The relationship between Geriatric Nutritional Risk Index (GNRI) and in-hospital mortality in critically ill patients with Acute Kidney Injury (AKI).

BACKGROUND: The role of the geriatric nutritional risk index (GNRI) as a prognostic factor in intensive care unit (ICU) patients with acute kidney injury (AKI) remains uncertain. OBJECTIVES: The aim of this study was to investigate the impact of the GNRI on mortality outcomes in critically ill patients with AKI. METHODS: For this retrospective study, we included 12,058 patients who were diagnosed with AKI based on ICD-9 codes from the eICU Collaborative Research Database. Based on the values of GNRI, nutrition-related risks were categorized into four groups: major risk (GNRI < 82), moderate risk (82 ≤ GNRI < 92), low risk (92 ≤ GNRI < 98), and no risk (GNRI ≥ 98). Multivariate analysis was used to evaluate the relationship between GNRI and outcomes. RESULTS: Patients with higher nutrition-related risk tended to be older, female, had lower blood pressure, lower body mass index, and more comorbidities. Multivariate analysis showed GNRI scores were associated with in-hospital mortality. (Major risk vs. No risk: OR, 95% CI: 1.90, 1.54-2.33, P < 0.001, P for trend < 0.001). Moreover, increased nutrition-related risk was negatively associated with the length of hospital stay (Coefficient: -0.033; P < 0.001) and the length of ICU stay (Coefficient: -0.108; P < 0.001). The association between GNRI scores and the risks of in-hospital mortality was consistent in all subgroups. CONCLUSIONS: GNRI serves as a significant nutrition assessment tool that is pivotal to predicting the prognosis of critically ill patients with AKI.

Aquaporin 1 is renoprotective in septic acute kidney injury by attenuating inflammation, apoptosis and fibrosis through inhibition of P53 expression.

Sepsis associated Acute kidney injury (AKI) is a common clinical syndrome characterized by suddenly decreased in renal function and urinary volume. This study was designed to investigate the role of Aquaporin 1 (AQP1) and P53 in the development of sepsis-induced AKI and their potential regulatory mechanisms. Firstly, transcriptome sequencing analysis of mice kidney showed AQP1 expression was reduced and P53 expression was elevated in Cecal ligation and puncture (CLP)-induced AKI compared with controls. Bioinformatics confirmed that AQP1 expression was remarkably decreased and P53 expression was obviously elevated in renal tissues or peripheral blood of septic AKI patients. Moreover, we found in vivo experiments that AQP1 mRNA levels were dramatically decreased and P53 mRNA significantly increased following the increased expression of inflammation, apoptosis, fibrosis, NGAL and KIM-1 at various periods in septic AKI. Meanwhile, AQP1 and P53 protein levels increased significantly first and then decreased gradually in kidney tissue and serum of rats in different stages of septic AKI. Most importantly, in vivo and vitro experiments demonstrated that silencing of AQP1 greatly exacerbates renal or cellular injury by up-regulating P53 expression promoting inflammatory response, apoptosis and fibrosis. Overexpression of AQP1 prevented the elevation of inflammation, apoptosis and fibrosis by down-regulating P53 expression in Lipopolysaccharide (LPS)-induced AKI or HK-2 cells. Therefore, our results suggested that AQP1 plays a protective role in modulating AKI and can attenuate inflammatory response, apoptosis and fibrosis via downregulating P53 in septic AKI or LPS-induced HK-2cells. The pharmacological targeting of AQP1 mediated P53 expression might be identified as potential targets for the early treatment of septic AKI.

Multiple Bee Stings and Acute Kidney Injury: A Case Report.

Acute kidney injury (AKI) is a common complication following multiple honey bee stings and usually presents after 24-48 hours following the incidence. The severity of AKI is related to the number of stings. A single sting can cause an allergic reaction, and as the stings increase, a higher amount of venom is inoculated, leading to systemic poisoning. Bee venom can have direct or indirect effects on the kidneys. AKI is a combination of toxic and ischemic acute tubular necrosis. Patients may require dialysis, and the usual renal recovery time is 4-120 days. The patient with multiple honey bee stings needs emergency medical treatment, sometimes in the ICU setting, with the aim of treating or preventing anaphylaxis reactions. A case of AKI due to multiple honey bee stings is presented, which is rare but a known occurrence. The patient survived with a recovery of renal function.

