Anemia and Growth Impairment in Children With Nonglomerular CKD

There is a continuing increase in the prevalence of pediatric chronic kidney disease (CKD) in the United States and worldwide. Due in part to systematic complications associated with CKD, developmental outcomes and quality of life remain suboptimal, even in an era of improved survival in children with CKD, including those with kidney failure.

Despite the availability of recombinant growth hormone (rHG) therapy, growth impairment is common in this patient population. Compared with children with CKD of normal height, those with CKD and short stature have worse quality of life and higher rates of morbidity and mortality. Growth impairment in children with CKD of nonglomerular origin, the most common etiology of pediatric CKD, is greater than that in children with glomerular CKD.

According to Oleh Akchurin, MD, PhD, and colleagues, there are few data available on the role of anemia in statural growth impairment in children with CKD. To date, no longitudinal studies have shown a relationship between anemia and statural growth over time in children with mild-to-moderate CKD of nonglomerular origin, and results of cross-sectional studies examining the association between anemia and statural growth have had conflicting results

The researchers conducted an analysis to quantify the relationship between hemoglobin and statural growth in children with mild-to-moderate CKD of nonglomerular origin followed longitudinally in the Chronic Disease in Children (CKiD) cohort study. Results were reported in the American Journal of Kidney Diseases [2023;81(4):457-465].

The exposure of interest was hemoglobin z scores, calculated using the Centers for Disease Control and Prevention (CDC) age-, sex-, and race-specific mean and standard deviation. The outcome of interest was age- and sex-specific height z scores, also determined using CDC scores. Height was measured at each annual visit, and the average of two measurements was used in determining a final z score. Eligible patients were CKiD participants younger than 22 years of age with nonglomerular CKD who had not reached final adult height.

Multivariable repeated measures paired person-visit analysis and multivariable repeated measures linear mixed model analysis were used to quantify the relationship between hemoglobin and height. Both models were adjusted for age, sex, body mass index (BMI), estimated glomerular filtration rate (eGFR), acidosis, and medication use.

The analysis cohort included 510 CKiD participants. At baseline, median eGFR was 53 mL/min/1.73 m², mean age was 8.7 years, 67.8% were male (n=346), 19.6% were Black (n=95), 12.4% were Hispanic (n=63), BMI z score was 0.3, and height z score was –0.5. A total of 65 participants (12.7%) had anemia at baseline.

There were associations between lower average hemoglobin z scores and older age, lower eGFR, and a greater prevalence of use of erythropoiesis-stimulating agents (ESA) and iron therapy. During the follow-up period that included 1763 person-visits, 67% of the cohort had declining hemoglobin z-score trajectories. The average hemoglobin level was within the anemic range of 17% of person-visit pairs based on the definitions of anemia in the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on anemia in CKD.

The reference group was 10-year-old female participants with values for all covariates (average hemoglobin z score ≥0; eGFR, 50 mL/min/1.73 m²; urinary protein-creatinine ratio, 0.5 mg/mg; serum bicarbonate, 25 mmol/L, and BMI z score of 0). After adjusting for covariates, the subgroups with average hemoglobin z scores of less than –2.0, –2.0 to less than –1.0, –1.0 to less than –0.5, and –0.5 to less than 0 had relative mean height z scores that were lower than the reference group (hemoglobin z score >0) by 0.35 (95% CI, –0.62 to –0.07), 0.24 (95% CI, –0.45 to –0.02), 0.16 (95% CI, –0.37 to 0.06), and 0.18 (95% CI, –0.36 to 0.01), respectively.

Even in children with average hemoglobin levels exceeding the KDIGO-defined threshold for anemia there was an association between the average hemoglobin z score and a lower height z score. Among person-visit pairs where the average hemoglobin z scores were less than –1.0, 49.9% were considered not anemic per the KDIGO guideline.

When stratified by age, in both unadjusted and adjusted models, there was a positive relationship between the hemoglobin z score and the mean height z score among person-visits between the ages of 6 and 14 years. In the adjusted model, the association was statistically significant for ages 8, 9, and 14 years. The strongest association in the 6 to 14 years age group was for participants 9 years of age, where a 1-standard deviation increase in average hemoglobin was associated with a 0.22-standard deviation increase in height at the subsequent visit (95% CI, 0.08-0.37).

In linear mixed-effects analyses, there was an association between a change in hemoglobin z score and a concurrent change in height z score (under within-person change from baseline) in the unadjusted model in participants with an initial hemoglobin z score of less than –1.0. Following adjustment for covariates in this group, inferences remained nearly identical. Consistent with the paired person-visit analysis, there was no significant association between a decrease in hemoglobin and a concurrent change in height among participants with an initial hemoglobin z score of –1.0 or greater.

There were some limitations to the study cited by the authors, including the observational nature of CKiD that limited the ability to define hemoglobin thresholds that could be used as treatment targets based on growth outcomes; the inability to examine potential interactions of the associations between hemoglobin and growth with inflammation, iron homeostasis, rGH therapy, ESAs, and iron therapy; and the possibility that the findings were subject to unmeasured confounding.

In conclusion, the researchers said, “Hemoglobin decline is associated with statural growth impairment in children with mild-to-moderate CKD of nonglomerular origin. Hemoglobin z scores of less than –1.0 in these children should trigger an evaluation of anemia. Development of hemoglobin targets for anemia treatment in children with CKD should consider the association between hemoglobin and growth, which may result in higher hemoglobin targets than those that have been set for adults with CKD. Finally, growth outcomes should be measured in future interventional studies testing novel approaches for the treatment of anemia in pediatric CKD, especially in the preadolescent and early adolescent age groups.”

Takeaway Points

1. Researchers reported results of an analysis quantifying the relationship between hemoglobin and statural growth in children with mild-to-moderate chronic kidney disease (CKD) of nonglomerular origin.
2. The analysis utilized data on 510 participants in the CKD in Children (CKiD) study; of those, 67% had declining hemoglobin z-score trajectories over the follow-up period that included 1763 person-visits.
3. Compared with average hemoglobin z scores of ≥0, there was an independent association between average hemoglobin z scores of less than –1.0 and significant growth impairment at the subsequent study visit.