Strategy For Treatment Of Acute Kidney Injury Research Articles

Megalin-targeted acetylcysteine polymeric prodrug ameliorates ischemia-reperfusion-induced acute kidney injury

Acute kidney injury (AKI), a condition associated with reactive oxygen species (ROS), causes high mortality in clinics annually. Active targeted antioxidative therapy is emerging as a novel strategy for AKI treatment. In this study, we developed a polymeric prodrug that targets the highly expressed Megalin receptor on proximal tubule cells, enabling direct delivery of N-Acetylcysteine (NAC) for the treatment of ischemia reperfusion injury (IRI)-induced AKI. We conjugated NAC with low molecular weight chitosan (LMWC), a biocompatible and biodegradable polymer consisting of glucosamine and N-acetylglucosamine, to enhance its internalization by tubular epithelial cells. Moreover, we further conjugated triphenylphosphonium (TPP), a lipophilic cation with a delocalized positive charge, to low molecular weight chitosan-NAC in order to enhance the distribution of NAC in mitochondria. Our study confirmed that triphenylphosphonium-low molecular weight chitosan-NAC (TLN) exhibits remarkable therapeutic effects on IRI-AKI mice. This was evidenced by improvements in renal function, reduction in oxidative stress, mitigation of pathological progress, and decreased levels of kidney injury molecule-1. These findings suggested that the polymeric prodrug TLN holds promising potential for IRI-AKI treatment.

Alkaline phosphatase treatment of acute kidney injury - an update.

Through improved insight in the increasing incidence and detrimental effects of acute kidney injury (AKI), its clinical relevance has become more and more apparent. Although treatment strategies for AKI have also somewhat improved, an adequate remedy still does not exist. Finding one is complicated by a multifactorial pathophysiology and by heterogeneity in the patient population. Alkaline phosphatase (AP) has been suggested as a therapy for sepsis-associated AKI because of its protective effects against lipopolysaccharide (LPS) induced inflammation and kidney injury in animals. However, translation of these protective effects into tangible clinical benefit has proven difficult. Because the anti-inflammatory properties of AP are likely not reliant on a direct effect on LPS itself, we postulate that other pathways are much more important in explaining the renoprotective properties ascribed to AP. The reevaluation of which properties of the AP enzyme are responsible for the benefit seen in the lab, is an important step to determine where the true potential of AP as a treatment strategy for AKI in the clinic lies. In this review, we will discuss how AP can prevent activation of harmful pro-inflammatory receptors, redirect cell-cell signaling, and protect barrier tissues, which together form the basis for current knowledge of the role of AP in the kidney. With this knowledge in mind and by analyzing currently available clinical evidence, we propose directions for new research that can determine whether AP as a treatment strategy for AKI has a future in the clinical field.

Acute Kidney Injury: From Diagnosis to Prevention and Treatment Strategies

Acute kidney injury (AKI) is characterized by an acute decrease in renal function that can be multifactorial in its origin and is associated with complex pathophysiological mechanisms. In the short term, AKI is associated with an increased length of hospital stay, health care costs, and in-hospital mortality, and its impact extends into the long term, with AKI being associated with increased risks of cardiovascular events, progression to chronic kidney disease (CKD), and long-term mortality. Given the impact of the prognosis of AKI, it is important to recognize at-risk patients and improve preventive, diagnostic, and therapy strategies. The authors provide a comprehensive review on available diagnostic, preventive, and treatment strategies for AKI.

