NDT Advance Access published December 29, 2013 Nephrol Dial Transplant (2013) 0: 1–8 doi: 10.1093/ndt/gft503
Full Review Epithelial transport during septic acute kidney injury Eric D. Morrell1, John A. Kellum2,3,4, Kenneth R. Hallows1,2,5 and Núria M. Pastor-Soler1,2,5 1
Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, S976.1 Scaife Hall, 3550 Terrace Street,
Pittsburgh, PA 15261, USA, 2The Center for Critical Care Nephrology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, 3
CRISMA (Clinical Research Systems Modeling of Acute Illness) Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA and 5Department of Cell Biology,
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Correspondence and offprint requests to: Kenneth R. Hallows; E-mail: [email protected]
A B S T R AC T A goal for scientists studying septic acute kidney injury (AKI) should be to formulate a conceptual model of disease that is able to coherently reconcile the molecular and inflammatory consequences of sepsis with impaired epithelial tubular function, diminished glomerular filtration rate (GFR) and ultimately kidney failure. Recent evidence has shed light on how sepsis modulates the tubular regulation of ion, glucose, urea and water transport and acid–base homeostasis in the kidney. The present review summarizes recent discoveries on changes in epithelial transport under septic and endotoxemic conditions as well as the mechanisms that link inflammation with impaired tubular membrane transport. This paper also proposes that the tubular dysfunction that is mediated by inflammation in sepsis ultimately leads to increased sodium and chloride delivery to the distal tubule and macula densa, contributing to tubuloglomerular feedback and impaired GFR. We feel that this conceptual model resolves many of the physiologic and clinical paradoxes that septic AKI presents to practicing researchers and clinicians. Keywords: AKI, ion transport, sepsis, toll-like receptor, tubuloglomerular feedback
INTRODUCTION Acute kidney injury (AKI) is a very common and especially formidable clinical problem facing acute care physicians. The most common cause of AKI in hospitalized patients is sepsis © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
[1], and AKI is not uncommon even in non-severe sepsis where hemodynamic changes are not readily apparent [2]. Despite its ubiquity in the hospital, historically little is known about how the basic epithelial transport mechanisms that modulate solute, volume and urea clearance are affected by sepsis-induced AKI. A goal for scientists studying septic AKI, and for this review, is to formulate a conceptual model of disease that is able to coherently reconcile the molecular and inflammatory consequences of sepsis with impaired tubular function, diminished glomerular filtration rate (GFR) and ultimately kidney failure. Experiments performed over the past 20 years that we will review have started to shed light on how sepsis modulates tubular transport function. Here we propose a model that links septic inflammation and tubular transport dysfunction with impaired GFR and kidney failure. For example, there has been a renewed interest over the past 5 years in the role of chloride in septic AKI [3]. Recent large clinical trials have shown that an increased serum chloride concentration may have a deleterious effect on overall kidney function, especially in septic patients [4, 5]. Tubular transport would be directly involved in these deleterious effects as septic AKI is mediated in part by tubular processes that increase chloride delivery to the distal tubule, and we suggest that this phenomenon may play a key role in overall organ dysfunction.
LINKING IMPAIRED SOLUTE TRANSPORT TO DECREASED GFR Seminal studies performed by Wilcox in the 1980s demonstrated the unique role of increased chloride in normal kidney 1
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T U B U L A R S O D I U M , P O TA S S I U M A N D C H LO R I D E T R A N S P O R T R E G U L AT I O N IN SEPTIC AKI Inflammation, one of the hallmark physiologic mediators of sepsis, can severely impair the intricate tubular mechanisms responsible for sodium, potassium and chloride regulation, even in the setting of normal cellular perfusion. The impairments can all lead to increased distal tubule chloride delivery, impairing GFR and overall renal function. Schmidt et al. [11, 12] have shown significant downregulation of Na+/H+ exchanger 3 (NHE3), Na+/K+-ATPase, renal outer medullary K+ channel (ROMK), epithelial Na+ channel (ENaC), Na+–K+– 2Cl−-cotransporter 2 (NKCC2), Na+–Cl− cotransporter (NCC), kidney specific chloride channel -1 and -2 (CLCK-1 and -2) and Barttin expression in an in vivo model of rat sepsis induced by intraperitoneal injection of liposaccharide (LPS). This finding has been reproduced independently with comparable models showing downregulation of NKCC2 and NHE3 [17, 18]; however, in one of the studies, the α-subunit of ENaC showed increased expression in response to LPS in
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the inner stripe of the outer medulla (ISOM) (β-ENaC was downregulated) [18]. The upregulation of the α-subunit of ENaC in the later study might be explained by the fact that measurements were taken at 6 h (as compared with at 6, 12 and 24 h in the Schmidt study), when increased levels of aldosterone might still be able to overwhelm only partially impaired transporters [12, 18]. A similar pattern of near ubiquitous downregulation of all tubular sodium transporters has been seen in multiple ischemia–reperfusion models of AKI as well [19–21]. In Schmidt’s model there was preserved arterial blood pressure with a lower dose of LPS, yet the downregulation of transporters was still observed [11, 12]. The decrease in sodium, potassium and chloride transport proteins in response to LPS corresponds with a markedly increased fractional excretion of sodium and chloride [11, 12]. The increased distal chloride delivery may also be due in part to a reduction in paracellular chloride reabsorption as well as significantly elevated levels of IL-1β, TNF-α and interferongamma (IFN-γ) (see Figures 1 and 2). Interestingly, knockout mice that are deficient in TNF-α, IL-1 or IFN-γ do not show any resistance to downregulation of the sodium, potassium or chloride transport proteins in response to LPS, indicating that perhaps multiple overlapping processes are involved (such as the TLR-4-mediated pathways) [11, 12]. In these same experiments, however, glucocorticoid treatment leads to inhibition of all three cytokines after exposure to LPS, with subsequent attenuation of all sodium, potassium and chloride transport protein dysfunction [11, 12]. Glucocorticoids are known to stimulate ENaC and ROMK through serum- and glucocorticoid-inducible kinase (SGK-1) [39] and so this may have counteracted any potential LPSmediated downregulatory process (Figure 2). There have been a number of proposed mediators that could link systemic inflammatory mediators such as TNF-α, IL-1 and LPS with impaired epithelial transport function, but much evidence points to a direct role for cyclooxygenase and prostaglandins, especially as mediators of distal sodium and chloride delivery. Rats exposed to exogenous IL-1 exhibit marked natriuresis and diuresis [40–46], and this physiologic phenomenon is largely due to sodium wasting in the cortical collecting duct [44, 45]. This change is accompanied by a corresponding increase in urinary prostaglandin E (PGE2) excretion and is inhibited by pre-treatment with a cyclooxygenase inhibitor, suggesting a possible role for PGE2 in the mechanisms connecting IL-1 with impaired sodium transport in the distal tubule (Figure 2) [40]. While various experiments have demonstrated a similar role for PGE2 on sodium handing in the thick ascending limb of Henle’s loop [42, 44, 46] and cortical collecting ducts [44], other experiments have failed to show a concomitant increase in prostaglandin synthesis in response to IL-1 administration [41]. In most of these experiments (but not all [43]), treatment with cyclooxygenase inhibitors such as indomethacin mitigated salt wasting in hyperinflammatory models of kidney injury [40–42, 46]. Chloride-mediated changes in renal hemodynamics also seem to be directly regulated by products of cyclooxygenase and thromboxane synthetase [15]. In this work using a rodent model, Bullivant et al. [15] demonstrated that hyperchloremia
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blood vessels in decreasing both kidney blood flow and GFR [6]. Hyperchloremia produces renal vasoconstriction and a fall in GFR that is likely mediated by distal tubular sensing of sodium and chloride [7]. In physiologically normal kidneys, decreases in arterial pressure result in increased proximal tubular NaCl reabsorption, decreased macula densa sensing of NaCl and subsequent activation of the renin–angiotensin system [7]. Through this macula densa-mediated mechanism, decreased kidney perfusion leads to increased efferent and decreased afferent arteriolar vasoconstriction that increases GFR [7]. When there are increased levels of chloride sensed by the macula densa, the opposite phenomenon occurs, leading to decreased GFR [6]. Subsequent studies have confirmed that high solute concentrations and flow rates of chloride distal to the proximal tubules lead to manipulation of tubuloglomerular feedback, ultimately diminishing GFR (Figure 1) [8–10]. The potentially deleterious effects of increased distal chloride delivery do not seem limited to kidney hemodynamics [3]. In cell culture models, chloride-rich microenvironments have been shown to be pro-inflammatory, leading to increased nitric oxide (NO) release, interleukin-6:interleukin-10 (IL-6: IL-10) ratios and NF-κB DNA binding [13]. In vivo models of sepsis involving rats have also demonstrated that resuscitation with high chloride-containing solutions promote a proinflammatory state with increased levels of IL-6, IL-10 and tumor necrosis factor-alpha (TNF-α), even in normotensive rats [14]. Chloride infusion upregulates thromboxane- and cyclooxygenase-mediated renal arterial vasoconstriction [15]. Finally, in isolated perfused rat kidneys, higher concentrations of chloride have been shown to significantly potentiate the vasoconstrictive effects of angiotensin II [16]. It is likely that processes in sepsis—independent of systemic chloride levels— that increase distal tubular chloride exposure lead to impaired renal function via both hemodynamic and inflammatory processes (Figure 1).
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F I G U R E 1 : Proposed mechanism for linking impaired solute transport with decreased GFR. Pro-inflammatory cytokines cause a downregulation of renal chloride entry transport proteins—specifically CLCK-1, CLCK-2, and Barttin—during sepsis [11], increasing distal delivery of chloride. Tubular dysfunction of sodium transport proteins, especially the downregulation of NHE3, Na+/K+-ATPase, ROMK, NKCC2 and NCC, also generates an increase in the lumen sodium concentration, and thus overall increases lumen positive potential [12]. This causes a decrease in paracellular chloride reabsorption, which ultimately leads to further increased chloride delivery to the thick ascending limb. The net effect is tubuloglomerular feedback and reduced GFR in that nephron.
F I G U R E 2 : Proposed overview of ion channel regulation during septic AKI. Inflammatory mediators such as LPS, IL-1 and TNF-α activate
various prostaglandin pathways (COX), leading to increased levels of PGE2. Increased PGE2 levels can modulate intracellular calcium stores as well as stimulate multiple downstream mediators including cAMP. In the proximal tubule, cAMP has been shown to indirectly inhibit NHE3 via PKA phosphorylation of the NHE regulatory factor NHERF-1 [22], which could lead to natriuresis secondary to PGE2-mediated stimulation of cAMP generation from cytokines [23]. More distally, increased intracellular calcium levels may decrease NHE3, NKCC2, ENaC and NCC activity, all via PKC-mediated processes [24–28]. In the distal convoluted tubule and cortical collecting duct, vasopressin, aldosterone and AMPK regulate ENaC [29–31] and aldosterone regulates NCC [32, 33]. These effects are mediated at least in part by Nedd4-2 [29–34], and these processes directly involve cAMP/PKA for vasopressin [35, 36] and SGK-1 for aldosterone [32, 37]. IKKβ has been shown to stimulate ENaC via Nedd4-2 phosphorylation [38], bringing forth a potential link between sepsis-mediated TLR-4 and sodium transport. The net effect of global ion channel downregulation is an increase in luminal sodium concentration, a decrease in lumen negative potential, less paracellular chloride reabsorption and increased distal chloride delivery.
