RESUMO
BACKGROUND: Sodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and the nonsteroidal mineralocorticoid receptor antagonist (ns-MRA) finerenone all individually reduce cardiovascular, kidney, and mortality outcomes in patients with type 2 diabetes and albuminuria. However, the lifetime benefits of combination therapy with these medicines are not known. METHODS: We used data from 2 SGLT2i trials (CANVAS [Canagliflozin Cardiovascular Assessment] and CREDENCE [Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation]), 2 ns-MRA trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease]), and 8 GLP-1 RA trials to estimate the relative effects of combination therapy versus conventional care (renin-angiotensin system blockade and traditional risk factor control) on cardiovascular, kidney, and mortality outcomes. Using actuarial methods, we then estimated absolute risk reductions with combination SGLT2i, GLP-1 RA, and ns-MRA in patients with type 2 diabetes and at least moderately increased albuminuria (urinary albumin:creatinine ratio ≥30 mg/g) by applying estimated combination treatment effects to participants receiving conventional care in CANVAS and CREDENCE. RESULTS: Compared with conventional care, the combination of SGLT2i, GLP-1 RA, and ns-MRA was associated with a hazard ratio of 0.65 (95% CI, 0.55-0.76) for major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). The corresponding estimated absolute risk reduction over 3 years was 4.4% (95% CI, 3.0-5.7), with a number needed to treat of 23 (95% CI, 18-33). For a 50-year-old patient commencing combination therapy, estimated major adverse cardiovascular event-free survival was 21.1 years compared with 17.9 years for conventional care (3.2 years gained [95% CI, 2.1-4.3]). There were also projected gains in survival free from hospitalized heart failure (3.2 years [95% CI, 2.4-4.0]), chronic kidney disease progression (5.5 years [95% CI, 4.0-6.7]), cardiovascular death (2.2 years [95% CI, 1.2-3.0]), and all-cause death (2.4 years [95% CI, 1.4-3.4]). Attenuated but clinically relevant gains in event-free survival were observed in analyses assuming 50% additive effects of combination therapy, including for major adverse cardiovascular events (2.4 years [95% CI, 1.1-3.5]), chronic kidney disease progression (4.5 years [95% CI, 2.8-5.9]), and all-cause death (1.8 years [95% CI, 0.7-2.8]). CONCLUSIONS: In patients with type 2 diabetes and at least moderately increased albuminuria, combination treatment of SGLT2i, GLP-1 RA, and ns-MRA has the potential to afford relevant gains in cardiovascular and kidney event-free and overall survival.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Pessoa de Meia-Idade , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Canagliflozina/uso terapêutico , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon , Albuminúria/tratamento farmacológico , Rim , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Peptídeo 1 Semelhante ao Glucagon/uso terapêuticoRESUMO
BACKGROUND: Persistent mineralocorticoid receptor activation is a pathologic response in type 2 diabetes and chronic kidney disease. Whereas mineralocorticoid receptor antagonists are beneficial in reducing cardiovascular complications, direct mechanistic pathways for these effects in humans are lacking. METHODS: The MAGMA trial (Mineralocorticoid Receptor Antagonism Clinical Evaluation in Atherosclerosis) was a randomized, double-blind, placebo-controlled trial in patients with high-risk type 2 diabetes with chronic kidney disease (not receiving dialysis) on maximum tolerated renin-angiotensin system blockade. The primary end point was change in thoracic aortic wall volume, expressed as absolute or percent value (ΔTWV or ΔPWV), using 3T magnetic resonance imaging at 12 months. Secondary end points were changes in left ventricle (LV) mass; LV fibrosis, measured as a change in myocardial native T1; and 24-hour ambulatory and central aortic blood pressures. Tertiary end points included plasma proteomic changes in 7596 plasma proteins using an aptamer-based assay. RESULTS: A total of 79 patients were randomized to placebo (n=42) or 25 mg of spironolactone daily (n=37). After a modified intent-to-treat, including available baseline data of study end points, patients who completed the trial protocol were included in the final analyses. At the 12-month follow-up, the average change in PWV was 7.1±10.7% in the placebo group and 0.87±10.0% in the spironolactone group (P=0.028), and ΔTWV was 1.2±1.7 cm3 in the placebo group and 0.037±1.9 cm3 in the spironolactone group (P=0.022). Change in LV mass was 3.1±8.4 g in the placebo group and -5.8±8.4 g in the spironolactone group (P=0.001). Changes in LV T1 values were significantly different between the placebo and spironolactone groups (26.0±41.9 ms in the placebo group versus a decrease of -10.1±36.3 ms in the spironolactone group; P=6.33×10-4). Mediation analysis revealed that the spironolactone effect on thoracic aortic wall volume and myocardial mass remained significant after adjustment for ambulatory and central blood pressures. Proteomic analysis revealed a dominant effect of spironolactone on pathways involving oxidative stress, inflammation, and leukocyte activation. CONCLUSIONS: Among patients with diabetes with moderate to severe chronic kidney disease at elevated cardiovascular risk, treatment with spironolactone prevented progression of aortic wall volume and resulted in regression of LV mass and favorable alterations in native T1, suggesting amelioration of left-ventricular fibrosis. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02169089.
