Renal perfusion in sepsis: from macro- to microcirculation

review

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Renal perfusion in sepsis: from macro- to microcirculation Emiel Hendrik Post1, John A. Kellum2, Rinaldo Bellomo3 and Jean-Louis Vincent1 1 Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium; 2Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and 3Centre for Integrated Critical Care, School of Medicine, The University of Melbourne, Parkville, Melbourne, Australia

The pathogenesis of sepsis-associated acute kidney injury is complex and likely involves perfusion alterations, a dysregulated inflammatory response, and bioenergetic derangements. Although global renal hypoperfusion has been the main target of therapeutic interventions, its role in the development of renal dysfunction in sepsis is controversial. The implications of renal hypoperfusion during sepsis probably extend beyond a simple decrease in glomerular filtration pressure, and targeting microvascular perfusion deficits to maintain tubular epithelial integrity and function may be equally important. In this review, we provide an overview of macro- and microcirculatory dysfunction in experimental and clinical sepsis and discuss relationships with kidney oxygenation, metabolism, inflammation, and function. Kidney International (2016) j.kint.2016.07.032

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http://dx.doi.org/10.1016/

KEYWORDS: acute kidney injury; renal hypoperfusion; sepsis Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Correspondence: Jean-Louis Vincent, Department of Intensive Care, Erasme Hospital, Route de Lennik 808, 1070 Anderlecht, Belgium. E-mail: jlvincent@ intensive.org Received 13 May 2016; revised 1 July 2016; accepted 7 July 2016 Kidney International (2016) -, -–-

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epsis is considered a dysregulated host response to a severe infection.1 This immune response can cause pronounced systemic hypotension, which has led to formulation of a hypothesis of ischemic acute kidney injury in septic shock.2,3 Indeed, in the case of suspected compromised tissue perfusion, early restoration of organ perfusion pressure is of paramount importance, yet patients can still die from multiorgan failure even when blood pressure has been adequately restored.4 Thus, perfusion alterations are more likely to be of microcirculatory origin, a phenomenon that has been observed in virtually every organ, including the kidney. In this article, we review the role of hemodynamics in the development of renal dysfunction during sepsis, from whole-organ renal blood flow (RBF) to the microcirculation and even beyond.

Renal blood flow in sepsis Experimental studies. The behavior of whole-organ RBF

during sepsis and septic shock remains a subject of controversy. Models of renal ischemia using total renal arterial stopflow do not accurately reproduce the clinical scenario of sepsis, and the literature on experimental sepsis and infusion of lipopolysaccharide or live bacteria shows marked hetereogeneity (Table 1).5 For example, in a sheep model of infusion of live bacteria, Di Giantomasso et al. reported that sepsis was associated with increased RBF.6 In the same model, Langenberg and colleagues demonstrated that this renal hyperemia did not prevent renal dysfunction.7 By contrast, Benes et al. demonstrated in 2 different pig models of septic shock that renal vascular resistance increased in animals with renal dysfunction.8 This renal vasoconstrictive response occurred in the presence of vasodilation in other parts of the body, suggesting blood flow redistribution. Indeed, systemic flow redistribution has been observed in a number of animal models of sepsis and septic shock,9,10 and may be caused by several factors, including increased renal sympathetic nerve activity (RSNA) and the release of vasoactive molecules, such as angiotensin II,11 endothelin-1, thromboxane A2, and leukotrienes.12–14 The intrinsic properties of renal autoregulation also comply with the concept of flow redistribution. In health, RBF is autoregulated at renal perfusion pressures (RPP) greater than approximately 60–100 mm Hg, depending on the species.15–17 This value is higher than for the heart18 and the brain,19 and allows a rapid reduction in RBF in case of hypovolemia, thus retaining circulating blood volume and 1

First author, year

Model

Fluid and vasopressors

Intervention

Observation

Pig

i.m. P. multicoda

Balanced solution, titrated to MAP

-

24 h

Cronenwett, 197884

Dog

i.v. P. aeruginosa

-

-

60 min

Stone, 197983

Dog

Septic blood transfusion

NaCl 0.45%, 2 ml/min

-

60 min

Auguste, 198085

Dog

E. coli perfusate

NA

-

75 min

Gullichsen, 1991146

Dog

i.v. LPS

-

-

4h

Weber, 1992151

Sheep

i.v. LPS

Ringer’s lactate, 50 ml/h

-

72 h

Bersten, 199550

Sheep

i.p. E. coli and B. fragillis

-

Epinephrine, DA

4h

Heemskerk, 1997153

Rat

i.v. LPS and E. colia

-

-

3h

Cohen, 200188

Pig

i.v. LPS

NaCl 0.9%, titrated to PAOP

L-NAME, SMT

6h

Di Giantomasso, 20036

Sheep

i.v. E. coli

Unknown, 2 ml/kg/h and gelofusine boluses titrated to CVP

NE

30 min

Albert, 200441

Rabbit

i.v. LPS

NaCl 0.9%, 4 ml/kg/h

AVP

90 min

Boffa, 200414

Mouse

i.p. LPS

NaCl 0.9%, 10 ml/kg at baseline

TXA2-R k/o,TXA2 antagonist

14 h

Boffa, 200542

Mouse

i.p. LPS

NaCl 0.9%, 10 ml/kg at baseline

NE, Ang II, L-NAME, AVP

3h

Ravikant, 1977

Key findings

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RBF, cortical and medullary flow increased at 24 h. No intrarenal redistribution. RBF maintained, intrarenal flow redistribution toward the corticomedullary junction. RBF increased, intrarenal redistrubtion toward the outer cortex. RBF unchanged, no signs of intrarenal flow redistribution. RBF decreased, renal VO2 and cortical tPO2 initially decreased, restored thereafter. Lactate uptake and glucose consumption unchanged. RBF decreased, partially restored after 24 h. Renal VO2 reduced, restoration after 24 h. TNaþ/VO2 persistently reduced. RBF increased with DA in healthy animals. Effect attenuated in sepsis. RBF decreased, renal VO2 unchanged, VO2/TNaþ increased. RBF increased, intrarenal redistribution towards medulla. L-NAME and SMT both decreased RBF, cortical and medullary flow, redistribution unchanged. RBF increased, no clear redistribution. NE administration increased RBF further and augmented medullary flow. With increasing dose: increased diastolic RBF velocity, increased cortical flow, minor increase medullary flow. Cortical flow values depressed at highest dose. RBF decrease attenuated in TXA2-R k/o and TXA2-antagonist treated mice. RBF decreased further with Ang II and L-NAME, but was largely unaffected by NE and AVP.

