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Pubblicazioni recenti - cardiorenal
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Twelve-lead electrocardiography identifies the therapeutic target of paroxysmal supraventricular tachycardia.
J Arrhythm2020 Feb;36(1):211-213. doi: 10.1002/joa3.12261.
Matsunaga Keiji, Inoue Tomoko, Miyake Yuichi, Ishizawa Makoto, Noma Takahisa, Minamino Tetsuo,
Abstract
Twelve-lead electrocardiography provides us the clue about the differential diagnosis between atrioventricular nodal reentrant tachycardia and atrioventricular reentrant tachycardia.
© 2019 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society.
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The primary cilia in diabetic kidney disease: a tubulocentric view?
Int J Biochem Cell Biol2020 Feb;():105718. doi: S1357-2725(20)30035-2.
Panchapakesan Usha, Pollock Carol,
Abstract
Diabetic kidney disease is growing exponentially. This review aims to discuss alternate therapeutic approaches beyond the glomerulocentric view and to consider a novel tubulocentric approach with focus on the primary cilia. Renin-angiotensin-aldosterone system blockade to decrease glomerular capillary pressure and prevent albuminuria has been the mainstay of treatment for diabetic and non-diabetic proteinuric kidney disease. Landmark clinical trials have also shown cardiorenal benefit with sodium-glucose linked co-transporter 2 inhibitors and glucagon-like peptide 1 receptor analogues in patients with type 2 diabetes. Effective renoprotective drugs seem to have a common mechanistic mode of reducing glomerular hyperfiltration/hypertension. In the tubules, primary cilia act as "antennae" to detect mechanosensory changes such as glomerular hyperfiltration and trgger intracellular signaling pathways. They are also implicated in obesity and metabolic disorders linked to diabetes. To conclude, primary cilia of the kidney tubules offer a novel therapeutic target and may complement the current glomerulocentric approaches.
Copyright © 2020. Published by Elsevier Ltd.
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Early Posttransplant Mobilization of M-MDSC Correlates with Increase in Soluble Immunosuppressive Factors and Predicts Cancer in Kidney Recipients.
Transplantation2020 Feb;():. doi: 10.1097/TP.0000000000003179.
Utrero-Rico Alberto, Laguna-Goya Rocio, Cano-Romero Francisco, Chivite-Lacaba Marta, Gonzalez-Cuadrado Cecilia, Rodríguez-Sánchez Elena, Ruiz-Hurtado Gema, Serrano Antonio, Fernández-Ruiz Mario, Justo Iago, González Esther, Andrés Amado, Paz-Artal Estela,
Abstract
BACKGROUND:
Myeloid-derived suppressor cells (MDSC) increase in patients with cancer and are associated with poor prognosis, however their role in transplantation is not yet understood. Here we aimed to study the MDSC effects on the evolution of kidney transplant recipients (KTR).
METHODS:
A cohort of 229 KTR was prospectively analyzed. Two myeloid cells subsets: CD11bCD33CD14CD15HLADR (monocytic MDSC, M-MDSC) and CD11bCD33CD14CD15HLA-DR (monocytes) were defined by flow cytometry. The suppressive capacity of myeloid cells was tested in cocultures with autologous lymphocytes. Suppressive soluble factors, cytokines, anti-HLA antibodies and total antioxidant capacity (TAC) were quantified in plasma.
RESULTS:
Pretransplant, M-MDSC and monocytes were similar in KTR and healthy volunteers (HV). M-MDSC increased immediately posttransplantation and suppressed CD4 and CD8 T cells proliferation. M-MDSC remained high for 1 year posttransplantation. Higher M-MDSC counts at day 14 posttransplant were observed in patients who subsequently developed cancer, and KTR with higher M-MDSC at day 14 had significantly lower malignancy-free survival. Day-14 M-MDSC >179.2 per microliter conferred 6.98 times (95% CI: 1.28-37.69) more risk to develop cancer, independently from age, gender and immunosuppression. Early posttransplant M-MDSC were lower in patients with enhanced alloimmune response as represented by anti-HLA sensitization. M-MDSC counts correlated with higher circulatory suppressive factors arginase-1 and IL-10, and lower TAC.
CONCLUSIONS:
Early posttransplant mobilization of M-MDSC predicts cancer and adds risk as an independent factor. M-MDSC may favor an immunosuppressive environment that promotes the tumoral development.
