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Biomarkers of Renal Function in Acute Coronary Syndromes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. (Uppsala Clinical Research Center)
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The thesis aimed to investigate cystatin C and creatinine-based estimates of glomerular filtration rate (eGFR), both at admission and during follow-up, on the combined endpoint of cardiovascular death and myocardial infarction in patients with acute coronary syndrome (ACS). We also evaluated two cystatin C assays and assessed genetic determinants of cystatin C concentrations.

We used the PLATelet inhibition and Patient Outcomes study, where all types of ACS patients (n=18624) were randomized to ticagrelor or clopidogrel treatment. Multivariable Cox regression models, including clinical variables and biomarkers (troponin and NT-proBNP), and c-statistics were calculated.

Cystatin C and the creatinine-based CKD-EPI equation exhibited similar significant prognostic impact on the combined endpoint, with Area Under Curves (AUC) 0.6923 and 0.6941, respectively. Follow-up samples of renal biomarkers did not improve risk prediction.

Patients randomized to ticagrelor treatment were associated with a non-sustained larger increase in renal markers at discharge, but neither the change nor the difference between the randomized groups affected cardiovascular risk.

Two different cystatin C assays exhibited good correlation 0.86 (95% confidence interval 0.85-0.86), however moderate level of agreement. Risk prediction with a combination of creatinine and cystatin C did not outperform the creatinine-based CKD-EPI equation, AUC: 0.6913 and 0.6924, respectively (n=13050).

The genetic polymorphism rs6048952 independently affected the cystatin C concentration with mean levels of 0.85mg/L, 0.80mg/L and 0.73mg/L for the A/A, A/G, and G/G genotypes, respectively.

The genetic polymorphism did not affect outcome overall, however in the non-ST-elevation ACS subgroup a signal that genetic polymorphism may be associated with cardiovascular death was observed (p=0.002).

In conclusion: cystatin C or eGFR, irrespective of equation or assay, are important cardiovascular risk factors in ACS patients. Nonetheless, the incremental value of adding any renal variable, to a multivariable risk model, is small. Further research on the impact of cystatin C genetic polymorphism is warranted.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 74 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 891
Keyword [en]
cystatin C, glomerular filtration rate, GFR, creatinine, acute coronary syndrome, ACS, kidney, renal, mortality, death, myocardial infarction
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology; Medicine; Internal Medicine
Identifiers
URN: urn:nbn:se:uu:diva-197852ISBN: 978-91-554-8643-3 (print)OAI: oai:DiVA.org:uu-197852DiVA: diva2:614574
Public defence
2013-05-24, Enghoffsalen, Ing 50, Akademiska Sjukhuset, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Note

PhD, i medicin.

Available from: 2013-05-03 Created: 2013-04-05 Last updated: 2013-08-30Bibliographically approved
List of papers
1. Cystatin C and Estimated Glomerular Filtration Rate as Predictors for Adverse Outcome in Patients with ST-Elevation and Non-ST-Elevation Acute Coronary Syndromes: Results from the Platelet Inhibition and Patient Outcomes Study
Open this publication in new window or tab >>Cystatin C and Estimated Glomerular Filtration Rate as Predictors for Adverse Outcome in Patients with ST-Elevation and Non-ST-Elevation Acute Coronary Syndromes: Results from the Platelet Inhibition and Patient Outcomes Study
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2012 (English)In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 58, no 1, 190-199 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

We evaluated the predictive ability of cystatin C and creatinine-based estimations of glomerular filtration rate (eGFR), including the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation, in acute coronary syndrome (ACS) patients with (STE-ACS) or without (NSTE-ACS) ST elevation in a large contemporary ACS population.

METHODS:

Concentrations of cystatin C and creatinine, as well as eGFR at randomization, were measured in 16 401 patients in the Platelet Inhibition and Patient Outcomes (PLATO) study and evaluated as predictors of the composite end point of cardiovascular death or myocardial infarction within 1 year. Two Cox proportional hazards models were used, the first adjusting for clinical characteristics and the second for clinical characteristics plus the biomarkers N-terminal pro-B-type natriuretic peptide, troponin I, and C-reactive protein.

