Medication Adherence and Growth in Children with CKD

Discussion

Nonadherence to prescribed treatment regimens is a major concern in the management of all chronic pediatric illnesses (11,12). However, there has been little investigation of the role that nonadherence plays in the outcomes of children with CKD (20). Growth impairment is a unique manifestation of pediatric CKD with major implications for quality of life, morbidity, and mortality during childhood and beyond (4,6,7). Despite the ability to modify many of the factors that contribute to growth delay, outcome studies demonstrate that optimal adult height is often not achieved in patients diagnosed with CKD during childhood (23,28). Thus, investigation of under-recognized risk factors for growth delay in pediatric CKD is critically important.

In this study utilizing the CKiD cohort, we reported the longitudinal use of prescribed medication groups that may affect growth velocity in pediatric patients with CKD. Active vitamin D was the most commonly prescribed medication across all visits, and the frequency of its use increased over time, which may be reflective of CKD progression. Of note, active vitamin D was used nearly twice as frequently as phosphate binders, which may reflect earlier changes in parathyroid hormone compared with serum phosphorus in the course of CKD. Iron supplements and alkali were the second and third most frequently prescribed medication groups, respectively. These frequency patterns are consistent with data from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) (29). We observed the use of iron supplementation to be almost twice that of ESAs over time (Figure 1). This difference was not previously reported by NAPRTCS (29). Thus, further investigation of the prevalence of iron deficiency in the CKiD cohort in relation to the use of iron supplementation adjusted for nonadherence may be warranted.

The reported frequency of rhGH use was higher in the CKiD study (9.0% at study entry) compared with NAPRTCS (6.2% at entry, averaged for 1994–2007) despite the children in the NAPRTCS CKD cohort being markedly shorter than the children in the CKiD cohort (baseline height z scores of −1.44 versus −0.68, respectively). This may reflect a shift in the treatment philosophy of the pediatric nephrology community in the past decade toward earlier use of rhGH in children with CKD. In addition, the prevalence of rhGH use increased slightly over time in the CKiD cohort (Figure 1).

It is concerning that adherence worsened over time for some of the medication groups (Figure 2). In future analyses, it would be warranted to characterize the subgroup of CKiD study participants who were persistently nonadherent versus those who became nonadherent later in the study.

We observed substantial variability of nonadherence between individual classes of medications over time. Nonadherence to nutritional vitamin D was the highest, followed by phosphate binders. Nutritional vitamin D may be viewed as optional by some families because it is purchased over the counter. It may also require out-of-pocket payment and may be difficult for low-income families to afford. Phosphate binders need to be taken with meals three times per day, a requirement that presents unique challenges for adherence, as previously documented in other pediatric cohorts. Nonadherence to ESAs and rhGH was 4% and 17%, respectively, over all person-visits in which these medications were prescribed. This striking difference in the rates of nonadherence to two injectable medications may possibly be related to the differences in time required to see the effects of these therapies. Although missing ESA injections may result in a rapid drop in hemoglobin and potentially a need for transfusion, nonadherence to rhGH injections does not result in any easily detectable effect for months. In addition, the effect of therapy with rhGH may be seen as cosmetic to some, in contrast with ESAs, which may have a more obvious and crucial effect on health. Finally, rhGH requires daily injections, whereas ESAs may be prescribed from three times per week to once a week. Hence, rhGH is likely more burdensome and presents more frequent opportunities for nonadherence each week.

We found that patients reporting nonadherence to rhGH had on average no change in height z score, whereas adherent patients experienced improvement of growth velocity. To the best of our knowledge, this is the first formal evidence that confirms the critical role of adherence with rhGH in achieving improved growth outcomes. Furthermore, our results indicate that a simple method of adherence assessment with a single question based on self-report may be effective in identifying those children who would likely grow poorly. This sets the stage for a possible interventional quality assurance program to improve adherence and growth based on simple screening.

Assessment of potential causes of nonadherence to rhGH and other medications was beyond the scope of this study. Our multivariate analysis demonstrated, however, that index values of height and GFR, along with CKD diagnosis, percentage of life with CKD, sex, age, race, family income, and maternal education did not modify the observed association between nonadherence and poor growth. There is a perception that shorter children may be more motivated to take rhGH because of peer concerns; however, this was not supported by our data, because there was no difference in nonadherence among those with height z scores≤3rd percentile versus >3rd percentile. More detailed analysis of the possible association between socioeconomic status, medication nonadherence, and growth is warranted, especially in light of the recent data regarding linear growth in children of low socioeconomic status (30,31). Analysis of parental and patient self-perceived barriers to adherence may provide additional clues and help to develop an effective intervention.

Surprisingly, there was no significant association between growth velocity and nonadherence with other groups of medications, particularly alkali, active vitamin D, and PO4 binders. It is well accepted that CKD–mineral bone disorder contributes to growth delay in CKD. However, limited research has been conducted to formally assess the magnitude of the effect that interventions to correct these comorbidities have on growth. In the available studies, serum phosphorous, calcium, albumin, and parathyroid hormone levels were poor predictors of short stature (32–36). Thus, it is possible that some of the current treatment strategies are ineffective in improving growth or that self-reported nonadherence does not necessarily identify a substantial enough degree of medication nonadherence to affect growth. Therefore, further study to evaluate the effect of various degrees of nonadherence to the individual medication groups (e.g., alkali) on the corresponding clinical parameters or biomarkers (e.g., acidosis/serum bicarbonate) is warranted.

Our study has obvious limitations. Although the CKiD study is the largest pediatric prospective CKD cohort studied to date in North America, the number of patients receiving treatment with certain pharmacologic medication groups (especially ESAs and rhGH) was modest. The magnitude of nonadherence that we reported also likely underestimates the true frequency of nonadherence as demonstrated in other studies that utilized self-reporting (37). In addition, evaluation of medication adherence in the CKiD study was carried out only once a year, although the optimal frequency of evaluating medication adherence has not been established in the literature. Finally, our definition of nonadherence was dichotomous and we did not account for the severity of nonadherence (i.e., a patient that missed five doses was treated the same way as another patient who missed one dose).

In summary, we report longitudinal data on the frequency of prescribed medication use and self-reported nonadherence in the CKiD cohort. Patients adherent to treatment with rhGH therapy demonstrated greater growth velocity, especially for those with a height<3rd percentile, compared with patients who were nonadherent with this therapy. These data emphasize the fact that nonadherence must be considered and evaluated in the setting of poor and/or no response to rhGH therapy in patients with CKD. Efforts designed to determine risk factors for nonadherence and possible corrective measures may result in improved medication adherence and the opportunity for improved patient outcomes.