HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: 294/4/F900    most recent 00357.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hoag, J. B. Articles by Simon, B. A. Search for Related Content PubMed PubMed Citation Articles by Hoag, J. B. Articles by Simon, B. A.

Effects of acid aspiration-induced acute lung injury on kidney function

Departments of ¹Medicine, Anesthesiology and ²Critical Care Medicine, ³Surgery and ⁴Pathology, The Johns Hopkins University, Baltimore, Maryland

Submitted 30 July 2007 ; accepted in final form 29 January 2008

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
Acute lung injury (ALI) in combination with acute kidney injury carries a mortality approaching 80% in the intensive care unit. Recently, attention has focused on the interaction of the lung and kidney in the setting of ALI and mechanical ventilation (MV). Small animal models of ALI and MV have demonstrated changes in inflammatory mediators, water channels, apoptosis, and function in the kidney early in the course of injury. The purpose of this investigation was to test the hypothesis that ALI and injurious MV cause early, measurable changes in kidney structure and function in a canine HCl aspiration model of ALI when hemodynamics and arterial blood gas tensions are carefully controlled. Intratracheal HCl induced profound ALI as demonstrated by increased shunt fraction and airway pressures compared with sham injury. Sham-injured animals had similar mean arterial pressure and arterial PCO₂ and HCO₃ levels compared with injured animals. Measurements of renal function including renal blood flow, urine flow, serum creatinine, glomerular filtration rate, urine albumin-to-creatinine ratio, and kidney histology scores were not different between groups. With maintenance of hemodynamic parameters and alveolar ventilation, ALI and injurious MV do not alter kidney structure and function early in the course of injury in this acid aspiration canine model. Kidney injury in large animal models may be more similar to humans and may differ from results seen in small animal models.

mechanical ventilation; biotrauma; renal function

Likewise, animal models of ALI and mechanical ventilation have been used in an effort to determine mechanisms of organ cross talk in response to injury. Most well-described are the influences of mechanical ventilation in the setting of ALI on hemodynamics, thus modifying renal blood flow. Positive end-expiratory pressure (PEEP) has a negative correlation with renal blood flow (12, 22). Blood gas tensions and acid base status can alter renal blood flow and thus impair renal function (2, 8, 25). The idea of "lung biotrauma" has been postulated as a mechanism of distant organ injury (16, 27). In this case, inflammatory mediators such as cytokines and chemokines that are released in response to lung injury spill into the systemic circulation and exert deleterious effects on distant organs (16, 27).

Small animal models of ALI demonstrated alterations in distant organ function in response to lung injury and mechanical ventilation. Large tidal volume ventilation, alone or in conjunction with acid aspiration, has been shown to alter aquaporins (AQP-2) and water channel [epithelial sodium channel (ENaC)] expression (13), local cytokine, including IL-1β, IL-6, VEGF (9, 23), and chemokine, including monocyte chemotactic protein 1 (MCP-1), IL-8, growth-related oncogene (GRO), concentrations (11), adhesion molecules production (ICAM-1) (23), inflammatory cell distribution, and apoptosis (11) in the kidneys in small animal models. These changes are manifested early, usually within 2 to 4 h of lung injury and mechanical ventilation. Although small animal models have strengths, a major problem has been that many mechanisms and interventions elucidated in rodents have not been borne out in humans. In these models, careful control of hemodynamics and intravascular volume, arterial blood gas tensions, as well as serial biochemical measurements in the same animal are generally not feasible. There may also be differences in organ function between large and small animals. We hypothesized that ALI and injurious mechanical ventilation (large V_T) would have minimal effect on the kidney if there were optimal control of hemodynamics and arterial blood gases. We tested our hypothesis in a well-established canine model of ALI with tight control of hemodynamics and maintenance of alveolar ventilation.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
Johns Hopkins University Institutional Animal Care and Use Committee approved all animal protocols, and they were consistent with National Institutes of Health Guide for the Care and Use of Laboratory Animals. All animals were housed in an animal facility with air-conditioning and light-dark cycle under pathogen-free condition and were provided free access to food and water during their housing.

