Netrin-1 and Semaphorin 3A Predict the Development of Acute Kidney Injury in Liver Transplant Patients

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Abstract

Acute kidney injury (AKI) is a serious complication after liver transplantation. Currently there are no validated biomarkers available for early diagnosis of AKI. The current study was carried out to determine the usefulness of the recently identified biomarkers netrin-1 and semaphorin 3A in predicting AKI in liver transplant patients. A total of 63 patients’ samples were collected and analyzed. AKI was detected at 48 hours after liver transplantation using serum creatinine as a marker. In contrast, urine netrin-1 (897.8±112.4 pg/mg creatinine), semaphorin 3A (847.9±93.3 pg/mg creatinine) and NGAL (2172.2±378.1 ng/mg creatinine) levels were increased significantly and peaked at 2 hours after liver transplantation but were no longer significantly elevated at 6 hours after transplantation. The predictive power of netrin-1, as demonstrated by the area under the receiver-operating characteristic curve for diagnosis of AKI at 2, 6, and 24 hours after liver transplantation was 0.66, 0.57 and 0.59, respectively. The area under the curve for diagnosis of AKI was 0.63 and 0.65 for semaphorin 3A and NGAL at 2 hr respectively. Combined analysis of two or more biomarkers for simultaneous occurrence in urine did not improve the AUC for the prediction of AKI whereas the AUC was improved significantly (0.732) only when at least 1 of the 3 biomarkers in urine was positive for predicting AKI. Adjusting for BMI, all three biomarkers at 2 hours remained independent predictors of AKI with an odds ratio of 1.003 (95% confidence interval: 1.000 to 1.006; P = 0.0364). These studies demonstrate that semaphorin 3A and netrin-1 can be useful early diagnostic biomarkers of AKI after liver transplantation.

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Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

Kianoush B Kashani, Ali Al-Khafaji, Thomas Ardiles … (2013)

Introduction Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI. Methods We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection. Results Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P 0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method. Conclusions Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI. Trial registration ClinicalTrials.gov number NCT01209169.

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Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication.

Frederick J Zimmerman, James Miner, Ian Graham … (2014)

We recently reported two novel biomarkers for acute kidney injury (AKI), tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), both related to G1 cell cycle arrest. We now validate a clinical test for urinary [TIMP-2]·[IGFBP7] at a high-sensitivity cutoff greater than 0.3 for AKI risk stratification in a diverse population of critically ill patients. We conducted a prospective multicenter study of 420 critically ill patients. The primary analysis was the ability of urinary [TIMP-2]·[IGFBP7] to predict moderate to severe AKI within 12 hours. AKI was adjudicated by a committee of three independent expert nephrologists who were masked to the results of the test. Urinary TIMP-2 and IGFBP7 were measured using a clinical immunoassay platform. The primary endpoint was reached in 17% of patients. For a single urinary [TIMP-2]·[IGFBP7] test, sensitivity at the prespecified high-sensitivity cutoff of 0.3 (ng/ml)(2)/1,000 was 92% (95% confidence interval [CI], 85-98%) with a negative likelihood ratio of 0.18 (95% CI, 0.06-0.33). Critically ill patients with urinary [TIMP-2]·[IGFBP7] greater than 0.3 had seven times the risk for AKI (95% CI, 4-22) compared with critically ill patients with a test result below 0.3. In a multivariate model including clinical information, urinary [TIMP-2]·[IGFBP7] remained statistically significant and a strong predictor of AKI (area under the curve, 0.70, 95% CI, 0.63-0.76 for clinical variables alone, vs. area under the curve, 0.86, 95% CI, 0.80-0.90 for clinical variables plus [TIMP-2]·[IGFBP7]). Urinary [TIMP-2]·[IGFBP7] greater than 0.3 (ng/ml)(2)/1,000 identifies patients at risk for imminent AKI. Clinical trial registered with www.clinicaltrials.gov (NCT 01573962).

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Risk factors of acute renal failure after liver transplantation.

