American Journal of Respiratory and Critical Care Medicine

Rationale: It is unclear how septic shock causes acute kidney injury (AKI) and whether this is associated with histological change.

Objectives: We aimed to determine the nature and extent of changes in renal structure and function over time in an ovine model of septic shock.

Methods: Fifteen sheep were instrumented with a renal artery flow probe and renal vein cannula. Ten were given intravenous Escherichia coli to induce septic shock, and five acted as controls. Animals were mechanically ventilated for 48 hours, while receiving protocol-guided parenteral fluids and a norepinephrine infusion to maintain mean arterial pressure. Renal biopsies were taken every 24 hours or whenever animals were oliguric for 2 hours. A renal pathologist, blinded to tissue source, systematically quantified histological appearance by light and electron microscopy for 31 prespecified structural changes.

Measurements and Main Results: Sheep given E. coli developed septic shock, oliguria, increased serum creatinine, and reduced creatinine clearance (AKI), but there were no changes over time in renal blood flow between groups (P > 0.30) or over time within groups (P > 0.50). Renal oxygen consumption increased only in nonseptic animals (P = 0.01), but there was no between-group difference in renal lactate flux (P > 0.50). There was little structural disturbance in all biopsies and, although some cellular appearances changed over time, the only difference between septic and nonseptic animals was mesangial expansion on electron microscopy.

Conclusions: In an intensive care–supported model of gram-negative septic shock, early AKI was not associated with changes in renal blood flow, oxygen delivery, or histological appearance. Other mechanisms must contribute to septic AKI.

Scientific Knowledge on the Subject

It is unclear how sepsis acutely alters renal function. Experimental studies have illustrated that glomerular filtration decreases with sepsis despite preservation of renal blood flow. Acute tubular necrosis and glomerular microthrombi have been proposed to contribute, based on observational postmortem studies.

What This Study Adds to the Field

This is the first prospective controlled study to simultaneously assess renal function, histology, and glomerular ultrastructure over time in septic shock. In a clinically relevant animal model, septic shock provoked a marked decrease in glomerular filtration, while renal blood flow was maintained. Systematic histological assessment of each functional component of the renal cortex revealed no cellular changes to account for the marked reduction in glomerular filtration. This study supports the notion that early septic acute kidney injury represents a functional disturbance within the kidney.

Acute decreases in renal function define acute kidney injury (AKI). AKI occurs in up to two-thirds of intensive care unit (ICU) patients and is independently associated with health-care use and mortality (13). Sepsis is the most common condition associated with AKI, and increasing sepsis severity is associated with more severe AKI (46).

Several mechanisms have been proposed to explain septic AKI. Systemic hypotension during septic shock has been thought to decrease renal blood flow and impair renal function (710). However, reliable measures of renal blood flow during septic shock are not available in humans (11) and relevant animal studies have contradicted this theory, revealing that blood flow to the kidney is actually preserved or increased (1215).

Structural changes to the kidney have also been considered to occur, with “acute tubular necrosis” frequently thought responsible for septic AKI (710, 16, 17). However, acute tubular necrosis is somewhat ill-defined and is infrequently reported in human and experimental septic AKI studies (1820). Other processes such as glomerular thrombosis, renal parenchymal inflammation, microvascular congestion, and apoptosis have also been proposed (710, 21), but the clinical significance of these is uncertain given that they have been noted only in post-mortem specimens. Studies of septic AKI histology are further confounded by selection bias, subjective grading scales, inconsistent definitions of AKI, variable use of parenteral fluids and catecholamines, the impact of the dying process itself, and an inability to determine whether abnormalities were present before the septic insult.

Given the major clinical impact of septic AKI, a better understanding of its pathogenesis is of vital importance. However, renal morphology studies in humans with septic AKI are not possible because of the risk of hemorrhage after biopsy, and functional studies are limited by an inability to reliably measure renal blood flow in the critically ill. Accordingly, using a controlled experimental model that closely simulated human septic AKI and its ICU treatment, we sought to concurrently determine the evolution of renal structural and functional changes. Some of the results of these studies have been previously reported in the form of an abstract (22).

Study Design

We conducted a prospective, blinded, controlled study of renal histology and function in an ovine model of septic shock. Approval for the study was obtained from institutional animal ethics committees and conducted according to the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes (23).