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[Vascular dysfunction in Cardiorenal Syndrome type 4].
G Ital Nefrol2020 Feb;37(1):. doi: 2020-vol1.
Sessa Concetto, Granata Antonio, Gaudio Agostino, Xourafa Anastasia, Malatino Lorenzo, Lentini Paolo, Fatuzzo Pasquale, Rapisarda Francesco, Castellino Pietro, Zanoli Luca,
Abstract
The Cardiorenal Syndrome type 4 (CRS-4) defines a pathological condition in which a primary chronic kidney disease (CKD) leads to a chronic impairment of cardiac function. The pathophysiology of CRS-4 and the role of arterial stiffness remain only in part understood. Several uremic toxins, such as uric acid, phosphates, advanced glycation end-products, asymmetric dimethylarginine, and endothelin-1, are also vascular toxins. Their effect on the arterial wall may be direct or mediated by chronic inflammation and oxidative stress. Uremic toxins lead to endothelial dysfunction, intima-media thickening and arterial stiffening. In patients with CRS-4, the increased aortic stiffness results in an increase of cardiac workload and left ventricular hypertrophy whereas the loss of elasticity results in decreased coronary artery perfusion pressure during diastole and increased risk of myocardial infarction. Since the reduction of arterial stiffness is associated with an increased survival in patients with CKD, the understanding of the mechanisms that lead to arterial stiffening in patients with CRS4 may be useful to select potential approaches to improve their outcome. In this review we aim at discussing current understanding of the pathways that link uremic toxins, arterial stiffening and impaired cardiac function in patients with CRS-4.
Copyright by Societŕ Italiana di Nefrologia SIN, Rome, Italy.
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Vascular effects of serelaxin in patients with stable coronary artery disease: a randomized placebo-controlled trial.
Cardiovasc Res2020 Feb;():. doi: cvz345.
Corcoran David, Radjenovic Aleksandra, Mordi Ify R, Nazir Sheraz A, Wilson Simon J, Hinder Markus, Yates Denise P, Machineni Surendra, Alcantara Jose, Prescott Margaret F, Gugliotta Barbara, Pang Yinuo, Tzemos Niko, Semple Scott I, Newby David E, McCann Gerry P, Squire Iain, Berry Colin,
Abstract
AIMS:
The effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD).
METHODS AND RESULTS:
In this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48?h intravenous infusion of serelaxin (30?µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47?h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47?h, Day 30, and Day 180; aortic distensibility at 47?h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n?=?25; placebo, n?=?26). After 2 and 6?h of serelaxin infusion, mean placebo-corrected blood pressure reductions of -9.6?mmHg (P?=?0.01) and -13.5?mmHg (P?=?0.0003) for systolic blood pressure and -5.2?mmHg (P?=?0.02) and -8.4?mmHg (P?=?0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47?h in global MPR (-0.24 vs. -0.13, P?=?0.44) or AIx (3.49% vs. 0.04%, P?=?0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n?=?5; placebo, n?=?7) to 180-day follow-up.
CONCLUSION:
In patients with stable CAD, 48?h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion.
© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.
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Benefits and Risks of Continuing Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Antagonists, and Mineralocorticoid Receptor Antagonists during Hospitalizations for Acute Heart Failure.
Cardiorenal Med2020 Feb;():1-16. doi: 10.1159/000504167.
Oliveros Estefania, Oni Ebenezer T, Shahzad Anum, Kluger Aaron Y, Lo Kevin Bryan, Rangaswami Janani, McCullough Peter A,
Abstract
BACKGROUND:
The renin-angiotensin-aldosterone axis plays a pivotal role in the pathophysiology of acute and chronic heart failure (HF) and represents an important target for guideline-directed medical therapy.
SUMMARY:
The use of appropriate directed medical therapies for inhibition of the renin-angiotensin-aldosterone axis in chronic HF has been the subject of several landmark clinical trials, with high levels of adherence exhibited in the outpatient setting. However, less clarity exists with respect to the initiation, continuation, and cessation of renin-angiotensin-aldosterone system inhibitors (RAASi) in the setting of acute HF and exacerbation of HF necessitating hospitalization. In this review, we summarize relevant aspects of the physiology of the renin-angiotensin-aldosterone axis in acute HF and during decongestion. We also summarize the available evidence for the risks and benefits of initiating and continuing RAASi in acute HF. Key Message: We offer a decision-making pathway for the use of RAASi in the setting of acute HF that would help guide the cardiologist and nephrologist caring for patients with acute HF and cardiorenal syndrome.
