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.

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)-β 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.

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.

Early diagnosis of acute kidney injury (AKI) is limited with current tools. MicroRNAs (miRNAs) are implicated in AKI pathogenesis in preclinical models, but less is known about their role in humans. We conducted a systematic review to identify dysregulated miRNAs in humans with AKI. We searched Ovid MEDLINE, Embase, Web of Science, and CENTRAL (August 21, 2023) for studies of human subjects with AKI. We excluded reviews and pre-clinical studies without human data. The primary outcome was dysregulated miRNAs in AKI. Two reviewers screened abstracts, reviewed full texts, performed data extraction and quality assessment (Newcastle Ottawa Scale). We screened 2,456 reports and included 92 for synthesis without meta-analysis. All studies except one were observational. Studies were grouped by etiology of AKI: cardiac surgery-associated (CS-AKI, n = 13 studies), sepsis (n = 25), nephrotoxic (n = 9), kidney transplant (n = 26), and other causes (n = 19). In total, 128 miRNAs were identified to be dysregulated across AKI studies (45 miRNAs upregulated, 55 downregulated, 28 both). miR-21 was the most frequently reported (n = 17 studies) and it was increased in all etiologies except CS-AKI where it was decreased (n = 3 studies). Study limitations included bias due to targeted approaches, absence of clinical data/controls, and miRNA normalization methods. Overall study quality was fair (median 5/9, range 2-8 points). Dysregulated miRNAs, particularly miR-21, have potential as AKI biomarkers. These results should be interpreted cautiously due to methodological limitations. Standardized methods and unbiased approaches are needed to validate candidate miRNA biomarkers. Registration: International Prospective Register of Systematic Reviews (PROSPERO CRD42020201253)

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.

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