Cause Of Acute Kidney Injury Research Articles

A Moderate Decrease in ADAMTS13 Activity Correlates with the Severity of STEC-HUS.

Atypical hemolytic uremic syndrome (HUS) develops as a result of damage to the endothelium of microvasculature vessels by Shiga toxin produced by enterohemorrhagic Escherichia coli (STEC-HUS). STEC-HUS remains the leading cause of acute kidney injury (AKI) in children aged 6 months to 5 years. The pathomorphological essence of the disease is the development of thrombotic microangiopathy (TMA). One of the key causes of TMA is an imbalance in the ADAMTS13-von Willebrand factor (vWF)-platelet system. The goal of the work was to clarify the role of a moderate decrease in ADAMTS13 activity in the pathogenesis of STEC-HUS. The activity of ADAMTS13 was determined in 138 children (4 months-14.7 years) in the acute period of STEC-HUS and the features of the course of the disease in these patients were analyzed. The study revealed a decrease in the activity and concentration of ADAMTS13 in 79.8% and 90.6% of patients, respectively. Measurements of von Willebrand factor antigen content and the activity of von Willebrand factor in the blood plasma of part of these patients were carried out. In 48.6% and 34.4% of cases, there was an increase in the antigen concentration and the activity of the Willebrand factor, respectively. Thrombocytopenia was diagnosed in 97.8% of children. We have demonstrated that moderately reduced ADAMTS13 activity correlates with the risk of severe manifestations of STEC-HUS in children; the rate of developing multiple organ failure, cerebral disorders, pulmonary edema, and acute kidney injury with the need for dialysis increases. It is assumed that reduction in ADAMTS13 activity may serve as a predictor of disease severity.

Gypenoside XVII attenuates renal ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress and NLRP3 inflammasome-triggered pyroptosis

BackgroundRenal ischemia-reperfusion (I/R) is one of the main causes of acute kidney injury (AKI), for which there is currently no effective treatment. Recently, the interaction between endoplasmic reticulum (ER) stress and pyroptosis during AKI has been investigated. AimThe purpose of this study was to investigate the protective effects of Gypenoside XVII (GP-17) against I/R-induced renal injury. MethodsIn this study, mice were divided into 6 groups, sham group, I/R group, GP-17 low-, medium-, high-dose group, and positive control 4-PBA group. The renal I/R was performed in mice by clamping the bilateral renal pedicles for 40 min, and then reperfusing for 24 h. Blood and kidney samples were collected for analysis. ResultsThe results showed that GP-17 improved renal function and alleviated renal histopathological abnormalities caused by I/R. In addition, GP-17 pretreatment significantly decreased the expression or phosphorylation of ER stress response proteins including BIP, p-PERK, and CHOP. Besides, GP-17 inhibited the expression of pyroptosis proteins including caspase-1, GSDMD, and apoptotic protein BAX. The inflammatory factor IL-1β in these GP-17 pretreatment groups was also significantly reduced. ConclusionGP-17 blocked NLRP3 inflammasome activation by inhibiting ERS, thereby inhibiting renal tubular cell pyroptosis and apoptosis, and prevented renal I/R injury.

Regulatory networks of circRNA- centred ceRNAs in sepsis-induced acute kidney injury

