Asunto(s)
Síndrome Metabólico , Encuestas Nutricionales , Obesidad , Insuficiencia Renal Crónica , Incontinencia Urinaria , Humanos , Síndrome Metabólico/epidemiología , Síndrome Metabólico/complicaciones , Obesidad/epidemiología , Obesidad/complicaciones , Incontinencia Urinaria/epidemiología , Incontinencia Urinaria/etiología , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/complicaciones , Estados Unidos/epidemiología , Diabetes Mellitus/epidemiologíaRESUMEN
SIGNIFICANCE STATEMENT: ESKD incidence has changed substantially in the past four decades, but differences by age and race have been unexplored. Using data from the United States Renal Data System, we found that ESKD incidence rose for Black and White teenagers, adults, and older adults for two decades beginning in 1980. Growth in incidence slowed for most groups by 1993, and by 2006, the annual percent change (APC) in ESKD incidence had declined for all groups, except White adults, for whom rates continued to rise. By 2019, ESKD incidence among Black and White adolescents nearly returned to 1980 levels, but no other group achieved that degree of improvement. Nonetheless, the ESKD incidence rate among Black American patients exceeds that of White patients in every age group. Distinct patterns in ESKD incidence among patients of different age, sex, and racial groups are shown. These findings could reflect changes in dialysis acceptance rates, access to preventive health care, incidence of diabetes mellitus, implementation of evidence-based guidelines for treatment of CKD, or other unrecognized factors. There may be population-specific opportunities to change the growth of the US ESKD population and address current racial disparities. BACKGROUND: Substantial changes in ESKD incidence over four decades among Black and White Americans of different ages have been incompletely explored. METHODS: We analyzed United States Renal Data System data from 1980 to 2019 to determine ESKD incidence trends among Black and White adolescent (13-17 years), adult (18-64 years), and older adult (≥65) populations. We used the National Cancer Institute Joinpoint Regression Program to estimate annual percent change (APC) in ESKD incidence and to define points in time where a statistically significant change in APC slope occurred for each group. RESULTS: ESKD incidence rose after 1980 for all groups, although the trends differed ( P < 0.001). Growth in incidence slowed for most by 1993, and by 2006, the APC in ESKD incidence had declined for all groups, except White adults, for whom rates continued to rise ( P < 0.05). By 2019, ESKD incidence among Black and White adolescents nearly returned to 1980 levels, but no other group achieved that degree of improvement. Nonetheless, the ESKD incidence among Black American patients exceeds that of White patients in every age group. CONCLUSIONS: Distinct patterns in ESKD incidence among patients of different age, sex, and racial groups are shown. These findings could reflect changes in dialysis acceptance rates, access to preventive health care, incidence of diabetes mellitus, implementation of evidence-based guidelines for treatment of CKD, or other unrecognized factors. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_03_13_ASN0000000000000310.mp3.
Asunto(s)
Diabetes Mellitus , Insuficiencia Renal Crónica , Adolescente , Anciano , Humanos , Negro o Afroamericano , Incidencia , Grupos Raciales , Estados Unidos/epidemiología , Blanco , Adulto Joven , Adulto , Persona de Mediana EdadRESUMEN
OBJECTIVE: To describe sex- and diagnosis-specific comorbidities, outcomes, and secular trends associated with ureteropelvic junction obstruction (UPJO) in a large, real-world population diagnosed with hydronephrosis in infancy. MATERIALS AND METHODS: We identified all infants ≤1 year old with ≥1 claim in the Optum Clinformatics 2007-2020 nationwide population database and used univariable and multivariable Cox regression analyses to estimate associations of demographic and clinical characteristics of infants with a UPJO diagnosis with surgical status. RESULTS: Of 22,349 infants with hydronephrosis (1.1% of infants; males-1.4%, females-0.7%), 1722 (7.7%; 7.9%-males, 7.2%-females) had UPJO. Follow-up was ≥1 year in 1198 (70%) and ≥3 years in 555 (32%) cases, and UPJO repair was performed in 542 children (31.5%; 32.3%-males, 29.5%-females); 77.7% within 1 year and 97.3% within 3 years. UPJO repair was associated with prior urinary tract infection (UTI) (hazard ratio (HR) 1.41, 95% confidence interval (CI) 1.12-1.76) and South (HR 1.42, 95% CI 1.14-1.78) or Midwest (HR 1.60, 95% CI 1.26-2.04) geographic region but did not change over time. CONCLUSION: This population-based study provides a real-world view of postnatally diagnosed hydronephrosis, focusing on UPJO, for which 522 cases (â¼1/3) had ≥3 years continuous coverage. UPJO-associated comorbidities were more common in females, and the frequencies of UPJO-associated surgery and comorbidities were higher than in other studies. Other than UTI, no other associated kidney or urinary tract diagnoses were associated with UPJO repair. We identified unique sex- and diagnosis-specific differences in associated comorbidities and interventions in children diagnosed with UPJO in the first year of life.
