Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 15.017
Filtrar
Mais filtros

Intervalo de ano de publicação
1.
Annu Rev Med ; 75: 205-217, 2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38039393

RESUMO

Home-based dialysis modalities offer both clinical and practical advantages to patients. The use of the home-based modalities, peritoneal dialysis and home hemodialysis, has been increasing over the past decade after a long period of decline. Given the increasing frequency of use of these types of dialysis, it is important for clinicians to be familiar with how these types of dialysis are performed and key clinical aspects of care related to their use in patients with end-stage kidney disease.


Assuntos
Hemodiálise no Domicílio , Falência Renal Crônica , Humanos , Diálise Renal , Falência Renal Crônica/terapia
2.
Annu Rev Med ; 74: 1-13, 2023 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-36108262

RESUMO

COVID-19 can cause acute kidney injury and may cause or exacerbate chronic kidney diseases, including glomerular diseases. SARS-CoV-2 infection of kidney cells has been reported, but it remains unclear if viral infection of kidney cells causes disease. The most important causes of kidney injury in patients with COVID-19 include impaired renal perfusion and immune dysregulation. Chronic kidney disease, especially kidney failure with kidney replacement therapy and kidney transplant, is associated with markedly increased COVID-19 mortality. Persons with severe kidney disease have been excluded from most clinical trials of COVID-19 therapies, so therapeutic approaches must be extrapolated from studies of patients without kidney disease. Some medications used to treat COVID-19 should be avoided or used at reduced dosages in patients with severe kidney disease and in kidney transplant recipients. Additional research is needed to determine the optimal strategies to prevent and treat COVID-19 in patients with kidney disease.


Assuntos
COVID-19 , Nefropatias , Transplante de Rim , Humanos , COVID-19/etiologia , SARS-CoV-2 , Transplante de Rim/efeitos adversos
3.
FASEB J ; 38(13): e23819, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38984942

RESUMO

Peritoneal dialysis is a common treatment for end-stage renal disease, but complications often force its discontinuation. Preventive treatments for peritoneal inflammation and fibrosis are currently lacking. Cyclo(His-Pro) (CHP), a naturally occurring cyclic dipeptide, has demonstrated protective effects in various fibrotic diseases, yet its potential role in peritoneal fibrosis (PF) remains uncertain. In a mouse model of induced PF, CHP was administered, and quantitative proteomic analysis using liquid chromatography-tandem mass spectrometry was employed to identify PF-related protein signaling pathways. The results were further validated using human primary cultured mesothelial cells. This analysis revealed the involvement of histone deacetylase 3 (HDAC3) in the PF signaling pathway. CHP administration effectively mitigated PF in both peritoneal tissue and human primary cultured mesothelial cells, concurrently regulating fibrosis-related markers and HDAC3 expression. Moreover, CHP enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) while suppressing forkhead box protein M1 (FOXM1), known to inhibit Nrf2 transcription through its interaction with HDAC3. CHP also displayed an impact on spleen myeloid-derived suppressor cells, suggesting an immunomodulatory effect. Notably, CHP improved mitochondrial function in peritoneal tissue, resulting in increased mitochondrial membrane potential and adenosine triphosphate production. This study suggests that CHP can significantly prevent PF in peritoneal dialysis patients by modulating HDAC3 expression and associated signaling pathways, reducing fibrosis and inflammation markers, and improving mitochondrial function.


Assuntos
Histona Desacetilases , Fibrose Peritoneal , Animais , Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Fibrose Peritoneal/metabolismo , Fibrose Peritoneal/prevenção & controle , Fibrose Peritoneal/patologia , Camundongos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Diálise Peritoneal/efeitos adversos , Peritônio/patologia , Peritônio/metabolismo
4.
Circ Res ; 132(8): 915-932, 2023 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-37053283

RESUMO

With a global burden of 844 million, chronic kidney disease (CKD) is now considered a public health priority. Cardiovascular risk is pervasive in this population, and low-grade systemic inflammation is an established driver of adverse cardiovascular outcomes in these patients. Accelerated cellular senescence, gut microbiota-dependent immune activation, posttranslational lipoprotein modifications, neuroimmune interactions, osmotic and nonosmotic sodium accumulation, acute kidney injury, and precipitation of crystals in the kidney and the vascular system all concur in determining the unique severity of inflammation in CKD. Cohort studies documented a strong link between various biomarkers of inflammation and the risk of progression to kidney failure and cardiovascular events in patients with CKD. Interventions targeting diverse steps of the innate immune response may reduce the risk of cardiovascular and kidney disease. Among these, inhibition of IL-1ß (interleukin-1 beta) signaling by canakinumab reduced the risk for cardiovascular events in patients with coronary heart disease, and this protection was equally strong in patients with and without CKD. Several old (colchicine) and new drugs targeting the innate immune system, like the IL-6 (interleukin 6) antagonist ziltivekimab, are being tested in large randomized clinical trials to thoroughly test the hypothesis that mitigating inflammation may translate into better cardiovascular and kidney outcomes in patients with CKD.


