Effect of Strict Blood Pressure Control and ACE-Inhibition on Progression of Chronic Renal Failure in Pediatric Patients
Condition: Children; Chronic Renal Failure; Hypertension; Acquired Kidney Disease; Congenital Kidney Disease
MeSH terms: Kidney Diseases; Renal Insufficiency; Kidney Failure, Chronic; Renal Insufficiency, Chronic; Hypertension; Disease Progression
Study type: Interventional
Phase: Phase 3

Summary: 
      In children with chronic kidney disease, progression to end-stage renal failure is associated
      with high patient morbidity and poor quality of life. In adults, inhibition of the renin
      angiotensin system (RAS) slows down the rate of renal failure progression. This concept is as
      yet unproven in children, in whom chronic renal failure (CRF) is more commonly due to
      hypo/dysplastic malformations than to acquired glomerulopathies as typical for adult chronic
      kidney disease. The current project aims at assessing the genetic and molecular mechanisms
      and cardiovascular consequences of progressive CRF and to develop a strategy of
      pharmacological renoprotection in children.
    

Detailed description: 
      Chronic kidney diseases affecting the nephron mass are characterized by a progressive decline
      of glomerular filtration rate (GFR) occurring irrespectively of the cause of the renal damage
      once a critical number of nephrons has been lost. Current clinical research efforts focus on
      preventive strategies to slow down or arrest disease progression. Systemic hypertension and
      glomerular hyperfiltration with resulting proteinuria and activation of vasoactive,
      profibrotic and proinflammatory systems have been identified as major causes of further
      nephron damage. Angiotensin converting enzyme (ACE) inhibitors are not only potent
      antihypertensive agents but also reduce proteinuria, glomerulosclerosis and
      tubulointerstitial fibrosis via reduction of the local angiotensin tone in the kidney, and
      have been demonstrated to slow down renal failure progression in adult patients.
      Childhood-onset ESRD is a rare but particularly devastating disease with poor life expectancy
      and quality of life. Chronic renal failure in children is caused by a different spectrum of
      nephropathies than in adults, with a preponderance of congenital or inherited abnormalities.
      Since hypertension, proteinuria and tubulointerstitial fibrosis are also common in pediatric
      chronic renal failure, there is a rationale for pharmacological renoprotection by ACE
      inhibition in children. The prospective, randomized European clinical trial launched by our
      consortium will provide the critical mass to assess several aspects of renoprotective therapy
      in children. Specifically, the trial is designed to address the following scientific
      objectives:

      Objective 1 is to evaluate whether ACE inhibition is equally effective in slowing down the
      progression rate of chronic renal failure in children with different congenital and acquired
      renal disorders. 400 pediatric patients will be stratified according to their underlying
      diseases, and the rate of loss in glomerular filtration rate will be assessed from 6 months
      before to 5 years after start of treatment with the ACE inhibitor ramipril.

      Objective 2 of the trial is to evaluate whether renal failure progression in patients treated
      with a fixed dose of ramipril can be further slowed down by additional antihypertensive
      treatment, achieving a blood pressure below the 50th percentile. To this end, patients will
      be randomized upon initiation of ramipril to either intensified (aiming below 50th percentile
      of 24-hour mean arterial pressure) or conventional antihypertensive treatment.

      Several gene polymorphisms have been described that may affect the rate of renal failure
      progression and/or the individual susceptibility to ACE inhibition. These polymorphisms
      include genes encoding for key proteins of the renin-angiotensin system and extracellular
      matrix turnover. In addition, we will screen for novel polymorphisms in genes determining
      structural proteins of the glomerular filter, and search for gene mutations causing renal
      hypo-/dysplasia. Objective 3 is to evaluate whether any of these mutations predict
      spontaneous disease progression and the therapeutic response to ACE inhibition and
      intensified blood pressure control.

      Glomerular endothelin (ET1) synthesis is upregulated in chronic renal failure, and urinary
      ET1 excretion is correlated with disease progression. ET1 antagonists partially preserve
      renal function and decrease proteinuria independent of the angiotensin tone. Objective 4 of
      the trial is to assess ET1 turnover before and after start of ACE inhibition, and to evaluate
      a possible predictive role of ET1 and/or ET1 degrading peptidase excretion for the
      persistence of proteinuria and disease progression during ACE inhibition and intensified
      antihypertensive therapy.

      Long-term survival of children with chronic renal failure is compromised by precocious
      atherosclerosis and excessive cardiovascular morbidity. Objective 5 is to assess and
      correlate prospectively the metabolic causes and morphological consequences of uremic
      cardiovascular disease in children, and to define their relationship with disease progression
      during ACE inhibition and intensified blood pressure control. Homocysteine metabolism,
      apolipoprotein variability, gene polymorphisms putatively involved in atherosclerosis,
      inflammation states, myocardial function and carotid intima-media thickness will be assessed
      and compared to a reference group of age-matched healthy children.
    

Intervention name(s): ACE Inhibition; Intensified Blood Pressure Control; Add-on Angiotensin Receptor Blockade
Intervention type(s): Drug; Drug; Drug
Intervention description(s): ACE inhibitor ramipril (6 mg/m²/day) will be given to all subjects.; Any antihypertensive drugs except ACE inhibitors and angiotensin receptor blockers will be allowed.; In patients who show persistent or breakthrough proteinuria at the end of the initial study period, telmisartan (50 mg/m²/day) will be added to the existing medication.
Other intervention name(s): Delix; Micardis
Intervention MeSH terms: Telmisartan
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Ramipril; Hypertension; Chronic renal failure; Disease progression; Left ventricular hypertrophy; Intima media thickness; Cardiovascular disease; Biomarkers; Gene polymorphisms