Mechanisms of acute kidney injury

In October 2012, an Acta Physiologica Symposium was held with regard to acute kidney injury (AKI). A series of articles from the symposium will appear in the following issues of Acta Physiologica. Acute kidney injury comprises a family of syndromes characterized by a sudden decrease in glomerular filtration rate. Only recently has it been acknowledged that even small changes in kidney function have important effects on outcomes. One of the first studies that demonstrated the importance of these minute changes in renal function was published in 1996 by Levy et al. (1996). The incidence of AKI in hospitalized patients shows an increase of approximately 11% per year (Xue et al. 2006) and increased from 610 pmp in 1988 to 2888 pmp in 2002 (Waikar et al. 2006). Severe renal failure has been recognized as a devastating disorder, long before the importance of minute changes in renal function was recognized. In fact, it was during the First World War when large numbers of wounded soldiers developed so-called war nephritis, as a consequence of shock, rhabdomyolysis and sepsis (Davies & Wells 1917). Today, the multitude of causes leading to AKI is commonly classified according to their origin as intrarenal, preand postrenal. The damage leading to AKI spans from functional dysregulation without overt morphological features to tubular destruction. Ischaemia/ reperfusion, sepsis/inflammation and rhabdomyolysis remain the leading factors of AKI. Consequently, these forms of AKI are highlighted by the contributions of this symposium series. Among the participants of the symposium are Scandinavian groups comprising researchers from Bergen, Copenhagen, Odense, Stockholm and Uppsala who work together with a research unit from Berlin (Forschergruppe 1368, Hemodynamic Mechanisms of AKI). This research unit comprises nine research groups from very different disciplines, such as nephrology, radiology, physiology and anatomy. The common interest of this research unit is clarifying haemodynamic mechanisms responsible for the many disorders leading to preand intrarenal AKI. Such disorders may involve direct vascular damage to the vessels determining glomerular filtration (Perlewitz et al. 2012), that is, the vasa afferentia and the vasa efferentia. Moreover, renal parenchymal hypoxia seems to play a pivotal role under a variety of clinical conditions leading to AKI. The balance between NO bioavailability and the production of cytochrome P450 (CYP) epoxides is decisive for the extent of damage. Also, vasoregulatory mediators by tubules and vessels are expect to be involved in AKI, as for other settings (Crawford et al. 2011, Jankowski et al. 2011, Ahmeda & Johns 2012). Acute kidney injury is of increasing relevance, and studies on hospitalization time underscore AKI’s socioeconomical importance. Prolonged hospitalization may give an indication of the severity of illness and may also serve as a marker for economic outcome and costs associated with a certain disease. As shown in a multicentre Austrian study, time of intensive care unit (ICU) stay of AKI patients treated with renal replacement therapy is, on average, 10 days longer than for other ICU patients (Metnitz et al. 2002). A harder end point than hospital stay is death, and it is well established that various forms of AKI are associated with increased mortality, even after correction for comorbidities (Kuitunen et al. 2006, Uchino et al. 2006). Increasing AKI severity is linked to increasing mortality in almost all studies (Xue et al. 2006). The precise mechanisms behind acute kidney injury remain to be unravelled. Data regarding renal hypoxia in the clinical situation of AKI are lacking, and our current concepts regarding renal oxygenation during AKI are presumptive. Although the understanding of the mechanisms leading to AKI remains scant, renal medullary hypoxia has been demonstrated to play a role under various experimental conditions (Dantzler et al. 2011, Damkjaer et al. 2012), also in those conditions leading to AKI, such as contrast-induced nephropathy (CIN) (Seeliger et al. 2012) or rhabdomyolysis. The particularly vulnerable kidney region is the outer medulla (Persson et al. 2005). This is an area remote from the vasa recta that supply the renal medulla with blood. The reason for the vulnerability of the outer medullary portion of the nephron is the relative high oxygen requirements because of salt reabsorption, in the face of meagre oxygen supply. The ascending limb of Henle’s loop has a high metabolic activity (O2 consumption because of active transmembrane ion transport), but oxygen delivery via the vasa recta is comparably scant. Moreover, in the region of the outer medulla, the descending vasa recta resemble arterioles, only later, in the deeper portion of the kidney, the vasa recta become more like capillaries. In consequence, oxygen diffusion through these vessels may be less pronounced in the outer medulla.