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Scientific Reports Jun 2024Anthropological and biophysical processes have shaped livestock genomes over Millenia and can explain their current geographic distribution and genetic divergence. We...
Anthropological and biophysical processes have shaped livestock genomes over Millenia and can explain their current geographic distribution and genetic divergence. We analyzed 57 Ethiopian indigenous domestic goat genomes alongside 67 equivalents of east, west, and north-west African, European, South Asian, Middle East, and wild Bezoar goats. Cluster, ADMIXTURE (K = 4) and phylogenetic analysis revealed four genetic groups comprising African, European, South Asian, and wild Bezoar goats. The Middle Eastern goats had an admixed genome of these four genetic groups. At K = 5, the West African Dwarf and Moroccan goats were separated from East African goats demonstrating a likely historical legacy of goat arrival and dispersal into Africa via the coastal Mediterranean Sea and the Horn of Africa. F, XP-EHH, and Hp analysis revealed signatures of selection in Ethiopian goats overlaying genes for thermo-sensitivity, oxidative stress response, high-altitude hypoxic adaptation, reproductive fitness, pathogen defence, immunity, pigmentation, DNA repair, modulation of renal function and integrated fluid and electrolyte homeostasis. Notable examples include TRPV1 (a nociception gene); PTPMT1 (a critical hypoxia survival gene); RETREG (a regulator of reticulophagy during starvation), and WNK4 (a molecular switch for osmoregulation). These results suggest that human-mediated translocations and adaptation to contrasting environments are shaping indigenous African goat genomes.
Topics: Animals; Goats; Ethiopia; Genome; Phylogeny; Stress, Physiological; Genetic Variation
PubMed: 38942813
DOI: 10.1038/s41598-024-65303-x -
Physiological Reports Jul 2024The central role of natriuretic peptides (NPs) in the complex cardio-renal integrated physiology and organ failure has been revealed over the last four decades. Atrial... (Review)
Review
The central role of natriuretic peptides (NPs) in the complex cardio-renal integrated physiology and organ failure has been revealed over the last four decades. Atrial natriuretic peptide (ANP), the oldest representative of the NPs family, is produced through conversion of proANP to the mature peptide by corin, a trans-membrane protease localized to the cardiac myocyte membrane. Similarly, brain natriuretic peptide (BNP) is generated by furin, which cleaves proBNP to BNP in myocytes. Though the components of NPs system, their synthesis and target organs are well established, understanding their role in the interplay between the heart and the kidney is steadily evolving. In this context, Feldman et al. (New England Journal of Medicine, 389, 1685) recently described patients with hypertension, cardiomyopathy, atrial arrhythmia and left atrial fibrosis, associated with a homozygous loss-of-function variant of the gene encoding corin (Cor). Notably, reduced baseline urinary electrolyte and creatinine excretion have been observed in one of the studied patients. This renal excretory functional impairment could be attributed to the lack of cardiac-derived ANP in these patients, as implied by Feldman et al. Yet, in this mini-review we suggest that this aberrant renal manifestation may principally stem from lack of local ANP production at renal tissue, as corin is normally expressed in proximal tubules, Henle's loop and collecting ducts, with locally produced ANP provoking Na and water exertion. Collectively, it seems that beside the classic well-established cardio-renal axis, the renal NPs system functions as local endocrine machinery in the regulation of sodium excretion.
Topics: Humans; Animals; Kidney; Serine Endopeptidases; Atrial Natriuretic Factor; Heart
PubMed: 38942727
DOI: 10.14814/phy2.16105 -
Korean Journal of Radiology Jul 2024This study aimed to evaluate the diagnostic efficacy and safety of low-contrast-dose, dual-source dual-energy CT before transcatheter aortic valve replacement (TAVR) in...
OBJECTIVE
This study aimed to evaluate the diagnostic efficacy and safety of low-contrast-dose, dual-source dual-energy CT before transcatheter aortic valve replacement (TAVR) in patients with compromised renal function.