The therapeutic targets and signaling mechanisms of ondansetron in the treatment of critical illness in the ICU.

Background: There is accumulating evidence regarding the benefits of the 5-HT3 receptor antagonist ondansetron for the treatment of critical illness due to its potential anti-inflammatory effect. This study attempted to determine the potential targets and molecular mechanisms of ondansetron's action against critical illnesses. Methods: A bioinformatics analysis of network pharmacology was conducted to demonstrate screening targets and the signaling pathways of ondansetron action against the most common critical illnesses such as acute kidney injury (AKI), sepsis, and acute respiratory distress syndrome (ARDS). Experiments of LPS-stimulated rat neutrophils with ondansetron treatment were conducted to further validate the relevant hypothesis. Results: A total of 198, 111, and 26 primary causal targets were identified from the data for the action of ondansetron against AKI, sepsis, and ARDS respectively. We found that the pathway of neutrophil extracellular traps (NETs) formation is statistically significantly involved in the action of ondansetron against these three critical illnesses. In the pathway of NETs formation, the common drug-disease intersection targets in these three critical illnesses were toll-like receptor 8 (TLR8), mitogen-activated protein kinase-14 (MAPK14), nuclear factor kappa-B1 (NFKB1), neutrophil elastase (NE), and myeloperoxidase (MPO). Considering these bioinformatics findings, we concluded that ondansetron anti-critical illness effects are mechanistically and pharmacologically implicated with suppression of neutrophils-associated inflammatory processes. It was also showed that after treatment of LPS-stimulated rat neutrophils with ondansetron, the key proteins NE, MPO, and Peptide Arginine Deaminase 4 (PAD4) in the NETs formation were significantly reduced, and the inflammatory factors IL-6, IL-1ß, TNF-α, and chemokine receptor (CXCR4) were also significantly decreased. Conclusion: The excessive formation of NETs may have important research value in the development and progression of critical illness. Ondansetron may reduce excessive inflammatory injury in critical diseases by reducing the formation of NETs via influencing the five targets: TLR8, NFKB1, MAPK14, NE, and MPO. Ondansetron and these primary predictive biotargets may potentially be used to treat critical illness in future clinical practice.

Targeting the epidermal growth factor receptor (EGFR/ErbB) for the potential treatment of renal pathologies.

Epidermal growth factor receptor (EGFR), which is referred to as ErbB1/HER1, is the prototype of the EGFR family of receptor tyrosine kinases which also comprises ErbB2 (Neu, HER2), ErbB3 (HER3), and ErbB4 (HER4). EGFR, along with other ErbBs, is expressed in the kidney tubules and is physiologically involved in nephrogenesis and tissue repair, mainly following acute kidney injury. However, its sustained activation is linked to several kidney pathologies, including diabetic nephropathy, hypertensive nephropathy, glomerulonephritis, chronic kidney disease, and renal fibrosis. This review aims to provide a summary of the recent findings regarding the consequences of EGFR activation in several key renal pathologies. We also discuss the potential interplay between EGFR and the reno-protective angiotensin-(1-7) (Ang-(1-7), a heptapeptide member of the renin-angiotensin-aldosterone system that counter-regulates the actions of angiotensin II. Ang-(1-7)-mediated inhibition of EGFR transactivation might represent a potential mechanism of action for its renoprotection. Our review suggests that there is a significant body of evidence supporting the potential inhibition of EGFR/ErbB, and/or administration of Ang-(1-7), as potential novel therapeutic strategies in the treatment of renal pathologies. Thus, EGFR inhibitors such as Gefitinib and Erlinotib that have an acceptable safety profile and have been clinically used in cancer chemotherapy since their FDA approval in the early 2000s, might be considered for repurposing in the treatment of renal pathologies.

