PXR-mediated Metabolism During Pregnancy and Cholestasis

Nuclear receptors, including the pregnane x receptor (PXR) and the farnesoid x receptor (FXR), regulate the expression of genes that maintain bile acid (BA) homeostasis. Intrahepatic cholestasis of pregnancy (ICP) is a common gestational liver disease and BAs are implicated in its pathogenesis. Rodents exhibit maternal liver growth in order to meet the metabolic demands of pregnancy. This process is found to precede changes in body weight, occur in the presence of raised serum BAs and is likely to be driven by a placental lactogen. While the growth is normally achieved by hepatocyte hypertrophy, potentially harmful hyperplasia makes a major contribution in mice lacking Fxr. Consistent with reports of raised serum BAs in normal pregnant women, hepatic BAs are found in association with pro-cholestatic gene expression in normal pregnant mice. Gestation could be a state of reduced Fxr function because BA-fed and Fxr-/- mice do not develop raised hepatic BAs during pregnancy. Sequencing and functional assessment of PXR variants revealed that polymorphisms in this gene are unlikely to contribute to the aetiology of ICP. Surprisingly, Pxr-/- mice have enhanced hepatic metabolism and are resistant to toxicity caused by lithocholic acid (LCA). Furthermore, while hepatic Pxr is activated by intraperitoneal injection of LCA, it is not activated by physiologically relevant LCA-feeding. Summary: Pregnancy causes liver growth, raised hepatic BA and pro-cholestatic gene expression in normal mice. In humans, these adaptations may expose predisposed individuals to gestational liver disease. Genetic variation in PXR does not contribute to ICP and Pxr may play only a limited role in mediating hepatic responses to toxic BAs

The American Association for the Surgery of Trauma renal injury grading scale: Implications of the 2018 revisions for injury reclassification and predicting bleeding interventions.

BackgroundIn 2018, the American Association for the Surgery of Trauma (AAST) published revisions to the renal injury grading system to reflect the increased reliance on computed tomography scans and non-operative management of high-grade renal trauma (HGRT). We aimed to evaluate how these revisions will change the grading of HGRT and if it outperforms the original 1989 grading in predicting bleeding control interventions.MethodsData on HGRT were collected from 14 Level-1 trauma centers from 2014 to 2017. Patients with initial computed tomography scans were included. Two radiologists reviewed the scans to regrade the injuries according to the 1989 and 2018 AAST grading systems. Descriptive statistics were used to assess grade reclassifications. Mixed-effect multivariable logistic regression was used to measure the predictive ability of each grading system. The areas under the curves were compared.ResultsOf the 322 injuries included, 27.0% were upgraded, 3.4% were downgraded, and 69.5% remained unchanged. Of the injuries graded as III or lower using the 1989 AAST, 33.5% were upgraded to grade IV using the 2018 AAST. Of the grade V injuries, 58.8% were downgraded using the 2018 AAST. There was no statistically significant difference in the overall areas under the curves between the 2018 and 1989 AAST grading system for predicting bleeding interventions (0.72 vs. 0.68, p = 0.34).ConclusionAbout one third of the injuries previously classified as grade III will be upgraded to grade IV using the 2018 AAST, which adds to the heterogeneity of grade IV injuries. Although the 2018 AAST grading provides more anatomic details on injury patterns and includes important radiologic findings, it did not outperform the 1989 AAST grading in predicting bleeding interventions.Level of evidencePrognostic and Epidemiological Study, level III

PXR-mediated metabolism during pregnancy and cholestasis

Nuclear receptors, including the pregnane x receptor (PXR) and the farnesoid x receptor (FXR), regulate the expression of genes that maintain bile acid (BA) homeostasis. Intrahepatic cholestasis of pregnancy (ICP) is a common gestational liver disease and BAs are implicated in its pathogenesis. Rodents exhibit maternal liver growth in order to meet the metabolic demands of pregnancy. This process is found to precede changes in body weight, occur in the presence of raised serum BAs and is likely to be driven by a placental lactogen. While the growth is normally achieved by hepatocyte hypertrophy, potentially harmful hyperplasia makes a major contribution in mice lacking Fxr. Consistent with reports of raised serum BAs in normal pregnant women, hepatic BAs are found in association with pro-cholestatic gene expression in normal pregnant mice. Gestation could be a state of reduced Fxr function because BA-fed and Fxr-/- mice do not develop raised hepatic BAs during pregnancy. Sequencing and functional assessment of PXR variants revealed that polymorphisms in this gene are unlikely to contribute to the aetiology of ICP. Surprisingly, Pxr-/- mice have enhanced hepatic metabolism and are resistant to toxicity caused by lithocholic acid (LCA). Furthermore, while hepatic Pxr is activated by intraperitoneal injection of LCA, it is not activated by physiologically relevant LCA-feeding. Summary: Pregnancy causes liver growth, raised hepatic BA and pro-cholestatic gene expression in normal mice. In humans, these adaptations may expose predisposed individuals to gestational liver disease. Genetic variation in PXR does not contribute to ICP and Pxr may play only a limited role in mediating hepatic responses to toxic BAs.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The Associations Between Initial Radiographic Findings and Interventions for Renal Hemorrhage After High-Grade Renal Trauma: Results from the Multi-institutional Genito-Urinary Trauma Study (MiGUTS).

