Established Acute Kidney Injury Research Articles

Subcutaneous injection of adipose stromal cell-secretome improves renal function and reduces inflammation in established acute kidney injury

BackgroundAdipose stromal cells (ASC) are a form of mesenchymal stromal cells that elicit effects primarily via secreted factors, which may have advantages for the treatment of injury or disease. Several previous studies have demonstrated a protective role for MSC/ASC on mitigating acute kidney injury but whether ASC derived factors could hasten recovery from established injury has not been evaluated.MethodsWe generated a concentrated secretome (CS) of human ASC under well-defined conditions and evaluated its ability to improve the recovery of renal function in a preclinical model of acute kidney injury (AKI) in rats. 24 h following bilateral ischemia/reperfusion (I/R), rats were randomized following determination of plasma creatinine into groups receiving vehicle -control or ASC-CS treatment by subcutaneous injection (2 mg protein/kg) and monitored for evaluation of renal function, structure and inflammation.ResultsRenal function, assessed by plasma creatinine levels, recovered faster in ASC-CS treated rats vs vehicle. The most prominent difference between the ASC-CS treated vs vehicle was observed in rats with the most severe degree of initial injury (Pcr > 3.0 mg/dl 24 h post I/R), whereas rats with less severe injury (Pcr < 2.9 mg/dl) recovered quickly regardless of treatment. The quicker recovery of ASC-treated rats with severe injury was associated with less tissue damage, inflammation, and lower plasma angiopoietin 2. In vitro, ASC-CS attenuated the activation of the Th17 phenotype in lymphocytes isolated from injured kidneys.ConclusionsTaken together, these data suggest that ASC-CS represents a potent therapeutic option to improve established AKI.

Hybrid Therapies for Supporting Critically Ill Patients with Acute Kidney Injury: When, how, and for Whom?

Acute kidney injury (AKI) is common in critically ill patients. There is no specific pharmacological treatment for established severe AKI. Therefore, the conventional therapeutic strategy is limited to the use of kidney replacement therapy (KRT) to maintain homeostasis. Hybrid therapies optimize the advantages of intermittent and continuous modalities of KRT, combining lower hourly efficiency, longer application time, at lesser cost, but also adding different physicochemical principles of extracorporeal clearance. The sum of convection and diffusion, with or without adsorption or apheresis, and in different time combinations gives hybrid techniques great flexibility in prescribing a personalized treatment adapted to the needs of each patient at any given time. Hybrid therapies are increasingly being used due to their flexibility, which is determined by the combination of equipment, membranes, and available resources (machines and health-care personnel experience). The required technology is widely available in most intensive care units and uses low-cost consumables compared to other types of AKI treatment modalities, favoring its widespread use. Hybrid therapies are feasible and provide a viable form of KRT, either alone or as a transition therapy from continuous kidney replacement therapy to intermittent hemodialysis. (Rev Invest Clin. 2023;75(6):337-47).

Assessment of rhabdomyolysis-induced acute kidney injury with chemical exchange saturation transfer magnetic resonance imaging.

Rhabdomyolysis (RM)-induced acute kidney injury (AKI) is a common renal disease with low survival rate and inadequate prognosis. In this study, we investigate the feasibility of chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) for assessing the progression of RM-induced AKI in a mouse model. AKI was induced in C57BL/6J mice via intramuscular injection of 7.5 mL/kg glycerol (n=30). Subsequently, serum creatinine (SCr), blood urea nitrogen (BUN), and hematoxylin-eosin (HE) and Masson staining, were performed. Longitudinal CEST-MRI was conducted on days 1, 3, 7, 15, and 30 after AKI induction using a 7.0-T MRI system. CEST-MRI quantification parameters including magnetization transfer ratio (MTR), MTR asymmetric analysis (MTRasym), apparent amide proton transfer (APT*), and apparent relayed nuclear Overhauser effect (rNOE*) were used to investigate the feasibility of detecting RM-induced renal damage. Significant increases of SCr and BUN demonstrated established AKI. The HE staining revealed various degrees of tubular damage, and Masson staining indicted an increase in the degree of fibrosis in the injured kidneys. Among CEST parameters, the cortical MTR presented a significant difference, and it also showed the best diagnostic performance for AKI [area under the receiver operating characteristic curve (AUC) =0.915] and moderate negative correlations with SCr and BUN. On the first day of renal damage, MTR was significantly reduced in cortex (22.7%±0.04%, P=0.013), outer stripe of outer medulla (24.7%±1.6%, P<0.001), and inner stripe of outer medulla (27.0%±1.5%, P<0.001) compared to the control group. Longitudinally, MTR increased steadily with AKI progression. The MTR obtained from CEST-MRI is sensitive to the pathological changes in RM-induced AKI, indicating its potential clinical utility for the assessment of kidney diseases.

