Renal Blood Flow Measurement in Early Clinical Sepsis-Can You Catch a Shadow?

1028 www.ccmjournal. org June 2018 • Volume 46 • Number 6 Sepsis is the leading condition associated with acute kidney injury (AKI) in hospital and the ICU, up to half of critically ill patients with septic shock developing sepsis-associated AKI (SA-AKI). Accordingly, there remains is a strong interest in understanding the pathogenesis of SAAKI to establish a physiologic rationale for targeted interventions. However, despite research stretching back to the 1940s, the pathogenesis of septic AKI is still not fully understood. A particularly controversial issue has been the nature and role of alterations in renal blood flow (RBF) during the development of SA-AKI. In this issue of Critical Care Medicine, Larsson et al (1) attempt the challenging task of measuring RBF and function in patients with clinical sepsis very early after ICU admission. The results of the study by Larsson et al (1) are interesting, but their interpretation is limited by several unavoidable constraints imposed by studying a real-world sepsis population. To understand the context of these results, it is necessary to understand the historic concepts of AKI and the role of RBF in its pathogenesis. Traditionally, the concept of “acute renal failure” complicating acute illnesses was based on ischemia as the major pathogenic mechanism, leading to ischemia reperfusion injury as the dominant animal model for AKI of all forms. Theories of the pathogenesis of SA-AKI were then fitted to this construct, a view summarized in an influential 2004 review (2) which suggested that—in septic shock—increases in renal sympathetic tone, circulating catecholamines, vasopressin, and angiotensin II combined to mediate intense renal vasoconstriction and thence decreased renal function and cause ischemic renal injury. However, this paradigm of septic AKI was soon challenged by observations in large animal (largely ovine) models of SAAKI involving by infusion of Gram-negative bacteria, where decreased glomerular filtration rate (GFR) and increases in creatinine were accompanied by substantial increases in RBF, occurring in the context of hyperdynamic, hypotensive shock (3). Furthermore, the same group demonstrated in a different model that when RBF was mechanically reduced to 10% of baseline, GFR dropped by rapidly but rebounded without renal compromise when perfusion was normalized (4). Thus, persuasive evidence was provided that large reduction in RBF could transiently lower GFR, but did not in isolation give rise to sustained, ischemic renal injury and, conversely, that a clinical AKI syndrome could similarly occur with increased RBF in the context of hyperdynamic shock. However, neither of these hemodynamic scenarios directly addressed the development of sustained AKI accompanied by tubular cell dysfunction, and to some extent, both can be regarded as hemodynamically mediated, potentially reversible changes in GFR as, to borrow old nomenclature, forms of “prerenal” or at least “pretubular” failure. To add to this confusion in over 50 years of research, the renal hemodynamic picture in sustained, severe AKI, of both septic and other causes, has been consistently one increased renovascular resistance and a reduced renal fraction of cardiac output, irrespective of normal, elevated, or decreased cardiac output or systemic blood pressure (5, 6). In the context of established AKI, several lines of evidence therefore suggest that RBF changes in established AKI are a consequence, rather than the cause of AKI, with afferent renal arteriole vasoconstriction being mediated by pathophysiologic activation of the tubuloglomerulo feedback mechanism after tubular injury. Thus, measurements of high or low blood RBF in animal models of SA-AKI, or of low RBF in established human AKI, have been limited in their ability to address whether global reductions in RBF play a role in the development of SA-AKI in humans. To answer this question requires capturing measurements of RBF as early as possible after presentation with sepsis, prior to development of AKI. Such measurements have proven very challenging to perform, and the current article by Larsson et al (1) provides an attempt to gather such data. In their study, Larsson et al (1) took eight patients with septic shock requiring vasopressors within 24 hours of admission to the ICU and measured systemic hemodynamics, GFR, renal plasma flow, and renal oxygen extraction, by catheterization of the renal vein and measurement of Cr-EDTA clearance, paraaminohippurate clearance (and its renal extraction ratio), and renal oxygen extraction. Carrying out these complex and invasive measurements, rapidly in even a small cohort critically ill patients, is a great achievement, something enabled by the Gothenburg group’s long experience in these now rarely used techniques. Thus, the article by Larsson et al (1) provides some unique insights, despite the limited number of observations. Overall, compared with a population of postcardiac surgical patients without AKI, RBF was nonsignificantly reduced, *See also p. e560.