Assuntos
Doenças Cardiovasculares , Insuficiência Renal Crônica , Humanos , Imunidade Inata , Inflamação , Estudos de Coortes , Doenças Cardiovasculares/epidemiologia
5.
Eur Heart J ; 45(15): 1339-1351, 2024 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-38426727

RESUMO

BACKGROUND AND AIMS: Patients with kidney failure have a higher risk of cardiovascular disease compared with the general population. Whilst temporal trends of myocardial infarction and stroke are declining in the general population, these have not been evaluated in patients with kidney failure. This study aimed to describe national trends in the incidence, treatment, and outcomes of myocardial infarction and stroke in patients with kidney failure (i.e. on dialysis or with a kidney transplant) over a 20-year period, stratified by age and sex. METHODS: In this retrospective national data linkage study, all patients with kidney failure in Scotland (UK) receiving kidney replacement therapy between January 1996 and December 2016 were linked to national hospitalization, prescribing, and death records. The primary outcomes were the incidence of myocardial infarction and stroke, and subsequent cardiovascular death. Generalized additive models were constructed to estimate age-standardized, sex-stratified incidence rates and trends in cardiovascular and all-cause death. RESULTS: Amongst 16 050 patients with kidney failure [52 (SD 15) years; 41.5% women], there were 1992 [66 (SD 12) years; 34.8% women] and 996 [65 (SD 13) years; 45.1% women] incident myocardial infarctions and strokes, respectively, between January 1996 and December 2016. During this period, the age-standardized incidence of myocardial infarction per 100 000 decreased in men {from 4376 [95% confidence interval (CI) 3998-4785] to 1835 (95% CI 1692-1988)} and women [from 3268 (95% CI 2982-3593) to 1369 (95% CI 1257-1491)]. Similarly, the age-standardized incidence of stroke per 100 000 also decreased in men [from 1978 (95% CI 1795-2175) to 799 (95% CI 729-875)] and women [from 2234 (95% CI 2031-2468) to 903 (95% CI 824-990)]. Compared with the general population, the incidence of myocardial infarction was four- to eight-fold higher in patients with kidney failure, whilst for stroke it was two- to four-fold higher. The use of evidence-based cardioprotective treatment increased over the study period, and the predicted probability of cardiovascular death within 1 year of myocardial infarction for a 66-year-old patient with kidney failure (mean age of the cohort) fell in men (76.6% to 38.6%) and women (76.8% to 38.8%), and also decreased in both sexes following stroke (men, from 63.5% to 41.4%; women, from 67.6% to 45.8%). CONCLUSIONS: The incidence of myocardial infarction and stroke has halved in patients with kidney failure over the past 20 years but remains significantly higher than in the general population. Despite improvements in treatment and outcomes, the prognosis of these patients following myocardial infarction and stroke remains poor.


Assuntos
Infarto do Miocárdio , Insuficiência Renal , Acidente Vascular Cerebral , Masculino , Humanos , Feminino , Idoso , Incidência , Estudos Retrospectivos , Diálise Renal/efeitos adversos , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/terapia , Infarto do Miocárdio/complicações , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/terapia , Acidente Vascular Cerebral/etiologia , Fatores de Risco
6.
J Cell Mol Med ; 28(10): e18381, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38780509

RESUMO

Peritoneal fibrosis is a common pathological response to long-term peritoneal dialysis (PD) and a major cause for PD discontinuation. Understanding the cellular and molecular mechanisms underlying the induction and progression of peritoneal fibrosis is of great interest. In our study, in vitro study revealed that signal transducer and activator of transcription 3 (STAT3) is a key factor in fibroblast activation and extracellular matrix (ECM) synthesis. Furthermore, STAT3 induced by IL-6 trans-signalling pathway mediate the fibroblasts of the peritoneal stroma contributed to peritoneal fibrosis. Inhibition of STAT3 exerts an antifibrotic effect by attenuating fibroblast activation and ECM production with an in vitro co-culture model. Moreover, STAT3 plays an important role in the peritoneal fibrosis in an animal model of peritoneal fibrosis developed in mice. Blocking STAT3 can reduce the peritoneal morphological changes induced by chlorhexidine gluconate. In conclusion, our findings suggested STAT3 signalling played an important role in peritoneal fibrosis. Therefore, blocking STAT3 might become a potential treatment strategy in peritoneal fibrosis.


