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OBJECTIVE: This study aims to appraise recommendations from an expert panel of surgical educators on optimizing surgical education and training in the setting of contemporary challenges. BACKGROUND: The Blue Ribbon Committee (BRC II), a group of surgical educators, was convened to make recommendations to optimize surgical training considering the current changes in the landscape of surgical education. Surgical trainees were recruited to assess their impressions of the recommendations. METHODS: A mixed-methods study design was employed, with a survey, followed by focus group interviews. Participating residents and fellows were recruited through a purposeful sampling approach. Descriptive statistics were applied to analyze the survey data, and a thematic data analysis on interview transcripts was employed. RESULTS: The majority of trainee respondents (n=16) thought that all of the subcommittee recommendations should be included in the final BRC II recommendations and paper. According to the interviews, overall, the feedback from the trainees was positive, with particular excitement around work-life integration, education support and faculty development, and funding pitfalls. Some themes about concerns included a lack of clarity about the recommendations, concern about some recommendations being in conflict with one another, and a disconnect between the initial BRC II survey and the subsequent recommendations. CONCLUSIONS: The residents gathered for this focus group were encouraged by the thought, effort, and intention that gathered the surgical leaders across the country to make the recommendations. While there were areas the trainees wanted clarity on, the overall opinion was in agreement with the recommendations.
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BACKGROUND: Recently the Society for Vascular Surgery (SVS) and Society for Thoracic Surgeons (STS) published contemporary guidelines clearly defining complicated versus uncomplicated acute type B aortic dissections (TBADs) with an additional high-risk grouping. Few studies have evaluated outcomes associated with "high-risk" TBADs. The objective of this study was to assess differences in demographics, clinical presentation, symptom onset, and outcomes in high-risk patients that underwent either thoracic endovascular aortic repair (TEVAR) or best medical management for acute TBAD compared to those with complicated and uncomplicated acute TBAD. METHODS: Patients admitted with acute TBADs from a single academic medical center from October 2011 to March 2020 were analyzed. Per the STS/SVS 2020 guidelines, high risk was defined as refractory pain/hypertension, bloody pleural effusion, aortic diameter >4 cm, false lumen diameter >22 mm, radiographic malperfusion, and early readmission, and complicated was defined as ruptured/malperfusion presentation. Uncomplicated patients were those without malperfusion/rupture and without high-risk features. The primary end-point was inpatient mortality. Secondary end-points included complications, reintervention, and survival. RESULTS: Of the 159 patients identified with acute TBAD, 63 (40%) met the high-risk criteria. In the high-risk cohort, 38 (60%) underwent TEVAR (HR-TEVAR), with refractory pain as the most common indication, while 25 (40%) were managed medically (HR-medical). Malperfusion or rupture was present in 63 (40%) patients (complicated TBAD (C-TBAD)), all of whom underwent TEVAR. An additional 33 patients had no high-risk features and were all managed medically (uncomplicated TBAD). There were no differences in age, body mass index, and race between groups. Among the 4 groups, there were variable distributions in sex, insurance status, and incidence of several baseline comorbidities including congestive heart failure, chronic obstructive pulmonary disease, and renal dysfunction (P < 0.05 for all). C-TBAD had increased length of stay (12, interquartile range [IQR] 9-22) compared to HR-TEVAR (11.5, IQR 7-15), HR-medical (6, IQR 5-8), and uncomplicated TBAD (7, IQR 5-10) (P < 0.01). C-TBAD had decreased days from admission to repair (0, IQR 0-2) compared to HR-TEVAR (3.5, IQR 1-8) (P < 0.01). C-TBAD patients had worse 3-year survival compared to other groups (log-rank P < 0.01), although when in-hospital mortality was excluded, survival was similar among groups (P = 0.37). Of patients initially managed medically, outpatient TEVAR was performed in 6 (24%) HR-medical and 4 (12%) uncomplicated patients, with no difference between rate of intervention between groups (P = 0.22). CONCLUSIONS: High-risk features, as defined in updated SVS/STS guidelines, are common in patients presenting with acute TBAD. High-risk patients had acceptable outcomes when managed either surgically or medically. High-risk patients that underwent TEVAR had improved perioperative outcomes and mortality compared to those undergoing TEVAR for C-TBAD, a finding which may help guide preoperative risk stratification and patient counseling.