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Table 1 | Experimental studies of renal perfusion in sepsis

Rabbit

i.v. LPS

-

Levosimendan, AVP, NE

36 h

Tiwari, 2005113

Mouse

i.p. LPS

-

L-NIL, Z-VAD

24 h

Langenberg, 20067

Sheep

i.v. E. coli

NaCl 0.9%, 1 ml/kg/h

-

48 h

Johannes, 2006133

Rat

i.v. LPS

NA

HES130/0.4, HES200/0.5, Ringer’s lactate

90 min

Yasuda, 2006130

Mouse

CLP

NaCl 0.9%, 1.5 ml at 6 and 12 h

Simvastatin

24 h

Wu, 2006114

Mouse

i.p. LPS

NaCl 0.9%, 1 ml after CLP, 1ml after 6 h

L-NIL

24 h

Wu, 200697

Mouse

i.p. LPS

-

-

48 h

Rat

i.p. LPS

-

APC

24 h

Mouse

CLP

L-NIL

22 h

Chvojka, 200899

Pig

Peritonitis

NaCl 0.9%, 1 ml after CLP, 1.5 ml after 6 h HES 130/0.4, 10 ml/kg/h, NE if shock

-

22 h

Fenhammar, 2008138

Pig

i.v. LPS

NaCl 0.9%, 20 ml/kg/h

Tezosentan

5h

Sheep

i.v. E. coli

-

Ang II

8h

Gupta, 2007139 Wu, 2007115

Wan, 200946

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RBF and renal VO2 maintained, cortical flow decreased and renal vein L/P ratio increased from 12 h onward. Attenuation of the decrease in RBF and cortical flow with tezosentan. RBF decreased with Ang II but increased UO and creatinine clearance.

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Faivre, 200589

GFR changed in the same direction. No effect on RBF, cortical or medullary flow with levosimendan alone. NE alone increased, and AVP, with or without levosimendan, depressed, medullary flow. L-NIL and Z-VAD improved peritubular capillary flow impairment, cortical injury, renal apoptosis, plasma creatinine and BUN after 18 h. RBF increased, creatinine clearance and UO reduced. Decrease in RBF, VO2 maintained, VO2/TNaþ increased, cortical and medullary mPO2 minimally affected. RBF partially restored by all fluids, oxygenation differentially affected. Interstitial edema at 6 h in control group. Edema, capillary flow impairment and tubular hypoxia attenuated after pretreatment with simvastatin. L-NIL attenuated peritubular capillary flow impairment, tubular epithelial ROS/RNS generation and tubular injury. Peritubular capillary flow impairment from 2 h onward, significant spatial correlation between peritubular flow impairment and tubular epithelial redox-alterations. Peritubular capillary flow impairment at 3 h improved with APC, improved BUN at 24 h. L-NIL attenuated peritubular capillary flow impairment and tubular injury.

First author, year

Model

Fluid and vasopressors

Intervention

Observation

Johannes, 2009

Rat

i.v. LPS

HES 130/0.4, 5 ml/kg/h

DXM supplemented fluid

5h

Johannes, 2009118

Rat

i.v. LPS

HES 130/0.4, 5 ml/kg/h

NTG, 1400W

5h

Johannes, 2009154

Rat

i.v. LPS

HES 130/0.4, 5 ml/kg/h

Flow reduction healthy rats

60 min

Johannes, 2009136

Rat

i.v. LPS

HES 130/0.4, 5 ml/kg/h

Iloprost

5h

Benes, 20118

Pig

i.v. P. aeruginosa and peritonitisa

HES 130/0.4, titrated to CVP and PAOP, NE if shock

-

22 h

Dyson, 2011152

Rat

i.v. LPS

Ringer’s lactate, 20 ml/kg/h

-

4h

Legrand, 2011100

Rat

i.v. LPS

NA

HES 130/0.4 from baseline, 2-hour delay

5h

Seely, 201198

Rat

CLP

NaCl 0.9%, 1 ml after CLP, 1.5 ml after 6 h

-

22 h

Aksu, 2012134

Rat

i.v. LPS

NA

HES-RA, HES-NaCl

4-5 h

Mouse

CLP

NaCl 0.9%, 1 ml after CLP, 40 ml/kg after 6

Resveratrol

18 h

Holthoff, 2012116

Key findings RBF and cortical mPO2 decrease further attenuated with dexamethasone suppletion, renal VO2 normalized. RBF decreased, renal VO2, cortical and outer medulla mPO2 decreased. Unaffected by NO donation or iNOS-inhibition. Flow reduction in health decreased renal VO2 without signs of microcirculatory hypoxia. Microcirculatory hypoxia in septic controls partially alleviated by fluid resuscitation. RBF decrease unaffected. Renal VO2 and VO2/TNaþ restored. Cortical and medullary mPO2 increased: increased oxygen extraction by improved microvascular function. RBF decreased and RVR increased in septic animals with, but not without, AKI. RBF decreased. Renal VO2 unchanged. Cortical and outer medulla mPO2 decreased and interstitial PO2 in cortex and medulla decreased: gradient unchanged. Late correction of RBF did not affect cortical microvascular perfusion and mPO2. RBF decreased after 2 h, perivascular perfusion deficits followed at 6 hours, signs of capillary leakage present after 10 h. HES-RA, but not HES-NaCl, attenuated the decrease in RBF and cortical microvascular perfusion. Increased cortical flow heterogeneity attenuated by both. RBF decrease attenuated, perivascular perfusion deficits attenuated, tubular epithelial RNS formation and tubular injury attenuated.

