A cute kidney injury (AKI) is a common complication in hospitalized patients, occurring in up to 20% of hospital admissions and 30% to 50% of intensive care unit admissions. AKI is an independent risk factor for death, with mortality rates as high as 50% in the intensive care unit. 1 The development of biomarkers that can identify AKI early and more reliably than serum creatinine rise has been a
Although dialysis has been used in the care of patients with acute kidney injury (AKI) for over 50 years, very little is known about the potential benefits of uremic control on systemic complications of AKI. Since the mortality of AKI requiring renal replacement therapy (RRT) is greater than half in the intensive care unit a better understanding of the potential of RRT to improve outcomes is urgently needed. Therefore, we sought to develop a technically feasible and reproducible model of RRT in a mouse model of AKI. Models of low and high dose peritoneal dialysis (PD) were developed and their effect on AKI, systemic inflammation, and lung injury after ischemic AKI was examined. High dose PD had no effect on AKI, but effectively cleared serum IL-6, and dramatically reduced lung inflammation while low dose PD had no effect on any of these three outcomes. Both models of RRT using PD in AKI in mice reliably lowered urea in a dose dependent fashion. Thus, use of these models of PD in mice with AKI has great potential to unravel the mechanisms by which RRT may improve the systemic complications that have led to increased mortality in AKI. In light of recent data demonstrating reduced serum IL-6 and improved outcomes with prophylactic PD in children, we believe our results are highly clinically relevant.
Although it is well established that acute kidney injury (AKI) is a proinflammatory state, little is known about the endogenous counter-inflammatory response. IL-6 is traditionally considered a pro-inflammatory cytokine that is elevated in the serum in both human and murine AKI. However, IL-6 is known to have anti-inflammatory effects. Here we sought to investigate the role of IL-6 in the counter-inflammatory response after AKI, particularly in regard to the anti-inflammatory cytokine IL-10. Ischemic AKI was induced by bilateral renal pedicle clamping. IL-10-deficient mice had increased systemic and lung inflammation after AKI, demonstrating the role of IL-10 in limiting inflammation after AKI. We then sought to determine whether IL-6 mediates IL-10 production. Wild-type mice with AKI had a marked upregulation of splenic IL-10 that was absent in IL-6-deficient mice with AKI. In vitro, addition of IL-6 to splenocytes increased IL-10 production in CD4 T cells, B cells, and macrophages. In vivo, CD4-deficient mice with AKI had reduced splenic IL-10 and increased lung myeloperoxidase activity. Thus, IL-6 directly increases IL-10 production and participates in the counter-inflammatory response after AKI.
Prerenal azotemia (PRA) is a major cause of acute kidney injury (AKI) and uncommonly studied in preclinical models. We sought to develop and characterize a novel model of PRA that meets the clinical definition: acute loss of GFR that returns to baseline with resuscitation. Adult male C57Bl/6J wild type (WT) and IL-6 -/- mice were studied. 4 mg of furosemide intraperitoneally (IP) or vehicle (Veh) was administered at time 0 hr and 3 hr to induce PRA from volume loss. Resuscitation began at 6 hr with 1 mL IP saline x 4 over 36 hours. Six hours after furosemide administration, measured GFR was 25% of baseline and returned to baseline after saline resuscitation at 48 hours. At 6 hours of PRA, plasma IL-6 was significantly increased, renal and liver histology were normal, renal and liver lactate were normal, and renal KIM-1 immunofluorescence was negative; 327 differentially regulated genes were upregulated in the liver and the acute phase response was the most significantly upregulated pathway; 25% of upregulated genes were suppressed in IL-6-/- mice, and the acute phase response was the most significantly suppressed pathway. Significantly upregulated genes and their proteins were also investigated and included: serum amyloid A2, serum amyloid A1, CXCL1, and haptoglobin; hepatic gene expression and plasma protein levels were all increased in WT PRA and were all reduced in IL-6-/- PRA. This work demonstrates previously unknown systemic effects of prerenal azotemia that includes IL-6-mediated upregulation of the hepatic acute phase response.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.