Children with chronic kidney disease (CKD) have higher rates of hospitalizations, metabolic abnormalities, cardiovascular disease, and growth restriction, compared to their healthy counterparts. 1-4 Growth failure is common in pediatric CKD; affecting up to 35% of these children. 5 Children with kidney failure and short stature have increased mortality risk compared to those children with preserved height. 6,7 Conversely, height gains have been associated with improved physical and social functioning in children with CKD. 8 To address the significant morbidity associated with pediatric CKD, it is critical to identify modifiable risk factors for poor outcomes; a gap I will address in this proposal.
Metabolic acidosis (MA) occurs frequently in pediatric CKD. 2 Analyzing the Chronic Kidney Disease in Children (CKiD) study data, the largest prospective, multicentered, study of children with CKD, we (Brown et al.) found that up to one third of participants had low serum bicarbonate levels (a proxy for MA), but only one third of this group reported treatment with alkali therapy. 4,9 MA has been linked to multiple adverse outcomes, including poor linear growth. 10-15 Growth failure in pediatric CKD is complex but studies of children with renal tubular acidosis have pointed to MA as a contributing factor. These studies, however, largely excluded children with abnormal estimated glomerular filtration rate, leaving the question of how MA affects growth as CKD worsens unanswered. The contribution of MA to growth failure has been examined, cross-sectionally, in the CKiD cohort with findings showing that children with a serum bicarbonate of <18 mEq/L had height standard deviation scores that were lower than those with a serum bicarbonate ≥22 mEq/L.4 Longitudinal studies that include multiple growth points are needed to understand the association of MA with linear growth along the complete CKD severity spectrum. It is critical that such studies include diverse populations of children with CKD in order to inform and improve treatment practices.
Currently, pediatric providers initiate alkali therapy when the serum bicarbonate level is <22 mEq/L.16 Despite that recommendation and the benefits of alkali supplementation reported in numerous studies of adult patients with CKD 10-13,17, randomized controlled clinical trial of alkali therapy focused on pediatric CKD patients are rare. As such, there is insufficient evidence to identify those children with CKD who would most benefit from alkali therapy and to quantify the magnitude of that benefit, particularly regarding linear growth. However, randomized controlled trials are difficult to conduct given the relatively rare nature of kidney disease in children limiting sample sizes for such studies and almost requiring such trials to be multi-site in nature. Target trial emulation is a relatively new analytical analytic framework that may address such instances where a randomized trial is less feasible. 18 Trial emulation offers the ability to leverage large observational data to simulate a randomized controlled trial and thus quantify the efficacy of a prescribed treatment for an identified population. To date, this strategy has rarely been employed in a pediatric CKD population but poses great potential for these children affected by rare pediatric diseases.