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Clinical and laboratorial findings of patients with idiopathic nephrotic syndrome and healthy controls matched by sex and age.
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Introduction: Renin angiotensin system (RAS) plays a role in idiopathic nephrotic syndrome (INS). Most studies investigated only the classical RAS axis. Therefore, the aims of the present study were to evaluate urinary levels of RAS molecules related to classical and to counter-regulatory axes in pediatric patients with INS, to compare the measurem...
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... and laboratory findings of INS patients and healthy controls are shown in Table 1. The control group (n=19) included 12 boys and 7 girls, ranging from 9 to 15 years old. ...
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... control group (n=19) included 12 boys and 7 girls, ranging from 9 to 15 years old. All controls had clinical and laboratory parameters within normal range (Table 1). No statistical differences between INS patients (n=31) and controls were found in age, sex distribution, body mass index, GFR, plasma levels of triglycerides, cholesterol, creatinine and albumin (p>0.05 for all comparisons, Table 1). ...
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... controls had clinical and laboratory parameters within normal range (Table 1). No statistical differences between INS patients (n=31) and controls were found in age, sex distribution, body mass index, GFR, plasma levels of triglycerides, cholesterol, creatinine and albumin (p>0.05 for all comparisons, Table 1). As expected, the values of proteinuria were significantly higher in INS patients than in healthy controls (Table 1). ...
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... statistical differences between INS patients (n=31) and controls were found in age, sex distribution, body mass index, GFR, plasma levels of triglycerides, cholesterol, creatinine and albumin (p>0.05 for all comparisons, Table 1). As expected, the values of proteinuria were significantly higher in INS patients than in healthy controls (Table 1). ...
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... regard to treatment, 6 among 31 (19%) INS patients were not receiving any medication at the time of urine collection, whereas the remaining patients needed at least one medication (Table 1). Sixteen among 25 (64%) patients of the INS group were receiving steroids and 9 (36%) cyclosporine, both isolated or in association with inhibitors of the RAS. ...
Citations
... This is consistent with the research conducted by Filha et al. [20] study observed no appreciable difference in blood pressure between the control group and INS patients. Clinicians caring for children with steroid sensitive and steroid resistant nephrotic syndrome frequently face arterial hypertension. ...
... Similarly, Filha et al. [20] uMCP-1 levels The study's findings revealed that post proteinuria regression, relapse rates were considerably greater in children with minimal change disease (MCD) than in the MCD group and controls. ...
... Additionally, our result is consistent with earlier research that discovered When compared to the control group and at the time of onset, MCP-1 levels in the urine of INS children were considerably greater [20,21]. ...
... This increase in Ang II can lead to glomerulopathy, due to increased intraglomerular pressure, affecting renal function and increasing serum urea concentrations. Similar results have been reported in the literature [10,46]. ...
IntroductionThe genetic component, including genes and their variants, plays a significant role in the pathophysiology of arterial hypertension (AH). Thus, clinical, epidemiological and genetic studies have been carried out to improve the understanding of disease mechanisms, improve diagnostic quality and contribute to prevention.Objective
To determine the association of risk factors, biochemical parameters and different ACE gene polymorphisms with AH.Method
The case-control study was carried out in the population of Ouro Preto, Brazil. The subjects answered a questionnaire containing clinical and sociodemographic data. The ACE gene polymorphisms rs4291, rs4363 and rs4335 were evaluated by real time-polymerase chain reaction (real-time PCR) in 310 people (155 hypertensive and 155 normotensive patients), in addition to biochemical parameters. A multivariate logistic regression model was used to identify factors associated with AH. Analysis of continuous variables was performed using the Kruskal-Wallis test to assess significance between groups and Dunn’s post-test for multiple comparisons.ResultsThe results showed that AH was associated with age, education, smoking, obesity and high levels of triglycerides, sodium, glucose and uric acid. Regarding the biochemical parameters, in hypertensive patients, the rs4363 and rs4335 polymorphisms were associated with high levels of triglycerides, urea and glucose; the rs4291 polymorphism was associated with elevated urea and glucose levels. No association was detected between SNPs and HA.ConclusionAH was associated with socioeconomic status, lifestyle habits and biochemical parameters. ACE polymorphisms may have influenced the levels of triglycerides, urea and glucose in hypertensive patients.
