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Journal of Atherosclerosis and... Jan 2024Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Both traditional and CKD-related factors are associated with... (Review)
Review
Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Both traditional and CKD-related factors are associated with CVD in CKD patients. Traditional factors that play an important role in the atherosclerotic process directly contribute to a higher risk of coronary artery disease in patients with early-stage CKD. Among CKD-related factors, CKD-mineral and bone disorder plays a critical role in the pathomechanism of nonatherosclerotic diseases, which increases the risk of cardiovascular morbidity and mortality in patients with advanced CKD. Higher serum phosphate levels were significantly associated with cardiovascular events and all-cause mortality in patients with or without CKD. An increased phosphate load, directly and indirectly, promotes arterial medial calcification and left ventricular hypertrophy, both of which predispose patients to coronary artery disease. Calciprotein particles that form in a hyperphosphatemic state promote the transformation of vascular smooth muscle cells (VSMCs) into osteoblastic cells, thereby providing a scaffold for medial calcification in the artery. Increases in fibroblast growth factor-23 and disturbed vitamin D metabolism induced by an excessive phosphate load play a significant role in the development of cardiomyocyte hypertrophy and cardiac fibrosis. Recently, hyperphosphatemia was reported to promote de novo cholesterol synthesis in VSMCs and macrophages, which is likely to contribute to statin resistance in patients with end-stage kidney disease. This review outlines the association between increased phosphate load and coronary artery disease in patients with CKD.
Topics: Humans; Phosphates; Coronary Artery Disease; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Hyperphosphatemia; Cardiovascular Diseases; Vascular Calcification
PubMed: 37766573
DOI: 10.5551/jat.RV22012 -
Annals of Oncology : Official Journal... Feb 2024Fibroblast growth factor receptor 3 (FGFR3) alterations are oncogenic drivers of urothelial carcinoma (UC). Pemigatinib is a selective, oral inhibitor of FGFR1-3 with...
BACKGROUND
Fibroblast growth factor receptor 3 (FGFR3) alterations are oncogenic drivers of urothelial carcinoma (UC). Pemigatinib is a selective, oral inhibitor of FGFR1-3 with antitumor activity. We report the efficacy and safety of pemigatinib in the open-label, single-arm, phase II study of previously treated, unresectable or metastatic UC with FGFR3 alterations (FIGHT-201; NCT02872714).
PATIENTS AND METHODS
Patients ≥18 years old with FGFR3 mutations or fusions/rearrangements (cohort A) and other FGF/FGFR alterations (cohort B) were included. Patients received pemigatinib 13.5 mg once daily continuously (CD) or intermittently (ID) until disease progression or unacceptable toxicity. The primary endpoint was centrally confirmed objective response rate (ORR) as per RECIST v1.1 in cohort A-CD. Secondary endpoints included ORR in cohorts A-ID and B, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
RESULTS
Overall, 260 patients were enrolled and treated (A-CD, n = 101; A-ID, n = 103; B, n = 44; unconfirmed FGF/FGFR status, n = 12). All discontinued treatment, most commonly due to progressive disease (68.5%). ORR [95% confidence interval (CI)] in cohorts A-CD and A-ID was 17.8% (10.9% to 26.7%) and 23.3% (15.5% to 32.7%), respectively. Among patients with the most common FGFR3 mutation (S249C; n = 107), ORR was similar between cohorts (A-CD, 23.9%; A-ID, 24.6%). In cohorts A-CD/A-ID, median (95% CI) DOR was 6.2 (4.1-8.3)/6.2 (4.6-8.0) months, PFS was 4.0 (3.5-4.2)/4.3 (3.9-6.1) months, and OS was 6.8 (5.3-9.1)/8.9 (7.5-15.2) months. Pemigatinib had limited clinical activity among patients in cohort B. Of 36 patients with samples available at progression, 6 patients had 8 acquired FGFR3 secondary resistance mutations (V555M/L, n = 3; V553M, n = 1; N540K/S, n = 2; M528I, n = 2). The most common treatment-emergent adverse events overall were diarrhea (44.6%) and alopecia, stomatitis, and hyperphosphatemia (42.7% each).
CONCLUSIONS
Pemigatinib was generally well tolerated and demonstrated clinical activity in previously treated, unresectable or metastatic UC with FGFR3 mutations or fusions/rearrangements.