Ovine Model

Description of the ovine model of septic shock is included in the online supplement. In brief, 15 mature female sheep (65–70 kg) were studied individually and anesthetized for insertion of carotid and pulmonary artery catheters, tracheostomy, and a urinary catheter. An incision was made in the left flank with dissection to the renal hilum and an ultrasonic flow probe placed around the left renal artery. The wound was closed with removable clips allowing subsequent access to the kidney for sequential renal biopsies under direct vision. Using radiological guidance, a cannula was placed via the jugular vein into the left renal vein.

After instrumentation, animals received protocol-guided sedation, ventilation, parenteral fluids, and norepinephrine infusion titrated to maintain normal mean arterial pressure of sheep (75 mm Hg) (24) (see Table E1 in the online supplement). Ten animals were rendered septic with intravenous Escherichia coli (108 organisms/kg) infused over 1 hour, while five sheep acted as nonseptic controls. Animal euthanasia occurred after 48 hours.

Assessment of Renal Function

Renal blood flow was measured continuously and recorded at 10-minute intervals. Urine production was measured hourly and pooled into 12-hour samples. Serum and urine biochemistry (sodium, creatinine, urea) were analyzed at baseline and repeated every 12 hours. Creatinine clearance is equivalent to the glomerular filtration rate in sheep (25), and fractional excretion of sodium was used as a measure of tubule function (26). Renal oxygen consumption and lactate flux were determined every 4 hours by measuring levels in arterial and renal venous blood multiplied by mean renal blood flow over the corresponding time period.

Renal Biopsies

A 16-gauge biopsy needle was used for sampling renal tissue at baseline, 24 hours, and 48 hours; or earlier if urine output was less than 0.2 ml/kg for two consecutive hours. Each biopsy comprised two samples of tissue, collected remote from previous biopsy sites and placed immediately into specimen containers of glutaraldehyde and formaldehyde.

Tissue Preparation

Renal tissue for light microscopic assessment was embedded in paraffin, sliced at 2 μm, and stained with hematoxylin and eosin. For ultrastructure assessment, 100-nm epoxy resin sections were stained with uranyl acetate and lead citrate, and examined with a transmission electron microscope (see METHODS in the online supplement).

Assessment of Renal Tissue

Functional components of the kidney (i.e., glomerulus, tubule, interstitium, nonglomerular blood vessels) and 31 predetermined histological changes (Table E2) were systematically assessed on every renal biopsy. A clinical pathologist expert in renal disease, unaware of timing and sepsis status of each sample, scored each histological change on a visual analog scale (range: 0 cm, absent; 10 cm, severe) for every biopsy in one sitting.

Statistical Analysis

Continuous data over time were analyzed by general estimating equations with robust standard errors. Histology scores were log-transformed and analyzed for a group-by-time interaction, group effect, and time effect with random-effects linear mixed models (27). Analyses were undertaken with Stata/MP (version 14.0; StataCorp, College Station, TX). Statistical significance was taken as P < 0.05. Data are described as means (±SD in tables, ±95% confidence intervals on graphs).

Group Characteristics

The septic group of sheep received E. coli at 0.9 (±0.2) × 108 organisms/kg and subsequently developed arterial hypotension requiring increasing amounts of norepinephrine to maintain target mean arterial pressure (Figure 1). Septic animals developed coagulopathy, elevated serum lactate, and a decrease in systemic vascular resistance (Table E3 and Figure E1). Cardiac output did not significantly change over time and was not different between nonseptic and septic sheep (Figure 1). There was no difference between groups in the amount of parenteral fluids administered (ml/kg/h; nonseptic, 3.5 ± 0.8 vs. septic, 4.0 ± 0.7; P = 0.21) or in central venous pressure (Figure E1).

In the nonseptic group, one animal died at 45 hours, associated with significant renal hemorrhage. In the septic group, five animals died before 48 hours (18, 18, 24, 29, and 33 h after E. coli infusion) (Figure E2).

Renal Function

Septic sheep developed AKI with a fourfold increase in serum creatinine and urea concentrations, and a significant decrease in creatinine clearance and urine output (Figure 2). The fraction of filtered sodium excreted in urine had a variable pattern within the first 24 hours of sepsis, but thereafter was similar to that in nonseptic sheep (Figure 2).