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Aneurisma de la Aorta Torácica , Disección Aórtica , Implantación de Prótesis Vascular , Procedimientos Endovasculares , Mortalidad Hospitalaria , Humanos , Disección Aórtica/cirugía , Disección Aórtica/mortalidad , Disección Aórtica/diagnóstico por imagen , Masculino , Femenino , Factores de Riesgo , Procedimientos Endovasculares/mortalidad , Procedimientos Endovasculares/efectos adversos , Resultado del Tratamiento , Anciano , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo , Factores de Tiempo , Implantación de Prótesis Vascular/mortalidad , Implantación de Prótesis Vascular/efectos adversos , Enfermedad Aguda , Aneurisma de la Aorta Torácica/cirugía , Aneurisma de la Aorta Torácica/mortalidad , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/etiología , Bases de Datos FactualesRESUMEN
Hand dysfunction is a common observation after arteriovenous fistula (AVF) creation for hemodialysis access and has a variable clinical phenotype; however, the underlying mechanism responsible is unclear. Grip strength changes are a common metric used to assess AVF-associated hand disability but has previously been found to poorly correlate with the hemodynamic perturbations post-AVF placement implicating other tissue-level factors as drivers of hand outcomes. In this study, we sought to test if expression of a mitochondrial targeted catalase (mCAT) in skeletal muscle could reduce AVF-related limb dysfunction in mice with chronic kidney disease (CKD). Male and female C57BL/6J mice were fed an adenine-supplemented diet to induce CKD prior to placement of an AVF in the iliac vascular bundle. Adeno-associated virus was used to drive expression of either a green fluorescent protein (control) or mCAT using the muscle-specific human skeletal actin (HSA) gene promoter prior to AVF creation. As expected, the muscle-specific AAV-HSA-mCAT treatment did not impact blood urea nitrogen levels (P = 0.72), body weight (P = 0.84), or central hemodynamics including infrarenal aorta and inferior vena cava diameters (P > 0.18) or velocities (P > 0.38). Hindlimb perfusion recovery and muscle capillary densities were also unaffected by AAV-HSA-mCAT treatment. In contrast to muscle mass and myofiber size which were not different between groups, both absolute and specific muscle contractile forces measured via a nerve-mediated in-situ preparation were significantly greater in AAV-HSA-mCAT treated mice (P = 0.0012 and P = 0.0002). Morphological analysis of the post-synaptic neuromuscular junction uncovered greater acetylcholine receptor cluster areas (P = 0.0094) and lower fragmentation (P = 0.0010) in AAV-HSA-mCAT treated mice. Muscle mitochondrial oxidative phosphorylation was not different between groups, but AAV-HSA-mCAT treated mice had lower succinate-fueled mitochondrial hydrogen peroxide emission compared to AAV-HSA-GFP mice (P < 0.001). In summary, muscle-specific scavenging of mitochondrial hydrogen peroxide significantly improves neuromotor function in mice with CKD following AVF creation.
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Fístula Arteriovenosa , Derivación Arteriovenosa Quirúrgica , Fallo Renal Crónico , Insuficiencia Renal Crónica , Humanos , Masculino , Femenino , Animales , Ratones , Catalasa , Peróxido de Hidrógeno , Ratones Endogámicos C57BL , Insuficiencia Renal Crónica/terapia , Diálisis Renal , Fuerza Muscular , Fallo Renal Crónico/terapiaRESUMEN
INTRODUCTION: Clinical practice guidelines have recommended an endovascular-first approach (ENDO) for the management of patients with chronic mesenteric ischemia (CMI), whereas an open mesenteric bypass (OMB) is proposed for subjects deemed to be poor ENDO candidates. However, the impact of a previous failed endovascular or open mesenteric reconstruction on a subsequent OMB is unknown. Accordingly, this study was designed to examine the results of a remedial OMB (R-OMB) after a failed ENDO or a primary OMB (P-OMB) for patients with recurrent CMI. METHODS: All patients who underwent an OMB from 2002 to 2022 at the University of Florida were reviewed. Outcomes after an R-OMB (ie, history of a failed ENDO or P-OMB) and P-OMB were compared. The primary end point was 30-day mortality, whereas secondary outcomes included complications, reintervention, and survival. The Kaplan-Meier methodology was used to estimate freedom from reintervention and all-cause mortality, whereas multivariable Cox proportional hazards modeling identified predictors of death. RESULTS: A total of 145 OMB procedures (R-OMB, n = 48 [33%]; P-OMB, n = 97 [67%]) were analyzed. A majority of R-OMB operations were performed for a failed stent (prior ENDO, n = 39 [81%]; prior OMB, n = 9 [19%]). R-OMB patients were generally younger (66 ± 9 years vs P-OMB, 69 ± 11 years; P = .09) and had lower incidence of smoking exposure (29% vs P-OMB, 48%; P = .07); however, there were no other differences in demographics or comorbidities. R-OMB was associated with less intraoperative transfusion (0.6 units vs P-OMB, 1.4 units; P = .01), but there were no differences in conduit choice or bypass configuration.The overall 30-day mortality and complication rates were 7% (n = 10/145) and 53% (n = 77/145), respectively, with no difference between the groups. Notably, R-OMB had decreased cardiac (6% vs P-OMB, 21%; P < .01) and bleeding complication rates (2% vs P-OMB, 15%; P = .01). The freedom from reintervention (1 and 5 years: R-OMB: 95% ± 4%, 83% ± 9% vs P-OMB: 97% ± 2%, 93% ± 5%, respectively; log-rank P = .21) and survival (1 and 5 years: R-OMB: 82% ± 6%, 68% ± 9% vs P-OMB: 84% ± 4%, 66% ± 7%; P = .91) were similar. Independent predictors of all-cause mortality included new postoperative hemodialysis requirement (hazard ratio [HR], 7.4, 95% confidence interval [CI], 3.1-17.3; P < .001), pulmonary (HR, 2.7, 95% CI, 1.4-5.3; P = .004) and cardiac (HR, 2.4, 95% CI, 1.1-5.1; P = .04) complications, and female sex (HR, 2.1, 95% CI, 1.03-4.8; P = .04). Notably, R-OMB was not a predictor of death. CONCLUSIONS: The perioperative and longer-term outcomes for a remedial OMB after a failed intraluminal stent or previous open bypass appear to be comparable to a P-OMB. These findings support the recently updated clinical practice guideline recommendations for an endovascular-first approach to treating recurrent CMI due to the significant perioperative complication risk of OMB. However, among the subset of patients deemed ineligible for endoluminal reconstruction after failed mesenteric revascularization, R-OMB results appear to be acceptable and highlight the utility of this strategy in selected patients.
