Strategy For Acute Kidney Injury Research Articles

Circulating endothelial microparticles: a promising biomarker of acute kidney injury after cardiac surgery with cardiopulmonary bypass

BackgroundCurrent diagnostic strategies for acute kidney injury (AKI) after cardiac surgery with cardiopulmonary bypass (CPB) are nonspecific and limited. Previously, we demonstrated that circulating microparticles (MPs) in patients with valve heart disease (VHD) and congenital heart diseases (CHD) induce endothelial dysfunction and neutrophil chemotaxis, which may result in kidney injury. We also found that circulating MPs increase after cardiac surgery with CPB and are related to cardiac function. However, the relationship between circulating MPs and AKI after CPB is unknown.MethodsEighty-five patients undergoing cardiac surgery with CPB were enrolled. Patients were divided into AKI and non-AKI groups based on the serum creatinine levels at 12 h and 3 d post-CPB. Circulating MPs were isolated from plasma, and their levels including its subtypes were detected by flow cytometer. Independent risk factors for the CPB-associated AKI (CPB-AKI) were determined by multivariate logistic regression analysis. Receiver operating characteristic (ROC) analysis was used to measure the prognostic potential of CPB-AKI.ResultsThe morbidity of AKI at 12 h and 3 d after cardiac surgery with CPB was 40% and 31.76%, respectively. The concentrations of total MPs and platelet-derived MPs (PMP) remained unchanged at 12 h and then increased at 3 d post-CPB, while that of endothelial-derived MPs (EMP) increased at both time points. In patients with AKI, PMP and EMP were elevated compared with the patients without AKI. However, no significant change was detected on monocyte-derived MPs (MMP) at 12 h and 3 d post-CPB. The logistic regression analysis showed that EMP was the independent risk factor for AKI both at 12 h and 3 d post-CPB. The area under ROC for the concentrations of EMP at 12 h and 3 d post-CPB was 0.86 and 0.91, with the specificity up to 0.88 and 0.91, respectively.ConclusionsCirculating EMP may serve as a potential biomarker of AKI after cardiac surgery with CPB.

Optimizing predictive strategies for acute kidney injury after major vascular surgery

BackgroundPostoperative acute kidney injury is common after major vascular surgery and is associated with increased morbidity, mortality, and cost. High-performance risk stratification using a machine learning model can inform strategies that mitigate harm and optimize resource use. It is hypothesized that incorporating intraoperative data would improve machine learning model accuracy, discrimination, and precision in predicting acute kidney injury among patients undergoing major vascular surgery. MethodsA single-center retrospective cohort of 1,531 adult patients who underwent nonemergency major vascular surgery, including open aortic, endovascular aortic, and lower extremity bypass procedures, was evaluated. The validated, automated MySurgeryRisk analytics platform used electronic health record data to forecast patient-level probabilistic risk scores for postoperative acute kidney injury using random forest models with preoperative data alone and perioperative data (preoperative plus intraoperative). The MySurgeryRisk predictions were compared with each other as well as with the American Society of Anesthesiologists physical status classification. ResultsMachine learning models using perioperative data had greater accuracy, discrimination, and precision than models using either preoperative data alone or the American Society of Anesthesiologists physical status classification (accuracy: 0.70 vs 0.64 vs 0.62, area under the receiver operating characteristics curve: 0.77 vs 0.68 vs 0.61, area under the precision-recall curve: 0.70 vs 0.58 vs 0.48). ConclusionIn predicting acute kidney injury after major vascular surgery, machine learning approaches that incorporate dynamic intraoperative data had greater accuracy, discrimination, and precision than models using either preoperative data alone or the American Society of Anesthesiologists physical status classification. Machine learning methods have the potential for real-time identification of high-risk patients who may benefit from personalized risk-reduction strategies.

