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Vinke JSJ, Francke MI, Eisenga MF, Hesselink DA, de Borst MH. Iron deficiency after kidney transplantation. Nephrol Dial Transplant 2020; 36:1976-1985. [PMID: 32910168 PMCID: PMC8577626 DOI: 10.1093/ndt/gfaa123] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Indexed: 12/30/2022] Open
Abstract
Iron deficiency (ID) is highly prevalent in kidney transplant recipients (KTRs) and has been independently associated with an excess mortality risk in this population. Several causes lead to ID in KTRs, including inflammation, medication and an increased iron need after transplantation. Although many studies in other populations indicate a pivotal role for iron as a regulator of the immune system, little is known about the impact of ID on the immune system in KTRs. Moreover, clinical trials in patients with chronic kidney disease or heart failure have shown that correction of ID, with or without anaemia, improves exercise capacity and quality of life, and may improve survival. ID could therefore be a modifiable risk factor to improve graft and patient outcomes in KTRs; prospective studies are warranted to substantiate this hypothesis.
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Affiliation(s)
- Joanna Sophia J Vinke
- Department of Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Marith I Francke
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Michele F Eisenga
- Department of Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Martin H de Borst
- Department of Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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2
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Fallet E, Rayar M, Landrieux A, Camus C, Houssel-Debry P, Jezequel C, Legros L, Uguen T, Ropert-Bouchet M, Boudjema K, Guyader D, Bardou-Jacquet E. Iron metabolism imbalance at the time of listing increases overall and infectious mortality after liver transplantation. World J Gastroenterol 2020; 26:1938-1949. [PMID: 32390704 PMCID: PMC7201152 DOI: 10.3748/wjg.v26.i16.1938] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/30/2020] [Accepted: 04/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver transplantation (LT) is the best treatment for patients with liver cancer or end stage cirrhosis, but it is still associated with a significant mortality. Therefore identifying factors associated with mortality could help improve patient management. The impact of iron metabolism, which could be a relevant therapeutic target, yield discrepant results in this setting. Previous studies suggest that increased serum ferritin is associated with higher mortality. Surprisingly iron deficiency which is a well described risk factor in critically ill patients has not been considered. AIM To assess the impact of pre-transplant iron metabolism parameters on post-transplant survival. METHODS From 2001 to 2011, 553 patients who underwent LT with iron metabolism parameters available at LT evaluation were included. Data were prospectively recorded at the time of evaluation and at the time of LT regarding donor and recipient. Serum ferritin (SF) and transferrin saturation (TS) were studied as continuous and categorical variable. Cox regression analysis was used to determine mortality risks factors. Follow-up data were obtained from the local and national database regarding causes of death. RESULTS At the end of a 95-mo median follow-up, 196 patients were dead, 38 of them because of infections. In multivariate analysis, overall mortality was significantly associated with TS > 75% [HR: 1.73 (1.14; 2.63)], SF < 100 µg/L [HR: 1.62 (1.12; 2.35)], hepatocellular carcinoma [HR: 1.58 (1.15; 2.26)], estimated glomerular filtration rate (CKD EPI Cystatin C) [HR: 0.99 (0.98; 0.99)], and packed red blood cell transfusion [HR: 1.05 (1.03; 1.08)]. Kaplan Meier curves show that patients with low SF (< 100 µg/L) or high SF (> 400 µg/L) have lower survival rates at 36 mo than patients with normal SF (P = 0.008 and P = 0.016 respectively). Patients with TS higher than 75% had higher mortality at 12 mo (91.4% ± 1.4% vs 84.6% ± 3.1%, P = 0.039). TS > 75% was significantly associated with infection related death [HR: 3.06 (1.13; 8.23)]. CONCLUSION Our results show that iron metabolism imbalance (either deficiency or overload) is associated with post-transplant overall and infectious mortality. Impact of iron supplementation or depletion should be assessed in prospective study.
