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It remains a substantial challenge to balance treatment efficacy and toxicity in geriatric patients with multiple myeloma (MM), primarily due to the dynamic nature of frailty. Here, we conducted a prospective study to evaluate the feasibility and benefits of dynamic frailty-tailored therapy (DynaFiT) in elderly patients. Patients with newly diagnosed MM (aged ≥ 65 years) received eight induction cycles of bortezomib, lenalidomide, and dexamethasone (daratumumab was recommended for frail patients), with treatment intensity adjusted according to longitudinal changes in the frailty category (IMWG-FI) at each cycle. Of 90 patients, 33 (37%), 16 (18%), and 41 (45%) were fit, intermediate fit, and frail at baseline, respectively. Of 75 patients who had geriatric assessment at least twice, 28 (37%) experienced frailty category changes at least once. At analysis, 15/26 (58%) frail patients improved (27% became fit and 31% became intermediate fit), 4/15 (27%) intermediate fit patients either improved or deteriorated (two for each), and 6/30 (20%) fit patients deteriorated. During induction, 34/90 (38%) patients discontinued treatment, including 10/33 (30%) fit, 4/16 (25%) intermediate fit, and 20/41 (49%) frail; 14/40 (35%) frail patients discontinued treatment within the first two cycles, mainly because of non-hematologic toxicity (mostly infections). For fit, intermediate-fit, and frail patients, the overall response rate was 100%, 93%, and 73%, respectively; one-year overall survival was 90%, 75%, and 54%, respectively. Therefore, the individualized DynaFiT is feasible and promising for heterogeneous elderly patients.
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Protocolos de Quimioterapia Combinada Antineoplásica , Dexametasona , Fragilidad , Lenalidomida , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/terapia , Anciano , Estudios Prospectivos , Masculino , Femenino , Anciano de 80 o más Años , Dexametasona/uso terapéutico , Dexametasona/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Lenalidomida/uso terapéutico , Lenalidomida/administración & dosificación , Bortezomib/uso terapéutico , Bortezomib/administración & dosificación , Medicina de Precisión/métodos , Anciano Frágil , Evaluación Geriátrica/métodos , Anticuerpos MonoclonalesRESUMEN
Background: The morbidity and mortality of chronic kidney disease (CKD) are increasing worldwide, making it a serious public health problem. Although a potential correlation between body water content and CKD progression has been suggested, the presence of a causal association remains uncertain. This study aimed to determine the causal effect of body water content on kidney function. Methods: Genome-wide association study summary data sourced from UK Biobank were used to evaluate single-nucleotide polymorphisms (SNPs) associated with whole-body water mass (BWM). The summary statistics pertaining to kidney function were extracted from the CKDGen consortium. The primary kidney function outcome measures included estimated glomerular filtration rate (eGFR), albuminuria, CKD stages 3-5, and rapid progression to CKD (CKDi25). Two-sample Mendelian randomization (MR) analysis estimated a potential causal relationship between the BWM and kidney function. The inverse variance weighted MR method was used as the primary analysis, accompanied by several sensitive MR analyses. Results: The increase of BWM exhibited a correlation with a reduction in eGFR (ß = -0.02; P = 6.95 × 10-16). Excluding 13 SNPs responsible for pleiotropy (P = 0.05), the increase of BWM was also associated with the decrease of the ratio of urinary albumin to creatinine (ß = -0.16; P = 5.91 × 10-36). For each standard deviation increase in BWM, the risk of CKD stages 3-5 increases by 32% (OR, 1.32; 95% CI, 1.19-1.47; P = 1.43 × 10-7), and the risk of CKDi25 increases by 22% (OR, 1.22; 95% CI, 1.07-1.38; P = 0.002). Conclusion: The increase of BWM is associated with impaired kidney function. Proactively managing body water content is of great significance in preventing the progression of CKD.
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Agua Corporal , Insuficiencia Renal Crónica , Humanos , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , RiñónRESUMEN
Background: Owing to individual heterogeneity, patients with idiopathic membranous nephropathy (IMN) exhibit varying sensitivities to immunotherapy. This study aimed to establish and validate a model incorporating pathological and clinical features using deep learning training to evaluate the response of patients with IMN to immunosuppressive therapy. Methods: The 291 patients were randomly categorized into training (n = 219) and validation (n = 72) cohorts. Patch-level convolutional neural network training in a weakly supervised manner was utilized to analyze whole-slide histopathological features. We developed a machine-learning model to assess the predictive value of pathological signatures compared to clinical factors. The performance levels of the models were evaluated using the area under the receiver operating characteristic curve (AUC) on the training and validation tests, and the prediction accuracies of the models for immunotherapy response were compared. Results: Multivariate analysis indicated that diabetes and smoking were independent risk factors affecting the response to immunotherapy in IMN patients. The model integrating pathologic features had a favorable predictive value for determining the response to immunotherapy in IMN patients, with AUCs of 0.85 and 0.77 when employed in the training and test cohorts, respectively. However, when incorporating clinical features into the model, the predictive efficacy diminishes, as evidenced by lower AUC values of 0.75 and 0.62 on the training and testing cohorts, respectively. Conclusions: The model incorporating pathological signatures demonstrated a superior predictive ability for determining the response to immunosuppressive therapy in IMN patients compared to the integration of clinical factors.