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Table 1 | (Continued)

i.v. E. coli

NaCl 0.8%, 1 ml/kg/h

Intrarenal L-NAME

8h

Ishikawa, 201245

Sheep

i.v. E. coli

NaCl 0.9%, 1 ml/kg/h

Intrarenal 1400W, AG and L-NAME

8h

Ishikawa, 201243

Sheep

i.v. E. coli

NaCl 0.9%, 1 ml/kg/h

Terlipressin single and multiple dose

6h

Wang, 2012120

Mouse

CLP

NaCl 0.9%, 1 ml after CLP, 40 ml/kg after 6 h

MnTMPyP

18 h

Almac, 2013140

Rat

i.v. LPS

HES 130/0.4, 5ml/kg/h

low and high dose APC

3h

Mouse

CLP

NaCl 0.9%, 1 ml after CLP, 1.5 ml after 6 h

Rolipram

18 h

Rat

CLP

Gelatin 4% after CLP, titrated to MAP

MAP reductions by acute bleeding

5–6 h

Patil, 2014121

Mouse

CLP

NaCl 0.9%, 1 ml after CLP

MitoTEMPO

24 h

Yang, 2014145

Dog

i.v. LPS

NaCl 0.9%, 4.3 ml/kg/h, titrated to CVP and PAOP

-

6h

Calzavacca, 201587

Sheep

i.v. E. coli

NaCl 0.9%, 1 ml/kg/h

-

72 h

Wang, 2015132

Mouse

CLP

NaCl 0.9%, 1 ml after CLP, 1.5 ml after 6 h

S1P1-agonist

18 h

Ergin, 2016135

Rat

i.v. LPS

NA

HES-RA, AQIX, NaCl 0.9%

7h

Holthoff, 2013137

Burban, 201323

5

RBF increase attenuated in both mild sepsis and septic shock, renal function not affected in both groups. RBF increase attenuated and UO increased with L-NAME, no effect on creatinine clearance from any of the three NOS inhibitors. RBF increase attenuated with single-dose terlipressin. Increased UO and creatinine clearance. Attenuated effect on creatinine clearance with multiple doses. RBF decreased, interstitial edema evident at 2 h, capillary flow impairment after 4 h. Only delayed MnTMPyP improved capillary leakage and capillary dysfunction. RBF and cortical and medullary mPO2 unaffected. TNaþ/VO2 improved with APC. RBF decrease, perivascular capillary leakage, peritubular capillary dysfunction, tubular hypoxia and injury attenuated with delayed rolipram. RNS generation unaffected. RBF decreased by NE. Renal autoregulation unchanged in sepsis, with or without NE. MitoTEMPO reduced mitochondrial oxygen radical production and improved mitochondrial function. Peritubular capillary dysfunction attenuated. Renal DO2 maintained, renal VO2 decreased, renal ATP levels decreased. RBF increased, cortical flow maintained, medullary perfusion and medullary tPO2 decreased. Pretreatment with S1P1-agonist reduced signs of capillary leakage but did not prevent early capillary hypoperfusion. Delayed treatment improved both. RBF decrease attenuated with HES-RA, but not with AQIX or NaCl, cortical and medullary (Continued on next page)

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Sheep

EH Post et al.: Renal macro- and microcirculation in sepsis

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Ishikawa, 201144

1400W, selective iNOS inhibitor; AG, aminoguanidine (partially selective iNOS inihibitor); AKI, acute kidney injury; Ang II, angiotensin II; APC, activated protein C; AQIX, fully balanced crystalloid solution; AVP, arginine vasopressin; BUN, blood urea nitrogen; CLP, cecal ligation and puncture; CVP, central venous pressure; DA, dopamine; DXM, dexamethasone; GFR, glomerular filtration rate; HES, hydroxyethyl starch; HES-NaCl, unbalanced HES solution; HES-RA, balanced HES solution; iNOS, inducible nitric oxide synthase; L/P, lactate/pyruvate; L-NAME, nonselective NOS inhibitor; L-NIL, selective iNOS inhibitor; LPS, lipopolysaccharide; MAP, mean arterial pressure; MitoTEMPO, mitochondria-targeted antioxidant; MnTMPyP, superoxide scavenger; mPO2, microvascular PO2; NA, not applicable; NE, norepinephrine; NTG, nitroglycerin; PAOP, pulmonary artery balloon-occluded pressure; ROS/RNS, reactive oxygen species/reactive nitrogen species; RVR, renal vascular resistance; S1P1, sphingosine-1-phosphate-1; SMT, selective iNOS inhibitor; Tnaþ, sodium reabsorption; tPO2, tissue PO2; TXA2-R k/o, thromboxane A2 receptor knockout; UO, urine output; VO2, oxygen consumption; Z-VAD, nonselective caspase inhibitor. a Two models.

Sheep Maiden, 2016143

i.v. E. coli

NaCl 0.9%, 3 ml/kg/h, NE if MAP < 75 mm Hg

48 h

increased renal oxidative stress. RBF unchanged with NE. Cortical oxygenation unaffected, medullary flow and tPO2 decreased with NE. RBF maintained, minimal signs of renal injury on light and electron microscopy. 32 h NE Sheep Lankadeva, 201690

i.v. E. coli

NaCl 0.9%, 1 ml/kg/h

mPO2 unaffected. HES may have

Intervention Model Species First author, year

Table 1 | (Continued) 6

EH Post et al.: Renal macro- and microcirculation in sepsis

Fluid and vasopressors

Observation

Key findings

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diverting blood toward more vital organs.20 The situation in sepsis is, however, less clear. Bellomo et al. studied renal passive pressure-flow relationships in dogs and found that ohmic renal resistance decreased after approximately 45 minutes of endotoxemia.21 However, these measurements were taken using a 5-second time frame, which is too short for the full renal autoregulatory response to occur.22 Burban et al. investigated renal autoregulation in a rodent model of abdominal sepsis by bleeding the animals to reduce RPP.23 They found that early sepsis did not alter the relationship between RBF and mean arterial pressure (MAP). However, blood loss can shift the lower autoregulatory threshold to higher pressures, which may have confounded their results.24 Clinical studies. Measurement of RBF at the bedside is challenging, and the available data in human sepsis are limited and often unreliable. Most studies have reported a decrease in RBF in human sepsis.25–27 Brenner et al. used a thermodilution technique to measure RBF in 6 patients with septic shock, 5 of whom had low to normal RBF. Relative RBF, or the fraction of cardiac output directed to the kidneys, was reduced in all patients and correlated well with the glomerular filtration rate (GFR).28 Redfors et al. measured RBF using retrograde thermodilution in 12 patients who had developed vasodilatory shock after cardiac surgery and also found low to normal RBF in all.29 Using renal Doppler at intensive care unit (ICU) admission in 34 patients with septic shock, Lerolle et al. found that the renal resistive index was higher in patients who later developed acute kidney injury (AKI),30 although indices derived from renal Doppler measurements may poorly reflect actual changes in renal hemodynamics.31 Prowle et al. reported a consistent reduction in relative RBF estimated by phase-contrast magnetic resonance imaging in 10 patients with sepsis and fully established AKI.32 However, absolute RBF did not correlate with GFR, and whether alterations in renal resistive index or RBF are the cause or consequence of AKI, or even just an epiphenomenon, remains unclear. Systemic hemodynamics, RBF, and kidney function Observational clinical studies. Many observational clinical