Preventive strategies for acute kidney injury in cancer patients

Acute kidney injury (AKI) is a common complication of cancer that occurs in up to 50% of neoplastic patients during the natural history of their disease; furthermore, it has a huge impact on key outcomes such as overall prognosis, length of hospitalization and costs. AKI in cancer patients has different causes, either patient-, tumour- or treatment-related. Patient-related risk factors for AKI are the same as in the general population, whereas tumour-related risk factors are represented by compression, obstruction, direct kidney infiltration from the tumour as well by precipitation, aggregation, crystallization or misfolding of paraprotein (as in the case of multiple myeloma). Finally, treatment-related risk factors are the most common observed in clinical practice and may present also with the feature of tumour lysis syndrome or thrombotic microangiopathies. In the absence of validated biomarkers, a multidisciplinary clinical approach that incorporates adequate assessment, use of appropriate preventive measures and early intervention is essential to reduce the incidence of this life-threatening condition in cancer patients.

Intestinal microbiota control acute kidney injury severity by immune modulation

Intestinal microbiota impacts the host immune system and influences the outcomes of chronic diseases. However, it remains uncertain whether acute kidney injury (AKI) impacts intestinal microbiota or vice versa. To determine this, we investigated the mechanistic link between AKI, microbiota, and immune response in ischemia/reperfusion injury. Microbiota alteration and its biological consequences after ischemia/reperfusion injury were examined and the effect of dysbiotic microbiota on the outcome of AKI was also assessed by colonizing germ-free mice with post-AKI microbiota. The role of Th17, Th1, Tregs cells and macrophage polarization in mediating the renoprotective effect of antibiotic induced microbiota depletion in ischemia/reperfusion injury was also determined. Increase of Enterobacteriacea, decrease of Lactobacilli, and Ruminococacceae were found to be the hallmarks of ischemia/reperfusion injury induced dysbiosis and were associated with a decreased levels of short-chain fatty acids, intestinal inflammation and leaky gut. Colonizing germ-free mice with post-AKI microbiota worsened ischemia/reperfusion injury severity with exaggerated inflammation in recipient mice compared to colonizing with microbiota from sham operated mice. Microbiota depletion by oral antibiotics protected against ischemia/reperfusion injury. This renoprotective effect was associated with reduced Th 17, Th 1 response along with expansion of regulatory T cells, and M2 macrophages. Our study demonstrated a unique bidirectional relationship between the kidney and the intestine during AKI. Intestinal dysbiosis, inflammation and leaky gut are consequences of AKI but they also represent an important modifier determining post-AKI severity. Thus, targeting the intestinal microbiota might provide a novel therapeutic strategy in AKI.

Evaluation of biomarkers effi ciency in predictive and early diagnostics of acute kidney damage in acute coronary syndrome (pilot study)

INTRODUCTION. Acute Kidney Injury (AKI) is a common complication of acute coronary syndromes (ACS), and associated with higher mortality and adverse outcomes. Despite advances in research over the past years, effective treatments for current AKI are not available. Prevention and early intervention remain the most effective strategies for AKI of any entity. THE AIM: This study aimed to explore a risk factors and biomarkers for predictive and early diagnostic of AKI in ACS.PATIENTS AND METHODS. Study was prospective and cohort, patients hospitalized with ACS in Pavlov First Saint Petersburg State Medical University were included. In case of exclusion of ACS, patients were determined in the comparison group, in case of confirmation of the diagnosis of ACS – in the study group. Biomaterial (blood and urine) was taken at admission (T1), 1 day after admission (T2) and 2 days after admission (T3). For the diagnosis of AKI, KDIGO 2012 criteria were used. The measured biomarkers at each point were NGAL, KIM-1, cystatin C, sST2, troponin I. RESULTS. The study included 73 patients, the diagnosis of ACS was confirmed in 40 patients and AKI development was in 15 patients, all from the ACS group. The most significant for predictive diagnosis was the assessment of the parameters of systemic hemodynamics and the severity of acute heart failure (AHF): heart rate>89 (AUC=0,798, p=0,001), GRACE Risk Score>133 (AUC=0,926, p=0,005). In evaluation the suitability of biomarkers in terms of prognostic diagnosis of AKI, urine NGAL>32 ng/ml (AUC=0,814 p=0,04) and sST2>23.4 ng/ml (AUC=0,718, p=0,02) showed the best results.CONCLUSIONS. In study of biomarkers efficiency, the use of urine sST2 and NGAL is most promising. Together with hemodynamic parameters, biomarkers have high predictive ability in the diagnosis of AKI in ACS.