ABSTRACT Sepsis is the primary cause of acute kidney injury (AKI) and is associated with high mortality rates. Growing evidence suggests that noncoding RNAs are vitally involved in kidney illnesses, whereas the role of circular RNAs (circRNAs) in sepsis-induced AKI (SAKI) remains largely unknown. In this present study, caecal ligation and puncture (CLP) in mice was performed to establish an SAKI model. The expression of circRNAs and mRNAs was analysed using circRNA microarray or next-generation sequencing. The results revealed that the expressions of 197 circRNAs and 2509 mRNAs were dysregulated. Validation of the selected circRNAs was performed by qRT-PCR. Bioinformatics analyses and chromatin immunoprecipitation demonstrated that NF-κB/p65 signalling induced the upregulation of circC3, circZbtb16, and circFkbp5 and their linear counterparts by p65 transcription in mouse tubular epithelial cells (mTECs). Furthermore, competitive endogenous RNA (ceRNA) networks demonstrated that some components of NF-κB signalling were potential targets of these dysregulated circRNAs. Among them, Tnf-α was increased by circFkbp5 through the downregulation of miR-760-3p in lipopolysaccharide (LPS)-stimulated mTECs. Knocking down circFkbp5 inhibited the p65 phosphorylation and apoptosis in injured mTECs. These findings suggest that the selected circRNAs and the related ceRNA networks provide new knowledge into the fundamental mechanism of SAKI and circFkbp5/miR-760-3p/Tnf-α axis might be therapeutic targets.

The Effect of Fingolimod on Renal Ischemia/Reperfusion Injury in a Rat Model.

Ischemia/reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) that induces inflammation and oxidative stress. The main goal of the current study was to assess the impact of fingolimod on kidney IRI in rats. For this purpose, 18 male Wistar rats (220-250g) were divided into three groups including (i) Sham, (ii) I/R, and (iii) fingolimod+I/R. The last group was pretreated with a single dose of fingolimod (1mg/kg) (intraperitoneal injection) before induction of the I/R injury. Kidney function, oxidative stress marker (malondialdehyde), and antioxidant markers (catalase, superoxide dismutase, glutathione, glutathione peroxidase, and total antioxidant capacity) were determined in the kidney tissue of the rats. Moreover, kidney samples were taken for histological analysis. Fingolimod pre-treatment could significantly improve the glutathione peroxidase (p<0.01) and glutathione (p<0.001) activities along with the total antioxidant capacity levels (p<0.001) when compared to the I/R group. Moreover, significant recovery of kidney function and histology was seen in the fingolimod+ I/R group compared to the I/R group (p<0.01). Fingolimod pretreatment could improve renal function, antioxidant capacity, and histological alterations after I/R injury. Hence, it might protect the kidney against IRI-related kidney damage including AKI and transplantation.

Alleviation of ischemia-reperfusion induced renal injury by chemically modified SOD2 mRNA delivered via lipid nanoparticles

Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury, which is a serious clinical condition with no effective pharmacological treatment. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) significantly alleviate kidney IRI; however, the underlying mechanisms and key molecules conferring renoprotection remain elusive. In this study, we characterized the protein composition of MSC-EVs using a proteomics approach and found that mitochondrial protein superoxide dismutase 2 (SOD2) was enriched in MSC-EVs. Using lipid nanoparticles (LNP), we successfully delivered chemically modified SOD2 mRNA into kidney cells and mice with kidney IRI. We demonstrated that SOD2 mRNA-LNP treatment decreased cellular reactive oxygen species (ROS) in cultured cells and ameliorated renal damage in IRI mice, as indicated by reduced levels of serum creatinine and restored tissue integrity compared with the control mRNA-LNP-injected group. Thus, the modulation of mitochondrial ROS levels through SOD2 upregulation by SOD2 mRNA-LNP delivery could be a novel therapeutic method for ischemia-reperfusion-induced acute kidney injury.

Malaria is the leading cause of acute kidney injury among a Zambian paediatric renal service cohort retrospectively evaluated for aetiologies, predictors of the need for dialysis, and outcomes.