MATERIALS AND METHODS
A total of 54 consecutive patients (female:male, 26:38; 81.9 ± 7.3 years) with reduced renal function underwent pre-TAVR dual-energy CT with a 30-mL contrast agent between June 2022 and March 2023. Monochromatic (40- and 50-keV) and conventional (120-kVp) images were reconstructed and analyzed. The subjective quality score, vascular attenuation, contrast-to-noise ratio (CNR), and signal-to-noise ratio (SNR) were compared among the imaging techniques using the Friedman test and post-hoc analysis. Interobserver reliability for aortic annular measurement was assessed using the intraclass correlation coefficient (ICC) and Bland-Altman analysis. The procedural outcomes and incidence of post-contrast acute kidney injury (AKI) were assessed.
RESULTS
Monochromatic images achieved diagnostic quality in all patients. The 50-keV images achieved superior vascular attenuation and CNR ( < 0.001 in all) while maintaining a similar SNR compared to conventional CT. For aortic annular measurement, the 50-keV images showed higher interobserver reliability compared to conventional CT: ICC, 0.98 vs. 0.90 for area and 0.97 vs. 0.95 for perimeter; 95% limits of agreement width, 0.63 cm² vs. 0.92 cm² for area and 5.78 mm vs. 8.50 mm for perimeter. The size of the implanted device matched CT-measured values in all patients, achieving a procedural success rate of 92.6%. No patient experienced a serum creatinine increase of ≥ 1.5 times baseline in the 48-72 hours following CT. However, one patient had a procedural delay due to gradual renal function deterioration.
CONCLUSION
Low-contrast-dose imaging with 50-keV reconstruction enables precise pre-TAVR evaluation with improved image quality and minimal risk of post-contrast AKI. This approach may be an effective and safe option for pre-TAVR evaluation in patients with compromised renal function.
Topics: Humans; Male; Female; Contrast Media; Aged, 80 and over; Transcatheter Aortic Valve Replacement; Tomography, X-Ray Computed; Aged; Acute Kidney Injury; Aortic Valve Stenosis; Radiography, Dual-Energy Scanned Projection; Radiation Dosage; Reproducibility of Results; Renal Insufficiency; Retrospective Studies; Signal-To-Noise Ratio
PubMed: 38942457
DOI: 10.3348/kjr.2023.1207 -
Drug Metabolism and Disposition: the... Jun 2024Recently, we have proposed simple methodology to derive clearance and rate constant equations, independent of differential equations, based on Kirchhoff's Laws, a common...
Recently, we have proposed simple methodology to derive clearance and rate constant equations, independent of differential equations, based on Kirchhoff's Laws, a common methodology from physics used to describe rate-defining processes either in series or parallel. Our approach has been challenged in three recent publications, two published in this journal, but notably what is lacking is that none evaluate experimental pharmacokinetic data. As reviewed here, manuscripts from our laboratory have evaluated published experimental data, demonstrating that the Kirchhoff's Laws approach explains (1) why all of the experimental perfused liver clearance data appear to fit the equation that was previously believed to be the well-stirred model, (2) why linear pharmacokinetic systemic bioavailability determinations can be greater than 1, (3) why renal clearance can be a function of drug input processes, and (4) why statistically different bioavailability measures may be found for urinary excretion versus systemic concentration measurements. Our most recent paper demonstrates (5) how the universally accepted steady-state clearance approach utilized by the field for the past 50 years leads to unrealistic outcomes concerning the relationship between liver-to-blood and hepatic availability , highlighting the potential for errors in pharmacokinetic evaluations based on differential equations. The Kirchhoff's Laws approach is applicable to all pharmacokinetic analyses of quality experimental data, those that were previously adequately explained with present pharmacokinetic theory, and those that were not The publications that have attempted to rebut our position do not address unexplained experimental data, and we show here why their analyses are not valid. The Kirchhoff's Laws approach to deriving clearance equations for linear systems in parallel or in series, independent of differential equations, successfully describes published pharmacokinetic data that has previously been unexplained. Three recent publications claim to refute our proposed methodology; these publications only make theoretical arguments, do not evaluate experimental data; never demonstrate that the Kirchhoff methodology provides incorrect interpretations of experimental pharmacokinetic data, including statistically significant data not explained by present pharmacokinetic theory. We demonstrate why these analyses are invalid.