Asunto(s)
Hidronefrosis , Obstrucción Ureteral , Infecciones Urinarias , Niño , Lactante , Masculino , Femenino , Humanos , Pelvis Renal/cirugía , Estudios Retrospectivos , Obstrucción Ureteral/diagnóstico , Hidronefrosis/diagnóstico , Riñón , Infecciones Urinarias/epidemiología , Infecciones Urinarias/complicacionesRESUMEN
PURPOSE: Diabetes and obesity, components of the metabolic syndrome (MetS), are risk factors for urinary incontinence (UI) and chronic kidney disease (CKD). We interrogated US population-based data to explore independent, sex-specific associations between nondiabetic MetS, with and without obesity, and UI and/or CKD. MATERIALS AND METHODS: We analyzed data from 8586 males and 8420 females ≥20 years from the National Health and Nutrition Examination Survey. Multivariable logistic regression models were used to examine associations of UI or CKD with diabetes and 4 nondiabetic obesity/metabolic phenotypes: non-MetS/nonobese, MetS/nonobese, non-MetS/obese, and MetS/obese. Multinominal logistic regression models were used to assess associations of co-occurring UI/CKD with obesity/metabolic phenotypes. RESULTS: Male MetS/obese participants had increased odds of any UI (1.25; 95% CI 1.00-1.57) and urgency UI (1.36; 1.03-1.80), compared with non-MetS/nonobese participants. Female MetS/obese participants had increased odds of any UI (2.16; 95% CI 1.76-2.66), stress UI (1.51; 1.21-1.87), and mixed UI (1.66; 1.31-2.11) compared with non-MetS/nonobese participants. The odds of co-occurring UI/CKD were increased relative to either condition alone in persons with diabetes, and in males with MetS/obese phenotypes and females with MetS phenotypes as compared to same sex participants with neither obesity nor MetS. CONCLUSIONS: We found novel associations between MetS/obese and urgency UI in males without diabetes, and between SUI and both MetS and obesity in females without diabetes. Odds estimates for UI/CKD were increased by existing obesity or MetS as compared to those for UI or CKD alone. Improved understanding of modifiable factors associated with UI will inform prevention and treatment opportunities.
