Apolipoprotein A-IV concentrations and clinical outcomes in a large chronic kidney disease cohort: Results from the GCKD study

Abstract

Background: Chronic kidney disease (CKD) represents a chronic proinflammatory state and is associated with very high cardiovascular risk. Apolipoprotein A-IV (apoA-IV) has antiatherogenic, antioxidative, anti-inflammatory and antithrombotic properties and levels increase significantly during the course of CKD.

Objectives: We aimed to investigate the association between apoA-IV and all-cause mortality and cardiovascular outcomes in the German Chronic Kidney Disease study.

Methods: This was a prospective cohort study including 5141 Caucasian patients with available apoA-IV measurements and CKD. The majority of the patients had an estimated glomerular filtration rate (eGFR) of 30-60 ml/min/1.73m² or an eGFR >60 ml/min/1.73m² in the presence of overt proteinuria. Median follow-up was 6.5 years. The association of apoA-IV with comorbidities at baseline and endpoints during follow-up was modelled adjusting for major confounders.

Results: Mean apoA-IV concentrations of the entire cohort were 28.9 ± 9.8 mg/dl. Patients in the highest apoA-IV quartile had the lowest high-sensitivity C-reactive protein values despite the highest prevalence of diabetes, albuminuria and the lowest eGFR. Each 10 mg/dl higher apoA-IV translated into lower odds of prevalent cardiovascular disease (1289 cases, odds ratio = 0.80, 95% confidence interval [CI] 0.72-0.86, p = 0.0000003). During follow-up, each 10 mg/dl higher apoA-IV was significantly associated with a lower risk for all-cause mortality (600 cases, hazard ratio [HR] = 0.81, 95% CI 0.73-0.89, p = 0.00004), incident major adverse cardiovascular events (506 cases, HR = 0.88, 95% CI 0.79-0.99, p = 0.03) and death or hospitalizations due to heart failure (346 cases, HR = 0.84, 95% CI 0.73-0.96, p = 0.01).

Conclusions: These data support a link between elevated apoA-IV concentrations and reduced inflammation in moderate CKD. ApoA-IV appears to be an independent risk marker for reduced all-cause mortality, cardiovascular events and heart failure in a large cohort of patients with CKD.

Keywords: all-cause mortality; apolipoprotein A-IV; cardiovascular disease; heart failure; high risk population; prospective study.

Fig 1

Mean (± standard deviation) apolipoprotein A‐IV (apoA‐IV) concentrations and number of patients stratified by estimated glomerular filtration rate (eGFR) and urine albumin–creatinine ratio (UACR) risk categories (including nephrotic range albuminuria >2220 mg/g) according to Kidney Disease Improving Global Outcomes guidelines in the German Chronic Kidney Disease (GCKD) study. Increasing concentrations of apoA‐IV are displayed with cell backgrounds in increasingly darker shades of blue (increment: 2.5 mg/dl in apoA‐IV concentration). Note: numbers of patients do not add up to the total number from GCKD with available apoA‐IV values due to missing values for eGFR and UACR.

Fig 2

Forest plots for all‐cause mortality, 3‐point and 4‐point major adverse cardiovascular events (MACE) and death and hospitalisation due to heart failure by quartiles of apoA‐IV concentrations. Quartile 1 comprises patients with the lowest apoA‐IV concentrations. Data shown were adjusted for age, sex, estimated glomerular filtration rate, ln‐urine albumin–creatinine ratio, serum albumin, low‐density lipoprotein cholesterol, smoking status, diabetes mellitus, statin use, ln‐triglycerides, body mass index, systolic and diastolic blood pressure and cardiovascular disease at baseline. CI, confidence interval.

Fig 3

Results of mediation analysis, splitting the total effect of apoA‐IV on incident outcomes into indirect effects (proportion mediated by inflammation) and direct effects of apoA‐IV (i.e., proportion of apoA‐IV effects on outcomes, which is not mediated by inflammation). The thickness of the arrows is proportional to the proportion mediated.