Mitochondrial transplantation ameliorates ischemia/reperfusion-induced kidney injury in rat

No real therapeutic modality is currently available for Acute kidney injury (AKI) and if any, they are mainly supportive in nature. Therefore, developing a new therapeutic strategy is crucial. Mitochondrial dysfunction proved to be a key contributor to renal tubular cell death during AKI. Thus, replacement or augmentation of damaged mitochondria could be a proper target in AKI treatment. Here, in an animal model of AKI, we auto-transplanted normal mitochondria isolated from healthy muscle cells to injured kidney cells through injection to renal artery. The mitochondria transplantation prevented renal tubular cell death, restored renal function, ameliorated kidney damage, improved regenerative potential of renal tubules, and decreased ischemia/reperfusion-induced apoptosis. Although further studies including clinical trials are required in this regard, our findings suggest a novel therapeutic strategy for treatment of AKI. Improved quality of life of patients suffering from renal failure and decreased morbidity and mortality rates would be the potential advantages of this therapeutic strategy.

Acute Kidney Injury in Children after Hematopoietic Cell Transplantation Is Associated with Elevated Urine CXCL10 and CXCL9.

Acute kidney injury (AKI) is nearly universally associated with worse outcomes, especially among children after hematopoietic stem cell transplant (HCT). Our objective was to examine urinary immune biomarkers of AKI after HCT to provide insights into novel mechanisms of kidney injury in this population. Studying patients undergoing allogeneic HCT provides a unique opportunity to examine immune markers of AKI because the risk of AKI is high and the immune system newly develops after transplant. Children (>2 years old) and young adults undergoing their first allogeneic HCT and enrolled in a prospective, observational cohort study at 2 large children's hospitals had urine collected pre-HCT and monthly for the first 4 months after HCT. Urine samples at each monthly time point were assayed for 8 immune-related biomarkers. AKI was defined as a 1.5-fold increase in the monthly serum creatinine value, which was recorded ±1 day from when the research urine sample was obtained, as compared with the pre-HCT baseline. Generalized estimating equation regression analysis evaluated the association between the monthly repeated measures (urinary biomarkers and AKI). A total of 176 patients were included from 2 pediatric centers. Thirty-six patients from 1 center were analyzed as a discovery cohort and the remaining 140 patients from the second center were analyzed as a validation cohort. AKI rates were 18% to 35% depending on the monthly time point after HCT. Urine CXCL10 and CXCL9 concentrations were significantly higher among children who developed AKI compared with children who did not (P < .01) in both cohorts. In order to gain a better understanding of the cellular source for these biomarkers in the urine, we also analyzed in vitro expression of CXCL10 and CXCL9 in kidney cell lines after stimulation with interferon-γ and interferon-α. HEK293-epithelial kidney cells demonstrated interferon-induced expression of CXCL10 and CXCL9, suggesting a potential mechanism driving the key finding. CXCL10 and CXCL9 are associated with AKI after HCT and are therefore promising biomarkers to guide improved diagnostic and treatment strategies for AKI in this high-risk population.

Size and temporal-dependent efficacy of oltipraz-loaded PLGA nanoparticles for treatment of acute kidney injury and fibrosis

Acute kidney injury (AKI) is associated with high mortality and morbidity with no effective treatment available at present, which greatly escalates the risk of chronic kidney disease. Nanotechnology-based drug delivery for targeting renal tubules offers a new strategy for AKI treatment but remains challenging due to the glomerular filtration barrier. To tackle this challenge, here we demonstrate that poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) of 100 nm diameter could selectively accumulate in mouse injury kidneys in correlation to the degree of kidney injury and administration time during the initial phase of renal ischemia-reperfusion injury. The NPs were located in renal tubular epithelial cells confirmed by immunofluorescence, which is critical for the progression of AKI. Taking advantage of the high accumulation and renal tubule targeting of the PLGA NPs in the ischemia-reperfusion (IR) kidney, we designed PLGA NPs loaded with Oltipraz (PLGA-Oltipraz NPs) to treat IR-induced AKI and renal fibrosis. In vitro results showed that compared to free Oltipraz, PLGA-Oltipraz NPs displayed a higher antioxidation effect with improved cell viability, lower contents of malondialdehyde, and higher activity of superoxide dismutase. The therapeutic efficacy of PLGA-Oltipraz NPs was further investigated in vivo. Mice with AKI treated with PLGA-Oltipraz NPs exhibited significantly reduced tubular necrosis, less collagen deposition, and better renal function at the initial phase as well as improved renal fibrosis at the recovery phase. This study establishes a promising approach for AKI and fibrosis treatment with PLGA-Oltipraz NPs. It also reveals the importance of size-selective NPs and drug administration time window to nanotherpeutics.

