Significance Statement Cells undergoing necrosis release extracellular high mobility group box (HMGB)-1, which triggers sterile inflammation upon AKI in mice. Neither deletion of HMGB1 from tubular epithelial cells, nor HMGB1 antagonism with small molecules, affects initial ischemic tubular necrosis and immediate GFR loss upon unilateral ischemia/reperfusion injury (IRI). On the contrary, tubular cell-specific HMGB1 deficiency, and even late-onset pharmacological HMGB1 inhibition, increased functional and structural recovery from AKI, indicating that intracellular HMGB1 partially counters the effects of extracellular HMGB1. In vitro studies indicate that intracellular HMGB1 decreases resilience of tubular cells from prolonged ischemic stress, as in unilateral IRI. Intracellular HMGB1 is a potential target to enhance kidney regeneration and to improve long-term prognosis in AKI. Background Late diagnosis is a hurdle for treatment of AKI, but targeting AKI-CKD transition may improve outcomes. High mobility group box-1 (HMGB1) is a nuclear regulator of transcription and a driver of necroinflammation in AKI. We hypothesized that HMGB1 would also modulate AKI-CKD transition in other ways. Methods We conducted single-cell transcriptome analysis of human and mouse AKI and mouse in vivo and in vitro studies with tubular cell-specific depletion of Hmgb1 and HMGB1 antagonists. Results HMGB1 was ubiquitously expressed in kidney cells. Preemptive HMGB1 antagonism with glycyrrhizic acid (Gly) and ethyl pyruvate (EP) did not affect postischemic AKI but attenuated AKI-CKD transition in a model of persistent kidney hypoxia. Consistently, tubular Hmgb1 depletion in Pax8 rtTA, TetO Cre, Hmgb1 fl/fl mice did not protect from AKI, but from AKI-CKD transition. In vitro studies confirmed that absence of HMGB1 or HMGB1 inhibition with Gly and EP does not affect ischemic necrosis of growth-arrested differentiated tubular cells but increased the resilience of cycling tubular cells that survived the acute injury to oxidative stress. This effect persisted when neutralizing extracellular HMGB1 with 2G7. Consistently, late-onset HMGB1 blockade with EP started after the peak of ischemic AKI in mice prevented AKI-CKD transition, even when 2G7 blocked extracellular HMGB1. Conclusion Treatment of AKI could become feasible when (1) focusing on long-term outcomes of AKI; (2) targeting AKI-CKD transition with drugs initiated after the AKI peak; and (3) targeting with drugs that block HMGB1 in intracellular and extracellular compartments.
BackgroundZinc is an essential trace element involved in multiple metabolic processes. Acute kidney injury (AKI) is associated with low plasma zinc, but outcomes with zinc supplementation in critically ill patients with AKI remain unknown. Our objective was to investigate the effectiveness of zinc supplementation in this patient population.MethodsCritically ill patients with AKI were identified from the Medical Informative Mart for Intensive Care IV database. Prosperity score matching (PSM) was applied to match patients receiving zinc treatment to those without zinc treatment. The association between zinc sulfate use and in-hospital mortality and 30-day mortality, need for renal replacement therapy (RRT), and length of stay was determined by logistic regression and Cox proportional hazards modeling.ResultsA total of 9,811 AKI patients were included in the study. PSM yielded 222 pairs of patients who received zinc treatment and those who did not. Zinc supplementation was associated with reduced in-hospital mortality (HR = 0.48 (95% CI: 0.28, 0.83) P = 0.009) and 30-day mortality (HR = 0.51 (95% CI, 0.30, 0.86) P = 0.012). In the subgroup analysis, zinc use was associated with reduced in-hospital mortality in patients with stage 1 AKI and those with sepsis.ConclusionsZinc supplementation was associated with improved survival in critically ill patients with AKI. The supplementation was especially effective in those with stage 1 AKI and sepsis. These results need to be verified in randomized controlled trials.
BackgroundAlbumin to fibrinogen ratio (AFR) is a demonstrated predictor of mortality in various diseases. The aim of this study was to evaluate the prognostic value of AFR to predict mortality in peritoneal dialysis (PD) patients.MethodsWe retrospectively analyzed 212 incident PD patients from January 2010 to December 2017 and followed them until December 2019. We used receiver operating curve (ROC) analysis to determine the optimal cut-off point for AFR at baseline to predict overall and cardiovascular mortality during the follow-up period. Kaplan-Meier curve and Cox regression analysis were applied to evaluate the association between AFR and all-cause and cardiovascular mortality.ResultsThe optimal threshold for AFR to predict mortality was 8.48. A low AFR was strongly correlated with worse all-cause and cardiovascular mortality in PD patients. Multivariate analysis revealed that elevated AFR was an independent marker predicting reduced all-cause and cardiovascular mortality (HR 2.41, 95% CI 1.11–5.22, P = 0.026; and HR 2.18, 95% CI 1.21–3.95, P = 0.010, respectively).ConclusionsPatients with a high AFR had reduced all-cause and cardiovascular mortality. AFR is a potential prognostic biomarker in PD patients.