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The role for inflammation leading to downregulation of sodium transport proteins has been reinforced by a recent study by Cantaluppi et al. [60]. In primary human proximal tubule epithelial cells exposed to human septic plasma, NHE3, the tight junction protein-1 zonula occludens-1 (ZO-1) and the diffusive glucose transporter (GLUT-2) levels were decreased [60]. However, decreased expression of these transporters was abrogated when a number of inflammatory mediators —including TNF-α, CD154 and Fas-L—were effectively filtered from the plasma by Amberchrom resin adsorption [60]. The idea that tubular impairment in solute handling can be ameliorated by broad manipulation (or impairment) of the inflammatory milieu is not new. After multiple clinical trials failed to show any benefit from single anti-cytokine treatment [61–63], there was a renewed interest in using steroids to treat sepsis. However, high-dose methylprednisolone does not improve survival, and may actually worsen outcomes by increasing susceptibility to secondary infections [64]. While controversial, there are some studies that suggest lower dose steroids may be beneficial in sepsis [65], as well as in patients with functional adrenal insufficiency [66]. In rat models of septic AKI, low-dose steroids have been shown to limit renal dysfunction [67]. While the exact mechanisms for impaired solute handling in sepsis and endotoxemia are not fully elucidated, it does appear that inflammatory cytokines play a large role in the process. Further research is needed to identify what inflammatory ‘milieu’ would be the most favorable one to counteract the detrimental effects of sepsis on kidney function. Finally, while it has been established in experiments utilizing endotoxemia that inhibiting inducible nitric oxide synthase (iNOS) can have a dramatic effect on GFR [68], endogenous NO has also been implicated as a mediator of epithelial sodium and chloride transport independent of its effects on vascular function [69]. It has long been known that NO has natriuretic and diuretic effects on animals, presumably through its impact on vasoregulation [69–71]. In non-septic studies, NO has been shown to inhibit NKCC2 [72] and apical sodium transport proteins in the cortical collecting duct [73]. More recently, septic models of AKI have linked endotoxemia with increased iNOS expression and downregulation of the NHE3 and NKCC2 transporters [18]. Regardless of the specific roles that inflammatory cytokines, PGE2, cAMP, Nedd4-2, or iNOS play in septic AKI, the overarching consequence of sepsis on these mediators seems to be increased delivery of sodium and chloride to the macula densa. We propose that this putative effect of septic inflammation—the increased delivery of sodium and chloride to the distal tubules and the macula densa—plays a critical role in the overall reduction in GFR and renal function.
AC I D – B A S E R E G U L AT I O N During sepsis, especially severe sepsis where multiple organ failure is common, metabolic acidosis becomes a formidable clinical problem [74, 75]. The role that impaired renal excretion of acid plays in contributing to the mortality and morbidity from sepsis is unknown. However, studies have
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reduced GFR by over 30%, and this effect could be prevented by pre-treatment with either indomethacin or thromboxane antagonists. The mechanistic consequences of implicating PGE2 and other prostaglandins in septic AKI are profound because there are so many potential targets for intervention associated with these mediators. For instance, in the proximal tubule, cyclic adenosine monophosphate (cAMP) has been shown to indirectly inhibit NHE3 via protein kinase A (PKA) phosphorylation of the NHE regulatory factor NHERF-1 [22], which could lead to natriuresis secondary to PGE2-mediated stimulation of cAMP generation from cytokines (Figure 2) [23]. PGE2 has also been shown to inhibit sodium reabsorption by increasing intracellular calcium levels, which may have direct inhibitory effects on the Na+/K+-ATPase and apical sodium transport proteins or indirect effects on sodium transport via protein kinase C (PKC)-mediated processes in the collecting duct [24–27]. This modulation of sodium transport via PGE2 and calcium sensing has also been demonstrated in the thick ascending limb involving the NKCC2 cotransporter [28]. In rabbit cortical collecting tubules, PGE2 administered in isolation has been shown to increase cAMP levels [47]. However, when co-administered with vasopressin, PGE2 decreases cAMP levels, leading to sodium wasting [47–49], as cAMP causes an increase in apical membrane sodium transport [50]. Other mechanisms have been proposed connecting cAMP to ENaC activation [49, 51, 52] as well as apoptosis in distal convoluted tubules via regulation of potassium channels [53]. The link between septic AKI and apical sodium handling in the distal convoluted tubule and cortical collecting duct likely also involves the E3 ubiquitin ligase Nedd4-2 (Figure 2). The influences of both vasopressin, aldosterone and AMP-activated kinase (AMPK) on ENaC [29–31] and aldosterone on NCC [32, 33] are mediated at least in part by Nedd4-2 [29– 34]. These processes directly involve cAMP/PKA for vasopressin [35, 36] and serum glucocorticoid regulated kinase-1 (SGK-1) for aldosterone [32, 37], which could also be related to PGE2 regulation as discussed above [54–56]. There is some recent evidence likewise suggesting cross-talk between the Nedd4-2 pathway of sodium regulation and NF-κB [38]. IκBkinase-β (IKKβ) has been shown to stimulate ENaC via Nedd4-2 phosphorylation [38], certainly bringing forth a potential link between sepsis-mediated toll-like receptor-4 (TLR-4) and sodium transport. In mouse CCD cells, LPS and TNF-α acutely promote basolateral Na+/K+-ATPase activation via cAMP-independent PKA activation, which ultimately increases sodium transport [57]. However, after 12–24 h it has been shown that activation of the NF-κB pathway transcriptionally downregulates SGK-1 expression, leading to a more chronic impaired ENaC function and the ultimate sodium wasting that is seen in septic AKI [58]. Aldosterone and endotoxin have been shown to independently activate NF-κB, thereby regulating SGK-1 in the collecting duct [58, 59]. It is clear that PGE2, cAMP and the other mediators mentioned above could play a role that interferes with those processes in septic AKI, leading to profound alterations in sodium and chloride handling.
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GLUCOSE AND UREA TRANSPORT
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Recent evidence has also demonstrated impaired Na+–glucose cotransporter -2 and -3 (SGLT-2 and -3), GLUT-2 and Na+/ K+-ATPase expression in mice injected with LPS [85]. The decreased expression of those transporters was associated with an increase in fractional excretion of glucose, decreased plasma glucose concentrations and decreased GFR [85]. However, they also found increased expression of the high affinity glucose transporters SGLT-1 and GLUT-1, which might have been related to the increased glucose exposure to the late proximal tubule (S3 segment) as a result of the dramatic upstream downregulation of SGLT-2 in the early proximal tubule (S1 segment) [85]. Administration of TNF-α, IL-1, IL-6 or INF-γ reproduced the alterations in glucose transporter
expression seen with LPS administration, although knockout mice for those cytokines were not resistant to the effects of LPS on glucose transporters [85]. As seen in their studies on sodium transporters, these authors were able to ameliorate the effects of LPS on the glucose transporters by large dose glucocorticoid administration [85]. The clinical significance of impaired glucose handling by the kidney during sepsis is unknown. Sepsis is generally considered a hypermetabolic state [86], and is associated with hyperglycemia in over 90% of critically ill patients [87]. In Schmidt’s study [85] above, hypoglycemia and increased fractional excretion of glucose occurred without concomitant hyperinsulinemia, which the authors felt demonstrated an insulin-independent renal glucose deprivation process. Reconciling this finding with clinical observation is not difficult; the overwhelming stress state in the septic patient likely induces a metabolic hyperglycemia that overwhelms any increase in renal wasting of glucose [87]. Nevertheless, their findings are significant in that they point to further distinctions between ischemic AKI and septic AKI. While LPS administration did induce hypotension in the Schmidt study, the effects of LPS on glucose handling were attenuated in the mice that were given steroids, despite no change in hemodynamics [85]. Additionally, in kidney ischemia–reperfusion models of AKI, SGLT-1 has been shown to be downregulated after injury, in contrast to the LPS model [88]. In a similar series of experiments, Schmidt et al. [89] found no change in protein expression using the renal arterial ligation model of ischemic AKI on the urea transporters UT-A1, UT-A2, UT-A3, UT-A4 and UT-B. However, they again demonstrated significant downregulation of all urea transporters after LPS exposure, and this downregulation was attenuated with glucocorticoid treatment [89]. Glucocorticoid attenuation in this model is surprising, given that in other rat experiments, administration of dexamethasone has been shown to independently downregulate UT-A1 and UT-A3 [90]. Knockout mice deficient in TNF-α, IL-1β, IL-6 and IFN-γ were not protected from the effects of LPS [89]. Urea is passively reabsorbed in different segments of the tubule to some degree. However, much of its reabsorption is facilitated by the above transporters located throughout the nephron, especially in the medullary collecting duct where it is significantly regulated by vasopressin [7, 91]. Approximately 50% of urea is reabsorbed in the kidney under normal conditions [7], with the rest excreted in the urine. The kidney’s overall ability to concentrate urine is dependent on medullary collecting duct reabsorption of urea, with subsequent increase in medullary osmolality [7]. In the experiments conducted by Schmidt, however, mice injected with LPS suffered a significant decrease in urea concentration in the inner medulla, and this correlated with a significant decrease in the expression of urea transporters [89]. It is unclear whether this impairment of urea reabsorption and overall urine concentrating ability seen in mouse septic AKI models occurs in humans. However, the differing effects seen in LPS-exposed mice compared with ischemia–reperfused mice strongly suggest their pathophysiological mechanisms are fundamentally different.
suggested that survivors of sepsis are better able to regulate their acid levels than non-survivors via clearance of lactate and unmeasured anions by the kidney [74]. The workhorses of acid–base regulation in the kidney are the NHE transporters [7]. They have been shown to be significantly downregulated in in vivo models of sepsis in mice exposed to intraperitoneal LPS injection [12]. It is unclear how this downregulation is mediated, but in non-septic Chinese hamster ovary cells, PKA and cAMP inhibit NHE activity [76], raising the question of whether these mediators influence acid handling in septic AKI (Figure 2). New evidence has also pointed to a possible role for SGK-2 and its stimulatory impact on NHE3 function in rat kidney proximal tubule cells [77]. The regulation of NHE3 by phosphorylation, trafficking and expression in non-septic models has been reviewed [78]. A direct role for TLR-4 receptor-mediated regulation of NHE transporter proteins has been recently proposed and supported by various experiments using highly selective inhibitors [79]. Good et al. [79] demonstrated decreased HCO− 3 absorption on both the basolateral and apical sides of isolated rat and mouse medullary thick ascending limbs (MTAL) that were exposed to LPS. Impaired HCO− 3 absorption was eliminated in TLR-4 −/− knockout mice [79]. Interestingly, they identified two separate mechanisms for basolateral and apical regulation: basolateral LPS inhibited HCO− 3 absorption via the Ras/MEK/ERK pathway, whereas apically administered LPS inhibited HCO− 3 absorption via the PI3K/mTOR/S6K pathway, suggesting that multiple independent TLR-4 pathways are involved in activating NHE1 and NHE3 separately [79, 80]. Further work has shown that ERK directly inhibits NHE3 via the TLR-4/MyD88/MEK/ERK signaling pathway [81], as is seen in aldosterone treatment models [82]. More recently, this same group has also identified a possible role for TLR-2 in impaired HCO− 3 absorption in medullary thick ascending limbs exposed to bacterial lipoprotein that is distinct from TLR-4 pathways, suggesting a role for TLR-2 in MTAL transport dysfunction in gram-positive sepsis [83]. However, they have also demonstrated that TLR-2 is required for LPS-induced TLR-4 signaling to impair NHE3, complicating the overall picture [84].