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Procedimientos Endovasculares , Isquemia Mesentérica , Insuficiencia del Tratamiento , Humanos , Masculino , Femenino , Isquemia Mesentérica/cirugía , Isquemia Mesentérica/mortalidad , Anciano , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/mortalidad , Estudios Retrospectivos , Persona de Mediana Edad , Enfermedad Crónica , Factores de Riesgo , Factores de Tiempo , Medición de Riesgo , Reoperación , Oclusión Vascular Mesentérica/cirugía , Oclusión Vascular Mesentérica/mortalidad , Oclusión Vascular Mesentérica/diagnóstico por imagen , Oclusión Vascular Mesentérica/fisiopatología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/mortalidad , Recurrencia , Implantación de Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/mortalidad , Implantación de Prótesis Vascular/instrumentación , Florida , Resultado del TratamientoRESUMEN
BACKGROUND: Venous thromboembolism (VTE) incidence after thoracic and fenestrated endovascular aortic repair (TEVAR/FEVAR) is high (up to 6-7%) relative to other vascular procedures; however, the etiology for this discrepancy remains unknown. Notably, patients undergoing TEVAR/FEVAR commonly receive cerebrospinal fluid drains (CSFDs) for neuroprotection, requiring interruption of perioperative anticoagulation and prolonged immobility. We hypothesized that CSFDs are a risk factor for VTE after TEVAR/FEVAR. METHODS: Consecutive TEVAR/FEVAR patients at a single center were reviewed (2011-2020). Cerebrospinal fluid drains (CSFDs) were placed based on surgeon preference preoperatively or for spinal cord ischemia (SCI) rescue therapy postoperatively. The primary end-point was VTE occurrence, defined as any new deep venous thrombosis (DVT) or pulmonary embolism (PE) confirmed on imaging within 30 days postoperatively. Routine postoperative VTE screening was not performed. Patients with and without VTE, and subjects with and without CSFDs were compared. Logistic regression was used to explore associations between VTE incidence and CSFD exposure. RESULTS: Eight hundred ninety-seven patients underwent TEVAR/FEVAR and 43% (n = 387) received a CSFD at some point during their care (preoperative: 94% [n = 365/387]; postoperative SCI rescue therapy: 6% [n = 22/387]). CSFD patients were more likely to have previous aortic surgery (44% vs. 37%; P = 0.028) and received more postoperative blood products (780 vs. 405 mL; P = 0.005). The overall VTE incidence was 2.2% (n = 20). 70% (14) patients with VTE had DVT, 50% (10) had PE, and 20% (4) had DVT and PE. Among TEVAR/FEVAR patients with VTE, 65% (n = 13) were symptomatic. Most VTEs (90%, n = 18) were identified inhospital and the median time to diagnosis was 12.5 (interquartile range 7.5-18) days postoperatively. Patients with VTE were more likely to have nonelective surgery (95% vs. 41%; P < 0.001), had higher American Society of Anesthesiologists classification (4.1 vs. 3.7; P < 0.001), required longer intensive care unit admission (24 vs. 12 days; P < 0.001), and received more blood products (1,386 vs. 559 mL; P < 0.001). Venous thromboembolism (VTE) incidence was 1.8% in CSFD patients compared to 3.5% in non-CSFD patients (odds ratio 0.70 [95% confidence interval 0.28-1.78, P = 0.300). However, patients receiving CSFDs postoperatively for SCI rescue therapy had significantly greater VTE incidence (9.1% vs. 1.1%; P = 0.044). CONCLUSIONS: CSFD placement was not associated with an increased risk of VTE in patients undergoing TEVAR/FEVAR. Venous thromboembolism (VTE) risk was greater in patients undergoing nonelective surgery and those with complicated perioperative courses. Venous thromboembolism (VTE) risk was greater in patients receiving therapeutic CSFDs compared to prophylactic CSFDs, highlighting the importance of careful patient selection for prophylactic CSFD placement.
