title: Sodium restriction on top of renin-angiotensin-aldosterone system blockade increases circulating levels of N-acetyl-seryl-aspartyl-lysyl-proline in chronic kidney disease patients.
abstract: 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 Naday) 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Arjan J
authors.initials: AJ
authors.lastname: Kwakernaak
authors.forename: Femke
authors.initials: F
authors.lastname: Waanders
authors.forename: Maartje C J
authors.initials: MC
authors.lastname: Slagman
authors.forename: Martin M
authors.initials: MM
authors.lastname: Dokter
authors.forename: Gozewijn D
authors.initials: GD
authors.lastname: Laverman
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
mesh_terms: D000107:Acetylation; D000328:Adult; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000097:blood*; D012084:Renin-Angiotensin System; D012982:Sodium, Dietary / Q000008:administration & dosage*
chemical_list: D009842:Oligopeptides; D012982:Sodium, Dietary