In the normal human kidney, fluid leaving the proximal tubule is isosmotic to plasma, and then is regulated by countercurrent multiplication in the loop of Henle [50]. Urine osmolality is then tightly regulated within the cortical collecting tubule by the neuropeptide vasopressin [92]. It has been shown that the vasopressin response to osmotic stimulation (administration of intraperitoneal hypertonic saline) in the hypothalamus is potentiated by LPS administration in rats [93, 94]. Concomitant with these effects in the hypothalamus, Grinevich et al. [95] demonstrated that LPS administration induced decreases in urine osmolality and downregulation of the V2 vasopressin receptor (V2R) and aquaporin-2 (AQP2) expression in the kidney, perhaps as a compensatory response to the potentiated vasopressin release in the hypothalamus. Interestingly, blood pressure was not impacted in this study, yet LPS injection was associated with a rapid increase in IL-1β and IL-6 expression in the renal medulla, suggesting that local increases in cytokines may play a role in the downregulation of V2R and AQP2 [95]. It is not clear to what extent the TLR-4 pathways play a role in this phenomenon, although the authors do suggest a possible mechanism mediated through NO synthase and cyclooxygenase, as discussed above regarding solute handling in the kidney. Wang et al. showed that aquaporin-1 (AQP-1) plays an important role in endotoxininduced AKI [17]. AQP-1 knockout mice were predisposed to more severe endotoxemic renal injury and impaired solute and water handling than wild-type mice [17]. They also showed a similar downregulation of AQP-2 (as has Olesen et al.) [18] and AQP-3 in their in vivo model of sepsis. Supporting a mechanism for impaired V2R function in septic AKI, Chagnon et al. [96] challenged rats with LPS and concomitantly administered arginine vasopressin [96]. They found that vasopressin’s ability to recruit AQP-2 was markedly impaired in septic AKI, which led to impaired water retention. This finding confirmed prior data in LPS-exposed rats showing that increases in endogenous vasopressin were not associated with subsequent elevations in AQP-2 expression, even in the setting of markedly increased free water excretion [97, 98]. Although iNOS has been implicated in some septic models [18], the molecular mechanisms contributing to the vasopressin/AQP-2 expression discordance seen in septic AKI are unknown. The impact of sepsis on other types of aquaporins is currently unknown.
CONCLUSION Septic AKI is a common and formidable problem for clinicians, especially intensivists and nephrologists. However, research over the past decade has provided new insights into septic AKI pathogenesis. Basic non-hemodynamic factors, such as the generation of inflammatory cytokines and prostaglandins, play a unique role in epithelium of the kidney tubules. These inflammatory mediators alter the ability of tubular cells to handle solutes, regulate intravascular volume
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and contribute to maintaining acid–base homeostasis in septic patients. The key theme from these recent studies is that sepsis impairs tubular transport in a manner that increases distal tubular delivery of sodium and chloride. We propose that this supraphysiologic delivery of solutes to the macula densa induces tubuloglomerular feedback and the ultimate reduction of GFR that occurs in septic AKI. Further studies to more directly test this hypothesis and better elucidate the mechanisms involved are warranted and should provide targets for future investigation and therapeutic intervention.
AC K N O W L E D G E M E N T S Work performed in our laboratories and the preparation of this review were supported by grants from the National institutes of Health: P30 DK079307 (Pittsburgh Center for Kidney Research) to N.M.P.S. and K.R.H., R01 DK084184 to N.M.P.S., the University of Pittsburgh, Department of Medicine Junior Scholar Awards to N.M.P.S., R01 DK075048 to K.R.H., R01 HL080926 to J.A.K. and R01 DK070910 to J.A.K.
C O N F L I C T O F I N T E R E S T S TAT E M E N T The authors declare that they have no competing interests or conflicts of interest. The work presented in this paper has not been published previously in whole or part.
REFERENCES 1. Uchino S, Kellum JA, Bellomo R et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005; 294: 813–818 2. Murugan R, Karajala-Subramanyam V, Lee M et al. Acute kidney injury in non-severe pneumonia is associated with an increased immune response and lower survival. Kidney Int 2010; 77: 527–535 3. Yunos NM, Bellomo R, Story D et al. Bench-to-bedside review: chloride in critical illness. Crit Care 2010; 14: 226 4. Yunos NM, Bellomo R, Hegarty C et al. Association between a chlorideliberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012; 308: 1566–1572 5. Yunos NM, Kim IB, Bellomo R et al. The biochemical effects of restricting chloride-rich fluids in intensive care. Crit Care Med 2011; 39: 2419–2424 6. Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest 1983; 71: 726–735 7. Hall JE, Guyton AC. Guyton and Hall Textbook of Medical Physiology. 12th edn. Philadelphia, PA: Saunders/Elsevier, 2011 8. Schnermann J, Ploth DW, Hermle M. Activation of tubulo-glomerular feedback by chloride transport. Pflugers Arch 1976; 362: 229–240 9. Salomonsson M, Gonzalez E, Kornfeld M et al. The cytosolic chloride concentration in macula densa and cortical thick ascending limb cells. Acta Physiol Scand 1993; 147: 305–313 10. Hashimoto S, Kawata T, Schnermann J et al. Chloride channel blockade attenuates the effect of angiotensin II on tubuloglomerular feedback in WKY but not spontaneously hypertensive rats. Kidney Blood Press Res 2004; 27: 35–42 11. Schmidt C, Hocherl K, Schweda F et al. Proinflammatory cytokines cause down-regulation of renal chloride entry pathways during sepsis. Crit Care Med 2007; 35: 2110–2119 12. Schmidt C, Hocherl K, Schweda F et al. Regulation of renal sodium transporters during severe inflammation. J Am Soc Nephrol 2007; 18: 1072–1083
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35. Snyder PM, Olson DR, Kabra R et al. cAMP and serum and glucocorticoid-inducible kinase (SGK) regulate the epithelial Na(+) channel through convergent phosphorylation of Nedd4-2. J Biol Chem 2004; 279: 45753–8 36. Butterworth MB, Helman SI, Els WJ. cAMP-sensitive endocytic trafficking in A6 epithelia. Am J Physiol Cell Physiol 2001; 280: C752–C762 37. Pao AC. SGK regulation of renal sodium transport. Curr Opin Nephrol Hypertens 2012; 21: 534–540 38. Edinger RS, Lebowitz J, Li H et al. Functional regulation of the epithelial Na+ channel by IkappaB kinase-beta occurs via phosphorylation of the ubiquitin ligase Nedd4-2. J Biol Chem 2009; 284: 150–157 39. Lang F, Shumilina E. Regulation of ion channels by the serum- and glucocorticoid-inducible kinase SGK1. FASEB J 2013; 27: 3–12 40. Beasley D, Dinarello CA, Cannon JG. Interleukin-1 induces natriuresis in conscious rats: role of renal prostaglandins. Kidney Int 1988; 33: 1059–1065 41. Caverzasio J, Rizzoli R, Dayer JM et al. Interleukin-1 decreases renal sodium reabsorption: possible mechanism of endotoxin-induced natriuresis. Am J Physiol 1987; 252 (5 Pt 2): F943–F946 42. Escalante BA, Ferreri NR, Dunn CE et al. Cytokines affect ion transport in primary cultured thick ascending limb of Henle’s loop cells. Am J Physiol 1994; 266 (6 Pt 1): C1568–C1576 43. Husted RF, Zhang C, Stokes JB. Concerted actions of IL-1beta inhibit Na+ absorption and stimulate anion secretion by IMCD cells. Am J Physiol 1998; 275 (6 Pt 2): F946–F954 44. Kohan DE. Interleukin-1 regulation of collecting duct prostaglandin E2 and cyclic nucleotide accumulation. J Lab Clin Med 1994; 123: 668–675 45. Kohan DE, Merli CA, Simon EE. Micropuncture localization of the natriuretic effect of interleukin 1. Am J Physiol 1989; 256 (5 Pt 2): F810–F813 46. Zeidel ML, Brady HR, Kohan DE. Interleukin-1 inhibition of Na(+)-K (+)-ATPase in inner medullary collecting duct cells: role of PGE2. Am J Physiol 1991; 261 (6 Pt 2): F1013–6 47. Sonnenburg WK, Smith WL. Regulation of cyclic AMP metabolism in rabbit cortical collecting tubule cells by prostaglandins. J Biol Chem 1988; 263: 6155–6160 48. Feraille E, Doucet A. Sodium-potassium-adenosinetriphosphatase-dependent sodium transport in the kidney: hormonal control. Physiol Rev 2001; 81: 345–418 49. Schafer JA. Abnormal regulation of ENaC: syndromes of salt retention and salt wasting by the collecting duct. Am J Physiol Renal Physiol 2002; 283: F221–F235 50. Taal MW, Brenner BM, Rector FC. Brenner & Rector’s the Kidney. 9th edn. Philadelphia, PA: Elsevier/Saunders, 2012 51. Yang LM, Rinke R, Korbmacher C. Stimulation of the epithelial sodium channel (ENaC) by cAMP involves putative ERK phosphorylation sites in the C termini of the channel’s beta- and gamma-subunit. J Biol Chem 2006; 281: 9859–9868 52. Chen J, Zhao M, He W et al. Increased dietary NaCl induces renal medullary PGE2 production and natriuresis via the EP2 receptor. Am J Physiol Renal Physiol 2008; 295: F818–F825 53. Duranton C, Rubera I, L’Hoste S et al. KCNQ1 K+ channels are involved in lipopolysaccharide-induced apoptosis of distal kidney cells. Cell Physiol Biochem 2010; 25: 367–378 54. Shigaev A, Asher C, Latter H et al. Regulation of sgk by aldosterone and its effects on the epithelial Na(+) channel. Am J Physiol Renal Physiol 2000; 278: F613–F619 55. Chen SY, Bhargava A, Mastroberardino L et al. Epithelial sodium channel regulated by aldosterone-induced protein sgk. Proc Natl Acad Sci USA 1999; 96: 2514–2519 56. Naray-Fejes-Toth A, Canessa C, Cleaveland ES et al. sgk is an aldosteroneinduced kinase in the renal collecting duct. Effects on epithelial na+ channels. J Biol Chem 1999; 274: 16973–8 57. Vinciguerra M, Hasler U, Mordasini D et al. Cytokines and sodium induce protein kinase A-dependent cell-surface Na,K-ATPase recruitment via dissociation of NF-kappaB/IkappaB/protein kinase A catalytic subunit complex in collecting duct principal cells. J Am Soc Nephrol 2005; 16: 2576–2585
Downloaded from http://ndt.oxfordjournals.org/ by guest on October 5, 2015
13. Kellum JA, Song M, Li J. Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells. Am J Physiol Regul Integr Comp Physiol 2004; 286: R686–R692 14. Kellum JA, Song M, Almasri E. Hyperchloremic acidosis increases circulating inflammatory molecules in experimental sepsis. Chest 2006; 130: 962–967 15. Bullivant EM, Wilcox CS, Welch WJ. Intrarenal vasoconstriction during hyperchloremia: role of thromboxane. Am J Physiol 1989; 256 (1 Pt 2): F152–F157 16. Quilley CP, Lin YS, McGiff JC. Chloride anion concentration as a determinant of renal vascular responsiveness to vasoconstrictor agents. Br J Pharmacol 1993; 108: 106–110 17. Wang W, Li C, Summer SN et al. Role of AQP1 in endotoxemia-induced acute kidney injury. Am J Physiol Renal Physiol 2008; 294: F1473–F1480 18. Olesen ET, de Seigneux S, Wang G et al. Rapid and segmental specific dysregulation of AQP2, S256-pAQP2 and renal sodium transporters in rats with LPS-induced endotoxaemia. Nephrol Dial Transplant 2009; 24: 2338–2349 19. Kwon TH, Frokiaer J, Han JS et al. Decreased abundance of major Na(+) transporters in kidneys of rats with ischemia-induced acute renal failure. Am J Physiol Renal Physiol 2000; 278: F925–F939 20. Van Why SK, Mann AS, Ardito T et al. Expression and molecular regulation of Na(+)-K(+)-ATPase after renal ischemia. Am J Physiol 1994; 267 (1 Pt 2): F75–F85 21. Wang Z, Rabb H, Haq M et al. A possible molecular basis of natriuresis during ischemic-reperfusion injury in the kidney. J Am Soc Nephrol 1998; 9: 605–613 22. Yun CH, Oh S, Zizak M et al. cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein. Proc Natl Acad Sci USA 1997; 94: 3010–3015 23. Lessa LM, Carraro-Lacroix LR, Crajoinas RO et al. Mechanisms underlying the inhibitory effects of uroguanylin on NHE3 transport activity in renal proximal tubule. Am J Physiol Renal Physiol 2012; 303: F1399–F1408 24. Hebert RL, Jacobson HR, Breyer MD. Prostaglandin E2 inhibits sodium transport in rabbit cortical collecting duct by increasing intracellular calcium. J Clin Invest 1991; 87: 1992–1998 25. Frindt G, Windhager EE. Ca2(+)-dependent inhibition of sodium transport in rabbit cortical collecting tubules. Am J Physiol 1990; 258 (3 Pt 2): F568–F582 26. Ling BN, Eaton DC. Effects of luminal Na+ on single Na+ channels in A6 cells, a regulatory role for protein kinase C. Am J Physiol 1989; 256 (6 Pt 2): F1094–F1103 27. Hebert RL, Jacobson HR, Breyer MD. PGE2 inhibits AVP-induced water flow in cortical collecting ducts by protein kinase C activation. Am J Physiol 1990; 259 (2 Pt 2): F318–F325 28. Hebert SC. Calcium and salinity sensing by the thick ascending limb: a journey from mammals to fish and back again. Kidney Int Suppl 2004; 66: S28–S33 29. Kamynina E, Debonneville C, Bens M et al. A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ channel. FASEB J 2001; 15: 204–214 30. Snyder PM, Steines JC, Olson DR. Relative contribution of Nedd4 and Nedd4-2 to ENaC regulation in epithelia determined by RNA interference. J Biol Chem 2004; 279: 5042–5046 31. Bhalla V, Oyster NM, Fitch AC et al. AMP-activated kinase inhibits the epithelial Na+ channel through functional regulation of the ubiquitin ligase Nedd4-2. J Biol Chem 2006; 281: 26159–26169 32. Arroyo JP, Lagnaz D, Ronzaud C et al. Nedd4-2 modulates renal Na+-Clcotransporter via the aldosterone-SGK1-Nedd4-2 pathway. J Am Soc Nephrol 2011; 22: 1707–1719 33. Ronzaud C, Loffing-Cueni D, Hausel P et al. Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension. J Clin Invest 2013; 123: 657–665 34. Pedersen NB, Hofmeister MV, Rosenbaek LL et al. Vasopressin induces phosphorylation of the thiazide-sensitive sodium chloride cotransporter in the distal convoluted tubule. Kidney Int 2010; 78: 160–169