Urinary Extracellular Vesicles Carrying Klotho Improve the Recovery of Renal Function in an Acute Tubular Injury Model.

Acute kidney injury, defined by a rapid deterioration of renal function, is a common complication in hospitalized patients. Among the recent therapeutic options, the use of extracellular vesicles (EVs) is considered a promising strategy. Here we propose a possible therapeutic use of renal-derived EVs isolated from normal urine (urine-derived EVs [uEVs]) in a murine model of acute injury generated by glycerol injection. uEVs accelerated renal recovery, stimulating tubular cell proliferation, reducing the expression of inflammatory and injury markers, and restoring endogenous Klotho loss. When intravenously injected, labeled uEVs localized within injured kidneys and transferred their microRNA cargo. Moreover, uEVs contained the reno-protective Klotho molecule. Murine uEVs derived from Klotho null mice lost the reno-protective effect observed using murine EVs from wild-type mice. This was regained when Klotho-negative murine uEVs were reconstituted with recombinant Klotho. Similarly, ineffective fibroblast EVs acquired reno-protection when engineered with human recombinant Klotho. Our results reveal a novel potential use of uEVs as a new therapeutic strategy for acute kidney injury, highlighting the presence and role of the reno-protective factor Klotho.

Systematic Review and Meta-Analysis of Preventative Strategies for Acute Kidney Injury in Patients Undergoing Elective Abdominal Aortic Aneurysm Repair

Abstract Objective : To assess the effect of various preventative interventions for reducing the incidence of postoperative acute kidney injury (AKI) in patients undergoing elective abdominal aortic aneurysm (AAA) repair. Methods : We included randomized controlled trials of 10 patients or more which tested a preventative intervention versus standard therapy or placebo in patients undergoing elective AAA repair using the open or endovascular approach. Studies including mixed patient populations such as those with aortic occlusive disease, thoracoabdominal aneurysms or ruptured aneurysms were ineligible for review. We searched Medline (1966 - 2019), EMBASE (1947 – 2019), CINAHL (1961 – 2019), Web of Science (1945 – 2019), Scopus (1966 - 2019), and The Cochrane Library (1996 – 2019) for trials available as published manuscripts in English. Study quality was assessed using the Cochrane Collaboration risk of bias tool. Where possible we pooled the results of similar interventions using random effects meta-analysis. Results : We included 17 trials involving 1443 participants. Most trials were small, single-centre studies, with varying definitions of AKI and a high or moderate risk of bias. The preventative strategies with possible protective effects were mannitol, a composite of antioxidant supplements, an open extraperitoneal approach, and human atrial natriuretic peptide (hANP). Curcumin, methylprednisolone, carbon dioxide contrast medium, haemodynamic monitoring and N-acetylcysteine were found to be ineffective. Six trials with a total of 355 participants reported on remote ischemic preconditioning (RIPC) and our meta-analysis showed no statistically significant difference between RIPC and standard treatment (OR 1.20, 95% CI 0.37, 3.89); although the results should be interpreted with caution due to considerable statistical heterogeneity (I2=70%). None of the interventions studied significantly reduced receipt of renal replacement therapy (RRT). Conclusion : Interventions that have shown some potential to reduce AKI after AAA repair include mannitol, a composite of antioxidant supplements, an open extraperitoneal approach and hANP. These conclusions are limited by the small size, high risk of bias and inconsistency of the included trials. Large, high quality, multi-centre randomized trials will help determine which interventions are effective in reducing the incidence of postoperative AKI among patients undergoing elective AAA repair.

Looking for a better definition and diagnostic strategy for acute kidney injury: a new proposal.

Looking for a better definition and diagnostic strategy for acute kidney injury: a new proposal.

Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury.

