Renal histopathology during experimental septic acute kidney injury and recovery.

OBJECTIVES: Our understanding of septic acute kidney injury is limited. We therefore assessed renal histopathological changes induced by septic acute kidney injury and their evolution during recovery. DESIGN: Prospective experimental study. SETTING: Physiology Research Institute. SUBJECTS: Twenty-two Merino sheep. INTERVENTION: We induced septic acute kidney injury by continuous i.v. infusion of Escherichia coli. We studied histology, immunohistochemistry, markers of apoptosis, and expression of nitric oxide synthase isoforms and hypoxia-inducible factor-1α. Analysis was performed on kidneys from normal sheep, sheep with septic acute kidney injury, and sheep after recovery from septic acute kidney injury. MEASUREMENTS AND MAIN RESULTS: In normal, septic, and recovery sheep, respectively, serum creatinine was (median) 82 (interquartile range, 70-85), 289 (171-477), and 70 (51-91) µmol/L and renal blood flow was 270 ± 42, 653 ± 210, and 250 ± 49 mL/min. There were no histological differences between baseline, acute kidney injury, and recovery sheep. There was no evidence of macrophage or myofibroblast infiltration, no evidence of caspase-3 cleavage to suggest activation of apoptotic pathways, and no increase in neutrophil gelatinase-associated lipocalin to suggest tubular injury. Similarly, quantification of apoptosis revealed no differences between the normal and septic groups (normal: median, 3; interquartile range, 0-5 cells per visual field and septic acute kidney injury: median, 3.5; interquartile range, 0-8 cells per visual field; p = 0.618), but in the recovery group, there was increased apoptosis (median, 14; interquartile range, 4-34 cells per visual field; p = 0.002). Expression of all nitric oxide synthase subtypes increased significantly in the renal cortex during septic acute kidney injury but tended to decrease in the medulla. Medullary hypoxia-inducible factor gene expression decreased from 1.00 (95% CI, 0.74-1.36) to 0.26 (95% CI, 0.09-0.76) in recovery (p = 0.0106). Both inducible nitric oxide synthase and neuronal nitric oxide synthase expressions correlated with renal blood flow. CONCLUSION: The lack of any tubular injury or increased apoptosis, the increased expression of all cortical nitric oxide synthase isoforms, and the link between inducible nitric oxide synthase and neuronal nitric oxide synthase with renal blood flow suggest in this experimental model that severe sepsis acute kidney injury can develop in the absence of histological or immunohistological changes and may be functional in nature.

Novel targets for sepsis-induced kidney injury: the glomerular arterioles and the sympathetic nervous system.

Sepsis and septic shock are the most common causes of acute kidney injury (AKI) in the intensive care unit, and mortality remains high despite improvements in our ability to support vital organs. The lack of development of effective treatments is partly because there has been little advance in our understanding of the pathophysiology of septic AKI, owing to the difficulty in conducting experiments on critically ill patients and use of inappropriate experimental models. Recently, however, a number of new concepts have emerged that challenge existing dogma and give insights into the causes of AKI. Traditionally, renal ischaemia has been proposed as the main cause of AKI, but it is becoming apparent that in sepsis with a hyperdynamic circulation, the most common situation in septic patients, there is an increase or at least no decrease in renal blood flow. In this review, the possible role of changes in pre- and postglomerular resistance in setting the increased level of renal blood flow in the presence of a decreased glomerular filtration rate is discussed. New evidence also indicates that the increased sympathetic nerve activity that occurs in sepsis may contribute to the induction of organ failure. Experimental studies indicate that inhibition of central sympathetic outflow with α(2)-adrenoceptor agonists or treatment with ß(1)-adrenoceptor antagonists might reduce mortality in experimental endotoxaemia and sepsis. The possibility that these beneficial actions are partly dependent on a reduction in the excessive cytokine release caused by marked and prolonged sympathetic activation is discussed.

Septic acute kidney injury: the glomerular arterioles.

