Impact of Chronic Kidney Disease on the Associations of Cardiovascular Biomarkers With Adverse Outcomes in Patients With Suspected or Known Coronary Artery Disease: The EXCEED‐J Study

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Abstract

Background

The impact of chronic kidney disease (CKD) on the prognostic utility of cardiovascular biomarkers in high‐risk patients remains unclear.

Methods and Results

We performed a multicenter, prospective cohort study of 3255 patients with suspected or known coronary artery disease (CAD) to investigate whether CKD modifies the prognostic utility of cardiovascular biomarkers. Serum levels of cardiovascular and renal biomarkers, including soluble fms‐like tyrosine kinase‐1 (sFlt‐1), N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), high‐sensitivity cardiac troponin‐I (hs‐cTnI), cystatin C, and placental growth factor, were measured in 1301 CKD and 1954 patients without CKD. The urine albumin to creatinine ratio (UACR) was measured in patients with CKD. The primary outcome was 3‐point MACE (3P‐MACE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The secondary outcomes were all‐cause death, cardiovascular death, and 5P‐MACE defined as a composite of 3P‐MACE, heart failure hospitalization, and coronary/peripheral artery revascularization. After adjustment for clinical confounders, sFlt‐1, NT‐proBNP, and hs‐cTnI, but not other biomarkers, were significantly associated with 3P‐MACE, all‐cause death, and cardiovascular death in the entire cohort and in patients without CKD. These associations were still significant in CKD only for NT‐proBNP and hs‐cTnI. NT‐proBNP and hs‐cTnI were also significantly associated with 5P‐MACE in CKD. The UACR was not significantly associated with any outcomes in CKD. NT‐proBNP and hs‐cTnI added incremental prognostic information for all outcomes to the model with potential clinical confounders in CKD.

Conclusions

NT‐proBNP and hs‐cTnI were the most powerful prognostic biomarkers in patients with suspected or known CAD and concomitant CKD.

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Most cited references 65

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Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.

Alan S Go, Glenn Chertow, Dongjie Fan … (2004)

End-stage renal disease substantially increases the risks of death, cardiovascular disease, and use of specialized health care, but the effects of less severe kidney dysfunction on these outcomes are less well defined. We estimated the longitudinal glomerular filtration rate (GFR) among 1,120,295 adults within a large, integrated system of health care delivery in whom serum creatinine had been measured between 1996 and 2000 and who had not undergone dialysis or kidney transplantation. We examined the multivariable association between the estimated GFR and the risks of death, cardiovascular events, and hospitalization. The median follow-up was 2.84 years, the mean age was 52 years, and 55 percent of the group were women. After adjustment, the risk of death increased as the GFR decreased below 60 ml per minute per 1.73 m2 of body-surface area: the adjusted hazard ratio for death was 1.2 with an estimated GFR of 45 to 59 ml per minute per 1.73 m2 (95 percent confidence interval, 1.1 to 1.2), 1.8 with an estimated GFR of 30 to 44 ml per minute per 1.73 m2 (95 percent confidence interval, 1.7 to 1.9), 3.2 with an estimated GFR of 15 to 29 ml per minute per 1.73 m2 (95 percent confidence interval, 3.1 to 3.4), and 5.9 with an estimated GFR of less than 15 ml per minute per 1.73 m2 (95 percent confidence interval, 5.4 to 6.5). The adjusted hazard ratio for cardiovascular events also increased inversely with the estimated GFR: 1.4 (95 percent confidence interval, 1.4 to 1.5), 2.0 (95 percent confidence interval, 1.9 to 2.1), 2.8 (95 percent confidence interval, 2.6 to 2.9), and 3.4 (95 percent confidence interval, 3.1 to 3.8), respectively. The adjusted risk of hospitalization with a reduced estimated GFR followed a similar pattern. An independent, graded association was observed between a reduced estimated GFR and the risk of death, cardiovascular events, and hospitalization in a large, community-based population. These findings highlight the clinical and public health importance of chronic renal insufficiency. Copyright 2004 Massachusetts Medical Society

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Revised equations for estimated GFR from serum creatinine in Japan.

Seiichi Matsuo, Enyu Imai, Masaru Horio … (2009)

