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Song I, Thompson EW, Verma A, MacLean MT, Duda J, Elahi A, Tran R, Raghupathy P, Swago S, Hazim M, Bhattaru A, Schneider C, Vujkovic M, Torigian DA, Kahn CE, Gee JC, Borthakur A, Kripke CM, Carson CC, Carr R, Jehangir Q, Ko YA, Litt H, Rosen M, Mankoff DA, Schnall MD, Shou H, Chirinos J, Damrauer SM, Serper M, Chen J, Rader DJ, Witschey WRT, Sagreiya H. Clinical correlates of CT imaging-derived phenotypes among lean and overweight patients with hepatic steatosis. Sci Rep 2024; 14:53. [PMID: 38167550 PMCID: PMC10761858 DOI: 10.1038/s41598-023-49470-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 12/08/2023] [Indexed: 01/05/2024] Open
Abstract
The objective of this study is to define CT imaging derived phenotypes for patients with hepatic steatosis, a common metabolic liver condition, and determine its association with patient data from a medical biobank. There is a need to further characterize hepatic steatosis in lean patients, as its epidemiology may differ from that in overweight patients. A deep learning method determined the spleen-hepatic attenuation difference (SHAD) in Hounsfield Units (HU) on abdominal CT scans as a quantitative measure of hepatic steatosis. The patient cohort was stratified by BMI with a threshold of 25 kg/m2 and hepatic steatosis with threshold SHAD ≥ - 1 HU or liver mean attenuation ≤ 40 HU. Patient characteristics, diagnoses, and laboratory results representing metabolism and liver function were investigated. A phenome-wide association study (PheWAS) was performed for the statistical interaction between SHAD and the binary characteristic LEAN. The cohort contained 8914 patients-lean patients with (N = 278, 3.1%) and without (N = 1867, 20.9%) steatosis, and overweight patients with (N = 1863, 20.9%) and without (N = 4906, 55.0%) steatosis. Among all lean patients, those with steatosis had increased rates of cardiovascular disease (41.7 vs 27.8%), hypertension (86.7 vs 49.8%), and type 2 diabetes mellitus (29.1 vs 15.7%) (all p < 0.0001). Ten phenotypes were significant in the PheWAS, including chronic kidney disease, renal failure, and cardiovascular disease. Hepatic steatosis was found to be associated with cardiovascular, kidney, and metabolic conditions, separate from overweight BMI.
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Affiliation(s)
- Isabel Song
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Elizabeth W Thompson
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Anurag Verma
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Matthew T MacLean
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jeffrey Duda
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Ameena Elahi
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Richard Tran
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Pavan Raghupathy
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Sophia Swago
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Mohamad Hazim
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Abhijit Bhattaru
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Carolin Schneider
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Marijana Vujkovic
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Drew A Torigian
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Charles E Kahn
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - James C Gee
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Arijitt Borthakur
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Colleen M Kripke
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Christopher C Carson
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Rotonya Carr
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA
| | - Qasim Jehangir
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Yi-An Ko
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Harold Litt
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Mark Rosen
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - David A Mankoff
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Mitchell D Schnall
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Haochang Shou
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Julio Chirinos
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Scott M Damrauer
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Marina Serper
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jinbo Chen
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Daniel J Rader
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Walter R T Witschey
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - Hersh Sagreiya
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA.
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Applications, Challenges, and Outlook for PBPK Modeling and Simulation: A Regulatory, Industrial and Academic Perspective. Pharm Res 2022; 39:1701-1731. [PMID: 35552967 DOI: 10.1007/s11095-022-03274-2] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 04/25/2022] [Indexed: 12/20/2022]
Abstract
Several regulatory guidances on the use of physiologically based pharmacokinetic (PBPK) analyses and physiologically based biopharmaceutics model(s) (PBBM(s)) have been issued. Workshops are routinely held, demonstrating substantial interest in applying these modeling approaches to address scientific questions in drug development. PBPK models and PBBMs have remarkably contributed to model-informed drug development (MIDD) such as anticipating clinical PK outcomes affected by extrinsic and intrinsic factors in general and specific populations. In this review, we proposed practical considerations for a "base" PBPK model construction and development, summarized current status, challenges including model validation and gaps in system models, and future perspectives in PBPK evaluation to assess a) drug metabolizing enzyme(s)- or drug transporter(s)- mediated drug-drug interactions b) dosing regimen prediction, sampling timepoint selection and dose validation in pediatric patients from newborns to adolescents, c) drug exposure in patients with renal and/or and hepatic organ impairment, d) maternal-fetal drug disposition during pregnancy, and e) pH-mediated drug-drug interactions in patients treated with proton pump inhibitors/acid-reducing agents (PPIs/ARAs) intended for gastric protection. Since PBPK can simulate outcomes in clinical studies with enrollment challenges or ethical issues, the impact of PBPK models on waivers and how to strengthen study waiver is discussed.