Acute kidney injury (AKI) is a serious condition that affects many intensive care unit (ICU) patients. The most common causes of AKI in the ICU are severe sepsis and septic shock. The mortality of AKI in septic critically ill patients remains high despite our increasing ability to support vital organs. This is partly due to our poor understanding of the pathogenesis of sepsis-induced renal dysfunction. However, new concepts are emerging to explain the pathogenesis of septic AKI, which challenge previously held dogma. Throughout the past half century, septic AKI has essentially been considered secondary to tubular injury, which, in turn, has been considered secondary to renal ischemia. This belief is curious because the hallmark of septic AKI and AKI in general is the loss of glomerular filtration rate (GFR). It would seem logical, therefore, to focus on the glomerulus in trying to understand why such loss of GFR occurs. Recent experimental observations suggest that, at least in the initial phases of septic AKI, profound changes occur which involve glomerular hemodynamics and lead to loss of GFR. These observations imply that changes in the vasoconstrictor tone of both the afferent and efferent arterioles are an important component of the pathogenesis of septic AKI.

Pathophysiology of septic acute kidney injury: a different view of tubular injury.

Septic acute kidney injury (AKI) is the most common form of AKI seen in critically ill patients in developed countries. Its pathogenesis has been traditionally attributed to ischemia secondary to decreased cardiac output and hypotension, which trigger sustained renal vasoconstriction and in turn exacerbate and sustain the ischemia. This paradigm is supported by the fact that many patients who develop AKI do so in the setting of hemodynamic instability and also by evidence that renal blood flow is decreased and renal vascular resistance increased when they are measured in patients with AKI. However, recent evidence shows that renal blood flow may vary from increased in some animal models to normal in some patients and to decreased in other patients. Furthermore, the induction of prolonged severe subtotal ischemia by acute occlusion of the renal artery does not seem to trigger subsequent renal vasoconstriction and, finally, experimental studies suggest that immune-mediated injury may be a more likely cause of tubular cell dysfunction than ischemia. These lines of evidence suggest that the pathogenesis of AKI is complex, does not simply involve ischemia, and may differ according to the etiological trigger.

Early and sustained systemic and renal hemodynamic effects of intravenous radiocontrast.

BACKGROUND AND AIMS: To measure the extended renal hemodynamic changes induced by intravenous radiocontrast. METHODS: Cross-ewes were studied in a randomized cross-over study. Intravenous saline or radiocontrast were administered, and continuous measurement of cardiac output and renal blood flow (RBF) was performed with flow probes. RESULTS: Radiocontrast induced early but transient increases in cardiac output with vasodilatation, followed by return to baseline values within 2 h. There was an initial decline in RBF (-5.2 +/- 4.5 vs. 2.1 +/- 5.3%; p < 0.0001) and decreased renal vascular conductance (-4.0 +/- 7.2 vs. 3.3 +/- 7.1%, p < 0.0001; vasoconstriction). This renal vasoconstriction resolved within 2 h and was followed by sustained (72 h) renal vasodilatation with higher RBF (270 +/- 13 vs. 236 +/- 11 ml/min; p < 0.0001). CONCLUSIONS: Radiocontrast induces short renal vasoconstriction followed by sustained vasodilatation and increased RBF. Short-term studies are not representative of the overall sustained renal hemodynamic effects of radiocontrast.

Angiotensin II in experimental hyperdynamic sepsis.

INTRODUCTION: Angiotensin II (Ang II) is a potential vasopressor treatment for hypotensive hyperdynamic sepsis. However, unlike other vasopressors, its systemic, regional blood flow and renal functional effects in hypotensive hyperdynamic sepsis have not been investigated. METHODS: We performed an experimental randomised placebo-controlled animal study. We induced hyperdynamic sepsis by the intravenous administration of live E. coli in conscious ewes after chronic instrumentation with flow probes around the aorta and the renal, mesenteric, coronary and iliac arteries. We allocated animals to either placebo or angiotensin II infusion titrated to maintain baseline blood pressure. RESULTS: Hyperdynamic sepsis was associated with increased renal blood flow (from 292 +/- 61 to 397 +/- 74 ml/min), oliguria and a decrease in creatinine clearance (from 88.7 +/- 19.6 to 47.7 +/- 21.0 ml/min, P < 0.0001). Compared to placebo, Ang II infusion restored arterial pressure but reduced renal blood flow (from 359 +/- 81 ml/min to 279 +/- 86 ml/min; P < 0.0001). However, despite the reduction in renal blood flow, Ang II increased urine output approximately 7-fold (364 +/- 272 ml/h vs. 48 +/- 18 ml/h; P < 0.0001), and creatinine clearance by 70% (to 80.6 +/- 20.7 ml/min vs.46.0 +/- 26 ml/min; P < 0.0001). There were no major effects of Ang II on other regional blood flows. CONCLUSIONS: In early experimental hypotensive hyperdynamic sepsis, intravenous angiotensin II infusion decreased renal blood while inducing a marked increase in urine output and normalizing creatinine clearance.