Loganetin protects against rhabdomyolysis-induced acute kidney injury by modulating the toll-like receptor 4 signalling pathway.

Acute kidney injury (AKI) is a rapid renal dysfunctional disease, for which no effective drugs or therapies are available to improve prognosis. Loganetin is a natural product with unknown bioactivities. Here, we identified a new protective effect and mechanism of Loganetin in a mouse model of AKI induced by rhabdomyolysis. AKI was induced using glycerol by i.m. injection in mice models. Thirty minutes and 24 and 48hr after injection of glycerol, the mice received 2 and 18mg·kg-1 of Loganetin i.p. respectively. Then mice blood and kidney were collected for various biochemical and histopathological studies. Mechanistic studies on modulation of AKI by Loganetin were performed using HK-2 cells and Toll-like receptor 4 (TLR4) knockout mice. In the Loganetin treated group, kidney damage and mortality rate were declined, and blood urea nitrogen and serum creatinine were much lower. Loganetin prevented damage to the tubular structures induced by glycerol and decreased apoptotic cells at the corticomedullary junction. In HK-2 cells, Loganetin could inhibit NF-κB pathway and pro-apoptotic genes expression. However, TLR4 was silenced by a specific shRNA, and the inhibitory effect of Loganetin in HK-2 cells vanished. Loganetin also down-regulated the expression of inflammation factors by suppressing TLR4 activity. All the results suggested that TLR4 plays a critical role in AKI development, and Loganetin ameliorates AKI by inhibiting TLR4 activity and blocking the JNK/p38 pathway, which provides a new strategy for AKI treatment.

The assessment of acute kidney injury in critically ill patients

Acute kidney injury (AKI) is common in critically ill patients and is associated with high morbidity and mortality. The availability of several biomarkers of kidney injury offers new tools for its early recognition and management. The early identification of high-risk patients provides an opportunity to develop strategies for the prevention, early diagnosis and treatment of AKI. Despite progress in critical care medicine over the past decade, the treatment strategies for AKI in critically ill patients, such as when to start renal replacement therapy, remain controversial. A recently proposed risk prediction score for AKI, based on routinely available clinical variables, presents a new means of identifying patients at high risk of AKI.

P2X7 receptor inhibition protects against ischemic acute kidney injury in mice.

Activation of the purinergic P2X7 receptor (P2X7R) has been associated with the development of experimental nephritis and diabetic and hypertensive nephropathy. However, its role in acute kidney injury (AKI) remains unknown. In this study, we examined the effects of P2X7R inhibition in a murine model of ischemia-reperfusion (I/R)-induced AKI using A438079, a selective inhibitor of P2X7R. At 24 h after I/R, mice developed renal dysfunction and renal tubular damage, which was accompanied by elevated expression of P2X7R. Early administration of A438079 immediately or 6 h after the onset of reperfusion protected against renal dysfunction and attenuated kidney damage whereas delayed administration of A438079 at 24 h after restoration of perfusion had no protective effects. The protective actions of A438079 were associated with inhibition of renal tubule injury and cell death and suppression of renal expression of monocyte chemotactic protein-1 and regulated upon expression normal T cell expressed and secreted (RANTES). Moreover, I/R injury led to an increase in phosphorylation (activation) of extracellular signal-regulated kinases 1/2 in the kidney; treatment with A438079 diminished this response. Collectively, these results indicate that early P2X7R inhibition is effective against renal tubule injury and proinflammatory response after I/R injury and suggest that targeting P2X7R may be a promising therapeutic strategy for treatment of AKI.