Assuntos
Diabetes Mellitus Tipo 2 , Fibrose , Antagonistas de Receptores de Mineralocorticoides , Insuficiência Renal Crônica , Espironolactona , Humanos , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Método Duplo-Cego , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Idoso , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/complicações , Espironolactona/uso terapêutico , Progressão da Doença , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Ventrículos do Coração/efeitos dos fármacos , Resultado do TratamentoRESUMO
BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) consistently improve heart failure and kidney-related outcomes; however, effects on major adverse cardiovascular events (MACE) across different patient populations are less clear. METHODS: This was a collaborative trial-level meta-analysis from the SGLT2i Meta-analysis Cardio-Renal Trialists Consortium, which includes all phase 3, placebo-controlled, outcomes trials of SGLT2i across 3 patient populations (patients with diabetes at high risk for atherosclerotic cardiovascular disease, heart failure [HF], or chronic kidney disease). The outcomes of interest were MACE (composite of cardiovascular death, myocardial infarction , or stroke), individual components of MACE (inclusive of fatal and nonfatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i versus placebo were meta-analyzed across trials and examined across key subgroups (established atherosclerotic cardiovascular disease, previous myocardial infarction, diabetes, previous HF, albuminuria, chronic kidney disease stages, and risk groups). RESULTS: A total of 78 607 patients across 11 trials were included: 42 568 (54.2%), 20 725 (26.4%), and 15 314 (19.5%) were included from trials of patients with diabetes at high risk for atherosclerotic cardiovascular disease, HF, or chronic kidney disease, respectively. SGLT2i reduced the rate of MACE by 9% (hazard ration [HR], 0.91 [95% CI, 0.87-0.96], P<0.0001) with a consistent effect across all 3 patient populations (I2=0%) and across all key subgroups. This effect was primarily driven by a reduction in cardiovascular death (HR, 0.86 [95% CI, 0.81-0.92], P<0.0001), with no significant effect for myocardial infarction in the overall population (HR, 0.95 [95% CI, 0.87-1.04], P=0.29), and no effect on stroke (HR, 0.99 [95% CI, 0.91-1.07], P=0.77). The benefit for cardiovascular death was driven primarily by reductions in HF death and sudden cardiac death (HR, 0.68 [95% CI, 0.46-1.02] and HR, 0.86 [95% CI, 0.78-0.95], respectively) and was generally consistent across subgroups, with the possible exception of being more apparent in those with albuminuria (Pinteraction=0.02). CONCLUSIONS: SGLT2i reduce the risk of MACE across a broad range of patients irrespective of atherosclerotic cardiovascular disease, diabetes, kidney function, or other major clinical characteristics at baseline. This effect is driven primarily by a reduction of cardiovascular death, particularly HF death and sudden cardiac death, without a significant effect on myocardial infarction in the overall population, and no effect on stroke. These data may help inform selection for SGLT2i therapies across the spectrum of cardiovascular-kidney-metabolic disease.
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Doenças Cardiovasculares , Inibidores do Transportador 2 de Sódio-Glicose , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Humanos , Doenças Cardiovasculares/mortalidade , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/complicações , Feminino , Masculino , Resultado do Tratamento , IdosoRESUMO
Kidney disease is associated with adverse consequences in many organs beyond the kidney, including the heart, lungs, brain, and intestines. The kidney-intestinal cross talk involves intestinal epithelial damage, dysbiosis, and generation of uremic toxins. Recent studies reveal that kidney injury expands the intestinal lymphatics, increases lymphatic flow, and alters the composition of mesenteric lymph. The intestinal lymphatics, like blood vessels, are a route for transporting potentially harmful substances generated by the intestines. The lymphatic architecture and actions are uniquely suited to take up and transport large macromolecules, functions that differentiate them from blood vessels, allowing them to play a distinct role in a variety of physiological and pathological processes. Here, we focus on the mechanisms by which kidney diseases result in deleterious changes in intestinal lymphatics and consider a novel paradigm of a vicious cycle of detrimental organ cross talk. This concept involves kidney injury-induced modulation of intestinal lymphatics that promotes production and distribution of harmful factors, which in turn contributes to disease progression in distant organ systems.
Assuntos
Nefropatias , Vasos Linfáticos , Humanos , Intestinos , Sistema LinfáticoRESUMO
Chronic kidney disease is associated with an increased risk for the development and progression of cardiovascular disorders including hypertension, dyslipidemia, and coronary artery disease. Chronic kidney disease may also affect the myocardium through complex systemic changes, resulting in structural remodeling such as hypertrophy and fibrosis, as well as impairments in both diastolic and systolic function. These cardiac changes in the setting of chronic kidney disease define a specific cardiomyopathic phenotype known as uremic cardiomyopathy. Cardiac function is tightly linked to its metabolism, and research over the past 3 decades has revealed significant metabolic remodeling in the myocardium during the development of heart failure. Because the concept of uremic cardiomyopathy has only been recognized in recent years, there are limited data on metabolism in the uremic heart. Nonetheless, recent findings suggest overlapping mechanisms with heart failure. This work reviews key features of metabolic remodeling in the failing heart in the general population and extends this to patients with chronic kidney disease. The knowledge of similarities and differences in cardiac metabolism between heart failure and uremic cardiomyopathy may help identify new targets for mechanistic and therapeutic research on uremic cardiomyopathy.