... INS patients had increased Ang II, Ang-(1-7), and ACE levels, while ACE2 concentrations were reduced. INS patients with proteinuria also had lower levels of ACE2 than those without proteinuria [50]. ...
... Since most pediatric patients with INS respond to steroids, this medication remains the initial therapy. A crosssectional study with INS children and adolescents at remitted and partially remitted stages showed that patients under steroid therapy, in comparison with those not receiving this medication, had significantly lower urinary levels of ACE2 and higher urinary levels of IP-10/CXCL-10 [50]. However, urinary levels of ACE, Ang II, and Ang-(1-7) did not significantly differ in these subgroups [50]. ...
... A crosssectional study with INS children and adolescents at remitted and partially remitted stages showed that patients under steroid therapy, in comparison with those not receiving this medication, had significantly lower urinary levels of ACE2 and higher urinary levels of IP-10/CXCL-10 [50]. However, urinary levels of ACE, Ang II, and Ang-(1-7) did not significantly differ in these subgroups [50]. ...
Idiopathic Nephrotic Syndrome (INS) is the most frequent etiology of glomerulopathy in pediatric patients and one of the most common causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in this population. In this review, we aimed to summarize evidence on the pathophysiological role and therapeutic potential of the Renin Angiotensin System (RAS) molecules for the control of proteinuria and for delaying the onset of CKD in patients with INS. This is a narrative review in which the databases PubMed, Web of Science, and SciELO were searched for articles about INS and RAS. We selected articles that evaluated the pathophysiological role of RAS and the effects of the alternative RAS axis as a potential therapy for INS. Several studies using rodent models of nephropathies showed that the treatment with activators of the Angiotensin-Converting Enzyme 2 (ACE2) and with Mas receptor agonists reduces proteinuria and improves kidney tissue damage. Another recent paper showed that the reduction of urinary ACE2 levels in children with INS correlates with proteinuria and higher concentrations of inflammatory cytokines, although, data with pediatric patients are still limited. The molecules of the alternative RAS axis comprise a wide spectrum, not yet fully explored, of potential pharmacological targets for kidney diseases. The effects of ACE2 activators and receptor Mas agonists show promising results that can be useful for nephropathies including INS.
... The pathophysiological mechanisms of proteinuria can be partially explained by increasing glomerular capillary permeability to proteins and reduced protein reabsorption capacity in the renal tubules. Still, exercise-induced-proteinuria is not fully understood, but it seems that the renin-angiotensin system and prostaglandins have an essential role in its development (Filha et al., 2019). ...
Introduction: The popularity of trail running and endurance sports has increased substantially in the last two decades. Research around trail running has focused mainly on acute injuries and medical problems considering physiological, biochemical, nutritional, aspects, and external loads. More recently, researchers have been concerned with investigating the short- and long-term effects of prolonged and strenuous exercise, given that trail running is one of the most physically and physiologically demanding sports, and can potentially lead to related chronic health problems. The link between these acute health problems and the development of subsequent chronic diseases is not clearly established. However, the relationship has been reported in certain populations (e.g., harvesters) that have similarities such as high physical load, exposure to adverse temperature conditions and severe dehydration. Considering the new technologies such as wearable devices, this thesis focuses on deepening the interrelation between internal and external load aspects related to acute muscle and kidney injury (AKI). This information will clarify the causality and potential consequences of muscle and kidney damage and how this could impact the long term.
Aims: The aims of this thesis were: a. delve into the findings on exertional rhabdomyolysis (ER) and AKI in endurance sports, emphasizing the diagnostic criteria used, the physical and environmental contextual conditions in which the ER and the AKI are developed. b. Analyze which external load indicators have the most influence on the biomarkers of muscle and kidney injury. c. Explore potential exposure to kidney disease in endurance athletes in countries with adverse hot and humid conditions. And d. Globally explore the variables of heat stress, dehydration and external workload as indicators of acute kidney injury in endurance running.