Asunto(s)
Diabetes Mellitus , Síndrome Metabólico , Insuficiencia Renal Crónica , Incontinencia Urinaria de Esfuerzo , Incontinencia Urinaria , Masculino , Humanos , Femenino , Síndrome Metabólico/complicaciones , Síndrome Metabólico/epidemiología , Encuestas Nutricionales , Obesidad/complicaciones , Obesidad/epidemiología , Diabetes Mellitus/epidemiología , Incontinencia Urinaria/etiología , Incontinencia Urinaria/complicaciones , Factores de Riesgo , Incontinencia Urinaria de Esfuerzo/complicaciones , Insuficiencia Renal Crónica/diagnósticoRESUMEN
INTRODUCTION: Nephrotoxin exposure is significantly associated with acute kidney injury (AKI) development. A standardized list of nephrotoxic medications to surveil and their perceived nephrotoxic potential (NxP) does not exist for non-critically ill patients. OBJECTIVE: This study generated consensus on the nephrotoxic effect of 195 medications used in the non-intensive care setting. METHODS: Potentially nephrotoxic medications were identified through a comprehensive literature search, and 29 participants with nephrology or pharmacist expertise were identified. The primary outcome was NxP by consensus. Participants rated each drug on a scale of 0-3 (not nephrotoxic to definite nephrotoxicity). Group consensus was met if ≥ 75% of responses were one single rating or a combination of two consecutive ratings. If ≥ 50% of responses indicated "unknown" or not used in the non-intensive care setting, the medication was removed for consideration. Medications not meeting consensus for a given round were included in the subsequent round(s). RESULTS: A total of 191 medications were identified in the literature, with 4 medications added after the first round from participants' recommendations. NxP index rating consensus after three rounds was: 14 (7.2%) no NxP in almost all situations (rating 0); 62 (31.8%) unlikely/possibly nephrotoxic (rating 0.5); 21 (10.8%) possibly nephrotoxic (rating 1); 49 (25.1%) possibly/probably nephrotoxic (rating 1.5); 2 (1.0%) probably nephrotoxic (rating 2); 8 (4.1%) probably/definite nephrotoxic (rating 2.5); 0 (0.0%) definitely nephrotoxic (rating 3); and 39 (20.0%) medications were removed from consideration. CONCLUSIONS: NxP index rating provides clinical consensus on perceived nephrotoxic medications in the non-intensive care setting and homogeneity for future clinical evaluations and research.
Asunto(s)
Lesión Renal Aguda , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Consenso , Técnica Delphi , Lesión Renal Aguda/inducido químicamente , FarmacéuticosRESUMEN
RATIONALE & OBJECTIVE: Acute kidney injury (AKI) carries high rates of morbidity and mortality. This study quantified various short- and long-term outcomes after hospitalization with AKI. STUDY DESIGN: Retrospective propensity score (PS)-matched cohort study. SETTING & PARTICIPANTS: Optum Clinformatics, a national claims database, was used to identify patients hospitalized with and without an AKI discharge diagnosis between January 2007 and September 2020. EXPOSURE: Among patients with prior continuous enrollment for at least 2years without AKI hospitalization, 471,176 patients hospitalized with AKI were identified and PS-matched to 471,176 patients hospitalized without AKI. OUTCOME(S): All-cause and selected-cause rehospitalizations and mortality 90 and 365 days after index hospitalization. ANALYTICAL APPROACH: After PS matching, rehospitalization and death incidences were estimated using the cumulative incidence function method and compared using Gray's test. The association of AKI hospitalization with each outcome was tested using Cox models for all-cause mortality and, with mortality as competing risk, cause-specific hazard modeling for all-cause and selected-cause rehospitalization. Overall and stratified analyses were performed to evaluate for interaction between an AKI hospitalization and preexisting chronic kidney disease (CKD). RESULTS: After PS matching, AKI was associated with higher rates of rehospitalization for any cause (hazard ratio [HR], 1.62; 95% CI, 1.60-1.65), end-stage renal disease (HR, 6.21; 95% CI, 1.04-36.92), heart failure (HR, 2.81; 95% CI, 2.66, 2.97), sepsis (HR, 2.62; 95% CI, 2.49-2.75), pneumonia (HR, 1.47; 95% CI, 1.37-1.57), myocardial infarction (HR, 1.48; 95% CI, 1.33-1.65), and volume depletion (HR, 1.64; 95% CI, 1.37-1.96) at 90 days after discharge compared with the group without AKI, with similar findings at 365 days. Mortality rate was higher in the group with AKI than in the group without AKI at 90 (HR, 2.66; 95% CI, 2.61-2.72) and 365 days (HR, 2.11; 95% CI, 2.08-2.14). The higher risk of outcomes persisted when participants were stratified by CKD status (P<0.01). LIMITATIONS: Causal associations between AKI and the reported outcomes cannot be inferred. CONCLUSIONS: AKI during hospitalization in patients with and without CKD is associated with increased risk of 90- and 365-day all-cause/selected-cause rehospitalization and death.
