Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Critical Care
Published in: Critical Care 1/2017

Open Access 01-12-2017 | Research

Circulating levels of soluble Fas (sCD95) are associated with risk for development of a nonresolving acute kidney injury subphenotype

Authors: Pavan K. Bhatraju, Cassianne Robinson-Cohen, Carmen Mikacenic, Susanna Harju-Baker, Victoria Dmyterko, Natalie S. J. Slivinski, W. Conrad Liles, Jonathan Himmelfarb, Susan R. Heckbert, Mark M. Wurfel

Published in: Critical Care | Issue 1/2017

Login to get access

Abstract

Background

Critically ill patients with acute kidney injury (AKI) can be divided into two subphenotypes, resolving or nonresolving, on the basis of the trajectory of serum creatinine. It is unknown if the biology underlying these two AKI recovery patterns is different.

Methods

We measured eight circulating biomarkers in plasma obtained from a cohort of patients admitted to an intensive care unit (ICU) (n = 1241) with systemic inflammatory response syndrome. The biomarkers were representative of several biologic processes: apoptosis (soluble Fas), inflammation (soluble tumor necrosis factor receptor 1, interleukin 6, interleukin 8) and endothelial dysfunction, (angiopoietin 1, angiopoietin 2, and soluble vascular cell adhesion molecule 1). We tested for associations between biomarker levels and AKI subphenotypes using relative risk regression accounting for multiple hypotheses with the Bonferroni correction.

Results

During the first 3 days of ICU admission, 868 (70%) subjects developed AKI; 502 (40%) had a resolving subphenotype, and 366 (29%) had a nonresolving subphenotype. Hospital mortality was 12% in the resolving subphenotype and 21% in the nonresolving subphenotype. Soluble Fas was the only biomarker associated with a nonresolving subphenotype after adjustment for age, body mass index, diabetes, and Acute Physiology and Chronic Health Evaluation III score (p = 0.005).

