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      Olfactomedin 4 as a novel loop of Henle‐specific acute kidney injury biomarker

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          Abstract

          Acute kidney injury (AKI) is associated with morbidity and mortality. Urinary biomarkers may disentangle its clinical heterogeneity. Olfactomedin 4 (OLFM4) is a secreted glycoprotein expressed in stressed neutrophils and epithelial cells. In septic mice, OLFM4 expression localized to the kidney's loop of Henle (LOH) and was detectable in the urine. We hypothesized that urine OLFM4 (uOLFM4) will be increased in patients with AKI and sepsis. Urine from critically ill pediatric patients was obtained from a prospective study based on AKI and sepsis status. uOLFM4 was quantified with a Luminex immunoassay. AKI was defined by KDIGO severe criteria. Sepsis status was extracted from the medical record based on admission diagnosis. Immunofluorescence on pediatric kidney biopsies was performed with NKCC2, uromodulin and OLFM4 specific antibodies. Eight patients had no sepsis, no AKI; 7 had no sepsis but did have AKI; 10 had sepsis, no AKI; 11 had sepsis and AKI. Patients with AKI had increased uOLFM4 compared to no/stage 1 AKI ( p = 0.044). Those with sepsis had increased uOLFM4 compared to no sepsis ( p = 0.026). uOLFM4 and NGAL were correlated ( r 2 0.59, 95% CI 0.304–0.773, p = 0.002), but some patients had high uOLFM4 and low NGAL, and vice versa. Immunofluorescence on kidney biopsies demonstrated OLFM4 colocalization with NKCC2 and uromodulin, suggesting expression in the thick ascending LOH (TALH). We conclude that AKI and sepsis are associated with increased uOLFM4. uOLFM4 and NGAL correlated in many patients, but was poor in others, suggesting these markers may differentiate AKI subgroups. Given OLFM4 colocalization to human TALH, we propose OLFM4 may be a LOH‐specific AKI biomarker.

          Abstract

          Acute kidney injury is a common and heterogeneous problem that would benefit from biomarkers that allow improved prognostication and ultimately treatment options. We show that Olfactomedin 4 (OLFM4) is present in human kidney following injury. Immunohistochemistry suggests OLFM4 co‐localizes with NKCC2 and uromodulin and may serve as an injury marker for the loop of Henle.

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          Acute renal failure in critically ill patients: a multinational, multicenter study.

          Although acute renal failure (ARF) is believed to be common in the setting of critical illness and is associated with a high risk of death, little is known about its epidemiology and outcome or how these vary in different regions of the world. To determine the period prevalence of ARF in intensive care unit (ICU) patients in multiple countries; to characterize differences in etiology, illness severity, and clinical practice; and to determine the impact of these differences on patient outcomes. Prospective observational study of ICU patients who either were treated with renal replacement therapy (RRT) or fulfilled at least 1 of the predefined criteria for ARF from September 2000 to December 2001 at 54 hospitals in 23 countries. Occurrence of ARF, factors contributing to etiology, illness severity, treatment, need for renal support after hospital discharge, and hospital mortality. Of 29 269 critically ill patients admitted during the study period, 1738 (5.7%; 95% confidence interval [CI], 5.5%-6.0%) had ARF during their ICU stay, including 1260 who were treated with RRT. The most common contributing factor to ARF was septic shock (47.5%; 95% CI, 45.2%-49.5%). Approximately 30% of patients had preadmission renal dysfunction. Overall hospital mortality was 60.3% (95% CI, 58.0%-62.6%). Dialysis dependence at hospital discharge was 13.8% (95% CI, 11.2%-16.3%) for survivors. Independent risk factors for hospital mortality included use of vasopressors (odds ratio [OR], 1.95; 95% CI, 1.50-2.55; P<.001), mechanical ventilation (OR, 2.11; 95% CI, 1.58-2.82; P<.001), septic shock (OR, 1.36; 95% CI, 1.03-1.79; P = .03), cardiogenic shock (OR, 1.41; 95% CI, 1.05-1.90; P = .02), and hepatorenal syndrome (OR, 1.87; 95% CI, 1.07-3.28; P = .03). In this multinational study, the period prevalence of ARF requiring RRT in the ICU was between 5% and 6% and was associated with a high hospital mortality rate.
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            Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes.