E.D. Morrell et al.
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79. Good DW, George T, Watts BA, III. Lipopolysaccharide directly alters renal tubule transport through distinct TLR4-dependent pathways in basolateral and apical membranes. Am J Physiol Renal Physiol 2009; 297: F866–F874 80. Good DW, George T, Watts BA, III. Nerve growth factor inhibits Na+/H+ exchange and formula absorption through parallel phosphatidylinositol 3kinase-mTOR and ERK pathways in thick ascending limb. J Biol Chem 2008; 283: 26602–26611 81. Watts BA, 3rd, George T, Sherwood ER et al. Basolateral LPS inhibits NHE3 and HCOFormula absorption through TLR4/MyD88-dependent ERK activation in medullary thick ascending limb. Am J Physiol Cell Physiol 2011; 301: C1296–C1306 82. Watts BA, III, George T, Good DW. Aldosterone inhibits apical NHE3 and HCO3-absorption via a nongenomic ERK-dependent pathway in medullary thick ascending limb. Am J Physiol Renal Physiol 2006; 291: F1005–F1013 83. Good DW, George T, Watts BA, III. Toll-like receptor 2 mediates inhibition of HCO(3)(-) absorption by bacterial lipoprotein in medullary thick ascending limb. Am J Physiol Renal Physiol 2010; 299: F536–F544 84. Good DW, George T, Watts BA, III. Toll-like receptor 2 is required for LPS-induced Toll-like receptor 4 signaling and inhibition of ion transport in renal thick ascending limb. J Biol Chem 2012; 287: 20208–20220 85. Schmidt C, Hocherl K, Bucher M. Regulation of renal glucose transporters during severe inflammation. Am J Physiol Renal Physiol 2007; 292: F804–F811 86. McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. Crit Care Clin 2001; 17: 107–124 87. van den Berghe G, Wouters P, Weekers F et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345: 1359–1367 88. Runembert I, Couette S, Federici P et al. Recovery of Na-glucose cotransport activity after renal ischemia is impaired in mice lacking vimentin. Am J Physiol Renal Physiol 2004; 287: F960–F968 89. Schmidt C, Hocherl K, Bucher M. Cytokine-mediated regulation of urea transporters during experimental endotoxemia. Am J Physiol Renal Physiol 2007; 292: F1479–F1489 90. Li C, Wang W, Summer SN et al. Downregulation of UT-A1/UT-A3 is associated with urinary concentrating defect in glucocorticoid-excess state. J Am Soc Nephrol 2008; 19: 1975–1981 91. Nielsen S, Terris J, Smith CP et al. Cellular and subcellular localization of the vasopressin-regulated urea transporter in rat kidney. Proc Natl Acad Sci USA 1996; 93: 5495–5500 92. Knepper MA. Molecular physiology of urinary concentrating mechanism: regulation of aquaporin water channels by vasopressin. Am J Physiol 1997; 272 (1 Pt 2): F3–12 93. Grinevich V, Ma XM, Jirikowski G et al. Lipopolysaccharide endotoxin potentiates the effect of osmotic stimulation on vasopressin synthesis and secretion in the rat hypothalamus. J Neuroendocrinol 2003; 15: 141–149 94. Grinevich V, Ma XM, Verbalis J et al. Hypothalamic pituitary adrenal axis and hypothalamic-neurohypophyseal responsiveness in water-deprived rats. Exp Neurol 2001; 171: 329–341 95. Grinevich V, Knepper MA, Verbalis J et al. Acute endotoxemia in rats induces down-regulation of V2 vasopressin receptors and aquaporin-2 content in the kidney medulla. Kidney Int 2004; 65: 54–62 96. Chagnon F, Vaidya VS, Plante GE et al. Modulation of aquaporin-2/vasopressin2 receptor kidney expression and tubular injury after endotoxin (lipopolysaccharide) challenge. Crit Care Med 2008; 36: 3054–3061 97. Jonassen TE, Graebe M, Promeneur D et al. Lipopolysaccharide-induced acute renal failure in conscious rats: effects of specific phosphodiesterase type 3 and 4 inhibition. J Pharmacol Exp Ther 2002; 303: 364–374 98. Versteilen AM, Heemskerk AE, Groeneveld AB et al. Mechanisms of the urinary concentration defect and effect of desmopressin during endotoxemia in rats. Shock 2008; 29: 217–222 Received for publication: 22.10.2013; Accepted in revised form: 18.11.2013
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58. de Seigneux S, Leroy V, Ghzili H et al. NF-kappaB inhibits sodium transport via down-regulation of SGK1 in renal collecting duct principal cells. J Biol Chem 2008; 283: 25671–25681 59. Leroy V, De Seigneux S, Agassiz V et al. Aldosterone activates NF-kappaB in the collecting duct. J Am Soc Nephrol 2009; 20: 131–144 60. Cantaluppi V, Weber V, Lauritano C et al. Protective effect of resin adsorption on septic plasma-induced tubular injury. Crit Care 2010; 14: R4 61. Fisher CJ, Jr., Dhainaut JF, Opal SM et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA 1994; 271: 1836–1843 62. Fisher CJ, Jr., Slotman GJ, Opal SM et al. Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. Crit Care Med 1994; 22: 12–21 63. Opal SM, Fisher CJ, Jr., Dhainaut JF et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, doubleblind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med 1997; 25: 1115–1124 64. Cronin L, Cook DJ, Carlet J et al. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med 1995; 23: 1430–1439 65. Annane D. Corticosteroids for septic shock. Crit Care Med 2001; 29 (7 Suppl.): S117–S120 66. Shenker Y, Skatrud JB. Adrenal insufficiency in critically ill patients. Am J Respir Crit Care Med 2001; 163: 1520–1523 67. Tsao CM, Ho ST, Chen A et al. Low-dose dexamethasone ameliorates circulatory failure and renal dysfunction in conscious rats with endotoxemia. Shock 2004; 21: 484–491 68. Schwartz D, Mendonca M, Schwartz I et al. Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats. J Clin Invest 1997; 100: 439–448 69. Plato CF, Stoos BA, Wang D et al. Endogenous nitric oxide inhibits chloride transport in the thick ascending limb. Am J Physiol 1999; 276 (1 Pt 2): F159–F163 70. Majid DS, Williams A, Navar LG. Inhibition of nitric oxide synthesis attenuates pressure-induced natriuretic responses in anesthetized dogs. Am J Physiol 1993; 264 (1 Pt 2): F79–F87 71. Majid DS, Williams A, Kadowitz PJ et al. Renal responses to intra-arterial administration of nitric oxide donor in dogs. Hypertension 1993; 22: 535–541 72. Ortiz PA, Hong NJ, Garvin JL. NO decreases thick ascending limb chloride absorption by reducing Na(+)-K(+)-2Cl(-) cotransporter activity. Am J Physiol Renal Physiol 2001; 281: F819–F825 73. Stoos BA, Carretero OA, Garvin JL. Endothelial-derived nitric oxide inhibits sodium transport by affecting apical membrane channels in cultured collecting duct cells. J Am Soc Nephrol 1994; 4: 1855–1860 74. Noritomi DT, Soriano FG, Kellum JA et al. Metabolic acidosis in patients with severe sepsis and septic shock: a longitudinal quantitative study. Crit Care Med 2009; 37: 2733–2739 75. Mecher C, Rackow EC, Astiz ME et al. Unaccounted for anion in metabolic acidosis during severe sepsis in humans. Crit Care Med 1991; 19: 705–711 76. Zhao H, Wiederkehr MR, Fan L et al. Acute inhibition of Na/H exchanger NHE-3 by cAMP. Role of protein kinase a and NHE-3 phosphoserines 552 and 605. J Biol Chem 1999; 274: 3978–3987 77. Pao AC, Bhargava A, Di Sole F et al. Expression and role of serum and glucocorticoid-regulated kinase 2 in the regulation of Na+/H+ exchanger 3 in the mammalian kidney. Am J Physiol Renal Physiol 2010; 299: F1496–F1506 78. Girardi AC, Di Sole F. Deciphering the mechanisms of the Na+/H+ exchanger-3 regulation in organ dysfunction. Am J Physiol Cell Physiol 2012; 302: C1569–C1587
Full Review Epithelial transport during septic acute kidney injury Eric D. Morrell1, John A. Kellum2,3,4, Kenneth R. Hallows1,2,5 and Núria M. Pastor-Soler1,2,5 1
Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, S976.1 Scaife Hall, 3550 Terrace Street,
Pittsburgh, PA 15261, USA, 2The Center for Critical Care Nephrology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, 3
CRISMA (Clinical Research Systems Modeling of Acute Illness) Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA and 5Department of Cell Biology,
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Correspondence and offprint requests to: Kenneth R. Hallows; E-mail: [email protected]
A B S T R AC T A goal for scientists studying septic acute kidney injury (AKI) should be to formulate a conceptual model of disease that is able to coherently reconcile the molecular and inflammatory consequences of sepsis with impaired epithelial tubular function, diminished glomerular filtration rate (GFR) and ultimately kidney failure. Recent evidence has shed light on how sepsis modulates the tubular regulation of ion, glucose, urea and water transport and acid–base homeostasis in the kidney. The present review summarizes recent discoveries on changes in epithelial transport under septic and endotoxemic conditions as well as the mechanisms that link inflammation with impaired tubular membrane transport. This paper also proposes that the tubular dysfunction that is mediated by inflammation in sepsis ultimately leads to increased sodium and chloride delivery to the distal tubule and macula densa, contributing to tubuloglomerular feedback and impaired GFR. We feel that this conceptual model resolves many of the physiologic and clinical paradoxes that septic AKI presents to practicing researchers and clinicians. Keywords: AKI, ion transport, sepsis, toll-like receptor, tubuloglomerular feedback
INTRODUCTION Acute kidney injury (AKI) is a very common and especially formidable clinical problem facing acute care physicians. The most common cause of AKI in hospitalized patients is sepsis © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
[1], and AKI is not uncommon even in non-severe sepsis where hemodynamic changes are not readily apparent [2]. Despite its ubiquity in the hospital, historically little is known about how the basic epithelial transport mechanisms that modulate solute, volume and urea clearance are affected by sepsis-induced AKI. A goal for scientists studying septic AKI, and for this review, is to formulate a conceptual model of disease that is able to coherently reconcile the molecular and inflammatory consequences of sepsis with impaired tubular function, diminished glomerular filtration rate (GFR) and ultimately kidney failure. Experiments performed over the past 20 years that we will review have started to shed light on how sepsis modulates tubular transport function. Here we propose a model that links septic inflammation and tubular transport dysfunction with impaired GFR and kidney failure. For example, there has been a renewed interest over the past 5 years in the role of chloride in septic AKI [3]. Recent large clinical trials have shown that an increased serum chloride concentration may have a deleterious effect on overall kidney function, especially in septic patients [4, 5]. Tubular transport would be directly involved in these deleterious effects as septic AKI is mediated in part by tubular processes that increase chloride delivery to the distal tubule, and we suggest that this phenomenon may play a key role in overall organ dysfunction.