© 2020 S. Karger AG, Basel.
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The Economic Implications of Hyperkalemia in a Medicaid Managed Care Population.
Am Health Drug Benefits2019 Nov;12(7):352-361.
Desai Nihar R, Reed Pamala, Alvarez Paula J, Fogli Jeanene, Woods Steven D, Owens Mary Kay,
Abstract
Background:
Hyperkalemia, defined as a serum potassium level >5 mEq/L that results from multiple mechanisms, is a serious medical condition that can lead to life-threatening arrhythmias and sudden cardiac death. The coexistence of cardiac and renal diseases (ie, cardiorenal syndrome) significantly increases the complexity of care, but its economic impact is not well-characterized in this understudied Medicaid managed care population with hyperkalemia.
Objective:
To calculate the economic impact of hyperkalemia on patients with cardiorenal syndrome in a Medicaid managed care population in the United States using real-world data.
Methods:
In this retrospective cohort study, we used a proprietary Medicaid managed care database from 1 southern state. The total study population included 3563 patients, including 973 patients with hyperkalemia and 2590 controls (without hyperkalemia), who were matched based on age, comorbidities, and Medicaid eligibility status and duration, during a 30-month period between 2013 and 2016. The inclusion criteria for the hyperkalemia cohort were age ?18 years, Medicaid-only insurance status, coded cardiorenal diagnosis, and a claim for hyperkalemia during the study period. The cost was determined using paid claims data.
Results:
The mean healthcare costs (medical and pharmacy per member per year [PMPY] for patients with hyperkalemia was higher than that for the control cohort without hyperkalemia ($56,002 vs $23,653, respectively). These cost differences were driven by medical costs accrued in the hyperkalemia and in the control cohorts ($49,648 and $18,399 PMPY, respectively). Two of the largest drivers of the medical cost variance were inpatient costs ($33,116 vs $10,629 PMPY for the hyperkalemia and control cohorts, respectively) and dialysis costs ($2716 vs $810 PMPY, respectively). The medical loss ratios were 552% for the hyperkalemia cohort and 260% for the control cohort. Both cohorts had revenue deficits to the health plan, but the hyperkalemia cohort had double the medical loss ratio compared with the control cohort.
Conclusions:
The findings from this Medicaid managed care population suggest that hyperkalemia increases healthcare utilization and costs, which were primarily driven by the costs associated with inpatient care and dialysis. Our findings demonstrate that the Medicaid beneficiaries who have cardiorenal comorbidities accrue high costs to the Medicaid health plan, and these costs are even higher if a hyperkalemia diagnosis is present. The very high medical loss ratio for the hyperkalemia cohort in our analysis indicates that enhanced monitoring and management of patients with hyperkalemia should be considered.
Copyright © 2019 by Engage Healthcare Communications, LLC.
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Mass clinical survey as a possible population strategy for the better control of hypertension in Japan.
Hypertens Res2020 Feb;():. doi: 10.1038/s41440-019-0381-9.
Tamura Kouichi, Yamaji Takahiro, Azushima Kengo, Wakui Hiromichi,
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T cell senescence accelerates Angiotensin II-induced target organ damage.
Cardiovasc Res2020 Feb;():. doi: cvaa032.
Pan Xiao-Xi, Wu Fang, Chen Xiao-Hui, Chen Dong-Rui, Chen Hong-Jin, Kong Ling-Ran, Ruan Cheng-Chao, Gao Ping-Jin,
Abstract
AIMS:
Aging is a risk factor for cardiovascular diseases and adaptive immunity has been implicated in angiotensin (Ang) II-induced target-organ dysfunction. Herein, we sought to determine the role of T-cell senescence in Ang II-induced target organ impairment and to explore the underlying mechanisms.