studies have reported significant associations between systemic hemodynamic instability and renal dysfunction in septic shock (Table 2). In septic shock patients treated with norepinephrine, Martin et al. showed that adequate restoration of MAP was associated with restored urine output and improved creatinine clearance.33 In 274 patients with sepsis, Dünser et al. found an association between the time spent with an MAP of less than 60 mm Hg during the first 24 hours of ICU stay and lower urine output, higher maximum plasma creatinine and increased need for renal replacement therapy.34 Badin et al. also demonstrated that patients with septic shock had a lower MAP during the first 12 hours of ICU stay when AKI was present at 72 hours than when it was not.35 Similarly, the FINNAKI trial found an association between the time spent in relative hypotension and the development of AKI in Kidney International (2016) -, -–-

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EH Post et al.: Renal macro- and microcirculation in sepsis

Table 2 | Clinical observational studies of MAP and renal function in sepsis First author, year

Design

Patients

Prospective descriptive

Septic shock

6

Martin, 199033

Retrospective cohort

Septic shock treated with NE

24

Lerolle, 200630 Dünser, 200934

Prospective cohort Retrospective cohort

Septic shock Sepsis and septic shock

34 274

Badin, 201135

Prospective cohort

Shock

217

Prowle, 201232

Prospective descriptive

Septic AKI

10

Poukkanen, 201336

Retrospective cohort

Sepsis

423

Legrand, 201337

Retrospective cohort

Sepsis

137

Wong, 201538

Retrospective cohort

Septic shock

107

Brenner, 1990

28

Number

Key findings Decreased RBF during shock, depressed RBF/CO that correlated well with GFR. Mean MAP from 52 to 89 mm Hg. UO restored at 3 h after start NE, creatinine clearance after 48 h. Early increase in RRI in patients with AKI after 5 d. Correlation hourly time integral of MAP and need for RRT, maximum plasma creatinine and UO. Time-averaged MAP between 72-82 mm Hg associated with higher incidence of AKI in septic shock with initial renal insult. Not in other shock types. Mostly reduced RBF, consistently reduced RBF/CO in all patients. Association between time spent in relative hypotension during first 24 h of shock and development of AKI. Association between low mean DAP and high CVP over the first 24 h of ICU stay and the occurrence of new or persistent AKI. Greater mean perfusion pressure deficit, mostly due to increased CVP, in patients with AKI.

AKI, acute kidney injury; CO, cardiac output; CVP, central venous pressure; DAP, diastolic arterial pressure; GFR, glomerular filtration rate; MAP, mean arterial pressure; NE, norepinephrine; RBF, renal blood flow; RRI, renal resistive index; RRT, renal replacement therapy; UO, urine output.

patients with sepsis.36 In a retrospective study of 137 patients with sepsis, lower mean diastolic arterial pressures over the first 24 hours following ICU admission were associated with an increased risk of developing AKI.37 However, the degree of hypotension may simply be a marker of disease severity, and some studies did not report an independent association of MAP or mean perfusion pressure with AKI.37,38 Moreover, AKI is also common in less severe sepsis. For example, in patients hospitalized for community-acquired pneumonia, Murugan and colleagues found that AKI occurred in more than one-third of patients despite the fact that only 16% were admitted to the ICU and fewer than 10% required vasopressors.39 Interventional experimental studies. Most experimental studies have suggested an attenuation of renal dysfunction with the administration of vasopressors in septic shock (Table 1).40–43 However, attempts to increase RBF independently from RPP have not always been effective. For example, when Ishikawa et al. infused a nonspecific nitric oxide synthase inhibitor into the renal artery of septic sheep, the increase in RBF was attenuated but renal function did not improve.44 In the same model, intrarenal infusion of a specific inducible nitric oxide synthase (iNOS) inhibitor failed to influence RBF or kidney function.45 On the other hand, the effect of angiotensin II infusion on urine output and creatinine clearance in a sheep model of hyperdynamic sepsis was striking.46 The use of dopamine has long been advocated to preserve RBF and prevent AKI in critical illness, including sepsis. Several experimental studies showed an increase in RBF and attenuation of renal dysfunction with dopamine in endotoxemia,47–49 but others did not.50 Recent work by our group showed that the selective dopamine-1 receptor agonist, fenoldopam, was ineffective at preserving RBF in a sheep model of septic shock.51 Kidney International (2016) -, -–-

Interventional clinical studies. Several small, nonblinded, interventional studies in human septic shock have reported a beneficial effect on urine output52–54 and creatinine clearance55–57 when using norepinephrine to increase RPP (Table 3). Other vasopressors, such as vasopressin or terlipressin, appear equally effective in improving urine output and creatinine clearance.58–63 However, the effects of increasing MAP to levels greater than 60–65 mm Hg are less clear. Deruddre and colleagues observed that increasing MAP from 65 to 75 mm Hg improved urine output, but increasing MAP to levels greater than 85 mm Hg yielded no further benefit.64 Several other studies have failed to show any beneficial effect of increasing RPP to levels greater than 65 mm Hg.65–67 The randomized, controlled SEPSISPAM trial, which included 776 patients with septic shock, showed no overall effect on renal function or the need for renal replacement therapy of increasing MAP to 80–85 mm Hg compared to a target of 70–75 mm Hg.68 There was, however, a notable exception in a predefined subpopulation of patients with chronic arterial hypertension, in whom a higher MAP resulted in lower plasma creatinine levels and a reduced need for renal replacement therapy. Chronic arterial hypertension is associated with compromised renal autoregulation, which could explain the altered relation between hemodynamics and renal function in these patients.69 The use of fluids to improve renal perfusion in sepsis is surrounded by similar controversy.70 Intravascular fluid administration may be counterproductive once intravascular volume has been restored, because fluid overload can further injure the kidney.71 Saline, in particular, may compromise renal perfusion and worsen AKI through a chloride-induced increase in renal vascular resistance.72,73 Indeed, in the Protocolized Care for Early Septic Shock (ProCESS) trial, 7