Animal preparation. Eleven male beagles (weight average 17.0 ± 1.0 kg) were anesthetized with pentobarbital sodium (10 mg/kg bolus then 1–3 mg·kg^–1·h^–1 iv) and relaxed with pancuronium (0.1 mg·kg^–1·h^–1 iv). Animals were orally intubated and mechanically ventilated (Lifecare PLV-102) using volume control with high V_T (25 ml/kg) and PEEP (5 cmH₂O). Respiratory rate was set to achieve an end-tidal carbon dioxide pressure (PET_CO2) of 30–35 mmHg and subsequently adjusted to maintain arterial pH between 7.20 and 7.45. Initial FI_O2 of 0.40 was increased as required to maintain arterial oxygen saturation (Sa_O2) of more than 88% or Pa_O2 of more than 60 mmHg. Recruitment maneuvers (PEEP increase to 25 cmH₂O) for 30 s were performed hourly during the study protocol. Animals were instrumented with femoral artery and vein catheters, a thermistor-tipped pulmonary artery catheter, and a Foley catheter. Airway [peak (P_pk), plateau (P_pl)], mean arterial (MAP), pulmonary artery (PAP), and central venous (CVP) pressures, as well as Sa_O2, P_ETCO2, and urine output were monitored throughout. Serial measurements of arterial and mixed venous blood gases quantified gas exchange. Venous admixture (Qs/Qt) was calculated using standard equations (20). All previously mentioned parameters plus pulmonary artery occlusion pressure (PAOP) and cardiac output (CO) were recorded at baseline, 30 min after injury or sham, and then hourly throughout the study protocol. Subjects received an initial saline bolus (40 ml/kg) and maintenance saline (15 ml·kg^–1·h^–1) during the experimental protocol. Additional intravenous saline was administered as a bolus (10 ml/kg) as needed for hypotension (MAP <60 mmHg) or CO depression (>30% decrease). Animals were killed at the conclusion of the study with supplemental pentobarbital sodium followed by exsanguination.

Lung injury/intratracheal HCl administration. After instrumentation and baseline measurements, animals were randomized to lung injury (n = 6) or sham control (n = 5). Under fiberoptic bronchoscopic visualization, a custom-made small-diameter catheter was inserted into the airway to a level just above the carina. The catheter had tiny holes at the distal end designed to partially aerosolize the hydrochloric acid (HCl) solution (or saline in sham animals). Animals were placed in the left lateral decubitus position. HCl (0.5 N, 0.75 ml/kg) or saline was injected into the airway through the catheter. Animals remained in that position for 2 min, and then the procedure was repeated in the right lateral decubitus position. Animals were then returned to the supine position for the remaining 300 min of the study.

Measurement of glomerular filtration rate. After instrumentation, a bolus dose (16 mg/kg) of inulin (MW 5,000, Sigma, St. Louis, MO) was administered intravenously over 1 h followed by a continuous infusion (40 mg·kg^–1·h^–1) maintained throughout the experimental protocol. Glomerular filtration rate (GFR) was calculated by measuring the clearance of inulin [(urine inulin concentration x urine flow rate)/plasma inulin concentration] according to the method of Smith et al. (28).

Measurement of renal blood flow. Renal blood flow (RBF) was measured by calculation of para-aminohippurate (PAH; MW 804.87, Sigma) clearance by a previously described method (30). In another set of animals (n = 2), direct measurements of RBF were made by the placement of unilateral renal artery flow probes (Transonic Systems, model T106, Ithaca, NY) through a flank incision.

Measurement of serum and urine electrolytes. Serum and urine samples were assessed for creatinine, osmolality, and sodium concentration. Serum (SCr) and urine (UCr) levels were measured using a 557A creatinine kit (Sigma Diagnostics, St. Louis, MO) and analyzed on a Cobas Mira S Plus automated analyzer (Roche Diagnostics, Indianapolis, IN). Urine albumin was measured using standard ELISA techniques (Bethyl Laboratories, Montgomery, TX). To correct for the effect of urine volume on albumin concentration, urine albumin-to-creatinine ratios were calculated (4).