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Procedimientos Endovasculares , Embolia Pulmonar , Isquemia de la Médula Espinal , Tromboembolia Venosa , Humanos , Reparación Endovascular de Aneurismas , Tromboembolia Venosa/diagnóstico por imagen , Tromboembolia Venosa/epidemiología , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/métodos , Resultado del Tratamiento , Factores de Riesgo , Isquemia de la Médula Espinal/diagnóstico , Isquemia de la Médula Espinal/epidemiología , Isquemia de la Médula Espinal/etiología , Embolia Pulmonar/etiología , Estudios RetrospectivosRESUMEN
Previous studies of the murine Ly49 and human KIR gene clusters implicated competing sense and antisense promoters in the control of variegated gene expression. In the current study, an examination of transcription factor genes defines an abundance of convergent and divergent sense/antisense promoter pairs, suggesting that competing promoters may control cell fate determination. Differentiation of CD34+ hematopoietic progenitors in vitro shows that cells with GATA1 antisense transcription have enhanced GATA2 transcription and a mast cell phenotype, whereas cells with GATA2 antisense transcription have increased GATA1 transcripts and an erythroblast phenotype. Detailed analyses of the AHR and RORC genes demonstrate the ability of competing promoters to act as binary switches and the association of antisense transcription with an immature/progenitor cell phenotype. These data indicate that alternative cell fates generated by promoter competition in lineage-determining transcription factors contribute to the programming of cell differentiation.
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Factor de Transcripción GATA1 , Factores de Transcripción , Ratones , Humanos , Animales , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Diferenciación Celular/genética , Regiones Promotoras Genéticas/genética , Factor de Transcripción GATA1/metabolismo , Factor de Transcripción GATA2/genética , Factor de Transcripción GATA2/metabolismoRESUMEN
For end-stage kidney disease (ESKD) patients, hemodialysis requires durable vascular access which is often surgically created using an arteriovenous fistula (AVF). However, some ESKD patients that undergo AVF placement develop access-related hand dysfunction (ARHD) through unknown mechanisms. In this study, we sought to determine if changes in the serum metabolome could distinguish ESKD patients that develop ARHD from those that have normal hand function following AVF creation. Forty-five ESKD patients that underwent first-time AVF creation were included in this study. Blood samples were obtained pre-operatively and 6-weeks post-operatively and metabolites were extracted and analyzed using nuclear magnetic resonance spectroscopy. Patients underwent thorough examination of hand function at both timepoints using the following assessments: grip strength manometry, dexterity, sensation, motor and sensory nerve conduction testing, hemodynamics, and the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. Nineteen of the forty-five patients displayed overt weakness using grip strength manometry (P < 0.0001). Unfortunately, the serum metabolome was indistinguishable between patients with and without weakness following AVF surgery. However, a significant correlation was found between the change in tryptophan levels and the change in grip strength suggesting a possible role of tryptophan-derived uremic metabolites in post-AVF hand-associated weakness. Compared to grip strength, changes in dexterity and sensation were smaller than those observed in grip strength, however, post-operative decreases in phenylalanine, glycine, and alanine were unique to patients that developed signs of motor or sensory disability following AVF creation.
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Fístula Arteriovenosa , Derivación Arteriovenosa Quirúrgica , Fallo Renal Crónico , Humanos , Lipidómica , Triptófano , Extremidad Superior , Fallo Renal Crónico/terapia , Diálisis Renal/efectos adversos , Derivación Arteriovenosa Quirúrgica/efectos adversos , Derivación Arteriovenosa Quirúrgica/métodos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Traditionally, acute uncomplicated type B aortic dissections are managed medically, and acute complicated dissections are managed surgically. Self-pay patients with medically managed acute uncomplicated type B aortic dissections may fare worse than their insured counterparts. METHODS: In this single-center, retrospective cohort study, demographics, follow-up, and outcomes of patients with acute type B aortic dissections from 2011 to 2020 were analyzed. RESULTS: In total, 159 patients presented with acute type B aortic dissections; 102 were complicated and managed with thoracic endovascular aortic repair, and 57 were uncomplicated and managed medically. A total of 32% (n = 51) were self-pay. Self-pay patients were from areas with worse area deprivation indices (71% vs 63%, P = .024). They more often reported alcohol abuse (28% vs 7%, P < .001), cocaine/methamphetamine use (16% vs 5%, P = .028), and nonadherence to home antihypertensives (35% vs 11%, P < .001). Self-pay patients less often had a primary care physician (65% vs 7%, P < .001) or took antihypertensives before admission (31% vs 58%, P = .003). Self-pay patients frequently required financial assistance at discharge (63%), most often using charity funds (46%). Few patients (7%) qualified for our hospital's financial assistance program, and most (78%) remained uninsured at the first follow-up. Self-pay acute uncomplicated type B aortic dissections patients had the lowest rate of follow-up (31% vs 66%, P < .001) and were more likely to represent emergently (75% vs 0%, P = .033) compared to insured acute uncomplicated type B aortic dissections patients. Self-pay patients were more likely to follow up after thoracic endovascular aortic repair for acute complicated type B aortic dissections (82% vs 31%, P < .001). CONCLUSION: Self-pay patients have multiple, interconnected, complex socioeconomic factors that likely influence preadmission risk for dissection and post-discharge adherence to optimal medical management. Further research is needed to clarify treatment strategies in this high-risk group.