Topics: Humans; Adolescent; Carcinoma, Transitional Cell; Antineoplastic Agents; Urinary Bladder Neoplasms; Genomics; Morpholines; Pyrimidines; Pyrroles
PubMed: 37956738
DOI: 10.1016/j.annonc.2023.10.794 -
Wiener Medizinische Wochenschrift (1946) Oct 2023Chronic kidney disease (CKD): abnormalities of kidney structure or function, present for over 3 months. Staging of CKD is based on GFR and albuminuria (not graded).... (Review)
Review
[Diagnosis and treatment of osteoporosis in patients with chronic kidney disease : Joint guidelines of the Austrian Society for Bone and Mineral Research (ÖGKM), the Austrian Society of Physical and Rehabilitation Medicine (ÖGPMR) and the Austrian Society of Nephrology (ÖGN)].
DEFINITION AND EPIDEMIOLOGY
Chronic kidney disease (CKD): abnormalities of kidney structure or function, present for over 3 months. Staging of CKD is based on GFR and albuminuria (not graded). Osteoporosis: compromised bone strength (low bone mass, disturbance of microarchitecture) predisposing to fracture. By definition, osteoporosis is diagnosed if the bone mineral density T‑score is ≤ -2.5. Furthermore, osteoporosis is diagnosed if a low-trauma (inadequate trauma) fracture occurs, irrespective of the measured T‑score (not graded). The prevalence of osteoporosis, osteoporotic fractures and CKD is increasing worldwide (not graded). PATHOPHYSIOLOGY, DIAGNOSIS AND TREATMENT OF CHRONIC KIDNEY DISEASE-MINERAL AND BONE DISORDER (CKD-MBD): Definition of CKD-MBD: a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following: abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; renal osteodystrophy; vascular calcification (not graded). Increased, normal or decreased bone turnover can be found in renal osteodystrophy (not graded). Depending on CKD stage, routine monitoring of calcium, phosphorus, alkaline phosphatase, PTH and 25-OH-vitamin D is recommended (2C). Recommendations for treatment of CKD-MBD: Avoid hypercalcemia (1C). In cases of hyperphosphatemia, lower phosphorus towards normal range (2C). Keep PTH within or slightly above normal range (2D). Vitamin D deficiency should be avoided and treated when diagnosed (1C).
DIAGNOSIS AND RISK STRATIFICATION OF OSTEOPOROSIS IN CKD
Densitometry (using dual X‑ray absorptiometry, DXA): low T‑score correlates with increased fracture risk across all stages of CKD (not graded). A decrease of the T‑score by 1 unit approximately doubles the risk for osteoporotic fracture (not graded). A T-score ≥ -2.5 does not exclude osteoporosis (not graded). Bone mineral density of the lumbar spine measured by DXA can be increased and therefore should not be used for the diagnosis or monitoring of osteoporosis in the presence of aortic calcification, osteophytes or vertebral fracture (not graded). FRAX can be used to aid fracture risk estimation in all stages of CKD (1C). Bone turnover markers can be measured in individual cases to monitor treatment (2D). Bone biopsy may be considered in individual cases, especially in patients with CKD G5 (eGFR < 15 ml/min/1.73 m) or CKD 5D (dialysis).
SPECIFIC TREATMENT OF OSTEOPOROSIS IN PATIENTS WITH CKD
Hypocalcemia should be treated and serum calcium normalized before initiating osteoporosis therapy (1C). CKD G1-G2 (eGFR ≥ 60 ml/min/1.73 m): treat osteoporosis as recommended for the general population (1A). CKD G3-G5D (eGFR < 60 ml/min/1.73 m to dialysis): treat CKD-MBD first before initiating osteoporosis treatment (2C). CKD G3 (eGFR 30-59 ml/min/1.73 m) with PTH within normal limits and osteoporotic fracture and/or high fracture risk according to FRAX: treat osteoporosis as recommended for the general population (2B). CKD G4-5 (eGFR < 30 ml/min/1.73 m) with osteoporotic fracture (secondary prevention): Individualized treatment of osteoporosis is recommended (2C). CKD G4-5 (eGFR < 30 ml/min/1.73 m) and high fracture risk (e.g. FRAX score > 20% for a major osteoporotic fracture or > 5% for hip fracture) but without prevalent osteoporotic fracture (primary prevention): treatment of osteoporosis may be considered and initiated individually (2D). CKD G4-5D (eGFR < 30 ml/min/1.73 m to dialysis): Calcium should be measured 1-2 weeks after initiation of antiresorptive therapy (1C).