Epidemiology of septic acute kidney injury.

The incidence of sepsis and acute kidney injury (AKI) are increasing in critically ill patients and both portend a higher risk of morbidity and death. Sepsis has consistently been shown to be a key contributing factor for the development of AKI. Numerous observational studies have found septic AKI to be highly common among the critically ill. Septic AKI patients are characterized by important differences in baseline demographics, acuity of illness and treatment intensity when compared with non-septic AKI. In particular, these patients are often older, have a higher prevalence of co-morbid illnesses, and are admitted for medical or emergency surgical indications. These patients show greater aberrancy in vital signs, laboratory parameters and need for vasoactive therapy and/or mechanical ventilation. Delays in initiation of appropriate antimicrobial therapy independently predict development of AKI in septic patients. Both delays to appropriate antimicrobials and initiation of renal support are also associated with higher mortality. Survival to ICU and/or hospital discharge for septic AKI patients is significantly lower when compared to patients with either non-septic AKI or sepsis alone. However, survivors of septic AKI show trends for greater rates of renal recovery and dialysis independence compared with non-septic AKI. The burden of septic AKI continues to increase and remains associated with an unacceptably high attributable morbidity and mortality. Accordingly, there is continued need to understand its epidemiology, not only to guide in management of these patients at the bedside, but also to stimulate advances in understanding its pathophysiology and in therapeutic interventions to potentially mitigate prognosis.

Septic acute kidney injury: new concepts.

Acute kidney injury (AKI) is a serious condition that affects many ICU patients. The most common causes of AKI in ICU are severe sepsis and septic shock. The mortality of AKI in septic critically ill patients remains high despite of our increasing ability to support vital organs. This is partly due to our poor understanding of the pathogenesis of sepsis-induced renal dysfunction. However, new concepts are emerging to explain the pathogenesis of septic AKI, which challenge previously held dogma. Throughout the past half century, septic AKI has essentially been considered secondary to kidney ischemia. However, recent models of experimental sepsis have challenged this notion by demonstrating that, in experimental states, which simulate the hemodynamic picture most typically seen in man (e.g. hyperdynamic sepsis) renal blood flow, actually increases as renal vascular resistance decreases. These experimental observations provide proof of concept that septic AKI can occur in the setting of renal hyperemia and that ischemia is not necessary for loss of glomerular filtration rate (GFR) to occur. They also suggest that similar hemodynamic event may occur in man. In addition, preliminary studies in septic sheep show that, when ATP is measured using an implanted phosphorus coil and magnetic resonance technology, renal bioenergetics are preserved in the setting of advanced septic shock. While these findings need to be confirmed, they challenge established paradigms and offer a new conceptual framework of reference for further investigation and intervention in man.

Pathophysiology of septic acute kidney injury: what do we really know?

Septic acute kidney injury accounts for close to 50% of all cases of acute kidney injury in the intensive care unit and, in its various forms, affects between 15% and 20% of intensive care unit patients. However, there is little we really know about its pathophysiology. Although hemodynamic factors might play a role in the loss of glomerular filtration rate, they may not act through the induction of renal ischemia. Septic acute renal failure may, at least in patients with a hyperdynamic circulation, represent a unique form of acute renal failure: hyperemic acute renal failure. Measurements of renal blood flow in septic humans are now needed to resolve this pivotal pathophysiological question. Whatever may happen to renal blood flow during septic acute kidney injury in humans, the evidence available suggests that urinalysis fails to provide useful diagnostic or prognostic information in this setting. In addition, nonhemodynamic mechanisms of cell injury are likely to be at work. These mechanisms are likely due to a combination of immunologic, toxic, and inflammatory factors that may affect the microvasculature and the tubular cells. Among these mechanisms, apoptosis may turn out to be important. It is possible that, as evidence accumulates, the paradigms currently used to explain acute renal failure in sepsis will shift from ischemia and vasoconstriction to hyperemia and vasodilation and from acute tubular necrosis to acute tubular apoptosis or simply tubular cell dysfunction or exfoliation. If this were to happen, our therapeutic approaches would also be profoundly altered.