Cytokine measurements. Serial serum samples were collected throughout the protocol and analyzed for cytokines (IL-6, IL-10, TNF-, and INF-) using standardized ELISA assays (R&D Systems, Minneapolis, MN). Intravenous lipopolysaccharide (LPS; 20 µg/kg, n = 2) was administered to a separate group of animals, otherwise treated similar to the injury group, to serve as a positive control for serum cytokine assays. Also, serum cytokines were measured in animals (n = 2) that received surgical placement of renal flow probes (n = 2).

Caspase-3 activity assay. Caspase-3 activity was measured in kidney and lung tissue homogenates using a fluorescence-based assay (Apo-One, Promega) as previously described (21).

Renal histology. Kidney histology scores were calculated on hemotoxylin eosin (H&E)-stained sections of kidney tissue from each animal. Scoring was performed under light microscopy at x200 power and confirmed at x400 power by an independent renal pathologist who was blinded to the treatment group of each subject. Scoring was based on the presence of isometric vacuolization of proximal tubular epithelium, epithelial necrosis or cell sloughing, and the presence of leukocyte infiltration. Scores ranged from 0 to 4 based on the severity of the processes (0 = absent, 1 = <10% of cortex, 2 = 10–25% of cortex, 3 = 26–50% of cortex involved, 4 = >50% of cortex involved). Scoring was performed on sections from both left and right kidneys of all subjects. For electron microscopic (EM) examination, small (1 cubic mm) portions of harvested kidneys were fixed overnight in 3% glutaraldehyde in phosphate buffer, and then washed and further fixed in 1% osmium tetroxide and embedded in Epon resin. Ultrathin sections of the tissues were cut and stained with uranyl acetate and lead citrate and were examined in a Philips CM12 transmission electron microscope.

Statistical analysis. Hemodynamic, pulmonary, and renal function and cytokine measurements were compared at each time point using Student's t-test and Mann-Whitney Rank Sum for nonnormally distributed data. ANOVA was performed to compare trends through the protocol. Data are presented as means ± SE with statistical significance defined at P < 0.05.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
Gas exchange and pulmonary mechanics. Intratracheal HCl-induced ALI resulted in a significant decrease in the ratio of the partial pressure of arterial oxygen to fractional oxygen inspired (P/F ratio; 84 ± 8 vs. 403 ± 56, P < 0.005) and increase in shunt fraction (50 ± 6 vs. 11 ± 3%, P < 0.001) compared with sham injury animals (Fig. 1). Airway plateau pressures reflected the severity of injury (ALI 28 ± 2 vs. sham 13 ± 1 cmH₂O, P < 0.001).

View larger version (14K): [in this window] [in a new window]   Fig. 1. Pulmonary mechanics and gas exchange. Plateau pressure increased after injury. PaO2/FIO2 ratio decreased in the injury group over the course of the experiment. P < 0.05 vs. baseline. *P < 0.05 vs. sham.

View larger version (148K): [in this window] [in a new window]   Fig. 2. Evidence of alveolar injury in dependent lung areas instilled with hydrochloric acid. A: extensive recent hemorrhage in peribronchial and perivascular connective tissue (arrows). B: alveolar edema, incipient hemorrhage, and early neutrophil influx (arrows). C: marked neutrophilic infiltration in alveolar spaces (arrows). D: tissue from control animal showing normal nondependent lung with preserved airway, pulmonary vessels, and alveolar tissue. Hemotoxylin and eosin, A: x10 lens; B: x20 lens.

View larger version (20K): [in this window] [in a new window]   Fig. 3. Hemodynamic measurements. Although both groups had a decrease in cardiac output, measurements were statistically significant only in the injury group after 60 min. Mean arterial pressure was not different compared with baseline or between groups. Mean pulmonary artery pressure increased from baseline toward the end of the protocol in the injury group. Although pulmonary artery occlusion pressure trended up, it was not statistically different from baseline or sham measurements. P < 0.05 vs. baseline. *P < 0.05 vs. sham.

