Estimated Kidney Tubular Secretion and Kidney, Cardiovascular, and Mortality Outcomes in CKD: The Systolic Blood Pressure Intervention Trial

Simon B. Ascher; Michael G. Shlipak; Ronit Katz; Alexander L. Bullen; Rebecca Scherzer; Stein I. Hallan; Alfred K. Cheung; Kalani L. Raphael; Michelle M. Estrella; Vasantha K. Jotwani; Jesse C. Seegmiller; Joachim H. Ix; Pranav S. Garimella

doi:10.1016/j.xkme.2022.100546

Estimated Kidney Tubular Secretion and Kidney, Cardiovascular, and Mortality Outcomes in CKD: The Systolic Blood Pressure Intervention Trial

Simon B. Ascher, Michael G. Shlipak, Ronit Katz, Alexander L. Bullen, Rebecca Scherzer, Stein I. Hallan, Alfred K. Cheung, Kalani L. Raphael, Michelle M. Estrella, Vasantha K. Jotwani, Jesse C. Seegmiller, Joachim H. Ix, Pranav S. Garimella

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

Abstract

RATIONAL & OBJECTIVE: Many drugs, metabolites, and toxins are cleared by the kidneys via tubular secretion. Whether novel endogenous measures of tubular secretion provide information about kidney, cardiovascular, and mortality risk is uncertain.

STUDY DESIGN: Longitudinal subgroup analysis of clinical trial participants.

SETTING & PARTICIPANTS: 2,089 Systolic Blood Pressure Intervention Trial participants with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 at baseline.

EXPOSURE: Summary score incorporating urine-to-plasma ratios of 10 endogenous secretion markers measured in paired urine and plasma samples at baseline.

OUTCOME: The primary outcome was longitudinal change in eGFR. Secondary outcomes included chronic kidney disease (CKD) progression (≥50% eGFR decline or incident kidney failure requiring dialysis or kidney transplantation), a cardiovascular disease (CVD) composite (myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, or death from cardiovascular causes), and mortality.

ANALYTICAL APPROACH: Linear mixed-effect models were used to evaluate the association between the secretion score and change in eGFR, and Cox proportional hazards models were used to evaluate associations with CKD progression, CVD, and mortality.

RESULTS: At baseline, mean age was 73 ± 9 years and eGFR was 46 ± 11 mL/min/1.73 m 2. During a median follow-up of 3.3 years, mean change in eGFR was -1.44% per year, and 72 CKD progression events, 272 CVD events, and 144 deaths occurred. In multivariable analyses, lower secretion score was associated with faster eGFR decline and greater risk of CKD progression, CVD, and mortality. After further adjustment for baseline eGFR and albuminuria, each 1-standard deviation lower secretion score was associated with faster eGFR decline (-0.65% per year; 95% CI, -0.84% to -0.46%), but not CKD progression (HR, 1.23; 95% CI, 0.96-1.58), CVD (HR, 1.02; 95% CI, 0.89-1.18), or mortality (HR, 0.90; 95% CI, 0.74-1.09). The secretion score association with eGFR decline appeared stronger in participants with baseline eGFR <45 mL/min/1.73 m 2 ( P for interaction < 0.001).

LIMITATIONS: Persons with diabetes and proteinuria >1 g/d were excluded.

CONCLUSIONS: Among SPRINT participants with CKD, lower estimated tubular secretion was associated with faster eGFR decline, independent of baseline eGFR and albuminuria, but not with CKD progression, CVD, or mortality.