Assuntos
Ácidos Aminossalicílicos , Fibroblastos , Fibrose Peritoneal , Fenótipo , Fator de Transcrição STAT3 , Transdução de Sinais , Fibrose Peritoneal/metabolismo , Fibrose Peritoneal/patologia , Fibrose Peritoneal/etiologia , Fibrose Peritoneal/genética , Fator de Transcrição STAT3/metabolismo , Animais , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Camundongos , Ácidos Aminossalicílicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Modelos Animais de Doenças , Peritônio/patologia , Peritônio/metabolismo , Interleucina-6/metabolismo , Matriz Extracelular/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Humanos , Clorexidina/análogos & derivados , Clorexidina/farmacologia , Diálise Peritoneal/efeitos adversos , Benzenossulfonatos
7.
Circulation ; 147(4): 296-309, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36335915

RESUMO

BACKGROUND: Non-vitamin K oral anticoagulants have become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation (AF). The effectiveness and safety of non-vitamin K oral anticoagulants in patients on hemodialysis is not well known. METHODS: From June 2017 through May 2022, AXADIA-AFNET 8 (Compare Apixaban and Vitamin K Antagonists in Patients With Atrial Fibrillation and End-Stage Kidney Disease), an investigator-initiated PROBE (prospective randomized open blinded end point) outcome assessment trial, randomized patients with AF on chronic hemodialysis to either apixaban (2.5 mg BID) or the vitamin K antagonist (VKA) phenprocoumon (international normalized ratio, 2.0 to 3.0). The composite primary safety outcome was defined by a first event of major bleeding, clinically relevant nonmajor bleeding, or all-cause death. The primary efficacy outcome was a composite of ischemic stroke, all-cause death, myocardial infarction, and deep vein thrombosis or pulmonary embolism. Our hypothesis was that apixaban is noninferior to VKA. RESULTS: Thirty-nine sites randomized 97 patients (30% women; mean age 75 years; mean CHA2DS2-VASc [congestive heart failure, hypertension, age ≥75 years, diabetes, stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female sex] score, 4.5; baseline characteristics balanced between groups): 48 to apixaban and 49 to VKA. The median follow-up time was 429 days (range, 37 to 1370) versus 506 days (range, 101 to 1379), respectively. Adherence to apixaban was >80% in 44 of 48 patients; the median time in therapeutic range on VKA was 50.7%. Composite primary safety outcome events occurred in 22 patients (45.8%) on apixaban and in 25 patients (51.0%) on VKA (hazard ratio, 0.93 [95% CI, 0.53-1.65]; Pnoninferiority=0.157). Composite primary efficacy outcome events occurred in 10 patients (20.8%) on apixaban and in 15 patients (30.6%) on VKA (P=0.51; log rank). There were no significant differences regarding individual outcomes (all-cause mortality, 18.8% versus 24.5%; major bleeding, 10.4% versus 12.2%; and myocardial infarction, 4.2% versus 6.1%, respectively). CONCLUSIONS: In this randomized trial comparing apixaban and VKA in patients with AF on hemodialysis with long follow-up, no differences were observed in safety or efficacy outcomes. Even on oral anticoagulation, patients with AF on hemodialysis remain at high risk of cardiovascular events. Larger randomized trials are needed to determine the optimal anticoagulation regimen for patients with AF on hemodialysis. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02933697.


Assuntos
Fibrilação Atrial , Infarto do Miocárdio , Acidente Vascular Cerebral , Humanos , Feminino , Idoso , Masculino , Femprocumona/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Estudos Prospectivos , Anticoagulantes/efeitos adversos , Acidente Vascular Cerebral/prevenção & controle , Hemorragia/induzido quimicamente , Piridonas/efeitos adversos , Diálise Renal/efeitos adversos , Infarto do Miocárdio/tratamento farmacológico , Resultado do Tratamento
8.
Artigo em Inglês | MEDLINE | ID: mdl-38961839

RESUMO

BACKGROUND: Epithelial to mesenchymal transition (EMT) is considered as one of the senescence processes; reportedly, anti-senescence therapies effectively reduce EMT. Some models have shown anti-senescence effects with the use of sodium-glucose cotransporter-2 (SGLT2) inhibitor. Therefore, our study investigated the anti-senescence effects of empagliflozin as a SGLT2 inhibitor in a peritoneal fibrosis model and their impact on EMT inhibition. METHODS: For in vitro study, human peritoneal mesothelial cells (HPMCs) were isolated and grown in a 96-well plate. The cell media were exchanged with serum-free M199 medium with D-Glucose, with or without empagliflozin. All animal experiments were carried out in male mice. Mice were randomly classified into three treatment groups based on peritoneal dialysis (PD) or empagliflozin. We evaluated changes in senescence and EMT markers in HPMCs and PD model. RESULTS: HPMCs treated with glucose transformed from cobble stone to spindle shape, resulting in EMT. Empagliflozin attenuated these morphologic changes. Reactive oxygen species production, DNA damage, senescence, and EMT markers were increased by glucose treatment; however, co-treatment with glucose and empagliflozin attenuated these changes. For the mice with PD, an increase in thickness, collagen deposition, staining for senescence or EMT markers of the parietal peritoneum was observed, which however, was attenuated by co-treatment with empagliflozin. p53, p21, and p16 increased in mice with PD compared to that in the control group; however, these changes were decreased by empagliflozin. CONCLUSION: Empagliflozin effectively attenuated glucose-induced EMT in HPMCs through a decrease in senescence. Co-treatment with empagliflozin improved peritoneal thickness and fibrosis in PD.

