Correction to: Myocardial Cytoskeletal Adaptations in Advanced Kidney Disease.
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PROVIDER: S-EPMC10111561 | biostudies-literature | 2023 Mar
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Correction to: Myocardial Cytoskeletal Adaptations in Advanced Kidney Disease.
Journal of the American Heart Association 20230309 6
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Project description:Background The myocardial cytoskeleton functions as the fundamental framework critical for organelle function, bioenergetics and myocardial remodeling. To date, impairment of the myocardial cytoskeleton occurring in the failing heart in patients with advanced chronic kidney disease has been largely undescribed. Methods and Results We conducted a 3-arm cross-sectional cohort study of explanted human heart tissues from patients who are dependent on hemodialysis (n=19), hypertension (n=10) with preserved renal function, and healthy controls (n=21). Left ventricular tissues were subjected to pathologic examination and next-generation RNA sequencing. Mechanistic and interference RNA studies utilizing in vitro human cardiac fibroblast models were performed. Left ventricular tissues from patients undergoing hemodialysis exhibited increased myocardial wall thickness and significantly greater fibrosis compared with hypertension patients (P<0.05) and control (P<0.01). Transcriptomic analysis revealed that the focal adhesion pathway was significantly enriched in hearts from patients undergoing hemodialysis. Hearts from patients undergoing hemodialysis exhibited dysregulated components of the focal adhesion pathway including reduced β-actin (P<0.01), β-tubulin (P<0.01), vimentin (P<0.05), and increased expression of vinculin (P<0.05) compared with controls. Cytoskeletal adaptations in hearts from the hemodialysis group were associated with impaired mitochondrial bioenergetics, including dysregulated mitochondrial dynamics and fusion, and loss of cell survival pathways. Mechanistic studies revealed that cytoskeletal changes can be driven by uremic and metabolic abnormalities of chronic kidney disease, in vitro. Furthermore, focal adhesion kinase silencing via interference RNA suppressed major cytoskeletal proteins synergistically with mineral stressors found in chronic kidney disease in vitro. Conclusions Myocardial failure in advanced chronic kidney disease is characterized by impairment of the cytoskeleton involving disruption of the focal adhesion pathway, mitochondrial failure, and loss of cell survival pathways.
| S-EPMC9075094 | biostudies-literature
Project description:Molecular changes underlying the failing heart in chronic kidney disease (CKD) remains largely undefined. To date, a severe paucity of translational studies investigating these changes utilizing human heart tissues from kidney failure patients exists. Moreover, no studies have examined alterations of the cardiac cytoskeleton in CKD, despite its central role in regulating organelle function, bioenergetics and myocardial remodeling. In this 3-arm cross-sectional controlled cohort study, we compared donor heart tissues from dialysis patients, to patients with hypertension with relatively preserved GFR, and healthy controls. We present evidence for transcriptomic changes in the hearts of dialysis patients, involving cytoskeletal dysregulation and dysfunction of mitochondrial bioenergetics.
2020-10-27 | GSE160145 | GEO
Project description:Myocardial adaptations in advanced kidney disease
| PRJNA672097 | ENA
Project description: Not available
| S-EPMC10695648 | biostudies-literature
Project description:Background and aimsCompensatory renal hypertrophy following unilateral nephrectomy (UNX) occurs in the remaining kidney. However, the long-term cardiac adaptive process to UNX remains poorly defined in humans. Our goal was to characterize myocardial structure and function in living kidney donors (LKDs), approximately 12 years after UNX.Methods and resultsCardiac function and structure in 15 Italian LKDs, at least 5 years after UNX (median time from donation = 8.4 years) was investigated and compared to those of age and sex matched U.S. citizens healthy controls (n = 15). Standard and speckle tracking echocardiography (STE) was performed in both LKDs and controls. Plasma angiotensin II, aldosterone, atrial natriuretic peptide (ANP), N terminus pro B-type natriuretic peptide (NT-proBNP), cyclic guanylyl monophosphate (cGMP), and amino-terminal peptide of procollagen III (PIIINP) were also collected. Median follow-up was 11.9 years. In LKDs, LV geometry and function by STE were similar to controls, wall thickness and volumes were within normal limits also by CMR. In LKDs, CMR was negative for myocardial fibrosis, but apical rotation and LV torsion obtained by STE were impaired as compared to controls (21.4 ± 7.8 vs 32.7 ± 8.9 degrees, p = 0.04). Serum creatinine and PIIINP levels were increased [1.1 (0.9-1.3) mg/dL, and 5.8 (5.4-7.6)] μg/L, respectively), while urinary cGMP was reduced [270 (250-355) vs 581 (437-698) pmol/mL] in LKDs. No LKD developed cardiovascular or renal events during follow-up.ConclusionsLong-term kidney donors have no apparent structural myocardial abnormalities as assessed by contrast enhanced CMR. However, myocardial deformation of the apical segments, as well as apical rotation, and LV torsion are reduced. The concomitant increase in circulating PIIINP level is suggestive of fibrosis. Further studies, focused on US and EU patients are warranted to evaluate whether these early functional modifications will progress to a more compromised cardiac function and structure at a later time.
