Hernando Gomez

A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury.

ABSTRACT Given that the leading clinical conditions associated with acute kidney injury (AKI), namely, sepsis, major surgery, heart failure, and hypovolemia, are all associated with shock, it is tempting to attribute all AKI to ischemia on the basis of macrohemodynamic changes. However, an increasing body of evidence has suggested that in many patients, AKI can occur in the absence of overt signs of global renal hypoperfusion. Indeed, sepsis-induced AKI can occur in the setting of normal or even increased renal blood flow. Accordingly, renal injury may not be entirely explained solely on the basis of the classic paradigm of hypoperfusion, and thus other mechanisms must come into play. Herein, we put forward a “unifying theory” to explain the interplay between inflammation and oxidative stress, microvascular dysfunction, and the adaptive response of the tubular epithelial cell to the septic insult. We propose that this response is mostly adaptive in origin, that it is driven by mitochondria, and that it ultimately results in and explains the clinical phenotype of sepsis-induced AKI.

Sepsis-induced acute kidney injury revisited: pathophysiology, prevention and future therapies.

Purpose of reviewAcute kidney injury (AKI) is a common complication in critically ill patients and is associated with increased morbidity and mortality. Sepsis is the most common cause of AKI. Considerable evidence now suggests that the pathogenic mechanisms of sepsis-induced AKI are different from those seen in other causes of AKI. This review focuses on the recent advances in this area and discusses possible therapeutic interventions that might derive from these new insights into the pathogenesis of sepsis-induced AKI. Recent findingsThe traditional paradigm that sepsis-induced AKI arises from ischemia has been challenged by recent evidence that total renal blood flow in is not universally impaired during sepsis, and AKI can develop in the presence of normal or even increased renal blood flow. Animal and human studies suggest that adaptive responses of tubular epithelial cells to injurious signals are responsible for renal dysfunction. Simultaneously occurring renal inflammation and microcirculatory dysfunction further amplify these mechanisms. SummaryAn understanding of the pathologic mechanisms of sepsis-induced AKI emphasizes the important role of maladaptive responses to the septic insult. Preventive and therapeutic measures should be based on counteracting these maladaptive responses of tubular epithelial cells, inflammation, and microvascular dysfunction.

International study on microcirculatory shock occurrence in acutely ill patients

Objectives:Microcirculatory alterations are associated with adverse outcome in subsets of critically ill patients. The prevalence and significance of microcirculatory alterations in the general ICU population are unknown. We studied the prevalence of microcirculatory alterations in a heterogeneous ICU population and its predictive value in an integrative model of macro- and microcirculatory variables. Design:Multicenter observational point prevalence study. Setting:The Microcirculatory Shock Occurrence in Acutely ill Patients study was conducted in 36 ICUs worldwide. Patients:A heterogeneous ICU population consisting of 501 patients. Interventions:None. Measurements and Main Results:Demographic, hemodynamic, and laboratory data were collected in all ICU patients who were 18 years old or older. Sublingual Sidestream Dark Field imaging was performed to determine the prevalence of an abnormal capillary microvascular flow index (< 2.6) and its additional value in predicting hospital mortality. In 501 patients with a median Acute Physiology and Chronic Health Evaluation II score of 15 (10–21), a Sequential Organ Failure Assessment score of 5 (2–8), and a hospital mortality of 28.4%, 17% exhibited an abnormal capillary microvascular flow index. Tachycardia (heart rate > 90 beats/min) (odds ratio, 2.71; 95% CI, 1.67–4.39; p < 0.001), mean arterial pressure (odds ratio, 0.979; 95% CI, 0.963–0.996; p = 0.013), vasopressor use (odds ratio, 1.84; 95% CI, 1.11–3.07; p = 0.019), and lactate level more than 1.5 mEq/L (odds ratio, 2.15; 95% CI, 1.28–3.62; p = 0.004) were independent risk factors for hospital mortality, but not abnormal microvascular flow index. In reference to microvascular flow index, a significant interaction was observed with tachycardia. In patients with tachycardia, the presence of an abnormal microvascular flow index was an independent, additive predictor for in-hospital mortality (odds ratio, 3.24; 95% CI, 1.30–8.06; p = 0.011). This was not true for nontachycardic patients nor for the total group of patients. Conclusions:In a heterogeneous ICU population, an abnormal microvascular flow index was present in 17% of patients. This was not associated with mortality. However, in patients with tachycardia, an abnormal microvascular flow index was independently associated with an increased risk of hospital death.

