Approach to growth hormone therapy in children with chronic kidney disease varies across North America: the Midwest Pediatric Nephrology Consortium report

Growth impairment remains common in pediatric chronic kidney disease (CKD), despite advances in care of children with CKD [1]. In the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) CKD registry, 36.9% had height standard deviation scores (SDS) < −1.88 at the time of enrollment [2]. In a more recent study cohort of North American children with mild to moderate CKD, the median height SDS was −0.55 at study entry [3]. In a European cohort of patients who received renal replacement therapy during childhood, the median final adult height SDS was −1.65 [4].

Short stature is associated with a lower quality of life (QOL) in children with CKD [5], and this lower QOL persists into adulthood [6]. Treatment with recombinant human growth hormone (rhGH) is associated with improved physical and social functioning according to parental reports [7]. It would be reasonable to expect that rhGH treatment improves QOL in children with CKD, but no direct evidence is currently available to support this assumption. In addition, rhGH therapy may provide health benefits not directly related to improved linear growth, such as increased lean body mass, improved appetite and nutrition, increased physical function and decreased fatigue [8, 9]. It is unknown if pediatric nephrologists consider these potential benefits of rhGH therapy in their therapeutic decisions.

Treatment with rhGH is FDA-approved in short children with CKD in the U.S. and rhGH has been used in children with CKD for over 25 years [10]. Yet, rhGH utilization in short children with CKD is quite low in both North America and many European countries [11, 12]. Some of the reported obstacles for use of rhGH are family refusal, non-compliance, severe hyperparathyroidism, poor nutrition, younger age, neurologic impairment, malignancy or scheduled transplant [13]. However, the perspectives of pediatric nephrologists about the barriers to rhGH utilization have never been systematically investigated.

There is a paucity of high-level evidence to direct evaluation of short children with CKD prior to prescription of rhGH therapy. Requirements for diagnostic testing related to rhGH insurance approval vary, with some insurers in the U.S. only requiring a bone age for short children over 12 years old whose height is below the 3rd percentile and an estimated GFR below 75 ml/min/1.73m². The U.S. physicians have considerable discretion in determining testing prior to seeking rhGH insurance approval. The most recent consensus paper written by a group of U.S. experts is now over 10 years old [9] and suggests that optimal preparation for starting rhGH therapy requires efforts at addressing modifiable factors related to growth failure and baseline hip and knee X-rays, funduscopic evaluation, and thyroid studies. There is no consensus on the value of baseline and subsequent GH-insulin like growth factor-1 (IGF-1) axis assessments in monitoring rhGH therapy in children with CKD.

RhGH treatment, in part due to its high cost, is further complicated by the logistic challenges involved in its prescription. Insurance approval, nutritional evaluation and monitoring, management of other CKD complications (such as CKD mineral bone disorder, anemia, and acidosis), optimization of dialysis, and potential involvement of endocrinology, all require system based approaches to rhGH therapy in order to deliver well organized care within the unique environment and available resources of each individual institution. These challenges and varying resources may contribute to practice variability in the prescription of rhGH.

We hypothesized that there is substantial variability in practice patterns and resources available to support rhGH treatment among pediatric nephrology centers, which may affect treatment decisions. Hence, we analyzed the key characteristics of rhGH treatment approaches by surveying pediatric nephrologists in the US and Canada.

Survey items were developed and piloted by the Midwest Pediatric Nephrology Consortium (MWPNC) CKD working group, reviewed and approved by the MWPNC Protocol Review Committee. Institutional Review Board (IRB) approval was obtained at the primary site (Weill Cornell Medicine). The survey (Additional file 1: Item S1) was distributed to physicians by the MWPNC and American Society of Pediatric Nephrology (ASPN) from October 2015 to January 2016 via email. The MWPNC involves 60 pediatric nephrology centers who work together in collaborative pediatric nephrology research. The ASPN is the premier organization of pediatric nephrologists in North America with approximately 150 pediatric nephrology groups/centers, including all of the MWPNC sites except those in Canada. The survey was anonymous and was not offered to fellows. Data were reported as median [interquartile range (IQR)] and frequency (percent). Responses were compared between “small” (4 or fewer nephrologists per center) and “large” (more than four nephrologists) centers by the Wilcoxon rank-sum test or Fisher’s exact test, as appropriate. Centers were categorized based on the median number of nephrologists per center in the cohort. All p-values were two-sided with statistical significance evaluated at the 0.05 alpha level. All analyses were performed in SAS Version 9.4 (SAS Institute, Inc., Cary, NC).

In this study, we describe contemporary pediatric nephrology practice variability in the approaches to growth hormone therapy for short stature in children with CKD. Our analysis was based on a large sample of participating pediatric nephrology centers in North America. Availability and utilization of ancillary resources was a major variable related to the size of the practice.

Available data indicate that rhGH is under-utilized in short children with CKD in the U.S. and Europe. An earlier study conducted by the MWPNC [13] found that 51% of children with CKD whose height fell below the 5th percentile had not received rhGH. In a recent European study including 13 countries, short stature was present in 30.1% of dialysis patients and only 25.1% of these short children were receiving rhGH. Moreover, only 7.6% of the 42.3% of transplant patients with short stature were receiving rhGH [12]. Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines provide limited recommendations for treatment of short stature in pediatric CKD [14]. A group of US experts developed a consensus statement about the assessment and treatment of short stature in pediatric patients with CKD in 2006 [9]. Acceptance of this consensus by the broader pediatric nephrology community and achievement of recommended practices has not been evaluated to date.

