Local modulation of the natriuretic peptide system in the rat remnant kidney

Background. The natriuretic peptide (NP) system plays a central role in the renal adaptations to acute volume expansion. However, the modulation of the NP system in chronic renal insufficiency (CRI) remains to be elucidated. In the present study, we evaluated cardiac haemodynamics, plasma type-B natriuretic peptide (BNP) levels and the expression of natriuretic peptide receptor A (NPR-A) and NPR-C in the renal cortex (RC) and medulla (RM) of Sham and 3/4 nephrectomized (3/4nx) rats, up to 26 weeks after surgery. Methods. Male Wistar-Han rats (190-220 g; n = 49) were randomly assigned to 3/4nx or Sham surgery. Two, 10 and 26 weeks after surgery, non-invasive blood pressure (BP) and left ventricular (LV) haemodynamics were performed, and urine and blood were collected for metabolic studies and plasma BNP determination. In addition, tissue samples from RC and RM were obtained for NPR-A and NPR-C quantification (RT-PCR and western blotting) as well as NPR-A immunodetection. Results. In 3/4nx rats, the progressive interstitial fibrosis and tubular atrophy were accompanied by a time-dependent increase of BP and impaired natriuretic response to volume expansion (VE). This was accompanied in 3/4nx rats by an early and time-dependent elevation of BNP circulating levels that was not associated with cardiac dysfunction or increased myocardial BNP gene expression. In 3/4nx rats, NPR-A expression in the remnant RM was consistently reduced at 2, 10 and 26 weeks, and this was accompanied by an increase in NPR-C expression in the remnant RC from 3/4nx rats. Conclusions. BP elevation and compromised natriuretic response to VE in 3/4nx rats is associated with increased circulating BNP levels in the absence of cardiac dysfunction. This is accompanied in 3/4nx rats by both impaired NPR-A expression in the RM and upregulation of NPR-C in the RC suggesting a novel mechanism for NP resistance in CRI

Time course and mechanisms of left ventricular systolic and diastolic dysfunction in monocrotaline-induced pulmonary hypertension

Although pulmonary hypertension (PH) selectively overloads the right ventricle (RV), neuroendocrine activation and intrinsic myocardial dysfunction have been described in the left ventricle (LV). In order to establish the timing of LV dysfunction development in PH and to clarify underlying molecular changes, Wistar rats were studied 4 and 6 weeks after subcutaneous injection of monocrotaline (MCT) 60 mg/kg (MCT-4, n = 11; MCT-6, n = 11) or vehicle (Ctrl-4, n = 11; Ctrl-6, n = 11). Acute single beat stepwise increases of systolic pressure were performed from baseline to isovolumetric (LVPiso). This hemodynamic stress was used to detect early changes in LV performance. Neurohumoral activation was evaluated by measuring angiotensin-converting enzyme (ACE) and endothelin-1 (ET-1) LV mRNA levels. Cardiomyocyte apoptosis was evaluated by TUNEL assay. Extracellular matrix composition was evaluated by tenascin-C mRNA levels and interstitial collagen content. Myosin heavy chain (MHC) composition of the LV was studied by protein quantification. MCT treatment increased RV pressures and RV/LV weight ratio, without changing LV end-diastolic pressures or dimensions. Baseline LV dysfunction were present only in MCT-6 rats. Afterload elevations prolonged tau and upward-shifted end-diastolic pressure dimension relations in MCT-4 and even more in MCT-6. MHC-isoform switch, ACE upregulation and cardiomyocyte apoptosis were present in both MCT groups. Rats with severe PH develop LV dysfunction associated with ET-1 and tenascin-C overexpression. Diastolic dysfunction, however, could be elicited at earlier stages in response to hemodynamic stress, when only LV molecular changes, such as MHC isoform switch, ACE upregulation, and myocardial apoptosis were present.Supported by Portuguese grants from FCT (POCI/SAU-FCF/60803/2004 and POCI/SAU-MMO/61547/2004) through Cardiovascular R&D Unit (FCT No. 51/94)

Doação de Rins Após Paragem Cardiocirculatória: O Papel da Oxigenação por Membrana Extracorporal