Asunto(s)
Lesión Renal Aguda , Insuficiencia Renal Crónica , Humanos , Readmisión del Paciente , Estudios de Cohortes , Estudios Retrospectivos , Hospitalización , Insuficiencia Renal Crónica/epidemiología , Lesión Renal Aguda/diagnóstico , Factores de RiesgoRESUMEN
Acute kidney injury (AKI) is a growing epidemic and is independently associated with increased risk of death, chronic kidney disease (CKD) and cardiovascular events. Randomized-controlled trials (RCTs) in this domain are notoriously challenging and many clinical studies in AKI have yielded inconclusive findings. Underlying this conundrum is the inherent heterogeneity of AKI in its etiology, presentation and course. AKI is best understood as a syndrome and identification of AKI subphenotypes is needed to elucidate the disease's myriad etiologies and to tailor effective prevention and treatment strategies. Conventional RCTs are logistically cumbersome and often feature highly selected patient populations that limit external generalizability and thus alternative trial designs should be considered when appropriate. In this narrative review of recent developments in AKI trials based on the Kidney Disease Clinical Trialists (KDCT) 2020 meeting, we discuss barriers to and strategies for improved design and implementation of clinical trials for AKI patients, including predictive and prognostic enrichment techniques, the use of pragmatic trials and adaptive trials.
Asunto(s)
Lesión Renal Aguda , Humanos , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/etiología , Lesión Renal Aguda/terapia , PronósticoRESUMEN
AKI is a complex clinical syndrome associated with an increased risk of morbidity and mortality, particularly in critically ill and perioperative patient populations. Most AKI clinical trials have been inconclusive, failing to detect clinically important treatment effects at predetermined statistical thresholds. Heterogeneity in the pathobiology, etiology, presentation, and clinical course of AKI remains a key challenge in successfully testing new approaches for AKI prevention and treatment. This article, derived from the "AKI" session of the "Kidney Disease Clinical Trialists" virtual workshop held in October 2021, reviews barriers to and strategies for improving the design and implementation of clinical trials in patients with, or at risk of, developing AKI. The novel approaches to trial design included in this review span adaptive trial designs that increase the knowledge gained from each trial participant; pragmatic trial designs that allow for the efficient enrollment of sufficiently large numbers of patients to detect small, but clinically significant, treatment effects; and platform trial designs that use one trial infrastructure to answer multiple clinical questions simultaneously. This review also covers novel approaches to clinical trial analysis, such as Bayesian analysis and assessing heterogeneity in the response to therapies among trial participants. We also propose a road map and actionable recommendations to facilitate the adoption of the reviewed approaches. We hope that the resulting road map will help guide future clinical trial planning, maximize learning from AKI trials, and reduce the risk of missing important signals of benefit (or harm) from trial interventions.
Asunto(s)
Enfermedad Crítica , Teorema de Bayes , Causalidad , HumanosRESUMEN
OBJECTIVE: Indices of cardiovascular disease (CVD) risk, vascular endothelial dilation, arterial stiffness and endothelial repair were examined in persons with HIV (PWH) on an antiretroviral therapy (ART) that included abacavir (ABC+) in comparison with PWH on ART without abacavir (ABC-), and with HIV seronegative (HIV-) individuals. APPROACH: The 115 participants (63% men), aged 30-50 years, did not have CVD, metabolic, endocrine, or chronic renal conditions. PWH were on stable ART for six-months or more. Vascular assessments included flow-mediated dilation (FMD), aortic, radial and femoral arterial stiffness (cAIx, crPWV, cfPWV), and thigh and calf arterial compliance (Vmax50). Endothelial repair was indexed by endothelial progenitor cell colony forming units (EPC-CFU). Traditional CVD risk measures included blood pressure, central adiposity, lipids, insulin resistance (HOMA-IR), CRP and ASCVD score. Analyses controlled for demographics (age, sex, education), medications (antihypertensive, statin/fibrate, antipsychotic), and substance abuse (ASSIST). RESULTS: No group differences were observed in central adiposity, HOMA-IR, CRP, or ASCVD risk score. However, the ABC- group displayed greater dyslipidemia. The ABC+ group displayed no difference on FMD, cAIx, cfPWV or calf Vmax50 compared with other groups. When CD4 count and viral load were controlled, no additional differences between the ABC+ and ABC- groups emerged. Analyses of crPWV and thigh Vmax50 suggested supported by a trend toward lower EPC-CFU in the HIV+ groups than the HIV- group. CONCLUSIONS: Findings indicate that ABC treatment of 30-50 year-old PWH on stable ART is not likely to contribute in a robust way to higher CVD risk.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Enfermedades Vasculares , Adulto , Fármacos Anti-VIH/efectos adversos , Recuento de Linfocito CD4 , Didesoxinucleósidos/uso terapéutico , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Vasculares/tratamiento farmacológicoRESUMEN
BACKGROUND: The role of kidney transplantation in differential survival in Black and White patients with childhood-onset kidney failure is unexplored. METHODS: We analyzed 30-year cohort data of children beginning RRT before 18 years of age between January 1980 and December 2017 (n=28,337) in the US Renal Data System. Cox regression identified transplant factors associated with survival by race. The survival mediational g-formula estimated the excess mortality among Black patients that could be eliminated if an intervention equalized their time with a transplant to that of White patients. RESULTS: Black children comprised 24% of the cohort and their crude 30-year survival was 39% compared with 57% for White children (log rank P<0.001). Black children had 45% higher risk of death (adjusted hazard ratio [aHR], 1.45; 95% confidence interval [95% CI], 1.36 to 1.54), 31% lower incidence of first transplant (aHR, 0.69; 95% CI, 0.67 to 0.72), and 39% lower incidence of second transplant (aHR, 0.61; 95% CI, 0.57 to 0.65). Children and young adults are likely to require multiple transplants, yet even after their first transplant, Black patients had 11% fewer total transplants (adjusted incidence rate ratio [aIRR], 0.89; 95% CI, 0.86 to 0.92). In Black patients, grafts failed earlier after first and second transplants. Overall, Black patients spent 24% less of their RRT time with a transplant than did White patients (aIRR, 0.76; 95% CI, 0.74 to 0.78). Transplantation compared with dialysis strongly protected against death (aHR, 0.28; 95% CI, 0.16 to 0.48) by time-varying analysis. Mediation analyses estimated that equalizing transplant duration could prevent 35% (P<0.001) of excess deaths in Black patients. CONCLUSIONS: Equalizing time with a functioning transplant for Black patients may equalize survival of childhood-onset ESKD with White patients.
Asunto(s)
Fallo Renal Crónico , Trasplante de Riñón , Insuficiencia Renal , Población Negra , Niño , Humanos , Fallo Renal Crónico/terapia , Diálisis Renal , Estudios Retrospectivos , Adulto JovenRESUMEN
The U.S. Food and Drug Administration (FDA) provides guidance for expanded access to experimental therapies, which in turn plays an important role in the Twenty-first Century Cures Act mandate to advance cell-based therapy. In cases of incurable diseases where there is a lack of alternative treatment options, many patients seek access to cell-based therapies for the possibility of treatment responses demonstrated in clinical trials. Here, we describe the use of the FDA's expanded access to investigational new drug (IND) to address rare and emergency conditions that include stiff-person syndrome, spinal cord injury, traumatic brain stem injury, complex congenital heart disease, ischemic stroke, and peripheral nerve injury. We have administered both allogeneic bone marrow-derived mesenchymal stem cell (MSC) and autologous Schwann cell (SC) therapy to patients upon emergency request using Single Patient Expanded Access (SPEA) INDs approved by the FDA. In this report, we present our experience with 10 completed SPEA protocols.
RESUMEN
AIMS: CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. METHODS AND RESULTS: Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. CONCLUSIONS: This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.