View larger version (19K): [in this window] [in a new window]   Fig. 4. Blood gas, fluid balance, and hemoglobin. Arterial PCO2 and pH were not different between groups throughout the experimental protocol. Hemoglobin increased in the injury group in the later times of the protocol, demonstrating the hemoconcentration seen in the injury animals. There was no difference in cumulative fluids administered over the experimental protocol. P < 0.05 vs. baseline. *P < 0.05 vs. sham.

View larger version (13K): [in this window] [in a new window]   Fig. 5. A: measurements of para-aminohippurate (PAH) in bronchoalveolar lavage samples from injury and sham animals. There was significant leakage of PAH into the alveolar spaces in injury animals, thus altering measurements of renal blood flow by PAH clearance (*P < 0.01). B: comparison of renal blood flow measurements using PAH and direct measurement with renal artery flow probes. Note the stability of measurements with renal flow probe in injured animals compared with PAH measurements in sham-treated animals throughout the experimental protocol. PAH measurements in injured animals were widely variable and tended to overestimate direct measurements.

Renal function. Measurements of renal function are shown in Fig. 6. Serum creatinine, urine sodium, and urine flow rate remained stable throughout the protocol and were not different between groups. Urine creatinine decreased from baseline in the sham group but was not different from the injury group. Urine osmolality in the sham group decreased significantly by 180 min and was significantly lower than the injury group. Urine albumin-to-creatinine ratio (Alb/Cr) increased significantly in the sham animals from baseline (0.5 ± 0.1) to 2.1 ± 0.9 at the end of the experiment (P < 0.008). Although a similar trend was observed in the injury group, it did not reach statistical significance. GFR remained stable throughout the protocol and was not different between groups. Moreover, loss of inulin into bronchoalveolar lavage (BAL) fluid as a potential confounder (as was seen with PAH) was not observed (data not shown).

View larger version (17K): [in this window] [in a new window]   Fig. 6. Renal outcome measurements. There was no difference in urine output, glomerular filtration rate (GFR), serum creatinine, or urine sodium between groups or over the course of the experiments. Urine osmolality decreased in the injury group in the later time points of the protocol, demonstrating preserved concentrating ability of the kidneys, and urine creatinine decreased in the control group in the setting of volume loading. Urine albumin-to-creatinine ratio increased over the experimental protocol but reached significance only in the sham group. P < 0.05 vs. baseline. *P < 0.05 vs. sham.

View larger version (124K): [in this window] [in a new window]   Fig. 7. Electron microscopy of kidney. Electron micrographs of kidneys from dogs receiving saline (A) or HCl aspiration (B) and then undergoing 5-h mechanical ventilation. The podocyte foot processes remained intact in the control kidney (thin arrows) but became partially effaced (thick arrows) in the kidney of the dog subjected to acid aspiration. A total of 2–3 glomeruli from each animal were examined and findings were similar in all glomeruli from the same animal. Uranyl acetate and lead citrate stain; original magnification of both electron micrographs x3,800.

View larger version (48K): [in this window] [in a new window]   Fig. 8. Serum cytokines in pg/ml measured at baseline and throughout the experiments. LPS induced significant increases compared with surgery and profound increases compared with both sham and injury groups in those measured.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
We established a canine model of severe ALI caused by acid aspiration and high tidal volume ventilation that leads to profound elevations in airway peak and plateau pressures and perturbation of gas exchange. Our degree of lung injury was more severe than described in the small animal models (9, 11, 13, 23). Hemodynamics and oxygenation were optimally controlled. Under these conditions, over a 5-h observation period, no alterations in inulin clearance, RBF, urine flow or electrolytes, or kidney histology were observed. However, both ALI and sham animals had increases in urine albumin excretion. Systemic cytokines did not increase in the face of profound lung injury.

Despite the severity of lung injury, alveolar ventilation and hemodynamic parameters were maintained within an acceptable range with aggressive management. Preservation of renal function is intimately tied to renal perfusion, thus maintenance of RBF is paramount. RBF is determined by complex interactions of driving pressure, autonomic nervous system tone, hormonal activation and inhibition. Although not entirely understood in the canine, autoregulatory RBF mechanisms are thought to function over a range of MAP between 70 and 170 mmHg (10, 14, 29). In our experiments, MAP remained stable and well within this range, compatible with preserved RBF. In one small animal study in which blood pressure was monitored continuously, MAP was maintained at 55–60 mmHg, a level much closer to the lower limit of intrinsic renal autoregulation (11), which may account for some of the alterations seen in renal function in that rabbit model of acid aspiration- and mechanical ventilation-associated lung injury.