Whilst malaria is a prominent aetiology associated with acute kidney injury (AKI) in many parts of Africa, a shift in the traditional AKI aetiologies has been witnessed in sections of the continent. Additionally, limited access to dialysis worsens patient outcomes in these low-resource settings. This retrospective cross-sectional study aimed to determine the associated aetiologies, predictors of need for dialysis and malaria-associated AKI (MAKI), and outcomes of AKI and dialysis among children evaluated by the renal service in Lusaka, Zambia. The study sampled all children aged 16 years or below, diagnosed with AKI between 2017 and 2021, by the renal unit at the University Teaching Hospitals- Children's Hospital (UTH-CH), and retrospectively abstracted their records for exposures and outcomes. AKI was defined using the Kidney Disease Improving Global Outcomes (KDIGO) 2012 criteria. Frequency and percentage distributions were used to describe the occurrence of AKI aetiologies and treatment outcomes. Predictors of the need for dialysis, MAKI, and poor treatment outcome were identified by using multivariable logistic regression models. A total of 126 children diagnosed with AKI were included in this study. Malaria was the most frequent aetiology of AKI(61.1% (77/126, 95% Confidence Interval (CI): 52.0%-69.7%)). Of the 126 children with AKI, 74.6% (94) underwent dialysis. Predictors of the need for dialysis were oliguria (p = 0.0024; Odds ratio (OR) = 7.5, 95% CI: 2.1-27.7) and anuria (p = 0.0211; OR = 6.4, 95% CI = 1.3, 30.7). A fifth (18.3%, 23/126) of the children developed chronic kidney disease (CKD), 5.6% (7/126) died and, a year later, 77% (97/126) were lost to follow-up. At UTH-CH, malaria is the most frequent aetiology among children with AKI undergoing dialysis and children from low-medium malaria incidence areas are at risk; a considerable proportion of children with AKI need dialysis and Tenchoff catheter use in AKI is advocated.

Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation

Shiga toxin (Stx)-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS) is the leading cause of acute kidney injury in children, with an associated mortality of up to 5%. The mechanisms underlying STEC-HUS and why the glomerular microvasculature is so susceptible to injury following systemic Stx infection are unclear. Transgenic mice were engineered to express the Stx receptor (Gb3) exclusively in their kidney podocytes (Pod-Gb3) and challenged with systemic Stx. Human glomerular cell models and kidney biopsies from patients with STEC-HUS were also studied. Stx-challenged Pod-Gb3 mice developed STEC-HUS. This was mediated by a reduction in podocyte vascular endothelial growth factor A (VEGF-A), which led to loss of glomerular endothelial cell (GEnC) glycocalyx, a reduction in GEnC inhibitory complement factor H binding, and local activation of the complement pathway. Early therapeutic inhibition of the terminal complement pathway with a C5 inhibitor rescued this podocyte-driven, Stx-induced HUS phenotype. This study potentially explains why systemic Stx exposure targets the glomerulus and supports the early use of terminal complement pathway inhibition in this devastating disease. This work was supported by the UK Medical Research Council (MRC) (grant nos. G0901987 and MR/K010492/1) and Kidney Research UK (grant nos. TF_007_20151127, RP42/2012, and SP/FSGS1/2013). The Mary Lyon Center is part of the MRC Harwell Institute and is funded by the MRC (A410).

Efficacy of On-line Hemodiafiltration for Rhabdomyolysis Presenting with Acute Kidney Injury due to Unexpected Drug Abuse.

Myoglobin is a well-known cause of acute kidney injury (AKI) due to rhabdomyolysis. However, whether or not removing serum myoglobin by on-line hemodiafiltration (OHDF) improves the kidney function remains unclear. We herein report a patient with a history of methamphetamine abuse who developed AKI due to rhabdomyolysis. A urinalysis and blood collection results obtained before and after OHDF demonstrated that OHDF improved the kidney function by removing a large amount of serum myoglobin rather than via urinary excretion. In conclusion, OHDF may prevent AKI progression effectively when the urine volume is insufficient.

