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Kidney360
Kidney360
KIDNEY
Kidney360
Kidney360
2641-7650
American Society of Nephrology

39024016
K360-2024-000202
10.34067/KID.0000000000000507
00006
3
Clinical Research
Acute Kidney Injury and ICU Nephrology
Endotrophin as a Biomarker for Severe Acute Kidney Injury and Major Adverse Kidney Events
https://orcid.org/0000-0003-2933-1594
Flannery Alexander H. 1 2
Bu Dawei 3
https://orcid.org/0009-0001-0755-3447
Botkins Madison 1
Gianella Fabiola 4
https://orcid.org/0000-0002-4348-2180
Zhang Ningyan 5
https://orcid.org/0000-0001-9309-2335
An Zhiqiang 5
Moe Orson W. 4 6
https://orcid.org/0000-0003-0680-3392
Scherer Philipp E. 3
https://orcid.org/0000-0002-2817-2459
Neyra Javier A. 4 7
1 Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, Kentucky
2 Division of Nephrology, Bone, and Mineral Metabolism, Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky
3 Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas
4 Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas
5 Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas
6 Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
7 Division of Nephrology, Department of Internal Medicine, University of Alabama at Birmingham, Birmingham, Alabama
Correspondence: Dr. Javier A. Neyra, email: jneyra@uabmc.edu
8 2024
18 7 2024
5 8 10871093
13 3 2024
5 7 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Visual Abstract

Key Points

Endotrophin (ETP), a circulating marker of fibroinflammation, is elevated in critically ill patients with AKI.

ETP is independently associated with major adverse kidney events at hospital discharge.

Sustained elevations of ETP at 5–7 days are associated with major adverse kidney events.

Background

The search for novel biomarkers in AKI continues, both for being able to predict adverse events in AKI but also for confirming pathogenic pathways as potential therapeutic targets. Endotrophin (ETP) is an emerging biomarker in a number of fibroinflammatory diseases. We sought to test the association of ETP with the development of a major adverse kidney event (MAKE) in critically ill adult patients.

Methods

Single-center prospective study of critically ill adult patients with stage 2–3 AKI and patients without AKI. Serum ETP was measured early in the first 3 days of critical care admission, 5–7 days later, and in some patients, 4–6 weeks later. The primary outcome was MAKE assessed at hospital discharge, a composite of mortality, RRT at discharge, and eGFR reduction of ≥25% from baseline.

Results

Among 121 patients evaluated in this study, serum ETP was significantly higher in patients with AKI versus those without (P < 0.05). In multivariable logistic regression analysis, higher tertiles of ETP were significantly associated with MAKE at discharge, controlled for relevant covariates. Furthermore, sustained elevations in ETP 5–7 days later, as opposed to reductions toward normal, were also associated with MAKE. In patients seen in the clinic 4–6 weeks post-AKI, ETP remained elevated. In the acute period, ETP levels correlated most with TNF-α and neutrophil gelatinase-associated lipocalin.

Conclusions

Higher levels of serum ETP early in the intensive care unit admission, as well as sustained elevations of ETP within a 5-day to 7-day period, are associated with MAKE at hospital discharge. ETP is a potential biomarker of AKI-related outcomes and a promising therapeutic target to minimize sequelae of AKI.

AKI
acute renal failure
CKD
epidemiology and outcomes
fibrosis
National Institute of Diabetes and Digestive and Kidney DiseasesK23DK128562 Alexander H. FlanneryNational Institute of Diabetes and Digestive and Kidney DiseasesU54DK137307 Javier A. NeyraCancer Prevention and Research Institute of TexasRP190561 Zhiqiang AnWelch FoundationAU-0042-20030616 Zhiqiang AnNational Institute of Diabetes and Digestive and Kidney DiseasesP30 DK-079328 Orson W. MoeNational Institute of Diabetes and Digestive and Kidney DiseasesR01 DK091392 Orson W. MoeNational Institute of Diabetes and Digestive and Kidney DiseasesR01 DK092461 Orson W. MoeNational Institute of Diabetes and Digestive and Kidney DiseasesR01DK128208 Javier A. NeyraNational Institute of Diabetes and Digestive and Kidney DiseasesR01DK133539 Javier A. NeyraNational Institute of Diabetes and Digestive and Kidney DiseasesU01DK12998 Javier A. NeyraNational Institutes of HealthK23DK128562 (PI: AHF). Not ApplicableNational Institute of Diabetes and Digestive and Kidney DiseasesR01DK131537 Philipp E. SchererNational Institute of Diabetes and Digestive and Kidney DiseasesK23DK128562 National Institute of Diabetes and Digestive and Kidney DiseasesU54DK137307 Cancer Prevention and Research Institute of TexasRP190561 Welch FoundationAU-0042-20030616 National Institute of Diabetes and Digestive and Kidney DiseasesP30 DK-079328 National Institute of Diabetes and Digestive and Kidney DiseasesR01 DK091392 National Institute of Diabetes and Digestive and Kidney DiseasesR01 DK092461 National Institute of Diabetes and Digestive and Kidney DiseasesR01DK128208 National Institute of Diabetes and Digestive and Kidney DiseasesR01DK133539 National Institute of Diabetes and Digestive and Kidney DiseasesU01DK12998 National Institutes of HealthK23DK128562 (PI: AHF). National Institute of Diabetes and Digestive and Kidney DiseasesR01DK131537 OPEN-ACCESSTRUE
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pmcIntroduction