Original language	English (US)
Article number	100546
Journal	Kidney Medicine
Volume	4
Issue number	12
DOIs	https://doi.org/10.1016/j.xkme.2022.100546
State	Published - Dec 2022

Bibliographical note

Funding Information:
Simon B. Ascher, MD, MPH, Michael G. Shlipak, MD, MPH, Ronit Katz, DPhil, Alexander L. Bullen, MD, MAS, Rebecca Scherzer, PhD, Stein I. Hallan, MD, PhD, Alfred K. Cheung, MD, Kalani L. Raphael, MD, MS, Michelle M. Estrella, MD, MHS, Vasantha K. Jotwani, MD, Jesse C. Seegmiller, PhD, Joachim H. Ix, MD, MAS, and Pranav S. Garimella, MBBS, MPH, Research idea and study design: SBA, MGS, RK, JHI, PSG; data acquisition: MGS, JHI; data analysis: RK; data interpretation: SBA, MGS, RK, ALB, RS, SIH, AKC, KLR, MME, VKJ, JCS, JHI, PSG; supervision or mentorship: MGS, JHI, PSG. Co-senior authors: JHI, PSG. SBA and MGS contributed equally to this work. JHI and PSG contributed equally to this work. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. This ancillary study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01DK098234 for MGS/JHI and K24DK110427 for JHI). PSG was supported by a career development grant from the NIDDK (K23DK114556). The funders had no role in study design, data collection, analysis, reporting, or the decision to submit for publication. The authors thank the participants and staff members of the Systolic Blood Pressure Intervention Trial, which sponsored by the National Institutes of Health (NIH), including the National Heart, Lung, and Blood Institute (NHLBI), the NIDDK, the National Institute on Aging (NIA), and the National Institute of Neurological Disorders and Stroke (NINDS), under Contract Numbers HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN268200900049C, and Inter-Agency Agreement Number A-HL-13–002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. The SPRINT investigators acknowledge the contribution of study medications (azilsartan and azilsartan combined with chlorthalidone) from Takeda Pharmaceuticals International, Inc. All components of the SPRINT study protocol were designed and implemented by the investigators. The investigative team collected, analyzed, and interpreted the data. All aspects of manuscript writing and revision were carried out by the coauthors. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of Veterans Affairs, or the US Government. For a full list of contributors to SPRINT, please see the supplementary acknowledgement list: www.sprinttrial.org/public/dspScience.cfm. We also acknowledge the support from the following CTSAs funded by NCATS: CWRU: UL1TR000439, OSU: UL1RR025755, U Penn: UL1RR024134& UL1TR000003, Boston: UL1RR025771, Stanford: UL1TR000093, Tufts: UL1RR025752, UL1TR000073 & UL1TR001064, University of Illinois: UL1TR000050, University of Pittsburgh: UL1TR000005, UT Southwestern: 9U54TR000017–06, University of Utah: UL1TR000105–05, Vanderbilt University: UL1 TR000445, George Washington University: UL1TR000075, University of CA, Davis: UL1 TR000002, University of Florida: UL1 TR000064, University of Michigan: UL1TR000433, Tulane University: P30GM103337 COBRE Award NIGMS, Wake Forest University: UL1TR001420. MGS has received consulting income from Cricket Health, Inc and Intercept Pharmaceuticals. JHI holds an investigator initiated research grant from Baxter International Inc, serves as a member of a data safety monitoring board for Sanifit Therapeutics, is a member of the scientific advisory board for Alpha Young, and has served on advisory boards for AstraZeneca and Ardelyx. The remaining authors declare that they have no relevant financial interests. The results were presented as a poster at the American Society of Nephrology (ASN) conference in San Diego, CA, November 2021. Received June 7, 2022 as a submission to the expedited consideration track with 3 external peer reviews. Direct editorial input from the Statistical Editor and the Editor-in-Chief. Accepted in revised form August 28, 2022.