PubMed: 38942444
DOI: 10.1124/dmd.124.001735 -
Urology Jun 2024To determine whether early vs. delayed autotransplantation are associated with adverse outcomes in patients undergoing renal autotransplantation.
OBJECTIVE
To determine whether early vs. delayed autotransplantation are associated with adverse outcomes in patients undergoing renal autotransplantation.
METHODS
Patients who underwent renal autotransplantation from June 2012 to September 2022 were divided into two groups based on timing of autotransplant in relation to initial intervention or diagnosis (early cohort: ≤1-year; delayed cohort: >1-year). Primary outcomes were perioperative complications, aborted surgery, renal function (glomerular filtration rate [GFR]), and postoperative complications at most recent follow-up.
RESULTS
Autotransplantation patients (N=72) were predominantly female (68%) and White (54%), with a median age of 49 years. 90% of patients had undergone previous interventions, including stenting (40%) and nephrostomy tubes (49%), primarily for obstruction (64%). Early vs. delayed cohorts had median preoperative disease durations of 143 (IQR 83-222) vs. 673 days (IQR 529-1,703, p<0.001), with similar median follow-up times (879 vs. 818 days, p=0.8). Groups were similar in demographics and comorbidities. There were no significant differences in rates of aborted surgery (15% vs. 4.2%, p=0.3), perioperative complications (15% vs. 17%, p>0.9), long-term complications (49% vs. 48%, p>0.9), or changes in GFR (median change +3 vs. +4, p=0.7). Outcomes were comparable across preoperative disease durations ranging from 6 to 24 months. These findings were confirmed following adjustments for sex, body mass index, American Society of Anesthesiologists classification, race, preoperative creatinine levels, laterality, gastroesophageal reflux disease, diabetes, hypertension, nephrolithiasis, hyperlipidemia, history of colon surgery, urologic surgery, abdominal surgery, and prior interventions in separate logistic models.
CONCLUSIONS
Disease duration before autotransplantation does not influence outcomes, offering reassurance for clinical decision-making in complex cases.
PubMed: 38942394
DOI: 10.1016/j.urology.2024.06.050 -
Annals of Vascular Surgery Jun 2024Investigate readmission rates, diagnoses associated with readmission, and associations with mortality through 90-days post-operatively after elective endovascular...
OBJECTIVES
Investigate readmission rates, diagnoses associated with readmission, and associations with mortality through 90-days post-operatively after elective endovascular thoracic and thoracoabdominal aortic repair overall and by extent of coverage.
METHODS
A cohort of index elective non-traumatic endovascular thoracic and thoracoabdominal aortic cases from 2010-2018 was derived from the Vascular Implant Surveillance and Interventional Outcomes Network. Cohort readmissions within 90-days postoperative were examined both overall and by Crawford extent (CE) of aortic coverage. Postoperative mortality was examined by reason for readmission and CE.
RESULTS
The cohort consisted of 2,093 patients who underwent endovascular thoracic and thoracoabdominal aortic repair (1,541 CE 0A/0B; 240 CE 1-3; 312 CE 4-5). Cumulative risk for 90-day readmission was 34.3% in CE 0A/0B repairs, 33.4% in CE4-5 repairs and 47.4% in CE 1-3 repairs. Compared to CE 0A/B, patients with CE 1-3 repairs experienced an increased risk of readmission within 90 days postoperatively after adjusting for preoperative factors (aHR 1.27(1.00,1.61) while the readmission risk for CE 4-5 repairs did not differ significantly (aHR 0.83 (0.64,1.06). Significant risk factors for 90-day readmission included COPD, dialysis dependence, limited ambulation, visceral/spinal ischemia, and in-hospital stroke. Discharge to home was protective against readmission (HR 0.65, CI 0.54-0.79). Patients with a readmission within 90-days had a 7.89-fold increase in 90-day mortality (HR 7.84; 5.17, 11.9) compared to those not readmitted.