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Abstract
Continuous renal replacement therapy is an important, yet challenging, treatment of critically ill patients with kidney dysfunction. Clotting within the dialysis filter or circuit leads to time off therapy and impaired delivery of prescribed treatment. Anticoagulation can be used to prevent this complication; however, doing so introduces risk for unintended complications such as bleeding or metabolic derangements in patients who are already critically ill. A thorough understanding of indications, therapeutic options, and monitoring principles is necessary for safe and effective use of this strategy. This review provides clinicians important information regarding when to anticoagulate, differences in pharmacologic agents, recommended doses, routes of drug delivery, and appropriate laboratory monitoring for patients receiving anticoagulation to support continuous renal replacement therapy.
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Terres AZ, Balbinot RS, Muscope ALF, Longen ML, Schena B, Cini BT, Luis Rost G, Balensiefer JIL, Eberhardt LZ, Balbinot RA, Balbinot SS, Soldera J. Evidence-based protocol for diagnosis and treatment of hepatorenal syndrome is independently associated with lower mortality. GASTROENTEROLOGIA Y HEPATOLOGIA 2022; 45:25-39. [PMID: 33746028 DOI: 10.1016/j.gastrohep.2021.02.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 01/22/2021] [Accepted: 02/05/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatorenal syndrome (HRS) is the deadliest complication of cirrhosis. The purpose of this study is to analyze if the use of a protocol for HRS is associated with higher survival in these patients. METHODS An evidence-based protocol for the diagnosis and treatment of HRS was instituted in 2013. Data from medical records from 2010 to 2016 were obtained by searching the hospital database for patients who received terlipressin, in the three years before and after the institution of the protocol. Data were reviewed to confirm the diagnosis of HRS and multiple variables were collected. Liver-specific scores were calculated and a stepwise Cox regression approach was used for univariate and multivariate analysis. RESULTS The study included 46 patients, 20 from the pre-protocol period and 26 from the post-protocol period. Respectively, mortality at 30 days, 90 days and 365 days was 75%, 75% and 90% for the pre-protocol period, and 61%, 69% and 80% for the post-protocol period. In the multivariate analysis, an aspartate aminotransferase (AST) of <40U/L, the pre-protocol period and higher Child-Turcotte-Pugh scores were associated with higher 30-day and 90-day mortality. The total mean dose of terlipressin and human albumin used per patient was reduced from 27mg to 22mg and from 236g to 144g, respectively, after the institution of the protocol. This was not associated with higher mortality. CONCLUSION The use of an evidence-based protocol for the treatment of HRS translated into a higher survival. The authors suggest that the use of evidence-based protocols for the diagnosis and treatment of HRS could reduce cost and mortality in tertiary hospitals.
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Affiliation(s)
- Alana Zulian Terres
- Internal Medicine, Hospital Pompeia, Caxias do Sul, RS, Brazil; Gastroenterology, Hospital Geral de Caxias do Sul (RS), Brazil
| | - Rafael Sartori Balbinot
- Residency in Internal Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil; Faculty of Medicine, Universidade de Caxias do Sul, Caxias do Sul, RS, Brazil
| | | | | | - Bruna Schena
- Faculty of Medicine, Universidade de Caxias do Sul, Caxias do Sul, RS, Brazil
| | - Bruna Teston Cini
- Faculty of Medicine, Universidade de Caxias do Sul, Caxias do Sul, RS, Brazil
| | - Gilberto Luis Rost
- Faculty of Medicine, Universidade de Caxias do Sul, Caxias do Sul, RS, Brazil
| | | | | | - Raul Angelo Balbinot
- Clinical Gastroenterology, Universidade de Caxias do Sul (UCS), Caxias do Sul, RS, Brazil; Department of Gastroenterology, Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - Silvana Sartori Balbinot
- Clinical Gastroenterology, Universidade de Caxias do Sul (UCS), Caxias do Sul, RS, Brazil; Department of Gastroenterology, Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - Jonathan Soldera
- Clinical Gastroenterology, Universidade de Caxias do Sul (UCS), Caxias do Sul, RS, Brazil; Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil.