Arterial PCO₂ and pH have similarly been demonstrated to influence RBF through autonomic activation or direct vasoactive interactions (2, 8, 25). In our experiments, these influences remained stable and not different between groups. CO fell slightly in injury group compared with sham but was equal by the end of the 5 h. Heart rate was not different between groups and not different over the course of the experiments. Thus, the alterations in CO were likely related to stroke volume. Since filling pressures remained constant throughout (or trended upward), this reduced stroke volume suggests reduced contractility. Previous studies showed that IT-HCl induces cardiac depression (26), but the mechanisms are not entirely understood. We could postulate a direct influence of acid treatment on autonomic function, although we failed to observe a significant systemic acidosis. Another possible cause of the change in stroke volume could be related to alterations in end diastolic volume from stiffening of the myocardium related to edema formation. We did not assess the myocardium of the injured animals histologically, but if there is leak of fluid in other tissues, it is possible that the myocardium suffered a similar reaction with an accumulation of intercellular fluid and reduced compliance. There may also have been a direct cardio-depressant effect of the medications used for anesthesia on CO (5, 6), although the drugs and doses used were the same between groups. Finally, increased airway pressures from maintaining tidal volume to the injured lung would increase intrathoracic pressure, reducing effective preload and increasing afterload, although the transmission of increased alveolar pressure to the intrathoracic space is somewhat mitigated by the increased lung stiffness. Nevertheless, the fall in CO had no apparent effect on MAP and RBF.

Animals received fluid replacement by protocol with predefined criteria for supplementation for hypotension and drops in CO, and fluid loading was withheld if cardiac filling pressures remained stable. In these experiments, no animal required fluid loading for hypotension. Animals did receive fluid boluses for drops in CO of greater than 30% from baseline; however, the magnitude of the fluid loading was similar between groups. As filling pressures remained within our predefined acceptable range, a strategy of continuing to fluid load the animals was not followed, and CO was allowed to decline. Moreover, with the severity of pulmonary edema in the injury group, persistent volume loading would likely have led to an increase in fluid extravasation into the lungs, thus worsening oxygenation, shunt fraction, and plateau pressures in the injured lungs. This compromise strategy led to a relative hypovolemia in the injured animals, evidenced by the progressive rise in hemoglobin, which did not compromise MAP or renal perfusion. If anything, one would expect this hypovolemia to have increased the risk of renal dysfunction.

RBF measurements through the clearance of PAH showed widely variable changes throughout the protocol. We suspected the cause of this variability arose from the assumption that all of the PAH in the animal is cleared through the kidney without extrarenal losses. To test this, we measured the concentration of PAH from BAL samples and found that there was significant loss of PAH into the protein-rich alveolar edema fluid induced by the lung injury. We therefore concluded that PAH clearance is not an accurate reflection of actual RBF in this lung injury model. We directly measured RBF with surgically placed renal artery flow probes in a subset of animals. These measurements showed stable RBF throughout the protocol. As MAP was maintained in the autoregulatory range of the kidney, RBF should also remain stable unless there is a direct effect of the ALI or mechanical ventilation on these autoregulatory mechanisms.

Given that pilot studies failed to show changes in serum creatinine, a late and insensitive marker of AKI, we set up inulin clearance measurements, the gold standard for GFR. Importantly, measurement of GFR by inulin clearance should be unaffected by extrarenal losses (although no increase in BAL inulin was found). GFR was unchanged throughout the experiments in both groups. In addition, urine creatinine did not change, although urine osmolality increased in the injury group with comparable urine volumes, representing the preserved ability of the kidney to concentrate urine to maintain intravascular volume with volume loss into lungs. There was no evidence of histological injury to the kidneys by H&E staining. Finally, since kidney apoptosis has been demonstrated in a lung injury model in rabbits (11), we assessed the degree of apoptosis by caspase-3 assays, which were not different in injured and sham animals in lung and kidney tissue lysates.