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Affiliation(s)
- Elodie Fallet
- Service des Maladies du Foie, CHU Rennes, University Rennes, Rennes 35033, France
| | - Michel Rayar
- Service de Chirurgie Hepatobilaire, CHU Rennes, University Rennes, Rennes 35033, France
| | - Amandine Landrieux
- Service des Maladies du Foie, CHU Rennes, University Rennes, Rennes 35033, France
| | - Christophe Camus
- Service de Réanimation médicale, CHU Rennes, University Rennes, Rennes 35033, France
| | - Pauline Houssel-Debry
- Service des Maladies du Foie, CHU Rennes, University Rennes, Rennes 35033, France
- Service de Chirurgie Hepatobilaire, CHU Rennes, University Rennes, Rennes 35033, France
| | - Caroline Jezequel
- Service des Maladies du Foie, CHU Rennes, University Rennes, Rennes 35033, France
| | - Ludivine Legros
- Service des Maladies du Foie, CHU Rennes, University Rennes, Rennes 35033, France
| | - Thomas Uguen
- Service des Maladies du Foie, CHU Rennes, University Rennes, Rennes 35033, France
| | | | - Karim Boudjema
- Service de Chirurgie Hepatobilaire, CHU Rennes, University Rennes, Rennes 35033, France
| | - Dominique Guyader
- Service des Maladies du Foie, CHU Rennes, University Rennes, Rennes 35033, France
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Litton E, Lim J. Iron Metabolism: An Emerging Therapeutic Target in Critical Illness. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2019; 23:81. [PMID: 30850005 PMCID: PMC6408790 DOI: 10.1186/s13054-019-2373-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2019. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2019. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.
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Affiliation(s)
- Edward Litton
- Intensive Care Unit, Fiona Stanley Hospital, Perth, Australia. .,School of Medicine, University of Western Australia, Perth, Australia.
| | - Jolene Lim
- Intensive Care Unit, Fiona Stanley Hospital, Perth, Australia
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Lan P, Pan KH, Wang SJ, Shi QC, Yu YX, Fu Y, Chen Y, Jiang Y, Hua XT, Zhou JC, Yu YS. High Serum Iron level is Associated with Increased Mortality in Patients with Sepsis. Sci Rep 2018; 8:11072. [PMID: 30038422 PMCID: PMC6056487 DOI: 10.1038/s41598-018-29353-2] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 07/03/2018] [Indexed: 12/26/2022] Open
Abstract
Iron is an essential nutrient for bacterial survival and thus higher iron levels may precipitate bacterial infections. We investigated the association between the serum iron level and prognosis in patients with sepsis by using the single-centre Medical Information Mart for Intensive Care III (MIMIC-III) database. Sepsis patients with iron parameters measured on ICU admission were included and stratified according to quartiles of serum iron levels. A total of 1,891 patients diagnosed with sepsis according to the Sepsis-3 criteria were included in this study, 324 of whom were septic shock. After adjusting for confounding variables, higher iron quartile was associated with an increase in 90-day mortality in the Cox regression analysis. Moreover, a stepwise increase in the risk of 90-day mortality was observed as the quartiles of serum iron levels increased in the patients with sepsis. In conclusion, higher serum iron levels were independently associated with increased 90-day mortality in this large cohort of patients with sepsis.
