Intensive Care Med (2007) 33:1498–1500DOI 10.1007/s00134-007-0735-7 E D I T O R I A L

Martin MatejovicPeter RadermacherMichael Joannidis

Acute kidney injury in sepsis:Is renal blood flow more than justan innocent bystander?

Published online: 16 June 2007© Springer-Verlag 2007

This editorial refers to the article available at:http://dx.doi.org/10.1007/s00134-007-0734-8

M. Matejovic (�)Charles University Medical School and Teaching Hospital,First Medical Department,Alej svobody 80, 30460 Plzen, Czech Republice-mail: matejovic@fnplzen.czTel.: +420-37-7103501Fax: +420-37-7103962

P. RadermacherUniversitätsklinikum Ulm, Sektion AnästhesiologischePathophysiologie und Verfahrensentwicklung,Ulm, Germany

M. JoannidisMedical University Innsbruck, Department of General InternalMedicine, Medical ICU,Innsbruck, Austria

Sir, The kidney is a common “victim organ” of various in-sults in critically ill patients, and, conversely, renal dys-function adds substantially to the morbidity and mortalityof these patients [1, 2]. Even relatively minor increments inserum creatinine levels coincide with markedly increasedmorbidity and mortality [3], highlighting the potentiallyimportant role of the kidney dysfunction during the nat-ural history of critical illness. Sepsis and septic shock arethe dominant cause of acute kidney injury (AKI), account-ing for nearly 50% of episodes of acute renal failure [4].Nevertheless, the exact understanding of pathophysiologicmechanisms of sepsis-induced AKI that would allow thedevelopment of new therapeutic strategies to prevent AKIor to hasten its recovery still remains a mystery.

In this issue of “Intensive Care Medicine” Langenberget al. [5] present a provocative, hypothesis-generating

insight into the behavior of renal hemodynamics both dur-ing the injurious and the recovery phase of sepsis-inducedkidney dysfunction. In a controlled, non-randomized,crossover sequential study, nine female sheep were instru-mented to continuously record systemic hemodynamicsand renal blood flow. These parameters, together withindices of renal glomerular (serum creatinine and itsclearance) and tubular function [fractional excretionof sodium (FENa) and urea (FEUn)] were followedduring a 96-h observation period. A week later, sepsiswas induced and maintained for 48 h by continuouslyinfusing live E. coli; thereafter, the E. coli infusion waswithdrawn, 240 mg of gentamycin were administered, andmonitoring continued for another 48 h to allow animalsto recover from sepsis. The authors’ key findings thathyperdynamic and normotensive circulation induced bybacterial challenge and fluid administration (1 ml/kg h–1

of normal saline) was accompanied by significant renalvasodilatation and increased renal artery blood flow.Amazingly, despite well-maintained global renal perfu-sion, glomerular filtration rate (GFR) deteriorated. Thiswas accompanied by reduced fractional sodium as wellas uric acid excretion as can be observed in so-calledpre-renal states. In contrast, recovery from sepsis wascharacterized by normalization of GFR despite renalvasoconstrictive response and return of the kidney bloodflow back to control values.

The study by Langenberg et al. [5] again opens the hotand unresolved debate on the role of renal blood flow insepsis-induced AKI. The concept of renal vasoconstrictionand kidney ischemia as a key pathogenetic factor in acuterenal failure is well embedded in the critical care andnephrology literature. Although this is certainly valid forall low-flow states, such as cardiogenic or hemorrhagicshock, during sepsis and other acute systemic inflamma-tory conditions the hemodynamic alterations within thekidney still remain controversial [6, 7]. While human

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data on renal hemodynamics in sepsis are scarce andunreliable [6], a recent systematic review of the availableexperimental evidence showed that about 30% of animalstudies reported unchanged or even increased renal bloodflow [6]. Furthermore, it is emphasized that the majorityof studies reporting a reduction in renal blood flow werederived from fairly heterogenous, short-term, and mostlyhypodynamic models characterized by a reduced cardiacoutput, which therefore only have a limited resemblanceto human pathophysiology. Utilizing a clinically morerelevant model of sepsis-induced AKI [8], the present [5]as well as a previous study [9] by Langenberg et al.completely challenge our conventional presumptionsuggesting that renal vasoconstriction is not necessarilya prerequisite for AKI to develop during hyperdynamicsepsis.

