Kim-1 Targeted Extracellular Vesicles: A New Therapeutic Platform for RNAi to Treat AKI.

BACKGROUND: AKI is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is available for AKI. RNA interference (RNAi) provides a new and potent method for gene therapy to tackle this issue. METHODS: We engineered red blood cell-derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs to treat experimental AKI in a mouse model after renal ischemia/reperfusion (I/R) injury and unilateral ureteral obstruction (UUO). Phage display identified peptides that bind to the kidney injury molecule-1 (Kim-1). RNA-sequencing (RNA-seq) characterized the transcriptome of ischemic kidney to explore potential therapeutic targets. RESULTS: REVs targeted with Kim-1-binding LTH peptide (REVLTH) efficiently homed to and accumulated at the injured tubules in kidney after I/R injury. We identified transcription factors P65 and Snai1 that drive inflammation and fibrosis as potential therapeutic targets. Taking advantage of the established REVLTH, siRNAs targeting P65 and Snai1 were efficiently delivered to ischemic kidney and consequently blocked the expression of P-p65 and Snai1 in tubules. Moreover, dual suppression of P65 and Snai1 significantly improved I/R- and UUO-induced kidney injury by alleviating tubulointerstitial inflammation and fibrosis, and potently abrogated the transition to CKD. CONCLUSIONS: A red blood cell-derived extracellular vesicle platform targeted Kim-1 in acutely injured mouse kidney and delivered siRNAs for transcription factors P65 and Snai1, alleviating inflammation and fibrosis in the tubules.

No difference in clinical outcome between fixed- and mobile-bearing TKA: a meta-analysis.

PURPOSE: To compare the clinical and radiographic results of fixed-bearing and mobile-bearing total knee arthroplasty (TKA). METHODS: We searched the PubMed, Medline, Embase, Cochrane Central Register of Controlled Trials, and Google Scholar databases from 1966 to January 2012. No language restriction was applied. Reference lists of all the selected articles were hand-searched for any additional trials. Trial quality was assessed using the modified Jadad scale. Two authors independently extracted data from all eligible studies, including study design, participants, interventions, and outcomes (Knee Society Score, range of movement, radiolucent line, patient preference, walking support, pain score, and complications). The data were using fixed-effects or random-effects models with mean differences and risk ratios for continuous and dichotomous variables, respectively. RESULTS: A total of 24 studies involving 2,799 patients were identified in this analysis. Meta-analysis showed lower pain score (OR, 0.66, 95% CI 0.46, 0.94) in mobile-bearing TKA than fixed-bearing TKA. There was no significant difference between the two treatment groups regarding Knee Society Score (SMD, -0.17, 95% CI: -0.60, 0.26), range of movement (SMD, -0.05, 95% CI: -0.63, 0.53), radiolucent line (OR, 1.03, 95% CI 0.74, 1.44), patient preference (OR, 1.15, 95% CI 0.82, 1.61), walking support (OR, 1.07, 95% CI 0.68, 1.70), and complications (OR, 0.85, 95% CI 0.59, 1.21). CONCLUSIONS: The available evidence suggested that there was no significant difference between clinical and radiographic results of fixed-bearing and mobile-bearing TKA except for pain score. Regarding clinical relevance, the less incidence of pain could be the advantage for selecting mobile-bearing TKA. LEVEL OF EVIDENCE: II.

Cemented versus uncemented hemiarthroplasty for displaced femoral neck fractures: an updated meta-analysis.

