- Improving Translation from Preclinical Studies to Clinical Trials in Acute Kidney Injury. [Journal Article]
- NNephron 2018 May 23; :1-5
- CONCLUSIONS: Preclinical models of AKI should closely mimic the complexity of human AKI, considering the importance of several comorbidities in determining the clinical course and outcomes in the human disease. Moreover, studies should test novel interventions in models where AKI is already established, instead of focusing only at primary prevention. AKI definitions and endpoints in animal studies should be similar to those applied in clinical studies; in particular, AKI biomarkers should be implemented to guide patient selection for clinical trials and monitor intervention efficacy. In this scenario, cell-cycle arrest biomarkers have been widely investigated as AKI predictors in both preclinical and clinical studies and they serve as useful tools for future interventional studies. A better understanding of human AKI through a large collection of biological samples and kidney biopsies and omics applications, and an iterative relationship between preclinical and clinical studies are critical steps to improve future preclinical models and clinical trials. Finally, given the great variability in clinical manifestation of AKI, a strong collaboration between research centers and industry is recommended. Key messages: Several methodological issues have hampered the translation of basic research findings in clinical studies, and overcoming these obstacles is necessary to achieve success.
- A dual role of miR-22 in rhabdomyolysis-induced acute kidney injury (AKI). [Journal Article]
- APActa Physiol (Oxf) 2018 May 23; :e13102
- CONCLUSIONS: miR-22 is a HIF repressor constitutively expressed in the adult kidney, and up-regulated in AKI. Specific inhibition of miR-22 is efficient in vivo, and profoundly affects renal gene expression in health and disease, including up-regulation of HIF. However, the net effect on rhabdomyolysis-induced AKI outcome is neutral or even negative. This article is protected by copyright. All rights reserved.
- Early prediction of contrast-induced acute kidney injury by a "bedside" assessment of Neutrophil Gelatinase-Associated Lipocalin during elective percutaneous coronary interventions. [Journal Article]
- PlosPLoS One 2018; 13(5):e0197833
- Contrast-induced acute kidney injury (CI-AKI) is a serious complication during percutaneous coronary interventions (PCI). Currently, the diagnosis of CI-AKI relies on serum creatinine (SCr) that is h...
Contrast-induced acute kidney injury (CI-AKI) is a serious complication during percutaneous coronary interventions (PCI). Currently, the diagnosis of CI-AKI relies on serum creatinine (SCr) that is however affected by several limitations potentially leading to delayed or missed diagnoses. In this study we examined the diagnostic accuracy of a "bedside" measurement of plasma Neutrophil Gelatinase-Associated Lipocalin (NGAL) in the early detection of CI-AKI in 97 patients undergoing elective PCI. The overall incidence of CI-AKI was 3%. A significant positive correlation was observed between 6-hours NGAL and post-PCI SCr (r = 0.339, p = 0.004) and a significant negative correlation between 6-hours NGAL and post-PCI CrCl (r = -0.303, p = 0.010). In patients with post-PCI SCr increase > 0.24 mg/dl (median SCr absolute increase), delta NGAL 0-6 hours and 6-hours NGAL values were higher compared with patients with SCr elevation below the defined threshold (p = 0.049 and p = 0.056). The ROC analysis showed that a 6 hours NGAL value > 96 ng/ml significantly predicted an absolute SCr increase > 0.24 mg/dl after contrast exposure with sensitivity of 53% and specificity of 74% (AUC 0.819, 95% CI: 0.656 to 0.983, p = 0.005). The use of bedside NGAL assessment may significantly hasten diagnosis and treatment of CI-AKI, with remarkable clinical prognostic consequences.
- Prevention of dehydration in hospital patients. [Journal Article]
- BJBr J Nurs 2018 May 24; 27(10):565-569
- Dehydration is widely linked to increased risk of mortality in patients who are acutely unwell, and it also increases the risk of further illness. Despite being recognised nationwide as a cause for c...
Dehydration is widely linked to increased risk of mortality in patients who are acutely unwell, and it also increases the risk of further illness. Despite being recognised nationwide as a cause for concern, 45% of hospital patients will become dehydrated upon admission, suggesting that more needs to be done to prevent dehydration. The use of bedside water devices allows patients to drink freely without assistance. Access to these can reduce a patient's length of stay in hospital and minimise the risk of developing a urinary tract infection. However, further research is needed to fully assess the impact of having such devices at the bedside.
