Objective: Sodium restriction potentiates the efficacy of the rennin–angiotensin–aldosterone system (RAAS)-blockade and improves long-term cardiovascular and renal protection, even independent of the better blood pressure control. The mechanisms underlying the potentiation of cardiorenal protection by sodium restriction are incompletely understood. RAAS-blockade with angiotensin-converting enzyme (ACE) inhibitors increases circulating levels of the anti-inflammatory and antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), which is assumed to contribute to its therapeutic effects. We hypothesized that sodium restriction on top of RAAS-blockade further increases AcSDKP, as a possible explanation for the enhanced effects of RAAS-blockade during sodium restriction.
Methods: To test this hypothesis, we performed a secondary analysis of a randomized clinical trial investigating 46 nondiabetic chronic kidney disease (CKD) patients (age 50 ± 13 years, 80% men) with overt proteinuria and mild to moderate renal insufficiency. Patients were subjected, in a crossover design, to four double-blind 6-week study periods with either regular sodium diet (194 ± 49 mmol Na+/day) or low sodium diet (102 ± 52 mmol Na+/day) on top of either lisinopril (40 mg/day; single RAAS-blockade) or lisinopril plus valsartan (320 mg/day; dual RAAS-blockade).
Results: Sodium restriction significantly increased circulating levels of AcSDKP during single and dual RAAS-blockade (P = 0.032 and 0.042, respectively). Linear mixed-model analysis confirmed that AcSDKP levels were increased in response to sodium restriction, irrespective of sex, age, creatinine clearance, blood pressure, BMI, single or dual RAAS-blockade, treatment sequence and other dietary factors, that is calcium and protein (P = 0.020).
Conclusion: In patients with nondiabetic CKD, we demonstrated that sodium restriction, on top of single and dual RAAS-blockade, increases circulating levels of the anti-inflammatory and antifibrotic peptide AcSDKP. The rise in AcSDKP may contribute to the increased protection of RAAS-blockade during sodium restriction.
aDepartment of Medicine, Division of Nephrology
bDepartment of Cardiology, University of Groningen, University Medical Center Groningen, Groningen
cDepartment of Medicine, Division of Nephrology, Ziekenhuisgroep Twente, Almelo, The Netherlands
Correspondence to Arjan J. Kwakernaak, Department of Medicine, Division of Nephrology, University Medical Center Groningen, P.O. Box 30001, NL-9700 RB Groningen, The Netherlands. Tel: +31 50 361 1564; fax: +31 50 361 9310; e-mail: firstname.lastname@example.org
Abbreviations: AcSDKP, N-Acetyl-Seryl-Aspartyl-Lysyl-Proline; RAAS, renin–angiotensin–aldosterone system; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin-II receptor antagonist
Received 7 March, 2013
Revised 15 June, 2013
Accepted 9 July, 2013