Background and Aims HMGB1, long form High Mobility Group Box 1, a highly conserved DNA chaperone stabilizes chromatin in the nucleus, regulates gene transcription, and supports DNA repair. In the cytosol, it regulates mitochondrial function, autophagy, and apoptosis. In addition, when secreted or passively released into the extracellular space during cell necrosis, it acts as danger signal (DAMP). As such HMGB1 amplifies necroinflammation in ischemic and toxic acute kidney injury. In contrast, little is known about the contribution of HMGB1 release from infiltrating immune cells in this context. We hypothesized that HMGB1 from resident and infiltrating myeloid cells would contribute to the progression of CKD by driving tubular atrophy and tissue remodeling. Method We generated myeloid deletion of HMGB1 by crossing Hmgb1 floxed mice (Hmgb1f/f) with endogenous Lyz2 promoter (Lyz2Cre/+) to investigate the role of myeloid cell HMGB1 in a model of chronic kidney disease induced by sodium oxalate-rich diet (50 μmol/g), i.e., calcium oxalate nephropathy. The Lyz2Cre/+ mice were on a C57BL/6J background and crossed with mice homozygous for the floxed Hmgb1 gene to generate mice with a constitutive deletion of the Hmgb1 gene in all myeloid cells. We used littermates of 6- or 8-week-old males for all experiments. Mice with no Lyz2Cre/+ but the homozygous of floxed Hmgb1 gene served as wildtype controls (Lyz2Cre/−Hmgb1f/f WT) and mice with Lyz2Cre/+ and the homozygous of floxed Hmgb1 gene were used as Lyz2Cre/+Hmgb1f/f KO. The primary endpoint for the comparison between Lyz2Cre/+Hmgb1f/f KO and WT mice was glomerular filtration rate at 21 days of oxalate feeding, assessed by FITC-sinistrin clearance. Plasma samples were collected only on day 21 before sacrifice by cervical dislocation. Urine samples were collected as well as GFR was measured from all experimental groups on day 0, day7, day14 and before sacrifice by cervical dislocation on day 21. Kidneys were harvested after sacrifice. The kidney was divided into two equal parts. One part was kept in RNA later solution at −80°C for RNA isolation and the second part was kept in 4% formalin to be embedded in paraffin for histology analysis. Results KO animals did not reveal any abnormalities within an observation phase of 6 months. Healthy mice showed normal kidney function parameters in urine and blood. Observation is continued and will be supplemented by histopathological analyzes at the age of 12 months. Primary endpoint: Deletion of HMGB1 from myeloid cells attenuated the decline of GFR as compared to WT control mice. Secondary endpoints: The difference in GFR was consistent with the respective levels of serum creatinine at day 21 upon oxalate-rich diet compared with controls. The ablation of HMGB1 in myeloid cells was associated with less tubulointerstitial fibrosis at day 21 after oxalate-rich diet Conclusion Our data suggest that HMGB1 release from myeloid cells promotes crystal-induced chronic kidney injury, which is consistent with the role of HMGB1 as an extracellular DAMP and persistent inflammation in CKD. However, this effect may also relate to the intracellular role of HMGB1 as a transcriptional regulator.
AbstractbackgroundFibrinogen to pre‐albumin ratio (FPR) is a promising predictor of mortality in various cancers. The aim of this study was to explore the prognostic value of FPR to predict mortality in peritoneal dialysis (PD) patients.MethodsWe retrospectively analyzed 324 incident PD patients form January 2011 to December 2020. Patients were stratified based on the optimal thresholds for FPR at baseline to predict overall and cardiovascular mortality during follow‐up. The association of FPR and all‐cause and cardiovascular mortality was evaluated by Kaplan–Meier curve and Cox regression analysis.ResultsAll patients were divided into three groups based on the optimal cutoff value of FPR. Higher FPR levels were strongly correlated with worse overall and cardiovascular mortality in PD patients. Compared with patients in the lowest FPR tertile (<14.3), those in the highest terile (≥18.8) had multivariable‐adjusted hazard ratios (95% CI confidence interval) of 3.37 (1.76–6.49) and 2.86 (1.31–6.23) for all‐cause and cardiovascular mortality, respectively. Significant differences in overall survival were observed across nearly all subgroups after stratification.ConclusionsPatients with a high FPR had increased all‐cause and cardiovascular mortality. FPR is a potential prognostic indicator in PD patients.
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