Strict blood-pressure control and progression of renal failure in children.
BACKGROUND
Although inhibition of the renin-angiotensin system delays the progression of renal failure in adults with chronic kidney disease, the blood-pressure target for optimal renal protection is controversial. We assessed the long-term renoprotective effect of intensified blood-pressure control among children who were receiving a fixed high dose of an angiotensin-converting-enzyme (ACE) inhibitor.


METHODS
After a 6-month run-in period, 385 children, 3 to 18 years of age, with chronic kidney disease (glomerular filtration rate of 15 to 80 ml per minute per 1.73 m(2) of body-surface area) received ramipril at a dose of 6 mg per square meter of body-surface area per day. Patients were randomly assigned to intensified blood-pressure control (with a target 24-hour mean arterial pressure below the 50th percentile) or conventional blood-pressure control (mean arterial pressure in the 50th to 95th percentile), achieved by the addition of antihypertensive therapy that does not target the renin-angiotensin system; patients were followed for 5 years. The primary end point was the time to a decline of 50% in the glomerular filtration rate or progression to end-stage renal disease. Secondary end points included changes in blood pressure, glomerular filtration rate, and urinary protein excretion.


RESULTS
A total of 29.9% of the patients in the group that received intensified blood-pressure control reached the primary end point, as assessed by means of a Kaplan-Meier analysis, as compared with 41.7% in the group that received conventional blood-pressure control (hazard ratio, 0.65; confidence interval, 0.44 to 0.94; P=0.02). The two groups did not differ significantly with respect to the type or incidence of adverse events or the cumulative rates of withdrawal from the study (28.0% vs. 26.5%). Proteinuria gradually rebounded during ongoing ACE inhibition after an initial 50% decrease, despite persistently good blood-pressure control. Achievement of blood-pressure targets and a decrease in proteinuria were significant independent predictors of delayed progression of renal disease.


CONCLUSIONS
Intensified blood-pressure control, with target 24-hour blood-pressure levels in the low range of normal, confers a substantial benefit with respect to renal function among children with chronic kidney disease. Reappearance of proteinuria after initial successful pharmacologic blood-pressure control is common among children who are receiving long-term ACE inhibition. (ClinicalTrials.gov number, NCT00221845.)
Elke
E
Wühl
Antonella
A
Trivelli
Stefano
S
Picca
Mieczyslaw
M
Litwin
Amira
A
Peco-Antic
Aleksandra
A
Zurowska
Sara
S
Testa
Augustina
A
Jankauskiene
Sevinc
S
Emre
Alberto
A
Caldas-Afonso
Ali
A
Anarat
Patrick
P
Niaudet
Sevgi
S
Mir
Aysin
A
Bakkaloglu
Barbara
B
Enke
Giovanni
G
Montini
Ann-Margret
AM
Wingen
Peter
P
Sallay
Nikola
N
Jeck
Ulla
U
Berg
Salim
S
Caliskan
Simone
S
Wygoda
Katharina
K
Hohbach-Hohenfellner
Jiri
J
Dusek
Tomasz
T
Urasinski
Klaus
K
Arbeiter
Thomas
T
Neuhaus
Jutta
J
Gellermann
Dorota
D
Drozdz
Michel
M
Fischbach
Kristina
K
Möller
Marianne
M
Wigger
Licia
L
Peruzzi
Otto
O
Mehls
Franz
F
Schaefer
D000293:Adolescent; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001794:Blood Pressure; D018660:Blood Pressure Monitoring, Ambulatory; D002648:Child; D002675:Child, Preschool; D003404:Creatinine / Q000652:urine; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000209:etiology; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000517:prevention & control; D008297:Male; D011507:Proteinuria / Q000209:etiology; D017257:Ramipril / Q000008:administration & dosage* / Q000009:adverse effects; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D003404:Creatinine; D017257:Ramipril