53 - Growth Differentiation Factor 15 and Linear Growth in Children with Chronic Kidney Disease

We previously showed that metabolites involved in energy metabolism significantly associate with height and short stature in children with chronic kidney disease (CKD). Growth depends on efficient mitochondrial oxidative phosphorylation to produce ATP.  Growth differentiation factor 15 (GDF-15), a member of the transforming growth factor-β superfamily, is produced in response to impaired mitochondrial oxidative phosphorylation capacity. In animal models, GDF-15 has been shown to impair growth through interference with growth hormone signaling in the liver. We hypothesized that in children with CKD, GDF-15 levels would associate with short stature and impaired linear growth.

Objective:

To determine the associations of GDF-15 with height Z-score, short stature, height velocity Z-score and impaired height velocity in children with CKD.

Design/Methods:

GDF-15 levels were measured in plasma samples obtained at the 6-month, 2-year and 4-year visits after enrollment into the Chronic Kidney Disease in Children (CKiD) cohort study. Height Z-scores were calculated for each visit concurrent with GDF-15 determinations. Short stature was defined as Z-score < -1.88.  Height velocity Z-score and impaired height velocity (Z-score< -1.88) were based on the calculated annualized height velocity from the baseline to 1 year visit for GDF-15 levels from the 6-month visit, and over the year following the 2- and 4-year visits for the GDF-15 levels at these visits. GEE models with exchangeable correlation structure were used to determine the associations of GDF-15 (in quartiles) with growth outcomes, after adjustment for age, sex, diagnosis (glomerular vs. non-glomerular), estimated glomerular filtration rate (GFR) and urine protein: creatinine ratio.

Results:

Table 1 shows participant characteristics at the 6-month visit (n=278).  Table 2 shows the results for the multivariable GEE modeling of GDF-15 associations with outcomes. Higher GDF-15 levels associated with lower height Z-score, short stature, lower height velocity Z-score and impaired height velocity. The highest GDF-15 quartile was associated with a 0.15 shorter height Z-score (p=0.04), 0.74 lower height velocity Z-score (p=0.007), and a 6.2-fold greater odds of impaired height velocity (p=0.0006).

Conclusion(s):

GDF-15 significantly associates with height and height velocity in children with CKD. GDF-15 may be a novel biomarker for, and mechanistically linked to, impaired linear growth in children with CKD.