AKI poses a significant short-term and long-term clinical and financial burden to the health care system.1,2 Maladaptive repair after an injury can be associated with dire sequelae, including CKD or ESKD.3 While years of research have led to a greater understanding of the clinical utility of various biomarkers in AKI, few have been discovered that represent both a useful biomarker and a viable therapeutic target of the AKI pathophysiological process.4

Endotrophin (ETP), discovered in 2012, is an emerging biomarker in a number of fibroinflammatory diseases, with increased circulating levels in a number of conditions, including liver diseases, heart failure, diabetes, lung diseases, and CKD, where it is associated with mortality.5,6 Importantly, preclinical data indicate that ETP may not only be a biomarker of the development of a fibroinflammatory disease but also a potential therapeutic target.5 Circulating levels of ETP were shown to be elevated at 1 year after AKI versus controls and predicted kidney disease progression and mortality.7 However, no studies to date have examined ETP in the acute period of AKI to evaluate the ability of ETP to predict short-term outcomes in AKI and assess the trajectory of circulating ETP levels to further consider ETP as a therapeutic approach earlier in the disease process. In this study, we sought to test the association of ETP with the development of major adverse kidney events (MAKE) in critically ill adult patients with and without AKI.

Methods

Study Participants

This was a secondary analysis of a single center from our previously published multicenter, prospective, observational study of critically ill adult patients at a tertiary care academic medical center from 2017 to 2019.8 Inclusion criteria included adult patients 18 years or older, admission to surgical or medical intensive care unit (ICU), and a known baseline eGFR ≥60 ml/min per 1.73 m2, which was calculated using the most recent outpatient serum creatinine within 6 months before admission using the 2021 CKD Epidemiology Collaboration equations.9 Exclusion criteria included patients with ESKD, AKI before ICU admission, prior solid organ transplant, or uroepithelial tumors.

By design, the study included ICU patients with new stage ≥2 AKI defined using the serum creatinine and urine output criteria based on Kidney Disease Improving Global Outcomes, as well as ICU patients without AKI.10 Serial blood samples were collected according to the following schedule: within the first 3 days of ICU admission (approximately 24 hours after AKI diagnosis for AKI patients) (time 1), 5–7 days after the initial sample collection (time 2), and 4–6 weeks later at a follow-up post-AKI clinic evaluation (time 3). For each patient, the medical record was reviewed for demographic, comorbidity, medication, and ICU-related therapies, including the Charlson Comorbidity Index to assess comorbidities and Acute Physiology and Chronic Health Evaluation II (APACHE II) score for severity of illness.11,12

The primary aim of the analysis was to determine whether ETP differed significantly between critically ill patients with and without AKI at different time points. The secondary aim was to evaluate the relationship of serum ETP assessed at baseline, as well as the change or delta (Δ) in ETP between the two initial time points, with the development of MAKE assessed at hospital discharge, represented by the composite of death, KRT, or reduction of eGFR to ≤75% of baseline.8,13

This study was approved by the institutional review board, and patients or their legally authorized representatives provided written, informed consent to participate in the study.