Artificial intelligence in early detection and prediction of pediatric/neonatal acute kidney injury: current status and future directions.

Acute kidney injury (AKI) has a significant impact on the short-term and long-term clinical outcomes of pediatric and neonatal patients, and it is imperative in these populations to mitigate the pathways leading to AKI and be prepared for early diagnosis and treatment intervention of established AKI. Recently, artificial intelligence (AI) has provided more advent predictive models for early detection/prediction of AKI utilizing machine learning (ML). By providing strong detail and evidence from risk scores and electronic alerts, this review outlines a comprehensive and holistic insight into the current state of AI in AKI in pediatric/neonatal patients. In the pediatric population, AI models including XGBoost, logistic regression, support vector machines, decision trees, naïve Bayes, and risk stratification scores (Renal Angina Index (RAI), Nephrotoxic Injury Negated by Just-in-time Action (NINJA)) have shown success in predicting AKI using variables like serum creatinine, urine output, and electronic health record (EHR) alerts. Similarly, in the neonatal population, using the "Baby NINJA" model showed a decrease in nephrotoxic medication exposure by 42%, the rate of AKI by 78%, and the number of days with AKI by 68%. Furthermore, the "STARZ" risk stratification AI model showed a predictive ability of AKI within 7days of NICU admission of AUC 0.93 and AUC of 0.96 in the validation and derivation cohorts, respectively. Many studies have reported the superiority of using biomarkers to predict AKI in pediatric patients and neonates as well. Future directions include the application of AI along with biomarkers (NGAL, CysC, OPN, IL-18, B2M, etc.) in a Labelbox configuration to create a more robust and accurate model for predicting and detecting pediatric/neonatal AKI.

An Exploratory Review on the Potential of Artificial Intelligence for Early Detection of Acute Kidney Injury in Preterm Neonates.

A preterm birth is a live birth that occurs before 37 completed weeks of pregnancy. Approximately 15 million babies are born preterm annually worldwide, indicating a global preterm birth rate of about 11%. Up to 50% of premature neonates in the gestational age (GA) group of <29 weeks' gestation will develop acute kidney injury (AKI) in the neonatal period; this is associated with high mortality and morbidity. There are currently no proven treatments for established AKI, and no effective predictive tool exists. We propose that the development of advanced artificial intelligence algorithms with neural networks can assist clinicians in accurately predicting AKI. Clinicians can use pathology investigations in combination with the non-invasive monitoring of renal tissue oxygenation (rSO2) and renal fractional tissue oxygenation extraction (rFTOE) using near-infrared spectroscopy (NIRS) and the renal resistive index (RRI) to develop an effective prediction algorithm. This algorithm would potentially create a therapeutic window during which the treating clinicians can identify modifiable risk factors and implement the necessary steps to prevent the onset and reduce the duration of AKI.

Hypernatremia: Epidemiology and Predictive Role in Emerging and Established Acute Kidney Injury.

Hypernatremia (plasma sodium > 145 mmol/L) reflects impaired water balance, and affected patients can suffer from severe neurologic symptoms. Hyponatremia, on the other hand, is the most frequent electrolyte disorder in hospitals. It may be diagnosed in acute kidney injury (AKI), but hyponatremia prior to the diagnosis of AKI has also predictive or prognostic value in the short term. Aim of the article was to summarize data on both, epidemiology and outcomes of in-hospital acquired hypernatremia ("In-hospital acquired" refers to the diagnosis of either hypo- or hypernatremia in patients, who did not exhibit any of these electrolyte imbalances upon admission to the hospital). It also aimed to discuss its predictive role in patients with emerging or established AKI. Five databases were searched for references: PubMed, Medline, Google Scholar, Scopus, and Cochrane Library. Studies published between 2000 and 2023 were screened. The following keywords were used: "hypernatremia", "mortality", "pathophysiology", "acute kidney injury", "AKI", "risk prediction", "kidney replacement therapy", "KRT", "renal replacement therapy", "RRT", "hyponatremia", and "heart failure". A total of 16 studies were deemed eligible for inclusion. Among these, 13 studies had a retrospective design, two investigations were published as secondary analyses from prospective trial cohorts, and one study was prospective in nature. Out of the 16 studies, 11 focused on the epidemiology and outcomes of hypernatremia, while five investigations were related to AKI and/or AKI-associated endpoints. The prevalence of hypernatremia diagnosed during hospitalization varied from 1.9% to 6.8%, with one exception where it was 30.8%. All studies demonstrated associations between hypernatremia and mortality, even over extended periods after discharge. In AKI patients, hypernatremia shows potential for predicting in-hospital death. In conclusion, hypernatremic individuals are at higher risk of death during in-hospital therapy. Also, the electrolyte disorder potentially qualifies as a future biomarker for AKI onset and AKI-associated mortality.