METHODS AND RESULTS:
Flow cytometric analysis revealed that T cell derived from aged mice exhibited immuno-senescence. Adoptive transfer of aged T cells to immunodeficient RAG1 KO mice accelerates Ang II-induced cardiovascular and renal fibrosis compared with young T cell transfer. Aged T cells also promote inflammatory factor expression and superoxide production in these target organs. In vivo and in vitro studies revealed that Ang II promotes IFN-? production in the aged T cells comparing to young T cells. Importantly, transfer of senescent T cell that IFN-? KO mitigates the impairment. Aged T cell-conditioned medium stimulates inflammatory factor expression and oxidative stress in Ang II-treated renal epithelial cells compared with young T cells, and these effects of aged T cell-conditioned medium are blunted after IFN-?-neutralizing antibody pretreatment.
CONCLUSIONS:
These results provide a significant insight into the contribution of senescent T cells to Ang II-induced cardiovascular dysfunction and provide an attractive possibility that targeting T cell specifically might be a potential strategy to treat elderly hypertensive patients with end-organ dysfunction.
TRANSLATIONAL PERSPECTIVE:
Aging is a risk factor for cardiovascular diseases. Adaptive immunity has been implicated in Ang II-induced target-organ dysfunction. Here, we utilized adoptive transfer of young or aged T cell into RAG1-/- mice and provide the direct evidence that senescent T-cell was more sensitive to Ang II stimulation and exerted an adverse impact on target-organ, in which senescent T cell-derived IFN-? may play a critical role. These findings might shed new light on the contribution of T-cell senescence to target-organ injury in age-related hypertension.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions please email: journals.permissions@oup.com.
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Effect of cosyntropin during adrenal venous sampling on subtype of primary aldosteronism: analysis of surgical outcome.
Eur J Endocrinol2020 Mar;182(3):265-273. doi: 10.1530/EJE-19-0860.
Kobayashi Hiroki, Nakamura Yoshihiro, Abe Masanori, Kurihara Isao, Itoh Hiroshi, Ichijo Takamasa, Takeda Yoshiyu, Yoneda Takashi, Katabami Takuyuki, Tsuiki Mika, Wada Norio, Ogawa Yoshihiro, Sakamoto Ryuichi, Kawashima Junji, Sone Masakatsu, Inagaki Nobuya, Yoshimoto Takanobu, Yamada Tetsuya, Okamoto Ryuji, Matsuda Yuichi, Fujita Megumi, Watanabe Minemori, Tamura Kouichi, Tanabe Akiyo, Naruse Mitsuhide, ,
Abstract
Objectives:
We investigated the clinical significance of ACTH stimulation during adrenal venous sampling (AVS) by surgical outcome of primary aldosteronism (PA).
Design:
Multicenter retrospective study by Japan PA study.
Method:
We allocated 314 patients with both basal and ACTH-stimulated AVS data who underwent adrenalectomy to three groups: basal lateralization index (LI) ?2 with ACTH-stimulated LI ?4 on the ipsilateral side (Unilateral (U) to U group, n = 245); basal LI <2 with ACTH-stimulated LI ?4 (Bilateral (B) to U group, n = 15); and basal LI ?2 with ACTH-stimulated LI <4 (U to B group, n = 54). We compared surgical outcomes among the groups using the Primary Aldosteronism Surgical Outcome (PASO) criteria.
Results:
Compared with U to U group, U to B group had poor clinical and biochemical outcomes and low rates of adrenal adenoma as pathological findings (P = 0.044, 0.006, and 0.048, respectively), although there were no significant differences between U to U and B to U groups. All patients in U to B group with clinical and biochemical benefits, however, had adrenal adenoma as pathological findings and could be well differentiated from those with poor surgical outcomes via basal LI (>8.3), but not ACTH-stimulated LI. These results were similar even when we defined each group based on a cut-off value of 4 for basal LI.
Conclusions:
Although PA patients in U to B group had worse surgical outcomes than did those in U to U group, basal LI could discriminate among patients with better surgical outcomes in U to B group.
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Impact of serum lipoprotein (a) level on coronary plaque progression and cardiovascular events in statin-treated patients with acute coronary syndrome: a yokohama-acs substudy.
J Cardiol2020 Feb;():. doi: S0914-5087(20)30020-4.
