiovascular events, stroke, malignancy and 5-year all-cause mortality) were analyzed.
RESULTS
21 of 182 patients had a history of fracture at the time of enrollment. 26 patients had a new fracture after enrollment. A total of 57 fractures occurred in 47 patients, the most common fracture site was the rib. Patients with fracture group had a higher proportion of elderly and female, higher serum phosphorus and B-type natriuretic peptide and lower hemoglobin, albumin, and potassium compared with those without fracture. Age (), hemoglobin (), and serum phosphorus () were the independent risk factors of new fractures in MHD patients. The incidence of malignancy and 5-year all-cause mortality in patients with fracture was higher than those without fracture (). But there was no significant difference in the incidence of acute myocardial infarction or stroke.
CONCLUSION
25.8% of maintenance hemodialysis patients had at least one fracture, with rib fractures accounting for the highest proportion. Age, hemoglobin and serum phosphorus were the independent risk factors of new fractures. The incidence of malignancy and 5-year all-cause mortality in patients with fracture was higher than those without fracture, but there was no significant difference in the incidence of acute myocardial infarction and stroke.
PubMed: 38706503
DOI: 10.2147/JMDH.S457193 -
Indian Journal of Nephrology 2024Health-related quality of life (HRQoL) has emerged as an important outcome measure inpatients with CKD. The lack of prospective studies on HRQoL and its relation with...
INTRODUCTION
Health-related quality of life (HRQoL) has emerged as an important outcome measure inpatients with CKD. The lack of prospective studies on HRQoL and its relation with hyperphosphatemia control measures among pre-dialysis patients necessitated the need for this study.
METHODS
This is a prospective, randomized, controlled, open-labelled studythat was conducted for one year on 120 CKD stages III and IV patients divided equally into three groups: Group 1, in which patients under went dietary phosphorus modification; Group 2, in which they were administered calcium-based phosphate binders; and Group 3, in which they were administered non-calcium-based phosphate binders. Patients were assessed for HRQoL, fibroblast growth factor 23 (FGF 23), intact parathyroid hormone (iPTH), phosphorus, and nutritional status, and dietary phosphorus control strategies at 0, 6, and 12 months. HRQoL was measured by using the 36-item Short Form Survey (SF-36) that included a physical component score (PCS) and mental component score (MCS). The scores is ranging from 0 to 100. Higher scores indicate better health status. Usingthe two-wayand one-way repeated measure ANOVA, we analyzed equality of group means, time intervals, and interactions.
RESULTS
At baseline, the mean PCS and MCS were equal in three groups. PCS improved significantly ( < 0.00) from baseline to one year in all the three groups: ingroup 1, the PCS score was 66.5 ± 13.5to 75.1 ± 9.76; in group 2, it was 68.9 ± 11.80 to 77.2 ± 7.50; and in group 3, it was 66.2 ± 12.16 to 73.8 ± 9.27. Initially, MCS declined substantially on the sixth month but recovered afterone year. Multiple regression analysis in 13 associated parameters yielded of 13.7% and 18.1% in PCS and MCS, respectively, indicating little contribution of various parameters.
CONCLUSION
There has been a significant positive change in PCSs in three hyperphosphatemia management groups over a period of 12 months. Among the three study groups, the incremental changes in PCS and MCS scores were insignificant.
PubMed: 38681013
DOI: 10.4103/ijn.ijn_6_23 -
Diagnostics (Basel, Switzerland) Apr 2024This retrospective study aimed to compare risk factors for vascular calcification (VC) between pre-hemodialysis (HD) and prevalent HD adult patients while investigating...
Comparative Analysis of Vascular Calcification Risk Factors in Pre-Hemodialysis and Prevalent Hemodialysis Adult Patients: Insights into Calcification Biomarker Associations and Implications for Intervention Strategies in Chronic Kidney Disease.