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Aprendizaje Profundo , Glomerulonefritis Membranosa , Humanos , Glomerulonefritis Membranosa/tratamiento farmacológico , Riñón/patología , Análisis Multivariante , InmunoterapiaRESUMEN
Renal fibrosis is a common pathway toward chronic kidney disease (CKD) and is the main pathological predecessor for end-stage renal disease; thus, preventing progressive CKD and renal fibrosis is essential to reducing their consequential morbidity and mortality. Emerging evidence has connected renal fibrosis to metabolic reprogramming; abnormalities in energy metabolism pathways, such as glycolysis, the tricarboxylic acid cycle, and lipid metabolism, are known to cause diseases of diverse etiologies. Cytokine interventions in affected metabolic pathways may significantly reduce the degree of fibrosis, highlighting therapeutic targets for drug development for renal fibrosis. Here, we discuss the relationship between glycolysis, lipid metabolism, mitochondrial and peroxisome dysfunction, and renal fibrosis in detail and propose that targeted therapies for specific metabolic pathways are expected to represent the next generation of treatments for renal fibrosis.
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Fallo Renal Crónico , Insuficiencia Renal Crónica , Humanos , Fibrosis , Metabolismo Energético , Insuficiencia Renal Crónica/patología , GlucólisisRESUMEN
Roxadustat is a recently approved hypoxia-inducible factor prolyl hydroxylase inhibitor that has demonstrated favorable safety and efficacy in the treatment of renal anemia. Recent studies found it also has potential for the treatment of other hypoxia-related diseases. Although clinical studies have not yet found significant adverse or off-target effects of roxadustat, clinicians must be vigilant about these possible effects. Hypoxia-inducible factor regulates the expression of many genes and physiological processes in response to a decreased level of oxygen, but its role in the pathogenesis of different diseases is complex and controversial. In addition to increasing the expression of hypoxia-inducible factor, roxadustat also has some effects that may be HIF-independent, indicating some potential off-target effects. This article reviews the pharmacological characteristics of roxadustat, its current status in the treatment of renal anemia, and its possible effects on other pathological mechanisms.
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Renal fibrosis is the result of renal tissue damage and repair response disorders. If fibrosis is not effectively blocked, it causes loss of renal function, leading to chronic renal failure. Metabolic reprogramming, which promotes cell proliferation by regulating cellular energy metabolism, is considered a unique tumor cell marker. The transition from oxidative phosphorylation to aerobic glycolysis is a major feature of renal fibrosis. Hypoxia-inducible factor-1 α (HIF-1α), a vital transcription factor, senses oxygen status, induces adaptive changes in cell metabolism, and plays an important role in renal fibrosis and glucose metabolism. This review focuses on the regulation of proteins related to aerobic glycolysis by HIF-1α and attempts to elucidate the possible regulatory mechanism underlying the effects of HIF-1α on glucose metabolism during renal fibrosis, aiming to provide new ideas for targeted metabolic pathway intervention in renal fibrosis.
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Glucólisis , Fosforilación Oxidativa , Fibrosis , Glucosa/metabolismo , Glucólisis/fisiología , Humanos , HipoxiaRESUMEN
Renal fibrosis is the inevitable common end-point of all progressive chronic kidney diseases. The underlying mechanisms of renal fibrosis are complex, and currently there is no effective therapy against renal fibrosis. Renal microvascular rarefaction contributes to the progression of renal fibrosis; however, an imbalance between proangiogenic and antiangiogenic factors leads to the loss of renal microvasculature. Vascular endothelial growth factor (VEGF) is the most important pro-angiogenic factor. Recent studies have unraveled the involvement of VEGF in the regulation of renal microvascular rarefaction and fibrosis via various mechanisms; however, it is not clear whether it has anti-fibrotic or pro-fibrotic effect. This paper reviews the available evidence pertaining to the function of VEGF in the fibrotic process and explores the associated underlying mechanisms. Our synthesis will help identify the future research priorities for developing specialized treatments for alleviating or preventing renal fibrosis. Abbreviation: VEGF: vascular endothelial growth factor; CKD: chronic kidney disease; ESKD: end-stage kidney disease; ER: endoplasmic reticulum; VEGFR: vascular endothelial growth factor receptor; AKI: acute kidney injury; EMT: epithelial-to-mesenchymal transition; HIF: hypoxia-inducible factor; α-SMA: α smooth muscle actin; UUO: unilateral ureteral obstruction; TGF-ß: transforming growth factor-ß; PMT: pericyte-myofibroblast transition; NO: nitric oxide; NOS: nitric oxide synthase; nNOS: neuronal nitric oxide synthase; iNOS: inducible nitric oxide synthase; eNOS: endothelial nitric oxide synthase; sGC: soluble guanylate cyclase; PKG: soluble guanylate cyclase dependent protein kinases; UP R: unfolded protein response.