Funding Information:
This ancillary study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ( R01DK098234 for MGS/JHI and K24DK110427 for JHI). PSG was supported by a career development grant from the NIDDK ( K23DK114556 ). The funders had no role in study design, data collection, analysis, reporting, or the decision to submit for publication. The authors thank the participants and staff members of the Systolic Blood Pressure Intervention Trial, which sponsored by the National Institutes of Health (NIH), including the National Heart, Lung, and Blood Institute (NHLBI), the NIDDK, the National Institute on Aging (NIA), and the National Institute of Neurological Disorders and Stroke ( NINDS ), under Contract Numbers HHSN268200900040C , HHSN268200900046C , HHSN268200900047C , HHSN268200900048C , HHSN268200900049C , and Inter-Agency Agreement Number A-HL-13–002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. The SPRINT investigators acknowledge the contribution of study medications (azilsartan and azilsartan combined with chlorthalidone) from Takeda Pharmaceuticals International, Inc. All components of the SPRINT study protocol were designed and implemented by the investigators. The investigative team collected, analyzed, and interpreted the data. All aspects of manuscript writing and revision were carried out by the coauthors. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of Veterans Affairs, or the US Government. For a full list of contributors to SPRINT, please see the supplementary acknowledgement list: www.sprinttrial.org/public/dspScience.cfm . We also acknowledge the support from the following CTSAs funded by NCATS: CWRU: UL1TR000439, OSU: UL1RR025755, U Penn: UL1RR024134& UL1TR000003, Boston: UL1RR025771, Stanford: UL1TR000093, Tufts: UL1RR025752, UL1TR000073 & UL1TR001064, University of Illinois: UL1TR000050, University of Pittsburgh: UL1TR000005, UT Southwestern: 9U54TR000017–06, University of Utah: UL1TR000105–05, Vanderbilt University: UL1 TR000445, George Washington University: UL1TR000075, University of CA, Davis: UL1 TR000002, University of Florida: UL1 TR000064, University of Michigan: UL1TR000433, Tulane University: P30GM103337 COBRE Award NIGMS, Wake Forest University: UL1TR001420.

Publisher Copyright:
© 2022 The Authors

Keywords

CKD progression
CVD
hypertension
kidney function decline
mortality
tubular secretion

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.xkme.2022.100546

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Cite this

Ascher, S. B., Shlipak, M. G., Katz, R., Bullen, A. L., Scherzer, R., Hallan, S. I., Cheung, A. K., Raphael, K. L., Estrella, M. M., Jotwani, V. K., Seegmiller, J. C., Ix, J. H., & Garimella, P. S. (2022). Estimated Kidney Tubular Secretion and Kidney, Cardiovascular, and Mortality Outcomes in CKD: The Systolic Blood Pressure Intervention Trial. Kidney Medicine, 4(12), Article 100546. https://doi.org/10.1016/j.xkme.2022.100546

Ascher, SB, Shlipak, MG, Katz, R, Bullen, AL, Scherzer, R, Hallan, SI, Cheung, AK, Raphael, KL, Estrella, MM, Jotwani, VK, Seegmiller, JC, Ix, JH & Garimella, PS 2022, 'Estimated Kidney Tubular Secretion and Kidney, Cardiovascular, and Mortality Outcomes in CKD: The Systolic Blood Pressure Intervention Trial', Kidney Medicine, vol. 4, no. 12, 100546. https://doi.org/10.1016/j.xkme.2022.100546

@article{f1b0e81fee3f47b3825498d18f3bdc7f,

title = "Estimated Kidney Tubular Secretion and Kidney, Cardiovascular, and Mortality Outcomes in CKD: The Systolic Blood Pressure Intervention Trial",

