Abstract
Background Higher baseline levels of soluble TNF receptors (TNFR1 and TNFR2) have been associated with progressive CKD. Whether longitudinal changes in these biomarkers of inflammation are also associated with worse kidney outcomes has been less studied. Methods We evaluated associations of longitudinal changes in TNFR1 and TNFR2 with ESKD in the African American Study of Kidney Disease and Hypertension (AASK; 38% female; 0% diabetes) and kidney function decline (first occurrence of ≥30 ml/min per 1.73 m2 or ≥50% eGFR decline if randomization eGFR ≥60 or <60 ml/min per 1.73 m2, respectively; ESKD) in the Veterans Affairs Nephropathy in Diabetes trial (VA NEPHRON-D; 99% male; 100% diabetes) using Cox models. Biomarkers were measured from samples collected at 0-, 12-, and 24-month visits for AASK (serum) and 0- and 12-month visits for VA NEPHRON-D (plasma). Biomarker slopes (AASK) were estimated using linear mixed-effects models. Covariates included sociodemographic/clinical factors, baseline biomarker level, and kidney function. Results There were 129 ESKD events over a median of 7.0 years in AASK (n5418) and 118 kidney function decline events over a median of 1.5 years in VA NEPHRON-D (n5754). In AASK, each 1 SD increase in TNFR1 and TNFR2 slope was associated with 2.98- and 1.87-fold higher risks of ESKD, respectively. In VA NEPHRON-D, each 1 SD increase in TNFR1 and TNFR2 was associated with 3.20- and 1.43-fold higher risks of kidney function decline, respectively. Conclusions Among individuals with and without diabetes, longitudinal increases in TNFR1 and TNFR2 were each associated with progressive CKD, independent of initial biomarker level and kidney function.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 996-1010 |
| Number of pages | 15 |
| Journal | Journal of the American Society of Nephrology |
| Volume | 33 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2022 |
ASJC Scopus subject areas
- Nephrology
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Longitudinal TNFR1 and TNFR2 and Kidney Outcomes : Results from AASK and VA NEPHRON-D. / Chen, Teresa K.; Coca, Steven G.; Estrella, Michelle M. et al.
In: Journal of the American Society of Nephrology, Vol. 33, No. 5, 05.2022, p. 996-1010.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Longitudinal TNFR1 and TNFR2 and Kidney Outcomes
T2 - Results from AASK and VA NEPHRON-D
AU - Chen, Teresa K.
AU - Coca, Steven G.
AU - Estrella, Michelle M.
AU - Appel, Lawrence J.
AU - Coresh, Josef
AU - Philbrook, Heather Thiessen
AU - Obeid, Wassim
AU - Fried, Linda F.
AU - Heerspink, Hiddo J.L.
AU - Ix, Joachim H.
AU - Shlipak, Michael G.
AU - Kimmel, Paul L.
AU - Parikh, Chirag R.
AU - Grams, Morgan E.
N1 - Funding Information: C.R. Parikh reports having consultancy agreements with Genfit Bio-pharmaceutical Company; reports receiving research funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Heart, Lung and Blood Institute (NHLBI); and reports serving on the Data Safety and Monitoring Board of Genfit. C.R. Parikh and S.G. Coca are members of the advisory board of, and own equity in, Renalytix. H. Thiessen Philbrook reports other interests/relationships as Statistical Editor, Kidney360. H.J.L. Heerspink reports consultancy agreements with AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, CSL Pharma, Chinook, Dimerix Fresenius, Gilead, Janssen, Merck, Mitsu-bishi Tanabe, Mundi Pharma, NovoNordisk, and Travere Pharmaceuticals; reports receiving research funding from AbbVie, AstraZeneca, Boehringer Ingelheim, and Janssen (grant funding direct to employer); and reports speakers bureau from AstraZeneca. J. Coresh reports consultancy agreements with Healthy.io, and Ultragenyx; reports having an ownership interest in Healthy.io; reports receiving research funding from the National Institutes of Health (NIH), National Kidney Foundation (NKF, which receives industry support); and reports being a scientific advisor or member of Healthy.io, and the NKF. J.H. Ix reports consultancy agreements with Ardelyx, AstraZeneca, Bayer, Jnana, and Sanifit; reports receiving research funding from Baxter International; and reports being a scientific advisor or member of AlphaYoung. L.J. Appel reports receiving honoraria from Wolters Kluwer; and reports other interests/relationships with Bloomberg Philanthropies. L. Fried reports having consultancy agreements with Bayer; reports being on the data safety monitoring boards of 3D Communications, CSL Behring, and Novonordisk; and reports being a consultant for Akebia/Fibrogen. M.M. Estrella reports receiving research funding from Bayer, and Booz Allen Hamilton, Inc.; reports receiving consulting fees from AstraZeneca, Boehringer Ingelheim, Eiland & Bonnin, and Professional Corporation; reports receiving honoraria from the American Kidney Fund, AstraZeneca, Boehringer Ingelheim, and