Acute Kidney Injury in Neonates: A Single-Center Experience

Background: Neonatal intensive care unit infants frequently experience acute kidney damage. Estimates of the prevalence of acute kidney vary depending on the definitions used. In Iraq, studies addressing the prevalence and risk factors of acute kidney injury in this age group are scarce, none of which has implicated the KDIGO diagnostic and staging criteria. Objectives: To describe the prevalence, demographics, risk factors, etiology, and staging of acute kidney injury using KDIGO criteria in the Neonatal intensive care unit and correlate these findings with patient outcomes. Methods: A retrospective study was conducted in the Neonatal Intensive Care Unit/ CWTH/ Medical City Complex/ Baghdad during the period from the 1st of August 2019 to the 15th of January 2020. All neonates diagnosed with acute kidney injury according to KDIGO –classification 2012 and admitted to the neonatal intensive care unit were included in this study. Demographics, clinical staging, and investigations were retrieved from patients' notes. Results: The prevalence of acute kidney damage was 7.2%. The mean gestational age of the patients was 36.8 ± 2.9 weeks, 58% of them were full-term, with a male-to-female ratio of 1.40:1. Stage I patients represented 35.1%, 43.2% were stage 2, and 21.6% had severe stage 3. Acute kidney injury-related mortality was 35.1%. The term female sex, high birth weight, and age younger than seven days at diagnosis predicted a bad prognosis. Vaginally delivered, stage III acute kidney injury-KDIGO, and peritoneal dialysis patients had the worst outcomes. Asphyxia was a major cause of acute kidney injury (P=0.001). High blood urea (P=0.01), low PH (P=0.009), low HCO3 (P=0.001), low WBC count (P=0.001), and low platelet count (0.001) were associated with unfavorable outcomes. Conclusions: The prevalence of acute kidney injury, according to KIDGO diagnostic and staging criteria, is 7.1%. Asphyxia, female gender, and vaginal deliveries are variables associated with poor prognosis in addition to advanced illness stage and laboratory indicators. Received: Dec. 2022 Accepted: Jun 2023 Published: Oct.2023

Epidemiology and outcome of acute kidney injury in hospitalized children: experience from a tertiary care hospital in Eastern India

Background: The aim of the study was to assess the etiology, clinical profile and short-term outcome of acute kidney injury in hospitalized children. Methods: A single centre prospective observational study conducted at a tertiary care hospital in eastern India. Consecutive hospitalized children aged between one month to twelve years who developed AKI according to AKIN criteria were included in the study. Relevant clinical and laboratory parameters as guide by clinical condition along with outcome of patients were recorded at the time of discharge and at one month and three months after discharge. Results: 116 hospitalized children who developed AKI were included in the study; 63 (54.3%) participants are above 5 years of age with male to female ratio of the study population was 1.07:1. Infections (46.5%), acute glomerulonephritis (19.8%), snake bite (11.2%) and post-surgery (8.6%) were the common causes of AKI. 43.1% of them had AKIN stage 3. 66.4% had oliguria, 33.6% had shock. 72.4% required admission at Pediatric Intensive Care Unit support, 32.4% required ionotrop support, 44.8% required mechaicanical ventilator support. Around 65% requrired dialysis support; of which 75% recieved hemodialysis and 25% requied peritoneal hemodialysis. Mortality rate was 44%. At discharge, 41.6% (n=27) of the patients had complete renal recovery from AKI. Percentage of partial renal recovery at the time of discharge, 1 month and 3 months after discharge were respectively 53.8%; 47.7% and 10%. 3 patients at the time of discharge and 2 patients after 3 months required persistent dialysis support. Number of factors are associated with poor outcome especially higher acute kidney injury state, critically ill patients and low serum albumin at admission. Conclusions: Infection is the leading cause of acute kidney injury in hospitalized children in this part of world. Mortality in critically ill children with acute kidney injury is high. Various clinical parameters at presentation are associated with poor short term renal outcome.