RESULTS:

The median cystatin C value was 0.83 mg/L. Increasing quartiles of cystatin C were strongly associated with poor outcome (6.9%, 7.1%, 9.5%, and 16.2%). The fully adjusted hazard ratios per SD of cystatin C in the NSTE-ACS and STE-ACS populations were 1.12 (95% CI 1.04-1.20) (n = 8053) and 1.06 (95% CI 0.97-1.17) (n = 5278), respectively. There was no significant relationship of cystatin C with type of ACS (STE or NSTE). c Statistics ranged from 0.6923 (cystatin C) to 0.6941 (CKD-EPI).

CONCLUSIONS:

Cystatin C concentration contributes independently in predicting the risk of cardiovascular death or myocardial infarction in NSTE-ACS, with no interaction by type of ACS. CKD-EPI exhibited the largest predictive value of all renal markers. Nevertheless, the additive predictive value of cystatin C or creatinine-based eGFR measures in the unselected ACS patient is small.

National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-165398 (URN)10.1373/clinchem.2011.171520 (DOI)000299052700032 ()22126936 (PubMedID)
Available from: 2012-01-05 Created: 2012-01-05 Last updated: 2017-12-08Bibliographically approved
2. Outcome and causes of renal deterioration evaluated by serial cystatin C measurements in acute coronary syndrome patients: Results from the PLATelet inhibition and patient Outcomes (PLATO) study
Open this publication in new window or tab >>Outcome and causes of renal deterioration evaluated by serial cystatin C measurements in acute coronary syndrome patients: Results from the PLATelet inhibition and patient Outcomes (PLATO) study
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2012 (English)In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 164, no 5, 728-734 p.Article in journal (Refereed) Published
Abstract [en]

Background: To investigate if ticagrelor treatment and other clinical characteristics were associated with increased cystatin C concentrations and if a deterioration in estimated renal function was associated with worse outcome in patients with acute coronary syndromes (ACS). Methods: Plasma cystatin C concentrations were determined within 24 hours of admission (baseline), at discharge, 1 month, and 6 months in the PLATO trial. The changes over time in relation to randomized treatment were analyzed by analysis of covariance. C-statistics and the relative Integrated Discrimination Improvement of the cystatin C concentrations regarding the primary outcome (cardiovascular death or myocardial infarction) was evaluated by multivariable analysis including background characteristics and biomarkers: N-terminal-pro-B-type natriuretic peptide and Troponin I. Results: Mean cystatin C concentrations in 2133 ticagrelor- and 2162 clopidogrel-treated patients were at baseline (0.86 mg/L and 0.86 mg/L), discharge (1.01 mg/L and 0.98 mg/L) (P <.0005), 1 month (1.00 mg/L and 0.98 mg/L) (P =.12), and 6 months (1.00 mg/L and 0.99 mg/L) (P =.17), respectively. Age, heart failure, and type of ACS were major determinants of the cystatin C concentration. c Statistics and the relative Integrated Discrimination Improvement of the primary outcome for the baseline cystatin C concentration were 0.687 and 5.2%, compared to 0.684 and 4.5% at discharge (n = 4034) and 0.693 and 5.1% at one month (n = 3096), respectively. Conclusions: Mean cystatin C concentrations increased in ACS patients, most importantly determined by age. The initial greater increase in ticagrelor-treated patients was not sustained over time. Risk prediction did not improve with serial measurements of renal markers.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-186226 (URN)10.1016/j.ahj.2012.08.017 (DOI)000310783100015 ()
Available from: 2012-11-28 Created: 2012-11-28 Last updated: 2017-12-07Bibliographically approved
3. Cystatin C- and Creatinine-based Estimates of Renal Function and Their Value for Risk Prediction in Patients with Acute Coronary Syndrome: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study
Open this publication in new window or tab >>Cystatin C- and Creatinine-based Estimates of Renal Function and Their Value for Risk Prediction in Patients with Acute Coronary Syndrome: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study
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2013 (English)In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 59, no 9, 1369-1375 p.Article in journal (Refereed) Published
Abstract [en]

Background: The estimated glomerular filtration rate (eGFR) independently predicts cardiovascular (CV) death or myocardial infarction (MI), and can be estimated by creatinine and cystatin C concentrations. We evaluated two different cystatin C assays, alone or combined with creatinine, in patients with acute coronary syndromes.