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Disección Aórtica , Implantación de Prótesis Vascular , Procedimientos Endovasculares , Humanos , Antihipertensivos , Estudios Retrospectivos , Cuidados Posteriores , Factores de Riesgo , Procedimientos Endovasculares/efectos adversos , Resultado del Tratamiento , Implantación de Prótesis Vascular/efectos adversos , Alta del Paciente , Disección Aórtica/terapia , Cobertura del SeguroRESUMEN
BACKGROUND: Endovascular repair of thoracoabdominal aortic aneurysms (TAAA) and juxtarenal aortic aneurysms (JAA) with fenestrated and/or branched endografts (B/FEVAR) has become common. Physician modified endografts for patients presenting with symptomatic or contained ruptures has made B/FEVAR a feasible option in nonelective settings. The purpose of this study was to describe our 10-year institutional experience with endovascular interventions for TAAA in elective and nonelective cases to evaluate differences in outcomes and the clinical risk factors associated with nonelective presentation. METHODS: A prospectively maintained database was retrospectively queried for patients undergoing B/FEVAR for TAAA and JAA at a single tertiary care academic institution between 1/2011 and 12/2020. Data collected included demographics, comorbidities, presenting symptoms, aneurysm characteristics, and clinical outcomes. Nonelective repair was defined as any patient that presented through the Emergency Department, as a hospital transfer, or as a direct admission from clinic and had aortic repair performed during the same admission. Univariate analyses were used to compare patients. The primary outcomes were 30-day and 1-year mortality. Secondary outcomes included perioperative complications and nonhome discharge. RESULTS: Between 1/201 and 12/2020, a total of 208 patients underwent B/FEVAR for TAAA (173) and JAA (35). Nonelective repair was performed in 44 (21%) patients with 39 for TAAA (23%) and 5 for JAA (14%). Nonelective patients were younger (71 ± 11 vs. 74 ± 7 years, P = 0.03), more likely to be self-pay or have Medicaid (11% vs. 2%, P = 0.02) and had a different race distribution compared to the elective cohort (P < 0.01). Thirty-day mortality was 4% (n = 6) in elective repairs and 7% (n = 3) in nonelective repairs. One-year mortality was 13% (n = 22) in elective repairs and 18% (n = 8) in nonelective repairs. There were no differences between patients receiving elective versus nonelective repair in 30-day (P = 0.40) or 1-year mortality (P = 0.47). Nonelective patients had longer median duration of stay (11 interquartile range (IQR) 6-15 vs. 5 IQR 4-8, P < 0.01), postoperative length of stay (7 IQR 5-12 vs. 4 IQR 3-7, P < 0.01), and more intensive care unit days (6 IQR 3-8 vs. 3 IQR 2-5, P < 0.01). There were no differences in other secondary outcomes between elective and nonelective patients including inpatient and access-related complications, re-interventions, and nonhome discharge (P > 0.05 for all comparisons). A composite "any complication" occurred more frequently in patients with nonelective repair (50% vs. 35%, P = 0.03). CONCLUSIONS: Endovascular repair for TAAA or JAA is a good option in patients undergoing nonelective surgical intervention, with comparable 30-day mortality, 1-year mortality, and perioperative morbidity to that of patients undergoing elective B/FEVAR.