CONCLUSIONS
Increasing extent of endovascular thoracic and thoracoabdominal aortic repair was associated with higher 90-day readmission rates. Readmission for all CE was associated with near 8-fold increased risk of mortality. Risk factors associated with increased risk for readmission included pulmonary insufficiency, renal disease, and poor functional status. These findings can inform stakeholders about investment of resources to improve processes of care that both target prevention and mitigate risk of readmission after elective endovascular thoracic and thoracoabdominal aortic repair.
PubMed: 38942375
DOI: 10.1016/j.avsg.2024.05.007 -
Annals of Vascular Surgery Jun 2024After autogenous arteriovenous (AV) access creation for end-stage renal disease, a majority of patients will continue on hemodialysis (HD), a minority will receive...
OBJECTIVES
After autogenous arteriovenous (AV) access creation for end-stage renal disease, a majority of patients will continue on hemodialysis (HD), a minority will receive definitive treatment with kidney transplantation, and a subset of patients will convert to peritoneal dialysis (PD). Our goal was to identify patient factors associated with early transition from HD to either kidney transplantation or PD.
METHODS
This is a case-control study of all patients with first-time AV access creation in the Vascular Quality Initiative (2011-2022) who had long-term follow-up. Patients who remained on HD after AV access creation were the control group while patients who received early kidney transplant or who converted to PD were the two case groups. Relationship among demographics, comorbidities, neighborhood social disadvantage, and functional status as they relate to renal replacement therapy modality was assessed.
RESULTS
There were 19,782 patients included; the average age was 62±15 years and 57% were male. During the follow-up period of a median 306 (71-403) days, 1.3% underwent a kidney transplantation and 2.3% underwent conversion to PD. On univariable analysis, rates of kidney transplantation or conversion to PD varied with race (P<.001), insurance status (P<.001), Area Deprivation Index (ADI) quintile (P<.001), and several medical comorbidities. On multivariable analysis, impaired ambulation, current smoking, Medicaid or Medicare insurance, Black race, heart failure, body mass index, and older age were associated with decreased transplantation rates. Conversion to PD was associated with ADI Q5, Q4, and Q3. Decreased conversion to PD was associated with impaired ambulation, Hispanic ethnicity, Black race, former smoking, medication-controlled diabetes, and older age.
CONCLUSION
Decreased kidney transplantation was associated with Black race and non-commercial health insurance but not ADI quintile, suggesting disparities exist beyond community-level access to care. Early kidney transplantation conveyed a 3-year survival benefit compared to HD and PD, which had similar survival. Further work is required to increase access to kidney transplantation and PD.
PubMed: 38942372
DOI: 10.1016/j.avsg.2024.06.002 -
Journal of Renal Nutrition : the... Jun 2024Health literacy (HL) encompasses an individual's ability to access, understand, and integrate health-related information. Routine use of functional, critical, and... (Review)
Review
Health literacy (HL) encompasses an individual's ability to access, understand, and integrate health-related information. Routine use of functional, critical, and communicative HL screening questionnaires shows promise in identifying those at risk for poor clinical outcomes. Although it is evident that low levels of HL are associated with poor clinical outcomes in end-stage renal disease, it is unclear how varying HL levels are associated with nutrition-specific adherence. Here, we present a summary of literature published between 2018 and 2023 examining relationships between HL and nutrition-related adherence among individuals on hemodialysis. A positive association between higher HL scores and adherence to nutrition-related recommendations was found in this population. Based on these findings, screening for low levels of HL using validated tools should be integrated into standard practice for nutrition assessment. Future studies are warranted to explore the dietitian's role in improving HL and to develop a standardized measure for nutrition-related adherence.
