Description of the condition
The prevalence of chronic kidney (CKD) disease in children is estimated to be between 30 to 100 cases/million children (Ardissino 2003). The chief causes include congenital abnormalities of the kidneys and urinary tract and inherited or acquired glomerulopathies. Common manifestations of CKD in childhood include malnutrition and growth failure, anaemia, mineral bone disease, hypertension and proteinuria. Loss of renal parenchyma, regardless of aetiology, is associated with progressive renal impairment due to glomerular hyperfiltration. A high proportion of patients with CKD therefore show progressive kidney dysfunction, resulting in end-stage kidney disease (ESKD) (Wong 2012). Regardless of underlying aetiology, the presence of hypertension is associated with cardiovascular morbidity and progressive kidney injury (Wuhl 2011). Proteinuria is also an important independent risk factor for disease progression in children and adults with CKD.
Description of the intervention
The diagnosis of hypertension in children is based on recommendations of the Fourth Task Force on Blood Pressure Control in Children; defined by age, sex and height specific percentiles of systolic and diastolic blood pressure (BP). These are further staged as normal, prehypertension and stage I or II hypertension (NHBPEP Working Group 2004). BP is considered normal when the systolic and diastolic values are less than the 90th percentile for the child’s age, sex, and height. Stage I hypertension is diagnosed if a child’s BP is greater than the 95th percentile but less than or equal to the 99th percentile plus 5 mm Hg. Stage II hypertension denotes systolic or diastolic BP exceeding these limits.
Antihypertensive agents of most classes, including angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), calcium channel blockers, adrenergic antagonists and diuretics have been shown to be effective and safe in achieving BP targets in children (Benjamin 2008). Agents targeting the renin-angiotensin-aldosterone system, including ACEi and ARB, have been used for reduction of proteinuria in patients with non-nephrotic and nephrotic range proteinuria. The effect of these agents is dose and time-dependent. Evidence from clinical studies in adults and children indicates that the rate of progression of CKD is lowered by pharmacological interventions, chiefly targeting the renin-angiotensin system (Casas 2005).
How the intervention might work
Hypertension and proteinuria are important features of CKD, which require prompt therapy (Staples 2010). The management of hypertension is necessary to prevent hypertension-associated morbidity and cardiovascular complications. Prospective studies show that management of hypertension and proteinuria are effective in retarding disease progression (Staples 2010). Control of systemic hypertension prevents elevation of glomerular pressure that could worsen kidney injury. Proteinuria can induce tubulointerstitial inflammation and fibrosis through oxidative stress and increased expression of growth factors and inflammatory mediators (Hirschberg 2005). Blockade of renin-angiotensin-aldosterone system preserves kidney function by reducing intraglomerular hypertension and through specific anti-inflammatory actions (Remuzzi 2005). Studies have also demonstrated that strict BP control, regardless of class of antihypertensive used, has additional benefits in retarding disease progression.
Why it is important to do this review
While there are multiple systematic reviews on efficacy and safety of antihypertensive agents in adults, including those with CKD, there are no published systematic reviews on the use of antihypertensive agents in children (Chaturvedi 2009). Studies in adults have examined various acute and chronic kidney outcomes, rates of disease progression and measures of extrarenal morbidity. Most studies on the efficacy and safety of antihypertensive agents in children have included patients with CKD, since renal parenchymal diseases constitute the leading cause of hypertension in these patients. We propose to do a systematic review of all randomised controlled trials (RCTs) on antihypertensive agents in children with CKD. These studies would chiefly include those where these agents have been used either for management of hypertension or reduction of proteinuria. Therapy with antihypertensive agents is expected to be associated with additional advantages in outcome, including retarding the rate of disease progression.
Findings of this systematic review will provide clinically relevant information on the efficacy, safety and dosing of antihypertensive agents for children with CKD. It shall also provide pooled objective evidence of efficacy of antihypertensive therapies in retarding disease progression, decreasing proteinuria and limiting cardiovascular damage. The relevance of this evidence-based resource will therefore be applicable to all children with CKD and hypertension, or proteinuria, or both requiring pharmacological treatment.