This retrospective study aimed to compare risk factors for vascular calcification (VC) between pre-hemodialysis (HD) and prevalent HD adult patients while investigating associations with calcification biomarkers. Baseline data from 30 pre-HD and 85 HD patients were analyzed, including iPTH, vitamin D, FGF 23, fetuin-A, sclerostin, and VC scores (Adragao method). Prevalence of VC was similar in both groups, but HD patients had more frequent VC scores ≥ 6. Pre-HD patients were older, with higher prevalence of hypertension and less frequent use of calcium phosphate binders. Both groups showed similar patterns of hyperphosphatemia, low vitamin D, and iPTH. Fetuin-A and sclerostin levels were higher in pre-HD, while FGF 23 was elevated in HD patients. Higher VC risk in pre-HD patients was associated with male gender, older age, lower fetuin-A and higher sclerostin, lower ferritin, and no vitamin D treatment, while in HD patients with higher sclerostin, FGF 23 and urea, and lower iPTH. Conclusion: Biomarkers could be measurable indicators of biological processes underlying VC in CKD patients that may serve as a potential guide for considering personalized therapeutic approaches. Further studies are needed to elucidate the underlying pathways.
PubMed: 38667470
DOI: 10.3390/diagnostics14080824 -
Arteriosclerosis, Thrombosis, and... Jun 2024Vascular calcification causes significant morbidity and occurs frequently in diseases of calcium/phosphate imbalance. Radiolabeled sodium fluoride positron emission...
BACKGROUND
Vascular calcification causes significant morbidity and occurs frequently in diseases of calcium/phosphate imbalance. Radiolabeled sodium fluoride positron emission tomography/computed tomography has emerged as a sensitive and specific method for detecting and quantifying active microcalcifications. We developed a novel technique to quantify and map total vasculature microcalcification to a common space, allowing simultaneous assessment of global disease burden and precise tracking of site-specific microcalcifications across time and individuals.
METHODS
To develop this technique, 4 patients with hyperphosphatemic familial tumoral calcinosis, a monogenic disorder of FGF23 (fibroblast growth factor-23) deficiency with a high prevalence of vascular calcification, underwent radiolabeled sodium fluoride positron emission tomography/computed tomography imaging. One patient received serial imaging 1 year after treatment with an IL-1 (interleukin-1) antagonist. A radiolabeled sodium fluoride-based microcalcification score, as well as calcification volume, was computed at all perpendicular slices, which were then mapped onto a standardized vascular atlas. Segment-wise mCS and mCS were computed to compare microcalcification score levels at predefined vascular segments within subjects.
RESULTS
Patients with hyperphosphatemic familial tumoral calcinosis had notable peaks in microcalcification score near the aortic bifurcation and distal femoral arteries, compared with a control subject who had uniform distribution of vascular radiolabeled sodium fluoride uptake. This technique also identified microcalcification in a 17-year-old patient, who had no computed tomography-defined calcification. This technique could not only detect a decrease in microcalcification score throughout the patient treated with an IL-1 antagonist but it also identified anatomic areas that had increased responsiveness while there was no change in computed tomography-defined macrocalcification after treatment.
CONCLUSIONS
This technique affords the ability to visualize spatial patterns of the active microcalcification process in the peripheral vasculature. Further, this technique affords the ability to track microcalcifications at precise locations not only across time but also across subjects. This technique is readily adaptable to other diseases of vascular calcification and may represent a significant advance in the field of vascular biology.
Topics: Humans; Positron Emission Tomography Computed Tomography; Sodium Fluoride; Hyperphosphatemia; Fluorine Radioisotopes; Male; Female; Fibroblast Growth Factor-23; Radiopharmaceuticals; Vascular Calcification; Adult; Predictive Value of Tests; Middle Aged; Adolescent; Young Adult; Calcinosis; Hyperostosis, Cortical, Congenital
PubMed: 38660800
DOI: 10.1161/ATVBAHA.123.320455