The consensus statement suggests evaluation of bone age, hip and knee x-rays, funduscopic exam and thyroid studies prior to rhGH therapy initiation. Bone age, also required by most payers for rhGH approval for children older than 12 year., was a routine part of the workup in most of the centers in this study. Thyroid function tests were reported by less than half of study participants, and hip and knee X-rays by less than third. Ophthalmologic evaluation was very infrequent, despite benign intracranial hypertension being the most frequent observed side effect of rhGH therapy. Serum IGF1 and IGFBP3 were part of the workup in the substantial number of centers, particularly in small centers where endocrinology consultation was more frequent. Overall, our data demonstrate significant variability in approaches to the initial assessment of short children with CKD prior to rhGH treatment initiation, and in many cases substantial differences from the 2006 Consensus Statement.

This study demonstrated significant variability in practice patterns relates to practice group size and resources. The majority of participating pediatric nephrologists cared for 1–5 short children with CKD treated with rhGH, and pediatric endocrinologists managed these patients in almost half of the smaller centers. The opportunities for rhGH management may be less frequent in smaller centers, potentially due to fewer resources resulting in outsourcing to endocrinology. Thus, almost 20% of pediatric nephrologists from small centers reported that they do not have any patients treated with rhGH in their practice. Our results demonstrate various models of interaction between pediatric nephrology and endocrinology in management of short stature in children with CKD. Investigation of whether this variability results in different outcomes was beyond the scope of our study, but would be of interest in future studies.

Both KDOQI and the 2006 Consensus Statement recommend nutritional optimization prior to starting rhGH [9, 14]. Dietary management of children with CKD is complex and time-consuming [15]. Pediatric renal dietitian support seems to be the optimal solution to these challenges. Our data demonstrated that >90% of nephrologists practicing in large centers had renal dietitian support. In contrast, only half nephrologists from small centers had such support. Our study was not designed to confirm whether renal dietitian unavailability led to rhGH underutilization and outcomes differences. However, it suggests that variability in nutritional support should be considered in organizing rhGH treatment programs for short children with CKD and ensuring their success.

In our study, family refusal was the leading cause of short children with CKD not receiving rhGH. This is consistent with an earlier report [13], where family refusal accounted for 18% of short children with CKD not being treated with rhGH. This significant number of refusals may indicate a need for developing specific counseling strategies targeting the issue of refusal. Our data indicated that fear of injections was the number one reason for family refusal, followed by side effect concerns. Alleviating fear of injections seems to be a promising target in increasing use of this therapy. Systematic analysis of treatment satisfaction of children with CKD who completed rhGH therapy may reveal the actual significance of the discomfort from injections. Cost of rhGH treatment was not reported as a significant reason for refusal, but this may be different beyond North America.

Medical contraindications were the second most common reported reason for not receiving rhGH in our study. This reason was reported more frequently by nephrologists practicing in large centers, possibly due to the overall higher complexity of patients with CKD in large centers. Difficulties with insurance approval were the third leading cause for rhGH underutilization. Importantly, insurance problems were reported more frequently in small centers, again suggesting that availability of resources may be affecting care in pediatric nephrology practices. Prior authorization was obtained by the nurses in the majority of both small and large centers but differences in the scope of nephrology nurses’ responsibilities in small vs. large centers may account for some of the insurance difficulties with rhGH approval.

The majority of pediatric nephrologists indicated that rhGH therapy improves QOL of children with CKD. It is important to highlight, however, that we still do not have direct evidence of such a benefit. Short stature in CKD is associated with worse QOL, particularly in the physical functioning domain [5]. Analysis of the large cohort of north American children with CKD showed an association between rhGH use and improved child’s physical and social functioning by parental report [7]. QOL studies in children with non-CKD related short stature treated with rhGH have yielded conflicting results [16, 17]. Evidence of improved QOL with rhGH treatment in CKD is needed, as it may help to impact use of this therapy in short children with CKD. It has been suggested that rhGH therapy may provide additional benefits, such as anabolic effects [8], in children with CKD [9]. More research is needed to investigate these and other potential benefits of rhGH therapy in pediatric CKD population, which in turn may increase the number of short children with CKD taking advantage of rhGH treatment.

Our study has some limitations. The study was not designed to fully investigate the root causes of differences in rhGH management in children with CKD between institutions and individual nephrologists. There may have been a selection bias because physicians who were taking care of more children treated with rhGH (e.g., those attending CKD designated clinics, dialysis medical directors, transplant nephrologists) could have been more interested in study participation than those seeing fewer patients with advanced CKD and ESRD.

This study found substantial variation in practice between pediatric nephrologists caring for short children with CKD. Practice size appears to be a major determinant of the logistic approach to rhGH management. Fear of injections was perceived as a most common obstacle to rhGH therapy initiation. Pediatric nephrologists believe that rhGH improves QOL in children with growth failure and CKD. Our data suggests that opportunities are available to standardize care to improve growth outcomes in children with CKD.