miR-486-5p protects against rat ischemic kidney injury and prevents the transition to chronic kidney disease and vascular dysfunction.

AIM: Acute kidney injury (AKI) increases the risk for progressive chronic kidney disease (CKD). MicroRNA (miR)-486-5p protects against kidney ischemia-reperfusion (IR) injury in mice, although its long-term effects on the vasculature and development of CKD are unknown. We studied whether miR-486-5p would prevent the AKI to CKD transition in rat, and affect vascular function. METHODS: Adult male rats were subjected to bilateral kidney IR followed by i.v. injection of liposomal-packaged miR-486-5p (0.5 mg/kg). Kidney function and histologic injury were assessed after 24 h and 10 weeks. Kidney endothelial protein levels were measured by immunoblot and immunofluorescence, and mesenteric artery reactivity was determined by wire myography. RESULTS: In rats with IR, miR-486-5p blocked kidney endothelial cell increases in intercellular adhesion molecule-1 (ICAM-1), reduced neutrophil infiltration and histologic injury, and normalized plasma creatinine (P<0.001). However, miR-486-5p attenuated IR-induced kidney endothelial nitric oxide synthase (eNOS) expression (P<0.05). At 10 weeks, kidneys from rats with IR alone had decreased peritubular capillary density and increased interstitial collagen deposition (P<0.0001), and mesenteric arteries showed impaired endothelium-dependent vasorelaxation (P<0.001). These changes were inhibited by miR-486-5p. Delayed miR-486-5p administration (96 h, 3 weeks after IR) had no impact on kidney fibrosis, capillary density, or endothelial function. CONCLUSION: In rats, administration of miR-486-5p early after kidney IR prevents injury, and protects against CKD development and systemic endothelial dysfunction. These protective effects are associated with inhibition of endothelial ICAM-1 and occur despite reduction in eNOS. miR-486-5p holds promise for the prevention of ischemic AKI and its complications.

Protecting the kidney in sepsis: resident macrophages to the rescue.

Kidney resident macrophages exert pro-inflammatory or reparative effects in experimental acute kidney injury, but their role in sepsis is unclear. In a mouse model of sepsis, Privratsky et al. show that kidney resident F4/80hi macrophages protect against kidney injury by expressing interleukin-1 receptor antagonist, which blocks interleukin-6 production selectively from endothelial cells. Discovery of this novel autocrine loop enhances opportunities for targeted therapies to diminish kidney injury during sepsis.

miRNA-486-5p: signaling targets and role in non-malignant disease.

MicroRNAs (miRNAs) are short non-coding RNAs, highly conserved between species, that are powerful regulators of gene expression. Aberrant expression of miRNAs alters biological processes and pathways linked to human disease. miR-486-5p is a muscle-enriched miRNA localized to the cytoplasm and nucleus, and is highly abundant in human plasma and enriched in small extracellular vesicles. Studies of malignant and non-malignant diseases, including kidney diseases, have found correlations with circulating miR-486-5p levels, supporting its role as a potential biomarker. Pre-clinical studies of non-malignant diseases have identified miR-486-5p targets that regulate major signaling pathways involved in cellular proliferation, migration, angiogenesis, and apoptosis. Validated miR-486-5p targets include phosphatase and tensin homolog (PTEN) and FoXO1, whose suppression activates phosphatidyl inositol-3-kinase (PI3K)/Akt signaling. Targeting of Smad1/2/4 and IGF-1 by miR-486-5p inhibits transforming growth factor (TGF)-ß and insulin-like growth factor-1 (IGF-1) signaling, respectively. Other miR-486-5p targets include matrix metalloproteinase-19 (MMP-19), Sp5, histone acetyltransferase 1 (HAT1), and nuclear factor of activated T cells-5 (NFAT5). In this review, we examine the biogenesis, regulation, validated gene targets and biological effects of miR-486-5p in non-malignant diseases.

Page kidney: Rare cause of acute kidney injury after complicated renal artery angioplasty.