the NKF; and reports being a scientific advisor or member of the CJASN Editorial Board. M.E. Grams reports receiving honoraria from academic institutions for giving grand rounds and American Diabetes Association for reviewing abstracts; reports being a scientific advisor or member for American Journal of Kidney Diseases, CJASN, JASN, NKF Scientific Advisory Board, Kidney Disease: Improving Global Outcomes Executive Committee, United States Renal Data System Scientific Advisory Board; and reports other interests/relationships with the NKF, which in turn receives funding from Abbvie, Relypsa, and Thrasos, among others. M. Shlipak reports consultancy agreements with Cricket Health, Intercept Pharmaceuticals, University of Washington Cardiovascular Health Study, and Veterans Medical; reports receiving research funding from Bayer Pharmaceuticals; reports being a scientific advisor or member of the American Journal of Kidney Diseases, Circulation, JASN, and Journal of the American Society of Nephrology; and has other interests/relationships as a Board Member of the Northern California Institute for Research and Education. P.L. Kimmel reports other interests or relationships as Co-Editor of Chronic Renal Disease Academic Press, Co-Editor of Psychosocial Aspects of Chronic Kidney Disease; and reports receiving Academic Press royalties. S. Coca reports receiving consulting fees from Bayer, Boehringer Ingelheim, CHF Solutions, ProKidney, Relypsa (now Vifor), Renalytix, and Takeda Pharmaceuticals in the past 3 years; reports having consultancy agreements with 3ive, Axon, and Reprieve Cardiovascular; reports having an ownership interest in pulseData; reports receiving research funding from ProKidney, Renalytix, Renal Research Institute, and XORTX; reports having patents and inventions with Renalytix; reports being a scientific advisor or member of Reprieve Cardiovascular; and reports other interests/relationships as Associate Editor for Kidney360, and on the Editorial Boards of CJASN, JASN, and Kidney International. T.K. Chen reports receiving research funding from NIH/NIDDK, and Yale University. Because L. Fried is an editor of the Journal of the American Society of Nephrology, she was not involved in the peer review process for this manuscript. A guest editor oversaw the peer review and decision-making process for this manuscript. All remaining authors have nothing to disclose. Funding Information: The African American Study of Kidney Disease and Hypertension was conducted by the AASK Investigators and supported by the NIDDK. The data and samples from the AASK trial reported here were supplied by the NIDDK Central Repositories via X01DK118497. This manuscript was not prepared in collaboration with Investigators of the AASK study and does not necessarily reflect the opinions or views of the AASK study, the NIDDK Central Repositories, the NIH, or the NIDDK. The AASK trial and cohort were supported by institutional grants from the NIH and NIDDK (M01 RR-00080, M01 RR-00071, M0100032, P20-RR11145, M01 RR00827, M01 RR00052, 2P20 RR11104, RR029887, DK 2818-02, DK057867, and DK048689), and the following pharmaceutical companies: AstraZeneca, Forest Laboratories, Glaxo-SmithKline, King Pharmaceuticals, Pfizer, Pharmacia, and Upjohn. The VA-NEPHRON D trial was supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development. The Investigator-Initiated Studies Program of Merck donated the study medications, losartan and lisinopril/placebo, for the VA NEPHRON-D study. CSP# 565 Combination Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy (VA NEPHRON-D) was conducted and supported by the Department of Veterans Affairs Cooperative Studies Program, Office of Research and Development. This analysis was carried out by the listed authors utilizing data that was specified and obtained under the Data Use Agreement between Department of Veterans Affairs Cooperative Studies Program and Johns Hopkins University, dated June 14, 2019. All statements, opinions, or views are solely of the author(s) and do not reflect official views of VA. The findings reported in this paper do not necessarily reflect the opinions of the NIDDK, the NIH, the Department of Health and Human Services of the government of the United States. We thank the participants of AASK and VA NEPHRON-D. Funding Information: This work is supported by a Yale University George M. O’Brien Center for Kidney Research Pilot and Feasibility Grant (under NIH/NIDDK grant P30DK079310) and NIH/NIDDK grant K08DK117068 (to T. Chen); NIDDK grant R01DK108803 and NIH/NHLBI grant K24HL155861 (to M. Grams); and NIH/NIDDK grant U01DK106962 (to C. Parikh and S. Coca). Biomarkers were measured by the Translational Research Core of the George M. O’Brien Kidney Center (NIH/NIDDK grant P30DK079310). Publisher Copyright: © 2022 by the American Society of Nephrology.