abstract = "RATIONAL & OBJECTIVE: Many drugs, metabolites, and toxins are cleared by the kidneys via tubular secretion. Whether novel endogenous measures of tubular secretion provide information about kidney, cardiovascular, and mortality risk is uncertain.STUDY DESIGN: Longitudinal subgroup analysis of clinical trial participants.SETTING & PARTICIPANTS: 2,089 Systolic Blood Pressure Intervention Trial participants with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 at baseline. EXPOSURE: Summary score incorporating urine-to-plasma ratios of 10 endogenous secretion markers measured in paired urine and plasma samples at baseline.OUTCOME: The primary outcome was longitudinal change in eGFR. Secondary outcomes included chronic kidney disease (CKD) progression (≥50% eGFR decline or incident kidney failure requiring dialysis or kidney transplantation), a cardiovascular disease (CVD) composite (myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, or death from cardiovascular causes), and mortality.ANALYTICAL APPROACH: Linear mixed-effect models were used to evaluate the association between the secretion score and change in eGFR, and Cox proportional hazards models were used to evaluate associations with CKD progression, CVD, and mortality.RESULTS: At baseline, mean age was 73 ± 9 years and eGFR was 46 ± 11 mL/min/1.73 m 2. During a median follow-up of 3.3 years, mean change in eGFR was -1.44% per year, and 72 CKD progression events, 272 CVD events, and 144 deaths occurred. In multivariable analyses, lower secretion score was associated with faster eGFR decline and greater risk of CKD progression, CVD, and mortality. After further adjustment for baseline eGFR and albuminuria, each 1-standard deviation lower secretion score was associated with faster eGFR decline (-0.65% per year; 95% CI, -0.84% to -0.46%), but not CKD progression (HR, 1.23; 95% CI, 0.96-1.58), CVD (HR, 1.02; 95% CI, 0.89-1.18), or mortality (HR, 0.90; 95% CI, 0.74-1.09). The secretion score association with eGFR decline appeared stronger in participants with baseline eGFR <45 mL/min/1.73 m 2 ( P for interaction < 0.001). LIMITATIONS: Persons with diabetes and proteinuria >1 g/d were excluded.CONCLUSIONS: Among SPRINT participants with CKD, lower estimated tubular secretion was associated with faster eGFR decline, independent of baseline eGFR and albuminuria, but not with CKD progression, CVD, or mortality.",

keywords = "CKD progression, CVD, hypertension, kidney function decline, mortality, tubular secretion",

author = "Ascher, {Simon B.} and Shlipak, {Michael G.} and Ronit Katz and Bullen, {Alexander L.} and Rebecca Scherzer and Hallan, {Stein I.} and Cheung, {Alfred K.} and Raphael, {Kalani L.} and Estrella, {Michelle M.} and Jotwani, {Vasantha K.} and Seegmiller, {Jesse C.} and Ix, {Joachim H.} and Garimella, {Pranav S.}",