The authors present a case of a patient who experienced a rare complication after attempted renal angioplasty and stenting, Page kidney. This patient presented with new onset hypertension secondary to bilateral renal artery stenosis and was referred for revascularization given hypertension refractory to medical management. The right renal artery underwent successful angioplasty and stenting; however, the left renal artery experienced recoil stenosis. Post-procedure the patient developed acute kidney injury secondary to Page kidney from subcapsular and extracapsular hematoma. This was managed conservatively with transfusions and the hematoma and acute kidney injury self-resolved over the next 4 months. This case highlights the importance of revascularization for refractory hypertension secondary to hemodynamically significant bilateral renal artery stenosis, the rare complication of Page kidney with attempted revascularization of renal artery stenosis and the involvement of a hypertension specialist in the decision of revascularization of renal artery stenosis.

micro-RNA-486-5p protects against kidney ischemic injury and modifies the apoptotic transcriptome in proximal tubules.

Acute kidney injury (AKI) carries high morbidity and mortality, and effective treatments are lacking. Preclinical models support involvement of micro-RNAs (miRs) in AKI pathogenesis, although effects on the kidney transcriptome are unclear. We previously showed that injection of cord blood endothelial colony forming cell-derived exosomes, enriched in miR-486-5p, prevented ischemic AKI in mice. To further define this, we studied direct effects of miR-486-5p in mice with kidney ischemia-reperfusion injury. RNA-Seq was used to compare the impact of miR-486-5p and exosomes on the transcriptome of proximal tubules and kidney endothelial cells 24 hours after ischemia-reperfusion. In mice with AKI, injection of miR-486-5p mimic increased its levels in proximal tubules and endothelial cells, and improved plasma creatinine, histological injury, neutrophil infiltration, and apoptosis. Additionally, miR-486-5p inhibited expression of its target phosphatase and tensin homolog, and activated protein kinase B. In proximal tubules, miR-486-5p or exosomes reduced expression of genes associated with ischemic injury and the tumor necrosis factor (TNF) pathway, and altered distinct apoptotic genes. In endothelial cells, genes associated with metabolic processes were altered by miR-486-5p or exosomes, although TNF pathway genes were not affected. Thus, our results suggest that miR-486-5p may have therapeutic potential in AKI.

MicroRNA in Human Acute Kidney Injury: A Systematic Review Protocol.

BACKGROUND: Acute kidney injury (AKI) is a common complication of hospitalization with high morbidity and mortality for which no effective treatments exist and for which current diagnostic tools have limitations for earlier identification. MicroRNAs (miRNAs) are small non-coding RNAs that have been implicated in the pathogenesis of AKI, and some miRNAs have shown promise as therapeutic tools in animal models of AKI. However, less is known about the role of miRNAs in human AKI. OBJECTIVE: To evaluate the role of miRNAs in human subjects with AKI. DESIGN: Systematic review and meta-analysis. MEASUREMENTS: Quantification of miRNA levels from human blood, urine, or kidney biopsy samples, and measures of renal function as defined in the study protocol. METHODS: A comprehensive search strategy for Ovid MEDLINE All, Embase, Web of Science, and CENTRAL will be developed to identify investigational studies that evaluated the relationship between miRNA levels and human AKI. Primary outcomes will include measurements of kidney function and miRNA levels. Study screening, review and data extraction will be performed independently by 2 reviewers. Study quality and certainty of evidence will be assessed with validated tools. A narrative synthesis will be included and the possibility for meta-analysis will be assessed according to characteristics of clinical and statistical heterogeneity between studies. LIMITATIONS: These include (1) lack of randomized trials of miRNAs for the prevention or treatment of human AKI, (2) quality of included studies, and (3) sources of clinical and statistical heterogeneity that may affect strength and reproducibility of results. CONCLUSION: Previous studies of miRNAs in different animal models of AKI have generated strong interest on their use for the prevention and treatment of human AKI. This systematic review will characterize the most promising miRNAs for human research and will identify methodological constraints from miRNA research in human AKI to help inform the design of future studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020201253.

