Risks for Adverse Events in a Population of Patients with Advanced CKD

Patients with chronic kidney disease (CKD) are at high risk for adverse outcomes that can include end-stage renal disease, cardiovascular events, and death. Patients with lower estimated glomerular filtration rate (eGFR) and/or higher albuminuria are generally at higher risk. However, according to Morgan E. Grams, MD, PhD, and colleagues, the absolute risks for ESRD, cardiovascular disease, and death in patients with advanced CKD are not well defined.

Previous studies on the absolute risk for adverse events in patients with advanced CKD have shown conflicting results: results of a clinical trial demonstrated a preponderance of ESRD, while data from a health system revealed a higher risk for death prior to progression to ESRD. Factors accounting for these differences may include differences in nephrology care or patient characteristics between the two study populations.

Dr. Grams et al. recently conducted a prospective cohort study designed to assess the frequency, timing, and risk associations of adverse outcomes by baseline patient characteristics. The study utilized data from participants in the Chronic Renal Insufficiency Cohort (CRIC) who had advanced CKD (defined as eGFR <30 mL/min/1.73 m2). The researchers sought to test the hypothesis that pre-ESRD outcomes of CKD and death would be common, and the frequency and sequence of adverse events over a 1-year time period would vary by baseline patient characteristics. Their secondary hypothesis was that the risk for subsequent mortality would be increased with the development of ESRD.

The outcomes of interest were development of ESRD, cardiovascular disease (congestive heart failure, stroke, myocardial infarction, or peripheral artery disease) and death. Results of the study were reported in the American Journal of Kidney Diseases [2017;70(3):337-346].

Of the 1798 eligible participants in the CRIC study, 807 had eGFR <30 mL/min/1.73 m2 and 991 who developed eGFR <30 mL/min/1.73 m2 during the course of a median follow-up of 5.5 years. At the first qualifying study visit (the first visit where the EGFR was <30 mL/min/1.73 m2), mean age was 59.9 years and mean time since enrollment in the CRIC study was 1.6 years. Of the eligible study participants, 45.8% were women, 46.2% were black, and 16.7% self-identified as Hispanic (either black or white). Ninety percent were under the care of a nephrologist. Average eGFR by the formula used in the CRIC study was 25 mL/min/1.73 m2, and mean proteinuria was estimated at 1.8 g/d, Ninety-five percent had hypertension and 61.6% had diabetes mellitus. Eighteen percent had an ejection fraction <45%.

When classified by first event (cardiovascular event, ESRD, or death), the 37.7% (n=678) who first developed ESRD were younger and had higher blood pressure and proteinuria. The 25.3% (n=455) whose first event prior to progression to ESRD was a cardiovascular event were older, had higher body mass index, were using more antihypertensive medications, had a higher prevalence of cardiovascular disease (history of myocardial infarction or coronary revascularization), and had a lower ejection fraction on electrocardiogram. Patients who had death as the first event (9.0%; n=162) had the oldest mean age and were much more likely to be smokers. Those who were event-free at the end of follow-up (21.4%; n=384) were also older (average, 63.1 years), with lower systolic blood pressure (mean, 120 mm Hg) and proteinuria (median protein excretion, 0.2 g/d) compared with the other participants.

Median time from the qualifying CRIC study visit to death or end of follow-up was 5.5 years; median time from the qualifying CRIC study visit to first event (cardiovascular disease event, ESRD, death, or end of follow-up) was 2.6 years. ESRD surpassed cardiovascular disease events as the most common first outcome at approximately 1.8 years of follow-up.

There were significant associations between patient characteristics at first observed eGFR <30 mL/min/1.73 m2 and first outcomes. Risk factors of cardiovascular events prior to progression to ESRD were older age, higher systolic blood pressure, the presence of diabetes and pre-existing cardiovascular disease, and lower ventricular ejection fraction. For death as a first event, risk factors included older age, black race, Hispanic ethnicity, and current smoking. Developing ESRD as a first event was associated with younger age, male sex, lower eGFR, higher proteinuria, and the absence of prior cardiovascular disease.

The researchers cited some limitations to the study, including using a CRIC-specific equation that incorporates both creatinine and cystatin C levels to estimate kidney function, possibly limiting the generalizability of the findings, and utilizing data from the CRIC study population that was specifically recruited for kidney disease, with the vast majority of participants receiving nephrology care.

In conclusion, the researchers said, “We report clinical outcomes among CRIC participants with eGFR <30 mL/min/1.73 m2, demonstrating that although ESRD is the most common first event over the long term, the risks for cardiovascular disease and each are interrelated, with each adverse outcome increasing the risk for subsequent events. The work represents a novel approach to outcomes assessment in CKD because it focuses on advanced CKD, considering multiple end points at once, with evaluation not only of the occurrence of events, but also the sequence. In clinical practice, an integrated approach to preventing cardiovascular disease, ESRD, and death—potentially through the reduction of blood pressure and proteinuria—may provide optimal care in patients with advanced CKD. Additional work to individualize outcome prediction may inform a personalized approach to patient counseling and medical decision making.”

Takeaway Points

  1. There are few data on the timing and sequence of adverse events such as progression to end-stage renal disease (ESRD), cardiovascular disease events, or death among patients with advanced chronic Kidney disease (CKD).
  2. Researchers utilized data from the Chronic Renal Insufficiency Cohort (CRIC) study to test the hypothesis that outcomes of cardiovascular disease events and death prior to progression to ESRD would be common, and that the frequency and sequence of the adverse events would vary by baseline patient characteristics.
  3. Participants who progressed to ESRD first were younger, and had higher blood pressure and proteinuria; those who had a pre-ESRD cardiovascular disease event were older, had higher body mass index, and were using more antihypertensive medications; those who had death as a first event had the oldest mean age and were much more likely to be smokers.