Cause of Death in Patients With Diabetic CKD Enrolled in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT)

Abstract

Background: The cause of death in patients with chronic kidney disease (CKD) varies with CKD severity, but variation has not been quantified.

Study design: Retrospective analysis of prospective randomized clinical trial.

Setting & participants: We analyzed 4,038 individuals with anemia and diabetic CKD from TREAT, a randomized trial comparing darbepoetin alfa and placebo.

Predictors: Baseline estimated glomerular filtration rate (eGFR) and protein-creatinine ratio (PCR).

Outcomes: Cause of death as adjudicated by a blinded committee.

Results: Median eGFR and PCR ranged from 20.6 mL/min/1.73 m(2) and 4.1 g/g in quartile 1 (Q1) to 47.0 mL/min/1.73 m(2) and 0.1 g/g in Q4 (P<0.01). Of 806 deaths, 441, 298, and 67 were due to cardiovascular (CV), non-CV, and unknown causes, respectively. Cumulative CV mortality at 3 years was higher with lower eGFR (Q1, 15.5%; Q2, 11.1%; Q3, 11.2%; Q4, 10.3%; P<0.001) or higher PCR (Q1, 15.2%; Q2, 12.3%; Q3, 11.7%; Q4, 9.0%; P<0.001). Similarly, non-CV mortality was higher with lower eGFR (Q1, 12.7%; Q2, 8.4%; Q3, 6.7%; Q4, 6.1%; P<0.001) or higher PCR (Q1, 10.3%; Q2, 7.9%; Q3, 9.4%; Q4, 6.4%; P=0.01). Sudden death was 1.7-fold higher with lower eGFR (P=0.04) and 2.1-fold higher with higher PCR (P<0.001). Infection-related mortality was 3.3-fold higher in the lowest eGFR quartile (P<0.001) and 2.8-fold higher in the highest PCR quartile (P<0.02). The overall proportion of CV and non-CV deaths was not significantly different across eGFR or PCR quartiles.

Limitations: Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia. Measured GFR was not available.

Conclusions: In diabetic CKD, both lower baseline GFR and higher PCR are associated with higher CV and non-CV mortality rates, particularly from sudden death and infection. Efforts to improve outcomes should focus on CV disease and early diagnosis and treatment of infection.

Keywords: Chronic kidney disease (CKD); Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT); anemia; cardiovascular (CV) disease; diabetic CKD; estimated glomerular filtration rate (eGFR); infection; mortality; protein-creatinine ratio (PCR); proteinuria; renal function; sudden death.

Figure 1

Cumulative mortality according to estimated glomerular filtration rate (eGFR) and proteinuria at baseline. Event rates according to baseline protein-creatinine ratio (PCR) and eGFR. Median PCR values are 4.08 g/g in quartile 1 (Q1), 0.85 g/g in Q2, 0.21 g/g in Q3, and 0.09 g/g in Q4. Median eGFRs are 20.6 mL/min/1.73 m² in Q1, 27.9 mL/min/1.73 m² in Q2, 35.5 mL/min/ 1.73 m² in Q3 and 47.0 mL/min/1.73 m² in Q4. Abbreviations: CV, cardiovascular; MI, myocardial infarction.

Figure 2

Annualized cause-specific mortality (non–competing risk) according to baseline (A) estimated glomerular filtration rate (eGFR) or (B) proteinuria. Abbreviation: CV, cardiovascular.