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Aneurisma de la Aorta Abdominal , Aneurisma de la Aorta Toracoabdominal , Implantación de Prótesis Vascular , Procedimientos Endovasculares , Humanos , Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/efectos adversos , Estudios Retrospectivos , Resultado del Tratamiento , Procedimientos Endovasculares/efectos adversos , Aneurisma de la Aorta Abdominal/diagnóstico por imagen , Aneurisma de la Aorta Abdominal/cirugía , Aneurisma de la Aorta Abdominal/complicaciones , Factores de Riesgo , Complicaciones PosoperatoriasRESUMEN
The objective of the present study was to determine if treatment with N-acetylcysteine (NAC) could reduce access-related limb dysfunction in mice. Male and female C57BL6J mice were fed an adenine-supplemented diet to induce chronic kidney disease (CKD) prior to the surgical creation of an arteriovenous fistula (AVF) in the iliac vascular bundle. AVF creation significantly increased peak aortic and infrarenal vena cava blood flow velocities, but NAC treatment had no significant impact, indicating that fistula maturation was not impacted by NAC treatment. Hindlimb muscle and paw perfusion recovery and muscle capillary density in the AVF limb were unaffected by NAC treatment. However, NAC treatment significantly increased the mass of the tibialis anterior (P = 0.0120) and soleus (P = 0.0452) muscles post-AVF. There was a significant main effect of NAC treatment on hindlimb grip strength at postoperative day 12 (POD 12) (P = 0.0003), driven by significantly higher grip strength in both male (P = 0.0273) and female (P = 0.0031) mice treated with NAC. There was also a significant main effect of NAC treatment on the walking speed at postoperative day 12 (P = 0.0447), and post hoc testing revealed an improvement in NAC-treated male mice (P = 0.0091). The area of postsynaptic acetylcholine receptors (P = 0.0263) and motor endplates (P = 0.0240) was also increased by NAC treatment. Interestingly, hindlimb skeletal muscle mitochondrial oxidative phosphorylation trended higher in NAC-treated female mice but was not statistically significant (P = 0.0973). Muscle glutathione levels and redox status were not significantly impacted by NAC treatment in either sex. In summary, NAC treatment attenuated some aspects of neuromotor pathology in mice with chronic kidney disease following AVF creation.NEW & NOTEWORTHY Hemodialysis via autogenous arteriovenous fistula (AVF) is the preferred first-line modality for renal replacement therapy in patients with end-stage kidney disease. However, patients undergoing AVF surgery frequently experience a spectrum of hand disability symptoms postsurgery including weakness and neuromotor dysfunction. Unfortunately, no treatment is currently available to prevent or mitigate these symptoms. Here, we provide evidence that daily N-acetylcysteine supplementation can attenuate some aspects of limb neuromotor function in a preclinical mouse model of AVF.
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Fístula Arteriovenosa , Derivación Arteriovenosa Quirúrgica , Fallo Renal Crónico , Insuficiencia Renal Crónica , Masculino , Femenino , Animales , Ratones , Acetilcisteína/farmacología , Diálisis Renal , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/etiología , Fallo Renal Crónico/terapia , Derivación Arteriovenosa Quirúrgica/efectos adversos , Estudios RetrospectivosRESUMEN
Objective: Hand disability after hemodialysis access surgery has been common yet has remained poorly understood. Arteriovenous fistula (AVF) hemodynamic perturbations have not reliably correlated with the observed measures of hand function. Chronic kidney disease (CKD) is known to precipitate myopathy; however, the interactive influences of renal insufficiency and ischemia on limb outcomes have remained unknown. We hypothesized that CKD would contribute to access-related hand dysfunction via altered mitochondrial bioenergetics. Using a novel murine AVF model, we sought to characterize the skeletal muscle outcomes in mice with and without renal insufficiency. Methods: Male, 8-week-old C57BL/6J mice were fed either an adenine-supplemented diet to induce renal insufficiency (CKD) or a casein-based control chow (CON). After 2 weeks of dietary intervention, the mice were randomly assigned to undergo iliac AVF surgery (n = 12/group) or a sham operation (n = 5/group). Measurements of aortoiliac hemodynamics, hindlimb perfusion, and hindlimb motor function were collected for 2 weeks. The mice were sacrificed on postoperative day 14 to assess skeletal muscle histopathologic features and mitochondrial function. To assess the late outcome trends, 20 additional mice had undergone CKD induction and sham (n = 5) or AVF (n = 15) surgery and followed up for 6 weeks postoperatively before sacrifice. Results: The adenine-fed mice had had a significantly reduced glomerular filtration rate and elevated blood urea nitrogen, confirming the presence of CKD. The sham mice had a 100% survival rate and AVF cohorts an 82.1% survival rate with an 84.4% AVF patency rate. The aorta and inferior vena cava velocity measurements and the vessel diameter had increased after AVF creation (P < .0001 vs sham). The AVF groups had had a 78.4% deficit in paw perfusion compared with the contralateral limb after surgery (P < .0001 vs sham). Mitochondrial function was influenced by the presence of CKD. The respiratory capacity of the CKD-sham mice (8443 ± 1509 pmol/s/mg at maximal energy demand) was impaired compared with that of the CON-sham mice (12,870 ± 1203 pmol/s/mg; P = .0001). However, this difference was muted after AVF creation (CKD-AVF, 4478 ± 3685 pmol/s/mg; CON-AVF, 5407 ± 3582 pmol/s/mg; P = .198). The AVF cohorts had had impairments in grip strength (vs sham; P < .0001) and gait (vs sham; P = .012). However, the presence of CKD did not significantly alter the measurements of gross muscle function. The paw perfusion deficits had persisted 6 weeks postoperatively for the AVF mice (P < .0001 vs sham); however, the myopathy had resolved (grip strength, P = .092 vs sham; mitochondrial respiration, P = .108 vs sham). Conclusions: CKD and AVF-induced distal limb ischemia both impaired skeletal muscle mitochondrial function. Renal insufficiency was associated with a baseline myopathy that was exacerbated by the acute ischemic injury resulting from AVF creation. However, ischemia was the primary driver of the observed phenotype of gross motor impairment. This model reliably reproduced the local and systemic influences that contribute to access-related hand dysfunction and provides a platform for further mechanistic and therapeutic investigation.