Laboratory Analysis

Serum was isolated from blood samples within 45–60 minutes after centrifugation at 1000×g at 4°C for 10 minutes, then samples maintained at −80°C. ETP was measured using ELISA. Ninety-six well-plates (Corning Costar) were coated with rabbit monoclonal anti-ETP antibodies prepared in house at 2 μg/ml concentration. Serum samples were titrated at a series of dilutions in 1× PBS, then added to an anti-ETP coated plate. A high affinity–specific anti-ETP antibody (ETN-1Rb) was used as secondary detection antibody. Anti-Rabbit Fab2-horseradish peroxidase antibody (Jackson ImmunoResearch) was used for detection of ETP signals, using the dilution suggested by the manufacturer. A purified ETP recombinant protein was titrated in a series of concentrations (0–50 ng/ml) to establish a standard curve for calculation of ETP in serum samples. Other biomarkers used in the analysis are as previously published.8 Other laboratory data obtained during routine clinical care were extracted from the electronic health record.

Statistical Analysis

The initial timepoint for ETP measurement was assessed as both absolute values and tertiles. Descriptive statistics for the cohort are expressed as medians and interquartile ranges and frequency (proportions). Categorical data are compared using the chi-squared test and continuous data with Kruskal-Wallis (three groups) or Wilcoxon rank-sum (two groups), as appropriate.

In the evaluation of MAKE, we constructed a multivariable logistic regression model with ETP tertile (lower tertile as reference) representing the independent variable of interest. The study team identified additional variables to include in the multivariable model based on imbalances in ETP tertiles that were hypothesized to influence the MAKE outcome. We used log-transformed serum neutrophil gelatinase-associated lipocalin (NGAL) to adjust for the presence and severity of kidney injury given prior data associating serum NGAL with MAKE, including outperformance over serum creatinine.14,15 In addition to ETP and NGAL, additional covariates included in the model were ICU type (medical versus surgical), nonrenal APACHE II, and Charlson Comorbidity Index. Variance inflation factors were assessed to evaluate potential for collinearity. As a sensitivity analysis, we constructed this regression model with survivors only to evaluate the more kidney-centric components of MAKE in isolation. In addition, we repeated the model in all patients, but used serum creatinine measurement at the initial time point in place of NGAL to evaluate the effect of controlling with a functional (creatinine) versus injury (NGAL) kidney marker. As a secondary outcome, the design of the study allowed for the evaluation of repeated measurements of ETP separated by 5–7 days. We evaluated the relationship between the ΔETP (initial measurement subtracted from the second measurement) and MAKE in the entire cohort and again in survivors only. Finally, we constructed heat maps to explore the relationship between ETP and other biomarkers analyzed in our biobank at the two initial time points.

Statistical analyses were conducted using Stata (StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX: StataCorp LLC). Statistical significance was set at a two-sided P value of <0.05.

Results

One hundred twenty-one patients were available for analysis with serum available for ETP measurements. At the initial time point measurement early in the ICU admission, patients with AKI demonstrated significantly higher levels of ETP compared with patients without AKI: 117.4 (59.8–141.9) ng/ml versus 11.5 (7.1–20.8) ng/ml (P < 0.001) (Table 1). This was also replicated at the second time point 5–7 days later. These data are summarized and displayed in Figure 1. ETP levels in the AKI subset of patients who returned to the clinic were reduced from the levels observed in the ICU, however, remained elevated when compared with the measurements in ICU patients without AKI. ETP levels at the two initial time points were both significantly higher for patients who died (P < 0.001 for both time points) and for those patients with a MAKE at hospital discharge (P < 0.001 for both time points) (Table 1).

Table 1 Endotrophin levels by outcome and timepoint

Outcome	ETP Time 1 (ng/ml)	ETP Time 2 (ng/ml)	ETP Time 3 (ng/ml)	
AKI status				
 AKI	117.4 (59.8–141.9) n=67	118.8 (53.6–138.8) n=54	46.4 (30.4–83.2) n=13	
 No AKI	11.5 (7.1–20.8) n=54	11.1 (5.3–19.8) n=43	—	
 P value	<0.001	<0.001	—	
Mortality				
 Death	132.2 (80.2–142.9) n=19	137.8 (133.6–153.4) n=9	—	
 Survival	32.9 (10.4–94.5) n=102	28.7 (11.1–110.0) n=88	46.4 (30.4–83.2) n=13	
 P value	<0.001	<0.001	—	
MAKEa				
 Yes	118.1 (72.5–140.2) n=47	121.6 (79.3–141.9) n=35	—	
 No	17.2 (7.9–46.4) n=74	14.3 (7.8–39.3) n=62)	—	
 P value	<0.001	<0.001	—	
ETP, endotrophin; MAKE, major adverse kidney event.

a Composite of death, KRT at discharge, or eGFR ≤75% of baseline at discharge.

