title: Safety and tolerability of high-dose angiotensin receptor blocker therapy in patients with chronic kidney disease: a pilot study.
abstract: BACKGROUND
  The progression of renal disease is ameliorated by drugs that inhibit the renin-angiotensin system (RAS). The doses used to slow the progression of renal disease may not completely suppress the RAS for 24 h and may explain why some patients do not obtain optimal renoprotective benefits from therapy. This pilot study was initiated to determine the safety and tolerability of using higher doses, than currently approved by the Food and Drug Administration, for the angiotensin-receptor blocker (ARB) candesartan cilexetil in patients with chronic kidney disease. We hypothesized that higher doses will be safe and well tolerated. Consequently, this should be a viable strategy for larger clinical trials evaluating the preservation of renal function.
  
  
  METHODS
  Twelve patients (10 males; age = 57 +/- 14 years) with a history of diabetic or non-diabetic chronic kidney disease were enrolled in an 8-week open-label trial. Patients received candesartan titrated to a targeted dosage of 160 mg/day (5 times above the currently approved maximum dose) and remained at that dosage for the subsequent 4 weeks. The safety and tolerability of the higher doses were determined by measures of blood pressure, serum creatinine and potassium.
  
  
  RESULTS
  Candesartan was well tolerated with no serious drug-related adverse events reported. Serum creatinine concentrations throughout the study were not different (p > 0.05) from baseline levels (2.0 +/- 0.5 mg/dl). Plasma potassium concentrations at 160 mg/day candesartan (4.9 +/- 0.7 mEq/l) were similar (p > 0.05) to those at baseline (4.8 +/- 0.5 mEq/l).
  
  
  CONCLUSIONS
  The results of this pilot study suggest that supramaximal doses of ARBs are safe and well tolerated in patients with chronic kidney disease, while reducing both blood pressure and proteinuria. This study demonstrates the need to further investigate the optimal dosing strategy for ARBs in reducing the progression of renal disease.
authors.affiliation: College of Arts and Sciences, Boston University, Boston, Mass, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Weinberg
authors.forename: Dion H
authors.initials: DH
authors.lastname: Zappe
authors.forename: Michael
authors.initials: M
authors.lastname: Ashton
authors.forename: Marc S
authors.initials: MS
authors.lastname: Weinberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D001562:Benzimidazoles / Q000008:administration & dosage*; D001713:Biphenyl Compounds; D002908:Chronic Disease; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D013777:Tetrazoles / Q000008:administration & dosage*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; C081643:candesartan