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Trends and outcomes of infective endocarditis in cirrhosis: a propensity-matched national study. Eur J Gastroenterol Hepatol 2021; 33:e580-e586. [PMID: 35048650 DOI: 10.1097/meg.0000000000002177] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND Cirrhosis is the most common cause of liver-related death and bacterial infection is a common comorbidity in cirrhosis. We aimed to study the trends and outcomes of infective endocarditis in cirrhosis. METHODS A propensity-matched analysis of the National Inpatient Sample database was performed to assess outcomes of infective endocarditis in adult patients (>18 years) from 2004-2013 with and without cirrhosis. Various outcomes were assessed for outcomes of infective endocarditis in cirrhosis. Multivariate regression analysis was performed for predictors of mortality in infective endocarditis. RESULTS There has been no significant change in incidence (3.3-3.6%, P = 0.27) and overall mortality (6.3-8.6%, P = 0.42) of infective endocarditis in cirrhosis. After propensity matching, patients with cirrhosis had significantly higher in-hospital mortality (15 vs. 10.6%, P < 0.001) and acute kidney injury (AKI) (31.8 vs. 28.5%, P < 0.001) as compared to no cirrhosis. Microbiological analysis revealed significantly higher rates of streptococci (35.3 vs. 31.9%, P < 0.001) and fungal infective endocarditis (0.03 vs. 0%, P < 0.001) and lower incidence of Gram-negative infective endocarditis (3.9 vs. 6.3%, P < 0.001) in cirrhosis. Cirrhosis patients had significantly less surgical intervention (10.2 vs. 30.3%, P < 0.001) along with overall total cost and length of stay as compared to no cirrhosis. On multivariate analysis, advanced age, AKI, shock and mechanical ventilation were positive predictors of mortality in infective endocarditis patients with cirrhosis patients. CONCLUSIONS Cirrhosis is an independent predictor of mortality in infective endocarditis with worse outcomes and less surgical intervention. Gram-negative infective endocarditis is lower in cirrhosis, whereas streptococci and fungal infective endocarditis are higher than noncirrhotic patients.
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Ponce D, Zamoner W, Dias DB, Pires da Rocha E, Kojima C, Balbi AL. The Role of Peritoneal Dialysis in the Treatment of Acute Kidney Injury in Patients With Acute-on-Chronic Liver Failure: A Prospective Brazilian Study. Front Med (Lausanne) 2021; 8:713160. [PMID: 34631735 PMCID: PMC8496932 DOI: 10.3389/fmed.2021.713160] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 08/27/2021] [Indexed: 11/25/2022] Open
Abstract
This study aimed to explore the role of peritoneal dialysis (PD) in acute-on-chronic liver disease (ACLD) in relation to metabolic and fluid control and outcome. Fifty-three patients were treated by PD (prescribed Kt/V = 0.40/session), with a flexible catheter, tidal modality, using a cycler and lactate as a buffer. The mean age was 64.8 ± 13.4 years, model of end stage liver disease (MELD) was 31 ± 6, 58.5% were in the intensive care unit, 58.5% needed intravenous inotropic agents including terlipressin, 69.5% were on mechanical ventilation, alcoholic liver disease was the main cause of cirrhosis and the main dialysis indications were uremia and hypervolemia. Blood urea and creatinine levels stabilized after four sessions at around 50 and 2.5 mg/dL, respectively. Negative fluid balance (FB) and ultrafiltration (UF) increased progressively and stabilized around 3.0 L and -2.7 L/day, respectively. Weekly-delivered Kt/V was 2.7 ± 0.37, and 71.7% of patients died. Five factors met the criteria for inclusion in the multivariable analysis. Logistic regression identified as risk factors associated with Acute Kidney Injury (AKI) in ACLD patients: MELD (OR = 1.14, CI 95% = 1.09-2.16, p = 0.001), nephrotoxic AKI (OR = 0.79, CI 95% = 0.61-0.93, p = 0.02), mechanical ventilation (OR = 1.49, CI 95% = 1.14-2.97, p < 0.001), and positive fluid balance (FB) after two PD sessions (OR = 1.08, CI 95% = 1.03-1.91, p = 0.007). These factors were significantly associated with death. In conclusion, our study suggests that careful prescription may contribute to providing adequate treatment for most Acute-on-Chronic Liver Failure (ACLF) patients without contraindications for PD use, allowing adequate metabolic and fluid control, with no increase in the number of infectious or mechanical complications. MELD, mechanical complications and FB were factors associated with mortality, while nephrotoxic AKI was a protective factor. Further studies are needed to better investigate the role of PD in ACLF patients with AKI.