Clinical significance of kidney immune complex deposition in children with acute interstitial nephritis disease

Background Acute interstitial nephritis (AIN) is a relatively rare cause of acute kidney injury (AKI) in children. Immune complex (IC) deposition was rare in renal pathology of AIN. Methods Based on the status and position of IC deposition, a total of 78 children with AIN were divided into two groups: the non-IC group and IC group. IC group was further divided into two subgroups: intraglomerular (IG)-IC group and extraglomerular (EG)-IC group. To compare the clinical and histological features, renal outcomes between groups. Results The IC deposition, IG-IC and EG-IC deposition were observed in 22 (28.21%), 12 (15.38%) and 10 (12.82%) children, respectively. The IC group demonstrated a higher frequency of AKI, higher level of Scr, urine N-acetyl-β-D-glucosidase (NAG) enzyme, retinol-binding protein (RBP), neutrophil gelatinase-associated lipocalin (NGAL), higher frequency of neutrophils, plasma cells and eosinophils infiltrate, higher scores of interstitial inflammation (i), total inflammation (ti) and interstitial edema, lower level of estimated glomerular filtration rate (eGFR) as compared to non-IC group (p < 0.05, p < 0.01). EG-IC deposition positively moderate correlated with levels of RBP, IG-IC deposition positively moderate correlated with plasma cell infiltrate, interstitial inflammation (i), total inflammation (ti) and interstitial edema. Interstitial inflammation, EG-IC deposition and interstitial edema were risk factors for AKD in AIN, and interstitial fibrosis/tubular atrophy (IF/TA) was a risk factor for CKD in children with AIN. Conclusion IG-IC and EG-IC deposition positively correlated with severe clinical manifestations, glomerular and tubular injuries, and EG-IC deposition was risk factor for the progression of AIN in children.

Catalytic Tunable Black Phosphorus/Ceria Nanozyme: A Versatile Oxidation Cycle Accelerator for Alleviating Cisplatin-Induced Acute Kidney Injury.

Oxidative stress is one leading inner cause of acute kidney injury (AKI) induced by cisplatin (DDP). Therefore, inhibiting oxidative stress is an important strategy to prevent the occurrence of DDP-induced AKI. Herein, a pH-selective "oxidative cycle accelerator" based on black phosphorus/ceria catalytic tunable nanozymes (BP@CeO2 -PEG) to effectively and persistently scavenge ROS for alleviating DDP-induced AKI is demonstrated. The BP@CeO2 -PEG nanozymes show pH-dependent multi-enzymatic activities, which are beneficial for selectively scavenging the excess ROS in renal tissues. In the neutral environment of kidneys, BP@CeO2 -PEG nanozymes can accelerateits catalytic "oxidative cycle" by increasing the ratio of Ce3+ /Ce4+ and improving the regeneration of ATP, effectively removing DDP-induced ROS. In addition, BP@CeO2 -PEG nanozymes can suppress the oxidative stress-triggered renal tubular epithelial cell apoptosis by inhibiting the PI3K/Akt signaling pathway. However, in the acidic environment of cancers, the presence of H+ inhibits the conversion of Ce4+ to Ce3+ , which in turn disrupts the oxidative cycle, resulting in the loss of ROS scavenging ability and ensuring the antitumor effect of DDP. Conclusively, the nanozymes offer an excellent antioxidant for alleviating cisplatin-induced AKI and extensive use in other ROS-based injuries.

Quantifying acute kidney injury in an Ischaemia-Reperfusion Injury mouse model using deep-learning-based semantic segmentation in histology.

This study focuses on ischaemia-reperfusion injury (IRI) in kidneys, a cause of acute kidney injury (AKI) and end-stage kidney disease (ESKD). Traditional kidney damage assessment methods are semi-quantitative and subjective. This study aims to use a convolutional neural network (CNN) to segment murine kidney structures after IRI, quantify damage via CNN-generated pathological measurements, and compare this to conventional scoring. The CNN was able to accurately segment the different pathological classes, such as Intratubular casts and Tubular necrosis, with an F1 score of over 0.75. Some classes, such as Glomeruli and Proximal tubules, had even higher statistical values with F1 scores over 0.90. The scoring generated based on the segmentation approach statistically correlated with the semiquantitative assessment (Spearman's rank correlation coefficient=0.94). The heatmap approach localised the intratubular necrosis mainly in the outer stripe of the outer medulla, while the tubular casts were also present in more superficial or deeper portions of the cortex and medullary areas. This study presents a CNN model capable of segmenting multiple classes of interest, including acute IRI-specific pathological changes, in a whole mouse kidney section and can provide insights into the distribution of pathological classes within the whole mouse kidney section.

