Optimizing growth in pediatric renal transplant recipients: An update

Abstract

Growth retardation is a significant complication observed in pediatric renal transplant recipients, originating from a multifactorial etiology. Factors contributing to growth impairment encompass pre-transplant conditions such as primary kidney disease, malnutrition, quality of care, growth deficits at the time of transplantation, dialysis adequacy, and the use of recombinant human growth hormone. Additionally, elements related to the renal transplant itself, such as living donors, corticosteroid usage, and graft functioning, further compound the challenge. Although renal transplantation is the preferred renal replacement therapy, its impact on achieving final height and normal growth in children remains uncertain. The consequences of growth delay extend beyond the physiological realm, negatively influencing the quality of life and social conditions of pediatric renal transplant recipients, and ultimately affecting their educational and employment outcomes. Despite advancements in graft survival rates, growth retardation remains a formidable clinical concern among children undergoing renal transplantation. Major risk factors for delayed final adult height include young age at transplantation, pre-existing short stature, and the use of specific immunosuppressive drugs, particularly steroids. Effective management of growth retardation necessitates early intervention, commencing even before transplantation. Strategies involving the administration of recombinant growth hormone both pre- and post-transplant, along with protocols aimed at minimizing steroid usage, are important for achieving catch-up growth. This review provides a comprehensive outline of the multifaceted nature of growth retardation in pediatric renal transplant recipients, emphasizing the importance of early and targeted interventions to mitigate its impact on the long-term well-being of these children from birth to adolescence.

Key Words: Growth; Pediatric; Chronic kidney disease; Renal transplant recipients; Recombinant human growth hormone

Core Tip: Growth retardation is a notable challenge among pediatric kidney transplant recipients. Key risk factors for delayed final adult height include early age at transplantation, pre-existing short stature due to chronic kidney disease and dialysis, and the use of certain immunosuppressive drugs, particularly steroids. To effectively manage growth retardation, early intervention is crucial, ideally beginning before transplantation. Important strategies include administering recombinant growth hormone both before and after the transplant, optimizing nutrition, and employing protocols designed to minimize steroid use. These approaches offer the best chances for achieving catch-up growth in renal transplant recipients.

INTRODUCTION

Children with chronic kidney disease (CKD) endure frequent hospitalizations and ongoing treatment, which significantly affect their quality of life. One of the most noticeable effects of CKD in children is poor growth, with stunted height being a common sign of chronic malnutrition. Growth assessment involves regularly measuring weight and height/length and comparing these against z-score charts, along with other anthropometric indicators like head circumference and mid-upper arm circumference. Data from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry shows that over 35% of children enrolled had stunted growth at the time of admission, with growth impairment being more severe in younger children (58% in those aged under 1 year, compared to 22% in those aged over 12 years). Additionally, the same data revealed that growth impairment worsens as the severity of the disease increases. Although recent advances in science have enabled better outcomes for children with CKD, in resource-limited settings, numerous children are still deprived of achieving optimal growth owing to the disease and its related factors.

Stunting is a key indicator of chronic growth impairment in children. A study by Wong et al[1] in the United States Renal Data System found that each SD decrease in height among children with stage V CKD is linked to a 14% increase in the risk of death[1]. Similarly, research by Furth et al[2] using data from the NAPRTCS indicated that children with a height standard deviation score (SDS) of -2.5 face a relative hazard of death of 2.07.

Stunting also correlates with increased hospitalizations. A study in the United States followed 1112 pediatric patients with end-stage renal disease from 1990 to 1995. It showed that children with severe or moderate growth failure had higher hospitalization rates compared to those with normal growth. Specifically, the relative risk for hospitalization was 1.14 (95%CI: 1.1-1.2) for those with moderate growth failure and 1.24 (95%CI: 1.2-1.3) for those with severe growth failure, even after adjusting for age, sex, race, cause, and duration of end-stage renal disease, and treatment type[2] (dialysis or transplant).

The growth of a child significantly affects his/her psychological and overall well-being as an adult. Short children are often embarrassed by peers, and it has been observed that height influences employment status, with unemployment being more prevalent among stunted individuals. Further, marital opportunities can be fewer among stunted individuals[3]. Hence, all measures to achieve adequate growth should be attempted in children with CKD, regardless of whether they undergo transplantation.

ETIOLOGY OF STUNTING

Growth failure in CKD arises from various factors, including intrauterine growth restriction, genetic influences like parental height and primary kidney disease, premature birth, and malnutrition, particularly in children with congenital kidney conditions. Additional contributors to stunted growth in CKD include CKD-mineral and bone disorder, metabolic acidosis, anemia, electrolyte imbalances, and hormonal disruptions.