Assuntos
Cardiomiopatias , Doenças Cardiovasculares , Insuficiência Cardíaca , Insuficiência Renal Crônica , Humanos , Cardiomiopatias/etiologia , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Insuficiência Renal Crônica/complicações , Doenças Cardiovasculares/metabolismoRESUMO
The pathophysiology of vascular disease is linked to accelerated biological aging and a combination of genetic, lifestyle, biological, and environmental risk factors. Within the scenario of uncontrolled artery wall aging processes, CKD (chronic kidney disease) stands out as a valid model for detailed structural, functional, and molecular studies of this process. The cardiorenal syndrome relates to the detrimental bidirectional interplay between the kidney and the cardiovascular system. In addition to established risk factors, this group of patients is subjected to a plethora of other emerging vascular risk factors, such as inflammation, oxidative stress, mitochondrial dysfunction, vitamin K deficiency, cellular senescence, somatic mutations, epigenetic modifications, and increased apoptosis. A better understanding of the molecular mechanisms through which the uremic milieu triggers and maintains early vascular aging processes, has provided important new clues on inflammatory pathways and emerging risk factors alike, and to the altered behavior of cells in the arterial wall. Advances in the understanding of the biology of uremic early vascular aging opens avenues to novel pharmacological and nutritional therapeutic interventions. Such strategies hold promise to improve future prevention and treatment of early vascular aging not only in CKD but also in the elderly general population.
Assuntos
Insuficiência Renal Crônica , Doenças Vasculares , Humanos , Idoso , Insuficiência Renal Crônica/terapia , Envelhecimento , Rim , Senescência Celular/fisiologiaRESUMO
Patients with chronic kidney disease (CKD) exhibit tremendously elevated risk for cardiovascular disease, particularly ischemic heart disease, due to premature vascular and cardiac aging and accelerated ectopic calcification. The presence of cardiovascular calcification associates with increased risk in patients with CKD. Disturbed mineral homeostasis and diverse comorbidities in these patients drive increased systemic cardiovascular calcification in different manifestations with diverse clinical consequences, like plaque instability, vessel stiffening, and aortic stenosis. This review outlines the heterogeneity in calcification patterning, including mineral type and location and potential implications on clinical outcomes. The advent of therapeutics currently in clinical trials may reduce CKD-associated morbidity. Development of therapeutics for cardiovascular calcification begins with the premise that less mineral is better. While restoring diseased tissues to a noncalcified homeostasis remains the ultimate goal, in some cases, calcific mineral may play a protective role, such as in atherosclerotic plaques. Therefore, developing treatments for ectopic calcification may require a nuanced approach that considers individual patient risk factors. Here, we discuss the most common cardiac and vascular calcification pathologies observed in CKD, how mineral in these tissues affects function, and the potential outcomes and considerations for therapeutic strategies that seek to disrupt the nucleation and growth of mineral. Finally, we discuss future patient-specific considerations for treating cardiac and vascular calcification in patients with CKD-a population in need of anticalcification therapies.
Assuntos
Doenças Cardiovasculares , Insuficiência Renal Crônica , Calcificação Vascular , Humanos , Insuficiência Renal Crônica/complicações , Calcificação Vascular/etiologia , Doenças Cardiovasculares/etiologia , Minerais , EnvelhecimentoRESUMO
Patients with chronic kidney disease (CKD) are at high risk to develop cardiovascular disease with its manifestations coronary artery disease, heart failure, arrhythmias, and sudden cardiac death. In addition, the presence of CKD has a major impact on the prognosis of patients with cardiovascular disease, leading to an increased morbidity and mortality if both comorbidities are present. Therapeutic options including medical therapy and interventional treatment are often limited in patients with advanced CKD, and in most cardiovascular outcome trials, patients with advanced CKD have been excluded. Thus, in many patients, treatment strategies for cardiovascular disease need to be extrapolated from trials conducted in patients without CKD. The current article summarizes the epidemiology, clinical presentation, and treatment options for the most prevalent manifestations of cardiovascular disease in CKD and discusses the currently available treatment options to reduce morbidity and mortality in this high-risk population.
Assuntos
Doenças Cardiovasculares , Doença da Artéria Coronariana , Insuficiência Renal Crônica , Humanos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/terapia , Coração , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapia , Doença da Artéria Coronariana/epidemiologia , Rim , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/prevenção & controle , Fatores de RiscoRESUMO
Hyperphosphatemia is a common feature in patients with impaired kidney function and is associated with increased risk of cardiovascular disease. This phenomenon extends to the general population, whereby elevations of serum phosphate within the normal range increase risk; however, the mechanism by which this occurs is multifaceted, and many aspects are poorly understood. Less than 1% of total body phosphate is found in the circulation and extracellular space, and its regulation involves multiple organ cross talk and hormones to coordinate absorption from the small intestine and excretion by the kidneys. For phosphate to be regulated, it must be sensed. While mostly enigmatic, various phosphate sensors have been elucidated in recent years. Phosphate in the circulation can be buffered, either through regulated exchange between extracellular and cellular spaces or through chelation by circulating proteins (ie, fetuin-A) to form calciprotein particles, which in themselves serve a function for bulk mineral transport and signaling. Either through direct signaling or through mediators like hormones, calciprotein particles, or calcifying extracellular vesicles, phosphate can induce various cardiovascular disease pathologies: most notably, ectopic cardiovascular calcification but also left ventricular hypertrophy, as well as bone and kidney diseases, which then propagate phosphate dysregulation further. Therapies targeting phosphate have mostly focused on intestinal binding, of which appreciation and understanding of paracellular transport has greatly advanced the field. However, pharmacotherapies that target cardiovascular consequences of phosphate directly, such as vascular calcification, are still an area of great unmet medical need.