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End-stage kidney disease, the most advanced stage of chronic kidney disease (CKD), requires renal replacement therapy or kidney transplant to sustain life. To accomplish durable dialysis access, the creation of an arteriovenous fistula (AVF) has emerged as a preferred approach. Unfortunately, a significant proportion of patients that receive an AVF experience some form of hand dysfunction; however, the mechanisms underlying these side effects are not understood. In this study, we used nuclear magnetic resonance spectroscopy to investigate the muscle metabolome following iliac AVF placement in mice with CKD. To induce CKD, C57BL6J mice were fed an adenine-supplemented diet for 3 wk and then randomized to receive AVF or sham surgery. Two weeks following surgery, the quadriceps muscles were rapidly dissected and snap frozen for metabolite extraction and subsequent nuclear magnetic resonance analysis. Principal component analysis demonstrated clear separation between groups, confirming a unique metabolome in mice that received an AVF. AVF creation resulted in reduced levels of creatine, ATP, and AMP as well as increased levels of IMP and several tricarboxylic acid cycle metabolites suggesting profound energetic stress. Pearson correlation and multiple linear regression analyses identified several metabolites that were strongly linked to measures of limb function (grip strength, gait speed, and mitochondrial respiration). In summary, AVF creation generates a unique metabolome profile in the distal skeletal muscle indicative of an energetic crisis and myosteatosis.NEW & NOTEWORTHY Creation of an arteriovenous fistula (AVF) is the preferred approach for dialysis access, but some patients experience hand dysfunction after AVF creation. In this study, we provide a detailed metabolomic analysis of the limb muscle in a murine model of AVF. AVF creation resulted in metabolite changes associated with an energetic crisis and myosteatosis that associated with limb function.
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Fístula Arteriovenosa , Derivación Arteriovenosa Quirúrgica , Fallo Renal Crónico , Insuficiencia Renal Crónica , Animales , Ratones , Adenina , Adenosina Monofosfato , Adenosina Trifosfato , Derivación Arteriovenosa Quirúrgica/efectos adversos , Creatina , Músculos , Diálisis Renal/métodos , Insuficiencia Renal Crónica/etiologíaRESUMEN
OBJECTIVE: Hemodialysis access-related hand dysfunction is a common clinical feature of patients with chronic kidney disease (CKD) after arteriovenous fistula (AVF) placement. The heterogeneity in symptoms and the lack of a predictive association with changes in hemodynamic alterations precipitated by the AVF suggest that other factors are involved in the mechanisms responsible for causing hand and limb dysfunction postoperatively. To the best of our knowledge, no suitable animal models have provided a platform for performing preclinical experiments designed to elucidate the biologic drivers of access-related hand dysfunction. Therefore, our objective was to develop a novel murine AVF model that could be used to study dialysis access-related limb dysfunction. METHODS: Male 8-week-old C57BL/6J mice (n = 15/group) were exposed to either an adenine-supplemented diet to induce CKD or casein-based chow (control). Four weeks after the diet intervention, the mice were randomly assigned to receive an iliac AVF (n = 10/group) or sham surgery (n = 5/group) on the left hindlimb. The mice were sacrificed 2 weeks after surgery, and AVF specimens and hindlimb skeletal muscles were collected for further analysis. RESULTS: Before AVF or sham surgery, the glomerular filtration rates were significantly reduced and the blood urea nitrogen levels were significantly elevated in the CKD groups compared with the controls (P < .05). AVF surgery was associated with an â¼80% patency rate among the survivors (four control and three CKD mice died postoperatively). Patency was verified by changes in hemodynamics using Doppler ultrasound imaging and altered histologic morphology. Compared with sham surgery, AVF surgery reduced ipsilateral hindlimb perfusion to the tibialis anterior muscle (20%-40%) and paw (40%-50%), which remained stable until euthanasia. Analysis of gastrocnemius muscle mitochondrial respiratory function uncovered a significant decrease (40%-50%) in mitochondrial function in the AVF mice. No changes were found in the muscle mass, myofiber cross-sectional area, or centrally nucleated fiber proportion in the extensor digitorum longus and soleus muscles between the sham and AVF mice. CONCLUSIONS: The results from the present study have demonstrated that iliac AVF formation is a practical animal model that facilitates examination of hemodialysis access-related limb dysfunction. AVF surgery produced the expected hemodynamic changes, and evaluation of the limb muscle revealed a substantial mitochondrial impairment that was present without changes in muscle size.