Renal blood flow did not change over time and did not differ between septic and nonseptic animals (ml/min; nonseptic, 417 ± 36 vs. septic, 387 ± 49; P = 0.39). Renal oxygen consumption increased in nonseptic animals over time (ml/min; nonseptic, 7.0 ± 2.3 vs. septic, 5.6 ± 1.4; P = 0.01) (Figure 3), while lactate flux across the kidney did not change over time or differ between groups (Figure 3).

Kidney Histopathology

Timing of the renal biopsies is outlined in Table 1. Overall, there was little histological disturbance in the renal biopsies (Figure 4). None of the histological parameters showed a significant group-by-time interaction, indicating that the two groups did not differ over the three time points. Histology scores for luminal necrotic cells and podocyte foot-process effacement increased over time (P < 0.01 for both) but were no different between groups (P > 0.5 for both). Mesangial expansion (electron microscopy) scored higher in the septic group (P = 0.01) but did not change over time (P > 0.50). Of note, there were no microthrombi observed and little evidence of inflammation, tubular cell necrosis, or vascular hemorrhage. A panel of light and electron histomicrographs representing the range of cellular changes observed is available in the online supplement (Figures E3 and E4).

Table 1. Timing of Renal Biopsies Taken from Septic and Nonseptic Sheep

 Biopsy 1Biopsy 2Biopsy 3
 NonsepticSepticNonsepticSepticNonsepticSeptic
Time of biopsy after Escherichia coli administration0 h0 h24 h21 ± 4 h48 h42 ± 10 h
Number of animals biopsied*n = 5n = 10n = 5n = 9n = 4n = 7
Urine output preceding each biopsy, ml/kg/h  1.5 ± 0.80.5 ± 0.41.8 ± 1.10.3 ± 0.3

*One renal biopsy in the nonseptic group at each time point had an insufficient number of glomeruli to assess.

P < 0.05 for difference between nonseptic and septic groups.

We performed an experimental study to assess the changes in renal function and histology over the first 48 hours of septic shock in an animal model that closely mimicked many of the features of a septic human in ICU. Septic shock induced a marked reduction in glomerular filtration despite preservation of renal blood flow, and no changes in oxygen consumption or lactate flux. Importantly, despite the marked loss of glomerular filtration, the histological appearance of the kidneys was largely the same as in controls. The lack of histopathological change is particularly remarkable given the severity of disease, dramatic increase in serum creatinine, need for high doses of norepinephrine, and lethality of the model.

Preservation of relatively normal histology despite marked changes in renal function may appear surprising. However, from as early as 1957, small observational studies noted relatively little structural change in the kidneys from septic patients who died with severe renal dysfunction (2830). Consistent with our controlled study, these case reports all remarked on the apparent discrepancy between profound functional impairment and little structural change.

More recent studies have observed histopathological changes in post-mortem renal tissue from septic patients with AKI, when compared with samples from nonseptic patients with normal renal function. Lerolle and colleagues noted acute tubular lesions, intense leukocytic infiltrate, tubular apoptosis, and occasionally glomerular microthrombi in 19 post-mortem renal biopsies (21). Takasu and colleagues found features of tubule injury in 39 septic AKI samples, but this occurred in only a small proportion of tubules (31). Interpreting the significance of abnormalities reported in these studies is confounded by the effect of premortal hemodynamic injury, age differences, preexisting renal disease, the potential influence of supportive therapies, and most of all, by selection bias (only the sickest people who had been in ICU for a long time and died despite treatment were chosen for post-mortem assessment). Indeed, Takasu and colleagues noted that their septic patient group had more features typical of chronic renal disease including glomerulosclerosis, interstitial fibrosis, and arteriolar hyalinosis. Furthermore, any histological changes observed in these post-mortem studies do not necessarily represent the pathological mechanisms that initiate or perpetuate septic AKI.