note = "Funding Information: Simon B. Ascher, MD, MPH, Michael G. Shlipak, MD, MPH, Ronit Katz, DPhil, Alexander L. Bullen, MD, MAS, Rebecca Scherzer, PhD, Stein I. Hallan, MD, PhD, Alfred K. Cheung, MD, Kalani L. Raphael, MD, MS, Michelle M. Estrella, MD, MHS, Vasantha K. Jotwani, MD, Jesse C. Seegmiller, PhD, Joachim H. Ix, MD, MAS, and Pranav S. Garimella, MBBS, MPH, Research idea and study design: SBA, MGS, RK, JHI, PSG; data acquisition: MGS, JHI; data analysis: RK; data interpretation: SBA, MGS, RK, ALB, RS, SIH, AKC, KLR, MME, VKJ, JCS, JHI, PSG; supervision or mentorship: MGS, JHI, PSG. Co-senior authors: JHI, PSG. SBA and MGS contributed equally to this work. JHI and PSG contributed equally to this work. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. This ancillary study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01DK098234 for MGS/JHI and K24DK110427 for JHI). PSG was supported by a career development grant from the NIDDK (K23DK114556). The funders had no role in study design, data collection, analysis, reporting, or the decision to submit for publication. The authors thank the participants and staff members of the Systolic Blood Pressure Intervention Trial, which sponsored by the National Institutes of Health (NIH), including the National Heart, Lung, and Blood Institute (NHLBI), the NIDDK, the National Institute on Aging (NIA), and the National Institute of Neurological Disorders and Stroke (NINDS), under Contract Numbers HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN268200900049C, and Inter-Agency Agreement Number A-HL-13–002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. The SPRINT investigators acknowledge the contribution of study medications (azilsartan and azilsartan combined with chlorthalidone) from Takeda Pharmaceuticals International, Inc. All components of the SPRINT study protocol were designed and implemented by the investigators. The investigative team collected, analyzed, and interpreted the data. All aspects of manuscript writing and revision were carried out by the coauthors. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of Veterans Affairs, or the US Government. For a full list of contributors to SPRINT, please see the supplementary acknowledgement list: www.sprinttrial.org/public/dspScience.cfm. We also acknowledge the support from the following CTSAs funded by NCATS: CWRU: UL1TR000439, OSU: UL1RR025755, U Penn: UL1RR024134& UL1TR000003, Boston: UL1RR025771, Stanford: UL1TR000093, Tufts: UL1RR025752, UL1TR000073 & UL1TR001064, University of Illinois: UL1TR000050, University of Pittsburgh: UL1TR000005, UT Southwestern: 9U54TR000017–06, University of Utah: UL1TR000105–05, Vanderbilt University: UL1 TR000445, George Washington University: UL1TR000075, University of CA, Davis: UL1 TR000002, University of Florida: UL1 TR000064, University of Michigan: UL1TR000433, Tulane University: P30GM103337 COBRE Award NIGMS, Wake Forest University: UL1TR001420. MGS has received consulting income from Cricket Health, Inc and Intercept Pharmaceuticals. JHI holds an investigator initiated research grant from Baxter International Inc, serves as a member of a data safety monitoring board for Sanifit Therapeutics, is a member of the scientific advisory board for Alpha Young, and has served on advisory boards for AstraZeneca and Ardelyx. The remaining authors declare that they have no relevant financial interests. The results were presented as a poster at the American Society of Nephrology (ASN) conference in San Diego, CA, November 2021. Received June 7, 2022 as a submission to the expedited consideration track with 3 external peer reviews. Direct editorial input from the Statistical Editor and the Editor-in-Chief. Accepted in revised form August 28, 2022. Funding Information: This ancillary study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ( R01DK098234 for MGS/JHI and K24DK110427 for JHI). PSG was supported by a career development grant from the NIDDK ( K23DK114556 ). The funders had no role in study design, data collection, analysis, reporting, or the decision to submit for publication. The authors thank the participants and staff members of the Systolic Blood Pressure Intervention Trial, which sponsored by the National Institutes of Health (NIH), including the National Heart, Lung, and Blood Institute (NHLBI), the NIDDK, the National Institute on Aging (NIA), and the National Institute of Neurological Disorders and Stroke ( NINDS ), under Contract Numbers HHSN268200900040C , HHSN268200900046C , HHSN268200900047C , HHSN268200900048C , HHSN268200900049C , and Inter-Agency Agreement Number A-HL-13–002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. The SPRINT investigators acknowledge the contribution of study medications (azilsartan and azilsartan combined with chlorthalidone) from Takeda Pharmaceuticals International, Inc. All components of the SPRINT study protocol were designed and implemented by the investigators. The investigative team collected, analyzed, and interpreted the data. All aspects of manuscript writing and revision were carried out by the coauthors. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of Veterans Affairs, or the US Government. For a full list of contributors to SPRINT, please see the supplementary acknowledgement list: www.sprinttrial.org/public/dspScience.cfm . We also acknowledge the support from the following CTSAs funded by NCATS: CWRU: UL1TR000439, OSU: UL1RR025755, U Penn: UL1RR024134& UL1TR000003, Boston: UL1RR025771, Stanford: UL1TR000093, Tufts: UL1RR025752, UL1TR000073 & UL1TR001064, University of Illinois: UL1TR000050, University of Pittsburgh: UL1TR000005, UT Southwestern: 9U54TR000017–06, University of Utah: UL1TR000105–05, Vanderbilt University: UL1 TR000445, George Washington University: UL1TR000075, University of CA, Davis: UL1 TR000002, University of Florida: UL1 TR000064, University of Michigan: UL1TR000433, Tulane University: P30GM103337 COBRE Award NIGMS, Wake Forest University: UL1TR001420. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = dec,

doi = "10.1016/j.xkme.2022.100546",

language = "English (US)",

volume = "4",

journal = "Kidney Medicine",

issn = "2590-0595",

publisher = "Elsevier Inc.",

number = "12",

}

TY - JOUR

T1 - Estimated Kidney Tubular Secretion and Kidney, Cardiovascular, and Mortality Outcomes in CKD

T2 - The Systolic Blood Pressure Intervention Trial

AU - Ascher, Simon B.