β-hydroxybutyrate ameliorates sepsis-induced acute kidney injury.

Sepsis is a major cause of acute kidney injury (AKI). Recent studies have demonstrated that β-hydroxybutyrate (β-HB) alleviates renal ischemia-reperfusion injury and cisplatin-induced renal injury in murine models. This study aimed to investigate whether β-HB ameliorates sepsis-induced AKI (SIAKI) in a lipopolysaccharide (LPS)-induced mouse sepsis model. SIAKI was induced by intraperitoneally injecting LPS to C57BL/6 male mice. β-HB was administrated intraperitoneally before LPS injection. The mice were divided into sham, β-HB, LPS, and β-HB + LPS groups. The histological damage score and serum creatinine level were significantly increased in the LPS group mice, but attenuated in the β-HB + LPS group mice. The expression of phosphorylated nuclear factor-κB tumor necrosis factor-α/interleukin-6 and the number of F4/80-positive macrophages in the β-HB + LPS group mice were lower than those in the LPS group mice. The number of TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells, cleaved caspase-3 expression, and Bax/Bcl-2 ratio in the β-HB + LPS group mice were lower than those in the LPS group mice. β-HB pre-treatment ameliorates SIAKI by reducing tubular apoptosis and inflammatory responses. Thus, β-HB pre-treatment could be a potential prophylactic strategy against SIAKI.

Renal Disease in Bangladesh Perspective

Bangladesh is one of the most densely populated areas in the world. Renal diseases are increasingly recognized and encompasses a large share of the health sector. About 20 million people are suffering from chronic kidney disease, and of them, approximately 35,000–40,000 develop endstage renal disease each year. Chronic glomerulonephritis, diabetes mellitus and hypertension are the principal causes of chronic kidney disease. Hypovolemia, sepsis, obstetric complications and drugs (including herbal and homeopathic remedies) are common causes of acute kidney injury. All three renal replacement therapy modalities (hemodialysis, peritoneal dialysis and renal transplantation) are performed in Bangladesh, yet only 25% of end-stage renal disease patients have access to treatment due to inadequate facilities and high healthcare costs. Nephrology as a specialty started its journey in 1973 in Bangladesh and now about 300 Nephrologists are managing the subject. Still there is huge need for more Nephrologists, as only one nephrologist is available for about every 0.8 million people. The country has improved financially from low- to low-middleincome country. Health sector is also more improving gradually. The government is now setting up renal care at rural level, introducing screening programs for early detection and prevention of kidney and other noncommunicable diseases. At the same time steps are under way to improve the advanced renal services at secondary and tertiary health institutes. Kidney transplantation started in 1982 and only live related transplantation are being done in several government and private organization. ABO-incompatible kidney transplantation has already been performed. Recently decease renal transplantation has also been performed. Research and training opportunities are expanding in collaboration with international organizations. Renal services appears up to date in this country but needs more and more enhancement to cope up the ever increasing burden.&#x0D; Bangladesh J Medicine 2023; 34(3): 180-185

KDM2B regulates inflammation and oxidative stress of sepsis via targeting NF-κB and AP-1 pathways.