BACKGROUND:Indications for intervention after high-grade renal trauma (HGRT) remain poorly defined. Certain radiographic findings can be used to guide the management of HGRT. We aimed to assess the associations between initial radiographic findings and interventions for hemorrhage after HGRT and to determine hematoma and laceration sizes predicting interventions. METHODS:The Genito-Urinary Trauma Study is a multi-center study including HGRT patients from 14 Level-1 trauma centers from 2014-2017. Admission CT scans were categorized based upon multiple variables, including vascular contrast extravasation (VCE), hematoma rim distance (HRD), and size of the deepest laceration. Renal bleeding interventions included: angioembolization, surgical packing, renorrhaphy, partial nephrectomy, and nephrectomy. Mixed effect Poisson regression was used to assess the associations. Receiver operating characteristic analysis was used to define optimal cut-offs for HRD and laceration size. RESULTS:In the 326 patients, injury mechanism was blunt in 81%. Forty-seven patients (14%) underwent 51 bleeding interventions including 19 renal angioembolizations, 16 nephrectomies, and 16 other procedures. In univariable analysis, presence of VCE was associated with a 5.9-fold increase in risk of interventions, and each centimeter increase in HRD was associated with 30% increase in risk of bleeding interventions. An HRD ≥3.5cm and renal laceration depth of ≥2.5cm were most predictive of interventions. In multivariable models, VCE and HRD were significantly associated with bleeding interventions. CONCLUSION:Our findings support the importance of certain radiographic findings in prediction of bleeding interventions after HGRT. These factors can be used as adjuncts to renal injury grading to guide clinical decision making. LEVEL OF EVIDENCE:Prognostic and Epidemiological Study, Level III

The associations between initial radiographic findings and interventions for renal hemorrhage after high-grade renal trauma: Results from the Multi-Institutional Genitourinary Trauma Study.

BackgroundIndications for intervention after high-grade renal trauma (HGRT) remain poorly defined. Certain radiographic findings can be used to guide the management of HGRT. We aimed to assess the associations between initial radiographic findings and interventions for hemorrhage after HGRT and to determine hematoma and laceration sizes predicting interventions.MethodsThe Genitourinary Trauma Study is a multicenter study including HGRT patients from 14 Level I trauma centers from 2014 to 2017. Admission computed tomography scans were categorized based on multiple variables, including vascular contrast extravasation (VCE), hematoma rim distance (HRD), and size of the deepest laceration. Renal bleeding interventions included angioembolization, surgical packing, renorrhaphy, partial nephrectomy, and nephrectomy. Mixed-effect Poisson regression was used to assess the associations. Receiver operating characteristic analysis was used to define optimal cutoffs for HRD and laceration size.ResultsIn the 326 patients, injury mechanism was blunt in 81%. Forty-seven (14%) patients underwent 51 bleeding interventions, including 19 renal angioembolizations, 16 nephrectomies, and 16 other procedures. In univariable analysis, presence of VCE was associated with a 5.9-fold increase in risk of interventions, and each centimeter increase in HRD was associated with 30% increase in risk of bleeding interventions. An HRD of 3.5 cm or greater and renal laceration depth of 2.5 cm or greater were most predictive of interventions. In multivariable models, VCE and HRD were significantly associated with bleeding interventions.ConclusionOur findings support the importance of certain radiographic findings in prediction of bleeding interventions after HGRT. These factors can be used as adjuncts to renal injury grading to guide clinical decision making.Level of evidencePrognostic and Epidemiological Study, Level III and Therapeutic/Care Management, Level IV

The Associations Between Initial Radiographic Findings and Interventions for Renal Hemorrhage After High-Grade Renal Trauma: Results from the Multi-institutional Genito-Urinary Trauma Study (MiGUTS).