Introduction: Chronic kidney disease is a prevalent disorder, with a significant number of late stage patients, which only options are renal replacement therapy and transplantation. Kidney transplantation is associated with higher quality of life and lower mortality. The increasing gap between the demand for kidneys and its availability for transplantation has prompted the research and development of an alternative source to the conventional brain dead donors, the donors after cardiac death. The latter need preservation techniques in order to offer similar functional results. In the present article, we proposed to review the recent evidence about the role of extracorporeal membrane oxygenation as preservation technique in the harvesting of kidneys from donors after circulatory death. Material and Methods: A literature research was conducted in PubMed/MEDLINE, using the following expressions: “kidney transplantation”; “non-heart-beating donor”; “donation after cardiac death”; “extracorporeal membrane oxygenation”; “abdominal normothermic perfusion”. Based on the selected articles, it was performed a non-systematic review, summarizing the recent evidence about the role of extracorporeal membrane oxygenation as preservation technique in the harvesting of kidneys from donors after circulatory death. Results: The evidence suggests that extracorporeal membrane oxygenation is better than the other preservation techniques used in donors after cardiac death, as it has been associated to improved renal allograft outcomes. Regarding the conventional deceased donors, the brain dead, this technique allows similar results, particularly when compared with expanded criteria donors. Discussion: Organ preservation through extracorporeal membrane oxygenation in cardiac death donors has favorable functional results and, for this reason, may contribute to increase the pool of donors. The logistical challenges of the technique restrict its implementation. Conclusion: In the long-term, should be created conditions so that extracorporeal membrane oxygenation in donors after cardiac death may be widely implemented, increasing the number of kidneys obtained for transplantation.Introdução: A doença renal crónica é uma patologia prevalente, sendo significativo o número de doentes em estádio terminal cujas alternativas se resumem à terapêutica de substituição da função renal e ao transplante, sendo o último associado a maior qualidade de vida e a menor mortalidade. A procura crescente de rins para transplante tem aumentado o desfasamento relativamente aos rins disponíveis. Esse desfasamento impulsionou a pesquisa e desenvolvimento de alternativas aos dadores cadáver em morte cerebral, sendo os dadores após paragem cardiocirculatória uma alternativa viável. Estes obrigam a técnicas de preservação de órgão distintas, de forma a poder oferecer resultados funcionais sobreponíveis. O objetivo deste artigo foi rever a evidência recente sobre o papel da utilização da oxigenação por membrana extracorporal como técnica de preservação, na colheita de rins de dadores após paragem cardiocirculatória. Material e Métodos: Foi efectuada uma pesquisa na base PubMed/MEDLINE, utilizando as expressões: “kidney transplantation”; “non-heart-beating donor”; “donation after cardiac death”; “extracorporeal membrane oxygenation”; “abdominal normothermic perfusion”. Com os artigos selecionados, realizou- se uma revisão não sistemática, sumarizando a evidência recente sobre a utilização da oxigenação por membrana extracorporal na colheita de rins de dadores após paragem cardiocirculatória. Resultados: Verificou-se que os estudos sugerem com unanimidade que a oxigenação por membrana extracorporal é superior às outras técnicas de preservação utilizadas em dadores após paragem cardiocirculatória, uma vez que está associada a melhores resultados a curto prazo do aloenxerto renal. Relativamente aos dadores convencionais, em morte cerebral, a técnica permite resultado semelhantes, quando comparada com os dadores de morte cerebral de critérios expandidos. Discussão: A preservação de órgãos através da oxigenação por membrana extracorporal nos dadores após paragem cardiocirculatória permite resultados funcionais favoráveis e, por esse motivo, poderá contribuir para o aumento do pool de dadores. As dificuldades logísticas associadas à implementação da técnica restringem a sua utilização. Conclusão: A longo prazo, deverão ser criadas condições para a implementação em mais centros da oxigenação por membrana extracorporal nos dadores após paragem cardiocirculatória, aumentando o pool de rins disponíveis para transplante

Randomized controlled trial of remote ischaemic conditioning in ST‑elevation myocardial infarction as adjuvant to primary angioplasty (RIC‑STEMI)