Conclusions

Identifying modifiable targets in the Fas-mediated pathway may lead to strategies for prevention and treatment of a clinically important form of AKI.
Appendix
Available only for authorised users
Literature
1.
Joannidis M, Metnitz PGH. Epidemiology and natural history of acute renal failure in the ICU. Crit Care Clin. 2005;21:239–49.CrossRefPubMed
2.
Hoste EAJ, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015;41:1411–23.CrossRefPubMed
3.
Clermont G, Acker CG, Angus DC, Sirio CA, Pinsky MR, Johnson JP. Renal failure in the ICU: comparison of the impact of acute renal failure and end-stage renal disease on ICU outcomes. Kidney Int. 2002;62:986–96.CrossRefPubMed
4.
Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis Quality Initiative workgroup. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204–12.CrossRefPubMedPubMedCentral
5.
Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294:813–8.CrossRefPubMed
6.
de Geus HRH, Bakker J, Lesaffre EMEH, le Noble JLML. Neutrophil gelatinase-associated lipocalin at ICU admission predicts for acute kidney injury in adult patients. Am J Respir Crit Care Med. 2011;183:907–14.CrossRefPubMed
7.
Siew ED, Ware LB, Bian A, Shintani A, Eden SK, Wickersham N, et al. Distinct injury markers for the early detection and prognosis of incident acute kidney injury in critically ill adults with preserved kidney function. Kidney Int. 2013;84:786–94.CrossRefPubMedPubMedCentral
8.
Nejat M, Pickering JW, Devarajan P, Bonventre JV, Edelstein CL, Walker RJ, et al. Some biomarkers of acute kidney injury are increased in pre-renal acute injury. Kidney Int. 2012;81:1254–62.CrossRefPubMedPubMedCentral
9.
Coca SG, King JT, Rosenthal RA, Perkal MF, Parikh CR. The duration of postoperative acute kidney injury is an additional parameter predicting long-term survival in diabetic veterans. Kidney Int. 2010;78:926–33.CrossRefPubMedPubMedCentral
10.
Perinel S, Vincent F, Lautrette A, Dellamonica J, Mariat C, Zeni F, et al. Transient and persistent acute kidney injury and the risk of hospital mortality in critically ill patients: results of a multicenter cohort study. Crit Care Med. 2015;43:e269–75.CrossRefPubMed
11.
Kellum JA, Sileanu FE, Bihorac A, Hoste EAJ, Chawla LS. Recovery after acute kidney injury. Am J Respir Crit Care Med. 2017;195:784–91.CrossRefPubMed
12.
Ricci Z, Polito A, Polito A, Ronco C. The implications and management of septic acute kidney injury. Nat Rev Nephrol. 2011;7:218–25.CrossRefPubMed
13.
Bhatraju PK, Mukherjee P, Robinson-Cohen C, O’Keefe GE, Frank AJ, Christie JD, et al. Acute kidney injury subphenotypes based on creatinine trajectory identifies patients at increased risk of death. Crit Care. 2016;20:372.CrossRefPubMedPubMedCentral
14.
Ko GJ, Jang HR, Huang Y, Womer KL, Liu M, Higbee E, et al. Blocking Fas ligand on leukocytes attenuates kidney ischemia-reperfusion injury. J Am Soc Nephrol. 2011;22:732–42.CrossRefPubMedPubMedCentral
15.
Yuan HT, Tipping PG, Li XZ, Long DA, Woolf AS. Angiopoietin correlates with glomerular capillary loss in anti-glomerular basement membrane glomerulonephritis. Kidney Int. 2002;61:2078–89.CrossRefPubMed
16.
Jongman RM, van Klarenbosch J, Molema G, Zijlstra JG, de Vries AJ, van Meurs M. Angiopoietin/Tie2 dysbalance is associated with acute kidney injury after cardiac surgery assisted by cardiopulmonary bypass. PLoS One. 2015;10:e0136205.CrossRefPubMedPubMedCentral
17.
Simmons EM, Himmelfarb J, Tugrul S, Chertow GM, Mehta RL, Paganini EP, et al. Plasma cytokine levels predict mortality in patients with acute renal failure. Kidney Int. 2004;65:1357–65.CrossRefPubMed
18.
Glavan BJ, Holden TD, Goss CH, Black RA, Neff MJ, Nathens AB, et al. Genetic variation in the FAS gene and associations with acute lung injury. Am J Respir Crit Care Med. 2011;183:356–63.CrossRefPubMed
19.
Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003;29:530–8.CrossRefPubMed
20.
Ko DC, Shukla KP, Fong C, Wasnick M, Brittnacher MJ, Wurfel MM, et al. A genome-wide in vitro bacterial-infection screen reveals human variation in the host response associated with inflammatory disease. Am J Hum Genet. 2009;85:214–27.CrossRefPubMedPubMedCentral
21.
Mikacenic C, Hahn WO, Price BL, Harju-Baker S, Katz R, Kain KC, et al. Biomarkers of endothelial activation are associated with poor outcome in critical illness. PLoS One. 2015;10:e0141251.CrossRefPubMedPubMedCentral
22.
Robinson-Cohen C, Katz R, Price BL, Harju-Baker S, Mikacenic C, Himmelfarb J, et al. Association of markers of endothelial dysregulation Ang1 and Ang2 with acute kidney injury in critically ill patients. Crit Care. 2016;20:207.CrossRefPubMedPubMedCentral
23.
Liu KD, Glidden DV, Eisner MD, Parsons PE, Ware LB, Wheeler A, et al. Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury. Crit Care Med. 2007;35:2755–61.CrossRefPubMedPubMedCentral
24.
Liu KL, Lee KT, Chang CH, Chen YC, Lin SM, Chu PH. Elevated plasma thrombomodulin and angiopoietin-2 predict the development of acute kidney injury in patients with acute myocardial infarction. Crit Care. 2014;18:R100.CrossRefPubMedPubMedCentral
25.
Siew ED, Matheny ME, Ikizler TA, Lewis JB, Miller RA, Waitman LR, et al. Commonly used surrogates for baseline renal function affect the classification and prognosis of acute kidney injury. Kidney Int. 2010;77:536–42.CrossRefPubMed
26.
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315:801–10.CrossRefPubMedPubMedCentral
27.
Rubin DB. Multiple imputation for nonresponse in surveys. Hoboken, NJ: John Wiley & Sons; 2004.
28.
29.
Siew ED, Davenport A. The growth of acute kidney injury: a rising tide or just closer attention to detail? Kidney Int. 2015;87:46–61.CrossRefPubMed
30.