Assuntos
Doenças Cardiovasculares , Hiperfosfatemia , Insuficiência Renal Crônica , Calcificação Vascular , Humanos , Fosfatos/metabolismo , Doenças Cardiovasculares/metabolismo , Hiperfosfatemia/tratamento farmacológico , Calcificação Vascular/etiologia , Hormônios/uso terapêuticoRESUMO
BACKGROUND: People with type 2 diabetes and albuminuria are at an elevated risk for cardiac and renal events. The optimal biomarkers to aid disease prediction and to understand the benefits of sodium-glucose cotransporter-2 inhibition remain unclear. METHODS: Among 2627 study participants in the CREDENCE trial (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), concentrations of NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T, growth differentiation factor-15, and IGFBP7 (insulin-like growth factor binding protein 7) were measured. The effect of canagliflozin on biomarker concentrations was evaluated. The prognostic potential of each biomarker on the primary outcome (a composite of end-stage kidney disease [dialysis, transplantation, or a sustained estimated glomerular filtration rate of <15 mL·min-1·1.73 m-2], doubling of the serum creatinine level, or renal death or cardiovascular death) was assessed. RESULTS: The median (quartiles 1 and 3) concentration of each biomarker was generally elevated: NT-proBNP, 180 ng/L (82, 442 ng/L); high-sensitivity cardiac troponin T, 19 ng/L (12, 29 ng/L); growth differentiation factor-15, 2595 ng/L (1852, 3775 ng/L); and IGFBP7, 121.8 ng/mL (105.4, 141.5 ng/mL). At 1 year, the biomarkers all rose by 6% to 29% in the placebo arm but only by 3% to 10% in the canagliflozin arm (all P<0.01 in multivariable linear mixed-effect models). Baseline concentrations of each biomarker were strongly predictive of cardiac and renal outcomes. When the biomarkers were analyzed together in a multimarker panel, individuals with high risk scores (hazard ratio [HR], 4.01 [95% CI, 2.52-6.35]) and moderate risk scores (HR, 2.39 [95% CI, 1.48-3.87]) showed a higher risk for the primary outcome compared with those with low risk scores. By 1 year, a 50% increase in NT-proBNP (HR, 1.11 [95% CI, 1.08-1.15]), high-sensitivity cardiac troponin T (HR, 1.86 [95% CI, 1.64-2.10]), growth differentiation factor-15 (HR, 1.45 [95% CI, 1.24-1.70]), and IGFBP7 (HR, 3.76 [95% CI, 2.54-5.56]) was associated with risk of the primary outcome. CONCLUSIONS: Multiple cardiorenal stress biomarkers are strongly prognostic in people with type 2 diabetes and albuminuria. Canagliflozin modestly reduced the longitudinal trajectory of rise in each biomarker. Change in the biomarker level in addition to the baseline level augments the primary outcome prediction. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02065791.
Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Humanos , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/tratamento farmacológico , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Albuminúria , Troponina T , Biomarcadores , Fatores de Diferenciação de CrescimentoRESUMO
BACKGROUND: Recommendations for apixaban dosing on the basis of kidney function are inconsistent between the US Food and Drug Administration and European Medicines Agency for patients with atrial fibrillation. Optimal apixaban dosing in chronic kidney disease remains unknown. METHODS: With the use of deidentified electronic health record data from the Optum Labs Data Warehouse, patients with atrial fibrillation and chronic kidney disease stage 4/5 initiating apixaban between 2013 and 2021 were identified. Risks of bleeding and stroke/systemic embolism were compared by apixaban dose (5 versus 2.5 mg), adjusted for baseline characteristics by the inverse probability of treatment weighting. The Fine-Gray subdistribution hazard model was used to account for the competing risk of death. Cox regression was used to examine risk of death by apixaban dose. RESULTS: Among 4313 apixaban new users, 1705 (40%) received 5 mg and 2608 (60%) received 2.5 mg. Patients treated with 5 mg apixaban were younger (mean age, 72 versus 80 years), with greater weight (95 versus 80 kg) and higher serum creatinine (2.7 versus 2.5 mg/dL). Mean estimated glomerular filtration rate was not different between the groups (24 versus 24 mL·min-1·1.73 m-2). In inverse probability of treatment weighting analysis, apixaban 5 mg was associated with a higher risk of bleeding (incidence rate 4.9 versus 2.9 events per 100 person-years; incidence rate difference, 2.0 [95% CI, 0.6-3.4] events per 100 person-years; subdistribution hazard ratio, 1.63 [95% CI, 1.04-2.54]). There was no difference between apixaban 5 mg and 2.5 mg groups in the risk of stroke/systemic embolism (3.3 versus 3.0 events per 100 person-years; incidence rate difference, 0.2 [95% CI, -1.0 to 1.4] events per 100 person-years; subdistribution hazard ratio, 1.01 [95% CI, 0.59-1.73]), or death (9.9 versus 9.4 events per 100 person-years; incidence rate difference, 0.5 [95% CI, -1.6 to 2.6] events per 100 person-years; hazard ratio, 1.03 [95% CI, 0.77-1.38]). CONCLUSIONS: Compared with 2.5 mg, use of 5 mg apixaban was associated with a higher risk of bleeding in patients with atrial fibrillation and severe chronic kidney disease, with no difference in the risk of stroke/systemic embolism or death, supporting the apixaban dosing recommendations on the basis of kidney function by the European Medicines Agency, which differ from those issued by the US Food and Drug Administration.