The endothelium in sepsis

ABSTRACT Sepsis affects practically all aspects of endothelial cell (EC) function and is thought to be the key factor in the progression from sepsis to organ failure. Endothelial functions affected by sepsis include vasoregulation, barrier function, inflammation, and hemostasis. These are among other mechanisms often mediated by glycocalyx shedding, such as abnormal nitric oxide metabolism, up-regulation of reactive oxygen species generation due to down-regulation of endothelial-associated antioxidant defenses, transcellular communication, proteases, exposure of adhesion molecules, and activation of tissue factor. This review covers current insight in EC-associated hemostatic responses to sepsis and the EC response to inflammation. The endothelial cell lining is highly heterogeneous between different organ systems and consequently also in its response to sepsis. In this context, we discuss the response of the endothelial cell lining to sepsis in the kidney, liver, and lung. Finally, we discuss evidence as to whether the EC response to sepsis is adaptive or maladaptive. This study is a result of an Acute Dialysis Quality Initiative XIV Sepsis Workgroup meeting held in Bogota, Columbia, between October 12 and 15, 2014.

Augmenting Autophagy to Treat Acute Kidney Injury during Endotoxemia in Mice

Objective To determine that 1) an age-dependent loss of inducible autophagy underlies the failure to recover from AKI in older, adult animals during endotoxemia, and 2) pharmacologic induction of autophagy, even after established endotoxemia, is of therapeutic utility in facilitating renal recovery in aged mice. Design Murine model of endotoxemia and cecal ligation and puncture (CLP) induced acute kidney injury (AKI). Setting Academic research laboratory. Subjects C57Bl/6 mice of 8 (young) and 45 (adult) weeks of age. Intervention Lipopolysaccharide (1.5 mg/kg), Temsirolimus (5 mg/kg), AICAR (100 mg/kg). Measurements and Main Results: Herein we report that diminished autophagy underlies the failure to recover renal function in older adult mice utilizing a murine model of LPS-induced AKI. The administration of the mTOR inhibitor temsirolimus, even after established endotoxemia, induced autophagy and protected against the development of AKI. Conclusions These novel results demonstrate a role for autophagy in the context of LPS-induced AKI and support further investigation into like interventions that have potential to alter the natural history of disease.

Characterization of tissue oxygen saturation and the vascular occlusion test: influence of measurement sites, probe sizes and deflation thresholds

IntroductionTissue oxygen saturation (StO2) and the vascular occlusion test (VOT) can identify tissue hypoperfusion in trauma and sepsis. However, the technique is neither standardized nor uses the same monitoring site. We hypothesized that baseline and VOT StO2 would be different in the forearm (F) and thenar eminence (TH) and that different minimal StO2 values during the VOT would result in different reoxygenation rates (ReO2).MethodsStO2 and its change during the VOT were simultaneously measured in the F and TH, with 15 mm and 25 mm probes, using the 325 InSpectra monitor in 18 healthy, adult volunteers. Two VOTs were done to a threshold thenar StO2 of 40% interchanging the 15 mm and 25 mm probes between sites. Two additional VOTs were done to thresholds of 50% and 30%. Baseline StO2 (BaseO2), the deoxygenation rate (DeO2) and ReO2 were compared between sites, probes and (%O2/minute) thresholds. Results are presented as the median (interquartile range), P-value.ResultsBaseO2, DeO2, ReO2, area under the curve and hyperemia duration values were different when comparing TH vs. F and 15 mm vs. 25 mm probes. ReO2 was different between different thresholds for the TH and 15 mm probes. TH15 mm vs. F15 mm: BaseO2, 90.4 (85.2, 93.5) vs. 85.2 (80.7, 90.2), P = 0.031; DO2, -12.1 (-16.2, -11.3) vs. -8.5 (-10.3, -7.8), P = 0.011; ReO2, 297.2 (213.7, 328.6), P < 0.0001; 15 mm vs. 25 mm probe: BaseO2, 97.2 (89.4, 94.7) vs. 87.3 (81.7, 90.9), P = 0.016; DeO2, -18.0 (-24.1, -14.8) vs. -9.9 (-15.3, -6.5), P < 0.0001; and ReO2, 401.6 (331.7, 543.2) vs. 160.5 (132.3, 366.9), P = 0.012, respectively. TH15 mm vs. TH25 mm: BaseO2, P = 0.020; DeO2, P < 0.0001; and ReO2, P < 0.0001. Threshold StO2 values (15 mm probe only): ReO2, P = 0.003; DeO2, P = 0.60. ReO2 at 40% and 50% StO2 thresholds, P = 0.01.ConclusionsBaseO2, DeO2 and ReO2 were different when measured in different anatomical sites (F and TH) and with different probe sizes, and ReO2 was different with differing VOT release StO2 threshold values. Thus, standardization of the site, probe and VOT challenge need to be stipulated when reporting data.

