617 - Associations of Height Velocity with Markers of Mitochondrial Function in Children with CKD

Publication Number: 617.3848

Amy J. Kogon, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States; Walter Faig, Childrens Hospital of Philadelphia, Chicago, IL, United States; Matthew B. Matheson, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States; Ramachandran Vasan, UT School of Public Health, San Antonio, San Antonio, TX, United States; Bradley A. Warady, Children's Mercy, Kansas City, MO, United States; Susan L. Furth, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Babette S.. Zemel, CHILDREN'S HOSPITAL OF PHILADELPHIA, PHILADELPHIA, PA, United States; Michelle Denburg, Children's Hospital of Philadelphia, Philadelphia, PA, United States

Background: Short stature occurs in 33% of children with chronic kidney disease (CKD) and associates with morbidity and mortality. Growth depends on efficient mitochondrial oxidative phosphorylation to produce ATP. We previously showed that growth differentiation factor 15 (GDF-15), a member of the transforming growth factor-β superfamily produced in response to impaired mitochondrial oxidative phosphorylation capacity, associated with impaired height velocity in children with CKD. Metabolomic studies offer a novel approach to identify relationships between mitochondrial function and growth.

Objective: To determine if GDF-15 associates with metabolites involved in mitochondrial function and mediates the relationship between energy metabolism and height velocity in children with CKD.

Design/Methods: Plasma metabolites (Metabolon) and GDF-15 levels were measured in plasma samples obtained at the 6-month, 2- and 4-year visits after enrollment in the Chronic Kidney Disease in Children (CKiD) study. Seventy-seven metabolites were chosen a priori based on their involvement in mitochondrial function. Annualized height velocity measures were converted to age- and sex-specific z-scores. GEE models with exchangeable correlation structure determined the associations of height velocity z-scores with standardized metabolite levels and GDF-15 levels, respectively, adjusting for age, sex, diagnosis (glomerular vs. non-glomerular), estimated glomerular filtration rate (GFR) and urine protein: creatinine ratio. To determine if GDF-15 mediates the relationships between metabolites and height velocity, GEE models of the associations between height velocity and the metabolites were compared to models which also included GDF-15. An FDR adjusted p-value < 0.05 was considered significant.

Results: There were 600 person-visits with GDF-15 data and 1,336 visits with metabolite levels (Table 1). Eight metabolites significantly associated with GDF-15. Twenty metabolites, primarily in the fatty acid metabolism pathway, significantly associated with height velocity (Table 2). Thirteen metabolites no longer significantly associated with height velocity after adjustment for GDF-15, suggesting that GDF-15 mediates the relationship between these metabolites and growth (Table 3).

Conclusion(s): Based on associations of height velocity with GDF-15 and metabolites involved in energy metabolism, these results suggest a relationship between impaired mitochondrial function and growth outcomes in children with CKD. Future work will interrogate specific metabolic pathways to understand the mechanisms by which altered metabolism interferes with growth.

Table 1. Descriptive Table for the 6-month visit


Table 2. Significant associations between metabolite levels with height velocity z score and GDF-15, adjusting for age, sex, CKD diagnosis, eGFR and urine protein: creatinine ratio.


Table 3. Metabolites that lose association with Growth velocity when accounting for GDF-15 in models, adjusting for age, sex, CKD diagnosis, eGFR and urine protein: creatinine ratio.