OBJECTIVES: To compare the outcomes of cemented and uncemented hemiarthroplasty for treating displaced femoral neck fractures. METHOD: We searched the PubMed, Medline, Embase, Cochrane Central Register of Controlled Trials, and Google Scholar databases from 1966 to Mar 2012. No language restriction was applied. Reference lists of all the selected articles were hand-searched for any additional trials. Trial quality was assessed using the modified Jadad Scale. Two authors independently extracted data from all eligible studies, including study design, participants, interventions, and outcomes (mortality, hospital stay, blood loss, operation time, residual pain, and complications). The data were using fixed-effects and random-effects models with mean differences and risk ratios for continuous and dichotomous variables, respectively. RESULTS: A total of 12 studies involving 1805 patients were identified in this analysis. Meta-analysis showed longer operation time (SMD, -0.43, 95 % CI -0.56, -0.30) in cemented versus uncemented hemiarthroplasty. There was no significant difference between the two treatment groups regarding mortality (OR, 1.08, 95 % CI 0.88, 1.34), hospital stay (SMD, -1.21, 95 % CI -2.24, -0.18), blood loss (SMD, -0.12, 95 % CI -0.33, 0.10), operation time (SMD, -0.43, 95 % CI -0.56, -0.30), residual pain (OR, 1.42, 95 % CI 0.99, 2.03), and complications (OR, 0.82, 95 % CI 0.63, 1.08). CONCLUSIONS: The available evidence suggested there was no significant difference between uncemented and cemented hemiarthroplasty in treating displaced femoral neck fractures.

Evidence-based computer-navigated total hip arthroplasty: an updated analysis of randomized controlled trials.

BACKGROUND: Total hip arthroplasty (THA) has evolved over the years to be a reliable, reproducible, and successful orthopedic procedure. Nowadays, THA is increasingly performed on patients using less invasive, tissue-preserving techniques. Accordingly, the use of computer navigation in total joint arthroplasty has become more prevalent. However, there is still lack of high-quality evidence to verify the most effective technique for THA. METHODS: A search was conducted in PubMed, Medline, Embase, Cochrane Central Register of Controlled Trials, and Google Scholar databases. Clinical trials published from 1966 to Feb 2012 that assess conventional techniques THA or computer-navigated techniques THA for placing the acetabular component. The main outcome measures included abduction angles, anteversion angles, percentage of acetabular outliers, operation time, decrease in Hb/24 h, and wound secretion/48 h. RESULTS: The pooled analysis across all studies showed a significant difference in anteversion angles and acetabular outliers (difference -0.22, 95% CI -0.67, 0.24; p = 0.346, I (2) = 71.9%) and (difference 8.34, 95% CI 4.15, 16.74; p = 0.000, I (2) = 0.0%). However, no significant difference in abduction angle and decrease in Hb/24 h (difference -0.22, 95% CI -0.67, 0.24; p = 0.346, I (2) = 71.9%) and (difference 0.03, 95% CI -0.36, 0.41; p = 0.888, I (2) = 0.0%). For the operation time, computer-navigated THA was longer (difference -0.73, 95% CI -1.32, -0.15; p = 0.014, I (2) = 74.4%). CONCLUSIONS: This meta-analysis demonstrated computer-navigated THA was a more favorable method for placing the acetabular component and decreased the number of acetabular cups implanted outside the desired range of alignment. More high-quality RCTs were needed to support the evidence.

Tourniquet used in anterior cruciate ligament reconstruction: a system review.

PURPOSE: To identify whether routine use of a tourniquet is a better choice for anterior cruciate ligament reconstruction. METHOD: We searched Amed, British Nursing Index, Embase, Pubmed, Scopus, Cochrane Library and Google Scholar. We used revised Jadad score to evaluate the trial quality. Each reference list was viewed for any ignored studies. Two reviews independently extracted data from all eligible trials, including study design, patients' characteristics, interventions and outcomes. The available data were using random effects models with mean differences for continuous variables. RESULTS: The only meta-analysis indicated there was no significant difference in operative time between the tourniquet and non-tourniquet groups (mean differences -5.71, 95 % CI -12.40, 0.99). The remaining outcomes had variations in the outcome measures, so it was not possible to perform meta-analysis. CONCLUSIONS: There was insufficient evidence to support the hypothesis that patients would benefit from routinely applying a tourniquet. More high-quality randomized controlled trials were needed to test the result.

CD8 T cells induce the peritubular capillary rarefaction during AKI to CKD transition.