AKI histology studies to date have largely focused on renal tubular changes. Given that AKI is typically defined by a reduction in glomerular filtration, assessing glomerular histology is particularly salient. Our study is unique, having systematically assessed and reported glomerular histology and ultrastructure in septic AKI. With light microscopy, glomerular appearance was indistinguishable between septic and nonseptic sheep. At an ultrastructural level, podocyte foot processes effaced over time, but this was not exacerbated by sepsis. Mesangial expansion was greater in the septic group, but the clinical significance of this is uncertain as it did not change over time and was not accompanied by similar changes at light microscopy. However, it is possible that the mesangium may contribute to the pathogenesis of septic AKI by changing intraglomerular vessel tone and blood flow. Mesangial cells provide structural support for the glomerular capillaries, are involved in regulating glomerular flow and ultrafiltration surface, and contain receptors to a wide array of inflammatory mediators and vasoactive agents (32). Mesangial expansion is typically seen in diabetic nephropathy and certain glomerulonephritides but its contribution to septic AKI is currently unknown.

In contrast to the early and marked reduction of glomerular filtration, tubular function was largely preserved. Although there was a higher fraction of filtered sodium excreted after sepsis induction, this had resolved by 24 hours, and was consistent with the unchanged histological appearance of the cortical tubules. Transient early natriuresis and diuresis have been noted in other models of sepsis with subsequent preservation of sodium reabsorption (14, 15, 3335).

A noteworthy aspect of this study was that renal blood flow and metabolic function were monitored concurrently with structural assessment. In this model, there was no change in renal blood flow or lactate flux and in septic animals, renal oxygen consumption did not increase. These findings are consistent with other experimental acute septic AKI studies that have also reported unchanged renal oxygen consumption (20, 36, 37), normal lactate flux (33, 36), and preserved renal ATP levels (38). Given these findings and the lack of sepsis-induced histological changes, it appears that in early septic AKI, the kidneys are not grossly ischemic from a biochemical or structural perspective.

More recently, a prespecified analysis of the Protocolized Care for Early Septic Shock (ProCESS) trial reports that the incidence, duration, severity, and recovery from AKI was not altered by the more frequent application of hemodynamic monitoring, parenteral fluids, catecholamines, and blood transfusion (39). This is consistent with the premise that gross hemodynamic changes alone do not contribute to the AKI of sepsis.

Identifying the molecular processes leading to cell death is an area of burgeoning interest in many diseases including acute kidney injury (40, 41). Cells can regulate their own death and involve a combination of processes including apoptosis, necroptosis, altered mitochondrial permeability, parthanatos, and ferroptosis. Each of these processes involves a unique series of molecular changes and target molecules such as phosphorylated mixed-lineage kinase domain–like (MLKL), receptor-interacting protein kinase 3 (RIPK3), cleaved caspases, poly(ADP-ribose) polymerase-1 (PARP-1), glutathione peroxidase 4, and cyclophilin D. Identifying these cell death markers was not possible on ovine tissue with the immunohistochemical techniques currently available. Although histological features of cell death were infrequent in this study, and no different between the septic and nonseptic groups, further research is required to develop experimental techniques that will allow us to understand how cells die in septic AKI.

The observation of rapid AKI development, lack of histologic injury, and preserved global renal blood flow in septic animals implies a redistribution of blood flow within the kidney during sepsis. This interpretation is supported by other studies that have reported higher oxygen content in the renal vein than the efferent arteriole (42), preservation of renal blood flow in the septic cortex but a decrease in the medulla (35), and by the lack of change in renal oxygen and lactate consumption. Previous scanning electron microscopy studies have revealed glomerular bypass vessels, most prevalent in the juxtamedullary region of the kidney, which may provide an anatomical basis for intrarenal shunt (4345). Such shunting and diminished glomerular filtration may be protective. It may help preserve circulating volume, limit exposure to filtered injurious mediators, limit tubular solute load, spare renal metabolic function, and avoid exposure to reactive oxygen species (46, 47).

This study addressed many limitations of earlier reports of renal structure and function in sepsis, being conducted in a controlled setting, with a relevant model of septic AKI (48). The model was typical of the clinical scenario, given that two-thirds of ICU patients with altered renal function develop these changes within 48 hours of admission (17) and that 80% with severe AKI receive mechanical ventilation and catecholamines (4, 5). The study controlled for variables that may alter renal function such as parenteral fluids, use of norepinephrine, timing of sepsis, and animal age. Renal morphology, hemodynamics, and function were assessed simultaneously over multiple time points and compared with control animals subject to the same protocol. Histological assessment was systematic, quantified the magnitude of prespecified cellular changes on a continuous scale, and was performed blindly by a single expert renal pathologist, avoiding bias and interobserver variation.