Methods: Plasma cystatin C, measured with assays from Gentian and Roche, and serum creatinine was analyzed in 16279 patients from the PLATelet inhibition and patient Outcomes trial. Pearson’s correlation and agreement (Bland–Altman) between methods was evaluated. Prognostic value in relation to CV death or MI during one year of follow up was evaluated by multivariable logistic regression analysis including clinical variables and biomarkers, c-statistics and relative Integrated Discrimination Improvement (IDI).

Results: Median cystatin C concentrations (interquartile intervals) were 0.83 (0.68 - 1.01) mg/L (Gentian) and 0.94 (0.80 - 1.14) mg/L (Roche). Overall correlation was 0.86 (95% confidence interval 0.85-0.86). The level of agreement was ±0.39mg/L (±2 standard deviations) (n=16279).

The area under curve (AUC) in the multivariable risk prediction model with cystatin C (Gentian, Roche) or Chronic Kidney Disease - Epidemiology (CKD-EPI) added was 0.6914, 0.6913 and 0.6932. Corresponding relative IDIs were 2.96%, 3.86% and 4.68%, respectively (n=13050). Addition of eGFR by the combined creatinine-cystatin C equation yielded AUC of 0.6923(Gentian) and 0.6924(Roche) with relative IDIs of 3.54% and 3.24% respectively.

Conclusions: Despite differences in cystatin C concentrations, overall correlation between the Gentian and Roche assays was good while agreement was moderate.  The combined creatinine-cystatin C equation did not outperform risk prediction compared to CKD-EPI.

Keyword
cystatin C, creatinine, glomerular filtration rate, myocardial infarction, acute coronary, syndrome, death, assay
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
urn:nbn:se:uu:diva-197704 (URN)10.1373/clinchem.2012.200709 (DOI)000325398600015 ()
Available from: 2013-04-04 Created: 2013-04-02 Last updated: 2017-12-06Bibliographically approved
4. Polymorphism of the cystatin C gene in patients with acute coronary syndromes: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study
Open this publication in new window or tab >>Polymorphism of the cystatin C gene in patients with acute coronary syndromes: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study
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2014 (English)In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 168, no 1, 96-102 p.Article in journal (Other academic) Published
Abstract [en]

Purpose: Plasma cystatin C is independently associated with cardiovascular (CV) risk in non-ST-elevation acute coronary syndromes (NSTE-ACS). The effect of genetic variability on cystatin C concentrations and outcome is unclear.

Methods: Plasma cystatin C concentrations were measured in blood, obtained within 24 hours of admission, in 16279 ACS patients from the PLATelet inhibition and patient Outcomes trial. 9978 patients were genome-wide genotyped with up to 2.5 million SNPs. The first occurrence of CV death or myocardial infarction (MI) within one year was evaluated by multivariable (clinical variables and biomarkers) Cox regression analysis and c-statistics both overall (all ACS) and in NSTE-ACS.

Results: We observed SNPs association with cystatin C levels (up to p=7.82 x 10-16). The most significant SNP (rs6048952) was adjacent the CST3 gene with additive effect on cystatin C concentrations: 0.85mg/L, 0.80mg/L and 0.73mg/L for the A/A, A/G and G/G genotypes respectively. Multivariable c-statistics regarding the combined endpoint (CV death or MI) was 0.6619. Adding cystatin C concentrations or genetically adjusted cystatin C levels, exhibited c-statistics of 0.6705 and 0.6703, respectively.

The overall hazard ratio for rs6048952 was 0.93 (95%CI 0.82-1.04) regarding the CV death or MI while 0.85 (95%CI 0.70-1.03) regarding CV death in all ACS patients. In the NSTE-ACS subgroup, the hazard ratio for rs6048952 was 0.72 (95%CI 0.54-0.95).

Conclusions: Genetic polymorphism, independently of kidney function, affects cystatin C concentrations, but does not appear to influence ischemic outcome in an overall ACS population. However, genetic variation appears to affect cardiovascular mortality in moderate-to-high risk NSTE-ACS patients.

Keyword
genetics, rs6048952, CST3, CST, cystatin C, acute coronary syndrome, mortality, death, myocardial infarction
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
urn:nbn:se:uu:diva-197712 (URN)10.1016/j.ahj.2014.03.010 (DOI)000338748800014 ()
Note

Published as Manuscript with the title: Genetic Polymorphism and Relationship to Cystatin C Concentrations and Outcome - Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study

Available from: 2013-04-04 Created: 2013-04-02 Last updated: 2017-12-06Bibliographically approved

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