At the time of study entry (), 7% of persons had reduced kidney function (eGFR<60 mL/min/1.73m2). Individuals with impaired kidney function at baseline were more likely to be older and have traditional risk factors for kidney disease such as hypertension, diabetes, and dyslipidemia. Whereas HIV viral load did not differ between those with and without reduced kidney function, CD4 counts and receipt of ART were lower in those with eGFR<60 mL/min/1.73m2. In addition, compared to included patients with no evidence of CKD, excluded individuals without prevalent CVD, who did not have eGFR or albuminuria measured, had a lower prevalence of comorbidities, abnormal clinical and HIV-related characteristics, and lower rates of CVD - suggesting that these individuals were not screened for CKD because they were at low risk for this condition.
Baseline Characteristics of 17,264 HIV-Infected Persons*
We analyzed a total of 219,913 outpatient eGFR measurements [9 (inter-quartile range [IQR] 3, 19) per subject] and 100,931 outpatient albuminuria measurements [4 (IQR 2, 8) per subject] over a median of 7 (IQR 3, 8) years. There were a total of 370 heart failure and 833 atherosclerotic CVD outcomes, comprised of 503 coronary, 219 cerebrovascular, and 118 peripheral arterial disease events, over 119,051 person-years of observation.
Rates of Atherosclerotic Cardiovascular Events and Heart Failure
We observed a stepwise increase in the incidence of CVD with increasing severity of time-updated albuminuria and reduced eGFR (). There was approximately a six-fold difference in rates between those with no signs of kidney disease (eGFR ≥60 mL/min/1.73m2 and no albuminuria) and the highest risk category (eGFR <30 mL/min/1.73m2 and albuminuria ≥100 mg/dL). We observed a similar pattern for the incidence of heart failure by the presence of albuminuria or reduced eGFR (). Heart failure events were rare in those with eGFR ≥60 mL/min/1.73m2 and no albuminuria (1.6 events per 1000 person-years), and increased 30-fold to 51 events per 1000 person-years in the highest risk group.
Incidence Rates of Atherosclerotic Cardiovascular Events (Panel A) and Heart Failure (Panel B), Stratified by Estimated Glomerular Filtration Rate and Dipstick Albuminuria Level.
Adjusted Risk of Atherosclerotic Cardiovascular Events and Heart Failure
In the multivariable models - adjusted for demographic characteristics and time-updated hypertension, diabetes, chronic obstructive lung disease, dyslipidemia, smoking, CD4 count, viral load, ART and albuminuria - level of eGFR was independently associated with increased risk of the composite outcome of atherosclerotic CVD (). Compared to those with normal or mildly reduced kidney function (eGFR <60 mL/min/1.73m2), those with an eGFR 45–59 mL/min/1.73m2 had a 46% increase in the adjusted risk of a vascular event, while those with an eGFR 30–44 mL/min/1.73m2 or <30 mL/min/1.73m2 had approximately a 100% increase in risk. The magnitude and strength of the associations between level of eGFR and heart failure were stronger than for CVD, with a greater than two-fold adjusted risk for eGFR 45–59 mL/min/1.73m2 or 30–44 mL/min/1.73m2, and a more than three-fold adjusted risk for <30 mL/min/1.73m2. For individual CVD outcomes, associations appeared somewhat stronger for coronary disease than cerebrovascular and peripheral arterial disease, but confidence intervals were too wide to detect heterogeneity across these outcomes.
Association of Kidney Function with Adverse Cardiovascular Outcomes*
As with eGFR categories, albuminuria levels were independently associated with both CVD events and heart failure, but with much stronger associations with heart failure (). Among the individual CVD outcomes, the association with albuminuria appeared strongest with peripheral arterial disease.
Association of Albuminuria with Adverse Cardiovascular Outcomes*
In order to determine whether reduced eGFR and albuminuria provided complementary information about CVD risk, we categorized individuals into mutually exclusive groups based on eGFR<60 mL/min/1.73m2 and/or albuminuria ≥30 mg/dL (). In this analysis, both reduced eGFR and albuminuria were independently associated with CVD and heart failure, and the effects appeared to be complementary. Increased risks were observed for all outcomes, but were particularly strong for heart failure and peripheral arterial disease.
Risk of Adverse Cardiovascular Outcomes by Mutually Exclusive Category of Albuminuria or Kidney Function*
In supplemental analyses, hazard ratios for eGFR and albuminuria changed minimally with additional adjustment for abacavir, tenofovir, or protease inhibitor exposure (data not shown). There was no evidence of effect modification by ART, CD4 count, and HIV viral load (p >0.1). The fully-adjusted associations between eGFR and CVD were larger or similar in magnitude when all individuals with eGFR measurements, irrespective of albuminuria measurement, were analyzed.