Estimation of glomerular filtration rate (GFR) is limited by differences in creatinine generation among ethnicities. Our previously reported GFR-estimating equations for Japanese had limitations because all participants had a GFR less than 90 mL/min/1.73 m2 and serum creatinine was assayed in different laboratories. Diagnostic test study using a prospective cross-sectional design. New equations were developed in 413 participants and validated in 350 participants. All samples were assayed in a central laboratory. Hospitalized Japanese patients in 80 medical centers. Patients had not participated in the previous study. Measured GFR (mGFR) computed from inulin clearance. Estimated GFR (eGFR) by using the modified isotope dilution mass spectrometry (IDMS)-traceable 4-variable Modification of Diet in Renal Disease (MDRD) Study equation using the previous Japanese Society of Nephrology Chronic Kidney Disease Initiative (JSN-CKDI) coefficient of 0.741 (equation 1), the previous JSN-CKDI equation (equation 2), and new equations derived in the development data set: modified MDRD Study using a new Japanese coefficient (equation 3), and a 3-variable Japanese equation (equation 4). Performance of equations was assessed by means of bias (eGFR - mGFR), accuracy (percentage of estimates within 15% or 30% of mGFR), root mean squared error, and correlation coefficient. In the development data set, the new Japanese coefficient was 0.808 (95% confidence interval, 0.728 to 0.829) for the IDMS-MDRD Study equation (equation 3), and the 3-variable Japanese equation (equation 4) was eGFR (mL/min/1.73 m2) = 194 x Serum creatinine(-1.094) x Age(-0.287) x 0.739 (if female). In the validation data set, bias was -1.3 +/- 19.4 versus -5.9 +/- 19.0 mL/min/1.73 m2 (P = 0.002), and accuracy within 30% of mGFR was 73% versus 72% (P = 0.6) for equation 3 versus equation 1 and -2.1 +/- 19.0 versus -7.9 +/- 18.7 mL/min/1.73 m(2) (P < 0.001) and 75% versus 73% (P = 0.06) for equation 4 versus equation 2 (P = 0.06), respectively. Most study participants had chronic kidney disease, and some may have had changing GFRs. The new Japanese coefficient for the modified IDMS-MDRD Study equation and the new Japanese equation are more accurate for the Japanese population than the previously reported equations.

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Chronic Kidney Disease.

Angela Webster, Evi V Nagler, Rachael Morton … (2017)

The definition and classification of chronic kidney disease (CKD) have evolved over time, but current international guidelines define this condition as decreased kidney function shown by glomerular filtration rate (GFR) of less than 60 mL/min per 1·73 m(2), or markers of kidney damage, or both, of at least 3 months duration, regardless of the underlying cause. Diabetes and hypertension are the main causes of CKD in all high-income and middle-income countries, and also in many low-income countries. Incidence, prevalence, and progression of CKD also vary within countries by ethnicity and social determinants of health, possibly through epigenetic influence. Many people are asymptomatic or have non-specific symptoms such as lethargy, itch, or loss of appetite. Diagnosis is commonly made after chance findings from screening tests (urinary dipstick or blood tests), or when symptoms become severe. The best available indicator of overall kidney function is GFR, which is measured either via exogenous markers (eg, DTPA, iohexol), or estimated using equations. Presence of proteinuria is associated with increased risk of progression of CKD and death. Kidney biopsy samples can show definitive evidence of CKD, through common changes such as glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Complications include anaemia due to reduced production of erythropoietin by the kidney; reduced red blood cell survival and iron deficiency; and mineral bone disease caused by disturbed vitamin D, calcium, and phosphate metabolism. People with CKD are five to ten times more likely to die prematurely than they are to progress to end stage kidney disease. This increased risk of death rises exponentially as kidney function worsens and is largely attributable to death from cardiovascular disease, although cancer incidence and mortality are also increased. Health-related quality of life is substantially lower for people with CKD than for the general population, and falls as GFR declines. Interventions targeting specific symptoms, or aimed at supporting educational or lifestyle considerations, make a positive difference to people living with CKD. Inequity in access to services for this disease disproportionally affects disadvantaged populations, and health service provision to incentivise early intervention over provision of care only for advanced CKD is still evolving in many countries.

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Author and article information

Contributors

Hiromichi Wada:

ORCID: https://orcid.org/0000-0002-8980-224X

hwada@kuhp.kyoto-u.ac.jp

Journal

Journal ID (nlm-ta): J Am Heart Assoc

Journal ID (iso-abbrev): J Am Heart Assoc

Journal ID (doi): 10.1002/(ISSN)2047-9980

Journal ID (publisher-id): JAH3

Journal ID (hwp): ahaoa

Title: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Electronic): 2047-9980

Publication date (Electronic): 20 January 2022

Publication date Collection: 01 February 2022

Volume: 11

Issue: 3 ( doiID: 10.1002/jah3.v11.3 )

Electronic Location Identifier: e023464

Affiliations

[ ¹ ] Division of Translational Research National Hospital Organization Kyoto Medical Center Kyoto Japan

[ ² ] Department of Cardiology National Hospital Organization Sendai Medical Center Sendai Japan

[ ³ ] Department of Clinical Research National Hospital Organization Saitama Hospital Wako Japan

[ ⁴ ] Department of Cardiovascular Medicine National Hospital Organization Kanazawa Medical Center Kanazawa Japan

[ ⁵ ] Division of Clinical Research National Hospital Organization Yokohama Medical Center Yokohama Japan