The histopathology of septic acute kidney injury: a systematic review.

INTRODUCTION: Sepsis is the most common trigger of acute kidney injury (AKI) in critically ill patients; understanding the structural changes associated with its occurrence is therefore important. Accordingly, we systematically reviewed the literature to assess current knowledge on the histopathology of septic AKI. METHODS: A systematic review of the MEDLINE, EMBASE and CINHAL databases and bibliographies of the retrieved articles was performed for all studies describing kidney histopathology in septic AKI. RESULTS: We found six studies reporting the histopathology of septic AKI for a total of only 184 patients. Among these patients, only 26 (22%) had features suggestive of acute tubular necrosis (ATN). We found four primate studies. In these, seven out of 19 (37%) cases showed features of ATN. We also found 13 rodent studies of septic AKI. In total, 23% showed evidence of ATN. In two additional studies performed in a dog model and a sheep model there was no evidence of ATN on histopathologic examination. Overall, when ATN was absent, studies reported a wide variety of kidney morphologic changes in septic AKI - ranging from normal (in most cases) to marked cortical tubular necrosis. CONCLUSION: There are no consistent renal histopathological changes in human or experimental septic AKI. The majority of studies reported normal histology or only mild, nonspecific changes. ATN was relatively uncommon.

Renal blood flow and function during recovery from experimental septic acute kidney injury.

OBJECTIVE: To measure renal blood flow (RBF) and renal function during recovery from experimental septic acute kidney injury (AKI). DESIGN: Controlled experimental study. SUBJECTS: Nine merino ewes. SETTING: University physiology laboratory. INTERVENTION: We recorded systemic and renal hemodynamics during a 96-h observation period (control) via implanted transit-time flow probes. We then compared this period with 96[Symbol: see text]h of septic AKI (48 h of Escherichia coli infusion) and subsequent recovery (48 h of observation after stopping E. coli). MEASUREMENTS AND RESULTS: Compared with the control period, E. coli infusion induced hyperdynamic sepsis (increased cardiac output and decreased blood pressure) and septic AKI (serum creatinine 65.4 +/- 8.7 vs. 139.9 +/- 33.0 micromol/l; creatinine clearance 73.8 +/- 12.2 vs. 40.2 +/- 17.2 ml/min; p < 0.05) with a mortality of 22%. RBF increased (278.8 +/- 33.9 vs. 547.9 +/- 124.8 ml/min; p < 0.05) as did renal vascular conductance (RVC). During recovery, we observed a decrease in RVC and RBF with all values returning to control levels. Indices of tubular function [fractional excretion of sodium (FENa) and urea (FEUn) and urinary sodium concentration (UNa)], which had been affected by sepsis, returned to control values after 18 h of recovery, as did serum creatinine. CONCLUSIONS: Infusion of E. coli induced a hyperdynamic circulatory state with hyperemic AKI. Recovery was associated with relative renal vasoconstriction and reduction in RBF and RVC back to control levels. Indices of tubular function normalized more rapidly than changes in RBF.

Urinary biomarkers in septic acute kidney injury.