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Affiliation(s)
- Daniela Ponce
- Department of Internal Medicine, Botucatu Medical School – University of São Paulo State – UNESP, São Paulo, Brazil
| | - Welder Zamoner
- Botucatu Medical School – University of São Paulo State – UNESP, São Paulo, Brazil
| | | | - Erica Pires da Rocha
- Botucatu Medical School – University of São Paulo State – UNESP, São Paulo, Brazil
| | - Christiane Kojima
- Botucatu Medical School – University of São Paulo State – UNESP, São Paulo, Brazil
| | - André Luís Balbi
- Department of Internal Medicine, Botucatu Medical School – University of São Paulo State – UNESP, São Paulo, Brazil
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Rey I, Effendi-Ys R. Association Between Serum IL-6, IL-10, IL-12, and IL-23 Levels and Severity of Liver Cirrhosis. Med Arch 2021; 75:199-203. [PMID: 34483450 PMCID: PMC8385729 DOI: 10.5455/medarh.2021.75.199-203] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 06/15/2021] [Indexed: 11/03/2022] Open
Abstract
Background Liver cirrhosis contributes to high liver-related mortality globally. Systemic inflammation mediated by immune cells contributes to the progression of liver cirrhosis. Growing evidence shows that several pro- and anti-inflammatory cytokines might have an important role in liver cirrhosis. Objective To evaluate the association between serum IL-6, IL-10, IL-12, and IL-23 levels and severity of liver cirrhosis. Methods This observational study was carried out at the Department of Internal Medicine, Universitas Sumatera Utara, Indonesia from March 2018 to August 2019. The severity of liver cirrhosis was assessed by using the Child-Pugh score. IL-6, IL-10, IL-12, and IL-23 levels, hepatitis and renal function were measured in all study subjects. Independent t-test and Mann-Whitney tests were conducted to observe differences between groups. Results A total of 78 liver cirrhosis patients were enrolled, mean age was 50.6±11.4. Median serum IL-6, IL-10, IL-12, and IL-23 levels were 24.5(2.6-46.4)pg/ml, 2.1(0.4-9.3)pg/ml, 3.5(1.4-20.8)pg/ml and 20.3(9.2-218)pg/ml, respectively. A higher IL-6 level was associated with more severe liver cirrhosis (p=0.001) and the presence of hepatic encephalopathy (p=0.018). Higher IL-23 level was found in patients with no hepatic encephalopathy (p=0.049). There was no association between serum cytokines levels and hepatitis viral infection status. Conclusion IL-6 is associated with the severity of liver cirrhosis.
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Affiliation(s)
- Imelda Rey
- Division of Gastroenterohepatology, Department of Internal Medicine, Universitas Sumatera Utara, Medan, Indonesia.,Haji Adam Malik General Hospital, Medan Indonesia
| | - Rustam Effendi-Ys
- Division of Gastroenterohepatology, Department of Internal Medicine, Universitas Sumatera Utara, Medan, Indonesia.,"dr. Pirngadi" General Hospital, Medan Indonesia
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Molinari M, Fernandez-Carrillo C, Dai D, Dana J, Clemente-Sanchez A, Dharmayan S, Kaltenmeier C, Liu H, Behari J, Rachakonda V, Ganesh S, Hughes C, Tevar A, Al Harakeh H, Emmanuel B, Humar A, Bataller R. Portal vein thrombosis and renal dysfunction: a national comparative study of liver transplant recipients for NAFLD versus alcoholic cirrhosis. Transpl Int 2021; 34:1105-1122. [PMID: 33780554 PMCID: PMC8360094 DOI: 10.1111/tri.13873] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/08/2021] [Accepted: 03/19/2021] [Indexed: 12/13/2022]
Abstract
The prevalence of portal vein thrombosis (PVT), renal dysfunction (RD), and simultaneous PVT/RD in liver transplantation (LT) is poorly understood. We analyzed the prevalence of PVT, RD, simultaneous PVT/RD, and the outcomes of adult recipients of LT for nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) between 2006 and 2016 in the United States. We found that the prevalence of PVT (7.2% → 11.3%), RD (33.8% → 39.2%), and simultaneous PVT/RD (2.4% → 4.5%) has increased significantly over the study period (all P‐values <0.05). NAFLD patients had a higher proportion of PVT (14.8% vs. 9.2%), RD (45.0% vs. 42.1%), and simultaneous PVT/RD (6.5% vs. 3.9%; all P‐values <0.05). 90‐day mortality was 3.8%, 6.3%, 6.8%, and 9.8% for PVT(−)/RD(−), PVT(−)/RD(+), PVT(+)/RD(−), and PVT(+)/RD(+) recipients, respectively (P < 0.01). 5‐year survival was 82.1%, 75.5%, 74.8%, and 71.1% for PVT(−)/RD(−), PVT(−)/RD(+), PVT(+)/RD(−), and PVT(+)/RD(+) recipients, respectively (P < 0.05). In conclusion, the prevalence of PVT, RD, and simultaneous PVT/RD has increased among LT recipients, especially for those with NAFLD. The short‐ and long‐term outcomes of recipients with PVT, RD, and simultaneous PVT/RD were inferior to patients without those risk factors irrespective of their indication for LT. No differences in patient outcomes were found between ALD and NAFLD recipients after stratification by risk factors.