Ischaemic heart disease (IHD) and myocardial infarction (MI) remain the leading cause of mortality in Europe [22]. ST-elevation myocardial infarction (STEMI) incidence declined due to aggressive control of risk factors while mortality was reduced by combined effects of timely primary percutaneous coronary intervention (PCI) and optimized medical therapy [4, 10]. An increasing number of survivors, however, are at risk of left ventricular (LV) dysfunction [17]. PCI worsens ischaemia–reperfusion injury (IRI), which later accounts for larger infarct size and ensuing heart failure (HF) [7]. Indeed, 6-month mortality figures after STEMI remain high, warranting a shift in focus towards HF prevention [6]. The rationale underlying protection by ischaemic conditioning has been extensively reviewed [11, 14], but translation to the clinics has been unwieldy [10, 12]. From various alternatives remote ischaemic conditioning (RIC) seems the most promising [10]. Myocardial salvage index was improved 30 days after PCI in STEMI patients assigned to concomitant RIC [2] as was long-term prognosis in post hoc analysis [21]. A recent meta-analysis concluded that RIC is a promising adjunctive treatment to PCI for prevention of IRI in STEMI [18]. Most importantly, larger studies addressing hard clinical endpoints as primary outcome measures are warranted [10]. Our aim was to test the hypothesis that RIC as adjuvant therapy to standard of care PCI (SOC) could reduce a combined primary outcome measure of cardiac mortality and hospitalization for HF on follow-up after STEMI

Diastolic tolerance to systolic pressures closely reflects systolic performance in patients with coronary heart disease

Abstract In animal experiments, elevating systolic pressures induces diastolic dysfunction and may contribute to congestion, a finding not yet translated to humans. Coronary surgery patients (63 ± 8 years) were studied with left ventricular (LV) pressure (n = 17) or pressure–volume (n = 3) catheters, immediately before cardiopulmonary bypass. Single-beat graded pressure elevations were induced by clamping the ascending aorta. Protocol was repeated after volume loading (n = 7). Consecutive patients with a wide range of systolic function were included. Peak isovolumetric LV pressure (LVPiso) ranged from 113 to 261 mmHg. With preserved systolic function, LVP elevations neither delayed relaxation nor increased filling pressures. With decreasing systolic function, diastolic tolerance to afterload progressively disappeared: relaxation slowed and filling pressures increased (diastolic dysfunction). In severely depressed systolic function, filling pressures increased even with minor LVP elevations, suggesting baseline load-dependent elevation of diastolic pressures. The magnitude of filling pressure elevation induced in isovolumetric heartbeats was closely and inversely related to systolic performance, evaluated by LVPiso (r = -0.96), and directly related to changes in the time constant of relaxation s (r = 0.95). The maximum tolerated systolic LVP (without diastolic dysfunction) was similarly correlated with LVPiso (r = 0.99). Volume loading itself accelerated relaxation, but augmented afterloadinduced upward shift of filling pressures (7.9 ± 3.7 vs. 3.0 ± 1.5; P\0.01). The normal human response to even markedly increased systolic pressures is no slowing of relaxation and preservation of normal filling pressures. When cardiac function deteriorates, the LV becomes less tolerant, responding with slowed relaxation and increased filling pressures. This increase is exacerbated by volume loading

Remdesivir for the Treatment of Hospitalised Patients with COVID-19 (DisCoVeRy): A Randomised, Controlled, Open-Label Trial

International audienceBackground: The antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in patients with COVID-19 requiring oxygen and/or ventilator support.Methods: In this European multicentre, open-label, parallel-group, randomised, controlled trial in adults hospitalised with COVID-19 (DisCoVeRy, NCT04315948; EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care alone or in combination with intravenous remdesivir (200 mg on day 1, then 100 mg once-daily for 9 days or until discharge). Treatment assignation was performed via web-based randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population.Findings: Between March 22nd, 2020 and January 21st, 2021, 857 participants were randomised to one of the two arms in 5 European countries and 832 participants were included for the evaluation of remdesivir (control, n=418; remdesivir, n=414). There was no difference in the clinical status neither at day 15 between treatment groups (OR for remdesivir, 0.98, 95% CI, 0.77 to 1.25, P=0.85) nor at day 29. The proportion of deaths at day 28 was not significantly different between control (8.9%) and remdesivir (8.2%) treatment groups (OR for remdesivir, 0.93 95%CI 0.57 to 1.52, P=0.77). There was also no difference on SARS-CoV-2 viral kinetics (effect of remdesivir on viral load slope, -0.004 log10 cp/10,000 cells/day, 95% CI, -0.03 to 0.02, P=0.75). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups.Interpretation: The use of remdesivir for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15 or day 29, nor with a reduction in mortality, nor with a reduction in SARS-CoV-2 RNA

The value of open-source clinical science in pandemic response: lessons from ISARIC

International audienc