AU - Shlipak, Michael G.

AU - Katz, Ronit

AU - Bullen, Alexander L.

AU - Scherzer, Rebecca

AU - Hallan, Stein I.

AU - Cheung, Alfred K.

AU - Raphael, Kalani L.

AU - Estrella, Michelle M.

AU - Jotwani, Vasantha K.

AU - Seegmiller, Jesse C.

AU - Ix, Joachim H.

AU - Garimella, Pranav S.

N1 - Funding Information: Simon B. Ascher, MD, MPH, Michael G. Shlipak, MD, MPH, Ronit Katz, DPhil, Alexander L. Bullen, MD, MAS, Rebecca Scherzer, PhD, Stein I. Hallan, MD, PhD, Alfred K. Cheung, MD, Kalani L. Raphael, MD, MS, Michelle M. Estrella, MD, MHS, Vasantha K. Jotwani, MD, Jesse C. Seegmiller, PhD, Joachim H. Ix, MD, MAS, and Pranav S. Garimella, MBBS, MPH, Research idea and study design: SBA, MGS, RK, JHI, PSG; data acquisition: MGS, JHI; data analysis: RK; data interpretation: SBA, MGS, RK, ALB, RS, SIH, AKC, KLR, MME, VKJ, JCS, JHI, PSG; supervision or mentorship: MGS, JHI, PSG. Co-senior authors: JHI, PSG. SBA and MGS contributed equally to this work. JHI and PSG contributed equally to this work. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. This ancillary study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01DK098234 for MGS/JHI and K24DK110427 for JHI). PSG was supported by a career development grant from the NIDDK (K23DK114556). The funders had no role in study design, data collection, analysis, reporting, or the decision to submit for publication. The authors thank the participants and staff members of the Systolic Blood Pressure Intervention Trial, which sponsored by the National Institutes of Health (NIH), including the National Heart, Lung, and Blood Institute (NHLBI), the NIDDK, the National Institute on Aging (NIA), and the National Institute of Neurological Disorders and Stroke (NINDS), under Contract Numbers HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN268200900049C, and Inter-Agency Agreement Number A-HL-13–002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. The SPRINT investigators acknowledge the contribution of study medications (azilsartan and azilsartan combined with chlorthalidone) from Takeda Pharmaceuticals International, Inc. All components of the SPRINT study protocol were designed and implemented by the investigators. The investigative team collected, analyzed, and interpreted the data. All aspects of manuscript writing and revision were carried out by the coauthors. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of Veterans Affairs, or the US Government. For a full list of contributors to SPRINT, please see the supplementary acknowledgement list: www.sprinttrial.org/public/dspScience.cfm. We also acknowledge the support from the following CTSAs funded by NCATS: CWRU: UL1TR000439, OSU: UL1RR025755, U Penn: UL1RR024134& UL1TR000003, Boston: UL1RR025771, Stanford: UL1TR000093, Tufts: UL1RR025752, UL1TR000073 & UL1TR001064, University of Illinois: UL1TR000050, University of Pittsburgh: UL1TR000005, UT Southwestern: 9U54TR000017–06, University of Utah: UL1TR000105–05, Vanderbilt University: UL1 TR000445, George Washington University: UL1TR000075, University of CA, Davis: UL1 TR000002, University of Florida: UL1 TR000064, University of Michigan: UL1TR000433, Tulane University: P30GM103337 COBRE Award NIGMS, Wake Forest University: UL1TR001420. MGS has received consulting income from Cricket Health, Inc and Intercept Pharmaceuticals. JHI holds an investigator initiated research grant from Baxter International Inc, serves as a member of a data safety monitoring board for Sanifit Therapeutics, is a member of the scientific advisory board for Alpha Young, and has served on advisory boards for AstraZeneca and Ardelyx. The remaining authors declare that they have no relevant financial interests. The results were presented as a poster at the American Society of Nephrology (ASN) conference in San Diego, CA, November 2021. Received June 7, 2022 as a submission to the expedited consideration track with 3 external peer reviews. Direct editorial input from the Statistical Editor and the Editor-in-Chief. Accepted in revised form August 28, 2022. Funding Information: This ancillary study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ( R01DK098234 for MGS/JHI and K24DK110427 for JHI). PSG was supported by a career development grant from the NIDDK ( K23DK114556 ). The funders had no role in study design, data collection, analysis, reporting, or the decision to submit for publication. The authors thank the participants and staff members of the Systolic Blood Pressure Intervention Trial, which sponsored by the National Institutes of Health (NIH), including the National Heart, Lung, and Blood Institute (NHLBI), the NIDDK, the National Institute on Aging (NIA), and the National Institute of Neurological Disorders and Stroke ( NINDS ), under Contract Numbers HHSN268200900040C , HHSN268200900046C , HHSN268200900047C , HHSN268200900048C , HHSN268200900049C , and Inter-Agency Agreement Number A-HL-13–002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. The SPRINT investigators acknowledge the contribution of study medications (azilsartan and azilsartan combined with chlorthalidone) from Takeda Pharmaceuticals International, Inc. All components of the SPRINT study protocol were designed and implemented by the investigators. The investigative team collected, analyzed, and interpreted the data. All aspects of manuscript writing and revision were carried out by the coauthors. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of Veterans Affairs, or the US Government. For a full list of contributors to SPRINT, please see the supplementary acknowledgement list: www.sprinttrial.org/public/dspScience.cfm . We also acknowledge the support from the following CTSAs funded by NCATS: CWRU: UL1TR000439, OSU: UL1RR025755, U Penn: UL1RR024134& UL1TR000003, Boston: UL1RR025771, Stanford: UL1TR000093, Tufts: UL1RR025752, UL1TR000073 & UL1TR001064, University of Illinois: UL1TR000050, University of Pittsburgh: UL1TR000005, UT Southwestern: 9U54TR000017–06, University of Utah: UL1TR000105–05, Vanderbilt University: UL1 TR000445, George Washington University: UL1TR000075, University of CA, Davis: UL1 TR000002, University of Florida: UL1 TR000064, University of Michigan: UL1TR000433, Tulane University: P30GM103337 COBRE Award NIGMS, Wake Forest University: UL1TR001420. Publisher Copyright: © 2022 The Authors

