Glomerular Hyperfiltration Increases Cardiovascular Risk in Healthy Individuals

Chronic kidney disease (CKD) is a risk factor for cardiovascular morbidity and mortality. Among individuals with supranormal estimated glomerular filtration rate, glomerular hyperfiltration (GHF), the risk of cardiovascular disease may also be increased. In high risk conditions such as diabetes, metabolic syndrome, hypertension, and smoking-related disorders, GHF may be a marker of vascular dysfunction and is associated with increased rates of cardiovascular events. The definition of GHF is highly variable, making interpretation of studies in this patient population complex. Further, it is unknown whether GHF is associated with abnormal vascular dysfunction in apparently healthy individuals.

Marie-Eve Dupuis, MD, and colleagues conducted a population-based cohort study to determine whether there is an association between GHF and increased cardiovascular risk in healthy individuals. The researchers used an epidemiologic definition of hyperfiltration with stratification for age and sex. Results of the study were reported in JAMA Network Open [2020;3(4):e202377].

The study utilized longitudinal follow-up data from the CARTaGENE population cohort. Enrollment occurred from August 2009 to October 2010, with follow-up available through March 31, 2016. Data analysis occurred in October 2019.  The cohort included 9515 healthy individuals, defined as those without hypertension, diabetes, cardiovascular disease, estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, or statin and/or aspirin use. The 9515 eligible patients 40 to 69 years of age were identified using health information accessed through the CARTaGENE research platform.

The primary outcome of interest was the risk of cardiovascular events, defined as a composite of cardiovascular mortality, myocardial infarction, unstable angina, heart failure, stroke, and transient ischemic attack (TIA). Cox and fractional polynomial regressions and propensity score matching were used to identify the risk of adverse cardiovascular events. Following stratification for sex and age, individuals with eGFR >95th percentile were compared with those with normal filtration rate, defined as eGFR in the 25th to 75th percentiles.

Of the 9515 healthy individuals, 42.6% (n=4050) were male, and median age was 50.4 years. A total of 473 had GHF (median eGFR, 112 mL/min/1.73 m2) and 4761 had normal GFR (control group; median eGFR, 92 mL/min/1.73 m2). There were wide variations in the ranges of eGFR for those with GHF or normal filtration rates according to each age decade and sex. Those with GHF were slightly younger, and more often African American or smokers.

With the exception of a slightly higher heart rate and augmentation index with GHF, hemodynamic parameters were similar between the GHF group and controls. Data on dietary habits were available in 45% (n=213) of those with GHF and 50% (n=2387) of controls; median daily protein and sodium were similar between the groups (61 g vs 63 g and 2.2 g vs 2.3 g, respectively).

Median follow-up was 70 months. During follow-up, there were 245 cardiovascular events overall (three cardiovascular deaths, 67 myocardial infarctions, 69 unstable angina episodes, 52 heart failure episodes, 34 strokes, and 20 TSAs). In the GHF group, there were 35 events in 473 individuals, for an incidence rate of 13.2 per 100 person-years; in the control group, there were 210 events in 4761 individuals, for an incidence rate of 7.7 per 100 person-years.

In both unadjusted and adjusted Cox regression analyses, there was an association between GHF and an increased risk of cardiovascular events compared with normal GFR (unadjusted hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.20-2.44; P=.003; adjusted HR, 1.88; 95% CI, 1.30-2.74; P=.001). In sensitivity analyses where GHF was defined following stratification for age decade, sex, and (1) race, (2) active smoking status, or (3) obesity, the association between GHF and CVE remained significant. Following exclusion of individuals with a cardiovascular event in the first 6 months and 12 months and after exclusion of TIA from the composite outcome, GHF remained significantly associated with cardiovascular events.

Using propensity score, 406 healthy individuals with GHF were matched with 406 controls of similar age and baseline characteristics. In that cohort, those with GHF had median eGFR of 112 mL/min/1.73 m2 compared with 94 mL/min/1.73 m2 in the control group. Results of unadjusted Cox regression analysis demonstrated an association between GHF and higher risk of cardiovascular events compared with normal filtration (HR, 2.20; 95% CI, 1.44-4.24; P=.02).

The researchers identified a subset of 597 CARTaGENE participants with stage 3a CKD to examine the cardiovascular event risk association with GHF compared with CKD. In unadjusted Cox regression analysis, healthy individuals with GHF had a cardiovascular event risk similar to that of participants with stage 3a CKD (HR, 0.90; 95% CI, 0.56-1.42; P=.64). This association was seen despite the healthy individuals with CKF having a more favorable hemodynamic and metabolic profile and a lesser burden of comorbidities at baseline.

In citing limitations to the study, the researchers included the possibility of selection bias; limiting the cohort to those 40 to 49 years of age; using estimated GFR rather than measured GFR; the availability of data on albuminuria in only a small subset of CARTaGENE participants; and the sample size that was insufficient to adequately assess the association between occurrence of individual types of cardiovascular events and GHF.

“Using data from the prospective CARTaGENE cohort, GHF was shown to be associated with a higher risk of cardiovascular events in healthy middle-aged individuals. Glomerular hyperfiltration could be an easily identifiable marker of an unfavorable milieu and vascular dysfunction. Therefore, identification of GHF in healthy individuals may provide an opportunity to implement preventive strategies to reduce the global burden of cardiovascular diseases,” the researchers said.

Takeaway Points

  1. Researchers conducted a prospective population-based cohort study to examine whether glomerular hyperfiltration (GHF) is associated with increased risk for cardiovascular events in healthy individuals.
  2. Compared with participants with normal filtration rate, those with GHF had an increased cardiovascular risk: hazard ratio, 1.88; 95% confidence interval, 1.30-2.74; P=.001.
  3. The risk of cardiovascular events among the healthy individuals with GHF was similar to that of participants with stage 3a chronic kidney disease.