Sodium intake, ACE inhibition, and progression to ESRD

Abstract

High sodium intake limits the antihypertensive and antiproteinuric effects of angiotensin-converting enzyme (ACE) inhibitors in patients with CKD; however, whether dietary sodium also associates with progression to ESRD is unknown. We conducted a post hoc analysis of the first and second Ramipril Efficacy in Nephropathy trials to evaluate the association of sodium intake with proteinuria and progression to ESRD among 500 CKD patients without diabetes who were treated with ramipril (5 mg/d) and monitored with serial 24-hour urinary sodium and creatinine measurements. Urinary sodium/creatinine excretion defined low (<100 mEq/g), medium (100 to <200 mEq/g), and high (≥200 mEq/g) sodium intake. During a follow-up of >4.25 years, 92 individuals (18.4%) developed ESRD. Among those with low, medium, and high sodium intakes, the incidence of ESRD was 6.1 (95% confidence interval [95% CI], 3.8-9.7), 7.9 (95% CI, 6.1-10.2), and 18.2 (95% CI, 11.3-29.3) per 100 patient-years, respectively (P<0.001). Patients with high dietary sodium exhibited a blunted antiproteinuric effect of ACE inhibition despite similar BP among groups. Each 100-mEq/g increase in urinary sodium/creatinine excretion associated with a 1.61-fold (95% CI, 1.15-2.24) higher risk for ESRD; adjusting for baseline proteinuria attenuated this association to 1.38-fold (95% CI, 0.95-2.00). This association was independent from BP but was lost after adjusting for changes in proteinuria. In summary, among patients with CKD but without diabetes, high dietary salt (>14 g daily) seems to blunt the antiproteinuric effect of ACE inhibitor therapy and increase the risk for ESRD, independent of BP control.

Figure 1.

In 500 patients with proteinuric chronic nephropathies, higher salt intake is associated with an increased risk of progression to ESRD. Kaplan-Meier survival curves show time to progression to ESRD in patients categorized in the LSD (dotted line), MSD (broken line), or HSD (continuous line) groups according to their urinary/creatinine ratio on follow-up.

Figure 2.

In 500 patients with proteinuric chronic nephropathies taking ramipril therapy, higher salt intake is associated with more proteinuria at baseline and less proteinuria reduction on follow-up, but does not appear to appreciably affect BP control. A and B, respectively, show 24-hour urinary protein excretion and mean arterial pressure during follow-up in patients categorized in LSD (dotted lines), MSD (broken lines), or HSD (continuous lines) groups according to their urinary sodium/creatinine ratio on follow-up. The two upper panels show mean and SEM values, whereas the two lower panels show median changes from baseline.

Figure 3.

In 172 patients with proteinuric chronic nephropathies taking non-RAS inhibitor therapy, higher salt intake tends to be associated with more proteinuria, but does not appear to appreciably affect proteinuria reduction on follow-up or BP control. A and B, respectively, show 24-hour urinary protein excretion and mean arterial pressure during follow-up in patients categorized in LSD (dotted lines), MSD (broken lines), or HSD (continuous lines) groups according to their urinary sodium/creatinine ratio on follow-up. The two upper panels show mean and SEM values, whereas the two lower panels show median changes from baseline.

Figure 4.

In 500 patients with proteinuric chronic nephropathies taking ramipril therapy, the association between salt intake and risk of progression to ESRD is lost when analyses were adjusted for changes in proteinuria on follow-up. The three curves show the association between urinary sodium/creatinine excretion on a continuous scale and ESRD according to three Cox proportional hazards models: unadjusted (model 1), adjusted for baseline proteinuria (model 2), and adjusted for baseline proteinuria and for changes in proteinuria during follow-up (model 3).