PY - 2022/12

Y1 - 2022/12

N2 - RATIONAL & OBJECTIVE: Many drugs, metabolites, and toxins are cleared by the kidneys via tubular secretion. Whether novel endogenous measures of tubular secretion provide information about kidney, cardiovascular, and mortality risk is uncertain.STUDY DESIGN: Longitudinal subgroup analysis of clinical trial participants.SETTING & PARTICIPANTS: 2,089 Systolic Blood Pressure Intervention Trial participants with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 at baseline. EXPOSURE: Summary score incorporating urine-to-plasma ratios of 10 endogenous secretion markers measured in paired urine and plasma samples at baseline.OUTCOME: The primary outcome was longitudinal change in eGFR. Secondary outcomes included chronic kidney disease (CKD) progression (≥50% eGFR decline or incident kidney failure requiring dialysis or kidney transplantation), a cardiovascular disease (CVD) composite (myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, or death from cardiovascular causes), and mortality.ANALYTICAL APPROACH: Linear mixed-effect models were used to evaluate the association between the secretion score and change in eGFR, and Cox proportional hazards models were used to evaluate associations with CKD progression, CVD, and mortality.RESULTS: At baseline, mean age was 73 ± 9 years and eGFR was 46 ± 11 mL/min/1.73 m 2. During a median follow-up of 3.3 years, mean change in eGFR was -1.44% per year, and 72 CKD progression events, 272 CVD events, and 144 deaths occurred. In multivariable analyses, lower secretion score was associated with faster eGFR decline and greater risk of CKD progression, CVD, and mortality. After further adjustment for baseline eGFR and albuminuria, each 1-standard deviation lower secretion score was associated with faster eGFR decline (-0.65% per year; 95% CI, -0.84% to -0.46%), but not CKD progression (HR, 1.23; 95% CI, 0.96-1.58), CVD (HR, 1.02; 95% CI, 0.89-1.18), or mortality (HR, 0.90; 95% CI, 0.74-1.09). The secretion score association with eGFR decline appeared stronger in participants with baseline eGFR <45 mL/min/1.73 m 2 ( P for interaction < 0.001). LIMITATIONS: Persons with diabetes and proteinuria >1 g/d were excluded.CONCLUSIONS: Among SPRINT participants with CKD, lower estimated tubular secretion was associated with faster eGFR decline, independent of baseline eGFR and albuminuria, but not with CKD progression, CVD, or mortality.