            Sepsis is the most common cause of acute kidney injury (AKI) in critical illness, but there is limited information on septic AKI. A prospective, observational study of critically ill patients with septic and nonseptic AKI was performed from September 2000 to December 2001 at 54 hospitals in 23 countries. A total of 1753 patients were enrolled. Sepsis was considered the cause in 833 (47.5%); the predominant sources of sepsis were chest and abdominal (54.3%). Septic AKI was associated with greater aberrations in hemodynamics and laboratory parameters, greater severity of illness, and higher need for mechanical ventilation and vasoactive therapy. There was no difference in enrollment kidney function or in the proportion who received renal replacement therapy (RRT; 72 versus 71%; P = 0.83). Oliguria was more common in septic AKI (67 versus 57%; P < 0.001). Septic AKI had a higher in-hospital case-fatality rate compared with nonseptic AKI (70.2 versus 51.8%; P < 0.001). After adjustment for covariates, septic AKI remained associated with higher odds for death (1.48; 95% confidence interval 1.17 to 1.89; P = 0.001). Median (IQR) duration of hospital stay for survivors (37 [19 to 59] versus 21 [12 to 42] d; P < 0.0001) was longer for septic AKI. There was a trend to lower serum creatinine (106 [73 to 158] versus 121 [88 to 184] mumol/L; P = 0.01) and RRT dependence (9 versus 14%; P = 0.052) at hospital discharge for septic AKI. Patients with septic AKI were sicker and had a higher burden of illness and greater abnormalities in acute physiology. Patients with septic AKI had an increased risk for death and longer duration of hospitalization yet showed trends toward greater renal recovery and independence from RRT.
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              Epidemiology of Acute Kidney Injury in Critically Ill Children and Young Adults.

              The epidemiologic characteristics of children and young adults with acute kidney injury have been described in single-center and retrospective studies. We conducted a multinational, prospective study involving patients admitted to pediatric intensive care units to define the incremental risk of death and complications associated with severe acute kidney injury.
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                Author and article information

                Contributors
                matthew.alder@cchmc.org
                Journal
                Physiol Rep
                Physiol Rep
                10.1002/(ISSN)2051-817X
                PHY2
                physreports
                Physiological Reports
                John Wiley and Sons Inc. (Hoboken )
                2051-817X
                19 September 2022
                September 2022
                : 10
                : 18 ( doiID: 10.1002/phy2.v10.18 )
                : e15453
                Affiliations
                [ 1 ] Division of Critical Care Medicine Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA
                [ 2 ] Division of Nephrology and Hypertension Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA
                [ 3 ] Division of Pathology and Laboratory Medicine Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA
                [ 4 ] Division of Nephrology and Hypertension Seattle Children's Hospital Seattle Washington USA
                [ 5 ] Department of Pediatrics University of Cincinnati College of Medicine Cincinnati Ohio USA
                Author notes
                [*] [* ] Correspondence

                Matthew N. Alder, Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7006, Cincinnati, OH 45229, USA.

                Email: matthew.alder@ 123456cchmc.org

                Author information
                https://orcid.org/0000-0003-2879-6576
                Article
                PHY215453 PHY2-2022-05-0238.R1
                10.14814/phy2.15453
                9483618
                36117416
                7f640cdd-855f-46d2-bd7d-cd10cfbfe3cd
                © 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 13 August 2022
                : 29 May 2022
                : 16 August 2022
                Page count
                Figures: 6, Tables: 1, Pages: 10, Words: 6637
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                September 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.8 mode:remove_FC converted:19.09.2022

                acute kidney injury,loop of henle,olfactomedin 4,septic aki,urine biomarker

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