CONTEXTE: L'insuffisance rénale aiguë (IRA) est une complication fréquente des hospitalisations avec morbidité et mortalité élevées. Il n'existe aucun traitement efficace contre l'IRA et les outils diagnostiques actuels qui permettent son dépistage précoce comportent des limites. Les microARN (miARN) sont de petits ARN non codants ayant été impliqués dans la pathogenèse de l'IRA; certains d'entre eux se sont révélés prometteurs comme outils thérapeutiques dans les modèles animaux de l'IRA. Le rôle des miARN dans l'IRA chez l'humain est cependant moins connu. OBJECTIF: Évaluer le rôle des miARN chez les sujets humains atteints d'IRA. TYPE D'ÉTUDE: Examen systématique et méta-analyze. MESURES: La quantification des taux de miARN chez l'humain à partir d'échantillons de sang, d'urine ou de biopsie rénale, et mesure de la fonction rénale telle que définie dans le protocole de l'étude. MÉTHODOLOGIE: Une stratégie de recherche exhaustive des bases de données Ovid MEDLINE All, Embase, Web of Science et CENTRAL sera élaborée afin de répertorier les études expérimentales ayant évalué la relation entre les taux de miARN et l'IRA chez l'humain. Les principaux critères d'évaluation comprendront la mesure de la fonction rénale et des taux de miARN. Deux examinateurs procéderont de façon indépendante à la sélection des études, à leur examen et à l'extraction des données. La qualité des études et la robustesse des données seront évaluées à l'aide d'outils validés. Une synthèse descriptive sera incluse et la possibilité d'une méta-analyze sera évaluée en fonction des caractéristiques de l'hétérogénéité clinique et statistique entre les études. LIMITES: Les limites de l'étude concernent notamment (i) le manque d'essais randomisés examinant les miARN pour la prévention ou le traitement de l'IRA humaine; (ii) la qualité des études incluses; et (iii) les sources d'hétérogénéité clinique et statistique susceptibles d'affecter la robustesse et la reproductibilité des résultats. CONCLUSION: Des études antérieures sur les miARN dans différents modèles animaux de l'IRA ont suscité un vif intérêt pour leur utilization dans la prévention et le traitement de l'IRA chez l'humain. Cet examen systématique caractérisera les miARN les plus prometteurs pour la recherche sur l'IRA humaine et définira les contraintes méthodologiques de telles études, ce qui aidera à orienter la conception des études futures.

Sex diversity in proximal tubule and endothelial gene expression in mice with ischemic acute kidney injury.

Female sex protects against development of acute kidney injury (AKI). While sex hormones may be involved in protection, the role of differential gene expression is unknown. We conducted gene profiling in male and female mice with or without kidney ischemia-reperfusion injury (IRI). Mice underwent bilateral renal pedicle clamping (30 min), and tissues were collected 24 h after reperfusion. RNA-sequencing (RNA-Seq) was performed on proximal tubules (PTs) and kidney endothelial cells. Female mice were resistant to ischemic injury compared with males, determined by plasma creatinine and neutrophil gelatinase-associated lipocalin (NGAL), histologic scores, neutrophil infiltration, and extent of apoptosis. Sham mice had sex-specific gene disparities in PT and endothelium, and male mice showed profound gene dysregulation with ischemia-reperfusion compared with females. After ischemia PTs from females exhibited smaller increases compared with males in injury-associated genes lipocalin-2 (Lcn2), hepatitis A virus cellular receptor 1 (Havcr1), and keratin 18 (Krt18), and no up-regulation of SRY-Box transcription factor 9 (Sox9) or keratin 20 (Krt20). Endothelial up-regulation of adhesion molecules and cytokines/chemokines occurred in males, but not females. Up-regulated genes in male ischemic PTs were linked to tumor necrosis factor (TNF) and Toll-like receptor (TLR) pathways, while female ischemic PTs showed up-regulated genes in pathways related to transport. The data highlight sex-specific gene expression differences in male and female PTs and endothelium before and after ischemic injury that may underlie disparities in susceptibility to AKI.

Mechanisms for hemodynamic instability related to renal replacement therapy: a narrative review.

Hemodynamic instability related to renal replacement therapy (HIRRT) is a frequent complication of all renal replacement therapy (RRT) modalities commonly used in the intensive care unit. HIRRT is associated with increased mortality and may impair kidney recovery. Our current understanding of the physiologic basis for HIRRT comes primarily from studies of end-stage kidney disease patients on maintenance hemodialysis in whom HIRRT is referred to as 'intradialytic hypotension'. Nonetheless, there are many studies that provide additional insights into the underlying mechanisms for HIRRT specifically in critically ill patients. In particular, recent evidence challenges the notion that HIRRT is almost entirely related to excessive ultrafiltration. Although excessive ultrafiltration is a key mechanism, multiple other RRT-related mechanisms may precipitate HIRRT and this could have implications for how HIRRT should be managed (e.g., the appropriate response might not always be to reduce ultrafiltration, particularly in the context of significant fluid overload). This review briefly summarizes the incidence and adverse effects of HIRRT and reviews what is currently known regarding the mechanisms underpinning it. This includes consideration of the evidence that exists for various RRT-related interventions to prevent or limit HIRRT. An enhanced understanding of the mechanisms that underlie HIRRT, beyond just excessive ultrafiltration, may lead to more effective RRT-related interventions to mitigate its occurrence and consequences.