Bicarbonate-Based Solution for the Management of Established Acute Kidney Injury: A Pilot Open-Label Observation Study.

Background Administration of intravenous (IV) solutions constitutes a key component of acute kidney injury (AKI) management. However, the optimal IV fluid solution in the setting of AKI remains uncertain. In this study, we assessed whether the use of bicarbonate-containing solution in patients with established AKI is associated with early renal recovery as compared to bicarbonate-free solutions. Methods We performed an open-label observational pilot study in 59 patients with established AKI. IV fluid solutions that were used include bicarbonate-based solution with low chloride content (80 mEq/L of 8% sodium bicarbonate in a solution that contains 77 mEq/L of sodium, 77 mEq/L of chloride and 25 g/L of glucose) or solutions without bicarbonate with high chloride content (0.9% normal saline, 0.45% half-saline, normal ringer, or 4% succinylated gelatine). We evaluated the association of IV fluids type with renal recovery. Results The median age of study participants was 66 years (inter-quartile range (IQR) 37-85), and 59% (n=35) were men. The prevalence of diabetes and chronic kidney disease (CKD) stages 1-3 were 34% (n=20) and 39% (n=23), respectively. Patients who received bicarbonate-based IV solutions had a greater reduction of serum creatinine (sCr) per day (delta sCr) as compared with patients who received bicarbonate-free solutions (-0.29±0.47 vs. 0.07±0.42; p=0.007). The renal recovery was faster in patients who received bicarbonate-based solutions as compared to the bicarbonate-free group (days from peak sCr to baseline sCr: 5.6±2.1 vs. 7.6±2.8; p < 0.001, respectively). Conclusions We observed faster renal recovery in patients with established AKI who received the bicarbonate-based solution with low chloride content. Our study findings require confirmation in larger cohorts.

Recombinant Alpha-1-Microglobulin (RMC-035) to Prevent Acute Kidney Injury in Cardiac Surgery Patients: Phase 1b Evaluation of Safety and Pharmacokinetics

Acute kidney injury (AKI) is a common complication in cardiac surgery patients and prevention is needed to improve clinical outcomes. Alpha-1-microglobulin (A1M) is a physiological antioxidant with strong tissue-protective and cell-protective properties that has demonstrated renoprotective effects. RMC-035, a recombinant variant of endogenous human A1M, is being developed for the prevention of AKI in cardiac surgery patients. In this phase 1b, randomized, double-blind, and parallel group clinical study, 12 cardiac surgery patients undergoing elective, open-chest, on-pump coronary artery bypass graft and/or valve surgery with additional predisposing AKI risk factors were enrolled to receive in total 5 intravenous doses of either RMC-035 or placebo. The primary objective was to evaluate the safety and tolerability of RMC-035. The secondary objective was to evaluate its pharmacokinetic properties. RMC-035 was well tolerated. The nature and frequency of adverse events (AEs) were consistent with the expected background rates in the underlying patient population with no AEs reported as related to study drug. No clinically relevant changes were observed for vital signs or laboratory parameters except for renal biomarkers. Several established AKI urine biomarkers were reduced at 4 hours after first dose administration in the treatment group, indicating a reduced perioperative tubular cell injury following RMC-035 treatment. Multiple intravenous doses of RMC-035 were well tolerated in patients undergoing cardiac surgery. Observed RMC-035 plasma exposures were safe and in the range of expected pharmacological activity. Furthermore, urine biomarkers suggest reduced perioperative kidney cell injury, warranting further investigation of RMC-035 as a potential renoprotective treatment.