OBJECTIVE: To appraise the literature on the value of urinary biomarkers in septic acute kidney injury (AKI). DESIGN: Systematic review. SETTING: Academic medical centre. PATIENTS AND PARTICIPANTS: Human studies of urinary biomarkers. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Fourteen articles fulfilled inclusion criteria. Most studies were small, single-centre, and included mixed medical/surgical adult populations. Few focused solely on septic AKI and all had notable limitations. Retrieved articles included data on low-molecular-weight proteins (beta2-microglobulin, alpha1-microglobulin, adenosine deaminase binding protein, retinol binding protein, cystatin C, renal tubular epithelial antigen-1), enzymes (N-acetyl-beta-glucosaminidase, alanine-aminopeptidase, alkaline phosphatase; lactate dehydrogenase, alpha/pi-glutathione-S-transferase, gamma-glutamyl transpeptidase), cytokines [platelet activating factor (PAF), interleukin-18 (IL-18)] and other biomarkers [kidney injury molecule-1, Na/H exchanger isoform-3 (NHE3)]. Increased PAF, IL-18, and NHE3 were detected early in septic AKI and preceded overt kidney failure. Several additional biomarkers were evident early in AKI; however, their diagnostic value in sepsis remains unknown. In one study, IL-18 excretion was higher in septic than in non-septic AKI. IL-18 also predicted deterioration in kidney function, with increased values preceding clinically significant kidney failure by 24-48 h. Detection of cystatin C, alpha1-microglobulin, and IL-18 predicted need for renal replacement therapy (RRT). CONCLUSIONS: Few clinical studies of urinary biomarkers in AKI have included septic patients. However, there is promising evidence that selected biomarkers may aid in the early detection of AKI in sepsis and may have value for predicting subsequent deterioration in kidney function. Additional prospective studies are needed to accurately describe their diagnostic and prognostic value in septic AKI.

A systematic review of urinary findings in experimental septic acute renal failure.

OBJECTIVE: In experimental septic acute renal failure, urinary analysis is used to help diagnose and classify renal injury. However, the scientific basis for such use has not been systematically evaluated. Thus, we appraised the value of common urinary findings for the diagnosis and classification of experimental septic acute renal failure. DESIGN: Systematic review. SETTING: Academic medical center and university-based research laboratory. SUBJECTS: Experimental studies describing urinary biochemistry, derived indexes, and microscopy in septic acute renal failure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty-seven articles fulfilled all inclusion criteria. Due to heterogeneity, no formal quantitative analysis was possible. The methods for induction of sepsis and models were variable. The urinary sodium, fractional excretion of sodium, and urine osmolality were reported in only four (15%), 21 (78%), and seven (26%) studies, respectively. The fractional excretion of sodium exhibited a decrease, no change, or an increase from baseline in 11 (52%), five (24%), and five (24%) studies, respectively. The urine osmolality decreased from baseline in all endotoxin-induced models but showed an early transient increase in six (22%) studies of cecal-ligation perforation. Proteinuria or urinary enzymuria was reported in only seven (26%) studies. Urinary microscopy was described in one study. Only ten studies (37%) simultaneously reported on histopathology. In all these studies, histology either was normal or showed minor ultrastructural changes on electron microscopy. CONCLUSIONS: No conclusions are possible on how several urinary tests perform in diagnosing or classifying acute renal failure or in predicting the presence of acute tubular necrosis in experimental sepsis. Additional research is necessary to define the diagnostic and prognostic value of urinalysis in experimental sepsis.

Pre-renal azotemia: a flawed paradigm in critically ill septic patients?

The term pre-renal azotemia (or on occasion 'pre-renal renal failure') is frequently used in textbooks and in the literature to indicate an acute syndrome characterized by the presence of an increase in the blood concentration of nitrogen waste products (urea and creatinine). This syndrome is assumed to be due to loss of glomerular filtration rate but is not considered to be associated with histopathological renal injury. Thus, the term is used to differentiate 'functional' from 'structural' acute kidney injury (AKI) where structural renal injury is taken to indicate the presence of so-called acute tubular necrosis (ATN). This paradigm is well entrenched in nephrology and medicine. However, growing evidence from experimental animal models, systematic analysis of the human and experimental literature shows that this paradigm is not sustained by sufficient evidence when applied to the syndrome of septic AKI, especially in critically ill patients. In such patients, several assumptions associated with the 'pre-renal azotemia paradigm' are violated. In particular, there is no evidence that ATN is the histopathological substrate of septic AKI, there is no evidence that urine tests can discriminate 'functional' from 'structural' AKI, there is no evidence that any proposed differentiation leads or should lead to different treatments, and there is no evidence that relevant experimentation can resolve these uncertainties. Given that septic AKI of critical illness now accounts for close to 50% of cases of severe AKI in developed countries, these observations call into question the validity and usefulness of the 'pre-renal azotemia paradigm' in AKI in general.

A technique for the simultaneous measurement of renal ATP, blood flow and pH in a large animal model of septic shock.