| S-EPMC4640880 | biostudies-literature
Project description:Patients with CKD suffer from food aversion, anorexia, and malnutrition. Although olfaction has a significant role in determining food flavor, our understanding of olfactory impairment and of the olfaction-nutrition axis in patients with kidney disease is limited. We quantified odor identification, odor threshold, and subjective odor perception in a cohort (n=161) comprising 36 participants with CKD, 100 participants with ESRD, and 25 controls. We investigated olfaction-nutrition associations in these participants and examined a novel intervention to improve olfaction in ESRD. The mean odor identification score was lower in patients with CKD (75.6%±13.1%; P=0.02) and ESRD (66.8%±15.1%; P<0.001) than in controls (83.6%±11.4%). Patients with ESRD exhibited higher odor threshold than the remaining participants exhibited. All groups had similar scores for subjective smell assessment. In multivariable adjusted analyses, kidney disease associated with increased odds of odor identification deficits (odds ratio, 4.80; 95% confidence interval, 1.94 to 11.89). A reduction in odor identification score was associated with higher subjective global assessment score and lower serum total cholesterol, LDL cholesterol, and albumin concentrations. We found no associations between odor threshold and nutritional parameters. In a proof of concept, 6-week, open-label clinical trial, intranasal theophylline (an epithelial membrane transport and proton secretion activator) increased odor identification score in five out of seven (71%) patients with ESRD. In conclusion, patients with kidney disease have olfactory deficits that may influence their nutritional status. Our preliminary results regarding olfactory improvement using intranasal theophylline warrant confirmation in a randomized controlled trial.
| S-EPMC5661283 | biostudies-literature
Project description:Purpose of reviewThe aim of this study was to present recent developments in pharmacotherapy of hypertension in patients with advanced chronic kidney disease (CKD).Recent findingsIn the AMBER trial, compared with placebo, the potassium-binder patiromer mitigated the risk of hyperkalaemia and enabled more patients with uncontrolled resistant hypertension and stage 3b/4 CKD to tolerate and continue spironolactone treatment; add-on therapy with spironolactone provoked a clinically meaningful reduction of 11-12 mmHg in unattended automated office SBP over 12 weeks of follow-up. In the BLOCK-CKD trial, the investigational nonsteroidal mineralocorticoid-receptor-antagonist (MRA) KBP-5074 lowered office SBP by 7-10 mmHg relative to placebo at 84 days with a minimal risk of hyperkalaemia in patients with advanced CKD and uncontrolled hypertension. The CLICK trial showed that the thiazide-like diuretic chlorthalidone provoked a placebo-subtracted reduction of 10.5 mmHg in 24-h ambulatory SBP at 12 weeks in patients with stage 4 CKD and poorly controlled hypertension.SummaryEnablement of more persistent spironolactone use with newer potassium-binding agents, the clinical development of novel nonsteroidal MRAs with a more favourable benefit-risk profile and the recently proven blood pressure lowering action of chlorthalidone are three therapeutic opportunities for more effective management of hypertension in high-risk patients with advanced CKD.
| S-EPMC9728619 | biostudies-literature
Project description:BackgroundClinical trials that have assessed the effect of revascularization in patients with stable coronary disease have routinely excluded those with advanced chronic kidney disease.MethodsWe randomly assigned 777 patients with advanced kidney disease and moderate or severe ischemia on stress testing to be treated with an initial invasive strategy consisting of coronary angiography and revascularization (if appropriate) added to medical therapy or an initial conservative strategy consisting of medical therapy alone and angiography reserved for those in whom medical therapy had failed. The primary outcome was a composite of death or nonfatal myocardial infarction. A key secondary outcome was a composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest.ResultsAt a median follow-up of 2.2 years, a primary outcome event had occurred in 123 patients in the invasive-strategy group and in 129 patients in the conservative-strategy group (estimated 3-year event rate, 36.4% vs. 36.7%; adjusted hazard ratio, 1.01; 95% confidence interval [CI], 0.79 to 1.29; P = 0.95). Results for the key secondary outcome were similar (38.5% vs. 39.7%; hazard ratio, 1.01; 95% CI, 0.79 to 1.29). The invasive strategy was associated with a higher incidence of stroke than the conservative strategy (hazard ratio, 3.76; 95% CI, 1.52 to 9.32; P = 0.004) and with a higher incidence of death or initiation of dialysis (hazard ratio, 1.48; 95% CI, 1.04 to 2.11; P = 0.03).ConclusionsAmong patients with stable coronary disease, advanced chronic kidney disease, and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of death or nonfatal myocardial infarction. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.).