Matsushita Kensuke, Hibi Kiyoshi, Komura Naohiro, Kimura Yuichiro, Matsuzawa Yasushi, Konishi Masaaki, Maejima Nobuhiko, Iwahashi Noriaki, Kosuge Masami, Ebina Toshiaki, Tamura Kouichi, Kimura Kazuo,
Abstract
BACKGROUND:
Lipoprotein (a) [Lp(a)] has been reported to be a residual risk factor in patients who have achieved target lipid levels. The aim of the present study was to investigate the associations of Lp(a) with plaque progression and major cardiovascular events in patients with acute coronary syndromes (ACS).
METHODS:
The Yokohama-ACS study included 102 patients with ACS who underwent intravascular ultrasound (IVUS) at baseline and at 10-month follow-up after percutaneous coronary intervention (PCI). The patients were randomly assigned to receive either moderate- or low-intensity statin therapy. IVUS was performed to measure the plaque volume at non-culprit lesions. We enrolled 76 patients for whom Lp(a) levels at 10-month follow-up were available.
RESULTS:
The patients were divided into 2 groups according whether their Lp(a) levels were ?20?mg/dl [low Lp(a) group; n?=?49] or >20?mg/dl [high Lp(a) group; n?=?27]. Baseline characteristics and low-density lipoprotein cholesterol levels at 10-month follow-up were similar in the low Lp(a) group and high Lp(a) group (87?±?29?mg/dl vs. 93?±?27?mg/dl, p?=?0.42). The low Lp(a) group had significant plaque regression, whereas the high Lp(a) group showed slight plaque progression (-6.8% vs. 2.5%, p?=?0.02). Ninety-five percent of the prognostic data were obtained 5 years after PCI. The cumulative event-free survival rate was significantly lower in the high Lp(a) group (p?=?0.02; log-rank test).
CONCLUSIONS:
Lp(a) levels may be an alternative predictor of further plaque regression and the likelihood of major adverse cardiovascular events in statin-treated ACS patients.
Copyright © 2020. Published by Elsevier Ltd.
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Subclinical Contrast-Induced Acute Kidney Injury in Patients Undergoing Cerebral Computed Tomography.
Cardiorenal Med2020 Feb;():1-12. doi: 10.1159/000505422.
Breglia Andrea, Godi Ilaria, Virzě Grazia Maria, Guglielmetti Gabriele, Iannucci Giuseppe, De Cal Massimo, Brocca Alessandra, Carta Mariarosa, Giavarina Davide, Ankawi Ghada, Passannante Alberto, Yun Xie, Biolo Gianni, Ronco Claudio,
Abstract
INTRODUCTION:
The nephrotoxicity of modern contrast media remains controversial. Novel biomarkers of kidney damage may help in identifying a subclinical structural renal injury not revealed by widely used markers of kidney function.
OBJECTIVE:
The aim of this study was to investigate clinical (contrast-induced acute kidney injury [CI-AKI]) and subclinical CI-AKI (SCI-AKI) after intra-arterial administration of Iodixanol and Iopamidol in patients with an estimated glomerular filtration rate (eGFR) ?60 mL/min/1.73 m2.
METHODS:
This is a prospective observational monocentric study. Urinary sample was collected at 4-8 h after contrast medium exposure to measure neutrophil gelatinase associated lipocalin (NGAL) and the product tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 ([TIMP-2] × [IGFBP7]), while blood samples were collected at 24 and 48 h after exposure to measure serum creatinine.
RESULTS:
One hundred patients were enrolled, of whom 53 were exposed to Iodixanol and 47 to Iopamidol. Patients in Iodixanol and Iopamidol groups were comparable in terms of demographics, pre-procedural and procedural data. No patient developed CI-AKI according KDIGO criteria, while 13 patients reported SCI-AKI after exposure to iodine-based medium contrast (3 patients in Iodixanol group and 10 patients in Iopamidol group), defined by positive results of NGAL and/or [TIMP-2] × [IGFBP7]. A positive correlation was found between NGAL and [TIMP-2] × [IGFBP7] in the analysed population (Spearman's rho 0.49, p < 0.001). In logistic regression analysis, Iopamidol exposure showed higher risk for SCI-AKI compared to Iodixanol (OR 4.5 [95% CI 1.16-17.52], p = 0.030), even after controlling for eGFR and volume of contrast medium used.
CONCLUSIONS:
This study showed that intra-arterial modern contrast media administration may have a nephrotoxic effect in a population without pre-existing chronic kidney disease. Further investigations on larger scale are warranted to confirm if Iopamidol exposed patients to increased risk of SCI-AKI compared to Iodixanol.