Long-Term Effects of Acute Kidney Injury Following Endovascular Femoropopliteal Intervention: Insights From a Multicenter Trial.

To examine the association between acute kidney injury (AKI) severity and duration with cardiovascular mortality, following endovascular treatment of femoropopliteal disease, and whether it is AKI in itself that confers an increased risk of cardiovascular mortality. A retrospective analysis of prospectively collected data obtained between 2014 and 2019 from 3 vascular centers. Renal function was followed up for a minimum of 90 days. Electronic records were queried to establish a cause of death, where applicable. Patients were excluded if unable to provide written informed consent or if presenting with acute limb ischemia. Primary outcomes were the hazard ratios for cardiovascular death (AKI patients vs no AKI; no AKI vs stage 1 AKI vs stage 3 AKI; and no AKI vs transient AKI vs established AKI). Propensity score-matched analysis was used to establish whether developing AKI, in patients with similar demographics and procedural characteristics, is associated with a higher risk of cardiovascular death. Overall 239 patients developed AKI, and this was associated with an increased risk of cardiovascular mortality (hazard risk [HR]: 4.3, 95% confidence intervals [CIs]: 2.1-6.8, pairwise comparison p value=0.006]. This was dependent on the severity of the AKI stage (HR 5.4, 95% CI: 2.4-7.3, pairwise comparison p value=0.01) and duration (HR 4.2, 95% CI: 2.3-6.2, pairwise comparison p value=0.04). The propensity score-matched analysis showed that even when patients are matched for comorbidity and procedural characteristics, AKI confers an increased risk of mortality (p=0.04). Acute kidney injury is common after femoropopliteal endovascular therapy. It confers an increased risk of long-term cardiovascular mortality, which is still present when renal decline is transient, and highest for patients with established decline in renal function. This is the first study in the setting of peripheral arterial disease to show that acute kidney injury has an adverse effect on cardiovascular mortality, in the long-term, that is dependent on its severity, and present even when the AKI is transient. We have also shown that this difference in cardiovascular mortality becomes more pronounced from the medium-term, and thus closer follow-up of these patients is required.

Urinary Collectrin (TMEM27) as Novel Marker for Acute Kidney Injury.

Acute kidney injury (AKI) is a leading complication in hospitalized patients of different disciplines due to various aetiologies and is associated with the risk of chronic kidney disease, the need for dialysis and death. Since nephrons are not supplied with pain signals, kidney injury is mostly diagnosed by serum creatinine with a time delay. Recent work has shown that certain urinary biomarkers are available for early detection of AKI. In total, 155 subjects, including 102 patients with AKI at various stages and 53 subjects without AKI, were enrolled, and their course and laboratory data were recorded. Urinary collectrin (TMEM27) was measured by a commercially available ELISA assay. Changes in serum creatinine were used to determine AKI stage. Patients with AKI presented with significantly lower levels of urinary collectrin compared to patients without AKI (1597 ± 1827 pg/mL vs. 2855 ± 2073; p = 0.001). Collectrin was found to inversely correlate with serum creatinine and stages of AKI. Collectrin levels were lowest in AKI stage III (1576 ± 1686 pg/mL; p = 0.001) and also significantly lower in stage II (1616 ± 2148 pg/mL; p = 0.021) and stage I (1630 ± 1956 pg/mL; p = 0.019) compared to subjects without AKI. An optimal minimum collectrin cut-off value of 1606 [95% CI 1258 to 1954] pg/mL was determined to detect AKI. In conclusion, urinary collectrin represents an indicator of AKI that, unlike all other established AKI biomarkers, decreases with stage of AKI and thus may be associated with a novel pathogenic pathway.

Therapeutic Effect of Extracellular Vesicles Derived from HIF Prolyl Hydroxylase Domain Enzyme Inhibitor-Treated Cells on Renal Ischemia/Reperfusion Injury