LINKING IMPAIRED SOLUTE TRANSPORT TO DECREASED GFR Seminal studies performed by Wilcox in the 1980s demonstrated the unique role of increased chloride in normal kidney 1
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T U B U L A R S O D I U M , P O TA S S I U M A N D C H LO R I D E T R A N S P O R T R E G U L AT I O N IN SEPTIC AKI Inflammation, one of the hallmark physiologic mediators of sepsis, can severely impair the intricate tubular mechanisms responsible for sodium, potassium and chloride regulation, even in the setting of normal cellular perfusion. The impairments can all lead to increased distal tubule chloride delivery, impairing GFR and overall renal function. Schmidt et al. [11, 12] have shown significant downregulation of Na+/H+ exchanger 3 (NHE3), Na+/K+-ATPase, renal outer medullary K+ channel (ROMK), epithelial Na+ channel (ENaC), Na+–K+– 2Cl−-cotransporter 2 (NKCC2), Na+–Cl− cotransporter (NCC), kidney specific chloride channel -1 and -2 (CLCK-1 and -2) and Barttin expression in an in vivo model of rat sepsis induced by intraperitoneal injection of liposaccharide (LPS). This finding has been reproduced independently with comparable models showing downregulation of NKCC2 and NHE3 [17, 18]; however, in one of the studies, the α-subunit of ENaC showed increased expression in response to LPS in
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the inner stripe of the outer medulla (ISOM) (β-ENaC was downregulated) [18]. The upregulation of the α-subunit of ENaC in the later study might be explained by the fact that measurements were taken at 6 h (as compared with at 6, 12 and 24 h in the Schmidt study), when increased levels of aldosterone might still be able to overwhelm only partially impaired transporters [12, 18]. A similar pattern of near ubiquitous downregulation of all tubular sodium transporters has been seen in multiple ischemia–reperfusion models of AKI as well [19–21]. In Schmidt’s model there was preserved arterial blood pressure with a lower dose of LPS, yet the downregulation of transporters was still observed [11, 12]. The decrease in sodium, potassium and chloride transport proteins in response to LPS corresponds with a markedly increased fractional excretion of sodium and chloride [11, 12]. The increased distal chloride delivery may also be due in part to a reduction in paracellular chloride reabsorption as well as significantly elevated levels of IL-1β, TNF-α and interferongamma (IFN-γ) (see Figures 1 and 2). Interestingly, knockout mice that are deficient in TNF-α, IL-1 or IFN-γ do not show any resistance to downregulation of the sodium, potassium or chloride transport proteins in response to LPS, indicating that perhaps multiple overlapping processes are involved (such as the TLR-4-mediated pathways) [11, 12]. In these same experiments, however, glucocorticoid treatment leads to inhibition of all three cytokines after exposure to LPS, with subsequent attenuation of all sodium, potassium and chloride transport protein dysfunction [11, 12]. Glucocorticoids are known to stimulate ENaC and ROMK through serum- and glucocorticoid-inducible kinase (SGK-1) [39] and so this may have counteracted any potential LPSmediated downregulatory process (Figure 2). There have been a number of proposed mediators that could link systemic inflammatory mediators such as TNF-α, IL-1 and LPS with impaired epithelial transport function, but much evidence points to a direct role for cyclooxygenase and prostaglandins, especially as mediators of distal sodium and chloride delivery. Rats exposed to exogenous IL-1 exhibit marked natriuresis and diuresis [40–46], and this physiologic phenomenon is largely due to sodium wasting in the cortical collecting duct [44, 45]. This change is accompanied by a corresponding increase in urinary prostaglandin E (PGE2) excretion and is inhibited by pre-treatment with a cyclooxygenase inhibitor, suggesting a possible role for PGE2 in the mechanisms connecting IL-1 with impaired sodium transport in the distal tubule (Figure 2) [40]. While various experiments have demonstrated a similar role for PGE2 on sodium handing in the thick ascending limb of Henle’s loop [42, 44, 46] and cortical collecting ducts [44], other experiments have failed to show a concomitant increase in prostaglandin synthesis in response to IL-1 administration [41]. In most of these experiments (but not all [43]), treatment with cyclooxygenase inhibitors such as indomethacin mitigated salt wasting in hyperinflammatory models of kidney injury [40–42, 46]. Chloride-mediated changes in renal hemodynamics also seem to be directly regulated by products of cyclooxygenase and thromboxane synthetase [15]. In this work using a rodent model, Bullivant et al. [15] demonstrated that hyperchloremia
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blood vessels in decreasing both kidney blood flow and GFR [6]. Hyperchloremia produces renal vasoconstriction and a fall in GFR that is likely mediated by distal tubular sensing of sodium and chloride [7]. In physiologically normal kidneys, decreases in arterial pressure result in increased proximal tubular NaCl reabsorption, decreased macula densa sensing of NaCl and subsequent activation of the renin–angiotensin system [7]. Through this macula densa-mediated mechanism, decreased kidney perfusion leads to increased efferent and decreased afferent arteriolar vasoconstriction that increases GFR [7]. When there are increased levels of chloride sensed by the macula densa, the opposite phenomenon occurs, leading to decreased GFR [6]. Subsequent studies have confirmed that high solute concentrations and flow rates of chloride distal to the proximal tubules lead to manipulation of tubuloglomerular feedback, ultimately diminishing GFR (Figure 1) [8–10]. The potentially deleterious effects of increased distal chloride delivery do not seem limited to kidney hemodynamics [3]. In cell culture models, chloride-rich microenvironments have been shown to be pro-inflammatory, leading to increased nitric oxide (NO) release, interleukin-6:interleukin-10 (IL-6: IL-10) ratios and NF-κB DNA binding [13]. In vivo models of sepsis involving rats have also demonstrated that resuscitation with high chloride-containing solutions promote a proinflammatory state with increased levels of IL-6, IL-10 and tumor necrosis factor-alpha (TNF-α), even in normotensive rats [14]. Chloride infusion upregulates thromboxane- and cyclooxygenase-mediated renal arterial vasoconstriction [15]. Finally, in isolated perfused rat kidneys, higher concentrations of chloride have been shown to significantly potentiate the vasoconstrictive effects of angiotensin II [16]. It is likely that processes in sepsis—independent of systemic chloride levels— that increase distal tubular chloride exposure lead to impaired renal function via both hemodynamic and inflammatory processes (Figure 1).
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F I G U R E 1 : Proposed mechanism for linking impaired solute transport with decreased GFR. Pro-inflammatory cytokines cause a downregulation of renal chloride entry transport proteins—specifically CLCK-1, CLCK-2, and Barttin—during sepsis [11], increasing distal delivery of chloride. Tubular dysfunction of sodium transport proteins, especially the downregulation of NHE3, Na+/K+-ATPase, ROMK, NKCC2 and NCC, also generates an increase in the lumen sodium concentration, and thus overall increases lumen positive potential [12]. This causes a decrease in paracellular chloride reabsorption, which ultimately leads to further increased chloride delivery to the thick ascending limb. The net effect is tubuloglomerular feedback and reduced GFR in that nephron.
F I G U R E 2 : Proposed overview of ion channel regulation during septic AKI. Inflammatory mediators such as LPS, IL-1 and TNF-α activate
various prostaglandin pathways (COX), leading to increased levels of PGE2. Increased PGE2 levels can modulate intracellular calcium stores as well as stimulate multiple downstream mediators including cAMP. In the proximal tubule, cAMP has been shown to indirectly inhibit NHE3 via PKA phosphorylation of the NHE regulatory factor NHERF-1 [22], which could lead to natriuresis secondary to PGE2-mediated stimulation of cAMP generation from cytokines [23]. More distally, increased intracellular calcium levels may decrease NHE3, NKCC2, ENaC and NCC activity, all via PKC-mediated processes [24–28]. In the distal convoluted tubule and cortical collecting duct, vasopressin, aldosterone and AMPK regulate ENaC [29–31] and aldosterone regulates NCC [32, 33]. These effects are mediated at least in part by Nedd4-2 [29–34], and these processes directly involve cAMP/PKA for vasopressin [35, 36] and SGK-1 for aldosterone [32, 37]. IKKβ has been shown to stimulate ENaC via Nedd4-2 phosphorylation [38], bringing forth a potential link between sepsis-mediated TLR-4 and sodium transport. The net effect of global ion channel downregulation is an increase in luminal sodium concentration, a decrease in lumen negative potential, less paracellular chloride reabsorption and increased distal chloride delivery.