First author, year

Patients

Number (int/ctrl)

Baseline MAP

Intervention

Open-label, nonrandomized, uncontrolled Open-label, nonrandomized, uncontrolled

Hyperdynamic septic shock Hyperdynamic septic shock

12 / –

48  11/ –

NE, 0.5 and 1.0 mg/kg/min

5/–

50  4 / –

NE, 0.03–0.5 mg/kg/min, titrated to SAP at 100–140 mm Hg

Desjars, 198955

Open-label, nonrandomized, uncontrolled

Septic shock

25 / –

54  10 / –

NE, 0.5–1.5 mg/kg/min

Martin, 199354

Double-blinded, randomized, controlled

Hyperdynamic septic shock

16 / 16

54  10 / 53  8

Redl-Wenzl, 199357

Open-label, nonrandomized, uncontrolled

Septic shock

56 / –

56  4 / –

NE, 0.1–2.0 mg/kg/min

Lherm, 199675

Open-label, nonrandomized, sequential Open-label, nonrandomized, sequential

Sepsis and septic shock Septic shock

14 / 15a

81  20 / 78  10

DA infusion, 2.0 mg/kg/min

17 / –

90  12 / –

DA, 2.5 mg/kg/min

Open-label, nonrandomized, uncontrolled

Severe sepsis

5/–

91 (67-150) / –d

DA, 2.5–10 mg/kg/min

Open-label, nonrandomized, uncontrolled Open-label, nonrandomized, uncontrolled

Septic shock

10 / –

65  1 / –

Septic shock, unresponsive to NE and DA Septic shock

17 / –

54  4 / –

NE, titrated to MAP of 65, 75, and 85 mm Hg terlipressin

14 / 12

51  3 / 81  7

Septic shock

10 / 10

54 (49–61) / 54 (48–62)

Open-label, randomized, controlled Double-blinded, randomized, controlled Open-label, nonrandomized, sequential

Septic shock

14 / 14

65 (62–68) / 66 (62–67)

Sepsis

150 / 150

78  11 / 75  10

Septic shock

11 / –

– / –e

NE, titrated to MAP of 65, 75, and 85 mm Hg

Double-blinded, randomized, controlled

Septic shock

15 / 15 / 15b

54  3 / 53  4 / 53  6

NE, AVP, terlipressin

Desjars, 1987

Hesselvik, 198953

Juste, 199877 Day, 200078

LeDoux, 200065 59

Leone, 2004

Albanèse, 200456 Albanèse, 200560

Bourgoin, 200566 Kidney International (2016) -, -–-

76

Morelli, 2005

Deruddre, 200764

Morelli, 200962

Open-label, nonrandomized, controlled Open-label, randomized, controlled

NE, 0.5–5 mg/kg/min and DA, 10–25 mg/kg/min

NE, titrated to MAP of 70 mm Hg NE, terlipressin

NE, titrated to MAP of 65 or 80 mm Hg Fenoldopam, 0.09 mg/kg/min

Key findings Mean MAP to 59 and 78 mm Hg. Increased UO with NE infusion. Mean MAP to 69 mm Hg. Average UO over 3 h during NE infusion increased in all patients. Mean MAP to 80 mm Hg. Creatinine clearance showed persistent improvement during NE-infusion. Mean MAP to 91 mm Hg. Oliguria resolved with NE. Similar results in DA-responders (approximately one-half of patients). Mean MAP to 82 mm Hg. Mean creatinine clearance from 75 to 102 ml/min after 48 h of NE therapy. Increased diuresis and creatinine clearance in septic patients without shock. Important inotropic effect, increased urine volume, no effect on creatinine clearance. Increased RBF with low, but not high, dose DA. No effect on creatinine clearance or UO at any dose. No effect on mean UO at either pressure level. Mean MAP to 69 mm Hg after 2 h, maintained for 24 h. UO and creatinine clearance increased. Improved UO and creatinine clearance. Mean MAP to 70 mm Hg with both NE and terlipressin. UO and creatinine clearance improved with both. MAP at 85 mm Hg did not affect UO or creatinine clearance. Attenuation increase of plasma creatinine in patients with sepsis. Mean MAP to 75 mm Hg improved UO and reduced RRI but did not affect creatinine clearance. No effect at 85 mm Hg. Similar effect on MAP with all vasopressors. UO unchanged but attenuated rise

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Table 3 | Clinical interventional studies of MAP and renal hemodynamics in sepsis

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e

Shock Open-label, nonrandomized, uncontrolled Schneider, 201467

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AHT, arterial hypertension; AVP, arginine vasopressin; DA, dopamine; DO2, oxygen delivery; GFR, glomerular filtration rate; MAP, mean arterial pressure; NE, norepinephrine; RRI, renal resistive index; RRT, renal replacement therapy; SAP, systolic arterial pressure; UO, urine output. a Sepsis / septic shock. b NE / AVP / Terlipressin. c 10 with septic shock. d Systolic pressure. e No values reported.

–/– 12c / –

NE, titrated to MAP of 60–65 or 80–85 mm Hg

NE, titrated to MAP of 65–70 or 70–85 mm Hg 73  14 / 74  15 388 / 388 Open-label, randomized, controlled Asfar, 201468

Septic shock

NE, titrated to MAP of 75 or 90 mm Hg Open-label, randomized, cross-over Redfors, 201129

Vasodilatory shock

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in plasma creatinine with AVP and terlipressin. Mean MAP to 75 mm Hg increased renal DO2, improved UO and GFR. No effect at 85 mm Hg. Mean MAP to 70-85 mmHg no effect on UO or renal function. Reduced incidence of RRT and attenuated increase in plasma creatinine in patients with pre-existent AHT. No effect on mean cortical blood volume, large inter-individual variability.