The development of chronic kidney disease (CKD) following an episode of acute kidney injury (AKI) is an increasingly recognized clinical problem. Inhibition of toll-like receptor 4 (TLR4) protects renal function in animal models of AKI and has become a viable therapeutic strategy in AKI. However, the impact of TLR4 inhibition on the chronic sequelae of AKI is unknown. Consequently, we examined the chronic effects of TLR4 inhibition in a model of ischemic AKI. Mice with a TLR4-deletion on a C57BL/6 background and wild-type (WT) background control mice (C57BL/6) were subjected to bilateral renal artery clamping for 19 min and reperfusion for up to 6 weeks. Despite the acute protective effect of TLR4 inhibition on renal function (serum creatinine 1.6 ± 0.4 mg/dL TLR4-deletion vs. 2.8 ± 0.3 mg/dL·WT) and rates of tubular apoptosis following ischemic AKI, we found no difference in neutrophil or macrophage infiltration. Furthermore, we observed significant protection from microvascular rarefaction at six weeks following injury with TLR4-deletion, but this did not alter development of fibrosis. In conclusion, we validate the acute protective effect of TLR4 signal inhibition in AKI but demonstrate that this protective effect does not mitigate the sequential fibrogenic response in this model of ischemic AKI.

Renoprotective approaches and strategies in acute kidney injury.

Acute kidney injury (AKI) is a major renal disease associated with high mortality rate and increasing prevalence. Decades of research have suggested numerous chemical and biological agents with beneficial effects in AKI. In addition, cell therapy and molecular targeting have been explored for reducing kidney tissue damage and promoting kidney repair or recovery from AKI. Mechanistically, these approaches may mitigate oxidative stress, inflammation, cell death, and mitochondrial and other organellar damage, or activate cytoprotective mechanisms such as autophagy and pro-survival factors. However, none of these findings has been successfully translated into clinical treatment of AKI. In this review, we analyze these findings and propose experimental strategies for the identification of renoprotective agents or methods with clinical potential. Moreover, we propose the consideration of combination therapy by targeting multiple targets in AKI.

Contrast-induced acute kidney injury: potential new strategies.

Contrast-induced acute kidney injury (CI-AKI) is an impairment of renal function following contrast media administration in the absence of an alternative cause. It represents a powerful predictor of poor early and late outcomes. Here, we review the major strategies to prevent CI-AKI. Hydration represents the gold standard as a prophylactic measure to prevent CI-AKI, acting by increasing urine flow rate and, thereby, by limiting the time of contact between the contrast media and the tubular epithelial cells. An optimal hydration regimen should be defined according to predefined clinical markers, such as urine flow rate, or left ventricular end-diastolic pressure. Recently, high-dose statins pretreatment has been included in the guidelines of CI-AKI prevention. However, uncertainty still exists on the efficacy of several compounds tested in both observational trials and randomized studies to prevent CI-AKI. Compounds evaluated include diuretics (furosemide), antioxidants (i.e. N-acetylcysteine and statins) and vasodilators (i.e. calcium antagonists, dopamine and fenoldopam). Hydration still represents the most reliable strategy to prevent CI-AKI. New prophylactic strategies for acute kidney injury are still under investigation.

The heat-shock protein-70–induced renoprotective effect is partially mediated by CD4+CD25+Foxp3+ regulatory T cells in ischemia/reperfusion-induced acute kidney injury

Recent reports suggest the presence of heat-shock protein (HSP)-reactive T cells with a regulatory phenotype in various inflammatory diseases. To test whether HSP exerts renoprotective effects through regulatory T cells (Tregs), ischemia/reperfusion injury was done with or without heat preconditioning in mice. Splenocytes from heat-preconditioned mice had Treg expansion and a reduced proliferative response upon mitogenic stimulus. T cells from heat-preconditioned mice failed to reconstitute postischemic injury when adoptively transferred to T cell-deficient nu/nu mice in contrast to those from control mice. Tregs were also increased in heat-preconditioned ischemic kidneys. Depleting Tregs before heat preconditioning abolished the renoprotective effect, while adoptive transfer of these cells back into Treg-depleted mice partially restored the beneficial effect of heat preconditioning. Inhibition of HSP70 by quercetin suppressed Treg expansion, as well as renoprotective effects. Transferring Tregs in quercetin-treated heat-preconditioned mice partially restored the beneficial effect of heat preconditioning. The specificity of immune cell HSP70 in renoprotection was confirmed by partial restoration of kidney injury when T cells from HSP70-deficient heat preconditioned mice were adoptively transferred to nu/nu mice. Thus, the renoprotective effect of HSP70 may be partially mediated by a direct immunomodulatory effect through Tregs. Better understanding of immunomodulatory mechanisms of various stress proteins might facilitate discovery of new preventive strategies in acute kidney injury.