© 2020 S. Karger AG, Basel.
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Hypertonic Saline: The Genesis of the Exodus of Fluid in Heart Failure?
JACC Heart Fail -
Real World Use of Hypertonic Saline in Refractory Acute Decompensated Heart Failure: A U.S. Center's Experience.
JACC Heart Fail2020 Jan;():. doi: S2213-1779(19)30875-3.
Griffin Matthew, Soufer Aaron, Goljo Erden, Colna Matthew, Rao Veena S, Jeon Sangchoon, Raghavendra Parinita, D'Ambrosi Julie, Riello Ralph, Coca Steven G, Mahoney Devin, Jacoby Daniel, Ahmad Tariq, Chen Michael, Tang W H Wilson, Turner Jeffrey, Mullens Wilfried, Wilson Francis P, Testani Jeffrey M,
Abstract
OBJECTIVES:
The purpose of this study was to investigate real world safety and efficacy of hypertonic saline therapy in cases of refractory acute decompensated heart failure (ADHF) at a large U.S. academic medical center.
BACKGROUND:
Hypertonic saline therapy has been described as a potential management strategy for refractory ADHF, but experience in the United States is limited.
METHODS:
A retrospective analysis was performed in all patients receiving hypertonic saline for diuretic therapy-resistant ADHF at the authors' institution since March 2013. The primary analytic approach was a comparison of the trajectory of clinical variables prior to and after administration of hypertonic saline, with secondary focus on predictors of treatment response.
RESULTS:
A total of 58 hypertonic saline administration episodes were identified across 40 patients with diuretic-therapy refractory ADHF. Prior to hypertonic saline administration, serum sodium, chloride, and creatinine concentrations were worsening but improved after hypertonic saline administration (p < 0.001, all). Both total urine output and weight loss significantly improved with hypertonic saline (p = 0.01 and <0.001, respectively). Diuretic efficiency, defined as change in urine output per doubling of diuretic dose, also improved over this period (p < 0.01). There were no significant changes in respiratory status or overcorrection of serum sodium with the intervention.
CONCLUSIONS:
In a cohort of patients who were refractory to ADHF, hypertonic saline administration was associated with increased diuretic efficiency, fluid and weight loss, and improvement of metabolic derangements, and no adverse respiratory or neurological signals were identified. Additional study of hypertonic saline as a diuretic adjuvant is warranted.
Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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Effects of Rikkunshito treatment on renal fibrosis/inflammation and body weight reduction in a unilateral ureteral obstruction model in mice.
Sci Rep2020 Feb;10(1):1782. doi: 10.1038/s41598-020-58214-0.
Wakui Hiromichi, Yamaji Takahiro, Azushima Kengo, Uneda Kazushi, Haruhara Kotaro, Nakamura Akiko, Ohki Kohji, Kinguchi Sho, Kobayashi Ryu, Urate Shingo, Suzuki Toru, Kamimura Daisuke, Minegishi Shintaro, Ishigami Tomoaki, Kanaoka Tomohiko, Matsuo Kohei, Miyazaki Tomoyuki, Fujikawa Tetsuya, Yamashita Akio, Tamura Kouichi,
Abstract
Chronic kidney disease (CKD) progresses to end-stage renal failure via renal tubulointerstitial fibrosis. Malnutrition, inflammation, and arteriosclerosis interact to exacerbate the poor prognosis of CKD, and their effective management is thus essential. The traditional Japanese medicine Rikkunshito (RKT) exerts appetite-stimulating effects via ghrelin, which attenuates inflammation and fibrosis. We evaluated the therapeutic effect of RKT in unilateral ureter obstruction (UUO)-induced renal fibrosis/inflammation and body weight loss in mice. UUO and sham-operated mice were fed a standard diet or diet containing 3.0% RKT. Renal fibrosis was investigated by histopathology and macrophage infiltration was determined by immunohistochemistry. Expression levels of genes associated with fibrosis, inflammation, ghrelin, and mitochondrial function were determined by quantitative reverse transcription-polymerase chain reaction and western blot analyses. RKT treatment partially prevented UUO-induced weight loss but failed to attenuate renal fibrosis and inflammation. Renal expression of sirtuin 1, a ghrelin-downstream signalling molecule, and gene expression of peroxisome proliferator-activated receptor-? coactivator 1? and Bcl-2/adenovirus E1B interacting protein 3 were unaffected by RKT. These results indicate that RKT inhibits weight loss but does not improve renal fibrosis or inflammation in a rapidly progressive renal fibrosis mouse model. RKT may have a protective effect on weight loss associated with CKD.
