Protecting the kidney during critical illness

Dr, Jones; Ht, Lee

doi:10.1097/aco.0b013e328013f83c

Cited by 23 publications

(20 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…5 The incidence of renal dysfunction in high-risk patients after major cardiovascular, hepatobiliary, or aortic surgery approaches 70%-80%. 3,4,6 Despite continued research searching for renal protective agents, there are no proven therapies to reduce AKI in the perioperative setting 1,7 Sphingolipids are pleiotropic regulators of kidney physiology that modulate diverse pathways of cell death, including necrosis, apoptosis, inflammation, and immunity. 8,9 In particular, phosphorylation of sphingosine by sphingosine kinases (SK1 and SK2) leads to the formation of sphingosine 1-phosphate (S1P), a lysophospholipid targeting G-protein-coupled receptor that has diverse extracellular as well as intracellular effects.…”

mentioning

confidence: 99%

Inhibition of Sphingosine 1-Phosphate Receptor 2 Protects against Renal Ischemia-Reperfusion Injury

Park

Kim²,

Brown³

et al. 2012

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Activation of the sphingosine 1-phosphate receptor 1 (S1P 1 R) protects against renal ischemia-reperfusion (IR) injury and inflammation, but the role of other members of this receptor family in modulating renal IR injury is unknown. We found that a selective S1P 2 R antagonist protected against renal IR injury in a dosedependent manner. Consistent with this observation, both S1P 2 R-deficient mice and wild-type mice treated with S1P 2 R small interfering RNA had reduced renal injury after IR. In contrast, a selective S1P 2 R agonist exacerbated renal IR injury. The S1P 2 R antagonist increased sphingosine kinase-1 (SK1) expression via Rho kinase signaling in renal proximal tubules; the S1P 2 R agonist decreased SK1. S1P 2 R antagonism failed to protect the kidneys of SK1-deficient mice or wild-type mice pretreated with an SK1 inhibitor or an S1P 1 R antagonist, suggesting that the renoprotection conferred by S1P 2 R antagonism results from pathways involving activation of S1P 1 R by SK1. In cultured human proximal tubule (HK-2) cells, the S1P 2 R antagonist selectively upregulated SK1 and attenuated both H 2 O 2 -induced necrosis and TNF-a/cycloheximideinduced apoptosis; the S1P 2 R agonist had the opposite effects. In addition, increased nuclear hypoxia inducible factor-1a was critical in mediating the renoprotective effects of S1P 2 R inhibition. Finally, induction of SK1 and S1P 2 R in response to renal IR and S1P 2 R antagonism occurred selectively in renal proximal tubule cells but not in renal endothelial cells. Taken together, these data suggest that S1P 2 R may be a therapeutic target to attenuate the effects of renal IR injury. AKI is a major clinical complication with high mortality, morbidity, and cost. 1,2 Renal ischemia and reperfusion (IR) injury is a major cause of perioperative AKI for patients undergoing surgery involving the kidney, liver, or aorta. 3,4 Unfortunately, the severity and incidence of AKI have been increasing, without any improvements in therapy or patient survival over the past 50 years. 5 The incidence of renal dysfunction in high-risk patients after major cardiovascular, hepatobiliary, or aortic surgery approaches 70%-80%. 3,4,6 Despite continued research searching for renal protective agents, there are no proven therapies to reduce AKI in the perioperative setting 1,7 Sphingolipids are pleiotropic regulators of kidney physiology that modulate diverse pathways of cell death, including necrosis, apoptosis, inflammation, and immunity. 8,9 In particular, phosphorylation of sphingosine by sphingosine kinases (SK1 and SK2) leads to the formation of sphingosine 1-phosphate (S1P), a lysophospholipid targeting G-protein-coupled receptor that has diverse extracellular as well as intracellular effects. 9 Of five G-protein-coupled receptors for S1P, activation of endothelial S1P 1 R receptor (S1P 1 R) reduces permeability and maintains the integrity of the vascular endothelial cell

show abstract

mentioning

confidence: 99%

Inhibition of Sphingosine 1-Phosphate Receptor 2 Protects against Renal Ischemia-Reperfusion Injury

Park

Kim²,

Brown³

et al. 2012

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…This is also true for the management of fluid balance [10][11][12]. In contrast, pharmacological monotherapies with N-acetylcysteine [13,14] or the selective dopamine 1-receptor agonist Fenoldopam [13] for example, only led to a slight modification of renal function.…”