Even more importantly, monitoring the recovery phasemakes this study particularly interesting, since researchinto the process of resolution of AKI has been very sparse.The authors provide, for the first time, the hemodynamicand functional pattern during the recovery from experi-mental sepsis-induced AKI. The association between thereduction of renal blood flow and functional improvementduring this condition is undoubtedly a striking finding, andthe results indicate that the renal vascular bed participatesin the systemic hemodynamic alterations not only duringsepsis, but also during its resolution.

Beyond these intriguing data, several controversialissues remain, and some aspects of the study need to beaddressed. An important question not resolved by thecurrent study is whether the interplay between the changesin global kidney blood flow and function during boththe injurious and recovery phases of AKI are causallylinked or just an epiphenomenon. Diminished glomerularfiltration with intact tubular functions as documented bydecreased FENa and FEUn indicate a “pre-renal pattern”of AKI. This observation contrasts with recent findingsthat during severe inflammation renal sodium transportersare downregulated [10]; thus, instead, a sodium wasting bythe kidney should ensue. Given the apparently generousrenal perfusion in the sheep model, it seems reasonableto argue that changes in intraglomerular hemodynamicsare likely involved in the deterioration of glomerularfiltration. Decreased renal vascular resistance affectingboth the afferent and efferent arterioles, with the effectpredominating on the latter vessels, might explain thefall in glomerular filtration, and the opposite changes inintraglomerular circulation might account for the restora-tion of glomerular filtration. The lack of effectiveness oreven worse outcome in clinical trials investigating variousvasodilatators in septic acute renal failure [11, 12], and,conversely, increased urine output and creatinine clearanceachieved by vasopressin-mediated action mostly on effer-ent arteriole [13] fit well with the foregoing hypothesis.

Taken together, a vasomotor nephropathy characterized byan imbalance in intraglomerular vasomotor control [14]and yet undefined disharmony of glomerular vascular bal-ancing mediators [15] may be a primary cause of early,“functional” AKI, preceding a pathophysiologically com-plex intrinsic renal structural injury (e.g., epithelial apop-tosis or even tubular necrosis) [16].

Furthermore, the study by Langenberg et al. [5] doesnot provide information about intrarenal distribution ofblood flow between cortex and medulla during the evo-lution and recovery phase of sepsis-associated AKI [5],although the authors’ group previously showed in anotherstudy that corticomedullary microvascular redistributiondoes not occur in hyperdynamic sepsis in sheep [17]. Theirobservation, however, cannot completely dismiss the po-tential for renal microcirculation to be the main “culprit”of acute renal failure. In fact, two recent long-term rodentmodels of sepsis-induced acute renal failure demonstratedmarked renal microvascular disturbances [18, 19]: Inthe study by Wu et al. an early and marked decline incortical peritubular capillary perfusion was associatedwith tubular redox stress and preceded the developmentof renal failure [19]. Interestingly, despite a full recoveryof renal function at 48 h, functional capillary densityrecovered only partially [19]. These findings are cor-roborated by an even more recent study by Gupta et al.,in which quantitative two-photon intravital microscopyrevealed markedly reduced peritubular capillary bloodflow in an endotoxemia model in rats [20]. Therefore,in the absence of methods to simultaneously determinerenal microcirculation, kidney energy metabolism andmediators involved in inflammation, vascular, body water,and electrolyte homeostasis, it is impossible to put the datafrom Langenberg et al.’s [5] study into a relevant complexpicture.

The key question is how to come up with useful infor-mation that might be of value to critical care physicians.Certainly, unraveling the fate and role of renal blood flowboth in the development of and recovery from septic AKImight pave the way for new treatment targets in sepsis-induced kidney dysfunction. If the results presented byLangenberg et al. [5] are to be confirmed and understood insufficient detail, strategies appropriately modulating intra-glomerular vasomotor balance might prove to augmentglomerular filtration. From the medullary perspective,however, strategies that enhance glomerular filtration may,at least in theory, adversely affect medullary oxygenationby increasing tubular transport capacity and energy re-quirements [21]. In this view, reduced glomerular filtrationmay, in fact, represent “acute renal success,” rather thanacute renal failure [22], which would be in analogy tothe recently presented hypothesis that multiorgan dysfunc-tion represents a “hibernation”-like adaptation character-ized by a consecutive reduction of energy demands that

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allows to buy time for organ repair [23]. Thus, a definitiveanswer to all of these intriguing questions remains to beprovided.

Although leaving important aspects open to specula-tion, the studies by Langenberg et al. [5, 9] provide im-portant insights into the increasingly challenging aspects

of critical care nephrology, which should stimulate furtherresearch in this direction.

Acknowledgements. This work was supported by research grantMSM 0021620819 (Replacement of and support to some vital or-gans).

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