Figure 1 ETP levels between AKI and no AKI groups at three time points: (1) early in ICU, (2) 5–7 days later, and (3) 4–6 weeks later. ETP, endotrophin; ICU, intensive care unit.

Patient characteristics assessed by ETP tertile are shown in Table 2. The highest ETP tertile tended to represent more severely ill patients, specifically with statistically significant differences in severity of illness measures, a greater degree of comorbidities, more need for interventions such as vasopressors and mechanical ventilation, a greater proportion and severity of AKI, and a greater proportion of medical ICU versus surgical ICU patients. When adjusted for ICU type, serum NGAL, nonrenal APACHE II, and Charlson Comorbidity Index, ETP tertile was independently associated with the development of MAKE at hospital discharge: odds ratio 12.81 (2.06–79.46) for third (higher) versus first (lower) tertile, odds ratio 5.27 (0.98–28.34) for second (middle) versus first (lower) tertile (Table 3). In sensitivity analysis, this observation persisted when limiting the cohort to survivors at hospital discharge and assessing the kidney-centric components of MAKE excluding mortality (Supplemental Table 1). When controlling for serum creatinine rather than NGAL, the directionality of the ETP association remained, albeit no longer statistically significant (Supplemental Table 2).

Table 2 Patient characteristics by endotrophin tertile at enrollment

Patient Demographic	Tertile 1 (n=42)	Tertile 2 (n=39)	Tertile 3 (n=40)	P Value	
Serum ETP (ng/ml)	8.4 (6.6–13.6)	48.5 (31.9–64.5)	138.2 (124.0–146.1)	<0.001	
Age (yr)	59 (45–64)	54 (48–71)	54 (43–65)	0.701	
Sex (% male)	21 (50.0)	24 (61.5)	26 (65.0)	0.351	
Race, n (%)				0.346	
 White	42 (100)	38 (97.4)	40 (100)		
 Black	0 (0)	1 (2.6)	0 (0)		
Weight (kg)	82.5 (67.9–96.0)	95.3 (80.0–110.0)	89.0 (69.2–120.0)	0.038	
ICU type, n (%)				<0.001	
 Surgical	31 (73.8)	17 (43.6)	11 (27.5)		
 Medical	11 (26.2)	22 (56.4)	29 (72.5)		
Diabetes, n (%)	8 (19.1)	12 (30.8)	16 (40.0)	0.115	
Hypertension, n (%)	20 (47.6)	29 (74.4)	19 (47.5)	0.021	
Heart failure, n (%)	2 (4.8)	6 (15.4)	2 (5.0)	0.146	
Liver disease, n (%)	5 (11.9)	7 (18.0)	14 (35.0)	0.032	
Cancer, n (%)	12 (28.6)	8 (20.5)	10 (25.0)	0.703	
Baseline eGFR (ml/min per 1.73 m2)	98.2 (84.5–106.0)	94.8 (82.2–108.4)	89.1 (76.6–103.5)	0.164	
Nonrenal APACHE II	14 (8–18)	16 (12–22)	22 (16–27)	<0.001	
Nonrenal SOFA	3 (2–5)	6 (2–8)	10 (7–12)	<0.001	
Charlson Comorbidity Index	2 (0–4)	3 (2–4)	3 (1–5)	0.032	
No. of vasopressors/inotropes	0 (0–0)	0 (0–1)	1 (1–3)	<0.001	
Mechanical ventilation, n (%)	20 (47.6)	23 (59.0)	34 (85.0)	0.002	
Serum creatinine at enrollment (mg/dl)	0.8 (0.6–0.9)	1.6 (0.9–2.5)	2.9 (1.9–3.5)	<0.001	
AKI, n (%)	3 (7.1)	24 (61.5)	40 (100)	<0.001	
 Stage 2a	1 (33.3)	2 (8.3)	8 (20.0)		
 Stage 3a	2 (66.7)	22 (91.7)	32 (80.0)		
APACHE II, Acute Physiology and Chronic Health Evaluation II; ETP, endotrophin; SOFA, sequential organ failure assessment.

a As a percentage of all AKI cases in the tertile.