The kidney is an easily affected organ with sepsis which is a main underlying cause of acute kidney injury (AKI). Histone-modifying lysine-specific demethylase 2B (KDM2B) is involved in numerous pathological processes, such as cell senescence and tumor development. However, the role of KDM2B in sepsis-induced AKI is unclear. To investigate the role of KDM2B on cell viability, inflammation and oxidative stress of sepsis-associated AKI, and the involved signaling pathways. An AKI model in vitro was established through lipopolysaccharide (LPS)-induction in HK-2 cells. Western blots were performed to evaluate the expression of KDM2B, cyclooxygenase 2 (COX2), inducible nitric oxide synthase (iNOS), p65, c-Jun and c-Fos, as well as p65 phosphorylation. Cell viability was measured using CCK-8 kit. ELISA was performed to analyze the production of layered double hydroxide (LDH), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-18, vascular cell adhesion molecule-1 (VCAM-1), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), and H2 O2 . The qPCR was used to evaluate the transcription level of TNF-α, IL-1β, IL-18, and VCAM-1. KDM2B knockdown alleviated LPS-induced cytotoxicity, decreased LDH release, and improved cell viability. KDM2B knockdown reduced concentration of inflammation-related molecules including TNF-α, IL-1β, IL-18, and VCAM-1, and inhibited their transcription. Moreover, KDM2B knockdown promoted the quantity of SOD and GSH, while declined the production of MDA, H2 O2 , COX2, and iNOS. Further, KDM2B played a role in LPS-induced HK-2 cell injury by activating nuclear factor κB (NF-κB) and activator protein 1 (AP-1) pathways. KDM2B knockdown reduced cytotoxicity, inflammation and oxidative stress in LPS-induced AKI via inhibiting NF-κB and AP-1 pathways, indicating KDM2B may be a promising therapeutic target for the treatment of sepsis-associated AKI.

IL-6 mediates the hepatic acute phase response after prerenal azotemia in a clinically defined murine model.

Prerenal azotemia (PRA) is a major cause of acute kidney injury and uncommonly studied in preclinical models. We sought to develop and characterize a novel model of PRA that meets the clinical definition: acute loss of glomerular filtration rate (GFR) that returns to baseline with resuscitation. Adult male C57BL/6J wild-type (WT) and IL-6-/- mice were studied. Intraperitoneal furosemide (4 mg) or vehicle was administered at time = 0 and 3 h to induce PRA from volume loss. Resuscitation began at 6 h with 1 mL intraperitoneal saline for four times for 36 h. Six hours after furosemide administration, measured glomerular filtration rate was 25% of baseline and returned to baseline after saline resuscitation at 48 h. After 6 h of PRA, plasma interleukin (IL)-6 was significantly increased, kidney and liver histology were normal, kidney and liver lactate were normal, and kidney injury molecule-1 immunofluorescence was negative. There were 327 differentially regulated genes upregulated in the liver, and the acute phase response was the most significantly upregulated pathway; 84 of the upregulated genes (25%) were suppressed in IL-6-/- mice, and the acute phase response was the most significantly suppressed pathway. Significantly upregulated genes and their proteins were also investigated and included serum amyloid A2, serum amyloid A1, lipocalin 2, chemokine (C-X-C motif) ligand 1, and haptoglobin; hepatic gene expression and plasma protein levels were all increased in wild-type PRA and were all reduced in IL-6-/- PRA. This work demonstrates previously unknown systemic effects of PRA that includes IL-6-mediated upregulation of the hepatic acute phase response.NEW & NOTEWORTHY Prerenal azotemia (PRA) accounts for a third of acute kidney injury (AKI) cases yet is rarely studied in preclinical models. We developed a clinically defined murine model of prerenal azotemia characterized by a 75% decrease in measured glomerular filtration rate (GFR), return of measured glomerular filtration rate to baseline with resuscitation, and absent tubular injury. Numerous systemic effects were observed, such as increased plasma interleukin-6 (IL-6) and upregulation of the hepatic acute phase response.

Nuclear factor-kappa B p50-induced microRNA-20a-3p plays a detrimental role in sepsis-induced acute kidney injury.