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Affiliation(s)
- Peng Lan
- Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Kong-Han Pan
- Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Shuo-Jia Wang
- Department of Epidemiology and Health Statistics, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Qiu-Cheng Shi
- Department of Infectious Disease, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yun-Xian Yu
- Department of Epidemiology and Health Statistics, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Ying Fu
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yan Chen
- Department of Infectious Disease, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yan Jiang
- Department of Infectious Disease, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xiao-Ting Hua
- Department of Infectious Disease, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jian-Cang Zhou
- Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| | - Yun-Song Yu
- Department of Infectious Disease, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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Popik W, Correa H, Khatua A, Aronoff DM, Alcendor DJ. Mesangial cells, specialized renal pericytes and cytomegalovirus infectivity: Implications for HCMV pathology in the glomerular vascular unit and post-transplant renal disease. ACTA ACUST UNITED AC 2018; 5. [PMID: 29977613 PMCID: PMC6027753 DOI: 10.15761/jts.1000248] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background Human Cytomegalovirus (HCMV) infection is problematic after kidney transplantation. Human mesangial cells along with human glomerular endothelial cells and podocytes constitute the renal glomerular vascular unit (GVU). HCMV infection of the GVU is poorly understood. Methods GVU cells infectivity was analysed by microscopy and immunofluorescence. Cytokines profiles were measured by Luminex assays. Renal tissue analysis for HCMV infection was performed by immunohistochemistry. Results Mesangial cells and glomerular endothelial cells but not podocytes were permissive for both lab adapted and clinical strains of HCMV. Luminex analysis of cytokines expressed by mesangial cells exposed to the SBCMV clinical strain was examined. A Tricell infection model of the GVU maintains >90% viability with a unique cytokine profile. Finally, we show αSMA stained mesangial cells permissive for HCMV in renal tissue from a transplant patient. Conclusions HCMV infection of mesangial cells induces angiogenic and proinflammatory cytokines that could contribute to glomerular inflammation.
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Affiliation(s)
- Waldemar Popik
- Department of Internal Medicine and 4Department of Microbiology and Immunology, Center for AIDS Health Disparities Research, Meharry Medical College, School of Medicine, 1005 Dr. D.B. Todd Jr. Blvd., Nashville, Tennessee 37208-3599 USA
| | - Hernan Correa
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA
| | - Atanu Khatua
- Meharry Medical College, School of Medicine, Centre for AIDS Health Disparities Research, 1005 Dr. D.B. Todd Jr. Blvd., Nashville, Tennessee 37208-3599, USA
| | - David M Aronoff
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA.,Division of Infectious Diseases, Department of Medicine, and Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Centre, Nashville, Tennessee 37232, USA
| | - Donald J Alcendor
- Meharry Medical College, School of Medicine, Centre for AIDS Health Disparities Research, 1005 Dr. D.B. Todd Jr. Blvd., Nashville, Tennessee 37208-3599, USA
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Fernández-Ruiz M, Parra P, Ruiz-Merlo T, López-Medrano F, San Juan R, Polanco N, González E, Andrés A, Aguado JM. Association between baseline serum hepcidin levels and infection in kidney transplant recipients: Potential role for iron overload. Transpl Infect Dis 2018; 20. [PMID: 29120522 DOI: 10.1111/tid.12807] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 05/23/2017] [Accepted: 07/13/2017] [Indexed: 01/28/2023]
Abstract
BACKGROUND The liver-synthesized peptide hepcidin is a key regulator of iron metabolism and correlates with total iron stores. We analyzed the association between pre-transplant hepcidin-25 levels and infection after kidney transplantation (KT). METHODS Serum hepcidin-25 levels were measured at baseline by high-sensitivity ELISA in 91 patients undergoing KT at our institution between December 2011 and March 2013. The impact of this biomarker on the incidence of post-transplant infection (excluding lower urinary tract infection) during the first year was assessed by Cox regression. RESULTS Mean hepcidin-25 level was 82.3 ± 67.4 ng/mL and strongly correlated with serum ferritin (Spearman's rho = 0.703; P < .001). There were no significant differences in hepcidin-25 levels between patients with or without overall infection (96.4 ± 67.5 vs 72.6 ± 66.7 ng/mL; P = .101). Such difference was evident for opportunistic (128.9 ± 75.0 vs 73.0 ± 62.3 ng/mL; P = .003) and, to a lesser extent, surgical-site infection (107.5 ± 73.3 vs 76.5 ± 65.2 ng/mL; P = .087). Patients with hepcidin-25 levels ≥72.5 ng/mL had higher 12-month cumulative incidence of overall infection (51.2% vs 29.2%; P = .032). After multivariate adjustment, hepcidin-25 ≥72.5 ng/mL acted as an independent risk factor for overall (adjusted hazard ratio [aHR] 3.86; 95% confidence interval [CI] 1.49-9.96; P = .005) and opportunistic infection (aHR 4.32; 95% CI 1.18-15.75; P = .027). CONCLUSION Elevated baseline serum hepcidin-25 levels were associated with increased risk of infection after KT, suggesting a role for iron overload in the individual susceptibility to post-transplant infection.