Introduction: Acute kidney injury (AKI) is a major public health problem worldwide. However, there is no definitive therapies to treat established AKI. In this study, we used FG-4592 to induce hypoxia inducible factor (HIF) expression in cells and then explored whether the extracellular vesicles (EVs) secreted by HIF-upregulated cells could alleviate ischemia/reperfusion injury (IRI)-induced AKI. Methods: FG-4592/HK2-EVs and FG-4592/HEK293-EVs were prepared by treating HK2 or HEK293 cells with FG-4592 for 24 h, respectively. HK2 cells under hypoxia were treated with FG-4592/HK2-EVs or FG-4592/HEK293-EVs to observe the therapeutic effect of EVs on H/R-induced apoptosis and inflammation. Mice were treated with FG-4592/HEK293-EVs after IRI to observe whether FG-4592/HEK293-EVs treatment could alleviate ischemic AKI. Results: The expression of HIF was induced by FG-4592 in a dose-dependent manner in HK2 and HEK293 cells under normoxia. In vitro, FG-4592/HK2-EVs and FG-4592/HEK293-EVs inhibited apoptosis and inflammation induced by H/R. In vivo, treatment with FG-4592/HEK293-EVs significantly ameliorated renal tubular injury and inflammation caused by IRI. In addition, the expression of HIF-1α in cells and kidneys was significantly downregulated by FG-4592/HK2-EVs and FG-4592/HEK293-EVs treatment. Conclusion: This study demonstrated that EVs derived from HK2 or HEK293 cells after FG-4592 treatment could alleviate renal tubular injury and inflammation, suggesting a novel therapeutic role of FG-4592/EVs in the treatment of AKI.

Definition of acute kidney injury impacts prevalence and prognosis in ACS patients undergoing coronary angiography

BackgroundDevelopment of acute kidney injury (AKI) in invasively managed patients with acute coronary syndrome (ACS) is associated with a markedly increased mortality risk. Different definitions of AKI are in use, leading to varying prevalence and outcome measurements. The aim of the present study is to analyze an ACS population undergoing coronary angiography for differences in AKI prevalence and outcome using four established AKI definitions.Methods944 patients (30% female) were enrolled in a prospective registry between 2003 and 2005 with 6-month all-cause mortality as outcome measure. Four established AKI definitions were used: an increase in serum creatinine (sCR) ≥ 1.5 fold, ≥ 0.3 mg/dl, and ≥ 0.5 mg/dl and a decrease in eGFR > 25% from baseline (AKIN 1, AKIN 2, CIN, and RIFLE definition groups, respectively).ResultsAKI rates varied widely between the different groups. Using the CIN definition, AKI frequency was lowest (4.4%), whereas it was highest if the RIFLE definition was applied (13.2%). AKIN 2 displayed a twofold higher AKI prevalence compared with AKIN 1 (10.2% vs. 5.3% (p < 0.001)). AKI was a strong risk factor for mid-term mortality, with distinctive variability between the definitions. The lowest mortality risk was found in the RIFLE group (HR 6.0; 95% CI 3.7–10.0; p < 0.001), whereas CIN revealed the highest risk (HR 16.7; 95% CI 9.9–28.1; p < 0.001).ConclusionPrevalence and outcome in ACS patients varied considerably depending on the AKI definition applied. To define patients with highest renal function-associated mortality risk, use of the CIN definition seems to have the highest prognostic relevance.

Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 as biomarkers of patients with established acute kidney injury.

Background/AimsUrinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been recently discovered and validated as sensitive biomarkers that can predict stage 2 or 3 acute kidney injury (AKI) development in high-risk patients. We aimed to assess whether these biomarkers could predict adverse outcomes and renal recovery in established AKI patients.MethodsThis was a single-center study prospectively enrolling 124 patients diagnosed with AKI. TIMP-2, IGFBP7, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule 1 (KIM-1) levels were measured at the time of diagnosis and the predictive performance of short-term outcomes and renal recovery was assessed.ResultsPatients were divided into 4 quartiles according to the initial urinary TIMP-2/IGFBP7 levels. Stage 3 AKI (odds ratio [OR], 17.86), classified by the Kidney Disease Improving Global Outcomes (KDIGO), as well as the third and fourth quartiles of TIMP-2/IGFBP7 (OR, 5.75 and 44.98, respectively), were found to be independent predictors of renal replacement therapy at the time of AKI diagnosis. In addition, KDIGO stage 3 AKI (OR, 2.468) or the third of fourth quartiles of urinary TIMP-2/IGFBP7 (OR, 1.896 and 3.622, respectively) were also found to be useful in predicting nonrecovery of renal function. In a separate analysis of patients with renal recovery at discharge, initial urinary TIMP-2/IGFBP7 or urinary IGFBP7 at discharge could also predict new-onset or progressive chronic kidney disease (CKD).ConclusionsIn AKI patients, urine TIMP-2/IGFBP7 could serve as a biomarker for predicting adverse outcomes, renal recovery, or the development and progression of CKD.