EH Post et al.: Renal macro- and microcirculation in sepsis

protocol-based care in septic shock resulted in more aggressive fluid resuscitation but not better renal outcomes.74 Attempts to selectively target RBF in human sepsis have been largely unsuccessful. A small nonblinded study in patients with normotensive sepsis and patients with septic shock suggested a beneficial effect of dopamine infusion on renal function only in the normotensive group.75 Similarly, prophylactic administration of fenoldopam in 150 septic patients without shock attenuated the increase in plasma creatinine that was observed in the control group.76 However, the use of dopamine was ineffective in 2 small open-label studies in septic shock and severe sepsis and in 1 larger double-blind, randomized, placebo-controlled trial in patients with systemic inflammatory response syndrome.77–79 Intrarenal flow in sepsis

Although whole-organ RBF can play a role in the development of renal dysfunction in sepsis, regional and microcirculatory flows may be equally relevant. In healthy steady-state conditions, approximately 80% of RBF flows through the renal cortex only.80 The medulla does not have a blood supply of its own and receives about 20% of the cortical blood flow from juxtamedullary efferent arterioles.81 The few studies available on intrarenal flow distribution during sepsis reported conflicting results, ranging from increased cortical and medullary flow without any clear redistribution,82 to preferentially cortical83 or medullary flow,84 to no signs of intrarenal flow alterations at all.85,86 Conversely, Calzavacca et al. recently showed in a sheep model of septic hyperemic renal dysfunction that reduced medullary blood flow and oxygen tension preceded the decrease in urine output and creatinine clearance.87 Studies of the effects of different drugs on intrarenal flow distribution in sepsis show similar varying results. In endotoxemic pigs, administration of a nonselective NOS-inhibitor and a selective iNOS-inhibitor worsened cortical flow and attenuated the increase in medullary flow that was observed in nontreated animals.88Albert et al. studied the use of vasopressin on regional flow in rabbits treated with endotoxin and found that it attenuated the decrease in RBF and increased cortical flow but left medullary perfusion largely unaltered.41 Faivre and colleagues studied the effects of levosimendan, a calcium sensitizer with vasodilating effects, in combination with norepinephrine and arginine vasopressin on cortical and medullary flow in endotoxemic rabbits.89 Renal and regional blood flows were not affected by levosimendan. Administration of vasopressin, however, depressed medullary flow, whereas norepinephrine increased it. More recently, Lankadeva et al. studied the use of norepinephrine in septic hyperemic renal dysfunction. In this study, norepinephrine did not affect whole-organ RBF but diminished medullary flow and oxygen tension.90 Predicting the consequences of altered intrarenal blood flow distribution in sepsis is complex. The kidney’s unique vascular anatomical arrangement facilitates arterio-venous oxygen shunting, both diffusive 91 and convective (Figure 1).92 This arrangement possibly serves to maintain a stable renal tissue 9

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EH Post et al.: Renal macro- and microcirculation in sepsis

O2

The presence of a periglomerular circulation offers an anatomical pathway for convectional oxygen shunting during sepsis.

O2

O2

O2

Diffusional shunting possibly adds to the development of medullary hypoxia in sepsis. Alternatively, decreased shunting effectiveness may also cause tubular injury through increased ROS production.

O2

Figure 1 | Renal oxygen shunting. Enhanced renal oxygen shunting can lead to medullary hypoxia, and a reduction in shunting effectiveness may also cause renal injury via an ROS-mediated pathway. Either way, a disturbance of the delicate intrarenal oxygen balance likely contributes to the development of renal dysfunction in sepsis and septic shock.

PO2 in the presence of variable RBF.93 However, it can also cause low medullary tissue PO2 when shunting is enhanced, leading to a variable degree of tubular hypoxia. Alternatively, a reduction in shunting effectiveness may also cause renal injury via an ROS-mediated pathway, a hypothesis that was proposed by O’Connor and colleagues.94 Either way, a disturbance of the delicate intrarenal oxygen balance is likely to contribute to the development of renal dysfunction in sepsis and septic shock, although additional studies in this area are needed to elucidate the exact mechanisms involved. Renal microcirculation in sepsis

Microcirculatory alterations are also likely to contribute to the development of AKI in sepsis. Several processes take place in the microcirculatory environment, including off-loading of oxygen, delivery of nutrients to the tissues, and regulation of fluid movement into the interstitium. Microcirculatory alterations during sepsis are widespread and can be present in virtually every organ, including the heart, the gut, the liver, and the brain.95 These alterations consist of reduced overall microcirculatory flow and increased flow heterogeneity, resulting in increased oxygen diffusion distances and areas of tissue hypoxia. Furthermore, microcirculatory alterations can lead to increased leukocyte transit time through the kidney, possibly potentiating inflammation.96 A large body of data suggests that the renal microcirculation is similarly affected during sepsis. Using intravital videomicroscopy in mice, Wu et al. demonstrated that the proportion of peritubular vessels showing normal, continuous flow was significantly decreased after 2 hours of endotoxemia.97 In a pediatric rat cecal ligation and puncture (CLP) model, a 10

decrease in peritubular microvascular flow was evidenced by an increased proportion of capillary vessels showing sluggish or no flow.98 In a porcine model of severe sepsis, reduced microcirculatory flow in the renal cortex occurred well before any changes in RBF were observed.99 These alterations can persist even when systemic hemodynamics are adequately corrected by fluid administration.100 The causes of microcirculatory flow alterations are incompletely understood, and a number of mechanisms have been proposed (Figure 2). Inflammatory cytokines cause increased expression of adhesion molecules101 and increased leukocyte trafficking,102 resulting in microthrombi formation and capillary plugging.103 The up- and/or down-regulation of a number of vasoactive compounds may cause a heterogeneous pattern of local vasodilation and constriction and areas of hypoxia.104 Additional pathways involve the production of reactive oxygen and nitrogen species, the formation of microparticles,105 and possibly circulating histones.106 Moreover, sepsis causes damage to the glycocalyx107 and disruption of the endothelial barrier,108 which results in capillary leakage and interstitial fluid sequestration. Interstitial edema contributes to both increased oxygen diffusion distances and decreased microvascular flow. Role of nitric oxide

The effects of iNOS on the renal microcirculation have been studied extensively.109 iNOS catalyzes the production of NO from L-arginine and is massively upregulated during sepsis. NO has vasodilatory properties and reacts with superoxide to form reactive nitrogen species. Renal iNOS expression during sepsis most likely occurs in neutrophils and macrophages,110 in the endothelium111 and in renal tubular epithelial cells.112 Kidney International (2016) -, -–-

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EH Post et al.: Renal macro- and microcirculation in sepsis

NADPH activation and eNOS uncoupling stimulate ROS formation. Upregulation of iNOS in neutrophils and macrophages results in NO release and RNS production. Other molecules affecting the renal microcirculation include: tezosentan, iloprost, rolipram and Z-VAD.

eNOS

L-NIL MitoTempo

L-arginine iNOS •NO

RNS/ROS Resveratrol

NADPH oxidase O2• eN OS NADPH

+

p120/β-catenin/ VE-cadherin

DXM

O2

4F

Simvastatin

+

NADP+H

SEW2871

+ Slit1/Robo4 VE-cadherin β-catenin p120

+ Loss of junctional integrity

S1P1 + Rac GTPase

BH4 (u nc ou ple d) O2

Damage to the glycocalyx and restructuring of junctional proteins results in increased capillary permeability and edema formation, increasing oxygen diffusion distance and compromising capillary flow.