A significant issue in CKD-related growth failure is reduced sensitivity to growth hormone (GH), which leads to a deficiency of functional insulin-like growth factor 1, partly because of decreased GH receptor expression in key organs like the liver. This reduced sensitivity is further exacerbated by disruptions in GH receptor signaling pathways, such as Janus kinase 2 and signal transducer and activator of transcription 5, which are inhibited by inflammation-induced suppressor of cytokine signaling. In addition, the overproduction of IGF-binding proteins, which increases IGF binding capacity, also contributes to the problem.

Moreover, uremia-related inhibitors, such as angiotensin II, and steroid treatments can interfere with the release of hypothalamic gonadotropin-releasing hormone, leading to lower levels of bioactive luteinizing hormone, which causes hypogonadism and reduced growth during puberty. Follicle-stimulating hormone and parathyroid hormone also play roles in this complex hormonal imbalance, contributing to growth failure in CKD.

Furthermore, the quality of medical management, including the adequacy of dialysis, significantly influences the likelihood of achieving optimal height in children with CKD. Proper treatment and management strategies are crucial to address these interconnected factors and improve growth outcomes (Table 1).

Table 1 Factors contributing to growth failure in children with chronic kidney disease and undergoing transplantation.

Factors
Genetic
Parental height
Sex
Syndromic kidney disease
Birth related
Prematurity
Small for gestational age
Intensive care requirement
Comorbidities
Other organ involvement
Including liver, heart
Age at onset of CKD
Severity of CKD and residual renal function
Metabolic disturbances
Salt and water metabolism
Metabolic acidosis
CKD-mineral bone disorder
Anemia
Malnutrition
Contributed by anorexia, Vomiting, altered taste sensation, nutrition losses, dietary restrictions
Protein-energy wasting
Infection and inflammation
Uremic toxins
Oxidative stress
Inflammatory cytokines
Hormonal disturbances affecting
Somatotropin hormone axis
Gonadotropic hormones axis
Gastrointestinal hormones

CKD: Chronic kidney disease.

INTERVENTIONS TO PREVENT POOR GROWTH

Early recognition of growth failure

Early recognition of the risk of growth faltering can significantly improve the effectiveness of interventions. An audit conducted in 2018 found that although 60% of patients undergoing renal replacement therapy or who had recently received a kidney transplant exhibited growth failure[4], only two of these patients were referred for GH therapy. When growth monitoring became a routine part of the healthcare process, the identification of growth issues increased to 80%[4].

Adding growth monitoring charts to regular clinical notes can enhance attention to growth tracking, potentially leading to improved height outcomes in children with CKD and those who have undergone kidney transplantation.

Maximizing nutritional support and early proactive enteral feeding

Filling energy gaps through various methods is crucial to meet the energy needs of chronically ill children. Providing nutritional counseling from the early stages of the disease and maintaining regular follow-ups with a nutrition team can have a positive impact on growth. It is vital to introduce supplementary feeding options early when oral intake is insufficient to support optimal growth.

A retrospective study involving 50 pre-pubertal children over the age of 2 years with CKD stages 2-5, who were awaiting kidney transplants, assessed the impact of enteral feeding using nasogastric or gastrostomy tubes. Height and weight measurements were taken after 1 year and 2 years. The study showed that the overall height SDS improved from -2.39 to -2.27 after 1 year and to -2.18 after 2 years (P = 0.02). The body mass index (BMI) SDS increased from -0.72 to 0.23 after 1 year and to 0.09 after 2 years of enteral feeding (P < 0.0001). Notably, the BMI remained stable without any signs of excessive weight gain[5].

Children with CKD often complain of loss of appetite and early satiety. Chronic inflammation caused by CKD, associated uremia, psychological factors such as depression and anxiety, and frequent hospital and clinic visits are among the many causes contributing to this, leading to suboptimal food intake. Early intervention, as mentioned above, helps to bridge the nutrient gap between intake and requirements, promoting better growth.

While tube feeding may be considered invasive, it can be better received by families and children when the child’s condition is stable. Early nutritional counseling and discussions about the possible requirement for tube feeding can help parents and caregivers become more accustomed to the concept, reducing cultural resistance. The same study also revealed that younger children and those not yet undergoing dialysis showed improved growth outcomes. This highlights the significance of initiating enteral feeding proactively in early childhood, when growth velocity is at its peak, before the disease progresses to more severe stages[5].

