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.
This review aims to look at the benefits and harms of therapy with antihypertensive agents in children with CKD.
Criteria for considering studies for this review
Types of studies
All RCTs and quasi-RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at the use of antihypertensive agents in children with CKD will be eligible, regardless of blinding, year of publication, language, publication status or study design (parallel or cross-over).
Types of participants
Children aged 12 months to 18 years with CKD, defined as three months of decreased glomerular filtration rate (GFR) below 60 mL/min/1.73 m² (Schwartz 2009a; Schwartz 2009b) with or without proteinuria or hypertension, receiving antihypertensive agents of any class shall be included. In studies where these patients form a subgroup, their data shall be included if discrete information on efficacy or safety of antihypertensive agents in the subgroup is available. The definitions of systolic and diastolic hypertension shall be those defined by the authors.
- Essential hypertension
- Hypertension secondary to endocrine causes and coarctation of aorta
- Hypertensive emergencies
- Renovascular hypertension in the absence of CKD.
Types of interventions
Interventions will include agents belonging to any antihypertensive class (e.g. ACEi, ARB, calcium channel blockers, adrenergic antagonists, diuretics), whether examined as monotherapy or combination therapy for two weeks or more.
Agents used specifically for hypertensive emergencies or urgencies, such as esmolol or nitroprusside, shall not be eligible. Comparisons may be between different doses of a drug or with another medication, placebo or no drug.
Types of outcome measures
Outcomes should be measured at one or more time points, two weeks post-treatment and beyond.
- Decline in systolic BP, or diastolic BP, or both
- Decline in proteinuria
- Dose-related change in systolic BP, or diastolic BP, or both
- Number of patients achieving target BP
- Change in serum creatinine (SCr), or estimated GFR (eGFR), or both
- Progression to ESKD
- Adverse effects and treatment withdrawals
- Change in levels of biochemical parameters (e.g. serum potassium, cholesterol, triglycerides, sugar, haemoglobin, alanine transaminase, aspartate transaminase)
- Absolute value or change in cardiovascular indices, such as echocardiographic estimates, carotid intima medial thickness, flow mediated brachial artery dilatation or peripheral vascular resistance or both, as measured by bioimpedance
Search methods for identification of studies
We will search the Cochrane Renal Group's Specialised Register through contact with the Trials' Search Co-ordinator using search terms relevant to this review. The Cochrane Renal Group’s Specialised Register contains studies identified from the following sources.
- Monthly searches of the Cochrane Central Register of Controlled Trials CENTRAL
- Weekly searches of MEDLINE OVID SP
- Handsearching of renal-related journals and the proceedings of major renal conferences
- Searching of the current year of EMBASE OVID SP
- Weekly current awareness alerts for selected renal journals
- Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
We will also search:
- Database of Abstracts of Reviews of Effectiveness (DARE)
- Other trial registries and resources, including OpenSIGLE, ISI Web of Science
- Cumulative Index to Nursing & Allied Health Literature (CINAHL, 1984 onwards).
The search strategy shall be designed to identify eligible studies from the above sources, using terms as described in Appendix 1. Such searches shall be conducted without language restriction. A lateral search using the related articles link in MEDLINE and review of bibliographic citations shall be done.
Searching other resources
Reviews, abstracts and proceedings of international nephrology, cardiology and hypertension conferences and reference lists of clinical practice guidelines, review articles and relevant studies shall be handsearched. Pharmaceutical companies, experts and authors of potentially eligible studies will be contacted for unpublished studies.
Data collection and analysis
Selection of studies
Databases shall be searched using the above strategy to identify citations with potential relevance. Articles whose titles or abstracts are clearly irrelevant shall be excluded; full text of remaining articles shall be retrieved and assessed for eligibility, by two independent authors, according to specified inclusion criteria, using a study selection form. A third author shall resolve any discrepancies.
