Novel targets for sepsis‐induced kidney injury: the glomerular arterioles and the sympathetic nervous system

Abstract

Sepsis and septic shock are the most common causes of acute kidney injury (AKI) in the intensive care unit, and mortality remains high despite improvements in our ability to support vital organs. The lack of development of effective treatments is partly because there has been little advance in our understanding of the pathophysiology of septic AKI, owing to the difficulty in conducting experiments on critically ill patients and use of inappropriate experimental models. Recently, however, a number of new concepts have emerged that challenge existing dogma and give insights into the causes of AKI. Traditionally, renal ischaemia has been proposed as the main cause of AKI, but it is becoming apparent that in sepsis with a hyperdynamic circulation, the most common situation in septic patients, there is an increase or at least no decrease in renal blood flow. In this review, the possible role of changes in pre- and postglomerular resistance in setting the increased level of renal blood flow in the presence of a decreased glomerular filtration rate is discussed. New evidence also indicates that the increased sympathetic nerve activity that occurs in sepsis may contribute to the induction of organ failure. Experimental studies indicate that inhibition of central sympathetic outflow with α(2)-adrenoceptor agonists or treatment with β(1)-adrenoceptor antagonists might reduce mortality in experimental endotoxaemia and sepsis. The possibility that these beneficial actions are partly dependent on a reduction in the excessive cytokine release caused by marked and prolonged sympathetic activation is discussed.

Renal effects of treatment with a TLR4-inhibitor in conscious septic sheep

“…Thus, renal hypoperfusion appears highly unlikely as a cause of septic AKI, given this experimental setting. A recently promoted hypothesis for sepsis-induced AKI is that the inflammatory response causes a preferential dilatation of renal efferent arterioles, increasing renal blood flow but reducing the hydrostatic pressure for glomerular filtration and thereby glomerular filtration rate (GFR) [32]. The most important vasodilator released in sepsis is NO, and it has been suggested that excessive intra-renal NO could be responsible for the reduction in postglomerular resistance [33].…”

Renal Hemodynamics in AKI

“…7,8 Recent experimental data from models of hyperdynamic sepsis in sheep questioned this paradigm, and data introduced the concept of decreased rather than increased glomerular vascular resistance, at least in early sepsis in ruminants. 11,12 Although the decline in GFR is mainly attributable to a profound lowering of the intraglomerular capillary pressure, the potential contributions of elevation of Bowman's pressure secondary to tubular obstruction and/or increased tubular flow in hyperfiltrating nephrons, impaired hydraulic permeability, and reduction of filtration surface area should be addressed by other studies in relevant animal models. Collectively, it is conceivable that a comparison of determinants of hypofiltration among progressors and nonprogressors of AKI as well as precise (semi)continuous monitoring of changes in GFR over extended periods of time should allow more sensitive investigations of the role of intrarenal hemodynamics during the development of AKI.…”

“…10 In contrast to this scenario, glomerular dynamics in the course of septic AKI are controversial. 7,8,11 The widely held concept of a fall in transcapillary hydraulic pressure caused by afferent arteriolar vasoconstriction leading to the reduction in GFR in sepsis has been largely derived from rodents challenged with large endotoxin bolus. 7,8 Recent experimental data from models of hyperdynamic sepsis in sheep questioned this paradigm, and data introduced the concept of decreased rather than increased glomerular vascular resistance, at least in early sepsis in ruminants.…”

Adaptation posologique chez le sujet obèse

“…En effet, les propriétés pharmacocinétiques et pharmacodynamiques des antibiotiques peuvent être affectées par les modifications physiopathologiques qui accompagnent cet état. Le traitement du choc septique augmente la pression intraglomérulaire et la perméabi-lité capillaire, favorisant un troisième secteur et résultant en une clairance rénale plus élevée [41]. À ce jour, cependant, la réflexion concernant les paramètres pharmacocinétiques est davantage adaptée au traitement des bactériémies.…”