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Affiliation(s)
- Michele Molinari
- Department of Surgery, UPMC Montefiore Hospital, Pittsburgh, PA, USA
| | - Carlos Fernandez-Carrillo
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.,Department of Surgery, University of Leeds, Leeds, UK
| | - Dongling Dai
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Jorgensen Dana
- Department of Surgery, UPMC Montefiore Hospital, Pittsburgh, PA, USA
| | - Ana Clemente-Sanchez
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Stalin Dharmayan
- Department of Surgery, UPMC Montefiore Hospital, Pittsburgh, PA, USA
| | | | - Hao Liu
- Department of Surgery, UPMC Montefiore Hospital, Pittsburgh, PA, USA
| | - Jaideep Behari
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Vikrant Rachakonda
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Swaytha Ganesh
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | | | - Amit Tevar
- Department of Surgery, UPMC Montefiore Hospital, Pittsburgh, PA, USA
| | - Hasan Al Harakeh
- Department of Surgery, UPMC Montefiore Hospital, Pittsburgh, PA, USA
| | - Bishoy Emmanuel
- Department of Surgery, UPMC Montefiore Hospital, Pittsburgh, PA, USA
| | - Abhinav Humar
- Department of Surgery, UPMC Montefiore Hospital, Pittsburgh, PA, USA
| | - Ramon Bataller
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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Yu Y, Bai M, Ma F, Zhang W, Li Y, Zhao L, Li L, Zhou M, Li L, Sun S. Regional citrate anticoagulation versus no-anticoagulation for continuous venovenous hemofiltration in patients with liver failure and increased bleeding risk: A retrospective case-control study. PLoS One 2020; 15:e0232516. [PMID: 32369523 PMCID: PMC7199954 DOI: 10.1371/journal.pone.0232516] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 04/16/2020] [Indexed: 01/01/2023] Open
Abstract
Objective There are controversial opinions on anticoagulation for continuous venovenous hemofiltration (CVVH) in patients with liver failure (LF) and increased bleeding risk. Therefore, we conducted a retrospective study to evaluate the efficacy and safety of regional citrate anticoagulation (RCA) versus no-anticoagulation for CVVH in these patients. Methods The included patients were divided into RCA and no-anticoagulation group according to the CVVH anticoagulation strategy they accepted for CVVH. Filter lifespan, bleeding, citrate accumulation, catheter occlusion, and totCa/ionCa ratio were evaluated as outcomes. Results In the original cohort, the filter lifespan of the RCA group (41 patients, 79 filters) was significantly longer than the no-anticoagulation group (62 patients, 162 filters) (> 72 hours vs 39.5 hours (IQR 31.2–47.8), P = 0.002). The adjusted results demonstrated that RCA could significantly reduce the risk of filter failure (HR = 0.459, 95%CI 0.26–0.82, P = 0.008). Four episodes of totCa/ionCa > 2.5 were observed in the RCA group and continuously accepted RCA-CVVH after the reduction of citrate dose and blood flow. No obvious citrate accumulation was observed in these patients. In the matched cohort, the filter lifespan of the RCA group was significantly longer than the no-anticoagulation group (P = 0.013) as well. No significant difference in the episodes of totCa/ionCa > 2.5 was observed between the two matched groups (P = 0.074). Both in the original cohort and the matched cohort, the bleeding, acidosis, alkalosis, and catheter occlusion incidences were not significantly different between the two groups. Conclusions In LF patients with increased bleeding risk who underwent CVVH, RCA could prolong the filter lifespan and be safely used with careful blood gas monitoring and citrate dose adjusting. Further prospective, randomized, control studies are warranted to obtain robust evidences.