Contrast medium-induced renal failure : Useful protective measures prior to contrast medium administration

Iodinated contrast is essential for diagnosis and treatment in contemporary interventional cardiology. An important complication of percutaneous intervention is contrast-induced nephropathy, which is associated with increased morbidity and mortality, while prolonged hospitalization is responsible for economic consequences. This article reviews the definition of contrast-induced nephropathy, the role of biomarkers in early diagnosis to identify high-risk patients and potential therapeutic options for preventing acute nephropathy. The optimization of patients' circulating volume remains the main aspect for preventing contrast-induced nephropathy, as recent studies confirm. Several medications are known to be nephrotoxic, whereas several are nephroprotective and the subject of recent research. Interventions to improve outcomes of established acute kidney injury have not been developed as yet. Prevention and early diagnosis are relevant factors in clinical management. It is important to identify patients at risk and to treat them preemptively.

RIPK1 inhibitor Cpd-71 attenuates renal dysfunction in cisplatin-treated mice via attenuating necroptosis, inflammation and oxidative stress.

Acute kidney injury (AKI) is a destructive clinical condition induced by multiple insults including ischemic reperfusion, nephrotoxic drugs and sepsis. It is characterized by a sudden decline in renal function, in addition to excessive inflammation, oxidative stress and programmed cell death of renal tubular epithelial cells. RIPK1-mediated necroptosis plays an important role in AKI. In the present study, we evaluated the treatment effects of Compound-71 (Cpd-71), a novel RIPK1 inhibitor, by comparing with Necrostatin-1 (Nec-1), a classic RIPK1 inhibitor, which has several drawbacks like the narrow structure-activity relationship (SAR) profile, moderate potency and non-ideal pharmacokinetic properties, in vivo and in vitro Our results showed that pretreatment of Cpd-71 attenuated cisplatin-induced renal injury, restored renal function and suppressed renal inflammation, oxidative stress and cell necroptosis. In addition, Cpd-71 inhibited renal damage while reducing the up-regulated serum creatinine (Cr) and blood urea nitrogen (BUN) levels in established AKI mice model. Consistently, we confirmed that Cpd-71 exhibited more effectively suppressive effect on cisplatin-induced renal tubular cell necroptosis than Nec-1, by physically binding to the allosteric type III ligand binding site of RIPK1, thereby reduced RIPK1 kinase activity, RIPK1/RIPK3 complex formation and phosphor-MLKL membrane translocation by molecular docking, Western blot, co-immunoprecipitation and cellular thermal shift assay (CETSA). Taken together, we currently showed that targeting RIPK1 with Cpd-71 may serve as a promising clinical candidate for AKI treatment.

Acute kidney injury: from creatinine to KIM‑1?

In addition to the early detection of an acute kidney injury (AKI), several problems or questions have to be addressed. These include the identification of the etiology, the severity (functional or structural), the prognosis (recovery or transition to chronic renal failure), the course of the disease (dialysis or not), and the identification of specific treatment options for AKI. The following article provides an overview of established and new AKI biomarkers as well as an outlook on the potential of future biomarker-associated models of AKI.

Incidence and impact on outcomes of acute kidney injury after a stroke: a systematic review and meta-analysis

BackgroundPatients with chronic kidney disease have worse outcomes after stroke. However, the burden of acute kidney injury after stroke has not been extensively investigated.MethodsWe used MEDLINE and Embase to conduct a systematic review and meta-analysis of published studies that provided data on the risk of AKI and outcomes in adults after ischemic and hemorrhagic stroke. Pooled incidence was examined using the Stuart-Ord method in a DerSimonian-Laird model. Pooled Odds Ratios and 95% confidence intervals were calculated for outcomes using a random effects model. This review was registered with PROSPERO (CRD42017064588).ResultsEight studies were included, five from the United States, representing 99.9% of included patients. Three studies used established acute kidney injury criteria based on creatinine values to define acute kidney injury and five used International Classification of Diseases coding definitions. Overall pooled incidence was 9.61% (95% confidence interval 8.33–10.98). Incidence for studies using creatinine definitions was 19.51% (95% confidence interval 12.75–27.32%) and for studies using coding definitions 4.63% (95% confidence interval 3.65–5.72%). Heterogeneity was high throughout. Mortality in stroke patients who sustained acute kidney injury was increased (Odds Ratio 2.45; 95% confidence interval 1.47–4.10). Three studies reported risk factors for acute kidney injury. There was sparse information on other outcomes.ConclusionsMortality in stroke patients who develop acute kidney injury is significantly increased. However the reported incidence of AKI after stroke varies widely and is underestimated using coding definitions. Larger international studies are required to identify potentially preventable factors to reduce acute kidney injury after stroke and improve outcomes.