Assuntos
Fibrilação Atrial , Embolia , Insuficiência Renal Crônica , Acidente Vascular Cerebral , Humanos , Idoso , Fibrilação Atrial/tratamento farmacológico , Anticoagulantes/efeitos adversos , Resultado do Tratamento , Acidente Vascular Cerebral/epidemiologia , Piridonas/efeitos adversos , Hemorragia/induzido quimicamente , Insuficiência Renal Crônica/tratamento farmacológico , Embolia/etiologiaRESUMO
BACKGROUND: Tissue fibrosis is a common pathway to failure in many organ systems and is the cellular and molecular driver of myriad chronic diseases that are incompletely understood and lack effective treatment. Recent studies suggest that gut microbe-dependent metabolites might be involved in the initiation and progression of fibrosis in multiple organ systems. MAIN BODY OF THE MANUSCRIPT: In a meta-organismal pathway that begins in the gut, gut microbiota convert dietary precursors such as choline, phosphatidylcholine, and L-carnitine into trimethylamine (TMA), which is absorbed and subsequently converted to trimethylamine N-oxide (TMAO) via the host enzyme flavin-containing monooxygenase 3 (FMO3) in the liver. Chronic exposure to elevated TMAO appears to be associated with vascular injury and enhanced fibrosis propensity in diverse conditions, including chronic kidney disease, heart failure, metabolic dysfunction-associated steatotic liver disease, and systemic sclerosis. CONCLUSION: Despite the high prevalence of fibrosis, little is known to date about the role of gut dysbiosis and of microbe-dependent metabolites in its pathogenesis. This review summarizes recent important advances in the understanding of the complex metabolism and functional role of TMAO in pathologic fibrosis and highlights unanswered questions.
Assuntos
Fibrose , Microbioma Gastrointestinal , Metilaminas , Metilaminas/metabolismo , Humanos , Animais , Disbiose/metabolismo , Oxigenases/metabolismoRESUMO
AIMS: To describe treatment pathways for key glucose-lowering therapies in individuals with chronic kidney disease (CKD) and type 2 diabetes (T2D) using retrospective data from DISCOVER CKD (NCT04034992). METHODS: Data were extracted from the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics data (2008-2020) and the US integrated Limited Claims and Electronic Health Records Database (LCED; 2012-2019). Eligible individuals were aged ≥18 years with CKD, identified by two consecutive estimated glomerular filtration rate (eGFR) measures (15-<75 mL/min/1.73 m2 ; 90-730 days apart; index date was the second measurement) and T2D. Chronological treatment pathways for glucose-lowering therapies prescribed on or after CKD index to end of follow-up were computed. Median time and proportion of overall follow-up time on treatment were described for each therapy by database and by eGFR and urinary albumin-to-creatinine ratio (UACR) categories. RESULTS: Of 36,951 and 4339 eligible individuals in the CPRD and LCED, respectively, median baseline eGFR was 67.8 and 64.9 mL/min/1.73 m2 ; 64.2 and 63.9% received metformin prior to index; and median (interquartile range) time on metformin during follow-up was 917 (390-1671) and 454 (192-850) days (accounting for ~75% of follow-up time in both databases). The frequency of combination treatment increased over time. There were trends towards decreased metformin prescriptions with decreasing eGFR and increasing UACR within each eGFR category. CONCLUSIONS: Individuals with CKD and T2D had many combinations of therapies and substantial follow-up time on therapy. These results highlight opportunities for improved CKD management.
Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Insuficiência Renal Crônica , Adolescente , Adulto , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Taxa de Filtração Glomerular , Glucose , Metformina/efeitos adversos , Metformina/uso terapêutico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/epidemiologia , Estudos RetrospectivosRESUMO
BACKGROUND: Chronic kidney disease (CKD) is characterized by increased myocardial mass despite near-normal blood pressure, suggesting the presence of a separate trigger. A potential driver is SIRPα (signal regulatory protein alpha)-a mediator impairing insulin signaling. The objective of this study is to assess the role of circulating SIRPα in CKD-induced adverse cardiac remodeling. METHODS: SIRPα expression was evaluated in mouse models and patients with CKD. Specifically, mutant, muscle-specific, or cardiac muscle-specific SIRPα KO (knockout) mice were examined after subtotal nephrectomy. Cardiac function was assessed by echocardiography. Metabolic responses were confirmed in cultured muscle cells or cardiomyocytes. RESULTS: We demonstrate that SIRPα regulates myocardial insulin/IGF1R (insulin growth factor-1 receptor) signaling in CKD. First, in the serum of both mice and patients, SIRPα was robustly secreted in response to CKD. Second, cardiac muscle upregulation of SIRPα was associated with impaired insulin/IGF1R signaling, myocardial dysfunction, and fibrosis. However, both global and cardiac muscle-specific SIRPα KO mice displayed improved cardiac function when compared with control mice with CKD. Third, both muscle-specific or cardiac muscle-specific SIRPα KO mice did not significantly activate fetal genes and maintained insulin/IGF1R signaling with suppressed fibrosis despite the presence of CKD. Importantly, SIRPα directly interacted with IGF1R. Next, rSIRPα (recombinant SIRPα) protein was introduced into muscle-specific SIRPα KO mice reestablishing the insulin/IGF1R signaling activity. Additionally, overexpression of SIRPα in myoblasts and cardiomyocytes impaired pAKT (phosphorylation of AKT) and insulin/IGF1R signaling. Furthermore, myotubes and cardiomyocytes, but not adipocytes treated with high glucose or cardiomyocytes treated with uremic toxins, stimulated secretion of SIRPα in culture media, suggesting these cells are the origin of circulating SIRPα in CKD. Both intracellular and extracellular SIRPα exert biologically synergistic effects impairing intracellular myocardial insulin/IGF1R signaling. CONCLUSIONS: Myokine SIRPα expression impairs insulin/IGF1R functions in cardiac muscle, affecting cardiometabolic signaling pathways. Circulating SIRPα constitutes an important readout of insulin resistance in CKD-induced cardiomyopathy.