Despite the above-described strengths, several complex limitations remained and must be considered. This was a nonhuman study and involved only one model of sepsis. Inducing sepsis with E. coli bacteremia allowed timing of the sepsis challenge to be standardized, but may not represent changes that could occur with other infectious sources or organisms. Other factors that alter renal structure or function such as nephrotoxins and comorbidities were not incorporated in this controlled study. Nevertheless, many pathophysiological features of the ovine model, including previously published data on systemic markers of inflammation (49), appear consistent with human sepsis. This model replicated only the first 48 hours of sepsis. Persistent renal dysfunction may involve other pathological processes that were not identified in this short-term model. Biopsies were limited to cortical tissue to limit the risk of renal hemorrhage from deeper biopsy; hence medullary tissue was not examined. Medullary perfusion and tissue oxygenation decrease during experimental sepsis (35), supporting the possibility that tubular injury may have been more noticeable in this region of the kidney. Cortical tubule ultrastructure was not assessed as cellular changes are patchy and foreshortened views make finding a representative cell prone to sampling error. Despite these limitations, changes isolated to medullary tubules or cortical tubule ultrastructure would be unlikely to account for the early and marked impairment of glomerular filtration of septic AKI. Although we describe the development of hemoconcentration with sepsis, we are unable to comment in detail on its effects on microvascular viscosity and how this may have contributed to the reduction of glomerular filtration. Biomarkers of renal tubule injury such as neutrophil gelatinase-associated lipocalin (NGAL) or kidney injury molecule 1 (Kim-1) were not available for assay in sheep. We detected some early changes in tubular function related to sodium excretion, but because of the pooling of urine over 12 hours, were unable to provide a more detailed understanding of its time course.

Incorporating a positive histological control into the study may have enhanced the validity of the study. However, it is uncertain what should represent a positive control and its potential to bias histological assessment. We considered that the use of a positive histological control was not warranted and negated by (1) the pathologist’s years of experience in analyzing renal tissue, (2) blinding to the sample origin and physiological parameters, (3) sensitivity of electron microscopy to detect cellular change, and (4) use of objective histological assessment. Finally, with a relatively small number of animals studied, the lack of appreciable histological difference between groups may represent a type II error. Although the histological appearance of individual elements did not significantly change with sepsis, it is possible that AKI may result from a combination of multiple small changes. Nevertheless, the aggregate of our findings, in concert with earlier observational studies, supports the notion that there is little structural injury in early septic AKI.

In conclusion, a large animal experimental model of septic shock that closely simulated the human condition allowed a controlled study of renal structure and function in early septic AKI. We found marked reduction of glomerular filtration despite preservation of renal blood flow and lack of histological changes in the kidney. Our findings support the view that early manifestations of AKI during septic shock are functional rather than structural in nature.

The authors thank Paul Sideris (Infectious Disease Laboratory, SA Pathology) for preparing solutions of Escherichia coli, and Dr. Binila Chacko, Dr. Faith Crichton, Luke Chester (R.N.), and Steph O’Connor (R.N.) for providing assistance with the animal model.

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Correspondence and requests for reprints should be addressed to Matthew J. Maiden, B.Sc., B.M. B.S., Ph.D., Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia 5000. E-mail:

Supported by partial funding from the Intensive Care Foundation (Project Grant) and University of Adelaide (Sando Grant). Monitoring equipment and infusion pumps were loaned from Philips, Edwards Lifesciences Corporation, and Baxter Healthcare.

Author Contributions: M.J.M., study conception, model development, study design and conduct, data collection and analysis, and manuscript preparation; S.O., study design, histopathology analysis, and manuscript review; J.K.B., electron microscopy and manuscript review; M.E.F., data analysis and manuscript review; M.J.C. and R.B., study design, data review, and manuscript review; T.R.K., study design, animal surgery, study conduct, and manuscript review; C.H.N. and J.E., study conduct, data collection, and manuscript review.

This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.201511-2285OC on March 11, 2016

Author disclosures are available with the text of this article at www.atsjournals.org.

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