MitoTempo Hypoxia and upregulation of iNOS in tubular epithelial cells promote ROS and RNS production. Signs of tubular injury include the loss of brush border, cast formation, vacuolization, and tubule dilation. Tubular cell swelling may further compromise microvascular flow.

O2•

PO2

RNS/ROS L-arginine iNOS

•NO MnTMPyP

L-NIL

Figure 2 | Proposed pathways of renal microvascular dysfunction and tubular injury in sepsis. Compounds studied in the context of renal microcirculatory dysfunction in sepsis are marked in red. 4F, synthetic apoliprotein A-I analogue; BH4, tetrahydrobiopterin; DXM, dexamethasone; eNOS, endothelial NOS; iNOS, inducible nitric oxide synthase; L-NIL, selective iNOS inhibitor; p120/b-cadherin/VE-cadherin, adherens junction molecules; RNS/ROS, reactive nitrogen species/reactive oxygen species; S1P1, sphingosine-1-phosphate-1; Slit1/Robo4, junctional proteins; Z-VAD, nonselective caspase inhibitor.

Tiwari et al. were the first to report a significant increase in the total number of perfused cortical peritubular vessels following the administration of an iNOS-inhibitor, L-NIL, in a mouse model of endotoxemia.113 Wu and colleagues observed early microcirculatory dysfunction and increases in plasma NO metabolite levels in mice infused with lipopolysaccharide,97 which led them to investigate the temporal relationship between iNOS up-regulation and kidney microcirculatory dysfunction in murine models of endotoxemia and polymicrobial sepsis.114,115 They not only found a temporal relationship—capillary dysfunction and iNOS up-regulation both occurred after 10 hours—but a spatial correlation as well: low flow vessels were colocalized with tubular epithelial cells positively stained for reactive nitrogen species, such as peroxynitrite, and ROS.115 The administration of resveratrol, Kidney International (2016) -, -–-

a peroxynitrite scavenger, improved peritubular microcirculatory flow in a murine CLP model.116 Endotoxemic rats treated with fluids and low-dose dexamethasone showed lower cortical iNOS expression and increased microvascular PO2.117 Conversely, when iNOS-inhibition was compared to NO donation in a lipopolysaccharide-infused rat model, cortical and medullary microvascular PO2 were similar in the 2 groups and unchanged compared to untreated controls.118 Reactive oxygen species

NADPH oxidase is the most important source of superoxide, the precursor of most reactive oxygen species, in endothelial cells.119 In a mouse CLP model, administration of the superoxide dismutase analogue MnTMPyP (a superoxide scavenger) resulted in an increased number of peritubular capillaries with 11

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continuous flow after ROS production in the tubular epithelium was reduced to control levels.120 Patil et al. showed an early beneficial effect of the mitochondria-targeted antioxidant MitoTEMPO (Enzo Life-Sciences, Farmingdale, NY) on the renal microcirculation in murine sepsis.121 Endothelial NOS (eNOS), which produces low amounts of NO in physiological circumstances, becomes “uncoupled” during experimental sepsis (i.e., it switches to harmful superoxide production, negatively affecting microvascular flow).122 Tetrahydrobiopterin (BH4) is an important cofactor for the production of NO by eNOS and its administration in an ovine model of septic shock resulted in improved systemic microcirculation and organ function, including kidney function.123 Although eNOS deficiency was shown to increase susceptibility to AKI in murine endotoxemia,124 it is unclear whether this was mediated through alterations in the renal microcirculation. Capillary leakage

Sluggish or stopped blood flow is not the only feature of microvascular dysfunction. Leakage from peritubular capillaries and the resultant renal interstitial edema can be observed as early as two hours after the onset of sepsis.120 The underlying mechanism is complex and in the case of the glomerular endothelium most likely results from the increased number and altered diameter of its fenestrae125,126 and from alterations in glycocalyx composition.127 To our knowledge, the specific effects of sepsis on the endothelial barrier of peritubular vessels have not yet been investigated. Nevertheless, the synthetic apoliprotein A-I analogue, 4F, did attenuate renal dysfunction in a rat CLP model by restoring the expression of the junctional proteins, Slit2 and Robo4, and increasing eNOS expression.128 Indeed, eNOS is also involved in the regulation of endothelial permeability.129 Yasuda et al. showed that the administration of simvastatin attenuated kidney dysfunction and renal vascular leakage in a mouse model of abdominal sepsis, possibly via altered eNOS-regulation.130 Sphingosine-1-phosphate-1 is another important regulator of endothelial integrity.131 Recently, Wang et al. found that treatment with a sphingosine-1-phosphate-1 agonist, even at 6 hours after induction of sepsis, enhanced the endothelial permeability barrier, leading to reduced perivascular leakage and improved peritubular microvascular flow.132 Fluids and the renal microcirculation

Fluids in septic shock are mainly considered a means to improve RPP and whole-organ RBF, but they have been studied in the context of renal microcirculation as well. Johannes et al. compared the use of 2 hydroxyethyl starch (HES) solutions with different molecular weights to Ringer’s lactate in a rat model of endotoxemia and found that all fluid types increased RBF.133 However, despite the absence of increased renal oxygen consumption with high molecular weight HES, renal microvascular PO2 remained unaffected in all groups. In the same model, Aksu et al. compared HES dissolved in Ringer’s acetate, or balanced HES, with HES dissolved in saline.134 In this study, 12

EH Post et al.: Renal macro- and microcirculation in sepsis

only balanced HES attenuated the decrease in RBF and mitigated cortical microvascular perfusion deficits. Conversely, when Ergin et al. compared balanced HES to a balanced crystalloid solution and saline, they found that none of these fluids affected cortical or medullary microvascular PO2.135 Vasodilators and other molecules