Data extraction and management
Data extraction will be carried out independently by two authors using standard data extraction forms. Studies reported in non-English language journals will be translated before assessment. Where more than one publication of one study exists, reports will be grouped together and the publication with the most complete data will be used in the analyses. Where relevant outcomes are only published in earlier versions these data will be used. Any discrepancy between published versions will be highlighted. Numeric data (tables or text) shall be preferred to graphical data to avoid measurement errors; the latter shall be confirmed by a second author. Since position might affect BP measurement, if available in more than one position, data shall be extracted as follows: (i) sitting, (ii) standing, and (iii) supine.
Assessment of risk of bias in included studies
- Was there adequate sequence generation (selection bias)?
- Was allocation adequately concealed (selection bias)?
- Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?
- Participants and personnel
- Outcome assessors
- Were incomplete outcome data adequately addressed (attrition bias)?
- Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
- Was the study apparently free of other problems that could put it at a risk of bias?
Discrepancies, if any, shall be resolved by the third author.
Measures of treatment effect
For dichotomous outcomes (target BP, ESKD, adverse effects) results will be expressed as risk ratios (RR) with 95% confidence intervals (CI). Where continuous scales of measurement are used to assess the effects of treatment (e.g. changes in systolic or diastolic BP, urine protein excretion, eGFR), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used.
Unit of analysis issues
Special issues in the analysis of studies with non-standard designs, such as cross-over RCTs and cluster-RCTs, shall be described.
Dealing with missing data
Any further information required from the original author will be requested by written correspondence (e.g. emailing to corresponding author) and any relevant information obtained in this manner will be included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention-to-treat, as-treated and per-protocol population will be carefully performed. Attrition rates (e.g. drop-outs, losses to follow-up, withdrawals) will be investigated. Issues of missing data and imputation methods (e.g. last-observation-carried-forward) will be critically appraised (Higgins 2011). In the case of missing values for standard deviation of the change in BP, or proteinuria, these shall be imputed based on information from the same study or other studies using the same dose.
Assessment of heterogeneity
Heterogeneity will be analysed using a Chi² test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.
Assessment of reporting biases
If possible, funnel plots will be used to assess for the potential existence of small study bias (Higgins 2011).
Data will be pooled using the random-effects model but the fixed-effect model will also be used to ensure robustness of the model chosen and susceptibility to outliers.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis will be used to explore possible sources of heterogeneity (e.g. participants, interventions and study quality). Heterogeneity among participants could be related to age (adolescent versus pre-adolescent), race, severity and aetiology of kidney disease and degree of proteinuria. Heterogeneity in treatments could be related to prior agent(s) used and the agent, dose and duration of antihypertensive therapy (more or less than three months). Heterogeneity in assessment of outcome may relate to method of measurement of BP (clinic, home or ambulatory BP monitoring), desired BP targets (e.g. below 50th or 75th percentile versus below 90th percentile), quantification of proteinuria (24 h versus spot urine protein:creatinine ratio or dipstick), estimation of GFR (based on clearance of creatinine versus cystatin or radionuclide) and method of creatinine estimation (enzymatic, modified Jaffe or isotope dilution mass spectrometry). Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various agents used. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared to no treatment or to another agent.
Where feasible, the robustness of the results shall be tested using sensitivity analyses, including comparisons of study quality and sponsoring agency (e.g. government versus industry).
We wish to thank the referees for their comments and feedback during the preparation of this protocol. The authors also acknowledge the help provided by the Cochrane Renal Group.
Appendix 1. Electronic search strategies
Appendix 2. Risk of bias assessment tool
Contributions of authors
- Draft the protocol: AB, AS
- Study selection: AS, AB
- Extract data from studies: AS, AB
- Enter data into RevMan: AS
- Carry out the analysis: AB, AS, RMP
- Interpret the analysis: AB, AS, RMP
- Draft the final review: AS, AB, FS
- Disagreement resolution: FS
- Update the review: AB, AS
Declarations of interest
Sources of support
- All India Institute of Medical Sciences, New Delhi, India.
- No sources of support supplied