Assuntos
Cardiomiopatias , Receptor IGF Tipo 1/metabolismo , Receptores Imunológicos/metabolismo , Insuficiência Renal Crônica , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Fibrose , Insulina/metabolismo , Camundongos , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Insuficiência Renal Crônica/complicaçõesRESUMO
BACKGROUND: Vascular calcification (VC) is a highly prevalent complication of chronic kidney disease (CKD) and is associated with the higher morbidity-mortality of patients with CKD. VDR (vitamin D receptor) has been proposed to play a role in the osteoblastic differentiation of vascular smooth muscle cells (VSMCs), but the involvement of vitamin D in VC associated to CKD is controversial. Our aim was to determine the role of local vitamin D signaling in VSMCs during CKD-induced VC. METHODS: We used epigastric arteries from CKD-affected patients and individuals with normal renal function, alongside an experimental model of CKD-induced VC in mice with conditional deletion of VDR in VSMC. In vitro, experiments in VSMC with or without VDR incubated in calcification media were also used. RESULTS: CKD-affected patients and mice with CKD showed an increase in VC, together with increased arterial expression of VDR compared with controls with normal renal function. Conditional gene silencing of VDR in VSMCs led to a significant decrease of VC in the mouse model of CKD, despite similar levels of renal impairment and serum calcium and phosphate levels. This was accompanied by lower arterial expression of OPN (osteopontin) and lamin A and higher expression of SOST (sclerostin). Furthermore, CKD-affected mice showed a reduction of miR-145a expression in calcified arteries, which was significantly recovered in animals with deletion of VDR in VSMC. In vitro, the absence of VDR prevented VC, inhibited the increase of OPN, and reestablished the expression of miR-145a. Forced expression of miR-145a in vitro in VDRwt VSMCs blunted VC and decreased OPN levels. CONCLUSIONS: Our study provides evidence proving that inhibition of local VDR signaling in VSMCs could prevent VC in CKD and indicates a possible role for miR-145a in this process.
Assuntos
MicroRNAs , Insuficiência Renal Crônica , Calcificação Vascular , Camundongos , Animais , Músculo Liso Vascular/metabolismo , Receptores de Calcitriol/genética , Calcificação Vascular/genética , Calcificação Vascular/prevenção & controle , Rim/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Vitamina D/metabolismo , Miócitos de Músculo Liso/metabolismoRESUMO
BACKGROUND: Sarcopenia is known to bring about adverse outcomes in elderly populations and dialysis patients. However, whether it is a risk factor in kidney transplant recipients (KTRs) has not yet been established. In the present study, the association of sarcopenia with mortality was investigated in KTRs. METHODS: We conducted a single-center prospective cohort study and recruited KTRs who were more than 1-year posttransplant from August 2017 to January 2018. The participants were followed for 5 years, and the Kaplan-Meier method and Cox proportional hazards model were used to assess patient survival. RESULTS: A total of 212 KTRs with a median age of 54 years and median transplant vintage of 79 months were enrolled in this study. Among them, 33 (16%) had sarcopenia according to the Asia Working Group for Sarcopenia 2019 at baseline. During the 5-year follow-up period, 20 (9.4%) died, 5 returned to dialysis after graft loss, and 4 were lost to follow-up. The 5-year overall survival rate was 90%. After 1:1 propensity score matching, a matched cohort with 60 KTRs was generated. The overall survival rate was significantly lower in the sarcopenia group compared to the non-sarcopenia group (p = 0.025, log-rank test). Furthermore, mortality risk was significantly higher in the sarcopenia group compared to the non-sarcopenia group (hazard ratio = 7.57, 95% confidence interval = 0.94-62). CONCLUSION: Sarcopenia was a predictor of mortality in KTRs. KTRs with suboptimal muscle status who were at risk for poor survival could have a clinical benefit by interventions for sarcopenia.
RESUMO
Chronic kidney disease (CKD) imposes a significant burden on healthcare systems worldwide, and diabetes is a major risk factor for CKD. There is currently no consensus in Hong Kong regarding the prioritisation of early identification and intervention for CKD. A comprehensive and Hong Kong-specific diabetes and CKD treatment guideline is also lacking. A multidisciplinary group of experts discussed issues surrounding the current management of CKD and reviewed evidence in the context of local experience to support recommendations. The experts used a modified Delphi approach to finalise recommendations. Consensus was regarded as ≥75% acceptability among all expert panel members. The panel members finalised 14 CKD-focused consensus statements addressing disease definition, screening, disease monitoring, lifestyle management, and treatment strategies. The recommendations provided are relevant to the Hong Kong healthcare setting and can be used as a guide by physicians across various specialties to facilitate the appropriate management of CKD.
