CKD in childhood is associated with multiple comorbidities, including growth failure (1⇓⇓–4). Earlier detection and management of reduced growth velocity have enhanced the growth potential for children with CKD (5). Despite these advances, nearly half of prepubertal children with ESKD will have short stature in adulthood (height <3rd percentile) (1,6,7). Short stature at initiation of dialysis is associated with increased risk of death and dialysis-related complications (8), and short stature pretransplant is associated with reduced graft survival (9). Impaired growth also places significant psychosocial burdens on the child and family, including reduced quality of life and ability for social advancement (10⇓–12). The etiology of growth impairment in CKD is multifactorial, including growth hormone (GH) resistance, salt wasting, metabolic acidosis, proteinuria, malnutrition, and anemia (3,13).
Metabolic acidosis is widely recognized as a cause of poor growth, and consensus guidelines recommend maintaining serum bicarbonate ≥22 mEq/L in children with CKD (2,14). There are several hypothesized mechanisms. Animal models suggest that acidosis activates catabolic pathways, leading to impaired muscle development (15) and protein wasting (16), and increased inflammation and cytokine release (17,18). Acidosis disrupts the somatotropic hormone axis, including reduced expression of IGF-1 and GH receptors, reduced IGF-1 levels and resistance to GH secretion, and reduced cellular proliferation at skeletal growth plates (19⇓⇓–22). However, few pediatric studies have examined whether metabolic acidosis is independently associated with growth failure in children with CKD (23⇓–25).
In this issue of Kidney360, Brown et al. (26) seek to characterize better the effect of metabolic acidosis, and treatment with alkali therapy, on linear growth in a large cohort of children with CKD in a longitudinal observational cohort study. The authors analyzed data from the Chronic Kidney Disease in Children (CKiD) study—a prospective, multicenter cohort of children with mild-moderate kidney impairment (eGFR 30–90 ml/min per 1.73 m2) (27). The authors included 1082 children 2–20 years of age, stratified by CKD diagnosis: nonglomerular (n=808) and glomerular disease (n=274). Serum bicarbonate was used as a surrogate marker of metabolic acidosis, defined as normal (≥22 mEq/L), low (19–22 mEq/L), and very low (≤18 mEq/L); height z score was the primary outcome. Adjusted analyses were reported using repeated-measures linear regression models, controlling for relevant demographic variables (age, sex, abnormal birth history, mid-parental height), eGFR (measured, if available), proteinuria, abnormal calcium or phosphate, intact parathyroid hormone, and CKD duration (years).
The authors reported four principal findings: (1) low and very low serum bicarbonate levels are associated with reduced height at baseline; (2) low and very low serum bicarbonate levels are associated with worse height z scores in children with CKD due to nonglomerular disease but not in glomerular disease; (3) metabolic acidosis has a greater adverse effect on height among children with nonglomerular disease and eGFR <45 ml/min per 1.73 m2; and (4) among children ≤13 years of age (i.e., prepubertal), treatment with alkali therapy is positively associated with improved growth.
Strengths
We have summarized the results of prior studies examining the effect of metabolic acidosis and/or its treatment on growth in children since 1975 (23⇓–25,28⇓⇓⇓⇓⇓⇓⇓⇓–37) (Table 1). Current evidence regarding metabolic acidosis and its association with growth impairment is mainly limited to populations with renal tubular acidosis (23,28⇓⇓⇓⇓⇓–34,37) and has not been longitudinally studied in children with CKD. The study by Brown et al. (26) aims to fill this knowledge gap and reports novel findings that treatment of metabolic acidosis with alkali therapy improves growth in children with CKD.
Summary of pediatric studies of association between metabolic acidosis and linear growth in children with or without CKD
The other strength is the uniqueness of the CKiD study, in which data are collected across 50 centers in North America, representing a heterogeneous, ethnically diverse population of children (27). These data increase the generalizability of the results obtained, which has been an important limitation of previous single-center studies (28⇓⇓⇓⇓⇓⇓–35,37).
Finally, the study findings draw particular attention to the undertreatment of metabolic acidosis in children with CKD in this cohort. Despite consensus recommendations to maintain normal serum bicarbonate levels, alkali therapy was reported in only 34% (122/360) of children with nonglomerular disease and 16% (16/97) of children with glomerular disease with low or very low serum bicarbonate levels (<22 mEq/L). Poor medication adherence has previously been reported in children with CKD and is recognized as an important modifiable factor in improving growth (38). This finding suggests that under-recognition and/or undertreatment of metabolic acidosis contributes to short stature in adults with a history of CKD in childhood.