Safety Lapses Prior to Initiation of Hemodialysis for Acute Kidney Injury in Hospitalized Patients: A Patient Safety Initiative.

Background: Safety lapses in hospitalized patients with acute kidney injury (AKI) may lead to hemodialysis (HD) being required before renal recovery might have otherwise occurred. We sought to identify safety lapses that, if prevented, could reduce the need for unnecessary HD after AKI; Methods: We conducted a retrospective observational study that included consecutive patients treated with HD for AKI at a large, tertiary academic center between 1 September 2015 and 31 August 2016. Exposures of interest were pre-specified iatrogenic processes that could contribute to the need for HD after AKI, such as nephrotoxic medication or potassium supplement administration. Other outcomes included time from AKI diagnosis to initial management steps, including Nephrology referral; Results: After screening 344 charts, 80 patients were included for full chart review, and 264 were excluded because they required HD within 72 h of admission, were deemed to have progression to end-stage kidney disease (ESKD), or required other renal replacement therapy (RRT) modalities in critical care settings such as continuous renal replacement therapy (CRRT) or sustained low efficiency dialysis (SLED). Multiple safety lapses were identified. Sixteen patients (20%) received an angiotensin converting enzyme inhibitor or angiotensin receptor blocker after AKI onset. Of 35 patients with an eventual diagnosis of pre-renal AKI due to hypovolemia, only 29 (83%) received a fluid bolus within 24 h. For 28 patients with hyperkalemia as an indication for starting HD, six (21%) had received a medication associated with hyperkalemia and 13 (46%) did not have a low potassium diet ordered. Nephrology consultation occurred after a median (IQR) time after AKI onset of 3.0 (1.0⁻5.7) days; Conclusions: Although the majority of patients had multiple indications for the initiation of HD for AKI, we identified many safety lapses related to the diagnosis and management of patients with AKI. We cannot conclude that HD initiation was avoidable, but, improving safety lapses may delay the need for HD initiation, thereby allowing more time for renal recovery. Thus, development of automated processes not only to identify AKI at an early stage but also to guide appropriate AKI management may improve renal recovery rates.

Interventions to prevent hemodynamic instability during renal replacement therapy in critically ill patients: a systematic review.

BACKGROUND: Hemodynamic instability related to renal replacement therapy (HIRRT) may increase the risk of death and limit renal recovery. Studies in end-stage renal disease populations on maintenance hemodialysis suggest that some renal replacement therapy (RRT)-related interventions (e.g., cool dialysate) may reduce the occurrence of HIRRT, but less is known about interventions to prevent HIRRT in critically ill patients receiving RRT for acute kidney injury (AKI). We sought to evaluate the effectiveness of RRT-related interventions for reducing HIRRT in such patients across RRT modalities. METHODS: A systematic review of publications was undertaken using MEDLINE, MEDLINE in Process, EMBASE, and Cochrane's Central Registry for Randomized Controlled Trials (RCTs). Studies that assessed any intervention's effect on HIRRT (the primary outcome) in critically ill patients with AKI were included. HIRRT was variably defined according to each study's definition. Two reviewers independently screened abstracts, identified articles for inclusion, extracted data, and evaluated study quality using validated assessment tools. RESULTS: Five RCTs and four observational studies were included (n = 9; 623 patients in total). Studies were small, and the quality was mostly low. Interventions included dialysate sodium modeling (n = 3), ultrafiltration profiling (n = 2), blood volume (n = 2) and temperature control (n = 3), duration of RRT (n = 1), and slow blood flow rate at initiation (n = 1). Some studies applied more than one strategy simultaneously (n = 5). Interventions shown to reduce HIRRT from three studies (two RCTs and one observational study) included higher dialysate sodium concentration, lower dialysate temperature, variable ultrafiltration rates, or a combination of strategies. Interventions not found to have an effect included blood volume and temperature control, extended duration of intermittent RRT, and slower blood flow rates during continuous RRT initiation. How HIRRT was defined and its frequency of occurrence varied widely across studies, including those involving the same RRT modality. Pooled analysis was not possible due to study heterogeneity. CONCLUSIONS: Small clinical studies suggest that higher dialysate sodium, lower temperature, individualized ultrafiltration rates, or a combination of these strategies may reduce the risk of HIRRT. Overall, for all RRT modalities, there is a paucity of high-quality data regarding interventions to reduce the occurrence of HIRRT in critically ill patients.