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The role for inflammation leading to downregulation of sodium transport proteins has been reinforced by a recent study by Cantaluppi et al. [60]. In primary human proximal tubule epithelial cells exposed to human septic plasma, NHE3, the tight junction protein-1 zonula occludens-1 (ZO-1) and the diffusive glucose transporter (GLUT-2) levels were decreased [60]. However, decreased expression of these transporters was abrogated when a number of inflammatory mediators —including TNF-α, CD154 and Fas-L—were effectively filtered from the plasma by Amberchrom resin adsorption [60]. The idea that tubular impairment in solute handling can be ameliorated by broad manipulation (or impairment) of the inflammatory milieu is not new. After multiple clinical trials failed to show any benefit from single anti-cytokine treatment [61–63], there was a renewed interest in using steroids to treat sepsis. However, high-dose methylprednisolone does not improve survival, and may actually worsen outcomes by increasing susceptibility to secondary infections [64]. While controversial, there are some studies that suggest lower dose steroids may be beneficial in sepsis [65], as well as in patients with functional adrenal insufficiency [66]. In rat models of septic AKI, low-dose steroids have been shown to limit renal dysfunction [67]. While the exact mechanisms for impaired solute handling in sepsis and endotoxemia are not fully elucidated, it does appear that inflammatory cytokines play a large role in the process. Further research is needed to identify what inflammatory ‘milieu’ would be the most favorable one to counteract the detrimental effects of sepsis on kidney function. Finally, while it has been established in experiments utilizing endotoxemia that inhibiting inducible nitric oxide synthase (iNOS) can have a dramatic effect on GFR [68], endogenous NO has also been implicated as a mediator of epithelial sodium and chloride transport independent of its effects on vascular function [69]. It has long been known that NO has natriuretic and diuretic effects on animals, presumably through its impact on vasoregulation [69–71]. In non-septic studies, NO has been shown to inhibit NKCC2 [72] and apical sodium transport proteins in the cortical collecting duct [73]. More recently, septic models of AKI have linked endotoxemia with increased iNOS expression and downregulation of the NHE3 and NKCC2 transporters [18]. Regardless of the specific roles that inflammatory cytokines, PGE2, cAMP, Nedd4-2, or iNOS play in septic AKI, the overarching consequence of sepsis on these mediators seems to be increased delivery of sodium and chloride to the macula densa. We propose that this putative effect of septic inflammation—the increased delivery of sodium and chloride to the distal tubules and the macula densa—plays a critical role in the overall reduction in GFR and renal function.
AC I D – B A S E R E G U L AT I O N During sepsis, especially severe sepsis where multiple organ failure is common, metabolic acidosis becomes a formidable clinical problem [74, 75]. The role that impaired renal excretion of acid plays in contributing to the mortality and morbidity from sepsis is unknown. However, studies have
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reduced GFR by over 30%, and this effect could be prevented by pre-treatment with either indomethacin or thromboxane antagonists. The mechanistic consequences of implicating PGE2 and other prostaglandins in septic AKI are profound because there are so many potential targets for intervention associated with these mediators. For instance, in the proximal tubule, cyclic adenosine monophosphate (cAMP) has been shown to indirectly inhibit NHE3 via protein kinase A (PKA) phosphorylation of the NHE regulatory factor NHERF-1 [22], which could lead to natriuresis secondary to PGE2-mediated stimulation of cAMP generation from cytokines (Figure 2) [23]. PGE2 has also been shown to inhibit sodium reabsorption by increasing intracellular calcium levels, which may have direct inhibitory effects on the Na+/K+-ATPase and apical sodium transport proteins or indirect effects on sodium transport via protein kinase C (PKC)-mediated processes in the collecting duct [24–27]. This modulation of sodium transport via PGE2 and calcium sensing has also been demonstrated in the thick ascending limb involving the NKCC2 cotransporter [28]. In rabbit cortical collecting tubules, PGE2 administered in isolation has been shown to increase cAMP levels [47]. However, when co-administered with vasopressin, PGE2 decreases cAMP levels, leading to sodium wasting [47–49], as cAMP causes an increase in apical membrane sodium transport [50]. Other mechanisms have been proposed connecting cAMP to ENaC activation [49, 51, 52] as well as apoptosis in distal convoluted tubules via regulation of potassium channels [53]. The link between septic AKI and apical sodium handling in the distal convoluted tubule and cortical collecting duct likely also involves the E3 ubiquitin ligase Nedd4-2 (Figure 2). The influences of both vasopressin, aldosterone and AMP-activated kinase (AMPK) on ENaC [29–31] and aldosterone on NCC [32, 33] are mediated at least in part by Nedd4-2 [29– 34]. These processes directly involve cAMP/PKA for vasopressin [35, 36] and serum glucocorticoid regulated kinase-1 (SGK-1) for aldosterone [32, 37], which could also be related to PGE2 regulation as discussed above [54–56]. There is some recent evidence likewise suggesting cross-talk between the Nedd4-2 pathway of sodium regulation and NF-κB [38]. IκBkinase-β (IKKβ) has been shown to stimulate ENaC via Nedd4-2 phosphorylation [38], certainly bringing forth a potential link between sepsis-mediated toll-like receptor-4 (TLR-4) and sodium transport. In mouse CCD cells, LPS and TNF-α acutely promote basolateral Na+/K+-ATPase activation via cAMP-independent PKA activation, which ultimately increases sodium transport [57]. However, after 12–24 h it has been shown that activation of the NF-κB pathway transcriptionally downregulates SGK-1 expression, leading to a more chronic impaired ENaC function and the ultimate sodium wasting that is seen in septic AKI [58]. Aldosterone and endotoxin have been shown to independently activate NF-κB, thereby regulating SGK-1 in the collecting duct [58, 59]. It is clear that PGE2, cAMP and the other mediators mentioned above could play a role that interferes with those processes in septic AKI, leading to profound alterations in sodium and chloride handling.
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GLUCOSE AND UREA TRANSPORT
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Recent evidence has also demonstrated impaired Na+–glucose cotransporter -2 and -3 (SGLT-2 and -3), GLUT-2 and Na+/ K+-ATPase expression in mice injected with LPS [85]. The decreased expression of those transporters was associated with an increase in fractional excretion of glucose, decreased plasma glucose concentrations and decreased GFR [85]. However, they also found increased expression of the high affinity glucose transporters SGLT-1 and GLUT-1, which might have been related to the increased glucose exposure to the late proximal tubule (S3 segment) as a result of the dramatic upstream downregulation of SGLT-2 in the early proximal tubule (S1 segment) [85]. Administration of TNF-α, IL-1, IL-6 or INF-γ reproduced the alterations in glucose transporter
expression seen with LPS administration, although knockout mice for those cytokines were not resistant to the effects of LPS on glucose transporters [85]. As seen in their studies on sodium transporters, these authors were able to ameliorate the effects of LPS on the glucose transporters by large dose glucocorticoid administration [85]. The clinical significance of impaired glucose handling by the kidney during sepsis is unknown. Sepsis is generally considered a hypermetabolic state [86], and is associated with hyperglycemia in over 90% of critically ill patients [87]. In Schmidt’s study [85] above, hypoglycemia and increased fractional excretion of glucose occurred without concomitant hyperinsulinemia, which the authors felt demonstrated an insulin-independent renal glucose deprivation process. Reconciling this finding with clinical observation is not difficult; the overwhelming stress state in the septic patient likely induces a metabolic hyperglycemia that overwhelms any increase in renal wasting of glucose [87]. Nevertheless, their findings are significant in that they point to further distinctions between ischemic AKI and septic AKI. While LPS administration did induce hypotension in the Schmidt study, the effects of LPS on glucose handling were attenuated in the mice that were given steroids, despite no change in hemodynamics [85]. Additionally, in kidney ischemia–reperfusion models of AKI, SGLT-1 has been shown to be downregulated after injury, in contrast to the LPS model [88]. In a similar series of experiments, Schmidt et al. [89] found no change in protein expression using the renal arterial ligation model of ischemic AKI on the urea transporters UT-A1, UT-A2, UT-A3, UT-A4 and UT-B. However, they again demonstrated significant downregulation of all urea transporters after LPS exposure, and this downregulation was attenuated with glucocorticoid treatment [89]. Glucocorticoid attenuation in this model is surprising, given that in other rat experiments, administration of dexamethasone has been shown to independently downregulate UT-A1 and UT-A3 [90]. Knockout mice deficient in TNF-α, IL-1β, IL-6 and IFN-γ were not protected from the effects of LPS [89]. Urea is passively reabsorbed in different segments of the tubule to some degree. However, much of its reabsorption is facilitated by the above transporters located throughout the nephron, especially in the medullary collecting duct where it is significantly regulated by vasopressin [7, 91]. Approximately 50% of urea is reabsorbed in the kidney under normal conditions [7], with the rest excreted in the urine. The kidney’s overall ability to concentrate urine is dependent on medullary collecting duct reabsorption of urea, with subsequent increase in medullary osmolality [7]. In the experiments conducted by Schmidt, however, mice injected with LPS suffered a significant decrease in urea concentration in the inner medulla, and this correlated with a significant decrease in the expression of urea transporters [89]. It is unclear whether this impairment of urea reabsorption and overall urine concentrating ability seen in mouse septic AKI models occurs in humans. However, the differing effects seen in LPS-exposed mice compared with ischemia–reperfused mice strongly suggest their pathophysiological mechanisms are fundamentally different.
suggested that survivors of sepsis are better able to regulate their acid levels than non-survivors via clearance of lactate and unmeasured anions by the kidney [74]. The workhorses of acid–base regulation in the kidney are the NHE transporters [7]. They have been shown to be significantly downregulated in in vivo models of sepsis in mice exposed to intraperitoneal LPS injection [12]. It is unclear how this downregulation is mediated, but in non-septic Chinese hamster ovary cells, PKA and cAMP inhibit NHE activity [76], raising the question of whether these mediators influence acid handling in septic AKI (Figure 2). New evidence has also pointed to a possible role for SGK-2 and its stimulatory impact on NHE3 function in rat kidney proximal tubule cells [77]. The regulation of NHE3 by phosphorylation, trafficking and expression in non-septic models has been reviewed [78]. A direct role for TLR-4 receptor-mediated regulation of NHE transporter proteins has been recently proposed and supported by various experiments using highly selective inhibitors [79]. Good et al. [79] demonstrated decreased HCO− 3 absorption on both the basolateral and apical sides of isolated rat and mouse medullary thick ascending limbs (MTAL) that were exposed to LPS. Impaired HCO− 3 absorption was eliminated in TLR-4 −/− knockout mice [79]. Interestingly, they identified two separate mechanisms for basolateral and apical regulation: basolateral LPS inhibited HCO− 3 absorption via the Ras/MEK/ERK pathway, whereas apically administered LPS inhibited HCO− 3 absorption via the PI3K/mTOR/S6K pathway, suggesting that multiple independent TLR-4 pathways are involved in activating NHE1 and NHE3 separately [79, 80]. Further work has shown that ERK directly inhibits NHE3 via the TLR-4/MyD88/MEK/ERK signaling pathway [81], as is seen in aldosterone treatment models [82]. More recently, this same group has also identified a possible role for TLR-2 in impaired HCO− 3 absorption in medullary thick ascending limbs exposed to bacterial lipoprotein that is distinct from TLR-4 pathways, suggesting a role for TLR-2 in MTAL transport dysfunction in gram-positive sepsis [83]. However, they have also demonstrated that TLR-2 is required for LPS-induced TLR-4 signaling to impair NHE3, complicating the overall picture [84].