PHYSICAL MEDICINE AND REHABILITATION
Resistance training prioritizing major muscle groups thrice weekly (1B). Aerobic exercise training for 40 min four times per week (1B). Coordination and balance exercises thrice weekly (1B). Flexibility exercise 3-7 times per week (1B).
Topics: Humans; Chronic Kidney Disease-Mineral and Bone Disorder; Calcium; Osteoporotic Fractures; Nephrology; Austria; Osteoporosis; Renal Insufficiency, Chronic; Bone Density; Vitamin D; Minerals; Phosphorus; Physical and Rehabilitation Medicine; Intercellular Signaling Peptides and Proteins
PubMed: 36542221
DOI: 10.1007/s10354-022-00989-0 -
Scientific Reports Sep 2023Hyperphosphatemia is a major risk for poor prognosis in patients with end-stage renal disease. However, the molecular mechanism behind this link remains elusive. We and...
Hyperphosphatemia is a major risk for poor prognosis in patients with end-stage renal disease. However, the molecular mechanism behind this link remains elusive. We and others have demonstrated that serum phosphorus levels correlate positively with circulating levels of calciprotein particles (CPPs). CPPs are colloidal mineral-protein complexes containing insoluble calcium-phosphate precipitates and have been reported to induce calcification in cultured vascular smooth muscle cells and inflammatory responses in cultured macrophages. Hence, we hypothesize that CPPs may be responsible for disorders associated with hyperphosphatemia. Using hyperphosphatemic miniature pigs receiving hemodialysis, here we show that removal of CPPs from the blood with a newly developed CPP adsorption column improves survival and alleviates complications including coronary artery calcification, vascular endothelial dysfunction, metastatic pulmonary calcification, left ventricular hypertrophy, and chronic inflammation. The present study identifies CPPs as an effective therapeutic target and justifies clinical trials to determine whether the CPP adsorption column may be useful as a medical device for improving clinical outcomes of hemodialysis patients.
Topics: Animals; Swine; Swine, Miniature; Adsorption; Hyperphosphatemia; Prognosis; Renal Dialysis; Calcinosis; Choristoma
PubMed: 37700060
DOI: 10.1038/s41598-023-42273-0 -
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 -
Kidney360 Nov 2023Tenapanor is a first-in-class, minimally systemic sodium–hydrogen exchanger 3 inhibitor with a mechanism of action distinct from phosphate binders. Tenapanor alone or...
KEY POINTS
Tenapanor is a first-in-class, minimally systemic sodium–hydrogen exchanger 3 inhibitor with a mechanism of action distinct from phosphate binders. Tenapanor alone or with phosphate binders led to 35%–49% of patients achieving serum phosphate ≤4.5 mg/dl over an 18-month period versus 22% at baseline. Tenapanor alone or with phosphate binders may help adults with CKD on maintenance dialysis achieve normal serum phosphate concentrations.
BACKGROUND
Most patients with ESKD and hyperphosphatemia have difficulty controlling serum phosphate (sP) concentrations 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).
METHODS
Patients who completed the Phase 3 PHREEDOM study could enroll in NORMALIZE. Patients enrolled in NORMALIZE who had received tenapanor during the PHREEDOM study (=111) added sevelamer carbonate if sP was >4.5 mg/dl. Patients who had received sevelamer carbonate during the PHREEDOM study (=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, defined as patients who received ≥1 dose of study drug and had ≥1 post-treatment sP measurement (=171). We assessed safety in all patients who received ≥1 dose of study drug (=172).
RESULTS
At the end point visit, 57 of 171 patients (33%) in the full analysis set achieved sP between 2.5 and 4.5 mg/dl. Eight of 23 patients (35%) who were on tenapanor alone at the end point 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 intact fibroblast growth factor-23 was significantly reduced; serum intact parathyroid hormone was significantly reduced among patients with intact parathyroid hormone ≥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 four patients (2%).