The road from AKI to CKD: the role of endothelin

The incidence of acute kidney injury (AKI) is increasing. It is now widely accepted that patients surviving an episode of AKI have a significant risk of progression to chronic kidney disease (CKD) and even end-stage renal failure. Zager and colleagues describe the role of endothelin-1 (ET-1) in the progression of AKI to CKD and provide a basis for the potential use of ET receptor antagonists as a therapeutic strategy in AKI.

Acute kidney injury: an intensivist’s perspective

The changing epidemiology of acute kidney injury (AKI) in adults and children has resulted in more patients being treated for kidney injury occurring in the context of multi-organ failure requiring treatment in the intensive care unit (ICU). AKI complicating critical illness has complex, multi-factorial etiology, and supportive care, including organ support, remains the mainstay of therapy. In the day-to-day management of AKI in the ICU two of the major challenges are the inadequacy of current diagnostics for the early identification of AKI and the relationship between hemodynamic resuscitation strategies and the development of AKI. This review focuses on these areas from the intensivist's perspective. Given that the diagnosis of AKI is often delayed, the prevention of complications and limitation of secondary renal injury are of particular importance. Fluid overload is increasingly being associated with adverse patient outcomes in critical illness and may contribute to persistent renal dysfunction. Thus, hemodynamic management strategies in AKI should be tailored to limit fluid overload as much as possible.

Current therapeutic strategies for acute kidney injury

Acute kidney injury (AKI) is characterized by a rapid decrease in kidney function and increased serum creatinine. The term acute renal failure (ARF) has been applied to such clinical manifestations. Despite several advances in the treatment of ARF, such as pharmacologic treatment and renal replacement therapy (RRT), the mortality rate among patients with ARF has changed little over the past four decades. It is widely recognized that ARF is associated with significantly increased morbidity and mortality especially in critically ill patients with ARF requiring RRT. Therefore, in order to improve outcomes in ARF patients, a new concept of AKI has been proposed. Recently the paradigm shift from ARF to AKI has been received by the research and clinical communities. In this review we will discuss the therapeutic strategies for AKI and focus on its management with an emphasis on RRT.

Reversal of anemia with allogenic RBC transfusion prevents post-cardiopulmonary bypass acute kidney injury in swine

Anemia during cardiopulmonary bypass (CPB) is strongly associated with acute kidney injury in clinical studies; however, reversal of anemia with red blood cell (RBC) transfusions is associated with further renal injury. To understand this paradox, we evaluated the effects of reversal of anemia during CPB with allogenic RBC transfusion in a novel large-animal model of post-cardiac surgery acute kidney injury with significant homology to that observed in cardiac surgery patients. Adult pigs undergoing general anesthesia were allocated to a Sham procedure, CPB alone, Sham+RBC transfusion, or CPB+RBC transfusion, with recovery and reassessment at 24 h. CPB was associated with dilutional anemia and caused acute kidney injury in swine characterized by renal endothelial dysfunction, loss of nitric oxide (NO) bioavailability, vasoconstriction, medullary hypoxia, cortical ATP depletion, glomerular sequestration of activated platelets and inflammatory cells, and proximal tubule epithelial cell stress. RBC transfusion in the absence of CPB also resulted in renal injury. This was characterized by endothelial injury, microvascular endothelial dysfunction, platelet activation, and equivalent cortical tubular epithelial phenotypic changes to those observed in CPB pigs, but occurred in the absence of severe intrarenal vasoconstriction, ATP depletion, or reductions in creatinine clearance. In contrast, reversal of anemia during CPB with RBC transfusion prevented the reductions in creatinine clearance, loss of NO bioavailability, platelet activation, inflammation, and epithelial cell injury attributable to CPB although it did not prevent the development of significant intrarenal vasoconstriction and endothelial dysfunction. In conclusion, contrary to the findings of observational studies in cardiac surgery, RBC transfusion during CPB protects pigs against acute kidney injury. Our study underlines the need for translational research into indications for transfusion and prevention strategies for acute kidney injury.