PubMed: 38942339
DOI: 10.1053/j.jrn.2024.06.008 -
Journal of Vascular and Interventional... Jun 2024The purpose of this study was to retrospectively analyze the degree of renal function deterioration after renal cryoablation in patients with a solitary functioning...
PURPOSE
The purpose of this study was to retrospectively analyze the degree of renal function deterioration after renal cryoablation in patients with a solitary functioning kidney based on ablation volume.
MATERIALS AND METHODS
Over a 15-year period, 81 percutaneous cryoablations were performed in solitary functioning kidneys. After exclusion of patients with baseline end-stage renal disease(ESRD) and insufficient follow up, analysis was performed on 65 procedures in 52 patients (40 male, mean age 63.5 years). The post-cryoablation renal function was based on the lowest serum creatinine within 6 months post-procedure. Renal function change was defined as percentage glomerular filtration rate(GFR) change. Volumetric analysis was performed on the target lesion, renal parenchyma, and ablation zone.
RESULTS
The median tumor diameter was 2.0cm (range 0.8-4.7cm). The median baseline GFR decreased from 56.4 mL/min/1.73m (range 17.5-89.7) to 46.9 (range 16.5-89.7) at median 95 days (p<0.001), equating to an -7.9% median renal function change (range -45.0 to +30.7). All patients had stage 2 or worse chronic kidney disease and baseline function did not correlate with renal function change. The median volume of ablated parenchyma was 19.7mL (range 2.4-87.3mL), equating to 8.1% (range 0.7-37.2%) of total parenchyma. The volume of parenchymal volume ablated correlated significantly with renal function loss, while age, hypertension, and diabetes mellitus did not. No patients developed ESRD within 1 year after cryoablation.
CONCLUSION
Cryoablation in solitary functioning kidneys resulted in a modest reduction in renal function, even in patients with chronic kidney disease and ablations up to 20% of renal parenchymal volume.
PubMed: 38942284
DOI: 10.1016/j.jvir.2024.06.018 -
The Journal of Clinical Investigation Jun 2024Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer driven by VHL loss and aberrant HIF-2α signaling. Identifying means to regulate HIF-2α thus has...
Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer driven by VHL loss and aberrant HIF-2α signaling. Identifying means to regulate HIF-2α thus has potential therapeutic benefit. Acetyl-CoA synthetase 2 (ACSS2) converts acetate to acetyl-CoA and is associated with poor patient prognosis in ccRCC. Here we tested the effects of ACSS2 on HIF-2α and cancer cell metabolism and growth in ccRCC models and clinical samples. ACSS2 inhibition reduced HIF-2α levels and suppressed ccRCC cell line growth in vitro, in vivo, and in cultures of primary ccRCC patient tumors. This treatment reduced glycolytic signaling, cholesterol metabolism, and mitochondrial integrity, all of which are consistent with loss of HIF-2α. Mechanistically, ACSS2 inhibition decreased chromatin accessibility and HIF-2α expression and stability. While HIF-2α protein levels are widely regulated through pVHL-dependent proteolytic degradation, we identify a potential pVHL-independent pathway of degradation via the E3 ligase MUL1. We show that MUL1 can directly interact with HIF-2α and that overexpression of MUL1 decreased HIF-2α levels in a manner partially dependent on ACSS2. These findings identify multiple mechanisms to regulate HIF-2α stability and ACSS2 inhibition as a strategy to complement HIF-2α-targeted therapies and deplete pathogenically stabilized HIF-2α.
Topics: Carcinoma, Renal Cell; Humans; Basic Helix-Loop-Helix Transcription Factors; Kidney Neoplasms; Cell Line, Tumor; Acetate-CoA Ligase; Signal Transduction; Animals; Mice; Gene Expression Regulation, Neoplastic; Von Hippel-Lindau Tumor Suppressor Protein; Ubiquitin-Protein Ligases; Neoplasm Proteins
PubMed: 38941296
DOI: 10.1172/JCI164249