PY - 2022/5
Y1 - 2022/5
N2 - Background Higher baseline levels of soluble TNF receptors (TNFR1 and TNFR2) have been associated with progressive CKD. Whether longitudinal changes in these biomarkers of inflammation are also associated with worse kidney outcomes has been less studied. Methods We evaluated associations of longitudinal changes in TNFR1 and TNFR2 with ESKD in the African American Study of Kidney Disease and Hypertension (AASK; 38% female; 0% diabetes) and kidney function decline (first occurrence of ≥30 ml/min per 1.73 m2 or ≥50% eGFR decline if randomization eGFR ≥60 or <60 ml/min per 1.73 m2, respectively; ESKD) in the Veterans Affairs Nephropathy in Diabetes trial (VA NEPHRON-D; 99% male; 100% diabetes) using Cox models. Biomarkers were measured from samples collected at 0-, 12-, and 24-month visits for AASK (serum) and 0- and 12-month visits for VA NEPHRON-D (plasma). Biomarker slopes (AASK) were estimated using linear mixed-effects models. Covariates included sociodemographic/clinical factors, baseline biomarker level, and kidney function. Results There were 129 ESKD events over a median of 7.0 years in AASK (n5418) and 118 kidney function decline events over a median of 1.5 years in VA NEPHRON-D (n5754). In AASK, each 1 SD increase in TNFR1 and TNFR2 slope was associated with 2.98- and 1.87-fold higher risks of ESKD, respectively. In VA NEPHRON-D, each 1 SD increase in TNFR1 and TNFR2 was associated with 3.20- and 1.43-fold higher risks of kidney function decline, respectively. Conclusions Among individuals with and without diabetes, longitudinal increases in TNFR1 and TNFR2 were each associated with progressive CKD, independent of initial biomarker level and kidney function.
AB - Background Higher baseline levels of soluble TNF receptors (TNFR1 and TNFR2) have been associated with progressive CKD. Whether longitudinal changes in these biomarkers of inflammation are also associated with worse kidney outcomes has been less studied. Methods We evaluated associations of longitudinal changes in TNFR1 and TNFR2 with ESKD in the African American Study of Kidney Disease and Hypertension (AASK; 38% female; 0% diabetes) and kidney function decline (first occurrence of ≥30 ml/min per 1.73 m2 or ≥50% eGFR decline if randomization eGFR ≥60 or <60 ml/min per 1.73 m2, respectively; ESKD) in the Veterans Affairs Nephropathy in Diabetes trial (VA NEPHRON-D; 99% male; 100% diabetes) using Cox models. Biomarkers were measured from samples collected at 0-, 12-, and 24-month visits for AASK (serum) and 0- and 12-month visits for VA NEPHRON-D (plasma). Biomarker slopes (AASK) were estimated using linear mixed-effects models. Covariates included sociodemographic/clinical factors, baseline biomarker level, and kidney function. Results There were 129 ESKD events over a median of 7.0 years in AASK (n5418) and 118 kidney function decline events over a median of 1.5 years in VA NEPHRON-D (n5754). In AASK, each 1 SD increase in TNFR1 and TNFR2 slope was associated with 2.98- and 1.87-fold higher risks of ESKD, respectively. In VA NEPHRON-D, each 1 SD increase in TNFR1 and TNFR2 was associated with 3.20- and 1.43-fold higher risks of kidney function decline, respectively. Conclusions Among individuals with and without diabetes, longitudinal increases in TNFR1 and TNFR2 were each associated with progressive CKD, independent of initial biomarker level and kidney function.
UR - http://www.scopus.com/inward/record.url?scp=85129780827&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85129780827&partnerID=8YFLogxK
U2 - 10.1681/ASN.2021060735
DO - 10.1681/ASN.2021060735
M3 - Article
C2 - 35314457
AN - SCOPUS:85129780827
SN - 1046-6673
VL - 33
SP - 996
EP - 1010
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
IS - 5
ER -