Urine dipstick blood and acute kidney injury in infants undergoing cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with hemolysis and acute kidney injury (AKI). The study aim was to determine if urine dipstick blood in infants after CPB was associated with AKI and urine neutrophil gelatinase-associated lipocalin (NGAL). METHODS: Infants who underwent CPB at a single center were enrolled prospectively between October 2017 and June 2019. Urine samples prior to CPB and 6 h after CPB cessation were analyzed in batch for NGAL and dipstick blood. AKI was defined using creatinine-based KDIGO criteria within 72 h of CPB. Spearman correlation examined associations between urine dipstick blood and NGAL at each time point. Linear regression estimated the associations between urine dipstick blood and log-transformed NGAL 6 h after CPB. Logistic regression estimated associations and compared discrimination between urine dipstick blood and NGAL for predicting AKI. RESULTS: At baseline, 7/63 samples (11%) had > trace blood. Six hours after CPB, 62/98 samples (63%) had > trace blood and 26% had 3 + (large) blood. In total, 18/98 (18%) with a 6-h post-CPB sample had postoperative AKI. Urine dipstick blood values correlated with urine NGAL 6 h after CPB (r = 0.52, p < 0.01), but not at baseline (r = 0.06, p = 0.66). Those with 3 + (large) blood on urine dipstick had 6 times higher mean NGAL values compared to those with negative/trace blood (mean ratio 6.6, 95%CI 3.1-14.4, p < 0.01). Those with 3 + (large) blood had 8 times higher odds of AKI (OR 7.99, 95%CI 1.5-41.9, p = 0.01). CONCLUSIONS: Urine dipstick blood post CPB may be a simple and inexpensive tool to help predict AKI in infants.

The connection between autophagy and ferroptosis in AKI: recent advances regarding selective autophagy.

Acute kidney injury (AKI) is a significant issue in public health, displaying a high occurrence rate and mortality rate. Ferroptosis, a form of programmed cell death (PCD), is characterized by iron accumulation and intensified lipid peroxidation. Recent studies have demonstrated the pivotal significance of ferroptosis in AKI caused by diverse stimuli, including ischemia-reperfusion injury (IRI), sepsis and toxins. Autophagy, a multistep process that targets damaged organelles and macromolecules for degradation and recycling, also plays an essential role in AKI. Previous research has demonstrated that autophagy deletion in proximal tubules could aggravate tubular injury and renal function loss, indicating the protective function of autophagy in AKI. Consequently, finding ways to stimulate autophagy has become a crucial therapeutic strategy. The recent discovery of the role of selective autophagy in influencing ferroptosis has identified new therapeutic targets for AKI and has highlighted the importance of understanding the cross-talk between autophagy and ferroptosis. This study aims to provide an overview of the signaling pathways involved in ferroptosis and autophagy, focusing on the mechanisms and functions of selective autophagy and autophagy-dependent ferroptosis. We hope to establish a foundation for future investigations into the interaction between autophagy and ferroptosis in AKI as well as other diseases.

Ecstasy-Induced Rhabdomyolysis Leading to Severe Acute Kidney Injury Requiring Temporary Hemodialysis: A High Risk for Recurrence With Repeated Exposure.

Ecstasy (3,4-methylenedioxymethyl-amphetamine, MDMA) is an illicit drug that has found widespread use. It is mostly used by adolescents and young adults, particularly during intense and prolonged dance parties for its mood-enhancing properties. Despite these pleasurable effects, users may have potentially serious side effects including death. One of the serious side effects is rhabdomyolysis, which can proceed to severe acute kidney failure. Due to different personal characteristics, some individuals taking the same dose of MDMA may experience more adverse effects than others. Individuals who experience adverse effects are more likely to experience them with each use. Our patient used MDMA two times in his life, and on each occasion, he had severe rhabdomyolysis with severe acute kidney injury (AKI) requiring temporary hemodialysis. Health professionals should screen all adolescents and young adults for illicit drug use during each encounter and counsel them against it.

Urban-rural differences in acute kidney injury mortality in the United States.