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Importance: National initiatives have emphasized the use of autogenous arteriovenous fistulas (AVFs) for hemodialysis, but their purported benefits have been questioned. Objective: To examine AVF usability, longer-term functional patency, and remedial procedures to facilitate maturation, manage complications, or maintain patency in the Hemodialysis Fistula Maturation (HFM) Study. Design, Setting, and Participants: The HFM Study was a multicenter (n = 7) prospective National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases cohort study performed to identify factors associated with AVF maturation. A total of 602 participants were enrolled (dialysis, kidney failure: 380; predialysis, chronic kidney disease [CKD]: 222) with AVF maturation ascertained for 535 (kidney failure, 353; CKD, 182) participants. Interventions: All clinical decisions regarding AVF management were deferred to the individual centers, but remedial interventions were discouraged within 6 weeks of creation. Main Outcomes and Measures: In this case series analysis, the primary outcome was unassisted maturation. Functional patency, freedom from intervention, and participant survival were summarized using Kaplan-Meier analysis. Results: Most participants evaluated (n = 535) were men (372 [69.5%]) and had diabetes (311 [58.1%]); mean (SD) age was 54.6 (13.6) years. Almost two-thirds of the AVFs created (342 of 535 [64%]) were in the upper arm. The AVF maturation rates for the kidney failure vs CKD participants were 29% vs 10% at 3 months, 67% vs 38% at 6 months, and 76% vs 58% at 12 months. Several participants with kidney failure (133 [37.7%]) and CKD (63 [34.6%]) underwent interventions to facilitate maturation or manage complications before maturation. The median time from access creation to maturation was 115 days (interquartile range [IQR], 86-171 days) but differed by initial indication (CKD, 170 days; IQR, 113-269 days; kidney failure, 105 days; IQR, 81-137 days). The functional patency for the AVFs that matured at 1 year was 87% (95% CI, 83.2%-90.2%) and at 2 years, 75% (95% CI, 69.7%-79.7%), and there was no significant difference for those receiving interventions before maturation. Almost half (188 [47.5%]) of the AVFs that matured had further intervention to maintain patency or treat complications. Conclusions and Relevance: The findings of this study suggest that AVF remains an accepted hemodialysis access option, although both its maturation and continued use require a moderate number of interventions to maintain patency and treat the associated complications.
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Derivación Arteriovenosa Quirúrgica , Diálisis Renal , Grado de Desobstrucción Vascular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Preclinical animal models of chronic kidney disease (CKD) are critical to investigate the underlying mechanisms of disease and to evaluate the efficacy of novel therapeutics aimed to treat CKD-associated pathologies. The objective of the present study was to compare the adenine diet and 5/6 nephrectomy (Nx) CKD models in mice. Male and female 10-wk-old C57BL/6J mice (n = 5-9 mice/sex/group) were randomly allocated to CKD groups (0.2-0.15% adenine-supplemented diet or 5/6 Nx surgery) or the corresponding control groups (casein diet or sham surgery). Following the induction of CKD, the glomerular filtration rate was reduced to a similar level in both adenine and 5/6 Nx mice (adenine diet-fed male mice: 81.1 ± 41.9 µL/min vs. 5/6 Nx male mice: 160 ± 80.9 µL/min, P = 0.5875; adenine diet-fed female mice: 112.9 ± 32.4 µL/min vs. 5/6 Nx female mice: 107.0 ± 45.7 µL/min, P = 0.9995). Serum metabolomics analysis indicated that established uremic toxins were robustly elevated in both CKD models, although some differences were observed between CKD models (i.e., p-cresol sulfate). Dysregulated phosphate homeostasis was observed in the adenine model only, whereas Ca2+ homeostasis was disturbed in male mice with both CKD models. Compared with control mice, muscle mass and myofiber cross-sectional areas of the extensor digitorum longus and soleus muscles were â¼18-24% smaller in male CKD mice regardless of the model but were not different in female CKD mice (P > 0.05). Skeletal muscle mitochondrial respiratory function was significantly decreased (19-24%) in CKD mice in both models and sexes. These findings demonstrate that adenine diet and 5/6 Nx models of CKD have similar levels of renal dysfunction and skeletal myopathy. However, the adenine diet model demonstrated superior performance with regard to mortality (â¼20-50% mortality for 5/6 Nx vs. 0% mortality for the adenine diet, P < 0.05 for both sexes) compared with the 5/6 Nx surgical model.NEW & NOTEWORTHY Numerous preclinical models of chronic kidney disease have been used to evaluate skeletal muscle pathology; however, direct comparisons of popular models are not available. In this study, we compared adenine-induced nephropathy and 5/6 nephrectomy models. Both models produced equivalent levels of muscle atrophy and mitochondrial impairment, but the adenine model exhibited lower mortality rates, higher consistency in uremic toxin levels, and dysregulated phosphate homeostasis compared with the 5/6 nephrectomy model.