Danyelle R A Rios, Nicolás R Robles, A M Brú … (2006)

The objective of this study was to determine the risk factors of postoperative acute renal failure (ARF) in orthotopic liver transplantation (OLT). We reviewed 184 consecutive OLT. Postoperative ARF was defined as a persistent rise of 50% increase or more of the S-creatinine (S-Cr). The patients were classified as early postoperative ARF (E-ARF) (first week) and late postoperative ARF (L-ARF) (second to fourth week). Preoperative variables were age, sex, comorbidity, indication for OLT, Child-Pugh stage, united network for organ sharing status, analysis of the blood and urine, and donor's data. Intraoperative variables were systolic arterial pressure, mean arterial pressure, pulmonary capillary wedge pressure, cardiac index, and systemic vascular resistance index. Surgical technique, number of blood products transfused, need for adrenergic agonist drugs, and intraoperative complications were also important. Postoperative variables were duration of stay in the intensive care unit, time on mechanic ventilation, liver graft dysfunction, need for adrenergic agonist drugs, units of blood products infused, episodes of acute rejection, re-operations, and bacterial infections. Firstly we carried out a univariate statistical analysis, and secondly a logistic regression analysis. The risk factors for E-ARF were: pretransplant ARF (odds ratio (OR)=10.2, P=0.025), S-albumin (OR=0.3, P=0.001), duration of treatment with dopamine (OR=1.6, P=0.001), and grade II-IV dysfunction of the liver graft (OR=5.6, P=0.002). The risk factors for L-ARF were: re-operation (OR=3.1, P=0.013) and bacterial infection (OR=2.9, P=0.017). The development of E-ARF is influenced by preoperative factors such as ARF and hypoalbuminemia, as well as postoperative factors such as liver dysfunction and prolonged treatment with dopamine. The predicting factors of L-ARF differ from E-ARF and correspond to postoperative causes such as bacterial infection and surgical re-operation.

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Giovanni Camussi: Role: Editor

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Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 7 October 2014

Volume: 9

Issue: 10

Electronic Location Identifier: e107898

Affiliations

[1 ]Vascular Biology Center, Georgia Regents University, Augusta, GA, United States of America

[2 ]Department of Nephrology, Dialysis & Internal Diseases, Medical University of Warsaw, Warsaw, Poland

[3 ]Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland

[4 ]Department of Biostatistics and Epidemiology, Georgia Regents University, Augusta, GA, United States of America

[5 ]Department of General and Nutritional Biochemistry, Medical University of Warsaw, Warsaw, Poland

University of Torino, Italy

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* E-mail: gramesh@ 123456gru.edu

Competing Interests: Dr. Ramesh has filed a provisional patent through Georgia Regents University for discovering semaphorin3A and a patent was awarded to Dr. Ramesh and Pennsylvania State University for discovering netrin-1 as an early diagnostic biomarker of injury and disease. The details are as follows: Ganesan Ramesh: “Netrin-1 as a Biomarker of Injury and Disease”, Provisional Patent Filed on 1/20/2009. Application No: 61/145,764. Ganesan Ramesh: “Netrin-1 as a Biomarker of Injury and Disease”, Provisional Patent Filed on 7/31/2009. Application No: 61/230,346. Ganesan Ramesh: “Semaphorin 3A as a Biomarker of injury and Disease” Provision Patent Filed. Application #61/711,007. However, this does not alter the authors’ adherence to all PLOS ONE policies on sharing data and materials.

Conceived and designed the experiments: LL JM GR. Performed the experiments: LL CJ UO MG. Analyzed the data: LL SL JM GR. Contributed reagents/materials/analysis tools: UO MG MD MK GR. Wrote the paper: LL JM CJ GR.

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Publisher ID: PONE-D-14-09995

DOI: 10.1371/journal.pone.0107898

PMC ID: 4188568

PubMed ID: 25289643

SO-VID: f96d747b-7b6f-412d-8af0-1adc8416c2e2

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Date received : 5 March 2014

Date accepted : 22 August 2014

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Pages: 8

Funding

This work was supported by an R01 grant (1R01DK083379 - 01A3) to Ganesan Ramesh from NIH-NIDDK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Netrin-1 and Semaphorin 3A Predict the Development of Acute Kidney Injury in Liver Transplant Patients

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Most cited references 27

Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication.

Risk factors of acute renal failure after liver transplantation.

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