| S-EPMC7274537 | biostudies-literature
Project description:BackgroundLittle evidence has been available to support the use of thiazide diuretics to treat hypertension in patients with advanced chronic kidney disease.MethodsWe randomly assigned patients with stage 4 chronic kidney disease and poorly controlled hypertension, as confirmed by 24-hour ambulatory blood-pressure monitoring, in a 1:1 ratio to receive chlorthalidone at an initial dose of 12.5 mg per day, with increases every 4 weeks if needed to a maximum dose of 50 mg per day, or placebo; randomization was stratified according to previous use of loop diuretics. The primary outcome was the change in 24-hour ambulatory systolic blood pressure from baseline to 12 weeks. Secondary outcomes were the change from baseline to 12 weeks in the urinary albumin-to-creatinine ratio, N-terminal pro-B-type natriuretic peptide level, plasma renin and aldosterone levels, and total body volume. Safety was also assessed.ResultsA total of 160 patients underwent randomization, of whom 121 (76%) had diabetes mellitus and 96 (60%) were receiving loop diuretics. At baseline, the mean (±SD) estimated glomerular filtration rate was 23.2±4.2 ml per minute per 1.73 m2 of body-surface area and the mean number of antihypertensive medications prescribed was 3.4±1.4. At randomization, the mean 24-hour ambulatory systolic blood pressure was 142.6±8.1 mm Hg in the chlorthalidone group and 140.1±8.1 mm Hg in the placebo group and the mean 24-hour ambulatory diastolic blood pressure was 74.6±10.1 mm Hg and 72.8±9.3 mm Hg, respectively. The adjusted change in 24-hour systolic blood pressure from baseline to 12 weeks was -11.0 mm Hg (95% confidence interval [CI], -13.9 to -8.1) in the chlorthalidone group and -0.5 mm Hg (95% CI, -3.5 to 2.5) in the placebo group. The between-group difference was -10.5 mm Hg (95% CI, -14.6 to -6.4) (P<0.001). The percent change in the urinary albumin-to-creatinine ratio from baseline to 12 weeks was lower in the chlorthalidone group than in the placebo group by 50 percentage points (95% CI, 37 to 60). Hypokalemia, reversible increases in serum creatinine level, hyperglycemia, dizziness, and hyperuricemia occurred more frequently in the chlorthalidone group than in the placebo group.ConclusionsAmong patients with advanced chronic kidney disease and poorly controlled hypertension, chlorthalidone therapy improved blood-pressure control at 12 weeks as compared with placebo. (Funded by the National Heart, Lung, and Blood Institute and the Indiana Institute of Medical Research; CLICK ClinicalTrials.gov number, NCT02841280.).
| S-EPMC9119310 | biostudies-literature
Project description:Autosomal dominant polycystic kidney disease (ADPKD) causes renal cysts and leads to end-stage renal disease in midlife due mainly to PKD1 gene mutations. Virtually no studies have explored gene therapeutic strategies for long-term effective treatment of PKD. Toward this aim, the severely cystic Pkd1-null mouse model was targeted with a series of transgene transfers using genomic Pkd1 under its regulatory elements (Pkd1wt), a kidney-targeted Pkd1 gene (SBPkd1), or Pkd1Minigene. The introduced Pkd1wt gene constructs with ∼8-fold overexpression display similar endogenous cellular profiles and full complementation of Pkd1−/− phenotype and establish the referral Pkd1 genomic length for proper regulation. SBPkd1 transgene transfer expressing 0.6- or 7-fold Pkd1 endogenous levels is sufficient to correct glomerular and proximal tubular cysts and to markedly postpone cysts in other tubular segments as well, showing that the small SB elements appreciably overlap with Pkd1 promoter/5′ UTR regulation. Renal-targeted Pkd1Minigene at high copy numbers conveys an expression level similar to that of the endogenous Pkd1 gene, with widespread and homogeneous weak Pkd1 cellular signal, partially rescuing all cystic tubular segments. These transgene transfers determine that Pkd1 intragenic sequences regulate not only expression levels but also spatiotemporal patterns. Importantly, our study demonstrates that Pkd1 re-expression from hybrid therapeutic constructs can ameliorate, with considerably extended lifespan, or eliminate PKD. Graphical abstract Trudel and colleagues establish the first referral Pkd1 gene segment for proper regulation and cure of the most severe polycystic kidney disease/PKD mouse model. The study also identifies a small renal regulatory cassette and intragenic region critical in the Pkd1 spatiotemporal expression pattern and levels that will instigate molecular therapy for PKD.
| S-EPMC10199405 | biostudies-literature