An adequately robust early TNF-α response is a hallmark of survival following trauma/hemorrhage

Background Trauma/hemorrhagic shock (T/HS) results in cytokine-mediated acute inflammation that is generally considered detrimental. Methodology/Principal Findings Paradoxically, plasma levels of the early inflammatory cytokine TNF-α (but not IL-6, IL-10, or NO2 -/NO3 -) were significantly elevated within 6 h post-admission in 19 human trauma survivors vs. 4 non-survivors. Moreover, plasma TNF-α was inversely correlated with Marshall Score, an index of organ dysfunction, both in the 23 patients taken together and in the survivor cohort. Accordingly, we hypothesized that if an early, robust pro-inflammatory response were to be a marker of an appropriate response to injury, then individuals exhibiting such a response would be predisposed to survive. We tested this hypothesis in swine subjected to various experimental paradigms of T/HS. Twenty-three anesthetized pigs were subjected to T/HS (12 HS-only and 11 HS + Thoracotomy; mean arterial pressure of 30 mmHg for 45–90 min) along with surgery-only controls. Plasma obtained at pre-surgery, baseline post-surgery, beginning of HS, and every 15 min thereafter until 75 min (in the HS only group) or 90 min (in the HS + Thoracotomy group) was assayed for TNF-α, IL-6, IL-10, and NO2 -/NO3 -. Mean post-surgery±HS TNF-α levels were significantly higher in the survivors vs. non-survivors, while non-survivors exhibited no measurable change in TNF-α levels over the same interval. Conclusions/Significance Contrary to the current dogma, survival in the setting of severe, acute T/HS appears to be associated with an immediate increase in serum TNF-α. It is currently unclear if this response was the cause of this protection, a marker of survival, or both. This abstract won a Young Investigator Travel Award at the SHOCK 2008 meeting in Cologne, Germany.

Adenosine monophosphate-activated protein kinase activation protects against sepsis-induced organ injury and inflammation

BACKGROUND Mortality in sepsis is most often attributed to the development of multiple organ failure. In sepsis, inflammation-mediated endothelial activation, defined as a proinflammatory and procoagulant state of the endothelial cells, has been associated with severity of disease. Thus, the objective of this study was to test the hypothesis that adenosine monophosphate-activated protein kinase (AMPK) activation limits inflammation and endothelium activation to protect against organ injury in sepsis. 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), which is an adenosine monophosphate analog, has been used to upregulate activity of AMPK. Compound C is a cell-permeable pyrrazolopyrimidine compound that inhibits AMPK activity. METHODS Wild-type mice underwent cecal ligation and puncture (CLP) or sham surgery. Mice were randomized to vehicle, AICAR, or compound C. Mouse kidney endothelial cells were used for in vitro experiments. Renal and liver function were determined by serum cystatin C, blood urea nitrogen (BUN), creatinine, and alanine aminotransferase. Serum cytokines were measured by enzyme-linked immunosorbent assay. Microvascular injury was determined using Evans blue dye and electron microscopy. Immunohistochemistry was used to measure protein levels of phospho-AMPK (p-AMPK), microtubule-associated protein 1A/1B-light chain 3 (LC3), and intracellular adhesion molecule. LC3 levels were used as a measure of autophagosome formation. RESULTS AICAR decreased liver and kidney injury induced by CLP and minimized cytokine elevation in vivo and in vitro. CLP increased renal and hepatic phosphorylation of AMPK and autophagic signaling as determined by LC3. Inhibition of AMPK with compound C prevented CLP-induced autophagy and exacerbated tissue injury. Additionally, CLP led to endothelial injury as determined by electron microscopy and Evans blue dye extravasation, and AICAR limited this injury. Furthermore, AICAR limited CLP and lipopolysaccharide (LPS)-induced upregulation of intracellular adhesion molecule in vivo and in vitro and decreased LPS-induced neutrophil adhesion in vitro. CONCLUSIONS In this model, activation of AMPK was protective, and AICAR minimized organ injury by decreasing inflammatory cytokines and endothelial activation. These data suggest that AMPK signaling influences sepsis or LPS-induced endothelial activation and organ injury.