BACKGROUND:Indications for intervention after high-grade renal trauma (HGRT) remain poorly defined. Certain radiographic findings can be used to guide the management of HGRT. We aimed to assess the associations between initial radiographic findings and interventions for hemorrhage after HGRT and to determine hematoma and laceration sizes predicting interventions. METHODS:The Genito-Urinary Trauma Study is a multi-center study including HGRT patients from 14 Level-1 trauma centers from 2014-2017. Admission CT scans were categorized based upon multiple variables, including vascular contrast extravasation (VCE), hematoma rim distance (HRD), and size of the deepest laceration. Renal bleeding interventions included: angioembolization, surgical packing, renorrhaphy, partial nephrectomy, and nephrectomy. Mixed effect Poisson regression was used to assess the associations. Receiver operating characteristic analysis was used to define optimal cut-offs for HRD and laceration size. RESULTS:In the 326 patients, injury mechanism was blunt in 81%. Forty-seven patients (14%) underwent 51 bleeding interventions including 19 renal angioembolizations, 16 nephrectomies, and 16 other procedures. In univariable analysis, presence of VCE was associated with a 5.9-fold increase in risk of interventions, and each centimeter increase in HRD was associated with 30% increase in risk of bleeding interventions. An HRD ≥3.5cm and renal laceration depth of ≥2.5cm were most predictive of interventions. In multivariable models, VCE and HRD were significantly associated with bleeding interventions. CONCLUSION:Our findings support the importance of certain radiographic findings in prediction of bleeding interventions after HGRT. These factors can be used as adjuncts to renal injury grading to guide clinical decision making. LEVEL OF EVIDENCE:Prognostic and Epidemiological Study, Level III

A nomogram predicting the need for bleeding interventions after high-grade renal trauma: Results from the American Association for the Surgery of Trauma Multi-institutional Genito-Urinary Trauma Study (MiGUTS).

BACKGROUND:The management of high-grade renal trauma (HGRT) and the indications for intervention are not well defined. The American Association for the Surgery of Trauma (AAST) renal grading does not incorporate some important clinical and radiologic variables associated with increased risk of interventions. We aimed to use data from a multi-institutional contemporary cohort to develop a nomogram predicting risk of interventions for bleeding after HGRT. METHODS:From 2014 to 2017, data on adult HGRT (AAST grades III-V) were collected from 14 level 1 trauma centers. Patients with both clinical and radiologic data were included. Data were gathered on demographics, injury characteristics, management, and outcomes. Clinical and radiologic parameters, obtained after trauma evaluation, were used to predict renal bleeding interventions. We developed a prediction model by applying backward model selection to a logistic regression model and built a nomogram using the selected model. RESULTS:A total of 326 patients met the inclusion criteria. Mechanism of injury was blunt in 81%. Median age and injury severity score were 28 years and 22, respectively. Injuries were reported as AAST grades III (60%), IV (33%), and V (7%). Overall, 47 (14%) underwent interventions for bleeding control including 19 renal angioembolizations, 16 nephrectomies, and 12 other procedures. Of the variables included in the nomogram, a hematoma size of 12 cm contributed the most points, followed by penetrating trauma mechanism, vascular contrast extravasation, pararenal hematoma extension, concomitant injuries, and shock. The area under the receiver operating characteristic curve was 0.83 (95% confidence interval, 0.81-0.85). CONCLUSION:We developed a nomogram that integrates multiple clinical and radiologic factors readily available upon assessment of patients with HGRT and can provide predicted probability for bleeding interventions. This nomogram may help in guiding appropriate management of HGRT and decreasing unnecessary interventions. LEVEL OF EVIDENCE:Prognostic and epidemiological study, level III

The American Association for the Surgery of Trauma renal injury grading scale: Implications of the 2018 revisions for injury reclassification and predicting bleeding interventions.

BackgroundIn 2018, the American Association for the Surgery of Trauma (AAST) published revisions to the renal injury grading system to reflect the increased reliance on computed tomography scans and non-operative management of high-grade renal trauma (HGRT). We aimed to evaluate how these revisions will change the grading of HGRT and if it outperforms the original 1989 grading in predicting bleeding control interventions.MethodsData on HGRT were collected from 14 Level-1 trauma centers from 2014 to 2017. Patients with initial computed tomography scans were included. Two radiologists reviewed the scans to regrade the injuries according to the 1989 and 2018 AAST grading systems. Descriptive statistics were used to assess grade reclassifications. Mixed-effect multivariable logistic regression was used to measure the predictive ability of each grading system. The areas under the curves were compared.ResultsOf the 322 injuries included, 27.0% were upgraded, 3.4% were downgraded, and 69.5% remained unchanged. Of the injuries graded as III or lower using the 1989 AAST, 33.5% were upgraded to grade IV using the 2018 AAST. Of the grade V injuries, 58.8% were downgraded using the 2018 AAST. There was no statistically significant difference in the overall areas under the curves between the 2018 and 1989 AAST grading system for predicting bleeding interventions (0.72 vs. 0.68, p = 0.34).ConclusionAbout one third of the injuries previously classified as grade III will be upgraded to grade IV using the 2018 AAST, which adds to the heterogeneity of grade IV injuries. Although the 2018 AAST grading provides more anatomic details on injury patterns and includes important radiologic findings, it did not outperform the 1989 AAST grading in predicting bleeding interventions.Level of evidencePrognostic and Epidemiological Study, level III