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BACKGROUND: In a post hoc analysis, the frequency of occurrence of an early decline (dip) in estimated glomerular filtration rate (eGFR) after initiation of dapagliflozin and its association with outcomes were evaluated in patients with heart failure and reduced ejection fraction randomized in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial. METHODS: Patients with heart failure with reduced ejection fraction with or without type 2 diabetes and an eGFR ≥30 mL·min-1·1.73 m-2 were randomized to placebo or dapagliflozin 10 mg daily. The primary outcome was the composite of worsening heart failure or cardiovascular death. The extent of the dip in eGFR between baseline and 2 weeks, patient characteristics associated with a >10% decline, and cardiovascular outcomes and eGFR slopes in participants experiencing this decline were investigated. Time-to-event outcomes were assessed in Cox regression from 14 days; eGFR slopes were assessed with repeated-measures mixed-effect models. RESULTS: The mean change in eGFR between day 0 and 14 was -1.1 mL·min-1·1.73 m-2 (95% CI, -1.5 to -0.7) with placebo and -4.2 mL·min-1·1.73 m-2 (95% CI, -4.6 to -3.9) with dapagliflozin, giving a between-treatment difference of 3.1 mL·min-1·1.73 m-2 (95% CI, 2.6-3.7). The proportions of patients randomized to dapagliflozin experiencing a >10%, >20%, and >30% decline in eGFR were 38.2%, 12.6%, and 3.4%, respectively; for placebo, they were 21.0%, 6.4%, and 1.3%, respectively. The odds ratio for a >10% early decline in eGFR with dapagliflozin compared with placebo was 2.36 (95% CI, 2.07-2.69; P<0.001). Baseline characteristics associated with a >10% decline in eGFR on dapagliflozin were older age, lower eGFR, higher ejection fraction, and type 2 diabetes. The hazard ratio for the primary outcome in patients in the placebo group experiencing a >10% decline in eGFR compared with ≤10% decline in eGFR was 1.45 (95% CI, 1.19-1.78). The corresponding hazard ratio in the dapagliflozin group was 0.73 (95% CI, 0.59-0.91; Pinteraction<0.001). A >10% initial decline in eGFR was not associated with greater long-term decline in eGFR or more adverse events. CONCLUSIONS: The average dip in eGFR after dapagliflozin was started was small and associated with better clinical outcomes compared with a similar decline on placebo in patients with heart failure with reduced ejection fraction. Large declines in eGFR were uncommon with dapagliflozin. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03036124.
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Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Disfunção Ventricular Esquerda , Compostos Benzidrílicos/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Taxa de Filtração Glomerular , Glucosídeos/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Disfunção Ventricular Esquerda/complicaçõesRESUMO
BACKGROUND: It is unclear whether replacing oral glucose tolerance test (OGTT) with hemoglobin A1c (HbA1c) measurement for diagnosing diabetes is justified. We aimed to assess the proportion of OGTT-diagnosed diabetes cases that can be confirmed by HbA1c and to examine whether individuals with OGTT diagnosis but nondiagnostic HbA1c are at higher risk of macrovascular and microvascular disease. METHODS: Participants were 5773 men and women from the population-based Whitehall II prospective cohort study in the United Kingdom. New OGTT diabetes cases diagnosed in clinical examinations in 2002 to 2004 and 2007 to 2009 were assessed for HbA1c confirmation (≥6.5%) in these and subsequent clinical examinations in 2012 to 2013 and 2015 to 2016. All participants were followed up for major cardiovascular events through linkage to electronic health records until 2017 and for incident chronic kidney disease (estimated glomerular filtration rate <60 mL·min-1·1.73 m-2) until the last clinical examination. In analysis of vascular disease risk, new OGTT-diagnosed diabetes cases with and without diagnostic HbA1c and preexisting diabetes cases were compared with diabetes-free participants. RESULTS: Of the 378 (59.3%) participants with OGTT-diagnosed diabetes, 224 were confirmed by HbA1c during 4.1 years (SD, 4.1 years) of follow-up. We recorded 942 cardiovascular events over 12.1 years. After adjustment for nonmodifiable risk factors and compared with the 4997 diabetes-free participants, 371 participants with new HbA1c-confirmed diabetes and 405 participants with preexisting diabetes had increased risk of cardiovascular disease (hazard ratio, 1.53 [95% CI, 1.12-2.10] and 1.85 [95% CI, 1.50-2.28], respectively). The corresponding hazard ratios in the analysis of incident chronic kidney disease (487 cases; follow-up, 6.6 years) were 1.69 (95% CI, 1.09-2.62) for 282 participants with new HbA1c-confirmed diabetes and 1.67 (95% CI, 1.22-2.28) for 276 participants with preexisting diabetes. In both analyses, OGTT cases with nondiagnostic HbA1c (n=149 and 107) had a risk (hazard ratio, 0.99-1.07) similar to that of the diabetes-free population. CONCLUSIONS: More than 40% of OGTT-diagnosed diabetes cases were not confirmed by HbA1c during an extended follow-up. However, because these individuals have a risk of cardiovascular disease and chronic kidney disease similar to that of the diabetes-free population, replacement of OGTT with HbA1c-based diagnosis appears justified.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus , Insuficiência Renal Crônica , Glicemia , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Estudos de Coortes , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Feminino , Teste de Tolerância a Glucose , Hemoglobinas Glicadas/análise , Humanos , Masculino , Estudos ProspectivosRESUMO
