Contributions to nephrology
-
Acute kidney injury (AKI) is associated with a heavy burden of morbidity and mortality, despite advances in intensive care and the management of high-risk patients. Numerous clinical trials have failed to ameliorate the outcomes of AKI. ⋯ Similarly, a multidisciplinary dialogue is making progress towards standardization of the clinical trial endpoints to prove efficacy and effectiveness in AKI research. Taken together with the increasing availability of timely, sensitive, and specific novel biomarkers of kidney damage, we are poised to use these tools to conduct successful clinical trials of agents for the prevention and treatment of this devastating clinical syndrome.
-
In order to prevent a disease, its temporal nature (or at least when it starts) needs to be clearly defined. In acute kidney injury (AKI), this is usually not possible because the current diagnostic criteria are retrospective. Contrast-induced nephropathy (CIN) and cardiac surgery-associated acute kidney injury (CSA-AKI) are both thought of as potentially preventable acute renal lesions because the timing of the insult is known precisely. ⋯ Despite this, progress in prevention has been slow, and to date there are no therapies indicated for preventing either CIN or CSA-AKI. The best we can currently do is to recommend aggressive parenteral hydration, avoid compounds we know are nephrotoxic, and avoid unnecessary hypoxia and hypotension. While there is still clearly a long way to go before either of these acute kidney conditions can be described as preventable, the use of major adverse kidney events - death, dialysis and incident or progressive chronic kidney disease at 90 days - as a composite endpoint in clinical trials of putative prevention agents would represent a significant step forwards.
-
Despite the identification of several of the cellular mechanisms thought to underlie the development of acute kidney injury (AKI), the pathophysiology of AKI is still poorly understood. It is clear, however, that instead of a single mechanism being responsible for its etiology, AKI is associated with an entire orchestra of failing cellular mechanisms. Renal microcirculation is the physiological compartment where these mechanisms come together and exert their integrated deleterious action. ⋯ Under pathological conditions, such as inflammation, shock or sepsis, however, the renal microcirculation becomes compromised, which results in a disruption of the homeostasis of nitric oxide, reactive oxygen species, and oxygen supply and utilization. This imbalance results in these compounds exerting pathogenic effects, such as hypoxemia and oxidative stress, resulting in further deterioration of renal microcirculatory function. Our hypothesis is that this sequence of events underlies the development of AKI and that integrated therapeutic modalities targeting these pathogenic mechanisms will be effective therapeutic strategies in the clinical environment.
-
The pathogenesis of sepsis-induced acute kidney injury (AKI) is not fully understood, and may involve altered systemic hemodynamics and renal circulation, renal hypoxia and perhaps direct tubular toxicity. Oxidative stress, induced by systemic and intrarenal generation of reactive oxygen species (ROS) can directly exert renal parenchymal damage and may intensify renal microvascular and functional dysregulation, with a feedforward loop of hypoxia and ROS generation. Herein we review compelling evidence that sepsis is associated with systemic and intrarenal intense oxidative and nitrosative stress with a depletion of antioxidant capacity. ⋯ Though oxidative and nitrosative stress are likely to participate in the pathogenesis of sepsis-induced AKI, it is impossible to clearly identify their isolated independent role and renal-specific effect since there are complex interactions involved linking various affected organs, ROS generation with altered systemic hemodynamics, compromised microcirculation, hypoxia and distorted cellular function. Facing this complex disease entity, alleviation of oxidative stress single-handedly is unlikely to be effective in the prevention of sepsis-associated renal dysfunction. However, the addition of antioxidants to a comprehensive treatment strategy seems a reasonable approach.
-
Endothelial cells play a key role in initiating and propagating the inflammatory response seen in ischemia, infections and sepsis. Situated in a key position between the epithelial cells and white blood cells (WBC), they interact and respond to signals from both cell types. ⋯ This last event is in large part responsible for a chronic reduction in regional perfusion, subsequent increased vulnerability to recurrent acute kidney injury, and acceleration of chronic kidney disease progression to end-stage renal disease. Glomerular endothelial dysfunction may lead to preglomerular shunting of blood flow allowing kidney blood flow to remain close to normal while resulting in a reduction in glomerular filtration rate.