BACKGROUND: Simultaneous measurement of renal blood flow, renal ATP, renal pH and mean arterial pressure (MAP) might help investigators understand the mechanisms responsible for acute renal failure (ARF) in sepsis. OBJECTIVES: (1) To develop a technique to simultaneously measure MAP, renal blood flow, renal ATP and renal pH in a large mammal during severe sepsis and after circulatory arrest; and (2) To describe preliminary observations during such measurements. METHODS: We implanted a custom-made phosphorus coil around the left kidney and a magnetic resonance-compatible blood flow probe around the renal artery of an adult Merino ewe. We induced severe sepsis by intravenous administration of Escherichia coli and obtained 31P magnetic resonance spectroscopic data at 3tesla, and continuous blood flow and MAP data before and during severe sepsis over several hours. We induced circulatory arrest with potassium chloride and measured the same 31P signal immediately and again 30 minutes later. RESULTS: We successfully and simultaneously measured MAP, renal blood flow, renal ATP and renal pH in a large mammal during severe sepsis and induced circulatory arrest. With these techniques, we observed that, despite marked hypotension, there were limited changes in renal ATP and renal pH, and that renal blood flow increased. A rapid and dramatic decrease in ATP and pH occurred with circulatory arrest. CONCLUSIONS: We have developed a technique to simultaneously monitor MAP, renal blood flow, ATP and pH in a large mammal during severe sepsis. Our initial observations indicate preservation of renal ATP in septic shock.

Selecting a vasopressor drug for vasoplegic shock after adult cardiac surgery: a systematic literature review.

The choice of vasopressors to treat vasodilatory shock after cardiac surgery is a matter of controversy. We have systematically reviewed the literature and found that the data are insufficient to guide choice of agent. However, we found sufficient evidence that when a target blood pressure can not be achieved with a single agent, addition of another is more likely to help achieve the blood pressure target. We also found that there is no evidence that vasopressors induce organ ischemia. Finally, the lack of high quality data indicate that large multicenter trials are needed in this field.

Urinary biochemistry and microscopy in septic acute renal failure: a systematic review.

BACKGROUND: Biochemistry and microscopy of urine are widely published diagnostic activities in patients with acute renal failure (ARF). However, their scientific basis in patients with septic ARF has not been assessed systematically. METHODS: We performed a systematic review of MEDLINE, EMBASE, CINHAL, and PubMed databases and bibliographies of retrieved articles for all studies describing urinary biochemistry, indices, and microscopy in patients with septic ARF. RESULTS: We identified 27 articles (1,432 patients). Because of substantial heterogeneity, no formal quantitative analysis could be performed. Urinary biochemistry or derived indices were reported in 24 articles (89%), and microscopy, in 7 articles (26%). The majority were small single-center reports and had serious limitations. For example, only 52% of patients were septic, only 54% of patients had ARF, many studies failed to include a control group, time from diagnosis of sepsis or ARF to measure of urinary tests was variable, and there were numerous potential confounders. Urinary sodium, fractional excretion of sodium, urinary-plasma creatinine ratio, urinary osmolality, urinary-plasma osmolality ratio, and serum urea-creatinine ratio showed variable and inconsistent results. Low-molecular-weight proteinuria was described in only 22% of articles. A few reports of urinary microscopy described muddy brown/epithelial cell casts and renal tubular cells in patients with septic ARF, whereas others described normal urinary sediment. CONCLUSION: The scientific basis for the use of urinary biochemistry, indices, and microscopy in patients with septic ARF is weak. More research is required to describe their accuracy, pattern, and time course in patients with septic ARF.

Urinary biochemistry in experimental septic acute renal failure.