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Affiliation(s)
- Mario Fernández-Ruiz
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - Patricia Parra
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - Tamara Ruiz-Merlo
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - Francisco López-Medrano
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - Rafael San Juan
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - Natalia Polanco
- Department of Nephrology, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - Esther González
- Department of Nephrology, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - Amado Andrés
- Department of Nephrology, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - José María Aguado
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
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Chow JK, Ganz T, Ruthazer R, Simpson MA, Pomfret EA, Gordon FD, Westerman ME, Snydman DR. Iron-related markers are associated with infection after liver transplantation. Liver Transpl 2017; 23:1541-1552. [PMID: 28703464 PMCID: PMC5696081 DOI: 10.1002/lt.24817] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 06/07/2017] [Accepted: 06/26/2017] [Indexed: 12/21/2022]
Abstract
Though serum iron has been known to be associated with an increased risk of infection, hepcidin, the major regulator of iron metabolism, has never been systematically explored in this setting. Finding early biomarkers of infection, such as hepcidin, could help identify patients in whom early empiric antimicrobial therapy would be beneficial. We prospectively enrolled consecutive patients (n = 128) undergoing first-time, single-organ orthotopic liver transplantation (OLT) without known iron overload disorders at 2 academic hospitals in Boston from August 2009 to November 2012. Cox regression compared the associations between different iron markers and the development of first infection at least 1 week after OLT; 47 (37%) patients developed a primary outcome of infection at least 1 week after OLT and 1 patient died. After adjusting for perioperative bleeding complications, number of hospital days, and hepatic artery thrombosis, changes in iron markers were associated with the development of infection post-OLT including increasing ferritin (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.12-2.05), rising ferritin slope (HR, 1.10; 95% CI, 1.03-1.17), and increasing hepcidin (HR, 1.43; 95% CI, 1.05-1.93). A decreasing iron (HR, 1.76; 95% CI, 1.20-2.57) and a decreasing iron slope (HR, 4.21; 95% CI, 2.51-7.06) were also associated with subsequent infections. In conclusion, hepcidin and other serum iron markers and their slope patterns or their combination are associated with infection in vulnerable patient populations. Liver Transplantation 23 1541-1552 2017 AASLD.
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Affiliation(s)
- Jennifer K.L Chow
- Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA, 02116, USA
| | - Tomas Ganz
- Departments of Medicine and Pathology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Robin Ruthazer
- Tufts Clinical and Translational Science Institute, Tufts Medical Center, Boston, MA, 02116, USA
| | - Mary Ann Simpson
- Department of Transplantation, Lahey Hospital and Medical Center, Burlington, MA, 01805 USA
| | - Elizabeth A. Pomfret
- Department of Transplantation, Lahey Hospital and Medical Center, Burlington, MA, 01805 USA,Division of Transplant Surgery, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Fredric D. Gordon
- Department of Transplantation, Lahey Hospital and Medical Center, Burlington, MA, 01805 USA
| | | | - David R. Snydman
- Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA, 02116, USA
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Disturbances in iron homeostasis result in accelerated rejection after experimental heart transplantation. J Heart Lung Transplant 2017; 36:732-743. [DOI: 10.1016/j.healun.2017.03.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Revised: 02/28/2017] [Accepted: 03/03/2017] [Indexed: 02/07/2023] Open
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