Asunto(s)
Insuficiencia Cardíaca , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Humanos , Minnesota , Calidad de Vida , Volumen Sistólico , Resultado del Tratamiento , Función Ventricular IzquierdaAsunto(s)
Informes Anuales como Asunto , Centers for Medicare and Medicaid Services, U.S./estadística & datos numéricos , Sistemas de Datos , Fallo Renal Crónico/epidemiología , National Institute of Diabetes and Digestive and Kidney Diseases (U.S.)/estadística & datos numéricos , Humanos , Fallo Renal Crónico/diagnóstico , Estados Unidos/epidemiologíaRESUMEN
Inclusion of women and minorities in clinical research is critical to fully assess the safety and efficacy of innovative therapies. With inadequate representation of demography, generalizability is impaired since pharmacokinetics and pharmacodynamics differ in these patient populations. This study was designed to analyze the voluntary participation rates of different demographic groups in cell-based therapy clinical trials conducted by the Interdisciplinary Stem Cell Institute (ISCI) at the University of Miami, Miller School of Medicine. ISCI conducted eight clinical trials between 2007 and 2017. The trials enrolled patients with ischemic and non-ischemic cardiomyopathy, idiopathic pulmonary fibrosis (IPF), aging-frailty, and Type-2 Diabetes. Participants received cell-based therapy (n = 218) or placebo (n = 33). Among the 251 participants, 29.5% were Hispanic and 20% were women. The proportion of individuals participating in each trial was compared to that of the respective disease populations attending University of Miami Health System clinics to calculate the participation to prevalence ratio (PPR). Distribution of women accurately reflected the population attending the University of Miami Health System in trials for dilated cardiomyopathy (DCM) and aging-frailty but was under-represented in others. Similarly, Hispanics and whites were accurately represented in three of the five disease fields, with Hispanics under-represented in frailty and diabetes, and whites over-represented in DCM and IPF. Black patients were accurately represented in the diabetes trial but were under-represented in all others. This study provides insight into challenges of achieving representative inclusion in research. Novel community engagement strategies are necessary to improve inclusion of women and under-represented minorities in clinical research of cell-based therapy.
RESUMEN
Therapies for heart failure with preserved ejection fraction (HFpEF) are lacking. Growth hormone-releasing hormone agonists (GHRH-As) have salutary effects in ischemic and nonischemic heart failure animal models. Accordingly, we hypothesized that GHRH-A treatment ameliorates chronic kidney disease (CKD)-induced HFpEF in a large-animal model. Female Yorkshire pigs (n = 16) underwent 5/6 nephrectomy via renal artery embolization and 12 wk later were randomized to receive daily subcutaneous injections of GHRH-A (MR-409; n = 8; 30 µg/kg) or placebo (n = 8) for 4 to 6 wk. Renal and cardiac structure and function were serially assessed postembolization. Animals with 5/6 nephrectomy exhibited CKD (elevated blood urea nitrogen [BUN] and creatinine) and faithfully recapitulated the hemodynamic features of HFpEF. HFpEF was demonstrated at 12 wk by maintenance of ejection fraction associated with increased left ventricular mass, relative wall thickness, end-diastolic pressure (EDP), end-diastolic pressure/end-diastolic volume (EDP/EDV) ratio, and tau, the time constant of isovolumic diastolic relaxation. After 4 to 6 wk of treatment, the GHRH-A group exhibited normalization of EDP (P = 0.03), reduced EDP/EDV ratio (P = 0.018), and a reduction in myocardial pro-brain natriuretic peptide protein abundance. GHRH-A increased cardiomyocyte [Ca2+] transient amplitude (P = 0.009). Improvement of the diastolic function was also evidenced by increased abundance of titin isoforms and their ratio (P = 0.0022). GHRH-A exerted a beneficial effect on diastolic function in a CKD large-animal model as demonstrated by improving hemodynamic, structural, and molecular characteristics of HFpEF. These findings have important therapeutic implications for the HFpEF syndrome.