Prehospital dynamic tissue oxygen saturation response predicts in-hospital lifesaving interventions in trauma patients.

BACKGROUND: Tissue oximetry (StO2) plus a vascular occlusion test is a noninvasive technology that targets indices of oxygen uptake and delivery. We hypothesize that prehospital tissue oximetric values and vascular occlusion test response can predict the need for in-hospital lifesaving interventions (LSI). METHODS: We conducted a prospective, blinded observational study to evaluate StO2 slopes to predict the need for LSI. We calculated the DeO2 slope using Pearsons coefficients of regression (r2) for the first 25% of descent and the ReO2 slope using the entire recovery interval. The primary outcome was LSI defined as the need for emergent operation or transfusion in the first 24 hours of hospitalization. We created multivariable logistic regression models using covariates of age, sex, vital signs, lactate, and mental status. RESULTS: We assessed StO2 in a convenience sample of 150 trauma patients from April to November of 2009. In-hospital mortality was 3% (95% confidence interval [CI], 1.1–7.6); 31% (95% CI, 24–39) were admitted to the intensive care unit, 6% (95% CI, 2.8–11.1) had an emergent operation, and 10% (95% CI, 5.7–15.9) required transfusion. Decreasing DeO2 was associated with a higher proportion of patients requiring LSI. In the multivariate model, the association between the need for LSI and DeO2, Glasgow Coma Scale, and age persists. CONCLUSION: Prehospital DeO2 is associated with need for LSI in our trauma population. Further study of DeO2 is warranted to determine whether it can be used as an adjunct triage criterion or an endpoint for resuscitation. LEVEL OF EVIDENCE: III, observational study.

IMMUNE CELL PHENOTYPE AND FUNCTION IN SEPSIS.

ABSTRACT Cells of the innate and adaptive immune systems play a critical role in the host response to sepsis. Moreover, their accessibility for sampling and their capacity to respond dynamically to an acute threat increases the possibility that leukocytes might serve as a measure of a systemic state of altered responsiveness in sepsis. The working group of the 14th Acute Dialysis Quality Initiative (ADQI) conference sought to obtain consensus on the characteristic functional and phenotypic changes in cells of the innate and adaptive immune system in the setting of sepsis. Techniques for the study of circulating leukocytes were also reviewed and the impact on cellular phenotypes and leukocyte function of nonextracorporeal treatments and extracorporeal blood purification therapies proposed for sepsis was analyzed. A large number of alterations in the expression of distinct neutrophil and monocyte surface markers have been reported in septic patients. The most consistent alteration seen in septic neutrophils is their activation of a survival program that resists apoptotic death. Reduced expression of HLA-DR is a characteristic finding on septic monocytes, but monocyte antimicrobial function does not appear to be significantly altered in sepsis. Regarding adaptive immunity, sepsis-induced apoptosis leads to lymphopenia in patients with septic shock and it involves all types of T cells (CD4, CD8, and Natural Killer) except T regulatory cells, thus favoring immunosuppression. Finally, numerous promising therapies targeting the host immune response to sepsis are under investigation. These potential treatments can have an effect on the number of immune cells, the proportion of cell subtypes, and the cell function.