Immunotherapy for Acute Kidney Injury
Acute renal failure, now referred to as acute kidney injury, is a common and clinically important problem. Acute kidney injury frequently occurs as a result of acute tubular necrosis (ATN), which is often caused by a reduction in systemic blood pressure or renal blood flow (e.g., as observed in severe sepsis or during renal transplantation). The disease course in ATN is variable, including prolonged dialysis-dependence and chronic renal dysfunction, but there is currently no specific therapy for ATN. There is increasing evidence that the inflammatory response in ATN significantly contributes to disease severity and outcome. In this review, we summarize recent developments in the understanding of how the immune system responds to dying cells, and the relevance of these discoveries to ATN. In particular, NLRP3 inflammasome activation and IL-1β-mediated neutrophil recruitment are likely to play a key role and may provide novel therapeutic targets for immunotherapy in ATN.
Acute renal failure, now referred to as acute kidney injury (AKI), is a common and clinically important problem, affecting between 5 and 10% of all hospitalized patients, and 30–40% of those admitted to a critical care setting. A number of pathologies cause AKI, the most common of which is acute tubular necrosis (ATN). ATN usually occurs as a result of a reduction in systemic blood pressure or renal blood flow (e.g., as observed in severe sepsis or during renal transplantation), or may be caused by exposure to nephrotoxins such as cisplatin, aminoglycosides and radiocontrast agents. ATN (regardless of the cause) is characterized histologically by the flattening of renal tubular epithelium, tubular dilatation and loss of tubular cell nuclei (Figure 1), and functionally by loss of electrolyte handling and solute clearance. The principle clinical manifestations observed are a reduction in urine output and a rise in serum urea and creatinine, sometimes necessitating renal support (dialysis). The disease course in ATN is variable, with some patients requiring prolonged renal replacement therapy for a number of weeks owing to delayed recovery and regeneration of tubular epithelial cells. Furthermore, the long-term outcome following ATN in both native and transplanted kidneys is also variable, with some patients recovering renal function completely while others develop renal scarring, which is associated with chronic renal dysfunction.
(Enlarge Image)
Figure 1.
Histological changes in acute tubular necrosis.
Typical changes in acute tubular necrosis include flattening of tubular epithelial cells and loss of tubular cell nuclei. Cellular debris may accumulate within the tubular lumen, forming casts.
AKI in native kidneys is associated with significant morbidity and mortality, with 20–40% mortality in the first year postdiagnosis in those patients requiring renal support. ATN in renal transplants is the most common cause of delayed graft function and is associated with an increased frequency of rejection in some studies and decreased short-term and long-term allograft function and survival. Furthermore, organ shortage has led to the increased use of deceased cardiac death donor kidneys, which are particularly susceptible to ATN.
Despite its clinical and economic importance, there are currently no specific treatments available for ATN. Patient management centers on optimizing fluid balance and removing nephrotoxins. Therefore, there is an urgent need to better understand the pathophysiological mechanisms involved in ATN in order to develop targeted therapies. A number of studies over the last decade have shown that the immune response to dying cells plays an important role in determining the severity of, and subsequent recovery from, a number of diseases, including ATN. We will review some of this evidence and consider how it may provide the basis for advances in the treatment of ATN.
Abstract and Introduction
Abstract
Acute renal failure, now referred to as acute kidney injury, is a common and clinically important problem. Acute kidney injury frequently occurs as a result of acute tubular necrosis (ATN), which is often caused by a reduction in systemic blood pressure or renal blood flow (e.g., as observed in severe sepsis or during renal transplantation). The disease course in ATN is variable, including prolonged dialysis-dependence and chronic renal dysfunction, but there is currently no specific therapy for ATN. There is increasing evidence that the inflammatory response in ATN significantly contributes to disease severity and outcome. In this review, we summarize recent developments in the understanding of how the immune system responds to dying cells, and the relevance of these discoveries to ATN. In particular, NLRP3 inflammasome activation and IL-1β-mediated neutrophil recruitment are likely to play a key role and may provide novel therapeutic targets for immunotherapy in ATN.
Introduction
Acute renal failure, now referred to as acute kidney injury (AKI), is a common and clinically important problem, affecting between 5 and 10% of all hospitalized patients, and 30–40% of those admitted to a critical care setting. A number of pathologies cause AKI, the most common of which is acute tubular necrosis (ATN). ATN usually occurs as a result of a reduction in systemic blood pressure or renal blood flow (e.g., as observed in severe sepsis or during renal transplantation), or may be caused by exposure to nephrotoxins such as cisplatin, aminoglycosides and radiocontrast agents. ATN (regardless of the cause) is characterized histologically by the flattening of renal tubular epithelium, tubular dilatation and loss of tubular cell nuclei (Figure 1), and functionally by loss of electrolyte handling and solute clearance. The principle clinical manifestations observed are a reduction in urine output and a rise in serum urea and creatinine, sometimes necessitating renal support (dialysis). The disease course in ATN is variable, with some patients requiring prolonged renal replacement therapy for a number of weeks owing to delayed recovery and regeneration of tubular epithelial cells. Furthermore, the long-term outcome following ATN in both native and transplanted kidneys is also variable, with some patients recovering renal function completely while others develop renal scarring, which is associated with chronic renal dysfunction.
(Enlarge Image)
Figure 1.
Histological changes in acute tubular necrosis.
Typical changes in acute tubular necrosis include flattening of tubular epithelial cells and loss of tubular cell nuclei. Cellular debris may accumulate within the tubular lumen, forming casts.
AKI in native kidneys is associated with significant morbidity and mortality, with 20–40% mortality in the first year postdiagnosis in those patients requiring renal support. ATN in renal transplants is the most common cause of delayed graft function and is associated with an increased frequency of rejection in some studies and decreased short-term and long-term allograft function and survival. Furthermore, organ shortage has led to the increased use of deceased cardiac death donor kidneys, which are particularly susceptible to ATN.
Despite its clinical and economic importance, there are currently no specific treatments available for ATN. Patient management centers on optimizing fluid balance and removing nephrotoxins. Therefore, there is an urgent need to better understand the pathophysiological mechanisms involved in ATN in order to develop targeted therapies. A number of studies over the last decade have shown that the immune response to dying cells plays an important role in determining the severity of, and subsequent recovery from, a number of diseases, including ATN. We will review some of this evidence and consider how it may provide the basis for advances in the treatment of ATN.
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