Use of recombinant human GH

Numerous studies have established the effectiveness of recombinant human GH (rhGH) in treating stunting in children with CKD. In a study by Modini and Seikaly[6], children treated with rhGH experienced a significantly higher height velocity compared to controls after 1 year. Similarly, a meta-analysis by Vimalachandra et al[7] indicated that the rhGH treatment group showed a trend toward a greater increase in height SDS. Moreover, a review of the NAPRTCS database revealed that the rhGH group had a steeper slope in the change in height SDS[8], demonstrating a more pronounced growth response. The catch-up growth achieved with rhGH is more pronounced in children with CKD, both in non-dialysis and dialysis patients, compared to those who have already received a transplant. This finding underscores the importance of early intervention to optimize height outcomes following transplantation.

rhGH may be considered for children with CKD who have been on dialysis for more than 6 mo and meet certain criteria, such as having short stature (below the 2^nd percentile), being significantly shorter than expected based on mid-parental height (more than three centile spaces below the mid-parental height centile), or experiencing slow growth (a drop in height of more than one centile space)[9]. Additionally, rhGH can be initiated in children who have received a kidney transplant but continue to experience growth failure after 1 year, especially in cases where a steroid-free immunosuppression regimen is not feasible. Another indication for rhGH therapy is in children with chronic renal failure due to nephropathic cystinosis who show persistent stunting[10].

rhGH has the potential to address GH insensitivity when administered at supra-physiological doses, stimulating IGF1 production, normalizing somatomedin activity, supporting longitudinal growth, and potentially improving adult height outcomes. However, rhGH treatment is not recommended for patients who have the following conditions[9]: (1) Severe secondary hyperparathyroidism with parathyroid hormone levels exceeding 500 pg/mL; (2) Closed epiphyses, indicating that the growth plates are no longer active; (3) A known allergy or hypersensitivity to the active ingredient or any other component in the medication; (4) Proliferative or severe non-proliferative diabetic retinopathy; and (5) Within the 1^st year after a kidney transplant.

Before starting rhGH therapy, it is essential to make the following assessments: (1) Regularly measure the patient’s height (or supine length for those under 2 years old). Considering the child’s age and CKD stage, calculate the height velocity over at least 6 mo and compare it with standardized growth charts; (2) Assess the child’s pubertal status to understand their developmental trajectory; (3) Evaluate growth potential by calculating the genetic target height using the parents’ heights and analyzing the left wrist’s epiphyseal status through radiography. It is important to note that adult height prediction methods are not suitable for children with CKD; (4) Consider factors such as age, primary kidney disease, other systemic conditions, CKD stage, adequacy of dialysis (for those on dialysis), graft function, and use of glucocorticoids (for post-transplant patients) when determining the appropriateness of rhGH therapy.

Before starting rhGH therapy, it is crucial to address other CKD-related issues that can limit growth, such as protein-calorie malnutrition, metabolic acidosis, electrolyte imbalances (like hyponatremia), dehydration, and mineral imbalances, including secondary hyperparathyroidism. Proper management of these conditions is essential for maximizing the benefits of rhGH therapy. If the height velocity in the 1^st year of rhGH treatment is less than 2 cm per year above baseline, we recommend checking patient adherence to rhGH therapy, including measuring IGF-1 Levels, ensuring the weight-adjusted rhGH dosage is correct, and evaluating nutritional and metabolic factors as recommended prior to starting rhGH therapy.

rhGH therapy should be discontinued in the following situations: (1) At the time of renal transplantation; (2) In patients with persistent severe secondary hyperparathyroidism, with parathyroid hormone levels exceeding 500 pg/mL; (3) If the patient develops a slipped capital femoral epiphysis; (4) If the patient shows no significant response to rhGH therapy despite optimal nutrition and metabolic management; (5) If there is accelerated bone maturation; or (6) If an unexplained drop in estimated glomerular filtration rate occurs.

Addressing potentially modifiable factors

Enhancing treatment protocols for kidney diseases and providing high-quality care, including adequate dialysis, can significantly affect growth outcomes[11]. More frequent and intensive dialysis sessions, such as daily online hemofiltration, which increases convective flow and uses ultrapure dialysate, can reduce cachexia and promote growth both before and after transplantation[11].

Other aspects of the treatment program also play a role in promoting growth. These include live donor transplants and minimizing steroid use after transplantation[12]. These factors have been identified as contributing to improved growth outcomes.

CONCLUSION

With advances in medical science and technology, more children with CKD are surviving and receiving kidney transplants. Ensuring these children achieve their maximum growth potential is crucial for enhancing their quality of life. Identifying growth faltering at its inception and addressing the diverse nature of malnutrition is essential. Achieving optimal growth before transplantation strongly predicts better growth after the procedure. Meticulous growth monitoring, timely nutritional interventions, judicious use of rhGH therapy, and a steadfast focus on growth-friendly medical approaches are vital components in the management of children with CKD and those undergoing transplants. These practices help to ensure that children reach their best possible growth outcomes.