Acute kidney injury (AKI) transformed to chronic kidney disease (CKD) is a critical clinical issue characterized by tubulointerstitial inflammation (TII) and fibrosis. However, the exact mechanism remains largely unclear. In this study, we used single-cell RNA sequencing (scRNA-seq) to obtain a high-resolution profile of T cells in AKI to CKD transition with a mice model of unilateral ischemia-reperfusion injury (uIRI). We found that T cells accumulated increasingly with the progression of AKI to CKD, which was categorized into 9 clusters. A notably increased proportion of CD8 T cells via self-proliferation occurred in the early stage of AKI was identified. Further study revealed that the CD8 T cells were recruited through CXCL16-CXCR6 pathway mediated by macrophages. Notably, CD8 T cells induced endothelial cell apoptosis via Fas ligand-Fas signaling. Consistently, increased CD8 T cell infiltration accompanied with peritubular capillaries (PTCs) rarefaction was observed in uIRI mice. More impressively, the loss of PTCs and renal fibrosis was remarkably ameliorated after the elimination of CD8 T cells. In summary, our study provides a novel insight into the role of CD8 T cells in the transition from AKI to CKD via induction of PTCs rarefaction, which could suggest a promising therapeutic target for AKI.

Mitochondrial fumarate promotes ischemia/reperfusion-induced tubular injury.

AIM: Mitochondrial dysfunction, a characteristic pathological feature of renal Ischemic/reperfusion injury (I/RI), predisposes tubular epithelial cells to maintain an inflammatory microenvironment, however, the exact mechanisms through which mitochondrial dysfunction modulates the induction of tubular injury remains incompletely understood. METHODS: ESI-QTRAP-MS/MS approach was used to characterize the targeted metabolic profiling of kidney with I/RI. Tubule injury, mitochondrial dysfunction, and fumarate level were evaluated using qPCR, transmission electron microscopy, ELISA, and immunohistochemistry. RESULTS: We demonstrated that tubule injury occurred at the phase of reperfusion in murine model of I/RI. Meanwhile, enhanced glycolysis and mitochondrial dysfunction were found to be associated with tubule injury. Further, we found that tubular fumarate, which resulted from fumarate hydratase deficiency and released from dysfunctional mitochondria, promoted tubular injury. Mechanistically, fumarate induced tubular injury by causing disturbance of glutathione (GSH) hemostasis. Suppression of GSH with buthionine sulphoximine administration could deteriorate the fumarate inhibition-mediated tubule injury recovery. Reactive oxygen species/NF-κB signaling activation played a vital role in fumarate-mediated tubule injury. CONCLUSION: Our studies demonstrated that the mitochondrial-derived fumarate promotes tubular epithelial cell injury in renal I/RI. Blockade of fumarate-mediated ROS/NF-κB signaling activation may serve as a novel therapeutic approach to ameliorate hypoxic tubule injury.

Erratum: Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury: Erratum.

[This corrects the article DOI: 10.7150/thno.54550.].

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.

Activation of HIF-1α C-terminal transactivation domain protects against hypoxia-induced kidney injury through hexokinase 2-mediated mitophagy.

The transcription factor hypoxia-inducible factor-1α (HIF-1α), as a master regulator of adaptive responses to hypoxia, possesses two transcriptional activation domains [TAD, N-terminal (NTAD), and C-terminal (CTAD)]. Although the roles of HIF-1α NTAD in kidney diseases have been recognized, the exact effects of HIF-1α CTAD in kidney diseases are poorly understood. Here, two independent mouse models of hypoxia-induced kidney injury were established using HIF-1α CTAD knockout (HIF-1α CTAD-/-) mice. Furthermore, hexokinase 2 (HK2) and mitophagy pathway are modulated using genetic and pharmacological methods, respectively. We demonstrated that HIF-1α CTAD-/- aggravated kidney injury in two independent mouse models of hypoxia-induced kidney injury, including ischemia/reperfusion-induced kidney injury and unilateral ureteral obstruction-induced nephropathy. Mechanistically, we found that HIF-1α CTAD could transcriptionally regulate HK2 and subsequently ameliorate hypoxia-induced tubule injury. Furthermore, it was found that HK2 deficiency contributed to severe renal injury through mitophagy inhibition, while mitophagy activation using urolithin A could significantly protect against hypoxia-induced kidney injury in HIF-1α C-TAD-/- mice. Our findings suggested that the HIF-1α CTAD-HK2 pathway represents a novel mechanism of kidney response to hypoxia, which provides a promising therapeutic strategy for hypoxia-induced kidney injury.