CONCLUSIONS
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.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
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 ESKD on Dialysis (NORMALIZE), NCT03988920.
Topics: Humans; Hyperphosphatemia; Renal Dialysis; Isoquinolines; Sulfonamides
PubMed: 37853560
DOI: 10.34067/KID.0000000000000280 -
Clinical Cancer Research : An Official... Oct 2023On September 30, 2022, the FDA granted accelerated approval to futibatinib for the treatment of adult patients with previously treated, unresectable, locally advanced or...
FDA Approval Summary: Futibatinib for Unresectable Advanced or Metastatic, Chemotherapy Refractory Intrahepatic Cholangiocarcinoma with FGFR2 Fusions or Other Rearrangements.
On September 30, 2022, the FDA granted accelerated approval to futibatinib for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions or other rearrangements. Approval was based on Study TAS-120-101, a multicenter open-label, single-arm trial. Patients received futibatinib 20-mg orally once daily. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) as determined by an independent review committee (IRC) according to RECIST v1.1. ORR was 42% (95% confidence interval, 32%-52%). Median DoR was 9.7 months. Adverse reactions occurring in ≥30% patients were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, and abdominal pain. The most common laboratory abnormalities (≥50%) were increased phosphate, increased creatinine, decreased hemoglobin, and increased glucose. Ocular toxicity (including dry eye, keratitis, and retinal epithelial detachment) and hyperphosphatemia are important risks of futibatinib, which are listed under Warnings and Precautions. This article summarizes the FDA's thought process and data supporting the approval of futibatinib.
Topics: Adult; Humans; Pyrimidines; Cholangiocarcinoma; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Drug Approval; Receptor, Fibroblast Growth Factor, Type 2; Pyrazoles; Pyrroles
PubMed: 37289037
DOI: 10.1158/1078-0432.CCR-23-1042 -
Theranostics 2024Vascular calcification (VC) is a life-threatening complication in patients with chronic kidney disease (CKD) caused mainly by hyperphosphatemia. However, the regulation...
Vascular calcification (VC) is a life-threatening complication in patients with chronic kidney disease (CKD) caused mainly by hyperphosphatemia. However, the regulation of VC remains unclear despite extensive research. Although serum- and glucocorticoid-induced kinase 3 (SGK3) regulate the sodium-dependent phosphate cotransporters in the intestine and kidney, its effect on VC in CKD remains unknown. Additionally, type III sodium-dependent phosphate cotransporter-1 (Pit-1) plays a significant role in VC development induced by high phosphate in vascular smooth muscle cells (VSMCs). However, it remains unclear whether SGK3 regulates Pit-1 and how exactly SGK3 promotes VC in CKD via Pit-1 at the molecular level. Thus, we investigated the role of SGK3 in the certified outflow vein of arteriovenous fistulas (AVF) and aortas of uremic mice. In our study, using uremic mice, we observed a significant upregulation of SGK3 and calcium deposition in certified outflow veins of the AVF and aortas, and the increase expression of SGK3 was positively correlated with calcium deposition in uremic aortas. , the downregulation of SGK3 reversed VSMCs calcification and phenotype switching induced by high phosphate. Mechanistically, SGK3 activation enhanced the mRNA transcription of Pit-1 through NF-κB, downregulated the ubiquitin-proteasome mediated degradation of Pit-1 via inhibiting the activity of neural precursor cells expressing developmentally downregulated protein 4 subtype 2 (Nedd4-2), an E3 ubiquitin ligase. Moreover, under high phosphate stimulation, the enhanced phosphate uptake induced by SGK3 activation was independent of the increased protein expression of Pit-1. Our co-immunoprecipitation and kinase assays confirmed that SGK3 interacts with Pit-1 through Thr468 in loop7, leading to enhanced phosphate uptake. Thus, it is justifiable to conclude that SGK3 promotes VC in CKD by enhancing the expression and activities of Pit-1, which indicate that SGK3 could be a therapeutic target for VC in CKD.