- Interleukin 1 Receptor (IL-1R1) Activation Exacerbates Toxin-Induced Acute Kidney Injury. [Journal Article]
- AJAm J Physiol Renal Physiol 2018 May 23
- Acute kidney injury (AKI) is a leading cause of morbidity and mortality. Cisplatin is an effective chemotherapeutic agent whose administration is limited by nephrotoxicity. Therapies to prevent cispl...
Acute kidney injury (AKI) is a leading cause of morbidity and mortality. Cisplatin is an effective chemotherapeutic agent whose administration is limited by nephrotoxicity. Therapies to prevent cisplatin-induced AKI are lacking. While tumor necrosis factor-α (TNF) plays a key role in the pathogenesis of cisplatin nephrotoxicity, the immune signaling pathways that trigger TNF generation in this context require elucidation. Sterile injury triggers the release and activation of both isoforms of interleukin(IL)-1, IL-1α and IL-1β, and stimulation of the interleukin-1 receptor (IL-1R1) by these ligands engages a pro-inflammatory signaling cascade that induces TNF induction. We therefore hypothesized that IL-1R1 activation exacerbates cisplatin-induced AKI by inducing TNF production thereby augmenting inflammatory signals between kidney parenchymal cells and infiltrating myeloid cells. IL-1R1+/+ (WT) and IL-1R1-/- (KO) mice were subjected to cisplatin-induced AKI. Compared to WT mice, IL-1R1 KO mice had attenuated AKI as measured by serum creatinine and BUN; renal NGAL mRNA levels; and blinded histological analysis of kidney pathology. In the cisplatin-injured kidney, IL-1R1 KO mice had diminished levels of whole kidney TNF and fewer Ly6G-expressing neutrophils. In addition, an unbiased machine learning analysis of intra-renal immune cells revealed a diminished number of CD11bint/CD11cint myeloid cells in IL-1R1 KO injured kidneys compared to IL-1R1 WT kidneys. Following cisplatin, IL-1R1 KO kidneys, compared to WTs, had fewer TNF-producing macrophages, CD11bint/CD11cint cells, and neutrophils, consistent with an effect of IL-1R1 to polarize intra-renal myeloid cells toward a pro-inflammatory phenotype. Interruption of IL-1-dependent signaling pathways warrants further evaluation to decrease nephrotoxicity during cisplatin therapy.
- Neutrophil exocytosis induces podocyte cytoskeletal reorganization and proteinuria in experimental glomerulonephritis. [Journal Article]
- AJAm J Physiol Renal Physiol 2018 May 23
- Acute glomerulonephritis is characterized by rapid glomerular neutrophil recruitment, proteinuria, and glomerular hypercellularity. The current study tested the hypothesis that release of neutrophil ...
Acute glomerulonephritis is characterized by rapid glomerular neutrophil recruitment, proteinuria, and glomerular hypercellularity. The current study tested the hypothesis that release of neutrophil granule contents plays a role in both loss of filtration barrier leading to proteinuria and the increase in glomerular cells. Inhibition of neutrophil exocytosis with a peptide inhibitor prevented proteinuria and attenuated podocyte and endothelial cell injury, but had no effect on glomerular hypercellularity in an experimental acute glomerulonephritis model in mice. Cultivation of podocytes with neutrophil granule contents disrupted cytoskeletal organization, an in vitro model for podocyte effacement and loss of filtration barrier. Activated cultured podocytes released cytokines that stimulated neutrophil chemotaxis, primed respiratory burst activity, and stimulated neutrophil exocytosis. We conclude that crosstalk between podocytes and neutrophils contributes to disruption of the glomerular filtration barrier in acute glomerulonephritis. Neutrophil granule products induce podocyte injury, but do not participate in the proliferative response of intrinsic glomerular cells.
- Graft function assessment in mouse models of single- and dual- kidney transplantation. [Journal Article]
- AJAm J Physiol Renal Physiol 2018 May 23
- Animal models of kidney transplantation (KTX) are widely used in studying immune response of hosts to implanted grafts. Additionally, KTX can be used in generating kidney-specific knockout animal mod...