AB - RATIONAL & OBJECTIVE: Many drugs, metabolites, and toxins are cleared by the kidneys via tubular secretion. Whether novel endogenous measures of tubular secretion provide information about kidney, cardiovascular, and mortality risk is uncertain.STUDY DESIGN: Longitudinal subgroup analysis of clinical trial participants.SETTING & PARTICIPANTS: 2,089 Systolic Blood Pressure Intervention Trial participants with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 at baseline. EXPOSURE: Summary score incorporating urine-to-plasma ratios of 10 endogenous secretion markers measured in paired urine and plasma samples at baseline.OUTCOME: The primary outcome was longitudinal change in eGFR. Secondary outcomes included chronic kidney disease (CKD) progression (≥50% eGFR decline or incident kidney failure requiring dialysis or kidney transplantation), a cardiovascular disease (CVD) composite (myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, or death from cardiovascular causes), and mortality.ANALYTICAL APPROACH: Linear mixed-effect models were used to evaluate the association between the secretion score and change in eGFR, and Cox proportional hazards models were used to evaluate associations with CKD progression, CVD, and mortality.RESULTS: At baseline, mean age was 73 ± 9 years and eGFR was 46 ± 11 mL/min/1.73 m 2. During a median follow-up of 3.3 years, mean change in eGFR was -1.44% per year, and 72 CKD progression events, 272 CVD events, and 144 deaths occurred. In multivariable analyses, lower secretion score was associated with faster eGFR decline and greater risk of CKD progression, CVD, and mortality. After further adjustment for baseline eGFR and albuminuria, each 1-standard deviation lower secretion score was associated with faster eGFR decline (-0.65% per year; 95% CI, -0.84% to -0.46%), but not CKD progression (HR, 1.23; 95% CI, 0.96-1.58), CVD (HR, 1.02; 95% CI, 0.89-1.18), or mortality (HR, 0.90; 95% CI, 0.74-1.09). The secretion score association with eGFR decline appeared stronger in participants with baseline eGFR <45 mL/min/1.73 m 2 ( P for interaction < 0.001). LIMITATIONS: Persons with diabetes and proteinuria >1 g/d were excluded.CONCLUSIONS: Among SPRINT participants with CKD, lower estimated tubular secretion was associated with faster eGFR decline, independent of baseline eGFR and albuminuria, but not with CKD progression, CVD, or mortality.

KW - CKD progression

KW - CVD

KW - hypertension

KW - kidney function decline

KW - mortality

KW - tubular secretion

UR - http://www.scopus.com/inward/record.url?scp=85144014216&partnerID=8YFLogxK

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U2 - 10.1016/j.xkme.2022.100546

DO - 10.1016/j.xkme.2022.100546

M3 - Article

C2 - 36507053

AN - SCOPUS:85144014216

SN - 2590-0595

VL - 4

JO - Kidney Medicine

JF - Kidney Medicine

IS - 12

M1 - 100546

ER -

Estimated Kidney Tubular Secretion and Kidney, Cardiovascular, and Mortality Outcomes in CKD: The Systolic Blood Pressure Intervention Trial

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