Table 3 Multivariable regression analysis for major adverse kidney events (dependent variable) and endotrophin tertile as the main independent variable

Variablea	OR with 95% Confidence Interval	P Value	
ETP tertile (versus first tertile)			
 Second tertile	5.27 (0.98 to 28.34)	0.053	
 Third tertile	12.81 (2.06 to 79.46)	0.006	
ICU type (versus surgical)	1.49 (0.54 to 4.14)	0.442	
NGAL, per 1-log unit	1.90 (1.10 to 3.26)	0.021	
Nonrenal APACHE II, per 1 unit	1.04 (0.98 to 1.10)	0.243	
Charlson Comorbidity Index, per 1 unit	1.14 (0.91 to 1.42)	0.267	
APACHE II, Acute Physiology and Chronic Health Evaluation II; ETP, endotrophin; ICU, intensive care unit; NGAL, neutrophil gelatinase–associated lipocalin; OR, odds ratio.

a Complete data available for 120 patients.

When ΔETP between the initial two time points was evaluated there was an association between ETP trajectory and outcomes. In patients who died or experienced MAKE at discharge, the ΔETP was significantly higher, indicating either an increase in the first time point or lack of a significant decrease at the second time point compared with the first one (Table 4). While numerically similar trends were observed in the sensitivity analysis of survivors only, these did not reach statistical significance (Supplemental Table 3).

Table 4 Changes in endotrophins over time and study outcomes

Outcome	Change in ETPs (Time 2−Time 1)	P Value	
Mortality		0.017	
 Yes	17.0 (0.8–40.4) n=9		
 No	−1.8 (−7.7 to 6.0) n=86		
MAKEa		0.026	
 Yes	5.9 (−6.4 to 21.4) n=35		
 No	−2.3 (−8.3 to 4.1) n=60		
ETP, endotrophin; MAKE, major adverse kidney event.

a Composite of death, KRT at discharge, or eGFR ≤75% of baseline at discharge.

Heatmaps showing the relationship between ETP and other biomarkers assessed in our biobank at the initial two time points are shown in Figure 2. At both time points, serum ETP was most closely correlated with serum NGAL and TNF-α and least correlated with IL-1β.

Figure 2 The figure depicts the correlations between these biomarkers. Heat map of ETP levels versus other cytokines included in the biobank at time point 1 (A) and 5–7 days later (B).

Discussion

In this study, serum ETP was significantly elevated in the acute ICU period after AKI in critically ill adult patients and was significantly associated with the development of MAKE assessed at hospital discharge, even when controlling for relevant covariates. Furthermore, sustained elevations of serum ETP at 5–7 days were also associated with MAKE, indicating that sustained release of ETP into the circulation may represent a driver of AKI progression or maladaptive repair in these patients.

ETP is a carboxyl-terminal cleavage product of collagen type IV α-3 (ColIVα3), a beaded microfilament within the extracellular matrix of many connective tissues, including the basement membrane of glomeruli.5 In healthy tissue, ColIVα3 provides integral structural support.6 However, in the context of disease, ColIVα3 becomes upregulated and ETP is cleaved from the α-3 chain where it is released into the extracellular matrix. Therefore, ETP can act as both a biomarker and a causative agent for pathogenesis, such as injurious fibrogenesis and inflammation.5 ETP may interact with local tissue in its vicinity or, once released into the circulation, affect distant organs in an endocrine fashion.5 Unlike other biomarkers, ETP may be particularly useful in AKI because it reflects structural remodeling that occurs within the kidney tissue during pathogenic fibrosis and can predict kidney disease progression and mortality beyond the acute phase, even when accounting for confounding variables such as age and comorbidities.5,6

ETP has shown promise as a biomarker in kidney diseases, both acute and chronic. In patients with CKD, serum levels of ETP were significantly associated with increased mortality. Patients in the highest quartile of ETP had a 12-fold increased risk of death compared with the lowest quartile.6 In an analysis from the AKI Risk in Derby study, plasma ETP levels at 1 year measured in 801 patients was significantly associated with the progression of kidney disease and mortality and outperformed eGFR in predicting progression of kidney disease.7

Our results are consistent with this finding as evidenced by the ETP levels observed in patients with AKI who were followed at 4–6 weeks after AKI. ETP levels at this visit were reduced from their peaks, but still noticeably higher than ETP levels of patients without AKI during their period of critical illness. Our study builds on the pathophysiologic relevance of ETP by demonstrating, through repeated measures, that early and sustained elevations are associated with short-term adverse kidney events in critically ill patients.