INTRODUCTION: Acute kidney injury (AKI) is associated with increased mortality. AKI-related mortality trends by US urban and rural counties were assessed. METHODS: In the cross-sectional study, based on the Centers for Disease Control and Prevention WONDER (Wide-ranging ONline Data for Epidemiologic Research) Multiple Cause of Death data, age-standardized mortality with AKI as the multiple cause was obtained among adults aged ≥25 years from 2001-2020, by age, sex, race and ethnicity, stratified by urban-rural counties. Joinpoint regressions were used to assess trends from 2001-2019 in AKI-related mortality rate. Pairwise comparison was used to compare mean differences in mortality between urban and rural counties from 2001-2019. RESULTS: From 2001-2020, age-standardized AKI-related mortality was consistently higher in rural than urban counties. AKI-related mortality (per 100,000 population) increased from 18.95 in 2001 to 29.46 in 2020 in urban counties and from 20.10 in 2001 to 38.24 in 2020 in rural counties. In urban counties, AKI-related mortality increased annually by 4.6% during 2001-2009 and decreased annually by 1.8% until 2019 (p<0.001). In rural counties, AKI-related mortality increased annually by 5.0% during 2001-2011 and decreased by 1.2% until 2019 (p<0.01). The overall urban-rural difference in AKI-related mortality was greater after 2009-2011. AKI-related mortality was significantly higher among older adults, men, and non-Hispanic Black adults than their counterparts in both urban and rural counties. Higher mortality was concentrated in rural counties in the Southern United States. CONCLUSIONS: Multidisciplinary efforts are needed to increase AKI awareness and implement strategies to reduce AKI-related mortality in rural and high-risk populations.

Scoping review exploring the evidence base on Vitis vinifera toxicity in dogs after ingestion: Clinical effects, treatments and types of V. vinifera.

BACKGROUND: Treatment of Vitis vinifera fruit (VVF) ingestion can be challenging due to no clear toxic dose, signalment factors and variable clinical signs. Current treatment guidance is generalised: decontamination, aggressive fluid therapy, monitoring and/or treatment of renal dysfunction. The objective of this study was to conduct a scoping review of scientific evidence regarding the ingestion of VVF in dogs. Three primary areas were reviewed: VVF types ingested, clinical signs reported and treatments given. The inclusion criterion was any paper presenting data on clinical signs or treatments of dogs that had ingested VVF (unprocessed VVF only). METHODS: The following databases were searched: CAB Abstracts, Medline, Embase and Scopus. No limits were placed on language or date. The review followed the Joanna Briggs Institute scoping review methodology. RESULTS: Twenty-four papers were identified. A wide range of VVF types were ingested, but the toxic dose was difficult to ascertain. The most commonly reported signs were gastrointestinal, renal, neurological and haematological. Treatment commonly consisted of fluid therapy, diuretics and antiemetics. LIMITATIONS: This scoping review neither explored cases of processed VVF ingestion nor did it chart laboratory findings; therefore, potentially clinically significant findings in these areas may have been missed. CONCLUSIONS: VVF ingestion typically causes gastrointestinal/renal dysfunction, with no clear toxicity attributable to VVF type. Treatments varied according to the presence/absence of clinical signs, and the prognosis was varied. Further research on current treatment efficacy is warranted, permitting an evidence-based, risk-benefit approach to be adopted by clinicians.

Recognition patterns of acute kidney injury in hospitalized patients.

Background: Acute kidney injury (AKI) during hospitalization is associated with increased complications and mortality. Despite efforts to standardize AKI management, its recognition in clinical practice is limited. Methods: To assess and characterize different patterns of AKI diagnosis, we collected clinical data, serum creatinine (sCr) levels, comorbidities and outcomes from adult patients using the Hospital Discharge Form (HDF). AKI diagnosis was based on administrative data and according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria by evaluating sCr variations during hospitalization. Additionally, patients were categorized based on the timing of AKI onset. Results: Among 56 820 patients, 42 900 (75.5%) had no AKI, 1893 (3.3%) had AKI diagnosed by sCr changes and coded in the HDF (full-AKI), 2529 (4.4%) had AKI reported on the HDF but not meeting sCr-based criteria (HDF-AKI) and 9498 (16.7%) had undetected AKI diagnosed by sCr changes but not coded in the HDF (KDIGO-AKI). Overall, AKI incidence was 24.5%, with a 68% undetection rate. Patients with KDIGO-AKI were younger and had a higher proportion of females, lower comorbidity burden, milder AKI stages, more frequent admissions to surgical wards and lower mortality compared with full-AKI patients. All AKI groups had worse outcomes than those without AKI, and AKI, even if undetected, was independently associated with mortality risk. Patients with AKI at admission had different profiles and better outcomes than those developing AKI later. Conclusions: AKI recognition in hospitalized patients is highly heterogeneous, with a significant prevalence of undetection. This variability may be affected by patients' characteristics, AKI-related factors, diagnostic approaches and in-hospital patient management. AKI remains a major risk factor, emphasizing the importance of ensuring proper diagnosis for all patients.

