title: Long-term safety of high-dose angiotensin receptor blocker therapy in hypertensive patients with chronic kidney disease.
abstract: BACKGROUND
  Reducing urinary protein excretion in patients with renal disease is an important therapeutic target to prevent the progression of renal and cardiovascular disease. Drugs such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARBs), which block the actions of the renin-angiotensin-aldosterone system, are recommended because they reduce blood pressure and proteinuria. Recently, the use of higher doses of ARBs, up to three times the maximal approved dose, resulted in further reductions in protein excretion. Despite the effectiveness of this therapeutic approach, no long-term safety analysis has been conducted in patients receiving high-dose ARB treatment.
  
  
  OBJECTIVE
  To study the long-term safety of high-dose ARB treatment.
  
  
  METHODS
  We observed 48 patients [44 men and 4 women; ages 64 +/- 15 years (mean +/- SD), weight 88 +/- 28 kg, estimated glomerular filtration rate 53 +/- 23 ml/min] receiving treatment with high doses (1.5-5 times greater than the maximum approved dose) of ARBs, for 40 +/- 24 months (range 6-98 months).
  
  
  RESULTS
  The average ARB dose tended to increase over time and was 3.2 +/- 1.2 times greater at the end of the study than that at the start. Systolic blood pressure was similar at the beginning and end of the study period (132 +/- 20 and 125 +/- 20 mmHg, respectively), but diastolic blood pressure showed a decrease throughout the study and was significantly reduced (P < 0.05) in association with 1.5x and 2x the maximum ARB dose (73 +/- 11 and 72 +/- 10 mmHg, respectively) when compared with baseline (78 +/- 11 mm Hg). There was a trend (P > 0.05) for increases in concentrations of serum potassium (0.2 +/- 0.9 mmol/l) and creatinine (0.3 +/- 0.7 mg/dl) with increases in dose from baseline to the end of the study. Serum creatinine concentration was greater (P < 0.05) at the periods of 3x and 4x the maximum dose, but this represented increases of only 12 and 20% from baseline, respectively.
  
  
  CONCLUSIONS
  High-dose ARB treatment in patients with chronic renal disease is not associated with any clinically significant long-term negative effects on serum creatinine or potassium and is thus a important therapeutic modality with which to achieve further reductions in urinary protein excretion.
authors.affiliation: College of Arts and Sciences, Boston University, Boston, Massachusetts, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Weinberg
authors.forename: Dion H
authors.initials: DH
authors.lastname: Zappe
authors.forename: Rajeev
authors.initials: R
authors.lastname: Ramadugu
authors.forename: Marc S
authors.initials: MS
authors.lastname: Weinberg
mesh_terms: D000328:Adult; D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers / Q000009:adverse effects*; D001794:Blood Pressure / Q000187:drug effects; D002908:Chronic Disease; D003404:Creatinine / Q000097:blood; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011188:Potassium / Q000097:blood
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D003404:Creatinine; D011188:Potassium