Methods: The four specific aims of this thesis were investigated through a systematic review, an exploration of the agreement and reliability of wearable devices for the quantification of renal and muscular load, and three cross-sectional observational studies on the effects of trail running on markers of muscular and renal injury at the level of external load, blood and urinary variables. For the systematic review, a digital search was carried out (PubMed [MEDLINE], Science Direct, [EMBASE] and Web of Science [WoS]) using the keywords “sport”, “exertional rhabdomyolysis”, “acute renal failure”, “acute kidney injury ". For the study of agreement and reliability of wearable devices (MARG sensors), 18 trail runners participated who ran two 12 km circuits using six MARG sensors in different parts of the body. The lineal relationship, the difference of means, the intraclass correlation and the bias of load variables were investigated. In the cross-sectional observational studies, a total of 67 participants were measured who ran a distance of approximately 35km where they were evaluated before and after running variables such as: serum creatine kinase, serum creatinine, serum urea nitrogen, serum albumin, urinary variables such as protein, bilirubin, glucose, leukocytes, erythrocytes, urobilinogen, urine specific gravity and relative variables of external load such as player load, impacts, entropy.
Results: A total of 43 publications were extracted from the systematic review (sample = 813) and 345 (43.5%) individuals were diagnosed with ER (creatinine kinase> 5000 IU / L) and 130 (16.39%) concomitantly with AKI (creatinine ≥ 1.88 mg / dL). Of the total cases of ER + AKI, 96.92% were in endurance runners. In the agreement and reliability study, good agreement and a substantial almost perfect reliability of the external load variables were obtained. Observational studies suggest that: a. There are pre-post differences in variables such as creatine kinase, creatinine, ureic nitrogen, albumin and bilirubin and protein in the urine, which suggests a significant muscle and renal injury due to trail running. Additionally, these internal load results are related to external load variables such as player load and impacts. It is important to note that the position of the L3-L5 sensors explains the behavior of internal blood load variables.
Conclusions: It was concluded that trail running is one of the sports that causes the most significant muscle and kidney damage, and inconsistencies were found between the studies in the diagnostic criteria for ER and AKI, which represented difficulty in interpreting the data. It can be concluded that the MARG sensors offer significant reliability, good agreement when evaluating the external load of six different segments of the body during the trail running. External load assessment devices are useful for measuring cumulative renal trauma due to impacts. A new hypothesis of the effect of running this type of event with mechanical forces on the kidney is derived. In this sense, variables such as impacts, player load and entropy can predict muscle and kidney damage. Additionally, urine tests can be useful to identify potential AKI cases on an outpatient basis.
... A recent study by Silva-Filha et al. [100] analyzed the role of both RAAS axes in pediatric patients with primary nephrotic syndrome (NS). Thirty-one patients with primary NS and 19 healthy controls underwent urine collection for measurement of RAAS molecules [99]. ...
... Thirty-one patients with primary NS and 19 healthy controls underwent urine collection for measurement of RAAS molecules [99]. The analysis showed that primary NS patients had reduced urinary levels of ACE2, but increased urinary concentrations of Ang II, Ang-(1-7), and ACE [100]. Additionally, reduced ACE2 levels were negatively correlated with proteinuria in patients with primary NS [100]. ...
... The analysis showed that primary NS patients had reduced urinary levels of ACE2, but increased urinary concentrations of Ang II, Ang-(1-7), and ACE [100]. Additionally, reduced ACE2 levels were negatively correlated with proteinuria in patients with primary NS [100]. Previous studies had already indicated that acquired or genetic deficiency of ACE2 increased kidney injury and proteinuria in other kidney diseases [61], probably due to potentiation of Ang II effects. ...
The last decade was crucial for our understanding of the renin-angiotensin-aldosterone system (RAAS) as a two-axis, counter-regulatory system, divided into the classical axis, formed by angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and the angiotensin type 1 receptor (AT1R), and the alternative axis comprising angiotensin-converting enzyme 2 (ACE2), angio-tensin-(1-7) (Ang-(1-7)), and the Mas receptor. Breakthrough discoveries also took place, with other RAAS endopeptides being described, including alamandine and angiotensin A. In this review, we characterize the two RAAS axes and the role of their components in pediatric kidney diseases, including childhood hypertension (HTN), pediatric glomerular diseases, congenital abnormalities of the kidney and urinary tract (CAKUT), and chronic kidney disease (CKD). We also present recent findings on potential interactions between the novel coronavirus, SARS-CoV-2, and components of the RAAS, as well as potential implications of coronavirus disease 2019 (COVID-19) for pediatric kidney diseases.