Dual effect of hemin on renal ischemia-reperfusion injury

Acute kidney injury (AKI) is a major public health concern, which is contributing to serious hospital complications, chronic kidney disease (CKD) and even death. Renal ischemia-reperfusion injury (IRI) remains a leading cause of AKI. The stress-responsive enzyme, heme oxygenase-1 (HO-1) mediates protection against renal IRI and may be preventively induced using hemin prior to renal insult. This HO-1 induction pathway called hemin preconditioning is largely known to be effective. Therefore, HO-1 might be an interesting therapeutic target in case of predictable AKI (e.g. partial nephrectomy or renal transplantation). However, the use of hemin to mitigate established AKI remains poorly characterized.Mice underwent bilateral renal IRI for 26 min or sham surgery. After surgical procedure, animals were injected either with hemin (5 mg/kg) or vehicle. Twenty-four hours later, mice were sacrificed. Despite strong HO-1 induction, hemin-treated mice exhibited significant renal damage and oxidative stress as compared to vehicle-treated mice. Interestingly, higher dose of hemin is associated with more severe IRI-induced AKI in a dose-dependent relation. To determine whether hemin preconditioning remains efficient to dampen postoperative hemin-amplified IRI-induced AKI, we pretreated mice either with hemin (5 mg/kg) or vehicle 24 h prior to surgical procedure. Then, all mice (hemin- and vehicle-pretreated) received postoperative injection of hemin (5 mg/kg) to amplify IRI-induced AKI. In comparison to vehicle, prior administration of hemin to renal IRI mitigated hemin-amplified IRI-induced AKI as attested by fewer renal damage, inflammation and oxidative stress. In conclusion, hemin may have a dual effect on renal IRI, protective or deleterious, depending on the timing of its administration.

Restoration of E-cadherin by PPBICA protects against cisplatin-induced acute kidney injury by attenuating inflammation and programmed cell death

E-cadherin is a major component of tubular adherent proteins that maintain intercellular contacts and cell polarity in epithelial tissue. It is involved in pathological processes of renal cell carcinoma and fibrotic diseases via epithelial–mesenchymal transition. Although studies have shown E-cadherin is significantly downregulated in acute kidney injury (AKI), its function in AKI is unknown. Here, we evaluated cell damage and inflammation in cisplatin-stimulated tubular epithelial cell lines after disrupting E-cadherin and restoring it with PPBICA, a small molecule identified by high-throughput screening. We also determined the therapeutic potential of restoring E-cadherin in vivo. Results show cisplatin reduced E-cadherin expression both in mouse kidney and proximal tubular epithelial cell lines (mTECs). PPBICA restored E-cadherin levels, which increased cell viability while attenuating programmed cell death. This may be mediated via deactivation of the RIPK1/RIPK3 axis and decreased caspase3 cleavage. In addition, PPBICA suppressed inflammatory response in cisplatin-treated mTECs, which correlated with suppressed NF-κB phosphorylation and promoter activity. In contrast, disruption of E-cadherin promoted cell damage and inflammation. PPBICA failed to further attenuate kidney damage in E-cadherin knockdown cells, indicating that PPBICA protects against mTECs through E-cadherin restoration. We also found that peritoneal injection of PPBICA in mice prevented loss of renal function and tubular damage by suppressing NF-κB-driven renal inflammation and RIPK-regulated programmed cell death. This was driven by restoration of E-cadherin in cisplatin nephropathy. Additionally, PPBICA attenuated cisplatin-induced kidney damage in an established AKI model, indicating its therapeutic potential in the treatment of AKI. In conclusion, E-cadherin plays functional roles in tubule integrity, programmed cell death, and renal inflammation. Our results underscore the potential of E-cadherin restoration as a novel therapeutic strategy for AKI.

Preventing EVAR Associated Acute Kidney Injury: The Optimal Strategy Remains Elusive

Preventing EVAR Associated Acute Kidney Injury: The Optimal Strategy Remains Elusive