A nomogram predicting the need for bleeding interventions after high-grade renal trauma: Results from the American Association for the Surgery of Trauma Multi-institutional Genito-Urinary Trauma Study (MiGUTS).

BACKGROUND:The management of high-grade renal trauma (HGRT) and the indications for intervention are not well defined. The American Association for the Surgery of Trauma (AAST) renal grading does not incorporate some important clinical and radiologic variables associated with increased risk of interventions. We aimed to use data from a multi-institutional contemporary cohort to develop a nomogram predicting risk of interventions for bleeding after HGRT. METHODS:From 2014 to 2017, data on adult HGRT (AAST grades III-V) were collected from 14 level 1 trauma centers. Patients with both clinical and radiologic data were included. Data were gathered on demographics, injury characteristics, management, and outcomes. Clinical and radiologic parameters, obtained after trauma evaluation, were used to predict renal bleeding interventions. We developed a prediction model by applying backward model selection to a logistic regression model and built a nomogram using the selected model. RESULTS:A total of 326 patients met the inclusion criteria. Mechanism of injury was blunt in 81%. Median age and injury severity score were 28 years and 22, respectively. Injuries were reported as AAST grades III (60%), IV (33%), and V (7%). Overall, 47 (14%) underwent interventions for bleeding control including 19 renal angioembolizations, 16 nephrectomies, and 12 other procedures. Of the variables included in the nomogram, a hematoma size of 12 cm contributed the most points, followed by penetrating trauma mechanism, vascular contrast extravasation, pararenal hematoma extension, concomitant injuries, and shock. The area under the receiver operating characteristic curve was 0.83 (95% confidence interval, 0.81-0.85). CONCLUSION:We developed a nomogram that integrates multiple clinical and radiologic factors readily available upon assessment of patients with HGRT and can provide predicted probability for bleeding interventions. This nomogram may help in guiding appropriate management of HGRT and decreasing unnecessary interventions. LEVEL OF EVIDENCE:Prognostic and epidemiological study, level III

Optimal timing of delayed excretory phase computed tomography scan for diagnosis of urinary extravasation after high-grade renal trauma.

BackgroundExcretory phase computed tomography (CT) scan is used for diagnosis of renal collecting system injuries and accurate grading of high-grade renal trauma. However, optimal timing of the excretory phase is not well established. We hypothesized that there is an association between excretory phase timing and diagnosis of urinary extravasation and aimed to identify the optimal excretory phase timing for diagnosis of urinary extravasation.MethodsThe Genito-Urinary Trauma Study collected data on high-grade renal trauma (grades III-V) from 14 Level I trauma centers between 2014 and 2017. The time between portal venous and excretory phases at initial CT scans was recorded. Poisson regression was used to measure the association between excretory phase timing and diagnosis of urinary extravasation. Predictive receiver operating characteristic analysis was used to identify a cutoff point optimizing detection of urinary extravasation.ResultsOverall, 326 patients were included; 245 (75%) had excretory phase CT scans for review either initially (n = 212) or only at their follow-up (n = 33). At initial CT with excretory phase, 46 (22%) of 212 patients were diagnosed with urinary extravasation. Median time between portal venous and excretory phases was 4 minutes (interquartile range, 4-7 minutes). Time of initial excretory phase was significantly greater in those diagnosed with urinary extravasation. Increased time to excretory phase was positively associated with finding urinary extravasation at the initial CT scan after controlling for multiple factors (risk ratio per minute, 1.15; 95% confidence interval, 1.09-1.22; p < 0.001). The optimal delay for detection of urinary extravasation was 9 minutes.ConclusionTiming of the excretory phase is a significant factor in accurate diagnosis of renal collecting system injury. A 9-minute delay between the early and excretory phases optimized detection of urinary extravasation.Level of evidenceDiagnostic tests/criteria study, level III