Proteinuria and Risk of CVD

A systematic review of studies on nondialysis patients with CKD (39 studies, 1,371,990 patients) found CKD to be associated with high risk for all-cause and cardiovascular mortality outcomes regardless of the presence of confounding factors and variation in study design, study population and CKD definitions.^[9] Indeed, patients with CKD are at greater risk for cardiovascular mortality than for progression to endstage renal disease (ESRD). In a large, health-maintenance organization study (n = 27,998) of patients with CKD (eGFR 15–90 ml/min/1.73 m²), the mortality rate was 24.9% and only 3.1% of patients progressed to dialysis.^[10] An even larger community population study (n = 1.1 million) demonstrated an independent graded association between reduced eGFR and increased risk of CVD outcomes and hospitalizations;^[11] only 3,171 patients (0.28%) started dialysis at 2.84 years of follow-up compared with 51,424 deaths (4.5%) and 138,291 CVD events (12.2%). These findings show that most patients with CKD die from CVD before progressing to ESRD, with the implication that patients who have ESRD are the survivors.

As discussed earlier in this review, proteinuria can be detected in early stages of CKD and predict rapid decline in renal filtration function. The aforementioned studies used eGFR as a measure of CKD and were limited by the absence of proteinuria measurements. Their findings, therefore, shed no light on whether patients with proteinuria, including those with no reduction in eGFR, are more likely to die from CVD than progress to ESRD. Competing risk factor analysis of ESRD and mortality in a prospective study performed in veterans administration patients with CKD (n = 220, mean eGFR = 38.2 ml/min/1.73 m²), who were followed for 7 years, revealed that proteinuria had a similar effect on progression to ESRD (hazard ratio, HR 1.37) and all-cause mortality (HR 1.26).^[12] In agreement with this study, posthoc analysis of the RENAAL (Reduction in Endpoint in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan) trial (mean baseline eGFR = 39.8 ml/min/1.73 m²) showed that proteinuria ≥3 g daily (n = 289) was associated with a renal end point of doubling of creatinine or ESRD in 85% of patients, and with cardiovascular end point in 44% of patients. In the same analysis, proteinuria <1.5 g daily (n = 859) was associated with renal and cardiovascular end points in 28% and 29% of patients, respectively, after adjusting for eGFR and multiple risk factors (Figure 1).^[13] Indeed, patients with baseline urinary protein excretion ≥1.3 g daily have been shown to benefit most from reduced CKD progression with angiotensin-converting-enzyme inhibitors (ACEIs).^[14,15] Increased level of baseline proteinuria (>1.5 g daily) was associated with increased risk for CVD only in those patients who also progressed to a renal end point. A retrospective study of 142 nondiabetic patients with nephrotic-range proteinuria (urine protein >3.5 g/24 h) followed for 5.6 years showed that 22.5% of patients progressed to ESRD, while 4.9% of patients died from coronary heart disease.^[16] This discrepancy in patients' outcomes might suggest different mechanisms for risk of ESRD and cardiovascular deaths in various populations with proteinuria and differing burden of endothelial dysfunction and atherosclerosis. These studies highlight the practical difficulty in differentiating whether increased renal and cardiovascular risk arises from proteinuria, reduced renal function or both.

Figure 1.

Enlarge

Relationship between CV and renal outcomes in patients with different baseline degrees of albuminuria in the RENAAL (reduction in endpoints in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan) trial.^{[13] a} n = 859. ^b n = 365. ^c n = 289. Abbreviations: CV, cardiovascular; ESRD, endstage renal disease; g/g, g albumin/g creatinine. Permission obtained from Lippincott Williams & Wilkins © de Zeeuw, D. et al. Circulation 110, 921-927 (2004).

Regardless of whether proteinuria predicts a greater risk of death from CVD or progression to ESRD, the condition has been consistently associated with increased risk for cardiovascular events and mortality in patients with and without diabetes. Patients with proteinuria had relative risks or hazard ratios for CVD events, CVD mortality and all-cause mortality of 1.6–5.5, 1.7–5.4 and 1.4– 2.9, respectively (Table 1). In addition, proteinuria has been implicated in myocardial disease of the left ventricle. The strong Heart study showed that patients with type 2 diabetes with proteinuria (mean serum creatinine 1.63 mg/dl) had worse left ventricular systolic function and impaired diastolic left ventricular filling compared with patients with normoalbuminuria (mean serum creatinine 0.85 mg/dl) or microalbuminuria (mean serum creatinine 0.86 mg/dl).^[17] Finally, proteinuria is also associated with increased risk for atherosclerotic events in the peripheral vasculature. Patients with proteinuria have been demonstrated to be at increased risk (relative risk 1.6–3.3) for incident stroke.^[18,19] In aggregate, these data suggest that proteinuria might be associated with systemic vascular disease that affects the glomeruli as well as other arterial systems in the body.