Clinical features associated with immune checkpoint inhibitor nephritis: a single-center clinical case series.

BACKGROUND: Acute kidney injury (AKI) has been well described as a complication of immune checkpoint inhibitor therapy. We present a series of patients, the majority with lung adenocarcinoma, who developed AKI while actively receiving immune checkpoint inhibitors. METHODS: This is a retrospectively analyzed clinical case series of six patients treated at City of Hope Comprehensive Cancer Center. Data were collected on gender, age, ethnicity, comorbidities, concomitant medications, type of malignancy, treatments, and renal function. All patients underwent renal biopsy for classification of the mechanism of AKI. Comprehensive genomic profiling (CGP) was performed on tumor tissue for all patients. RESULTS: Patterns of AKI included acute interstitial nephritis and acute tubular necrosis. Contributing factors included the use of concomitant medications known to contribute to AKI. All but two patients had full resolution of the AKI with the use of steroids. There were several mutations found on CGP that was notable including an Exon 20 insertion as well as multiple NF1 and TP53 mutations. There was high PD-L1 expression on tumor tissue noted in two out of six patients. In addition to AKI, a subset of patients had proteinuria with biopsies revealing corresponding glomerular lesions of minimal change disease and focal and segmental glomerulosclerosis. CONCLUSIONS: Our case series demonstrates that AKI from immune checkpoint inhibitors has a variable presentation that may require an individualized treatment approach. Further studies are needed to identify biomarkers that may help identify those at risk and guide the management of this condition.

ISG15 accelerates acute kidney injury and the subsequent AKI-to-CKD transition by promoting TGFßR1 ISGylation.

Rationale: Acute kidney injury (AKI) has substantial rates of mortality and morbidity, coupled with an absence of efficacious treatment options. AKI commonly transits into chronic kidney disease (CKD) and ultimately culminates in end-stage renal failure. The interferon-stimulated gene 15 (ISG15) level was upregulated in the kidneys of mice injured by ischemia-reperfusion injury (IRI), cisplatin, or unilateral ureteral obstruction (UUO), however, its role in AKI development and subsequent AKI-to-CKD transition remains unknown. Methods: Isg15 knockout (Isg15 KO) mice challenged with bilateral or unilateral IRI, cisplatin, or UUO were used to investigate its role in AKI. We established cellular models with overexpression or knockout of ISG15 and subjected them to hypoxia-reoxygenation, cisplatin, or transforming growth factor- ß1 (TGF-ß1) stimulation. Renal RNA-seq data obtained from AKI models sourced from public databases and our studies, were utilized to examine the expression profiles of ISG15 and its associated genes. Additionally, published single cell RNA-seq data from human kidney allograft biopsies and mouse IRI model were analyzed to investigate the expression patterns of ISG15 and the type I TGF-ß receptor (TGFßR1). Western blotting, qPCR, co-immunoprecipitation, and immunohistochemical staining assays were performed to validate our findings. Results: Alleviated pathological injury and renal function were observed in Isg15 KO mice with IRI-, cisplatin-, or UUO-induced AKI and the following AKI-to-CKD transition. In hypoxia-reoxygenation, cisplatin or TGF-ß1 treated HK-2 cells, knockout ISG15 reduced stimulus-induced cell fibrosis, while overexpression of ISG15 with modification capacity exacerbated cell fibrosis. Immunoprecipitation assays demonstrated that ISG15 promoted ISGylation of TGFßR1, and inhibited its ubiquitination. Moreover, knockout of TGFßR1 blocked ISG15's fibrosis-exacerbating effect in HK-2 cells, while overexpression of TGFßR1 abolished the renal protective effect of ISG15 knockout during IRI-induced kidney injury. Conclusions: ISG15 plays an important role in the development of AKI and subsequent AKI-to-CKD transition by promoting TGFßR1 ISGylation.