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Affiliation(s)
- Yan Yu
- Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Shaanxi, China
| | - Ming Bai
- Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Shaanxi, China
- * E-mail: (MB); (SS)
| | - Feng Ma
- Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Shaanxi, China
| | - Wei Zhang
- Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Shaanxi, China
| | - Yangping Li
- Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Shaanxi, China
| | - Lijuan Zhao
- Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Shaanxi, China
| | - Li Li
- Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Shaanxi, China
| | - Meilan Zhou
- Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Shaanxi, China
| | - Lu Li
- Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Shaanxi, China
| | - Shiren Sun
- Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Shaanxi, China
- * E-mail: (MB); (SS)
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Hu ZH, Kong YY, Ren JJ, Huang TJ, Wang YQ, Liu LX. Kidney and lung tissue modifications after BDL-induced liver injury in mice are associated with increased expression of IGFBPrP1 and activation of the NF-κB inflammation pathway. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2020; 13:192-202. [PMID: 32211099 PMCID: PMC7061808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 01/23/2020] [Indexed: 06/10/2023]
Abstract
BACKGROUND Hepatorenal and hepatopulmonary syndrome are common clinical diseases; however, their mechanisms have not been fully elucidated. Our aim was to determine whether liver injury by bile duct ligation (BDL) causes modifications in kidney and lung tissue in mice, and to explore the possible mechanism of these changes. METHODS BDL in mice was used as a research model. Pathologic changes of liver, kidney, and lung tissue were observed by hematoxylin-eosin (H&E) staining. The expression of IGFBPrP1, NF-κB, TNF-α, and IL-6 were investigated in liver, kidney, and lung tissue by immunohistochemical staining and western blot. The correlation between IGFBPrP1 and NF-κB, TNF-α, and IL-6 protein expression in liver, kidney, and lung tissues of each group was analyzed by the Pearson method. RESULTS H&E staining showed, after BDL administration in mice, different degrees of inflammatory change in liver, kidney, and lung tissues of mice in each group. The results of immunohistochemical staining and western blot analysis showed increased expressions of IGFBPrP1, NF-κB, TNF-α, and IL-6 after BDL. Pearson correlation analysis showed that IGFBPrP1 positively correlated with the expressions of NF-κB, TNF-α, and IL-6. CONCLUSION Liver injury caused by bile duct ligation can lead to kidney and lung tissue injury in mice. The mechanism of injury may be related to the high expression of liver injury factor IGFBPrP1, transcription factor NF-κB, proinflammatory cytokine TNF-α, and IL-6 in kidney and lung tissue. Moreover, an increased expression level of IGFBPrP1 may be accompanied by the activation of the NF-κB inflammatory pathway.
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Affiliation(s)
- Zhi-Hui Hu
- Department of Gastroenterology and Hepatology, The First Hospital of Shanxi Medical UniversityTaiyuan 030001, China
| | - Yang-Yang Kong
- Department of Gastroenterology and Hepatology, The First Hospital of Shanxi Medical UniversityTaiyuan 030001, China
| | - Jun-Jie Ren
- Department of Gastroenterology and Hepatology, The First Hospital of Shanxi Medical UniversityTaiyuan 030001, China
| | - Ting-Juan Huang
- Department of Gastroenterology and Hepatology, The First Hospital of Shanxi Medical UniversityTaiyuan 030001, China
| | - Yan-Qin Wang
- Department of Gastroenterology and Hepatology, The First Hospital of Shanxi Medical UniversityTaiyuan 030001, China
| | - Li-Xin Liu
- Department of Gastroenterology and Hepatology, The First Hospital of Shanxi Medical UniversityTaiyuan 030001, China
- Experimental Center of Science and Research, The First Hospital of Shanxi Medical UniversityTaiyuan 030001, China
- Key Laboratory of Cell Physiology, Department of The Ministry of Education, Shanxi Medical UniversityTaiyuan 030001, China
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Wyawahare M, Krishna Reddy SS, Priyamvada PS, Rajendiran S. Utility of Urinary Neutrophil gelatinase associated lipocalin (NGAL) in decompensated cirrhosis. Indian J Nephrol 2020; 30:391-397. [PMID: 33840958 PMCID: PMC8023034 DOI: 10.4103/ijn.ijn_254_19] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/29/2019] [Accepted: 11/10/2019] [Indexed: 01/23/2023] Open