Interventions to prevent hemodynamic instability during renal replacement therapy for acute kidney injury: a systematic review protocol.

BACKGROUND: Hemodynamic instability during renal replacement therapy (HIRRT) in the form of intradialytic hypotension (IDH) is a frequent complication of hemodialysis in end-stage kidney disease (ESKD), and most studies have focused on this chronic population. However, HIRRT is also an important concern for critically ill ICU patients with acute kidney injury (AKI), complicating an estimated 30% of dialysis treatments in this population. HIRRT can exacerbate organ hypoperfusion in the setting of critical illness and may negatively impact renal recovery in the AKI population. This is a protocol for a systematic review to synthesize the evidence surrounding dialysis-related interventions used to minimize HIRRT in critically ill patients with RRT-requiring AKI. This protocol has been registered with the International Prospective Register of Systematic Reviews (PROSPERO) database. METHODS/DESIGN: We will search MEDLINE, EMBASE, and CENTRAL databases in collaboration with a health information specialist using a comprehensive search strategy. We will also supplement our search with a scan of the "gray literature" to identify relevant ongoing trials or conference abstracts. Observational studies and clinical trials will be included in our analysis. Our outcomes will include the incidence of HIRRT, dialysis-related complications, in-hospital mortality, and renal recovery. Prior to our search, we performed an initial search of these databases and PROSPERO, which yielded no prior or ongoing systematic reviews on this topic. Two reviewers will independently screen the list of identified abstracts using pre-defined inclusion and exclusion criteria. Two reviewers will then independently extract data from selected studies and undertake an assessment of their quality using validated tools. DISCUSSION: HIRRT is a common complication of renal replacement therapy not only in ESKD but also in the critically ill AKI population. It can result in early discontinuation of dialysis, further organ injury from hypoperfusion, and possibly negatively impact renal recovery. This systematic review will synthesize the existing evidence on the interventions employed to predict or prevent episodes HIRRT in critically ill patients with RRT-requiring AKI. This systematic review will allow for an understanding the current evidence for interventions to limit HIRRT in AKI and, in doing so, may also highlight areas in need of further research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016037754.

Functional analysis of the TRIB1 associated locus linked to plasma triglycerides and coronary artery disease.

BACKGROUND: The TRIB1 locus has been linked to hepatic triglyceride metabolism in mice and to plasma triglycerides and coronary artery disease in humans. The lipid-associated single nucleotide polymorphisms (SNPs), identified by genome-wide association studies, are located ≈30 kb downstream from TRIB1, suggesting complex regulatory effects on genes or pathways relevant to hepatic triglyceride metabolism. The goal of this study was to investigate the functional relationship between common SNPs at the TRIB1 locus and plasma lipid traits. METHODS AND RESULTS: Characterization of the risk locus reveals that it encompasses a gene, TRIB1-associated locus (TRIBAL), composed of a well-conserved promoter region and an alternatively spliced transcript. Bioinformatic analysis and resequencing identified a single SNP, rs2001844, within the promoter region that associates with increased plasma triglycerides and reduced high-density lipoprotein cholesterol and coronary artery disease risk. Further, correction for triglycerides as a covariate indicated that the genome-wide association studies association is largely dependent on triglycerides. In addition, we show that rs2001844 is an expression trait locus (eQTL) for TRIB1 expression in blood and alters TRIBAL promoter activity in a reporter assay model. The TRIBAL transcript has features typical of long noncoding RNAs, including poor sequence conservation. Modulation of TRIBAL expression had limited impact on either TRIB1 or lipid regulatory genes mRNA levels in human hepatocyte models. In contrast, TRIB1 knockdown markedly increased TRIBAL expression in HepG2 cells and primary human hepatocytes. CONCLUSIONS: These studies demonstrate an interplay between a novel locus, TRIBAL, and TRIB1. TRIBAL is located in the genome-wide association studies identified risk locus, responds to altered expression of TRIB1, harbors a risk SNP that is an eQTL for TRIB1 expression, and associates with plasma triglyceride concentrations.