Bagshaw SM, Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, et al. Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol. 2007;2:431–9.CrossRefPubMed
31.
Hahn WO, Mikacenic C, Price BL, Harju-Baker S, Katz R, Himmelfarb J, et al. Host derived biomarkers of inflammation, apoptosis, and endothelial activation are associated with clinical outcomes in patients with bacteremia and sepsis regardless of microbial etiology. Virulence. 2016;7:387–94.CrossRefPubMedPubMedCentral
32.
Liu KD, Thompson BT, Ancukiewicz M, Steingrub JS, Douglas IS, Matthay MA, et al. Acute kidney injury in patients with acute lung injury: impact of fluid accumulation on classification of acute kidney injury and associated outcomes. Crit Care Med. 2011;39:2665–71.CrossRefPubMedPubMedCentral
33.
34.
Bagshaw SM, George C, Bellomo R, ANZICS Database Management Committee. Early acute kidney injury and sepsis: a multicentre evaluation. Crit Care. 2008;12:R47.CrossRefPubMedPubMedCentral
35.
Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 2005;16:3365–70.CrossRefPubMed
36.
Tanaka M, Suda T, Takahashi T, Nagata S. Expression of the functional soluble form of human Fas ligand in activated lymphocytes. EMBO J. 1995;14:1129–35.PubMedPubMedCentral
37.
Park DR, Thomsen AR, Frevert CW, Pham U, Skerrett SJ, Kiener PA, et al. Fas (CD95) induces proinflammatory cytokine responses by human monocytes and monocyte-derived macrophages. J Immunol. 2003;170:6209–16.CrossRefPubMed
38.
Cascino I, Fiucci G, Papoff G, Ruberti G. Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing. J Immunol. 1995;154:2706–13.PubMed
39.
Bhatraju P, Hsu C, Mukherjee P, Glavan BJ, Burt A, Mikacenic C, et al. Associations between single nucleotide polymorphisms in the FAS pathway and acute kidney injury. Crit Care. 2015;19:368.CrossRefPubMedPubMedCentral
40.
Schelling JR, Nkemere N, Kopp JB, Cleveland RP. Fas-dependent fratricidal apoptosis is a mechanism of tubular epithelial cell deletion in chronic renal failure. Lab Invest. 1998;78:813–24.PubMed
41.
Ortiz-Arduan A, Danoff TM, Kalluri R, González-Cuadrado S, Karp SL, Elkon K, et al. Regulation of Fas and Fas ligand expression in cultured murine renal cells and in the kidney during endotoxemia. Am J Physiol. 1996;271:F1193–201.PubMed
42.
Góes MA, Iizuka IJ, Quinto BM, Dalboni MA, Monte JC, Santos BC, et al. Serum soluble-Fas, inflammation, and anemia in acute kidney injury. Artif Organs. 2013. doi:10.​1111/​aor.​12019.
43.
Iwashyna TJ, Burke JF, Sussman JB, Prescott HC, Hayward RA, Angus DC. Implications of heterogeneity of treatment effect for reporting and analysis of randomized trials in critical care. Am J Respir Crit Care Med. 2015;192:1045–51.CrossRefPubMedPubMedCentral
44.
Han S, Lee SJ, Kim KE, Lee HS, Oh N, Park I, et al. Amelioration of sepsis by TIE2 activation-induced vascular protection. Sci Transl Med. 2016;8:335ra55.CrossRefPubMed
45.
46.
Swanton C, Govindan R. Clinical implications of genomic discoveries in lung cancer. N Engl J Med. 2016;374:1864–73.CrossRefPubMed
47.
Perianayagam MC, Murray SL, Balakrishnan VS, Guo D, King AJ, Pereira BJ, et al. Serum soluble Fas (CD95) and Fas ligand profiles in chronic kidney failure. J Lab Clin Med. 2000;136:320–7.CrossRefPubMed
48.
Doughty L, Clark RSB, Kaplan SS, Sasser H, Carcillo J. sFas and sFas ligand and pediatric sepsis-induced multiple organ failure syndrome. Pediatr Res. 2002;52:922–7.CrossRefPubMed
49.
Paunel-Görgülü A, Flohé S, Scholz M, Windolf J, Lögters T. Increased serum soluble Fas after major trauma is associated with delayed neutrophil apoptosis and development of sepsis. Crit Care. 2011;15:R20.CrossRefPubMedPubMedCentral
50.
Zekri ARN, El-Din HMA, Bahnassy AA, Zayed NA, Mohamed WS, El-Masry SH, et al. Serum levels of soluble Fas, soluble tumor necrosis factor-receptor II, interleukin-2 receptor and interleukin-8 as early predictors of hepatocellular carcinoma in Egyptian patients with hepatitis C virus genotype-4. Comp Hepatol. 2010;9:1.CrossRefPubMedPubMedCentral
51.
Jodo S, Kobayashi S, Nakajima Y, Matsunaga T, Nakayama N, Ogura N, et al. Elevated serum levels of soluble Fas/APO-1 (CD95) in patients with hepatocellular carcinoma. Clin Exp Immunol. 1998;112:166–71.CrossRefPubMedPubMedCentral
52.
Akhmedkhanov A, Lundin E, Guller S, Lukanova A, Micheli A, Ma Y, et al. Circulating soluble Fas levels and risk of ovarian cancer. BMC Cancer. 2003;3:33.CrossRefPubMedPubMedCentral
Metadata
Title
Circulating levels of soluble Fas (sCD95) are associated with risk for development of a nonresolving acute kidney injury subphenotype
Authors
Pavan K. Bhatraju
Cassianne Robinson-Cohen
Carmen Mikacenic
Susanna Harju-Baker
Victoria Dmyterko
Natalie S. J. Slivinski
W. Conrad Liles
Jonathan Himmelfarb
Susan R. Heckbert
Mark M. Wurfel
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2017
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-017-1807-x

Other articles of this Issue 1/2017

Critical Care 1/2017 Go to the issue

Editorial

Towards precision medicine for sepsis patients

Research

New setting of neurally adjusted ventilatory assist for noninvasive ventilation by facial mask: a physiologic study

Research

The accuracy of transcranial Doppler in excluding intracranial hypertension following acute brain injury: a multicenter prospective pilot study

Commentary

Retinal involvement in sepsis: from the eye of the patient to the eye of the beholder

Research

The association of time and medications with changes in bone mineral density in the 2 years after critical illness

Research

Comparison of mortality prediction models in acute respiratory distress syndrome undergoing extracorporeal membrane oxygenation and development of a novel prediction score: the PREdiction of Survival on ECMO Therapy-Score (PRESET-Score)