There was a significant increase in urine albumin-to-creatinine ratio in control animals, and a trend for increase in the lung injury group. This finding suggests that there is a direct effect of either mechanical ventilation or anesthesia on permeability in the kidney. As protein-rich fluid accumulates in the alveolar space in response to ALI from acid aspiration, losses of albumin into the edema fluid in the lung may have reduced the concentration gradient for loss in the kidney. Previously, microalbuminuria has been proposed as a marker of a renal microvascular leak phenomenon in the setting of mechanical ventilation/lung injury (3, 7) possibly related to inflammation and neutrophil infiltration. Moreover, an association between hypoxemia and microalbuminuria in the setting of chronic obstructive lung disease has been defined (15), suggesting that an interaction between inflammation and hypoxemia may be playing a role in this microvascular phenomenon.

To examine possible ultrastructural changes associated with the increased urine albumin/creatinine ratio, we performed EM examination of two canine kidneys at the end of mechanical ventilation. We found that, unlike the case with the control (sham-treated) animal, the kidney from the canine with acid aspiration lung injury showed partial effacement of the glomerular podocyte foot processes (Fig. 7). This partial effacement could reflect podocyte injury responsible for the albuminuria developed in acid-aspirated canines, although the sham-treated animals did not demonstrate foot process effacement and had a similar or even greater degree of albuminuria as the injured animals. Diffuse effacement of glomerular podocyte foot processes is seen in patients with minimal change disease and many other diseases with significant albuminuria, although these changes are not specific for any particular pathophysiological mechanism. We also found very segmental mesangial electron-dense deposits in the control kidney, the significance of which is unclear.

We expected to find an increase in systemic cytokines with IT-HCl and large tidal volume mechanical ventilation. We found no differences in cytokine levels. We were initially concerned about the sensitivity of these canine assays; therefore, in a limited number of animals, we administered intravenous LPS and observed a marked increase, thus validating the assay. Similarly, we found a transient increase in circulating IL-6, IL-10, and TNF- in the two animals surgically instrumented with flow probes, further increasing our confidence in the assays. As an aside, this surgery-induced inflammation reinforces the need for appropriate sham surgery and nonsurgical controls in studies in which inflammatory responses may be important and suggests caution in interpreting these markers in models in which surgical stress is encountered. At the time of these studies, canine-specific assays were limited to the use of only these four cytokines. More recently, a broader number of cytokine proteins can be measured in canines. Of note, we attempted to measure neutrophil gelatinase-associated lipocalin, a putative specific marker of kidney injury (18, 19), but there was inadequate cross reactivity of the canine protein to existing human and rodent probes.

These results demonstrate that in an optimally controlled hemodynamic and renal perfusion model of canine acid aspiration-induced ALI, there is no significant short-term alteration in renal structure or function. However, there are a number of limitations to our study. One is related to the small number of animals in each of the study groups, given the significant cost of canine work. It is possible that small changes in renal function may be found with larger sample sizes. Also, this study was designed to determine the effects of ALI and mechanical ventilation early in the course of injury. In small animal models, changes can be seen early (<2 h in some cases) after induction of lung injury. It is possible that when followed longer, evidence of kidney dysfunction could be observed in this model. We did not perform mRNA studies or inflammatory markers in kidney, as performed in previous small animal studies.

In conclusion, although significant clinical and small animal data suggest a kidney-lung interaction in the setting of ALI and mechanical ventilation, we were not able to demonstrate in this canine aspiration model early in the course of injury when hemodynamic and alveolar ventilation influences were controlled. It is possible that transient hypotension that is readily apparent in patients as they develop ALI and are sedated and intubated for mechanical ventilatory assistance, or unmeasured hemodynamic influences in the small animal models, may propagate a lung-kidney interaction in this setting. As patients with ALI/ARDS continue to die from multisystem organ failure, finding mechanisms linking distant organs function and dysfunction is of paramount importance.

	GRANTS

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
This work was supported by National Heart, Lung, and Blood Institute Acute Lung Injury SCCOR Program HL-073994.