Hemodialysis: The Life Boat for AKI Patients in the COVID Cytokine Storm.

Background: Interleukin-6 (IL-6), a biomarker of hyperinflammatory immune response, can be used to determine the severity of coronavirus disease 2019 (COVID-19) in patients with multi-organ involvement requiring critical care. The aim of our study is to understand the utility of hemodialysis, not only in terms of reducing renal burden, but also improving the outcome by tackling the COVID cytokine storm syndrome. Materials and Methods: In this prospective, observational study, 126 patients admitted to the COVID intensive care unit (ICU) wards were treated with hemodialysis for acute kidney injury (AKI). Patients' routine baseline blood parameters were evaluated. IL-6 was measured predialysis in all patients and on the day of discharge in the patients who survived. Results: Out of total 126 patients, 79 were survivors and 47 were nonsurvivors. Among nonsurvivors, majority were older (P = 0.009). Both the groups had a higher percentage of males (78.72% and 55.69% in survivors and nonsurvivors, respectively). Mean neutrophil lymphocyte ratio (NLR) and D-dimer level were significantly higher in nonsurvivors compared to survivors (P < 0.001). Mean serum urea, creatinine, and IL-6 levels were significantly greater in nonsurvivors (P < 0.001). Mean number of hemodialysis sessions received by survivors was higher. The curve between delta IL-6 and delta serum creatinine for survivors showed a significant positive association (r = 0.819, P < 0.001). Conclusion: Our study establishes IL-6 as a poor outcome predictor in COVID ICU patients with AKI. It also emphasizes the use of hemodialysis as a cost-effective lifesaving therapeutic interventional modality to not only improve the renal outcome, but also curb the cytokine storm by reducing IL-6 levels.

Diagnostic Utility of Urine Microscopy in Kidney Diseases.

Urine sediment analysis is a highly valuable yet underutilized test in today's advanced medical landscape. The analysis of urine sediment is a simple, cost-effective, and powerful diagnostic tool in the hands of a skilled nephrologist, generally in all kidney diseases and particularly more so in the setting of acute kidney injury (AKI). The impact of AKI is far-reaching and encompasses elevated mortality rates, increased morbidity, longer hospital stays, and higher overall healthcare expenses. Timely and compartmental diagnosis of AKI with the use of a simple urine sediment analysis leads to targeted therapeutic strategies and also serves as a prognostic guide. The widespread use of automated analysis in recent times has its own set of limitations, as it fails to identify pathological casts, crystals, and dysmorphic red blood cells (RBCs). Hence, it is the need of the hour to learn this time-honored art of urine sediment analysis, to provide comprehensive patient care.

Impact of Preoperative Chemotherapy on Postoperative Renal Dysfunction After Major Abdominal Surgery: A Prospective Observational Study.

Introduction The administration of anti-cancer drugs and major abdominal surgeries have been independently identified to have a negative effect on renal function. The objectives of the study are to determine the incidence of acute kidney injury (AKI) in patients undergoing major elective abdominal surgery following chemotherapy and identify the independent predictors of postoperative AKI among such cancer patients in a tertiary care cancer institute in North India. Methods The prospective observational study included 149 patients aged 18 years or more, scheduled for elective major abdominal cancer surgery. Based on the administration of preoperative chemotherapy, the participants were divided into two study cohorts (Group 1: received preoperative chemotherapy; Group 2: did not receive preoperative chemotherapy). Patients' preoperative characteristics, including the use of preoperative chemotherapeutic agents and intraoperative factors, were evaluated for associations with the development of AKI postoperatively using the Chi-square test and Mann-Whitney U test. Multivariable logistic regression was employed to identify the factors after adjusting for potential confounders. Results The overall incidence of postoperative AKI in major abdominal oncosurgery was 24.2% among our study participants, which was significantly higher among patients receiving preoperative chemotherapy (32.4%) as compared to those who did not receive preoperative chemotherapy (16%) (p=0.019). Besides preoperative chemotherapy, the present study also noted that high levels of preoperative urinary protein-to-creatinine ratio (UPCR) and intraoperative use of vasopressors were significantly associated with an increased risk of postoperative AKI development in the final model, after adjustment for all potential confounders. A preoperative UPCR≥0.345 predicted the development of postoperative AKI with 77.8% sensitivity and 83.2% specificity. Conclusion Considering the magnitude of the problem, identification of determinants of postoperative AKI in major abdominal surgeries in cancer patients may help anesthetists and surgeons in early detection of AKI, so that prompt precautionary measures can be put in place that can potentially impact prognosis.

