Urea levels and cardiovascular disease in patients with chronic kidney disease

Abstract

Background: Elevated serum urea levels are common in moderate-to-advanced CKD. Several studies have shown that urea is a direct and indirect uremic toxin, especially with regard to cardiovascular disease. We sought to determine whether serum urea levels are associated with adverse cardiovascular events and death before renal replacement therapy (RRT) in patients with CKD.

Methods: CKD-REIN is a prospective cohort of CKD nephrology outpatients not receiving maintenance dialysis. The 2507 patients included in the analysis were divided into three groups according to the baseline serum urea level (T1 < 10.5, T2:10.5 to 15.1, and T3 ≥ 15.1 mmol/L). Cox proportional hazard models were used to estimate hazard ratios (HRs) for first atheromatous or nonatheromatous cardiovascular (CV) events, and all-cause mortality before RRT. The models were adjusted for baseline comorbidities, laboratory data, and medications.

Findings: Of the 2507 included patients (median [interquartile range (IQR)] age: 69[61-77]; mean (standard deviation) eGFR 33.5(11.6) mL/min/1.73 m²), 54% had a history of cardiovascular disease. After multiple adjustments for cardiovascular risk factors (including eGFR), patients in T3 had a higher risk of atheromatous and nonatheromatous cardiovascular events than patient in T1 (n events = 451, HR[95%CI]: 1.93[1.39-2.69]). The adjusted HRs for death before RRT (n events = 407) were 1.31[0.97; 1.76] and 1.73[1.22; 2.45] for patients T2 and those in T3, respectively.

Interpretation: Our data suggested that urea is a predictor of cardiovascular outcomes beyond CV risk factors including eGFR.

Keywords: cardiovascular disease; chronic kidney disease; urea; uremic toxin.

Graphical Abstract

FIGURE 1:

Study flowchart. eGFR, estimated glomerular filtration rate.

FIGURE 2:

Adjusted HRs for fatal and nonfatal atheromatous or non-atheromatous cardiovascular events, according to the baseline serum urea level. HR, hazard ratio; CI, confidence interval. Adjusted for age at baseline, sex, smoking status, baseline estimated glomerular filtration rate, urine albumin- or protein-to-creatinine ratio, body mass index, diabetes, systolic blood pressure, history of cardiovascular disease, anaemia, serum albumin, high-sensitivity C-reactive protein and prescriptions of diuretics, statins and antiplatelet agents at baseline.

FIGURE 3:

Hazard ratio for fatal and nonfatal atheromatous or non-atheromatous cardiovascular events, according to the baseline serum urea level (mmol/L). The continuous line represents predictions with penalized splines in Cox models (95% confidence intervals). Ticks on the x-axis represent the distribution of the baseline serum urea level. Hazard ratios are adjusted for age at baseline, sex, smoking status, baseline estimated glomerular filtration rate, urine albumin- or protein-to-creatinine ratio, body mass index, diabetes, systolic blood pressure, history of cardiovascular disease, anaemia, serum albumin, high-sensitivity C-reactive protein and prescriptions of diuretics, statins and antiplatelet agents at baseline.

FIGURE 4:

Adjusted HRs for major cardiovascular events, according to the baseline serum urea level. HR, hazard ratio; CI, confidence interval. Adjusted for age at baseline, sex, smoking status, baseline estimated glomerular filtration rate, urine albumin- or protein-to-creatinine ratio, body mass index, diabetes, systolic blood pressure, history of cardiovascular disease, anaemia, serum albumin, high-sensitivity C-reactive protein and prescriptions of diuretics, statins and antiplatelet agents at baseline of diuretics, prescription of statins and prescription of antiplatelet agents at baseline.

FIGURE 5:

Adjusted HRs for death before renal replacement therapy according to the baseline serum urea level. HR, hazard ratio; CI, confidence interval. Adjusted for age at baseline, sex, smoking status, baseline estimated glomerular filtration rate, urine albumin- or protein-to-creatinine ratio, body mass index, diabetes, systolic blood pressure, history of cardiovascular disease, anaemia, serum albumin, high-sensitivity C-reactive protein, history of acute kidney injury, diuretic prescription, proton pump inhibitor prescription and prescriptions of statins and antiplatelet agents at baseline.