BACKGROUND: Several biochemical urine tests and derived indices are reported as useful in the diagnosis of acute renal failure (ARF) and its classification in prerenal (hypoperfusion) or intrarenal (acute tubular) necrosis. However, they have not been adequately studied in sepsis, the most frequent cause of ARF in ICU. METHODS: In 10 female Merino ewes, we implanted flow probes around the pulmonary and renal arteries to measure cardiac output and renal blood flow (RBF) continuously. Cardiovascular variables were monitored and urine samples collected during a 48 h control period and one week later during a 48 h period of hyperdynamic sepsis induced by an infusion of live Escherichia coli. RESULTS: Infusion of live E. coli induced systemic hyperdynamic sepsis with renal vasodilatation and increased RBF. Serum creatinine increased from 73.3 +/- 15.1 to 276.9 +/- 156.3 micromol/l (P < 0.05) and creatinine clearance decreased from 84.6 +/- 21.4 to 27.5 +/- 21.4 ml/min (P < 0.05). Urine sodium concentration (UNa) decreased significantly from 164.5 +/- 50.4 to 14.6 +/- 14.3 mmol/l, fractional excretion of sodium (FeNa) from 1.5 +/- 0.17 to 0.12 +/- 0.11%, fractional excretion of urea nitrogen (FeUn) from 62.7 +/- 9.5 to 11.5 +/- 15.4%, and urine osmolality from 724.8 +/- 277.1 mosmol/l to 329.0 +/- 52.1 mosmol/l. The u/p creatinine ratio did not change. CONCLUSION: Sustained Gram-negative sepsis induced a hyperdynamic state and hyperaemic ARF. Despite increased renal perfusion, UNa, FeNa and FeUn decreased significantly. Our findings suggest that, in sepsis, these urinary biochemical changes are not reliable markers of renal hypoperfusion.

Renal vascular resistance in sepsis.

AIMS: To assess changes in renal vascular resistance (RVR) in human and experimental sepsis and to identify determinants of RVR. METHODS: We performed a systematic interrogation of two electronic reference libraries using specific search terms. Subjects were animals and patients involved in experimental and human studies of sepsis and septic acute renal failure, in which the RVR was assessed. We obtained all human and experimental articles reporting RVR during sepsis. We assessed the role of various factors that might influence the RVR during sepsis using statistical methods. RESULTS: We found no human studies, in which the renal blood flow (and, therefore, the RVR) was measured with suitably accurate direct methods. Of the 137 animal studies identified, 52 reported a decreased RVR, 16 studies reported no change in RVR, and 69 studies reported an increased RVR. Consciousness of animals, duration of measurement, method of induction of sepsis, and fluid administration had no effect on the RVR. On the other hand, on univariate analysis, size of the animals (p < 0.001), technique of measurement (p = 0.017), recovery after surgery (p = 0.004), and cardiac output (p < 0.001) influenced the RVR. Multivariate analysis, however, showed that only cardiac output (p = 0.028) and size of the animals (p = 0.031) remained independent determinants of the RVR. CONCLUSIONS: Changes in RVR during sepsis in humans are unknown. In experimental sepsis, several factors not directly related to sepsis per se appear to influence the RVR. A high cardiac output and the use of large animals predict a decreased RVR, while a decreased cardiac output and the use of small animals predict an increased RVR.

Renal blood flow in sepsis.

INTRODUCTION: To assess changes in renal blood flow (RBF) in human and experimental sepsis, and to identify determinants of RBF. METHOD: Using specific search terms we systematically interrogated two electronic reference libraries to identify experimental and human studies of sepsis and septic acute renal failure in which RBF was measured. In the retrieved studies, we assessed the influence of various factors on RBF during sepsis using statistical methods. RESULTS: We found no human studies in which RBF was measured with suitably accurate direct methods. Where it was measured in humans with sepsis, however, RBF was increased compared with normal. Of the 159 animal studies identified, 99 reported decreased RBF and 60 reported unchanged or increased RBF. The size of animal, technique of measurement, duration of measurement, method of induction of sepsis, and fluid administration had no effect on RBF. In contrast, on univariate analysis, state of consciousness of animals (P = 0.005), recovery after surgery (P < 0.001), haemodynamic pattern (hypodynamic or hyperdynamic state; P < 0.001) and cardiac output (P < 0.001) influenced RBF. However, multivariate analysis showed that only cardiac output remained an independent determinant of RBF (P < 0.001). CONCLUSION: The impact of sepsis on RBF in humans is unknown. In experimental sepsis, RBF was reported to be decreased in two-thirds of studies (62 %) and unchanged or increased in one-third (38%). On univariate analysis, several factors not directly related to sepsis appear to influence RBF. However, multivariate analysis suggests that cardiac output has a dominant effect on RBF during sepsis, such that, in the presence of a decreased cardiac output, RBF is typically decreased, whereas in the presence of a preserved or increased cardiac output RBF is typically maintained or increased.