BACKGROUND: This is the second update of the original Cochrane review published in 2013 (issue 6), which was updated in 2016 (issue 11). Pruritus occurs in patients with disparate underlying diseases and is caused by different pathologic mechanisms. In palliative care patients, pruritus is not the most prevalent but is a burdening symptom. It can cause considerable discomfort and negatively affect patients' quality of life. OBJECTIVES: To assess the effects of different pharmacological treatments compared with active control or placebo for preventing or treating pruritus in adult palliative care patients. SEARCH METHODS: For this update, we searched CENTRAL (the Cochrane Library), MEDLINE (OVID) and Embase (OVID) up to 6 July 2022. In addition, we searched trial registries and checked the reference lists of all relevant studies, key textbooks, reviews and websites, and we contacted investigators and specialists in pruritus and palliative care regarding unpublished data. SELECTION CRITERIA: We included randomised controlled trials (RCTs) assessing the effects of different pharmacological treatments, compared with a placebo, no treatment, or an alternative treatment, for preventing or treating pruritus in palliative care patients. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the identified titles and abstracts, performed data extraction and assessed the risk of bias and methodological quality. We summarised the results descriptively and quantitatively (meta-analyses) according to the different pharmacological interventions and the diseases associated with pruritus. We assessed the evidence using GRADE and created 13 summary of findings tables. MAIN RESULTS: In total, we included 91 studies and 4652 participants in the review. We added 42 studies with 2839 participants for this update. Altogether, we included 51 different treatments for pruritus in four different patient groups. The overall risk of bias profile was heterogeneous and ranged from high to low risk. The main reason for giving a high risk of bias rating was a small sample size (fewer than 50 participants per treatment arm). Seventy-nine of 91 studies (87%) had fewer than 50 participants per treatment arm. Eight (9%) studies had low risk of bias in the specified key domains; the remaining studies had an unclear risk of bias (70 studies, 77%) or a high risk of bias (13 studies, 14%). Using GRADE criteria, we judged that the certainty of evidence for the primary outcome (i.e. pruritus) was high for kappa-opioid agonists compared to placebo and moderate for GABA-analogues compared to placebo. Certainty of evidence was low for naltrexone, fish-oil/omega-3 fatty acids, topical capsaicin, ondansetron and zinc sulphate compared to placebo and gabapentin compared to pregabalin, and very low for cromolyn sodium, paroxetine, montelukast, flumecinol, and rifampicin compared to placebo. We downgraded the certainty of the evidence mainly due to serious study limitations regarding risk of bias, imprecision, and inconsistency. For participants suffering from uraemic pruritus (UP; also known as chronic kidney disease (CKD)-associated pruritus (CKD-aP)), treatment with GABA-analogues compared to placebo likely resulted in a large reduction of pruritus (visual analogue scale (VAS) 0 to 10 cm): mean difference (MD) -5.10, 95% confidence interval (CI) -5.56 to -4.55; five RCTs, N = 297, certainty of evidence: moderate. Treatment with kappa-opioid receptor agonists (difelikefalin, nalbuphine, nalfurafine) compared to placebo reduced pruritus slightly (VAS 0 to 10 cm, MD -0.96, 95% CI -1.22 to -0.71; six RCTs, N = 1292, certainty of evidence: high); thus, this treatment was less effective than GABA-analogues. Treatment with montelukast compared to placebo may result in a reduction of pruritus, but the evidence is very uncertain (two studies, 87 participants): SMD -1.40, 95% CI -1.87 to -0.92; certainty of evidence: very low. Treatment with fish-oil/omega-3 fatty acids compared to placebo may result in a large reduction of pruritus (four studies, 160 observations): SMD -1.60, 95% CI -1.97 to -1.22; certainty of evidence: low. Treatment with cromolyn sodium compared to placebo may result in a reduction of pruritus, but the evidence is very uncertain (VAS 0 to 10 cm, MD -3.27, 95% CI -5.91 to -0.63; two RCTs, N = 100, certainty of evidence: very low). Treatment with topical capsaicin compared with placebo may result in a large reduction of pruritus (two studies; 112 participants): SMD -1.06, 95% CI -1.55 to -0.57; certainty of evidence: low. Ondansetron, zinc sulphate and several other treatments may not reduce pruritus in participants suffering from UP. In participants with cholestatic pruritus (CP), treatment with rifampicin compared to placebo may reduce pruritus, but the evidence is very uncertain (VAS: 0 to 100, MD -42.00, 95% CI -87.31 to 3.31; two RCTs, N = 42, certainty of evidence: very low). Treatment with flumecinol compared to placebo may reduce pruritus, but the evidence is very uncertain (RR > 1 favours treatment group; RR 2.32, 95% CI 0.54 to 10.1; two RCTs, N = 69, certainty of evidence: very low). Treatment with the opioid antagonist naltrexone compared to placebo may reduce pruritus (VAS: 0 to 10 cm, MD -2.42, 95% CI -3.90 to -0.94; two RCTs, N = 52, certainty of evidence: low). However, effects in participants with UP were inconclusive (percentage of difference -12.30%, 95% CI -25.82% to 1.22%, one RCT, N = 32). In palliative care participants with pruritus of a different nature, the treatment with the drug paroxetine (one study), a selective serotonin reuptake inhibitor, compared to placebo may reduce pruritus slightly by 0.78 (numerical analogue scale from 0 to 10 points; 95% CI -1.19 to -0.37; one RCT, N = 48, certainty of evidence: low). Most adverse events were mild or moderate. Two interventions showed multiple major adverse events (naltrexone and nalfurafine). AUTHORS CONCLUSIONS: Different interventions (GABA-analogues, kappa-opioid receptor agonists, cromolyn sodium, montelukast, fish-oil/omega-3 fatty acids and topical capsaicin compared to placebo) were effective for uraemic pruritus. GABA-analogues had the largest effect on pruritus. Rifampin, naltrexone and flumecinol tended to be effective for cholestatic pruritus. However, therapies for patients with malignancies are still lacking. Due to the small sample sizes in most meta-analyses and the heterogeneous methodological quality of the included trials, the results should be interpreted cautiously in terms of generalisability.