Preclinical data support the notion of ETP as more than a biomarker but a therapeutic target in fibroinflammatory diseases. In a podocyte injury model using the podocyte apoptosis through targeted activation of caspase-8 model initiated by dimerizer injection, ETP-targeting monoclonal antibodies were administered twice per week over 5 weeks (starting 3 days after dimerizer) and resulted in significantly decreased inflammatory and fibrotic gene expression, collagen, and proteinuria.16 Furthermore, an increase in kidney function was observed with a 24.9% increase in podocytes compared with immediately after the ablation procedure.16 A number of gain-of-function experiments have demonstrated the fibroinflammatory role of ETP in other preclinical settings, both in the liver and in adipose tissue.17,18

Our study is strengthened by a well-defined selection of patients without kidney disease at baseline and by repeated measurements allowing for the examination of ETP trajectory and the association of MAKE at hospital discharge. While our study supports the role that ETP may play in AKI progression and repair, it is not without limitations. First, these data represent a single-center and a relatively small sample size. Second, while severe AKI is represented in this cohort stage 1 AKI is not, thus the results may not be extrapolated to all forms of AKI. Third, while we attempted to adjust for relevant confounders, including NGAL as a marker of kidney injury at time of initial ETP measurement, the sample size limited the number of covariates to include in the models and residual confounding remains a limitation in studies of this nature. Finally, various forms of liver disease undoubtedly contribute to elevated plasma ETP levels. We and many others have examined this.19 Similarly, heart failure can contribute as well.20 However, it is apparent that the magnitude of changes in ETP levels reported here are significantly more dramatic than the changes contributed by any of the other comorbidities. Hence, we believe the primary factor driving ETP levels up is in fact kidney injury.

Serum ETP is elevated in critically ill adult patients with severe AKI compared with patients without AKI. Higher levels of serum ETP early in the course of ICU admission, as well as sustained elevations of ETP within a 5-day to 7-day period, were associated with MAKE assessed at hospital discharge. Further research is warranted on the role of ETP as a biomarker of AKI-related outcomes and as a therapeutic target to minimize sequalae of AKI.

Supplementary Material

Acknowledgments

We would like to acknowledge Daniel T. Manion, MS, for his assistance with data visualization.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/KN9/A571.

Funding

O.W. Moe was supported by the Charles Pak Foundation. A.H. Flannery: National Institute of Diabetes and Digestive and Kidney Diseases (K23DK128562). J.A. Neyra: National Institute of Diabetes and Digestive and Kidney Diseases (U54DK137307, R01DK128208, R01DK133539, and U01DK12998). Z. An: Cancer Prevention and Research Institute of Texas (RP190561) and Welch Foundation (AU-0042-20030616). O.W. Moe: National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK-079328, R01 DK091392, R01 DK092461). P.E. Scherer: National Institute of Diabetes and Digestive and Kidney Diseases (R01DK131537). This work was supported by National Institutes of Health (K23DK128562, PI: A.H. Flannery).

Author Contributions

Conceptualization: Alexander H. Flannery, Orson W. Moe, Javier A. Neyra, Philipp E. Scherer.

Data curation: Zhiqiang An, Dawei Bu, Fabiola Gianella, Javier A. Neyra, Ningyan Zhang.

Formal analysis: Dawei Bu, Alexander H. Flannery, Fabiola Gianella.

Funding acquisition: Philipp E. Scherer.

Methodology: Alexander H. Flannery, Philipp E. Scherer.

Project administration: Orson W. Moe.

Supervision: Javier A. Neyra.

Writing – original draft: Madison Botkins, Dawei Bu, Alexander H. Flannery, Javier A. Neyra.

Writing – review & editing: Fabiola Gianella, Orson W. Moe, Philipp E. Scherer.

Data Sharing Statement

All data are included in the manuscript and/or supporting information.

Supplemental Material

This article contains the following supplemental material online at http://links.lww.com/KN9/A570.

Supplemental Table 1. Multivariable regression analysis for major adverse kidney events (dependent variable) and endotrophin tertile as the main independent variable in survivors.

Supplemental Table 2. Multivariable regression analysis for major adverse kidney events (dependent variable) and endotrophin tertile as the main independent variable using serum creatinine to control for kidney function.

Supplemental Table 3. Changes in endotrophins over time and study outcomes in survivors.
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