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Rarefacción Microvascular , Insuficiencia Renal Crónica , Animales , Fibrosis , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico , Guanilil Ciclasa Soluble , Factor de Crecimiento Transformador beta/metabolismo , Factor A de Crecimiento Endotelial VascularRESUMEN
PURPOSE: Renal fibrosis (RF) is the main pathological feature of chronic kidney disease (CKD). The main focus of research on treatment for CKD is to develop strategies that delay or prevent RF from progressing to end-stage renal disease (ESRD). Inflammation and oxidative stress occur during all stages of CKD. The magnesium cation (Mg2+) can reduce inflammation and oxidative stress, regulate apoptosis, and improve RF, and magnesium-based therapies are promising new treatments that can prevent RF. We reviewed the current evidence on the effects of magnesium in RF and examined the possible mechanism of magnesium in delaying RF. METHODS: We searched PubMed, Web of Science, and EMBASE for articles on magnesium and fibrosis, with a focus on magnesium and RF. RESULTS: Inflammation, oxidative stress, and apoptosis are related to the occurrence of CKD. Previous research showed that Mg2+ inhibits the differentiation of inflammatory cells, down-regulates the production of inflammatory cytokines, reduces inflammation, and reduces the production of reactive oxygen species (ROS) and oxidative stress. In addition, Mg2+ also regulates apoptosis and protects renal tubular function. Magnesium may also regulate TRPM6/7, promote the secretion of klotho protein and improve renal fibrosis. Therefore, Mg2+ can protect the kidney from damage and slow down the progression of RF through many molecular and cellular effects. Some of the anti-fibrotic effects of Mg2+ may be related to its antagonism of intracellular Ca2+. CONCLUSION: Magnesium may prevent the progression of renal fibrosis and delay CKD by reducing renal inflammation and oxidative stress, and by regulating fibrosis-related signaling pathways and cytokines.
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Magnesio , Insuficiencia Renal Crónica , Citocinas/metabolismo , Fibrosis , Humanos , Inflamación/metabolismo , Riñón/patología , Magnesio/metabolismo , Magnesio/uso terapéutico , Estrés Oxidativo , Insuficiencia Renal Crónica/metabolismoRESUMEN
There are several causes of chronic kidney disease, but all of these patients have renal fibrosis. Although many studies have examined the pathogenesis of renal fibrosis, there are still no effective treatments. A healthy and balanced metabolism is necessary for normal cell growth, proliferation, and function, but metabolic abnormalities can lead to pathological changes. Normal energy metabolism is particularly important for maintaining the structure and function of the kidneys because they consume large amounts of energy. We describe the metabolic reprogramming that occurs during renal fibrosis, which includes changes in fatty acid metabolism and glucose metabolism, and the relationship of these changes with renal fibrosis. We also describe the potential role of novel drugs that disrupt this metabolic reprogramming and the development of fibrosis, and current and future challenges in the treatment of fibrosis.
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With the continuous improvement in living standards, lifestyle changes and ageing of the population, the prevalence of chronic kidney disease (CKD) has increased significantly, and its prevention and treatment have become important public health issues worldwide. Renal fibrosis is the main pathological basis of CKD progression to end-stage renal disease. Preventing the progression of renal fibrosis has always been the focus of clinical and scientific research. Ulinastatin is a serine protease inhibitor that is found in human blood and urine and inhibits the inflammatory response, regulates immunity and improves the microcirculation. It is widely used in patients with sepsis and septic shock in clinical practice. Recent studies have shown that ulinastatin can also play an important anti-fibrotic and organ protective role and can provide a new therapeutic hope for CKD patients. This review mainly introduced the research progress of UTI in inflammation, oxidative stress, apoptosis, acute kidney injury and renal fibrosis. By investigating the role of ulinastatin in CKD, we can determine the possible mechanisms for its renal protection and improvement of renal fibrosis, so as to provide new ideas for the treatment of CKD.