9.
Kidney Int ; 106(1): 35-49, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38705274

RESUMO

Frailty is a condition that is frequently observed among patients undergoing dialysis. Frailty is characterized by a decline in both physiological state and cognitive state, leading to a combination of symptoms, such as weight loss, exhaustion, low physical activity level, weakness, and slow walking speed. Frail patients not only experience a poor quality of life, but also are at higher risk of hospitalization, infection, cardiovascular events, dialysis-associated complications, and death. Frailty occurs as a result of a combination and interaction of various medical issues in patients who are on dialysis. Unfortunately, frailty has no cure. To address frailty, a multifaceted approach is necessary, involving coordinated efforts from nephrologists, geriatricians, nurses, allied health practitioners, and family members. Strategies such as optimizing nutrition and chronic kidney disease-related complications, reducing polypharmacy by deprescription, personalizing dialysis prescription, and considering home-based or assisted dialysis may help slow the decline of physical function over time in subjects with frailty. This review discusses the underlying causes of frailty in patients on dialysis and examines the methods and difficulties involved in managing frailty among this group.


Assuntos
Fragilidade , Qualidade de Vida , Diálise Renal , Humanos , Fragilidade/diagnóstico , Fragilidade/epidemiologia , Fragilidade/fisiopatologia , Diálise Renal/efeitos adversos , Idoso , Idoso Fragilizado , Polimedicação , Avaliação Geriátrica , Fatores de Risco , Falência Renal Crônica/terapia , Falência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/complicações
10.
Kidney Int ; 105(5): 953-959, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38431214

RESUMO

It is estimated that >50% of patients with end-stage kidney disease (ESKD) in low-resource countries are unable to access dialysis. When hemodialysis is available, it often has high out-of-pocket expenditure and is seldom delivered to the standard recommended by international guidelines. Hemodialysis is a high-cost intervention with significant negative effects on environmental sustainability, especially in resource-poor countries (the ones most likely to be affected by resultant climate change). This review discusses the rationale for peritoneal dialysis (PD) as a more resource and environmentally efficient treatment with the potential to improve dialysis access, especially to vulnerable populations, including women and children, in lower-resource countries. Successful initiatives such as the Saving Young Lives program have demonstrated the benefit of PD for acute kidney injury. This can then serve as a foundation for later development of PD services for end-stage kidney disease programs in these countries. Expansion of PD programs in resource-poor countries has proven to be challenging for various reasons. It is hoped that if some of these issues can be addressed, PD will be able to permit an expansion of end-stage kidney disease care in these countries.


Assuntos
Injúria Renal Aguda , Falência Renal Crônica , Diálise Peritoneal , Criança , Humanos , Feminino , Diálise Peritoneal/efeitos adversos , Falência Renal Crônica/terapia , Diálise Renal/efeitos adversos , Injúria Renal Aguda/terapia , Gastos em Saúde
11.
Kidney Int ; 105(2): 259-268, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38008159

RESUMO

Health care on a global scale significantly contributes to carbon emissions, with high-income countries being the primary culprits. Within health care, dialysis plays a significant role as a major source of emissions. Low- and middle-income countries have a high burden of kidney disease and are facing an increasing demand for dialysis. This reality presents multiple opportunities to plan for environmentally sustainable and quality kidney care. By placing a stronger emphasis on primary and secondary prevention of kidney disease and its progression, within the framework of universal health coverage, as well as empowering patients to enhance self-care, we can significantly reduce the need for costly and environmentally detrimental kidney replacement therapy. Mandating the adoption of lean and innovative low-carbon dialysis practices while also promoting the growth of kidney transplantation would enable low- and middle-income countries to take the lead in implementing environmentally friendly nephrology practices and reducing costs, thus optimizing sustainability and the well-being of individuals living with kidney disease.


Assuntos
Nefropatias , Nefrologia , Humanos , Países em Desenvolvimento , Diálise Renal , Nefropatias/terapia , Carbono
12.
Antimicrob Agents Chemother ; 68(4): e0164723, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38376186