Abstract
Background and Aims: Renal failure occurring in the setting of cirrhosis increases mortality by more than threefold. Serum creatinine, the conventional marker for renal dysfunction has inherent limitations in identifying and categorizing renal dysfunction in patients with chronic liver disease (CLD). Neutrophil gelatinase associated lipocalin (NGAL) is a novel biomarker which gets upregulated as early as 2-6 hours following the insult to renal tubules. In this study, we aim to check the utility of uNGAL to identify the different phenotypes of renal dysfunction in patients with CLD. We also intend to assess the utility of NGAL to predict 90-day transplant-free survival in patients with CLD. Methods: A total number of 120 adult patients, with cirrhosis of liver were recruited. Those with pre-existing renal parenchymal disease, receiving nephrotoxic medications, spontaneous bacterial peritonitis, septic shock, proteinuria, hematuria, urinary tract infection and anuria were excluded. Urine samples for NGAL was measured at admission and at 48 hours thereafter. Patients were followed up for 90 days post admission. Results: Among the study population, 16 patients (13.3%) had normal kidney function, 43 (35.8%) had prerenal azotemia and 54 (45%) had Hepatorenal Syndrome (HRS - AKI) and 7 (5.8%) had acute tubular necrosis (ATN). Urinary NGAL (uNGAL) levels were considerably lower in patients with normal kidney function and prerenal azotemia. An uNGAL level of 124 ng/ml on admission could distinguish severe forms of renal injury, with a sensitivity of 86% and specificity of 84%. The non survivors had higher uNGAL levels at admission [209.6 ng/ml (118.7-376.8) vs. 123 (33.6-344.3); P = 0.013].The receiver operated curves for uNGAL and serum creatinine at admission did not show any significant difference for predicting 90 day mortality (AUC for uNGAL: 0.632 vs 0.580 for serum creatinine; difference in AUC 0.053, P value 0.17). Conclusion: uNGAL levels are elevated in patients with HRS-AKI and ATN. A higher uNGAL level at admission was suggestive of severe renal dysfunction. An elevated uNGAL on admission is associated with inferior survival. However, uNGAL is not superior to serum creatinine in predicting 90-day mortality.
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Wang JB, Gu Y, Zhang MX, Yang S, Wang Y, Wang W, Li XR, Zhao YT, Wang HT. High expression of type I inositol 1,4,5-trisphosphate receptor in the kidney of rats with hepatorenal syndrome. World J Gastroenterol 2018; 24:3273-3280. [PMID: 30090007 PMCID: PMC6079285 DOI: 10.3748/wjg.v24.i29.3273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 06/19/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To detect the expression of type I inositol 1,4,5-trisphosphate receptor (IP3RI) in the kidney of rats with hepatorenal syndrome (HRS). METHODS One hundred and twenty-five Sprague-Dawley rats were randomly divided into four groups to receive an intravenous injection of D-galactosamine (D-GalN) plus lipopolysaccharide (LPS; group G/L, n = 50), D-GalN alone (group G, n = 25), LPS alone (group L, n = 25), and normal saline (group NS, n = 25), respectively. At 3, 6, 9, 12, and 24 h after injection, blood, liver, and kidney samples were collected. Hematoxylin-eosin staining of liver tissue was performed to assess hepatocyte necrosis. Electron microscopy was used to observe ultrastructural changes in the kidney. Western blot analysis and real-time PCR were performed to detect the expression of IP3RI protein and mRNA in the kidney, respectively. RESULTS Hepatocyte necrosis was aggravated gradually, which was most significant at 12 h after treatment with D-galactosamine/lipopolysaccharide, and was characterized by massive hepatocyte necrosis. At the same time, serum levels of biochemical indicators including liver and kidney function indexes were all significantly changed. The structure of the renal glomerulus and tubules was normal at all time points. Western blot analysis indicated that IP3RI protein expression began to rise at 3 h (P < 0.05) and peaked at 12 h (P < 0.01). Real-time PCR demonstrated that IP3RI mRNA expression began to rise at 3 h (P < 0.05) and peaked at 9 h (P < 0.01). CONCLUSION IP3RI protein expression is increased in the kidney of HRS rats, and may be regulated at the transcriptional level.