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Long-Term Blood Pressure Lowering and cGMP Activating Actions of the Novel ANP Analogue MANP.
Am J Physiol Regul Integr Comp Physiol2020 Feb;():. doi: 10.1152/ajpregu.00354.2019.
Chen Yang, Schaefer Jacob J, Iyer Seethalakshmi R, Harders Gerald E, Pan Shuchong, Sangaralingham S Jeson, Chen Horng H, Redfield Margaret M, Burnett John C,
Abstract
BACKGROUND:
Based on the cardiac hormone atrial natriuretic peptide (ANP) and its seminal role in blood pressure (BP) homeostasis, we investigated the chronic BP lowering actions of a novel ANP analogue currently entering clinical trials for hypertension. Previous reports demonstrate that this analogue MANP activates the guanylyl cyclase A receptor (GC-A) and results in more potent biological actions compared to ANP, and thus may represent a new therapeutic drug for hypertension.
OBJECTIVES:
A major goal was to establish that chronic subcutaneous (SC) delivery of MANP is feasible and hypotensive together with cGMP effects. We investigated the BP lowering and cGMP-activating actions of acute and chronic SC delivery in normal and hypertensive rats. Further, we explored vascular mechanisms of MANP in human aortic smooth muscle cells (HASMC) and ex vivo in isolated arteries.
METHODS AND RESULTS:
In normal rats with a single SC injection, MANP promoted robust dose-dependent BP lowering actions and natriuresis, together with cGMP activation. Most importantly in hypertensive rats, once a day SC injection of MANP for 7 days induced cGMP elevation and long-term BP reduction compared to Vehicle. Mechanistically, in HASMC, MANP activated cGMP and attenuated angiotensin II mediated increases in intracellular Ca levels while directly vasorelaxing arterial rings.
CONCLUSION:
Our study demonstrates for the first time the effectiveness of SC administration of MANP for 7 days and provides innovative, vascular mechanisms of BP regulation supporting its continued development as a novel therapeutic for hypertension.
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IL11 in cardiac and renal fibrosis: late to the party but a central player.
Br J Pharmacol2020 Feb;():. doi: 10.1111/bph.15013.
Corden Benjamin, Adami Eleonora, Sweeney Mark, Schafer Sebastian, Cook Stuart A,
Abstract
Fibrosis is a pathophysiological hallmark of cardiorenal disease. In the heart, fibrosis leads to contractile dysfunction and arrhythmias; in the kidney it is the final common pathway for multiple diseases and predicts end-stage renal failure. Despite this, there are currently no specific anti-fibrotic treatments available for cardiac or renal disease. Recently and unexpectedly, interleukin-11 (IL11) was found to be of major importance for cardiorenal fibroblast activation and fibrosis. In mouse models, IL11 overexpression causes fibrosis of the heart and kidney whilst genetic deletion of Il11ra1 protects against fibrosis and preserves organ function. Neutralizing antibodies against IL11 or IL11RA have been developed that have anti-fibrotic activity in human fibroblasts and protect against fibrosis in murine models of disease. While IL11 biology has been little studied, and we suggest largely misunderstood, its autocrine activity in myofibroblasts appears non-redundant for fibrosis, which offers new opportunities to better understand and potentially target cardiorenal fibrosis.
This article is protected by copyright. All rights reserved.
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Intravascular Volume Modulates the Outcome Predictive Capacity of Clinical Renal Function Biomarkers in Clinically "Euvolemic" Chronic Heart Failure Patients.
Kidney Dis (Basel)2020 Jan;6(1):50-58. doi: 10.1159/000502210.
Miller Wayne L, Grill Diane E, Qian Qi,
Abstract
Background:
Cardiorenal interconnections are complex and may in part be mediated by the extent of intravascular volume expansion. The impact of subclinical volume excess on outcomes in heart failure (HF) patients with chronic kidney disease (CKD) has not been examined previously.