RESUMO

For antimicrobial agents in particular, plasma protein binding (PPB) plays a pivotal role in deciphering key properties of drug candidates. Animal models are generally used in the preclinical development of new drugs to predict their effects in humans using translational pharmacokinetics/pharmacodynamics (PK/PD). Thus, we compared the protein binding (PB) of cefazolin as well as bacterial growth under various conditions in vitro. The PB extent of cefazolin was studied in human, bovine, and rat plasmas at different antibiotic concentrations in buffer and media containing 20-70% plasma or pure plasma using ultrafiltration (UF) and equilibrium dialysis (ED). Moreover, bacterial growth and time-kill assays were performed in Mueller Hinton Broth (MHB) containing various plasma percentages. The pattern for cefazolin binding to plasma proteins was found to be similar for both UF and ED. There was a significant decrease in cefazolin binding to bovine plasma compared to human plasma, whereas the pattern in rat plasma was more consistent with that in human plasma. Our growth curve analysis revealed considerable growth inhibition of Escherichia coli at 70% bovine or rat plasma compared with 70% human plasma or pure MHB. As expected, our experiments with cefazolin at low concentrations showed that E. coli grew slightly better in 20% human and rat plasma compared to MHB, most probably due to cefazolin binding to proteins in the plasma. Based on the example of cefazolin, our study highlights the interspecies differences of PB with potential impact on PK/PD. These findings should be considered before preclinical PK/PD data can be extrapolated to human patients.


Assuntos
Antibacterianos , Anti-Infecciosos , Humanos , Animais , Bovinos , Ratos , Antibacterianos/farmacologia , Cefazolina/farmacologia , Ligação Proteica , Escherichia coli/metabolismo , Proteínas Sanguíneas/metabolismo
13.
Antimicrob Agents Chemother ; 68(3): e0157923, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38349160

RESUMO

Adequate dosing of antimicrobials is paramount for treating infections in critically ill patients undergoing kidney replacement therapy; however, little is known about antimicrobial removal by sustained low-efficiency dialysis (SLED). The objective was to quantify the removal of cefepime, daptomycin, meropenem, piperacillin-tazobactam, and vancomycin in patients undergoing SLED. Adult patients ≥18 years with acute kidney injury (AKI) or end-stage kidney disease receiving one of the select antimicrobials and requiring SLED were included. Blood and dialysate flow rates were maintained at 250 and 100 mL/min, respectively. Simultaneous arterial and venous blood samples for the analysis of antibiotic concentrations were collected hourly for 8 hours during SLED (on-SLED). Arterial samples were collected every 2 hours for up to 6 hours while not receiving SLED (off-SLED) for the calculation of SLED clearance, half-life (t1/2) on-SLED and off-SLED, and the fraction of removal by SLED (fD). Twenty-one patients completed the study: 52% male, mean age (±SD) 53 ± 13 years, and mean weight of 98 ± 30 kg. Eighty-six percent had AKI, and 4 patients were receiving cefepime, 3 daptomycin, 10 meropenem, 6 piperacillin-tazobactam, and 13 vancomycin. The average SLED time was 7.3 ± 1.1 hours, and the mean ultrafiltration rate was 95 ± 52 mL/hour (range 10-211). The t1/2 on-SLED was substantially lower than the off-SLED t1/2 for all antimicrobials, and the SLED fD varied between 44% and 77%. An 8-hour SLED session led to significant elimination of most antimicrobials evaluated. If SLED is performed, modification of the dosing regimen is warranted to avoid subtherapeutic concentrations.


Assuntos
Injúria Renal Aguda , Daptomicina , Terapia de Substituição Renal Híbrida , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Feminino , Meropeném/uso terapêutico , Vancomicina/uso terapêutico , Cefepima/uso terapêutico , Daptomicina/uso terapêutico , Diálise Renal , Antibacterianos , Combinação Piperacilina e Tazobactam/uso terapêutico , Estado Terminal , Injúria Renal Aguda/tratamento farmacológico , Estudos Retrospectivos
14.
Oncologist ; 29(4): e455-e466, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-37995303

RESUMO

BACKGROUND: CDK4/6 inhibitors (CDK4/6i) have shown great efficacy in prolonging progression-free survival and is the current standard of care for hormone positive (HR(+)) metastatic breast cancer (mBC). Despite well tolerability and ease of use, the most common side effect of CDK4/6i is myelosuppression, with neutropenia the most prevalent adverse effect. Studies show that the prevalence and severity of neutropenia are more marked in Asian patients, although details remain obscure. METHODS: In this study, we retrospectively analyzed 105 Taiwanese patients who received palbociclib for HR(+) HER2(-) mBC at the Taipei Veterans General Hospital. To investigate a possible genetic association for high prevalence of neutropenia, we queried the Taiwan Biobank with publicly available germline databases (ALFA, gnomAD, ExAC, 1000 Genomes project, HapMap), for the allele frequencies of 4 neutropenia-related SNPs (ABCB1_rs1045642, ABCB1_rs1128503, ERCC1_rs3212986, ERCC1_rs11615) and compared between different ethnicities. In addition, one of the patients was a long-term patient with peritoneal dialysis. We quantified the levels of palbociclib in her serum and peritoneal fluid by liquid chromatography-mass spectrometry (LC-MS). RESULTS: Interestingly, in our cohort, early neutropenia nadir (occurred within 56 days of start) was associated with worse treatment outcome, while occurrence of grade 3/4 neutropenia was associated with better outcome. We observed an extremely high incidence of neutropenia (96.2% any grade, 70.4% grade 3/4). In the analyzed germline databases, we discovered a higher SNP frequency of the T allele in ABCB1_rs1128503, a lower frequency of T allele in ABCB1_rs1045642, and a higher SNP frequency of G allele in ERCC1_rs11615. We observed that palbociclib levels in peritoneal dialysate ranged from around 20-50 ppb, and serum levels reached 100-110 ppb during drug administration and decreased to <10 ppb during discontinuation. CONCLUSION: Our retrospective analysis of real world palbociclib use reveals an association with grade 3/4 neutropenia with better outcome and early neutropenia nadir with worse outcome. Our findings of Asian specific SNPs support a predisposition toward profound and prevalent neutropenia in Asian patients under CDK4/6i. We also report the first pharmacokinetics analysis on a patient with peritoneal dialysis receiving CDK4/6i. In summary, our study provides novel clinical and genotypic insights into CDK4/6i associated neutropenia.


