Background Ischemia-reperfusion AKI (IR-AKI) is estimated to affect 2%-7% of all hospitalized patients. The significant morbidity and mortality associated with AKI indicates urgent need for effective treatments. Previous studies have shown activation of the vascular angiopoietin-Tie2 tyrosine kinase signaling pathway abrogates ischemia-reperfusion injury (IRI). We extended previous studies to (1) determine the molecular mechanism(s) underlying kidney injury and protection related to decreased or increased activation of Tie2, respectively, and (2) to test the hypothesis that deletion of the Tie2 inhibitory phosphatase vascular endothelial protein tyrosine phosphatase (VE-PTP) or injection of a new angiopoietin mimetic protects the kidney from IRI by common molecular mechanism(s).Methods Bilateral IR-AKI was performed in VE-PTP wild-type or knockout mice and in C57BL/6J mice treated with Hepta-ANG1 or vehicle. Histologic, immunostaining, and single-cell RNA sequencing analyses were performed. ResultsThe phosphatase VE-PTP, which negatively regulates the angiopoietin-Tie2 pathway, was upregulated in kidney endothelial cells after IRI, and genetic deletion of VE-PTP in mice protected the kidney from IR-AKI. Injection of Hepta-ANG1 potently activated Tie2 and protected the mouse kidney from IRI. Single-cell RNAseq analysis of kidneys from Hepta-ANG1-treated and vehicle-treated mice identified endothelial-specific gene signatures and emergence of a new glomerular endothelial subpopulation associated with improved kidney function. Overlap was found between endothelial-specific genes upregulated by Hepta-ANG1 treatment and those downregulated in HUVECs with constitutive FOXO1 activation, including Entpd1/ENTPD1 that modulates purinergic receptor signaling.Conclusions Our data support a key role of the endothelium in the development of IR-AKI, introduce Hepta-ANG1 as a putative new therapeutic biologic, and report a model to explain how IRI reduces Tie2 signaling and how Tie2 activation protects the kidney.
Tunneled dialysis catheters (TDCs) remain the predominant vascular access for initiation of hemodialysis (HD) worldwide. TDCs are also utilized in a significant number of prevalent patients for continuation of dialysis and during the periods of complications related to arteriovenous (AV) accesses. TDC placement is a routine procedure, but can be associated with mechanical and infectious complications related to placement. Imaging guidance with ultrasound and fluoroscopy has made the placement of TDC safer and more successful. Adequate operator training, careful technique, utilization of a checklist, and barrier precautions are essential to avoid problems related to TDC placement.
Introduction Hypokalemia is known to occur in association with therapeutically induced hypothermia and is usually managed by the administration of potassium (K+). Methods We reviewed data from 74 patients who underwent therapeutic hypothermia protocol at our medical institution. Results In 4 patients in whom close data on serum K+ and temperature was available, a strong positive correlation between serum K+ and body temperature was found during the rewarming phase when serum K+ increased. Based on the close positive relationship between serum K+ and total body temperature, we hypothesize that serum K+ falls during hypothermia owing to decreased activity of temperature dependent K+ exit channels that under normal conditions are sufficiently active to match cellular K+ intake via Na+/K+/ATPase. Upon rewarming, reactivation of these channels results in a rapid increase in serum K+ as a result of K+ exit down its concentration gradient. Conclusion Administration of K+ during hypothermia should be done cautiously and avoided during rewarming to avoid potentially life threatening hyperkalemia. K+ exit via temperature dependent K+ channels provides a logical explanation for the rebound hyperkalemia. K+ exit channels may play a bigger role than previously appreciated in the regulation of serum K+ during normal and pathophysiological conditions.
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