In the normal human kidney, fluid leaving the proximal tubule is isosmotic to plasma, and then is regulated by countercurrent multiplication in the loop of Henle [50]. Urine osmolality is then tightly regulated within the cortical collecting tubule by the neuropeptide vasopressin [92]. It has been shown that the vasopressin response to osmotic stimulation (administration of intraperitoneal hypertonic saline) in the hypothalamus is potentiated by LPS administration in rats [93, 94]. Concomitant with these effects in the hypothalamus, Grinevich et al. [95] demonstrated that LPS administration induced decreases in urine osmolality and downregulation of the V2 vasopressin receptor (V2R) and aquaporin-2 (AQP2) expression in the kidney, perhaps as a compensatory response to the potentiated vasopressin release in the hypothalamus. Interestingly, blood pressure was not impacted in this study, yet LPS injection was associated with a rapid increase in IL-1β and IL-6 expression in the renal medulla, suggesting that local increases in cytokines may play a role in the downregulation of V2R and AQP2 [95]. It is not clear to what extent the TLR-4 pathways play a role in this phenomenon, although the authors do suggest a possible mechanism mediated through NO synthase and cyclooxygenase, as discussed above regarding solute handling in the kidney. Wang et al. showed that aquaporin-1 (AQP-1) plays an important role in endotoxininduced AKI [17]. AQP-1 knockout mice were predisposed to more severe endotoxemic renal injury and impaired solute and water handling than wild-type mice [17]. They also showed a similar downregulation of AQP-2 (as has Olesen et al.) [18] and AQP-3 in their in vivo model of sepsis. Supporting a mechanism for impaired V2R function in septic AKI, Chagnon et al. [96] challenged rats with LPS and concomitantly administered arginine vasopressin [96]. They found that vasopressin’s ability to recruit AQP-2 was markedly impaired in septic AKI, which led to impaired water retention. This finding confirmed prior data in LPS-exposed rats showing that increases in endogenous vasopressin were not associated with subsequent elevations in AQP-2 expression, even in the setting of markedly increased free water excretion [97, 98]. Although iNOS has been implicated in some septic models [18], the molecular mechanisms contributing to the vasopressin/AQP-2 expression discordance seen in septic AKI are unknown. The impact of sepsis on other types of aquaporins is currently unknown.
CONCLUSION Septic AKI is a common and formidable problem for clinicians, especially intensivists and nephrologists. However, research over the past decade has provided new insights into septic AKI pathogenesis. Basic non-hemodynamic factors, such as the generation of inflammatory cytokines and prostaglandins, play a unique role in epithelium of the kidney tubules. These inflammatory mediators alter the ability of tubular cells to handle solutes, regulate intravascular volume
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and contribute to maintaining acid–base homeostasis in septic patients. The key theme from these recent studies is that sepsis impairs tubular transport in a manner that increases distal tubular delivery of sodium and chloride. We propose that this supraphysiologic delivery of solutes to the macula densa induces tubuloglomerular feedback and the ultimate reduction of GFR that occurs in septic AKI. Further studies to more directly test this hypothesis and better elucidate the mechanisms involved are warranted and should provide targets for future investigation and therapeutic intervention.
AC K N O W L E D G E M E N T S Work performed in our laboratories and the preparation of this review were supported by grants from the National institutes of Health: P30 DK079307 (Pittsburgh Center for Kidney Research) to N.M.P.S. and K.R.H., R01 DK084184 to N.M.P.S., the University of Pittsburgh, Department of Medicine Junior Scholar Awards to N.M.P.S., R01 DK075048 to K.R.H., R01 HL080926 to J.A.K. and R01 DK070910 to J.A.K.
C O N F L I C T O F I N T E R E S T S TAT E M E N T The authors declare that they have no competing interests or conflicts of interest. The work presented in this paper has not been published previously in whole or part.
REFERENCES 1. Uchino S, Kellum JA, Bellomo R et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005; 294: 813–818 2. Murugan R, Karajala-Subramanyam V, Lee M et al. Acute kidney injury in non-severe pneumonia is associated with an increased immune response and lower survival. Kidney Int 2010; 77: 527–535 3. Yunos NM, Bellomo R, Story D et al. Bench-to-bedside review: chloride in critical illness. Crit Care 2010; 14: 226 4. Yunos NM, Bellomo R, Hegarty C et al. Association between a chlorideliberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012; 308: 1566–1572 5. Yunos NM, Kim IB, Bellomo R et al. The biochemical effects of restricting chloride-rich fluids in intensive care. Crit Care Med 2011; 39: 2419–2424 6. Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest 1983; 71: 726–735 7. Hall JE, Guyton AC. Guyton and Hall Textbook of Medical Physiology. 12th edn. Philadelphia, PA: Saunders/Elsevier, 2011 8. Schnermann J, Ploth DW, Hermle M. Activation of tubulo-glomerular feedback by chloride transport. Pflugers Arch 1976; 362: 229–240 9. Salomonsson M, Gonzalez E, Kornfeld M et al. The cytosolic chloride concentration in macula densa and cortical thick ascending limb cells. Acta Physiol Scand 1993; 147: 305–313 10. Hashimoto S, Kawata T, Schnermann J et al. Chloride channel blockade attenuates the effect of angiotensin II on tubuloglomerular feedback in WKY but not spontaneously hypertensive rats. Kidney Blood Press Res 2004; 27: 35–42 11. Schmidt C, Hocherl K, Schweda F et al. Proinflammatory cytokines cause down-regulation of renal chloride entry pathways during sepsis. Crit Care Med 2007; 35: 2110–2119 12. Schmidt C, Hocherl K, Schweda F et al. Regulation of renal sodium transporters during severe inflammation. J Am Soc Nephrol 2007; 18: 1072–1083
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35. Snyder PM, Olson DR, Kabra R et al. cAMP and serum and glucocorticoid-inducible kinase (SGK) regulate the epithelial Na(+) channel through convergent phosphorylation of Nedd4-2. J Biol Chem 2004; 279: 45753–8 36. Butterworth MB, Helman SI, Els WJ. cAMP-sensitive endocytic trafficking in A6 epithelia. Am J Physiol Cell Physiol 2001; 280: C752–C762 37. Pao AC. SGK regulation of renal sodium transport. Curr Opin Nephrol Hypertens 2012; 21: 534–540 38. Edinger RS, Lebowitz J, Li H et al. Functional regulation of the epithelial Na+ channel by IkappaB kinase-beta occurs via phosphorylation of the ubiquitin ligase Nedd4-2. J Biol Chem 2009; 284: 150–157 39. Lang F, Shumilina E. Regulation of ion channels by the serum- and glucocorticoid-inducible kinase SGK1. FASEB J 2013; 27: 3–12 40. Beasley D, Dinarello CA, Cannon JG. Interleukin-1 induces natriuresis in conscious rats: role of renal prostaglandins. Kidney Int 1988; 33: 1059–1065 41. Caverzasio J, Rizzoli R, Dayer JM et al. Interleukin-1 decreases renal sodium reabsorption: possible mechanism of endotoxin-induced natriuresis. Am J Physiol 1987; 252 (5 Pt 2): F943–F946 42. Escalante BA, Ferreri NR, Dunn CE et al. Cytokines affect ion transport in primary cultured thick ascending limb of Henle’s loop cells. Am J Physiol 1994; 266 (6 Pt 1): C1568–C1576 43. Husted RF, Zhang C, Stokes JB. Concerted actions of IL-1beta inhibit Na+ absorption and stimulate anion secretion by IMCD cells. Am J Physiol 1998; 275 (6 Pt 2): F946–F954 44. Kohan DE. Interleukin-1 regulation of collecting duct prostaglandin E2 and cyclic nucleotide accumulation. J Lab Clin Med 1994; 123: 668–675 45. Kohan DE, Merli CA, Simon EE. Micropuncture localization of the natriuretic effect of interleukin 1. Am J Physiol 1989; 256 (5 Pt 2): F810–F813 46. Zeidel ML, Brady HR, Kohan DE. Interleukin-1 inhibition of Na(+)-K (+)-ATPase in inner medullary collecting duct cells: role of PGE2. Am J Physiol 1991; 261 (6 Pt 2): F1013–6 47. Sonnenburg WK, Smith WL. Regulation of cyclic AMP metabolism in rabbit cortical collecting tubule cells by prostaglandins. J Biol Chem 1988; 263: 6155–6160 48. Feraille E, Doucet A. Sodium-potassium-adenosinetriphosphatase-dependent sodium transport in the kidney: hormonal control. Physiol Rev 2001; 81: 345–418 49. Schafer JA. Abnormal regulation of ENaC: syndromes of salt retention and salt wasting by the collecting duct. Am J Physiol Renal Physiol 2002; 283: F221–F235 50. Taal MW, Brenner BM, Rector FC. Brenner & Rector’s the Kidney. 9th edn. Philadelphia, PA: Elsevier/Saunders, 2012 51. Yang LM, Rinke R, Korbmacher C. Stimulation of the epithelial sodium channel (ENaC) by cAMP involves putative ERK phosphorylation sites in the C termini of the channel’s beta- and gamma-subunit. J Biol Chem 2006; 281: 9859–9868 52. Chen J, Zhao M, He W et al. Increased dietary NaCl induces renal medullary PGE2 production and natriuresis via the EP2 receptor. Am J Physiol Renal Physiol 2008; 295: F818–F825 53. Duranton C, Rubera I, L’Hoste S et al. KCNQ1 K+ channels are involved in lipopolysaccharide-induced apoptosis of distal kidney cells. Cell Physiol Biochem 2010; 25: 367–378 54. Shigaev A, Asher C, Latter H et al. Regulation of sgk by aldosterone and its effects on the epithelial Na(+) channel. Am J Physiol Renal Physiol 2000; 278: F613–F619 55. Chen SY, Bhargava A, Mastroberardino L et al. Epithelial sodium channel regulated by aldosterone-induced protein sgk. Proc Natl Acad Sci USA 1999; 96: 2514–2519 56. Naray-Fejes-Toth A, Canessa C, Cleaveland ES et al. sgk is an aldosteroneinduced kinase in the renal collecting duct. Effects on epithelial na+ channels. J Biol Chem 1999; 274: 16973–8 57. Vinciguerra M, Hasler U, Mordasini D et al. Cytokines and sodium induce protein kinase A-dependent cell-surface Na,K-ATPase recruitment via dissociation of NF-kappaB/IkappaB/protein kinase A catalytic subunit complex in collecting duct principal cells. J Am Soc Nephrol 2005; 16: 2576–2585
Downloaded from http://ndt.oxfordjournals.org/ by guest on October 5, 2015
13. Kellum JA, Song M, Li J. Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells. Am J Physiol Regul Integr Comp Physiol 2004; 286: R686–R692 14. Kellum JA, Song M, Almasri E. Hyperchloremic acidosis increases circulating inflammatory molecules in experimental sepsis. Chest 2006; 130: 962–967 15. Bullivant EM, Wilcox CS, Welch WJ. Intrarenal vasoconstriction during hyperchloremia: role of thromboxane. Am J Physiol 1989; 256 (1 Pt 2): F152–F157 16. Quilley CP, Lin YS, McGiff JC. Chloride anion concentration as a determinant of renal vascular responsiveness to vasoconstrictor agents. Br J Pharmacol 1993; 108: 106–110 17. Wang W, Li C, Summer SN et al. Role of AQP1 in endotoxemia-induced acute kidney injury. Am J Physiol Renal Physiol 2008; 294: F1473–F1480 18. Olesen ET, de Seigneux S, Wang G et al. Rapid and segmental specific dysregulation of AQP2, S256-pAQP2 and renal sodium transporters in rats with LPS-induced endotoxaemia. Nephrol Dial Transplant 2009; 24: 2338–2349 19. Kwon TH, Frokiaer J, Han JS et al. Decreased abundance of major Na(+) transporters in kidneys of rats with ischemia-induced acute renal failure. Am J Physiol Renal Physiol 2000; 278: F925–F939 20. Van Why SK, Mann AS, Ardito T et al. Expression and molecular regulation of Na(+)-K(+)-ATPase after renal ischemia. Am J Physiol 1994; 267 (1 Pt 2): F75–F85 21. Wang Z, Rabb H, Haq M et al. A possible molecular basis of natriuresis during ischemic-reperfusion injury in the kidney. J Am Soc Nephrol 1998; 9: 605–613 22. Yun CH, Oh S, Zizak M et al. cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein. Proc Natl Acad Sci USA 1997; 94: 3010–3015 23. Lessa LM, Carraro-Lacroix LR, Crajoinas RO et al. Mechanisms underlying the inhibitory effects of uroguanylin on NHE3 transport activity in renal proximal tubule. Am J Physiol Renal Physiol 2012; 303: F1399–F1408 24. Hebert RL, Jacobson HR, Breyer MD. Prostaglandin E2 inhibits sodium transport in rabbit cortical collecting duct by increasing intracellular calcium. J Clin Invest 1991; 87: 1992–1998 25. Frindt G, Windhager EE. Ca2(+)-dependent inhibition of sodium transport in rabbit cortical collecting tubules. Am J Physiol 1990; 258 (3 Pt 2): F568–F582 26. Ling BN, Eaton DC. Effects of luminal Na+ on single Na+ channels in A6 cells, a regulatory role for protein kinase C. Am J Physiol 1989; 256 (6 Pt 2): F1094–F1103 27. Hebert RL, Jacobson HR, Breyer MD. PGE2 inhibits AVP-induced water flow in cortical collecting ducts by protein kinase C activation. Am J Physiol 1990; 259 (2 Pt 2): F318–F325 28. Hebert SC. Calcium and salinity sensing by the thick ascending limb: a journey from mammals to fish and back again. Kidney Int Suppl 2004; 66: S28–S33 29. Kamynina E, Debonneville C, Bens M et al. A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ channel. FASEB J 2001; 15: 204–214 30. Snyder PM, Steines JC, Olson DR. Relative contribution of Nedd4 and Nedd4-2 to ENaC regulation in epithelia determined by RNA interference. J Biol Chem 2004; 279: 5042–5046 31. Bhalla V, Oyster NM, Fitch AC et al. AMP-activated kinase inhibits the epithelial Na+ channel through functional regulation of the ubiquitin ligase Nedd4-2. J Biol Chem 2006; 281: 26159–26169 32. Arroyo JP, Lagnaz D, Ronzaud C et al. Nedd4-2 modulates renal Na+-Clcotransporter via the aldosterone-SGK1-Nedd4-2 pathway. J Am Soc Nephrol 2011; 22: 1707–1719 33. Ronzaud C, Loffing-Cueni D, Hausel P et al. Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension. J Clin Invest 2013; 123: 657–665 34. Pedersen NB, Hofmeister MV, Rosenbaek LL et al. Vasopressin induces phosphorylation of the thiazide-sensitive sodium chloride cotransporter in the distal convoluted tubule. Kidney Int 2010; 78: 160–169
E.D. Morrell et al.