Assuntos
Neoplasias da Mama , Neutropenia , Piperazinas , Piridinas , Feminino , Humanos , Estudos Retrospectivos , Prevalência , Receptor ErbB-2/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Neutropenia/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quinase 4 Dependente de Ciclina
15.
Biochem Biophys Res Commun ; 693: 149376, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38104523

RESUMO

Peritoneal dialysis (PD) and prolonged exposure to PD fluids (PDF) induce peritoneal membrane (PM) fibrosis and hypervascularity, leading to functional PM degeneration. 2-deoxy-glucose (2-DG) has shown potential as PM antifibrotic by inhibiting hyper-glycolysis induced mesothelial-to-mesenchymal transition (MMT). We investigated whether administration of 2-DG with several PDF affects the permeability of mesothelial and endothelial barrier of the PM. The antifibrotic effect of 2-DG was confirmed by the gel contraction assay with embedded mesothelial (MeT-5A) or endothelial (EA.hy926) cells cultured in Dianeal® 2.5 % (CPDF), BicaVera® 2.3 % (BPDF), Balance® 2.3 % (LPDF) with/without 2-DG addition (0.2 mM), and qPCR for αSMA, CDH2 genes. Moreover, 2-DG effect was tested on the permeability of monolayers of mesothelial and endothelial cells by monitoring the transmembrane resistance (RTM), FITC-dextran (10, 70 kDa) diffusion and mRNA expression levels of CLDN-1 to -5, ZO1, SGLT1, and SGLT2 genes. Contractility of MeT-5A cells in CPDF/2-DG was decreased, accompanied by αSMA (0.17 ± 0.03) and CDH2 (2.92 ± 0.29) gene expression fold changes. Changes in αSMA, CDH2 were found in EA.hy926 cells, though αSMA also decreased under LPDF/2-DG incubation (0.42 ± 0.02). Overall, 2-DG mitigated the PDF-induced alterations in mesothelial and endothelial barrier function as shown by RTM, dextran transport and expression levels of the CLDN-1 to -5, ZO1, and SGLT2. Thus, supplementation of PDF with 2-DG not only reduces MMT but also improves functional permeability characteristics of the PM mesothelial and endothelial barrier.


Assuntos
Diálise Peritoneal , Fibrose Peritoneal , Humanos , Transportador 2 de Glucose-Sódio/metabolismo , Desoxiglucose/farmacologia , Desoxiglucose/metabolismo , Células Endoteliais , Diálise Peritoneal/efeitos adversos , Peritônio/patologia , Soluções para Diálise/metabolismo , Soluções para Diálise/farmacologia , Fibrose Peritoneal/metabolismo , Glucose/metabolismo , Células Epiteliais/metabolismo , Células Cultivadas
16.
J Intern Med ; 295(1): 79-90, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37827529

RESUMO

BACKGROUND: Chronic kidney disease (CKD) is an age-related disease that displays multiple features of accelerated ageing. It is currently unclear whether the two treatment options for end-stage kidney disease (dialysis and kidney transplantation [KT]) ameliorate the accelerated uremic ageing process. METHODS: Data on clinical variables and blood DNA methylation (DNAm) from CKD stage G3-G5 patients were used to estimate biological age based on blood biomarkers (phenotypic age [PA], n = 333), skin autofluorescence (SAF age, n = 199) and DNAm (Horvath, Hannum and PhenoAge clocks, n = 47). In the DNAm cohort, we also measured the change in biological age 1 year after the KT or initiation of dialysis. Healthy subjects recruited from the general population were included as controls. RESULTS: All three DNAm clocks indicated an increased biological age in CKD G5. However, PA and SAF age tended to produce implausibly large estimates of biological age in CKD G5. By contrast, DNAm age was 4.9 years (p = 0.005) higher in the transplantation group and 5.9 years (p = 0.001) higher in the dialysis group compared to controls. This age acceleration was significantly reduced 1 year after KT, but not after 1 year of dialysis. CONCLUSIONS: Kidney failure patients displayed an increased biological age as estimated by DNAm clocks compared to population-based controls. Our results suggest that KT, but not dialysis, partially reduces the age acceleration.