Present address of J. B. Hoag: Division of Pulmonary and Critical Care, Drexel University College of Medicine, 245 N. 15th Street, Mail Stop 107, Philadelphia, PA 19102 (e-mail: JHoag@DrexelMed.edu).

	ACKNOWLEDGMENTS

 
We thank T. Burman for expert animal handling and assistance with the animal procedures. We also thank Dr. M. Lie for assistance with the caspase-3 assays. We are similarly grateful to Dr. P. Devarajan and his team for NGAL analysis of the samples.

	FOOTNOTES

 

Address for reprint requests and other correspondence: B. A. Simon, Dept. of Anesthesiology and Critical Care Medicine, The Johns Hopkins Univ., 600 North Wolfe St., Tower 711, Baltimore, MD 21287-8711 (e-mail: bsimon{at}jhmi.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 

1. Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342: 1301–1308, 2000.[Abstract/Free Full Text]
2. Anand IS, Chandrashekhar Y, Ferrari R, Sarma R, Guleira R, Jindal SK, Wahi PL, Poole-Wilson PA, Harris P. Pathogenesis of congestive state in chronic obstructive pulmonary disease. Studies of body water and sodium, renal function, hemodynamics, and plasma hormones during edema and after recovery. Circulation 86: 12–21, 1992.[Abstract/Free Full Text]
3. Brudney CS, Gosling P, Manji M. Pulmonary and renal function following cardiopulmonary bypass is associated with systemic capillary leak. J Cardiothorac Vasc Anesth 19: 188–192, 2005.[CrossRef][Web of Science][Medline]
4. Dezier JF, Le Reun M, Poirier JY. Usefulness of the urinary albumin/creatinine ratio in screening for microalbuminuria. Presse Med 18: 897–900, 1988.
5. Gibbs JM, Tait AR, Sykes MK. The cardiovascular effects of pancuronium in the dog during pentobarbitone anaesthesia. Anaesth Intensive Care 4: 135–137, 1976.[Medline]
6. Gilmore JP. Pentobarbital sodium anesthesia in the dog. Am J Physiol 209: 404–408, 1965.[Abstract/Free Full Text]
7. Gosling P, Czyz J, Nightingale P, Manji M. Microalbuminuria in the intensive care unit: clinical correlates and association with outcomes in 431 patients. Crit Care Med 34: 2158–2166, 2006.[CrossRef][Web of Science][Medline]
8. Guignard JP, Torrado A, Mazouni SM, Gautier E. Renal function in respiratory distress syndrome. J Pediatr 88: 845–850, 1976.[CrossRef][Web of Science][Medline]
9. Gurkan OU, O'Donnell C, Brower R, Ruckdeschel E, Becker PM. Differential effects of mechanical ventilatory strategy on lung injury and systemic organ inflammation in mice. Am J Physiol Lung Cell Mol Physiol 285: L710–L718, 2003.[Abstract/Free Full Text]
10. Hall SV, Johnson EE, Hedley-Whyte J. Renal hemodynamics and function with continuous positive-pressure ventilation in dogs. Anesthesiology 41: 452–461, 1974.[CrossRef][Web of Science][Medline]
11. Imai Y, Parodo J, Kajikawa O, de Perrot M, Fischer S, Edwards V, Cutz E, Liu M, Keshavjee S, Martin TR, Marshall JC, Ranieri VM, Slutsky AS. Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA 289: 2104–2112, 2003.[Abstract/Free Full Text]
12. Kaukinen S, Eerola R. Positive end expiratory pressure ventilation, renal function and renin. Ann Clin Res 11: 58–62, 1979.[Web of Science][Medline]
13. King L, Dodd-o OJ, Becker P, Haas M, Chien CC, Burne-Taney MJ, Rabb H. Mechanical ventilation in mice leads to renal inflammation and dysregulation of transporters. J Am Soc Nephrol 14: 564A, 2003.
14. Kinter WB, Pappenheimer JR. Role of red blood corpuscles in regulation of renal blood flow and glomerular filtration rate. Am J Physiol 185: 399–406, 1956.[Abstract/Free Full Text]