[ ⁶ ] Department of Cardiology National Hospital Organization Ehime Medical Center Toon Japan

[ ⁷ ] Institute for Clinical Research National Hospital Organization Kure Medical Center and Chugoku Cancer Center Kure Japan

[ ⁸ ] Department of Cardiology National Hospital Organization Kobe Medical Center Kobe Japan

[ ⁹ ] Division of Cardiology National Hospital Organization Hokkaido Medical Center Sapporo Japan

[ ¹⁰ ] Department of Cardiology National Hospital Organization Sagamihara National Hospital Sagamihara Japan

[ ¹¹ ] Division of Clinical Research National Hospital Organization Hakodate National Hospital Hakodate Japan

[ ¹² ] Department of Cardiology National Hospital Organization Okayama Medical Center Okayama Japan

[ ¹³ ] Department of Cardiology National Hospital Organization Higashihiroshima Medical Center Higashihiroshima Japan

[ ¹⁴ ] Department of Cardiology National Hospital Organization Kyushu Medical Center Fukuoka Japan

[ ¹⁵ ] Department of Cardiology National Hospital Organization Kumamoto Medical Center Kumamoto Japan

[ ¹⁶ ] Department of Cardiology National Hospital Organization Nagasaki Kawatana Medical Center Nagasaki Japan

[ ¹⁷ ] Department of Clinical Research National Hospital Organization Tochigi Medical Center Utsunomiya Japan

[ ¹⁸ ] Intensive Care Unit Saiseikai Kumamoto Hospital Kumamoto Japan

[ ¹⁹ ] Department of Acute Care and General Medicine Saiseikai Kumamoto Hospital Kumamoto Japan

[ ²⁰ ] Department of Cardiology National Hospital Organization Kyoto Medical Center Kyoto Japan

[ ²¹ ] Department of Endocrinology, Metabolism, and Hypertension Clinical Research Institute National Hospital Organization Kyoto Medical Center Kyoto Japan

[ ²² ] Clinical Research Institute National Hospital Organization Kyoto Medical Center Kyoto Japan

[ ²³ ] Division of Community and Family Medicine Jichi Medical University Shimotsuke Japan

Author notes

[*] [* ] Correspondence to: Hiromichi Wada, MD, PhD, Division of Translational Research, National Hospital Organization Kyoto Medical Center, 1‐1, Mukaihata‐cho, Fukakusa, Fushimi‐ku, Kyoto 612‐8555, Japan. E‐mail: hwada@ 123456kuhp.kyoto-u.ac.jp

[ * ]

A complete list of the EXCEED‐J Study Investigators can be found in the Supplemental Material.

Author information

Hiromichi Wada https://orcid.org/0000-0002-8980-224X

Tsuyoshi Shinozaki https://orcid.org/0000-0001-8808-2001

Masahiro Suzuki https://orcid.org/0000-0003-3861-0026

Yoichi Ajiro https://orcid.org/0000-0002-1975-203X

Junichi Funada https://orcid.org/0000-0001-8810-0425

Toshihiro Nakamura https://orcid.org/0000-0002-7172-6242

Moritake Iguchi https://orcid.org/0000-0001-5029-1203

Toru Kusakabe https://orcid.org/0000-0001-8644-3539

Mitsuru Abe https://orcid.org/0000-0002-3956-4239

Masaharu Akao https://orcid.org/0000-0002-2348-7646

Article

Publisher ID: JAH37018

DOI: 10.1161/JAHA.121.023464

PMC ID: 9238479

PubMed ID: 35048713

SO-VID: eee29001-b07a-4d00-ab33-d62574278e98

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

History

Date received : 04 August 2021

Date accepted : 15 November 2021

Page count

Figures: 2, Tables: 3, Pages: 14, Words: 11031

Funding

Funded by: Health Labour Sciences Research Grant

Funded by: AMED , doi 10.13039/100009619;

Award ID: JP17ek0210008

Funded by: National Hospital Organization

Custom metadata

source-schema-version-number 2.0

cover-date February 1, 2022

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.4 mode:remove_FC converted:03.05.2022

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: biomarker,cardiovascular events,chronic kidney disease,coronary artery disease,mortality,prospective cohort study,biomarkers,clinical studies,nephrology and kidney

Data availability:

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: biomarker, cardiovascular events, chronic kidney disease, coronary artery disease, mortality, prospective cohort study, biomarkers, clinical studies, nephrology and kidney

Impact of Chronic Kidney Disease on the Associations of Cardiovascular Biomarkers With Adverse Outcomes in Patients With Suspected or Known Coronary Artery Disease: The EXCEED‐J Study

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Abstract

Background

Methods and Results

Conclusions

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Cardiovascular Innovations and Applications

Most cited references 65

Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.

Revised equations for estimated GFR from serum creatinine in Japan.

Chronic Kidney Disease.

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