Although somewhat counterintuitive, the use of vasodilators has been advocated to help recruit constricted microvessels in the septic kidney. Experimental studies on this subject have, however, shown varying results. As described above, Johannes et al. reported no beneficial effect on microvascular oxygenation with the use of the NO donor nitroglycerin.118 In contrast, administration of the prostacyclin analogue iloprost improved cortical microvascular oxygenation in rat endotoxemia,136 as did the selective phosphodiesterase-IV inhibitor rolipram in a mouse model of CLP.137 Other molecular inhibitors and analogues that have been studied in the context of renal microcirculatory dysfunction in various animal models of septic shock include the endothelin-1 receptor antagonist tezosentan138 and the nonselective caspase inhibitor Z-VAD.113 Furthermore, the antithrombotic and anti-inflammatory drug, activated protein C, improved peritubular perfusion in a rat model of endotoxemia, possibly through downregulation of renal iNOS,139 but failed to improve cortical and medullary microvascular PO2 in another, more severe model.140 Early versus late sepsis

Interestingly, some data suggest that the factors involved in renal microcirculatory dysfunction may change as sepsis progresses. In a pediatric rat model of septic renal dysfunction, Seely et al. showed that reduced whole-organ RBF preceded the decrease in microcirculatory flow,98 suggesting that early microcirculatory flow impairment may just be a manifestation of an upstream deficit. When Legrand et al. compared early and delayed fluid administration in a rat model of endotoxemia, they found that early resuscitation maintained RBF at normal levels and attenuated microcirculatory deficiencies, whereas delayed initiation restored RBF but did not affect microcirculatory flow.100 These observations may imply that microcirculatory dysfunction is maintained by different pathways in late versus early sepsis. Indeed, when the effects of sphingosine-1phosphate-1 as a regulator of endothelial permeability were investigated in murine septic shock, early administration did not benefit capillary flow despite an improvement in vascular permeability, whereas delayed administration improved capillary permeability and restored microvascular perfusion to baseline levels.132 The authors explained these findings by attributing the early sluggish microcirculatory flow to a low RPP and late dysfunction to capillary leakage and interstitial edema, which was in this case prevented by the intervention.132 Similarly, only delayed administration of the superoxidescavenger MnTMPyP reversed peritubular microcirculatory alterations in this model.120 Kidney International (2016) -, -–-

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Renal metabolism and tubular injury in sepsis

Summary and conclusion

The primary function of the capillaries is oxygen delivery, which suggests that the chain of events leading from microcirculatory dysfunction to organ failure should include cellular hypoxia. However, renal histological findings in sepsis are not consistent with signs of widespread structural damage or cell death,141–143 and results from studies on kidney metabolism are somewhat contradictory. For example, kidney ATP levels remained constant during a 4-hour infusion of live Escherichia coli in sheep144 but were significantly reduced after 6 hours of endotoxemia in dogs.145 Conversely, in 2 studies using canine models of short-term endotoxemia, the kidney was found to be a net consumer, not producer, of lactate.146,147 In health, renal oxygen consumption (VO2) correlates well with RBF because Naþ reabsorption (TNaþ), and thus Naþdelivery, is the primary determinant of renal VO2.148 This theoretically implies that renal hypoperfusion and decreased GFR in sepsis will result in reduced renal oxygen demand. Furthermore, mitochondrial downregulation could also adapt tubular oxygen demand to decreased oxygen delivery.149 This effect, however, may depend on the vasoactive agent that is used to manipulate renal hemodynamics.150 Moreover, in sepsis, many studies have reported that renal VO2 was maintained, even when RBF was reduced.29,146,151,152 An increased VO2/ TNaþ-ratio has been reported in different experimental sepsis models, suggesting that either TNaþ is less efficient or that oxygen-consuming processes unrelated to filtration become active.133,151,153 Indeed, Johannes et al. demonstrated that hypoperfusion associated with endotoxemia induced areas of microcirculatory hypoxia, whereas there were almost no oxygenation deficits in flow-matched healthy controls.154 These findings suggest that renal hypoperfusion in sepsis results in a perfusion–metabolism mismatch that possibly warrants treatment. Indeed, in experimental septic renal dysfunction, low tubular cell oxygen tension has been evidenced by positive pimonidazole staining of tubular epithelial cells.120,130 Moreover, the consistent observation of an altered redox state in tubular cells adjacent to no-flow capillary vessels further supports this hypothesis.97,114,115 How these oxygenation deficits translate to tubular injury in the absence of necrosis, or even changes on electron microscopy,143 is not clear, although hypoxia-induced ROS formation96,155 appears to be the most plausible mechanism.113,115,116 Furthermore, determining causality between microcirculatory flow deficits and tubular injury can be difficult because interventions almost never act specifically on the renal microcirculation alone, and results from experimental studies thus remain fundamentally associative in nature. Because of this, the temporal relationship between variables is often used to support the claim of causality. In this context, all experimental studies that have assessed microcirculatory dysfunction and renal functional failure in sepsis show that the former precedes, or coincides with, the latter,8,98,99,115 as was true for tubular injury.113,115,116 Moreover, any beneficial effect on kidney function in experimental sepsis was associated with a similar functional improvement in the renal microcirculation.113,115,116,120,130,137,138

The contribution of renal hypoperfusion to sepsis-associated AKI is more complex than previously thought, and reduced RPP and local microvascular deficits may both play pivotal roles. A considerable body of evidence shows that the correction of low RPP in septic shock may be effective in raising glomerular filtration pressure and restoring urine output and GFR in some patients.68 Whether restoring RPP with judicious use of fluids and vasopressors also benefits the tubular epithelium is unknown. To our knowledge, there are no clinical studies in septic shock that have measured the effects of altering RPP on tubular injury. Furthermore, the relationship between tubular injury and diminished GFR in sepsis remains unclear, although a role of tubuloglomerular feedback or vascular conducted responses has been proposed.96,156 Nevertheless, given the association between microvascular hypoperfusion, cellular hypoxia, ROS formation, and tubular injury, targeting the tubular epithelium through the alleviation of peritubular perfusion deficits would seem to be a rational strategy, especially early in the course of AKI. Difficulties related to the early detection of AKI and to monitoring renal microcirculation in vivo, as well as the large number of possible mediators involved, make identification and application of renal microvascular therapy a daunting task. Finally, factors that affect the nature of microvascular perfusion deficits, such as the stage of sepsis and the presence of comorbidities, also need to be taken into account.

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DISCLOSURE

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