15. Komurcuoglu A, Kalenci S, Kalenci D, Komurcuoglu B, Tibet G. Microalbuminuria in chronic obstructive pulmonary disease. Monaldi Arch Chest Dis 59: 269–272, 2003.[Medline]
16. Kuiper JW, Groeneveld ABJ, Slutsky AS, Plotz FB. Mechanical ventilation and acute renal failure. Crit Care Med 33: 1408–1415, 2005.[CrossRef][Web of Science][Medline]
17. Mehta RL, Pascual MT, Gruta CG, Zhuang S, Chertow GM. Redefining predictive models in critically ill patients with acute renal failure. J Am Soc Nephrol 13: 1350–1357, 2002.[Abstract/Free Full Text]
18. Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch J, Devarajan P. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 14: 2534–2543, 2003.[Abstract/Free Full Text]
19. Mishra J, Dent C, Tarabishi R, Mitsnefes M, Ma Q, Kelly C, Ruff SM, Zahedi K, Shao M, Bean J, Barasch J, Devarajan P. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 365: 1231–1238, 2005.[CrossRef][Web of Science][Medline]
20. Nunn J. Nunn's Applied Respiratory Physiology. Boston, MA: Butterworth-Heinemann, 1987, p. 165–168.
21. Petrache I, Natarajan V, Zhen L, Medler TR, Richter AT, Cho C, Hubbard WC, Berdyshev EV, Tuder RM. Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice. Nat Med 11: 491–498, 2005.[CrossRef][Web of Science][Medline]
22. Priebe HJ, Heimann JC, Hedley-Whyte J. Mechanisms of renal dysfunction during positive end-expiratory pressure ventilation. J Appl Physiol 50: 643–649, 1981.[Abstract/Free Full Text]
23. Rabb H, Wang Z, Nemoto T, Hotchkiss J, Yokota N, Soleimani M. Acute renal failure leads to dysfunction of lung salt and water channels. Kidney Int 63: 600–606, 2003.[CrossRef][Web of Science][Medline]
24. Ranieri VM, Giunta F, Suter PM, Slutsky AS. Mechanical ventilation as a mediator of multisystem organ failure in acute respiratory distress syndrome. JAMA 284: 43–44, 2000.[Free Full Text]
25. Rose CE, Kimmel DP, Godine RL, Kaiser DL, Carey RM. Synergistic effects of acute hypoxemia and hypercapnic acidosis in conscious dogs. Renal dysfunction and activation of the renin-angiotensin system. Circ Res 53: 202–213, 1983.[Abstract/Free Full Text]
26. Schertel ER, Pratt JW, Schaefer SL, Valentine AK, McCreary MR, Myerowitz PD. Effect of acid-aspiration-induced lung injury on left ventricular function. Surgery 119: 81–88, 1996.[CrossRef][Web of Science][Medline]
27. Slutsky AS, Tremblay LN. Multiple system organ failure. Is mechanical ventilation a contributing factor? Am J Respir Crit Care Med 157: 1721–1725, 1998.[Free Full Text]
28. Smith HW, Goldring W, Chasis H. The measurement of the tubular excretory mass, effective blood flow and filtration in the human kidney. J Clin Invest 17: 263–278, 1938.[CrossRef][Web of Science][Medline]
29. Thompson DD, Kavaler F, Lozano R, Pitts RF. Evaluation of cell separation hypothesis of autoregulation of renal blood flow and filtration. Blood flow, filtration rate and PAH extraction as functions of arterial pressure in normal and anemic dogs. Am J Physiol 191: 493–500, 1957.[Abstract/Free Full Text]
30. Udassin R, Haskel Y, Seror D, Welbourne TC. Plasma-to-lumen clearance of para-aminohippurate can replace ⁵¹Cr EDTA clearance in the evaluation of intestinal mucosal injury. Pediatr Surg Int 13: 112–114, 1998.[CrossRef][Web of Science][Medline]

This Article Abstract Full Text (PDF) All Versions of this Article: 294/4/F900    most recent 00357.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hoag, J. B. Articles by Simon, B. A. Search for Related Content PubMed PubMed Citation Articles by Hoag, J. B. Articles by Simon, B. A.