Limitations
The main limitations reflect the challenge of studying growth in children with CKD using an observational study design. Growth impairment in children with CKD is multifactorial and highly complex. The authors performed adjusted analyses to account for relevant comorbidities but were limited by the availability of data for some variables, including measured GFR and nutrition status.
Another important limitation of the study is that time-varying effects of confounders, especially GFR, could not be accounted for in the analysis. Previous studies in children with CKD have shown that worsening GFR is associated with worsening acidosis (36,39); furthermore, acidosis has also been associated with CKD progression (36,40⇓–42). In addition, measured GFR was missing in approximately half of the cohort. Although measuring GFR is often impractical and resource intensive (3,43⇓–45) in children, eGFR is less accurate at higher severity of CKD due to increased tubular secretion of creatinine, and measured GFR remains the gold standard (46). To address some of these limitations, the authors performed additional analyses in which GFR was analyzed as an effect modifier. In this analysis, both eGFR and measured GFR were stratified into two categories—≥45 and <45 ml/min per 1.73 m2—to examine further the association between metabolic acidosis and height within GFR groups. Results showed that in children with nonglomerular disease, low and very low serum bicarbonate levels were associated with impaired growth at GFR <45 ml/min per 1.73 m2 only. However, using measured GFR, very low serum bicarbonate levels was associated with impaired growth in both GFR categories. The study findings were unchanged and remained nonsignificant in children with glomerular CKD. Although CKD duration was included as a covariate, children with glomerular diseases were older, had a shorter duration of CKD, and were generally taller, which could explain the discrepant results. These supplemental analyses suggest that the true effect of CKD in the analyses requires further study.
The authors also noted that only 10% of the children in the overall cohort were using GH during the study period. However, sensitivity analysis excluding children treated with GH did not yield different results in children with nonglomerular disease. Other important covariates were not reflected in the study. Although mid-parental height was included in adjusted analyses, the authors do not account for prenatal factors and syndromic short stature (1,35). There was also limited nutritional data in the study. Although only 4% of the cohort was underweight by body mass index, nutritional management undoubtedly serves an important role in the management of children with CKD and impaired growth (47⇓⇓–50). Anemia is also an important contributor to impaired growth (51,52), and anemia severity may be affected by metabolic acidosis (53). Although the authors note that there were significantly higher rates of anemia in the very low bicarbonate group, this was not accounted for in the adjusted models. Finally, although calcium, phosphate, and intact parathyroid hormone were included in the adjusted models, the authors were not able to report on vitamin D data and other hormonal disturbances (i.e., hypothyroidism), which all play a role in adequate growth in children with CKD (54).
Conclusions
Despite these limitations, this study by Brown et al. (26) presents clinically relevant evidence of the deleterious effect of metabolic acidosis on growth in children with CKD. The study also underscores the importance of alkali therapy on improved growth in this cohort. This relatively inexpensive, well-tolerated, and conservative approach to optimizing linear growth can have a profound effect on long-term morbidity and social integration in this population (14,55,56).
Larger observational studies, accounting for time-varying comorbidities, will further strengthen our understanding of the effect of metabolic acidosis in CKD. Future randomized controlled trials studying the potential dose-dependent effects of alkali therapy on linear growth are also needed.
Future studies should also assess the effect and treatment of metabolic acidosis on other CKD comorbidities. Previous evidence suggests that acidosis may contribute to CKD progression and other nutritional parameters (23,36,40,55,57); small studies have also shown that alkali therapy may improve nutritional status and quality of life (41). Furthermore, studies are needed to examine the effect of acidosis on neurodevelopmental and patient-reported outcomes, including quality of life and mental health.
Children with CKD and their families face tremendous physical and psychosocial burdens. Growth impairment is well-established in children with CKD and results in significant morbidity. Treatment of metabolic acidosis may be a particularly effective option for improving outcomes in this population.
Disclosures
All authors have nothing to disclose.
Funding
None.
Acknowledgments
The content of this article reflects the personal experience and views of the author(s) and should not be considered medical advice or recommendations. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or Kidney360. Responsibility for the information and views expressed herein lies entirely with the author(s).
Author Contributions
R. Chanchlani was responsible for methodology and supervision; and both authors wrote the original draft of the manuscript and reviewed and edited the manuscript.
Footnotes
See related article, “Longitudinal Associations between Low Serum Bicarbonate and Linear Growth in Children with Chronic Kidney Disease” on pages 666–676.
- Received February 4, 2022.
- Accepted March 9, 2022.
- Copyright © 2022 by the American Society of Nephrology
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