Objectives:
To assess the impact of volume-kidney interactions on outcomes in clinically "euvolemic" chronic HF patients (NYHA class II) with coexisting CKD.
Methods:
Plasma volume (PV) was prospectively measured in 110 stable HF patients with different degrees of renal function using a standardized radiolabeled albumin indicator-dilution technique. To examine the interactive roles of volume expansion and biomarkers of CKD, the cohort was dichotomized by median PV and then further stratified by cohort median serum creatinine, eGFR, and BUN, and analyzed for outcomes of HF-related mortality and 1st hospitalization.
Results:
PV was expanded above normal in 76% of the cohort. Over 1.5 years of follow-up, sCr and BUN above and eGFR below cohort median stratified higher risks for the composite endpoint only in ambulatory HF patients with a severe degree of PV expansion (median PV expansion ?+26%; = 0.02). With less expansion (<+26% expansion), these biomarkers reflecting worse renal function did not discriminate risk ( = 0.578). The percentage of subjects experiencing composite outcome events was, however, comparable for both greater and lesser degrees of PV expansion in HF patients with stable clinical status.
Conclusions:
In clinically stable chronic HF patients with coexisting CKD, substantial subclinical PV expansion is common even when patients are considered clinically to be euvolemic, and, importantly, the extent of PV expansion impacts outcomes including early HF mortality. Better kidney function appears to mitigate the effects of excess PV expansion, while less volume expansion appears to limit the risk of worse renal function as reflected by clinical biomarkers of renal function. Thus, the extent of volume expansion impacts the capacity of standard clinical biomarkers of CKD to differentiate outcome risk in ambulatory chronic (NYHA class II) HF patients.
Copyright © 2019 by S. Karger AG, Basel.
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Extraglycemic Effects of SGLT2 Inhibitors: A Review of the Evidence.
Diabetes Metab Syndr Obes2020 ;13():161-174. doi: 10.2147/DMSO.S233538.
Bonora Benedetta Maria, Avogaro Angelo, Fadini Gian Paolo,
Abstract
Patients with type 2 diabetes (T2D) are often overweight/obese and affected by arterial hypertension, dyslipidaemia, and have high serum levels of uric acid. Moreover, T2D patient have a higher risk of developing cardiovascular or renal complications, which are leading causes of morbidity and mortality in this population. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a new class of glucose-lowering medications that block the reabsorption of glucose in the kidney, thereby increasing urinary glucose excretion, and lowering blood glucose levels. The beneficial effects of SGLT2 inhibition extend beyond glycaemic control, and include improvement in blood pressure, body weight, uric acid concentrations, liver steatosis, oxidative stress, and inflammation. In dedicated cardiovascular outcome trials, SGLT2i treatment was associated with a significant reduction in the rate of cardiovascular events and renal endpoints. In this review, we summarize the evidence for extra-glycemic effects of SGLT2i and the potential mechanisms driving cardiorenal protection exerted by this class of medications.
© 2020 Bonora et al.
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Pseudoxanthoma Elasticum and Cardiorenal Disease: A Case Report.
Eur J Case Rep Intern Med2020 ;7(1):001260. doi: 10.12890/2019_001260.
D'Marco Luis, Soto Carlos, Dapena Fabiola,
Abstract
Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterized by calcification of elastic fibres, skin lesions, fundus lesions and systemic vascular complications. PXE affects approximately 1 in 160,000 people, typically appearing as a formation of yellow papules containing abnormally calcified elastic fibres. The renal involvement of PXE has been reported. Several factors are known to promote soft tissue and accelerated arterial calcification in chronic kidney disease, including systemic inflammation, altered calcium and phosphate homeostasis, hypertension and a deficiency of endogenous calcification inhibitors. Given the impact of this disease, nephrologists may seek additional supportive features to improve and avoid the risk of complications. Moreover, PXE per se represents an interesting model to evaluate vascular disease in the early stages of renal disease.
LEARNING POINTS:
Pseudoxanthoma elasticum represents a rare disease that can involve renal problems.Vascular compromise in patients affected by pseudoxanthoma elasticum shares some components observed in patients with chronic kidney disease.Disorders of mineral and bone metabolism may coexist or be hidden in patients with pseudoxanthoma elasticum.
© EFIM 2019.
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