Sepsis is the most common cause of acute kidney injury (AKI). Based on microarray-based clustering analysis of miRNAs altered in the kidneys of LPS-AKI mice, miR-20a-3p was upregulated in the kidney tissues of lipopolysaccharide (LPS)-treated mice. We aimed to reveal the functions of miR-20a-3p in septic AKI by establishing the LPS-stimulated mouse model of AKI and constructing the LPS-stimulated HK-2 cells. Reverse transcription-quantitative PCR was used to quantify miR-20a-3p expression and inflammation-associated factors including MCP-1, TNF-α, and IL-6. Silencing of miR-20a-3p reduced inflammation and apoptosis in kidneys as well as alleviated AKI symptoms in mice. The LPS-induced inflammatory response and apoptosis in HK-2 cells were rescued by miR-20a-3p silence. Moreover, nuclear factor-kappa B (NF-κB) is a transcriptional factor for miR-20a-3p to increase its expression. The binding of NF-κB p50 and miR-20a-3p promoter was verified by ChIP assay. To sum up, miR-20a-3p is transcriptionally activated by NF-κB p50, playing a harmful role in sepsis-induced AKI by inducing inflammation and apoptosis.

Hemolytic Uremic Syndrome-Induced Acute Kidney Injury Treated via Immunomodulation with the Selective Cytopheretic Device

Introduction: Shiga-toxin associated-hemolytic uremic syndrome (STEC-HUS) is a severe cause of acute kidney injury (AKI) in children. Although most children recover, about 5% die and 30% develop chronic renal morbidity. HUS pathophysiology includes activated neutrophils damaging vascular endothelial cells. Therapeutic immunomodulation of activated neutrophils may alter the progression of disease. We present 3 pediatric patients treated with the selective cytopheretic device (SCD). Methods: We describe a 12 y.o. (patient 1) and two 2 y.o. twins (patients 2 and 3) with STEC-HUS requiring continuous renal replacement therapy (CRRT) who were enrolled in two separate studies of the SCD. Results: Patient 1 presented with STEC-HUS causing AKI and multisystem organ failure and received 7 days of SCD and CRRT treatment. After SCD initiation, the patient had gradual recovery of multi-organ dysfunction, with normal kidney and hematologic parameters at 60-day follow-up. Patients 2 and 3 presented with STEC-HUS with AKI requiring dialysis. Each received 24 h of SCD therapy. Thereafter, both gradually improved, with normalization (patient 2) and near-normalization (patient 3) of kidney function at 60-day follow-up. Conclusion: Immunomodulatory treatment with the SCD was associated with improvements in multisystem stigmata of STEC-HUS-induced AKI and was well-tolerated without any device-related adverse events.

A long way to diagnosis: clinical case of acute renal injury in a patient with Takayasu arteritis

The purpose of the study. Demonstration of differential diagnostic search for the causes of acute kidney injury (AKI) in a young man.Materials and methods. Clinical observation of a patient with Takayasu arteritis (TAK).Results. The presented clinical observation describes the late diagnosis of TAK at the stage of severe ischemic lesions of the internal organs (myocardial infarction, cerebral infarction, occlusion of the lumen of the arteries of the left lower limb with the development of gangrene, occlusion of the renal arteries with the outcome of left kidney shrive­ling). Most likely, thrombotic occlusion of the right renal arteries caused the development of severe AKI. During the examination, the diagnosis of TAK was made, other possible nosologies were excluded. Taking into account the late diagnosis of the disease, the minimal severity of the inflammatory process, the high risk of complications, therapy with glucocorticoids in a small dose, anticoagulants was carried out. Against this background, recovery of intrarenal blood flow and diuresis was noted, but high rates of azotemia remained, requiring continued dialysis. After 3 months, the loss of renal functions was detected.Conclusions. The development of vascular lesions of internal organs with signs of critical ischemia (heart, brain, vessels of the lower extremities, kidneys, etc.) in young patients, dictates the need for a differential diagnostic search for the cause, first of all, the exclusion of the systemic process (systemic vasculitis, antiphospholipid syndrome, diffuse con­nective tissue diseases). It is important to accumulate experience in managing patients with TAK in order to timely diagnose, start therapy early and prevent the development of irreversible lesions of internal organs.