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79. Good DW, George T, Watts BA, III. Lipopolysaccharide directly alters renal tubule transport through distinct TLR4-dependent pathways in basolateral and apical membranes. Am J Physiol Renal Physiol 2009; 297: F866–F874 80. Good DW, George T, Watts BA, III. Nerve growth factor inhibits Na+/H+ exchange and formula absorption through parallel phosphatidylinositol 3kinase-mTOR and ERK pathways in thick ascending limb. J Biol Chem 2008; 283: 26602–26611 81. Watts BA, 3rd, George T, Sherwood ER et al. Basolateral LPS inhibits NHE3 and HCOFormula absorption through TLR4/MyD88-dependent ERK activation in medullary thick ascending limb. Am J Physiol Cell Physiol 2011; 301: C1296–C1306 82. Watts BA, III, George T, Good DW. Aldosterone inhibits apical NHE3 and HCO3-absorption via a nongenomic ERK-dependent pathway in medullary thick ascending limb. Am J Physiol Renal Physiol 2006; 291: F1005–F1013 83. Good DW, George T, Watts BA, III. Toll-like receptor 2 mediates inhibition of HCO(3)(-) absorption by bacterial lipoprotein in medullary thick ascending limb. Am J Physiol Renal Physiol 2010; 299: F536–F544 84. Good DW, George T, Watts BA, III. Toll-like receptor 2 is required for LPS-induced Toll-like receptor 4 signaling and inhibition of ion transport in renal thick ascending limb. J Biol Chem 2012; 287: 20208–20220 85. Schmidt C, Hocherl K, Bucher M. Regulation of renal glucose transporters during severe inflammation. Am J Physiol Renal Physiol 2007; 292: F804–F811 86. McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. Crit Care Clin 2001; 17: 107–124 87. van den Berghe G, Wouters P, Weekers F et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345: 1359–1367 88. Runembert I, Couette S, Federici P et al. Recovery of Na-glucose cotransport activity after renal ischemia is impaired in mice lacking vimentin. Am J Physiol Renal Physiol 2004; 287: F960–F968 89. Schmidt C, Hocherl K, Bucher M. Cytokine-mediated regulation of urea transporters during experimental endotoxemia. Am J Physiol Renal Physiol 2007; 292: F1479–F1489 90. Li C, Wang W, Summer SN et al. Downregulation of UT-A1/UT-A3 is associated with urinary concentrating defect in glucocorticoid-excess state. J Am Soc Nephrol 2008; 19: 1975–1981 91. Nielsen S, Terris J, Smith CP et al. Cellular and subcellular localization of the vasopressin-regulated urea transporter in rat kidney. Proc Natl Acad Sci USA 1996; 93: 5495–5500 92. Knepper MA. Molecular physiology of urinary concentrating mechanism: regulation of aquaporin water channels by vasopressin. Am J Physiol 1997; 272 (1 Pt 2): F3–12 93. Grinevich V, Ma XM, Jirikowski G et al. Lipopolysaccharide endotoxin potentiates the effect of osmotic stimulation on vasopressin synthesis and secretion in the rat hypothalamus. J Neuroendocrinol 2003; 15: 141–149 94. Grinevich V, Ma XM, Verbalis J et al. Hypothalamic pituitary adrenal axis and hypothalamic-neurohypophyseal responsiveness in water-deprived rats. Exp Neurol 2001; 171: 329–341 95. Grinevich V, Knepper MA, Verbalis J et al. Acute endotoxemia in rats induces down-regulation of V2 vasopressin receptors and aquaporin-2 content in the kidney medulla. Kidney Int 2004; 65: 54–62 96. Chagnon F, Vaidya VS, Plante GE et al. Modulation of aquaporin-2/vasopressin2 receptor kidney expression and tubular injury after endotoxin (lipopolysaccharide) challenge. Crit Care Med 2008; 36: 3054–3061 97. Jonassen TE, Graebe M, Promeneur D et al. Lipopolysaccharide-induced acute renal failure in conscious rats: effects of specific phosphodiesterase type 3 and 4 inhibition. J Pharmacol Exp Ther 2002; 303: 364–374 98. Versteilen AM, Heemskerk AE, Groeneveld AB et al. Mechanisms of the urinary concentration defect and effect of desmopressin during endotoxemia in rats. Shock 2008; 29: 217–222 Received for publication: 22.10.2013; Accepted in revised form: 18.11.2013
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58. de Seigneux S, Leroy V, Ghzili H et al. NF-kappaB inhibits sodium transport via down-regulation of SGK1 in renal collecting duct principal cells. J Biol Chem 2008; 283: 25671–25681 59. Leroy V, De Seigneux S, Agassiz V et al. Aldosterone activates NF-kappaB in the collecting duct. J Am Soc Nephrol 2009; 20: 131–144 60. Cantaluppi V, Weber V, Lauritano C et al. Protective effect of resin adsorption on septic plasma-induced tubular injury. Crit Care 2010; 14: R4 61. Fisher CJ, Jr., Dhainaut JF, Opal SM et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA 1994; 271: 1836–1843 62. Fisher CJ, Jr., Slotman GJ, Opal SM et al. Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. Crit Care Med 1994; 22: 12–21 63. Opal SM, Fisher CJ, Jr., Dhainaut JF et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, doubleblind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med 1997; 25: 1115–1124 64. Cronin L, Cook DJ, Carlet J et al. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med 1995; 23: 1430–1439 65. Annane D. Corticosteroids for septic shock. Crit Care Med 2001; 29 (7 Suppl.): S117–S120 66. Shenker Y, Skatrud JB. Adrenal insufficiency in critically ill patients. Am J Respir Crit Care Med 2001; 163: 1520–1523 67. Tsao CM, Ho ST, Chen A et al. Low-dose dexamethasone ameliorates circulatory failure and renal dysfunction in conscious rats with endotoxemia. Shock 2004; 21: 484–491 68. Schwartz D, Mendonca M, Schwartz I et al. Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats. J Clin Invest 1997; 100: 439–448 69. Plato CF, Stoos BA, Wang D et al. Endogenous nitric oxide inhibits chloride transport in the thick ascending limb. Am J Physiol 1999; 276 (1 Pt 2): F159–F163 70. Majid DS, Williams A, Navar LG. Inhibition of nitric oxide synthesis attenuates pressure-induced natriuretic responses in anesthetized dogs. Am J Physiol 1993; 264 (1 Pt 2): F79–F87 71. Majid DS, Williams A, Kadowitz PJ et al. Renal responses to intra-arterial administration of nitric oxide donor in dogs. Hypertension 1993; 22: 535–541 72. Ortiz PA, Hong NJ, Garvin JL. NO decreases thick ascending limb chloride absorption by reducing Na(+)-K(+)-2Cl(-) cotransporter activity. Am J Physiol Renal Physiol 2001; 281: F819–F825 73. Stoos BA, Carretero OA, Garvin JL. Endothelial-derived nitric oxide inhibits sodium transport by affecting apical membrane channels in cultured collecting duct cells. J Am Soc Nephrol 1994; 4: 1855–1860 74. Noritomi DT, Soriano FG, Kellum JA et al. Metabolic acidosis in patients with severe sepsis and septic shock: a longitudinal quantitative study. Crit Care Med 2009; 37: 2733–2739 75. Mecher C, Rackow EC, Astiz ME et al. Unaccounted for anion in metabolic acidosis during severe sepsis in humans. Crit Care Med 1991; 19: 705–711 76. Zhao H, Wiederkehr MR, Fan L et al. Acute inhibition of Na/H exchanger NHE-3 by cAMP. Role of protein kinase a and NHE-3 phosphoserines 552 and 605. J Biol Chem 1999; 274: 3978–3987 77. Pao AC, Bhargava A, Di Sole F et al. Expression and role of serum and glucocorticoid-regulated kinase 2 in the regulation of Na+/H+ exchanger 3 in the mammalian kidney. Am J Physiol Renal Physiol 2010; 299: F1496–F1506 78. Girardi AC, Di Sole F. Deciphering the mechanisms of the Na+/H+ exchanger-3 regulation in organ dysfunction. Am J Physiol Cell Physiol 2012; 302: C1569–C1587