Asunto(s)
Cardiotónicos/farmacología , Hormona Liberadora de Hormona del Crecimiento/agonistas , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Renal Crónica/tratamiento farmacológico , Sermorelina/análogos & derivados , Volumen Sistólico/fisiología , Animales , Nitrógeno de la Urea Sanguínea , Calcio/metabolismo , Conectina/genética , Conectina/metabolismo , Creatinina/sangre , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Hormona Liberadora de Hormona del Crecimiento/genética , Hormona Liberadora de Hormona del Crecimiento/metabolismo , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Péptido Natriurético Encefálico/sangre , Péptido Natriurético Encefálico/genética , Nefrectomía/métodos , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología , Sermorelina/farmacología , PorcinosRESUMEN
INTRODUCTION: Accumulating evidence supports the use of mesenchymal stem/stromal cells (MSCs), particularly bone marrow derived, as a safe and promising biologic therapy for promoting tissue repair and regeneration in various chronic diseases and disorders. Despite growing evidence that MSCs are potent anti-inflammatory mediators that can provide substantial benefits in acute organ injury, there are limited clinical trials utilizing MSCs in acute care settings, such as in the emergency department (ED) or intensive care unit (ICU). OBJECTIVE: This article reviews the current state of MSC-based therapeutics and further explores the untapped potential role to treat various acute, life-threating injuries in the ED and ICU. DISCUSSION: All clinical trials using MSCs in acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), sepsis and acute kidney injury (AKI) demonstrated safety. While some also demonstrate clinical efficacy, efficacy data is inconsistent, with some studies limited by sample size, cell integrity and different dosages, necessitating further studies. CONCLUSION: MSCs are potentially promising novel biologic therapeutics for clinical application in AMI, ARDS, sepsis, AKI and COVID-19 that have demonstrated safety in all clinical trials. More rigorous clinical trials are necessary and warranted to determine the efficacy of MSCs as a novel therapeutic in an acute setting, such as the ED.
Asunto(s)
COVID-19/epidemiología , Insuficiencia Cardíaca/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/citología , Comorbilidad , Insuficiencia Cardíaca/epidemiología , Humanos , Unidades de Cuidados Intensivos/estadística & datos numéricos , Pandemias , SARS-CoV-2RESUMEN
AIMS: Sex differences impact the occurrence, presentation, prognosis, and response to therapy in heart disease. Particularly, the phenotypic presentation of patients with non-ischaemic dilated cardiomyopathy (NIDCM) differs between men and women. However, whether the response to mesenchymal stem cell (MSC) therapy is influenced by sex remains unknown. We hypothesize that males and females with NIDCM respond similarly to MSC therapy. METHODS AND RESULTS: Male (n = 24) and female (n = 10) patients from the POSEIDON-DCM trial who received MSCs via transendocardial injections were evaluated over 12 months. Endothelial function was measured at baseline and 3 months post-transendocardial stem cell injection (TESI). At baseline, ejection fraction (EF) was lower (P = 0.004) and end-diastolic volume (EDV; P = 0.0002) and end-systolic volume (ESV; P = 0.0002) were higher in males vs. females. In contrast, baseline demographic characteristics, Minnesota Living with Heart Failure Questionnaire (MLHFQ), and 6-min walk test (6MWT) were similar between groups. EF improved in males by 6.2 units (P = 0.04) and in females by 8.6 units (P = 0.04; males vs. females, P = 0.57). EDV and ESV were unchanged over time. The MLHFQ score, New York Heart Association (NYHA) class, endothelial progenitor cell-colony forming units, and serum tumour necrosis factor alpha improved similarly in both groups. CONCLUSION: Despite major differences in phenotypic presentation of NIDCM in males and females, this study is the first of its kind to demonstrate that MSC therapy improves a variety of parameters in NIDCM irrespective of patient sex. These findings have important clinical and pathophysiologic implications regarding the impact of sex on responses to cell-based therapy for NIDCM.