Assuntos
Transplante de Rim , Insuficiência Renal Crônica , Humanos , Lactente , Pré-Escolar , Diálise Renal , Envelhecimento/genética , Metilação de DNA , Insuficiência Renal Crônica/terapia , Epigênese Genética
17.
Small ; 20(3): e2302550, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37726238

RESUMO

The structural coloration of textiles with bionic photonic crystals (PCs) is expected to become a critical approach to the ecological coloration of textiles. Rapid and large-area preparation of PC structurally colored textiles can be achieved via self-assembly of high mass fractions of liquid photonic crystals (LPCs). However, the rapid and large-scale manufacturing of LPCs remains a challenge. In this work, the pH regulator is added in the process of emulsion polymerization to solve the problem of phase transformation caused by the thermal decomposition of the initiator to produce H+ , directly achieving 40 wt.% PS nanospheres in the dispersion. Then oligomers and small-molecule salts are removed from the system via dialysis, and the pre-crystallized LPC system is efficiently prepared. Adjusting the particle size and the mass fraction of nanospheres is shown to be an efficient way to control the optical properties of LPCs. The rapid and large-area preparation of PC structural color fabric and the patterned PC structural color fabric with an iridescent effect is implemented by using LPCs as the assembly intermediate. By constructing the encapsulation layer on the surface of the PC structural color fabric, the consistency of high structural stability and high color saturation of the PC is realized.

18.
Am J Kidney Dis ; 83(1): 47-57.e1, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37657633

RESUMO

RATIONALE & OBJECTIVE: The integrated home dialysis model proposes the initiation of kidney replacement therapy (KRT) with peritoneal dialysis (PD) and a timely transition to home hemodialysis (HHD) after PD ends. We compared the outcomes of patients transitioning from PD to HHD with those initiating KRT with HHD. STUDY DESIGN: Observational analysis of the Canadian Organ Replacement Register (CORR). SETTINGS & PARTICIPANTS: All patients who initiated PD or HHD within the first 90 days of KRT between 2005 and 2018. EXPOSURE: Patients transitioning from PD to HHD (PD+HHD group) versus patients initiating KRT with HHD (HHD group). OUTCOME: (1) A composite of all-cause mortality and modality transfer (to in-center hemodialysis or PD for 90 days) and (2) all hospitalizations (considered as recurrent events). ANALYTICAL APPROACH: A propensity score analysis for which PD+HHD patients were matched 1:1 to (1) incident HHD patients ("incident-match" analysis) or (2) HHD patients with a KRT vintage at least equivalent to the vintage of PD+HHD patients at the transition time ("vintage-matched" analysis). Cause-specific hazards models (composite outcome) and shared frailty models (hospitalization) were used to compare groups. RESULTS: Among 63,327 individuals in the CORR, 163 PD+HHD patients (median of 1.9 years in PD) and 711 HHD patients were identified. In the incident-match analysis, compared to the HHD patients, the PD+HHD group had a similar risk of the composite outcome (HR, 0.88 [95% CI, 0.58-1.32]) and hospitalizations (HR, 1.04 [95% CI, 0.76-1.41]). In the vintage-match analysis, PD+HHD patients had a lower hazard for the composite outcome (HR, 0.61 [95% CI, 0.40-0.94]) but a similar hospitalization risk (HR, 0.85 [95% CI, 0.59-1.24]). LIMITATIONS: Risk of survivor bias in the PD+HHD cohort and residual confounding. CONCLUSIONS: Controlling for KRT vintage, the patients transitioning from PD to HHD had better clinical outcomes than the incident HHD patients. These data support the use of integrated home dialysis for patients initiating home-based KRT. PLAIN-LANGUAGE SUMMARY: The integrated home dialysis model proposes the initiation of dialysis with peritoneal dialysis (PD) and subsequent transition to home hemodialysis (HHD) once PD is no longer feasible. It allows patients to benefit from initial lifestyle advantages of PD and to continue home-based treatments after its termination. However, some patients may prefer to initiate dialysis with HHD from the outset. In this study, we compared the long-term clinical outcomes of both approaches using a large Canadian dialysis register. We found that both options led to a similar risk of hospitalization. In contrast, the PD-to-HHD model led to improved survival when controlling for the duration of kidney failure.