... Indeed, in chronic kidney disease patients without a history of cardiovascular disease, there was a significant decrease in circulating ACE2 activity and zinc levels when compared with healthy control subjects [96,97]. Since proteinuria was associated with lower blood levels of sACE2 protein [153] and chronic kidney disease patients had higher urinary zinc excretion than healthy controls [97], low sACE2 activity in chronic renal diseases and protection from SARS might derive from a higher sACE2 and/or Zn 2+ renal excretion. Indeed, sACE2 is detectable in urine of healthy subjects and urinary sACE2 protein levels are elevated in patients with chronic renal diseases and in hypertensive patients treated with the Ang II type 1 receptor blocker (ARB) olmesartan [41,154]. ...
The article describes the rationale for inhibition of the renin-angiotensin system (RAS) pathways as specific targets in patients infected by SARS-CoV-2 in order to prevent positive feedback-loop mechanisms. Based purely on experimental studies in which RAS pathway inhibitors were administered in vivo to humans/rodents, a reasonable hypothesis of using inhibitors that block both ACE and ACE2 zinc metalloproteases and their downstream pathways in COVID-19 patients will be proposed. In particular, metal (zinc) chelators and renin inhibitors may work alone or in combination to inhibit the positive feedback loops (initially triggered by SARS-CoV-2 and subsequently sustained by hypoxia independently on viral trigger) as both arms of renin-angiotensin system are upregulated, leading to critical, advanced and untreatable stages of the disease.
... On the other hand, in chronic kidney disease patients without a history of cardiovascular disease, there was a significant decrease in circulating ACE2 activity when compared with healthy control subjects [78]. Since proteinuria was associated with lower blood levels of ACE2 protein [79], low ACE2 activity in chronic renal diseases and protection from SARS might derive from a higher sACE2 renal excretion. Indeed, ACE2 is detectable in urine of healthy subjects and urinary ACE2 protein levels are elevated in patients with chronic renal diseases and in hypertensive patients treated with the Ang II type 1 receptor blocker (ARB) olmesartan [24] [80]. ...
The renin-angiotensin system (RAS) comprises a biochemical cascade that hydrolyzes angiotensinogen into several different bioactive peptides, which can activate different receptors promoting plenty of specific effects. The aim of this study was to evaluate the presence of the putative product of alamandine, the pentapeptide alamandine-(1-5) in the circulation and its biological activity. To accomplish this we have used mass spectrometry (MALDI/TOF/TOF, LC-MS/MS) and several methodologies including isolated blood vessels, isolated perfused hearts, isolated cardiomyocytes, blood pressure recording in freely-moving normotensive and hypertensive rats (SHR), high resolution echocardiography (VEVO 2100), central administration (ICV infusion and microinjection in the insular cortex), cell culture (endothelial cells and GPCR-transfected CHO cells) and wild type and Mas, MrgD or AT2R deficient mice. Our results show that alamandine-(1-5) circulates in the human and rodent blood and promotes many biological central and peripheral actions. More importantly, its plasma concentration is increased in pediatric nephropathic patients. A major role for plasma ACE activity in the formation of alamandine-(1-5) from alamandine was observed using plasma samples from Angiotensinogen-KO mice. Alamandine-(1-5) increased Baroreflex sensitivity and produced a long-lasting (~6 hours) anti-hypertensive effect in SHR, associated with a significant reduction in cardiac output. A particularly important effect of this pentapeptide was observed in isolated perfused heart and cardiomyocyte contractility (reduced inotropism). It was capable of stimulating NO production through all receptors from the renin-angiotensin protective arm, (MAS, MrgD and AT2R) in CHO-transfected cells. Our data shows that Alamandine-(1-5) exhibits selective actions that set it apart from traditional concepts of the vasodilatory axis of the RAS and that are possibly intricately linked to a complex interplay between Mas, MrgD and AT2 receptors. This novel finding suggests that RAS may possess a complexity that surpasses our current understanding.
