ABSTRACT
Necroptosis, a pathway of regulated necrosis, involves recruitment and activation of RIPK1, RIPK3 and MLKL, leading to cell membrane rupture, cell death and release of intracellular contents causing further injury and inflammation. Necroptosis is believed to play an important role in the pathogenesis of kidney ischemia-reperfusion injury (IRI). However, the dynamics of necroptosis in kidney IRI is poorly understood, in part due to difficulties in detecting phosphorylated MLKL (pMLKL), the executioner of the necroptosis pathway. Here, we investigated the temporal and spatial activation of necroptosis in a mouse model of unilateral warm kidney IRI, using a robust method to stain pMLKL. We identified the period 3-12 hrs after reperfusion as a critical phase for the activation of necroptosis in proximal tubular cells. After 12 hrs, the predominant pattern of pMLKL staining shifted from cytoplasmic to membrane, indicating progression to the terminal phase of necroptotic cell death. Mlkl-ko mice exhibited reduced kidney inflammation at 12 hrs and lower serum creatinine and tubular injury at 24 hrs compared to wild-type littermates. Interestingly, we observed increased apoptosis in the injured kidneys of Mlkl-ko mice, suggesting a relationship between necroptosis and apoptosis in kidney IRI. Together, our findings confirm the role of necroptosis and necroinflammation in kidney IRI, and identify the first 3 hrs following reperfusion as a potential window for targeted treatments.
Subject(s)
Necroptosis , Reperfusion Injury , Animals , Mice , Kidney/pathology , Necrosis/pathology , Inflammation/metabolism , Reperfusion Injury/metabolismABSTRACT
Ischemia-reperfusion injury (IRI) is the outcome of an inflammatory process that is triggered when an organ undergoes a transient reduction or cessation of blood flow, followed by re-establishment of perfusion. In the clinical setting, IRI contributes to significant acute kidney injury, patient morbidity and mortality, and adverse outcomes in transplantation. Tubular cell death by necrosis and apoptosis is a central feature of renal IRI. Recent research has challenged traditional views of cell death by identifying new pathways in which cells die in a regulated manner but with the morphologic features of necrosis. This regulated necrosis (RN) takes several forms, with necroptosis and ferroptosis being the best described. The precise mechanisms and relationships between the RN pathways in renal IRI are currently the subject of active research. The common endpoint of RN is cell membrane rupture, resulting in the release of cytosolic components with subsequent inflammation and activation of the immune system. We review the evidence and mechanisms of RN in the kidney following renal IRI, and discuss the use of small molecule inhibitors and genetically modified mice to better understand this process and guide potentially novel therapeutic interventions.
Subject(s)
Acute Kidney Injury/pathology , Kidney Transplantation/adverse effects , Kidney Tubules/pathology , Microvessels/pathology , Reperfusion Injury/pathology , Acute Kidney Injury/etiology , Acute Kidney Injury/prevention & control , Animals , Apoptosis/drug effects , Apoptosis/genetics , Clinical Trials, Phase II as Topic , Disease Models, Animal , Epithelial Cells/pathology , Ferroptosis/drug effects , Ferroptosis/genetics , Humans , Kidney Failure, Chronic/surgery , Kidney Tubules/cytology , Mice , Mice, Transgenic , Microvessels/drug effects , Necroptosis/drug effects , Necroptosis/genetics , Necrosis/etiology , Necrosis/pathology , Oxazepines/pharmacology , Oxazepines/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinases/genetics , Protein Kinases/metabolism , Randomized Controlled Trials as Topic , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Regional Blood Flow/drug effects , Regional Blood Flow/genetics , Reperfusion Injury/drug therapy , Reperfusion Injury/etiology , Signal Transduction/drug effects , Signal Transduction/genetics , Treatment Outcome , Triazoles/pharmacology , Triazoles/therapeutic useSubject(s)
Acute Kidney Injury/etiology , Diet Fads/adverse effects , Oxalates/adverse effects , Acute Kidney Injury/diagnosis , Acute Kidney Injury/urine , Adult , Humans , Kidney/chemistry , Kidney/pathology , Male , Oxalates/analysis , Oxalates/urine , Recommended Dietary Allowances , Risk FactorsABSTRACT
Background: The increasing burden of chronic kidney disease (CKD) underpins the importance for improved early detection and management programs in primary care to delay disease progression and reduce mortality rates. eMAP:CKD is a pilot program for primary care aimed at addressing the gap between current and best practice care for CKD. Methods: Customized software programs were developed to integrate with primary care electronic health records (EHRs), allowing real-time prompting for CKD risk factor identification, testing, diagnosis and management according to Kidney Health Australia's (KHA) best practice recommendations. Primary care practices also received support from a visiting CKD nurse and education modules. Patient data were analyzed at baseline (150 910 patients) and at 15 months (175 917 patients) following the implementation of the program across 21 primary care practices. Results: There was improvement in CKD risk factor recognition (29.40 versus 33.84%; P < 0.001) and more complete kidney health tests were performed (3.20 versus 4.30%; P < 0.001). There were more CKD diagnoses entered into the EHR (0.48 versus 1.55%; P < 0.001) and more patients achieved KHA's recommended management targets (P < 0.001). Conclusion: The eMAP:CKD program has shown an improvement in identification of patients at risk of CKD, appropriate testing and management of these patients, as well as increased documentation of CKD diagnosis entered into the EHRs. We have demonstrated efficacy in overcoming the verified gap between current and best practice in primary care. The success of the pilot program has encouraging implications for use across the primary care community as a whole.
Subject(s)
Electronic Health Records/statistics & numerical data , Primary Health Care/organization & administration , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/therapy , Adult , Australia/epidemiology , Disease Management , Disease Progression , Humans , Male , Renal Insufficiency, Chronic/epidemiologyABSTRACT
BACKGROUND: There are limited published data on the types and appropriateness of oral and intravenous (IV) antibiotics prescribed to patients receiving haemodialysis. This information is critical to optimise antibiotic prescribing. Therefore this study aims to describe the patterns of use and the appropriateness of oral and IV antibiotics prescribed to patients receiving haemodialysis. METHODS: This was a prospective, observational study across four community and two hospital inpatient haemodialysis units in Melbourne, Australia. Data were collected from July 2014 to January 2015 from participants. Antibiotic regimens prescribed were compared with nationally available antibiotic guidelines and then classified as being either appropriate, inappropriate or not assessable by an expert multidisciplinary team using the National Antimicrobial Prescribing Survey tool. RESULTS: Overall, 114 participants consented to this study where 55.3% (63/114) received antibiotics and 235 antibiotic regimens were prescribed at a rate of 69.1 antibiotic regimens/100 patient-months. The most common oral antibiotics prescribed were amoxycillin/clavulanic acid and cephalexin. The most common IV antibiotics prescribed were vancomycin, piperacillin/tazobactam, cephazolin and ceftriaxone. The percentage of inappropriate antibiotic regimens prescribed were 34.9% (15/43) in the community setting and 22.1% (40/181) in the hospital setting. Furthermore, 29.4% (30/102) of oral and 20.5% (25/122) of IV antibiotic regimens were inappropriate with incorrect dosing as the primary reason. CONCLUSION: Although this study is limited by the sample size, it describes the high antibiotic exposure that patients receiving haemodialysis experience. Of concern is inappropriate dose and frequency being a major issue. This requires interventions focused on the quality use of medicines and antimicrobial stewardship aspects of prescribing in this population.