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MESH Headings
- Animals
- Disease Models, Animal
- Galactosamine/toxicity
- Hepatocytes/pathology
- Hepatorenal Syndrome/chemically induced
- Hepatorenal Syndrome/pathology
- Humans
- Inositol 1,4,5-Trisphosphate Receptors/genetics
- Inositol 1,4,5-Trisphosphate Receptors/metabolism
- Kidney/blood supply
- Kidney/cytology
- Kidney/pathology
- Kidney/ultrastructure
- Lipopolysaccharides/toxicity
- Liver/cytology
- Liver/drug effects
- Liver/pathology
- Male
- Microscopy, Electron
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/pathology
- Myocytes, Smooth Muscle/ultrastructure
- Necrosis
- RNA, Messenger/metabolism
- Rats
- Rats, Sprague-Dawley
- Specific Pathogen-Free Organisms
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Affiliation(s)
- Jing-Bo Wang
- Liver Cirrhosis Ward, the Sixth People’s Hospital of Shenyang, Shenyang 110006, Liaoning Province, China
| | - Ye Gu
- Liver Cirrhosis Ward, the Sixth People’s Hospital of Shenyang, Shenyang 110006, Liaoning Province, China
| | - Ming-Xiang Zhang
- Liver Cirrhosis Ward, the Sixth People’s Hospital of Shenyang, Shenyang 110006, Liaoning Province, China
| | - Shun Yang
- Liaoning Cancer Hospital & Institute, Shenyang 110042, Liaoning Province, China
| | - Yan Wang
- Liver Cirrhosis Ward, the Sixth People’s Hospital of Shenyang, Shenyang 110006, Liaoning Province, China
| | - Wei Wang
- Liver Cirrhosis Ward, the Sixth People’s Hospital of Shenyang, Shenyang 110006, Liaoning Province, China
| | - Xi-Ran Li
- Liver Cirrhosis Ward, the Sixth People’s Hospital of Shenyang, Shenyang 110006, Liaoning Province, China
| | - Yi-Tong Zhao
- Liver Cirrhosis Ward, the Sixth People’s Hospital of Shenyang, Shenyang 110006, Liaoning Province, China
| | - Hai-Tao Wang
- Department of General Surgery, the Second Affiliated Hospital of Shenyang Medical College, Shenyang 110002, Liaoning Province, China
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Terra C, Mattos ÂZD, Pereira G, Farias AQ, Kondo M, Mattos AAD, Medeiros Filho JEMD, Strauss E, Dutra FRD, Mazza M, Lopes EP, Pereira TS, Schiavon LL, Carvalho Filho RJD, Fagundes C, Bittencourt PL. RECOMMENDATIONS OF THE BRAZILIAN SOCIETY OF HEPATOLOGY FOR THE MANAGEMENT OF ACUTE KIDNEY INJURY IN PATIENTS WITH CIRRHOSIS. ARQUIVOS DE GASTROENTEROLOGIA 2018; 55:314-320. [PMID: 30540097 DOI: 10.1590/s0004-2803.201800000-71] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Accepted: 06/11/2018] [Indexed: 12/11/2022]
Abstract
Acute kidney injury is a common complication of cirrhosis, occurring in up to 20% of patients hospitalized with cirrhosis. This field is rapidly changing, with significant advances in classification, biomarkers and therapy over the last few years. On the behalf of the Brazilian Society of Hepatology, a panel of experts in Hepatology and Nephrology reviewed published evidence to integrate findings and develop the recommendations presented in this manuscript.
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Affiliation(s)
- Carlos Terra
- Universidade do Estado do Rio de Janeiro, Faculdade de Medicina, Departamento de Gastroenterologia, RJ, Brasil
- Hospital Federal de Lagoa, Departamento de Gastroenterologia, Rio de Janeiro, RJ, Brasil
| | - Ângelo Zambam de Mattos
- Universidade Federal de Ciências da Saúde de Porto Alegre, Programa de Pós-Graduação em Medicina: Hepatologia, RS, Brasil
| | - Gustavo Pereira
- Hospital Federal de Bonsucesso, Serviço de Gastroenterologia e Hepatologia, Rio de Janeiro, RJ, Brasil
| | - Alberto Queiroz Farias
- Universidade de São Paulo, Faculdade de Medicina, Departamento de Gastroenterologia, SP, Brasil
| | - Mario Kondo
- Universidade Federal de São Paulo, Faculdade de Medicina, Departamento de Gastroenterologia, SP, Brasil
| | - Angelo Alves de Mattos
- Universidade Federal de Ciências da Saúde de Porto Alegre, Programa de Pós-Graduação em Medicina: Hepatologia, RS, Brasil
| | | | - Edna Strauss
- Universidade de São Paulo, Faculdade de Medicina, Departamento de Patologia, SP, Brasil
| | | | - Marcelo Mazza
- Universidade Federal do Paraná, Faculdade de Medicina, Departamento de Nefrologia, Curitiba, PR, Brasil
| | - Edmundo Pessoa Lopes
- Universidade Federal de Pernambuco, Faculdade de Medicina, Departamento de Medicina Clínica, Recife, PE, Brasil
| | - Tiago Sevá Pereira
- Universidade Estadual de Campinas, Faculdade Ciências Médicas, Disciplina de Gastroenterologia, Campinas, SP, Brasil
| | - Leonardo Lucca Schiavon
- Universidade Federal de Santa Catarina, Faculdade de Medicina, Departamento de Clínica Médica, Florianópolis, SC, Brasil
| | | | - Cláudia Fagundes
- Hospital Federal de Bonsucesso, Serviço de Nefrologia, Rio de Janeiro, RJ, Brasil
- Hospital São Francisco, Unidade de Transplante Renal, Rio de Janeiro, RJ, Brasil
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