Animal models of kidney transplantation (KTX) are widely used in studying immune response of hosts to implanted grafts. Additionally, KTX can be used in generating kidney-specific knockout animal models by transplantation of kidneys from donors with global knockout of a gene to wild type recipients or vise verse. Dual kidney transplantation (DKT) provides a more physiological environment for recipients than single kidney transplantation (SKT). However, DKT in mice is rare due to technical challenges. In this study, we successfully performed DKT in mice and compared the hemodynamic response and graft function with SKT. The surgical time, complications and survival rate of DKT were not significantly different from SKT, where survival rates were above 85%. Mice with DKT showed less injury and quicker recovery with lower plasma creatinine (Pcr) and higher GFR than SKT mice (Pcr = 0.34 and 0.17 mg/dl in DKT vs. 0.50 and 0.36 mg/dl in SKT at 1 and 3 days, respectively; GFR = 215 and 131 µl/min for DKT and SKT, respectively). In addition, the DKT exhibited better renal functional reserve and long-term outcome of renal graft function than SKT based on the response to acute volume expansion. In conclusion, we have successfully generated a mouse DKT model. The hemodynamic responses of DKT better mimic physiological situations with less kidney injury and better recovery than SKT because of reduced confounding factors such as single nephron hyperfiltration. We anticipate DKT in mice will provide an additional tool for evaluation of renal significance in physiology and disease.
- Crosstalk between Connexin 32 and mitochondrial apoptotic signaling pathway plays a pivotal role in renal ischemia reperfusion-induced acute kidney injury. [Journal Article]
- ARAntioxid Redox Signal 2018 May 23
- Perioperative acute kidney injury (AKI) resulting from renal ischemia reperfusion (IR) is not conducive to the postoperative surgical recovery. Our previous study demonstrated that reactive oxygen sp...
Perioperative acute kidney injury (AKI) resulting from renal ischemia reperfusion (IR) is not conducive to the postoperative surgical recovery. Our previous study demonstrated that reactive oxygen species (ROS) transmitted by gap junction (GJ) composed of connexin32 (Cx32) contributed to AKI. However, the precise pathophysiologic mechanisms were unknown. The present study focuses on the underlying mechanisms related to ROS transmitted by Cx32 responsible for AKI aggravation.
- N-(2-hydroxyphenyl)acetamide and its gold nanoparticle conjugation prevent glycerol-induced acute kidney injury by attenuating inflammation and oxidative injury in mice. [Journal Article]
- MCMol Cell Biochem 2018 May 22
- The protective activity of N-(2-hydroxyphenyl)acetamide (NA-2) and NA-2-coated gold nanoparticles (NA-2-AuNPs) in glycerol-treated model of acute kidney injury (AKI) in mice was investigated. NA-2 (5...
The protective activity of N-(2-hydroxyphenyl)acetamide (NA-2) and NA-2-coated gold nanoparticles (NA-2-AuNPs) in glycerol-treated model of acute kidney injury (AKI) in mice was investigated. NA-2 (50 mg/kg) and NA-2-AuNPs (30 mg/kg) were given to the animals for four days followed by 24-h water deprivation and injection of 50% glycerol (10 ml/kg im). The animals were sacrificed on the next day. Blood and kidneys were collected for biochemical investigations (urea and creatinine), histological studies (hematoxylin and eosin; and periodic acid-Schiff staining), immunohistochemistry (actin and cyclooxygenase-2, Cox-2), and real-time RT-PCR (inducible nitric oxide synthase, iNOS; nuclear factor-κB p50, NFκB; hemeoxygenase-1, HO-1; and kidney injury molecule-1, Kim-1). NA-2 protected renal tubular necrosis and inflammation, though the result of NA-2-AuNPs was better than compound alone and it also exhibited the activity at far less dose. The test compound and its gold nano-formulation decreased the levels of serum urea and creatinine level in the treated animals. Both NA-2 and NA-2-AuNPs also conserved actin cytoskeleton, and lowered COX-2 protein expression. Moreover, the mRNA expressions of iNOS and NFkB p50 were down-regulated, and HO-1 and Kim-1 genes were up-regulated. We conclude that NA-2 and NA-2-AuNPs ameliorates kidney inflammation and injury in glycerol-induced AKI animal model via anti-oxidant and anti-inflammatory mechanisms which make it a suitable candidate for further studies. We believe that these findings will contribute in the understanding of the mechanism of action of paracetamol-like drugs and can be considered for clinical research for the prevention of AKI.
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- Acute kidney injury, agranulocytosis, drug-induced liver injury, and posterior reversible encephalopathy syndrome caused by high-dose methotrexate-possible role of low activity ABC and SLC drug transporters. [Letter]
- EJEur J Clin Pharmacol 2018 May 22