Section: Objectivesmentioning

confidence: 99%

Validation of a clinical score to determine the risk of acute renal failure after cardiac surgery

Heise¹,

Sundermann²,

Braeuer³

et al. 2010

European Journal of Cardio-Thoracic Surgery

View full text Add to dashboard Cite

Objective: Preoperative assessment of risk factors for postoperative acute renal failure (ARF) is a key point in the management of cardiac surgery patients. A reliable evaluation of individual risk permits the efficient application of prophylactic and therapeutic measures to patients with increased risk of ARF. In 2005, Thakar published a scoring system to determine the ARF risk prior to surgery. The score allowed calculation of the incidence of postoperative ARF requiring dialysis (ARF-D) with a high level of precision. Methods: In order to examine the reproducibility of the results on different patient populations, we retrospectively applied the scoring system to 3508 cardiac surgery patients at the Goettingen University Hospital. Results: We found a qualitative correlation between the score value and ARF-D, but prognostic significance, when judged by the area under the receiver operating characteristic (ROC) curve, was considerably reduced. Also, the incidence of ARF-D in the Goettingen population was remarkably higher than the incidence shown by Thakar for patients with the same score. Conclusions: The correlation between score values and incidence of ARF-D shows that the Thakar score is qualitatively transferable to cardiac surgery patients from other centres. Though the score allows the discrimination between patients with higher or lower risks of ARF-D within the Goettingen collective, it was not suitable to estimate the real incidence of postoperative ARF-D with sufficient precision. #

show abstract

“…In the perioperative period, hemodynamic changes and decreased renal blood flow often cause ischemia-reperfusion (IR) injury that leads to AKI. Despite continued advances in understanding the pathophysiology of AKI, there is no conclusive evidence that any of the currently available treatments offers renal protection during surgery (17,43).…”

mentioning

confidence: 99%

“…acute kidney injury; acute renal failure; apoptosis; inflammation; lentivirus; necrosis ACUTE KIDNEY INJURY (AKI) remains a major clinical problem during the perioperative period (17,19). Development of AKI frequently leads to multiorgan failure and sepsis, leading to increased morbidity and mortality in hospitalized patients.…”

mentioning

confidence: 99%

Selective renal overexpression of human heat shock protein 27 reduces renal ischemia-reperfusion injury in mice

Kim¹,

Park²,

Kim³

et al. 2010

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

We have previously shown that exogenous and endogenous A(1) adenosine receptor (A(1)AR) activation protected against renal ischemia-reperfusion (IR) injury in mice by induction and phosphorylation of heat shock protein 27 (HSP27). With global overexpression of HSP27 in mice, however, there was a paradoxical increase in systemic inflammation with increased renal injury after an ischemic insult due to increased NK1.1 cytotoxicity. In this study, we hypothesized that selective renal expression of HSP27 in mice would improve renal function and reduce injury after IR. Mice were subjected to renal IR injury 2 days after intrarenal injection of saline or a lentiviral construct encoding enhanced green fluorescent protein (EGFP) or human HSP27 coexpressing EGFP (EGFP-huHSP27). Mice with kidney-specific reconstitution of huHSP27 had significantly lower plasma creatinine, renal necrosis, apoptosis, and inflammation as demonstrated by decreased proinflammatory cytokine mRNA induction and neutrophil infiltration. In addition, there was better preservation of the proximal tubule epithelial filamentous (F)-actin cytoskeleton in the huHSP27-reconstituted groups than in the control groups. Furthermore, huHSP27 overexpression led to increased colocalization with F-actin in renal proximal tubules. Taken together, these findings have important clinical implications, as they imply that kidney-specific expression of HSP27 through lentiviral delivery is a viable therapeutic option in attenuating the effects of renal IR.

show abstract

Protecting the kidney during critical illness

Abstract: Despite the present lack of therapies for the treatment and prevention of acute renal failure, there are reasons to be optimistic. Recent research has led to the development of several different strategies that may provide a breakthrough in the treatment of acute renal failure.

Cited by 23 publications

References 70 publications

Inhibition of Sphingosine 1-Phosphate Receptor 2 Protects against Renal Ischemia-Reperfusion Injury

Inhibition of Sphingosine 1-Phosphate Receptor 2 Protects against Renal Ischemia-Reperfusion Injury

Validation of a clinical score to determine the risk of acute renal failure after cardiac surgery

Selective renal overexpression of human heat shock protein 27 reduces renal ischemia-reperfusion injury in mice

Contact Info

Product

Resources

About