Topics: Animals; Humans; Mice; Calcium; Glucocorticoids; Myocytes, Smooth Muscle; Neural Stem Cells; Phosphates; Protein Serine-Threonine Kinases; Renal Insufficiency, Chronic; Sodium; Transcription Factors; Vascular Calcification
PubMed: 38169564
DOI: 10.7150/thno.87317 -
Journal of Molecular and Cellular... Oct 2023Cardiovascular calcification can occur in vascular and valvular structures and is commonly associated with calcium deposition and tissue mineralization leading to...
Cardiovascular calcification can occur in vascular and valvular structures and is commonly associated with calcium deposition and tissue mineralization leading to stiffness and dysfunction. Patients with chronic kidney disease and associated hyperphosphatemia have an elevated risk for coronary artery calcification (CAC) and calcific aortic valve disease (CAVD). However, there is mounting evidence to suggest that the susceptibility and pathobiology of calcification in these two cardiovascular structures may be different, yet clinically they are similarly treated. To better understand diversity in molecular and cellular processes that underlie hyperphosphatemia-induced calcification in vascular and valvular structures, we exposed aortic vascular smooth muscle cells (AVSMCs) and aortic valve interstitial cells (AVICs) to high (2.5 mM) phosphate (Ph) conditions in vitro, and examined cell-specific responses. To further identify hyperphosphatemic-specific responses, parallel studies were performed using osteogenic media (OM) as an alternative calcific stimulus. Consistent with clinical observations made by others, we show that AVSMCs are more susceptible to calcification than AVICs. In addition, bulk RNA-sequencing reveals that AVSMCs and AVICs activate robust ossification-programs in response to high phosphate or OM treatments, however, the signaling pathways, cellular processes and osteogenic-associated markers involved are cell- and treatment-specific. For example, compared to VSMCs, VIC-mediated calcification involves biological processes related to osteo-chondro differentiation and down regulation of 'actin cytoskeleton'-related genes, that are not observed in VSMCs. Furthermore, hyperphosphatemic-induced calcification in AVICs and AVSMCs is independent of P13K signaling, which plays a role in OM-treated cells. Together, this study provides a wealth of information suggesting that the pathogenesis of cardiovascular calcifications is significantly more diverse than previously appreciated.
Topics: Humans; Aortic Valve; Aortic Valve Stenosis; Calcinosis; Muscle, Smooth, Vascular; Hyperphosphatemia; Cells, Cultured; Phosphates; Vascular Calcification
PubMed: 37579636
DOI: 10.1016/j.yjmcc.2023.08.001 -
International Journal of Molecular... May 2024Chronic kidney disease (CKD) is associated with significant reductions in lean body mass and in the mass of various tissues, including skeletal muscle, which causes... (Review)
Review
Chronic kidney disease (CKD) is associated with significant reductions in lean body mass and in the mass of various tissues, including skeletal muscle, which causes fatigue and contributes to high mortality rates. In CKD, the cellular protein turnover is imbalanced, with protein degradation outweighing protein synthesis, leading to a loss of protein and cell mass, which impairs tissue function. As CKD itself, skeletal muscle wasting, or sarcopenia, can have various origins and causes, and both CKD and sarcopenia share common risk factors, such as diabetes, obesity, and age. While these pathologies together with reduced physical performance and malnutrition contribute to muscle loss, they cannot explain all features of CKD-associated sarcopenia. Metabolic acidosis, systemic inflammation, insulin resistance and the accumulation of uremic toxins have been identified as additional factors that occur in CKD and that can contribute to sarcopenia. Here, we discuss the elevation of systemic phosphate levels, also called hyperphosphatemia, and the imbalance in the endocrine regulators of phosphate metabolism as another CKD-associated pathology that can directly and indirectly harm skeletal muscle tissue. To identify causes, affected cell types, and the mechanisms of sarcopenia and thereby novel targets for therapeutic interventions, it is important to first characterize the precise pathologic changes on molecular, cellular, and histologic levels, and to do so in CKD patients as well as in animal models of CKD, which we describe here in detail. We also discuss the currently known pathomechanisms and therapeutic approaches of CKD-associated sarcopenia, as well as the effects of hyperphosphatemia and the novel drug targets it could provide to protect skeletal muscle in CKD.
Topics: Humans; Renal Insufficiency, Chronic; Muscle, Skeletal; Animals; Sarcopenia
PubMed: 38791164
DOI: 10.3390/ijms25105117