Asunto(s)
Cardiomiopatía Dilatada/cirugía , Trasplante de Células Madre Mesenquimatosas , Adulto , Anciano , Biomarcadores/sangre , Cardiomiopatía Dilatada/sangre , Cardiomiopatía Dilatada/patología , Cardiomiopatía Dilatada/fisiopatología , Células Progenitoras Endoteliales/metabolismo , Células Progenitoras Endoteliales/patología , Tolerancia al Ejercicio , Femenino , Florida , Estado Funcional , Disparidades en el Estado de Salud , Humanos , Masculino , Trasplante de Células Madre Mesenquimatosas/efectos adversos , Persona de Mediana Edad , Calidad de Vida , Recuperación de la Función , Factores Sexuales , Volumen Sistólico , Factores de Tiempo , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/sangre , Función Ventricular Izquierda , Remodelación VentricularRESUMEN
BACKGROUND: Non-ischemic dilated cardiomyopathy (NIDCM) responds variably to intramyocardial injection of mesenchymal stem cells (MSCs). We hypothesized that NIDCM genotype may influence responsiveness to MSC therapy and performed genotyping on all patients in the POSEIDON-DCM trial. METHODS: POSEIDON-DCM patients (nâ¯=â¯34) underwent genetic sequence analysis and deletion/duplication testing. The results were classified as positive for pathological variants (PV+; nâ¯=â¯8), negative for any variants (V-; nâ¯=â¯6), or as variants of uncertain significance (VUS; nâ¯=â¯20). All outcomes of therapy were analysed for each category of genetic results. FINDINGS: The 3 groups were indistinguishable at baseline with regard to ejection fraction (EF), demographics, medication use, or functional parameters. V- patients had an increase in EF at 12 months: +13.6% (IQR = +7.8%; +20.5%; pâ¯=â¯0.002), compared with VUS (+6.5%; IQR = +0.9%, +11.1%; pâ¯=â¯0.005) and PV+(-5.9%; IQR = -12.7%, +1.0; pâ¯=â¯0.2; pâ¯=â¯0.01 between groups). Six-minute walk distance improved in V- patients, but not in VUS and PV+. V- patients improved MLHFQ, compared to the other 2 groups, which did not improve over time. EPCCFUs increased by 9.7⯱â¯1.9 in V- (pâ¯=â¯0.009) compared to VUS and PV+ patients. V- patients had one-year survival (100%) compared with VUS (85%) and PV+ (40%; pâ¯=â¯0.015 log-rank). Similarly, MACE rates were lower in V- (0%) than PV+ (61.9%) or VUS (42.2%; pâ¯=â¯0.021 log-rank). INTERPRETATION: Our findings support the concept that the genetic profile of NIDCM patients plays a role in responsiveness to MSC therapy, with V- patients more likely to benefit and the converse for PV+. This observation emphasizes the need for further genetic studies, because of important implications for the management of NIDCM syndromes.
Asunto(s)
Cardiomiopatía Dilatada/etiología , Cardiomiopatía Dilatada/terapia , Predisposición Genética a la Enfermedad , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/mortalidad , Femenino , Perfil Genético , Variación Genética , Humanos , Masculino , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/citología , Persona de Mediana Edad , Pronóstico , Sitios de Carácter Cuantitativo , Resultado del TratamientoRESUMEN
INTRODUCTION: The electrophysiologic impact of cell-based therapy on the injured myocardium remains highly controversial. We aimed to perform a meta-analysis of studies comparing arrhythmia burden following transendocardial stem cell therapy vs placebo in patients with chronic ischemic heart disease (CIHD). METHODS AND RESULTS: PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched. No restriction of stem cell type was specified. The outcomes included sustained supraventricular or ventricular arrhythmias (VAs), sudden cardiac death (SCD), and resuscitated sudden cardiac arrest (SCA). Effect sizes were reported as odds ratio (OR) and 95% CI. Poisson regression was used to account for zero-events data. Twelve randomized trials that included 736 patients (384 in the cell therapy group and 352 in the placebo group) were analyzed. Six different cell types were used. Follow-up ranged from 6 to 12 months. There was a significant decrease in risk of SCD in the cell therapy group, (FE OR, 0.19 [0.04, 0.93]; P = .04). In subgroup analysis, there was a significantly lower risk of SCD or resuscitated SCA in the cell therapy group limited to studies that did not use skeletal myoblasts, (FE OR, 0.23 [0.06, 0.83]; P = .03). There was no significant difference in the incidence of sustained VA between groups (FE OR, 0.91 [0.47, 1.77]; P = .8), even after stratifying by cell type. There was no difference in supraventricular arrhythmias between groups. CONCLUSION: Nonskeletal myoblast transendocardial cell therapy was associated with a significantly lower risk of SCD or resuscitated SCA compared to control, with no proarrhythmic effects.