Identification of a Novel ECM Remodeling Macrophage Subset in AKI to CKD Transition by Integrative Spatial and Single-Cell Analysis.

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is a critical clinical issue. Although previous studies have suggested macrophages as a key player in promoting inflammation and fibrosis during this transition, the heterogeneity and dynamic characterization of macrophages are still poorly understood. Here, we used integrated single-cell RNA sequencing and spatial transcriptomic to characterize the spatiotemporal heterogeneity of macrophages in murine AKI-to-CKD model of unilateral ischemia-reperfusion injury. A marked increase in macrophage infiltration at day 1 was followed by a second peak at day 14 post AKI. Spatiotemporal profiling revealed that injured tubules and macrophages co-localized early after AKI, whereas in late chronic stages had spatial proximity to fibroblasts. Further pseudotime analysis revealed two distinct lineages of macrophages in this transition: renal resident macrophages differentiated into the pro-repair subsets, whereas infiltrating monocyte-derived macrophages contributed to chronic inflammation and fibrosis. A novel macrophage subset, extracellular matrix remodeling-associated macrophages (EAMs) originating from monocytes, linked to renal fibrogenesis and communicated with fibroblasts via insulin-like growth factors (IGF) signalling. In sum, our study identified the spatiotemporal dynamics of macrophage heterogeneity with a unique subset of EAMs in AKI-to-CKD transition, which could be a potential therapeutic target for preventing CKD development.

Obeticholic acid ameliorates sepsis-induced renal mitochondrial damage by inhibiting the NF-κb signaling pathway.

Acute kidney injury (AKI), a common complication of sepsis, might be caused by overactivated inflammation, mitochondrial damage, and oxidative stress. However, the mechanisms underlying sepsis-induced AKI (SAKI) have not been fully elucidated, and there is a lack of effective therapies for AKI. To this end, this study aimed to investigate whether obeticholic acid (OCA) has a renoprotective effect on SAKI and to explore its mechanism of action. Through bioinformatics analysis, our study confirmed that the mitochondria might be a critical target for the treatment of SAKI. Thus, a septic rat model was established by cecal ligation puncture (CLP) surgery. Our results showed an evoked inflammatory response via the NF-κB signaling pathway and NLRP3 inflammasome activation in septic rats, which led to mitochondrial damage and oxidative stress. OCA, an Farnesoid X Receptor (FXR) agonist, has shown anti-inflammatory effects in numerous studies. However, the effects of OCA on SAKI remain unclear. In this study, we revealed that pretreatment with OCA can inhibit the inflammatory response by reducing the synthesis of proinflammatory factors (such as IL-1ß and NLRP3) via blocking NF-κB and alleviating mitochondrial damage and oxidative stress in the septic rat model. Overall, this study provides insight into the excessive inflammation-induced SAKI caused by mitochondrial damage and evidence for the potential use of OCA in SAKI treatment.

Hair-straightening cosmetics containing glyoxylic acid induce crystalline nephropathy.

We recently reported the case of a patient who experienced three consecutive episodes of acute kidney injury, all of them following a "Brazilian" hair-straightening treatment. The cream used for the straightening procedure contained glyoxylic acid. To examine possible underlying mechanisms causing kidney injury, four groups of mice were exposed to topical application of (i) the straightening product, (ii) a cream containing 10% glyoxylic acid, (iii) a cream containing 10% glycolic acid or (iv) a control cream. Application of glycolic acid slightly increased urine oxalate excretion, while glyoxylic acid and the straightening product dramatically increased urine oxalate excretion and caused calcium oxalate nephropathy after transcutaneous absorption. Thus, glyoxylic acid was presumptively absorbed through the skin, metabolized to oxalate and promoted crystallization of calcium oxalate in urine. Hence, cosmetic products containing glyoxylic acid may induce acute kidney injury and should be discontinued. Further studies are needed to investigate the metabolism of glycolic acid and glyoxylic acid following topical application.