Assuntos
Falência Renal Crônica , Diálise Peritoneal , Humanos , Canadá , Hemodiálise no Domicílio/métodos , Falência Renal Crônica/terapia , Diálise Peritoneal/métodos , Diálise Renal/métodos
19.
Am J Kidney Dis ; 83(4): 445-455, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38061534

RESUMO

RATIONALE & OBJECTIVE: Hemodialysis catheter dysfunction is an important problem for patients with kidney failure. The optimal design of the tunneled catheter tip is unknown. This study evaluated the association of catheter tip design with the duration of catheter function. STUDY DESIGN: Observational cohort study using data from the nationwide REDUCCTION trial. SETTING & PARTICIPANTS: 4,722 adults who each received hemodialysis via 1 or more tunneled central venous catheters in 37 Australian nephrology services from December 2016 to March 2020. EXPOSURE: Design of tunneled hemodialysis catheter tip, classified as symmetrical, step, or split. OUTCOME: Time to catheter dysfunction requiring removal due to inadequate dialysis blood flow assessed by the treating clinician. ANALYTICAL APPROACH: Mixed, 3-level accelerated failure time model, assuming a log-normal survival distribution. Secular trends, the intervention, and baseline differences in service, patient, and catheter factors were included in the adjusted model. In a sensitivity analysis, survival times and proportional hazards were compared among participants' first tunneled catheters. RESULTS: Among the study group, 355 of 3,871 (9.2%), 262 of 1,888 (13.9%), and 38 of 455 (8.4%) tunneled catheters with symmetrical, step, and split tip designs, respectively, required removal due to dysfunction. Step tip catheters required removal for dysfunction at a rate 53% faster than symmetrical tip catheters (adjusted time ratio, 0.47 [95% CI, 0.33-0.67) and 76% faster than split tip catheters (adjusted time ratio, 0.24 [95% CI, 0.11-0.51) in the adjusted accelerated failure time models. Only symmetrical tip catheters had performance superior to step tip catheters in unadjusted and sensitivity analyses. Split tip catheters were infrequently used and had risks of dysfunction similar to symmetrical tip catheters. The cumulative incidence of other complications requiring catheter removal, routine removal, and death before removal were similar across the 3 tip designs. LIMITATIONS: Tip design was not randomized. CONCLUSIONS: Symmetrical and split tip catheters had a lower risk of catheter dysfunction requiring removal than step tip catheters. FUNDING: Grants from government (Queensland Health, Safer Care Victoria, Medical Research Future Fund, National Health and Medical Research Council, Australia), academic (Monash University), and not-for-profit (ANZDATA Registry, Kidney Health Australia) sources. TRIAL REGISTRATION: Registered at ANZCTR with study number ACTRN12616000830493. PLAIN-LANGUAGE SUMMARY: Central venous catheters are widely used to facilitate vascular access for life-sustaining hemodialysis treatments but often fail due to blood clots or other mechanical problems that impede blood flow. A range of adaptations to the design of tunneled hemodialysis catheters have been developed, but it is unclear which designs have the greatest longevity. We analyzed data from an Australian nationwide cohort of patients who received hemodialysis via a tunneled catheter and found that catheters with a step tip design failed more quickly than those with a symmetrical tip. Split tip catheters performed well but were infrequently used and require further study. Use of symmetrical rather than step tip hemodialysis catheters may reduce mechanical failures and unnecessary procedures for patients.


Assuntos
Cateterismo Venoso Central , Cateteres Venosos Centrais , Adulto , Humanos , Cateterismo Venoso Central/efeitos adversos , Estudos de Coortes , Cateteres de Demora/efeitos adversos , Austrália , Diálise Renal , Cateteres Venosos Centrais/efeitos adversos
20.
Am J Kidney Dis ; 84(1): 18-27, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38447708

RESUMO

RATIONALE & OBJECTIVE: Infection prevention efforts in dialysis centers can avert patient morbidity and mortality but are challenging to implement. The objective of this study was to better understand how the design of the work system might contribute to infection prevention in outpatient dialysis centers. STUDY DESIGN: Mixed methods, observational study. SETTING & PARTICIPANTS: Six dialysis facilities across the United States visited by a multidisciplinary team over 8 months. ANALYTICAL APPROACH: At each facility, structured macroergonomic observations were undertaken by a multidisciplinary team using the SEIPS 1.0 model. Ethnographic observations were collected about staff encounters with dialysis patients including the content of staff conversations. Selective and axial coding were used for qualitative analysis and quantitative data were reported using descriptive statistics. RESULTS: Organizational and sociotechnical barriers and facilitators to infection prevention in the outpatient dialysis setting were identified. Features related to human performance, (eg, alarms, interruptions, and task stacking), work system design (eg, physical space, scheduling, leadership, and culture), and extrinsic factors (eg, patient-related characteristics) were identified. LIMITATIONS: This was an exploratory evaluation with a small sample size. CONCLUSIONS: This study used a systematic macroergonomic approach in multiple outpatient dialysis facilities to identify infection prevention barriers and facilitators related to human performance. Several features common across facilities were identified that may influence infection prevention in outpatient care and warrant further exploration.


Assuntos
Instituições de Assistência Ambulatorial , Controle de Infecções , Diálise Renal , Humanos , Controle de Infecções/métodos , Estados Unidos/epidemiologia , Ergonomia/métodos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA