Growth and development following paediatric kidney transplantation: Mechanisms, influencing factors, and clinical management

Abstract

Paediatric kidney transplantation substantially improves survival and quality of life in children with end-stage kidney disease. However, impaired linear growth and broader developmental challenges remain common after transplantation. This article provides an evidence-based narrative review of the mechanisms, clinical determinants, monitoring strategies, and management options for post-transplant growth and development in paediatric kidney recipients, with particular emphasis on the growth hormone (GH)-insulin-like growth factor 1 axis, graft function, immunosuppression, nutrition, GH therapy, and long-term follow-up. Current evidence indicates that post-transplant growth is influenced by age at transplantation, pretransplant growth status, graft function, cumulative corticosteroid exposure, nutritional and metabolic status, and the selective use of recombinant human GH. Younger age at transplantation and steroid-sparing strategies are consistently associated with better height outcomes, whereas chronic graft dysfunction, persistent inflammation, and metabolic complications may attenuate catch-up growth. Emerging biomarkers and precision-medicine tools are promising, but most remain insufficiently validated for routine growth-focused decision-making. Optimising growth after paediatric kidney transplantation requires early transplantation when feasible, preservation of graft function, careful balancing of rejection prevention against growth toxicity, multidisciplinary nutritional and endocrine support, and structured long-term follow-up. The evidence base is expanding, but high-quality multicentre longitudinal studies are still needed.

Key Words: Paediatric kidney transplantation; Growth and development; Growth hormone; Immunosuppression; Graft function; Narrative review

Core Tip: Paediatric kidney transplantation markedly improves survival in children with end-stage kidney disease, yet post-transplant growth and developmental impairment remain a major challenge. This review highlights the multifactorial mechanisms underlying poor growth after paediatric kidney transplantation, including immunosuppressive exposure, incomplete renal recovery, nutritional deficits, and transplant-related complications. It further summarises emerging predictive models and personalised interventions, emphasising early transplantation, steroid-sparing or optimised immunosuppressive strategies, and careful use of growth hormone as key approaches to improve long-term growth and developmental outcomes.

INTRODUCTION

Chronic kidney disease (CKD) in children is frequently accompanied by growth failure. This complication affects not only physical health but also quality of life and psychological well-being. The mechanisms underlying growth impairment in CKD are complex and include mineral and bone metabolism disorders, metabolic acidosis, malnutrition, and abnormalities of hormonal axes. For example, CKD-mineral and bone disorder is an important pathological basis for growth impairment in children and may involve structural and functional abnormalities of the growth plate that disrupt normal skeletal development[1]. In addition, growth hormone (GH) resistance is common in patients with CKD and may inhibit key regulators of the GH signalling pathway, including suppressor of cytokine signalling 2, which is closely associated with restricted growth in children[2].

Kidney transplantation is the preferred treatment for children with end-stage kidney disease because it prolongs survival and can substantially improve growth and developmental outcomes. Multiple studies have shown increases in height standard deviation scores (SDSs) after transplantation, with particularly pronounced catch-up growth in children younger than six years[3,4]. Nevertheless, post-transplant growth recovery varies between individuals and is closely related to age at transplantation, pretransplant nutritional status, and immunosuppressive regimen. Although immunosuppression is essential for preventing rejection, long-term glucocorticoid exposure may inhibit skeletal growth and impair GH-axis function[3]. Immunosuppressive agents may also affect bone metabolism and mineral balance through several pathways, contributing to persistent post-transplant mineral and bone disorders that limit further improvements in growth and development[5,6].

Growth and development after paediatric kidney transplantation are shaped by disease-related, treatment-related, socioeconomic, and psychosocial factors. Children from lower socioeconomic backgrounds or less supportive living environments may have poorer cognitive and growth outcomes, suggesting that comprehensive care should include attention to overall quality of life[7]. Long-term post-transplant management should also address psychosocial adaptation. A supportive family environment and robust social support can improve quality of life and treatment adherence[8]. Table 1 and Figure 1 summarize the review scope and evidence synthesis approach.

Figure 1 Conceptual framework of mechanisms and modifiable factors influencing post-transplant growth and development in paediatric kidney transplantation. CKD: Chronic kidney disease; GH: Growth hormone; MBD: Mineral and bone disorder; IGF-1: Insulin-like growth factor-1; SDS: Standard deviation scores; rhGH: Recombinant human growth hormone.

Table 1 Representative studies relevant to post-transplant growth and development in paediatric kidney transplantation.

Ref.	Design/population	Domain	Key findings relevant to growth	Main implication
Yu et al[4], 2025	Single-centre cohort; paediatric kidney transplant recipients in China	Long-term growth outcomes	Height-for-age z-score improved after transplantation; transplant age and height at transplantation influenced later stature	Supports early transplantation and long-term graft preservation
Noguchi et al[28], 2022	Retrospective single-centre cohort; 60 transplants	Catch-up growth	Catch-up growth was more likely in younger recipients and was negatively affected by rejection episodes	Age at transplantation and rejection control matter for growth recovery
Kizilbash et al[23], 2022	Review of steroid avoidance/withdrawal strategies	Immunosuppression	Steroid minimisation did not consistently increase acute rejection in modern regimens and was associated with better growth and metabolic profiles	Favours steroid-sparing protocols in suitable low-risk children
Tourlamain et al[43], 2023	Paediatric kidney transplant recipients	Corticosteroid exposure	Early corticosteroid withdrawal was associated with improved adult height outcomes	Cumulative steroid exposure remains clinically relevant for linear growth
Jagodzinski et al[48], 2022	Prospective two-centre paediatric cohort	Growth hormone	Pre-transplant rhGH treatment was associated with superior post-transplant anthropometric outcomes	rhGH may be beneficial in selected children with persistent growth failure
Stabouli et al[51], 2022	Clinical practice recommendations	Nutrition/metabolic risk	Obesity, metabolic syndrome, and cardiometabolic risk require structured assessment and management after transplantation	Growth promotion should be integrated with cardiometabolic surveillance
Prytuła et al[81], 2025	Paediatric kidney transplant recipients	Metabolic acidosis	Growth is multifactorial; correction of metabolic acidosis alone is unlikely to fully restore linear growth	Metabolic management should complement, not replace, broader growth strategies
Selected studies[57,61,62,70]	Biomarker and machine-learning literature	Monitoring/prediction	Emerging biomarkers and predictive models are promising but focus mainly on rejection or graft outcomes rather than validated growth-specific endpoints	Routine use for growth-focused care still requires further validation

rhGH: Recombinant human growth hormone.

PHYSIOLOGICAL MECHANISMS UNDERLYING GROWTH AND DEVELOPMENT FOLLOWING PAEDIATRIC KIDNEY TRANSPLANTATION

Effects of CKD on the growth axis

CKD exerts profound adverse effects on children’s growth and development, primarily through multiple disruptions to the growth axis. First, CKD induces GH resistance, a key mechanism underlying growth retardation in paediatric CKD. GH plays a crucial role in renal development and skeletal growth. Under normal circumstances, it promotes bone and soft tissue growth by stimulating the liver and other tissues to secrete insulin-like growth factor-1 (IGF-1). However, CKD patients frequently exhibit impaired GH signalling, resulting in reduced IGF-1 bioactivity. Consequently, growth effects remain limited even when GH levels are normal or elevated. This state of GH resistance arises partly from impaired downstream signalling of GH receptors due to renal insufficiency, coupled with increased expression of intracellular inhibitory factors (such as suppressor of cytokine signalling 2) triggered by chronic inflammation. These factors suppress GH signalling, thereby affecting IGF-1 synthesis and action[9,10].

Nevertheless, although kidney transplantation improves the metabolic milieu and may partially restore the GH-IGF-1 axis, spontaneous catch-up growth is incomplete in many children. The role of recombinant human GH (rhGH) after transplantation therefore deserves a more explicit discussion. Current literature suggests that rhGH is most relevant for children with persistent growth failure after optimisation of graft function, nutrition, metabolic status, and immunosuppression. Treatment decisions should account for age, residual growth potential, pubertal status, graft stability, and the feasibility of reducing steroid exposure. Importantly, the literature supports benefit in selected paediatric recipients, but it does not justify indiscriminate use; timing, indications, and monitoring remain centre-dependent and should be individualised[11,12].

Metabolic disorders and malnutrition are also significant factors exacerbating growth retardation in children with CKD. Malnutrition frequently results from inadequate intake, metabolic abnormalities, and chronic inflammation. Prolonged malnutrition not only compromises energy supply but also reduces sensitivity of the GH/IGF-1 axis, intensifying GH resistance[13]. Chronic inflammation is prevalent in CKD, with pro-inflammatory factors such as tumour necrosis factor-α (TNF-α) directly affecting bone metabolism and growth. TNF-α levels correlate negatively with bone metabolism markers and height z-scores, suggesting that inflammatory states exacerbate bone mineral disorder and growth restriction[14]. Furthermore, thyroid dysfunction is observed in some paediatric CKD patients, manifesting as reduced free thyroxine and free triiodothyronine levels, which subsequently impairs growth and neurodevelopment[15].

Collectively, CKD severely inhibits skeletal growth and overall development in children through multiple mechanisms: Inducing GH resistance, disrupting IGF-1 signalling, triggering mineral metabolism disorders, and exacerbating chronic inflammation and malnutrition. Future clinical management should employ comprehensive interventions targeting these mechanisms, including nutritional support, correction of metabolic abnormalities, anti-inflammatory therapy, and timely administration of rhGH therapy to promote normal growth and development in paediatric CKD patients[16-18].

Recovery of the GH axis following kidney transplantation

Corticosteroids remain the immunosuppressive agents most consistently associated with impaired post-transplant growth. Their adverse effects are mediated through inhibition of chondrocyte proliferation, suppression of osteoblast activity, perturbation of calcium and bone metabolism, and interference with the GH-IGF-1 axis and pubertal development[19-21]. The clinically relevant message is not merely that high-dose steroids are harmful, but that cumulative corticosteroid exposure over time may compromise linear growth, especially in younger children with substantial remaining growth potential[22,23].

In contrast, contemporary maintenance regimens based on tacrolimus and mycophenolate are generally used to enable steroid-sparing strategies rather than to directly accelerate growth. The optimal balance is therefore to minimise rejection risk while reducing steroid burden whenever immunological risk, graft stability, and centre expertise permit. Evidence supporting fixed very-low-dose prednisolone as growth-neutral in paediatric recipients is limited; available paediatric data suggest that even low-level maintenance steroid exposure should be interpreted in the context of cumulative dose, treatment duration, age, and concomitant steroid-sparing therapy[22-24].

Nevertheless, studies indicate that while kidney transplantation markedly improves GH axis function, the postoperative application of rhGH remains cautious. Variations exist across centres regarding the criteria and timing for initiating rhGH therapy, underscoring the importance of multidisciplinary collaboration. Multicentre studies demonstrate that during the first five years after transplantation, children under 13 years of age exhibit markedly elevated height SDSs, with discontinuation of glucocorticoids closely associated with improved height gain. This further corroborates the positive impact of renal function recovery on the GH-IGF-1 axis and growth[19-21].

In summary, renal transplantation constitutes a key mechanism for enhancing postoperative growth and development in children by improving renal function and metabolic environment, thereby facilitating partial restoration of the GH-IGF-1 axis. Future clinical management should prioritise dynamic monitoring and assessment of the postoperative GH axis, integrating nutritional support and endocrine therapy to provide individualised growth promotion strategies for paediatric kidney transplant recipients.

Mechanisms by which immunosuppressants affect growth

Immunosuppressive agents are essential therapeutic measures following paediatric kidney transplantation, primarily aimed at preventing graft rejection and ensuring long-term survival of the transplanted kidney. However, these agents exert significant effects on children’s growth and development, particularly through their inhibitory impact on skeletal growth and pubertal maturation—a major clinical challenge for paediatric kidney transplant recipients.

Corticosteroids, as one of the traditional immunosuppressants, significantly inhibit bone growth when used as a long-term therapy. They affect bone metabolism through multiple mechanisms, including suppressing osteoblast function, promoting bone resorption, and disrupting calcium metabolism, thereby limiting skeletal development. Furthermore, corticosteroids can influence sex hormone secretion, delaying the pubertal development process and further exacerbating height growth limitations. Clinical studies demonstrate a strong association between long-term maintenance corticosteroid therapy and growth retardation following paediatric kidney transplantation[22]. Although corticosteroid avoidance or tapering strategies have emerged in recent years, showing advantages in reducing corticosteroid-related toxicity—including improvements in growth velocity, body mass index (BMI), blood pressure, and lipid metabolism—their application remains controversial and is not suitable for all patients[23]. In contrast, other immunosuppressants exert lesser effects on growth. Calcineurin inhibitors (such as cyclosporine A and tacrolimus) currently form the core of maintenance immunosuppression in paediatric kidney transplantation. Research indicates that their impact on childhood growth and development is milder than that of corticosteroids. Clinical data indicate that switching immunosuppressive regimens, such as transitioning from cyclosporine A to tacrolimus, primarily addresses corticosteroid-related adverse effects and rejection episodes, with relatively limited impact on growth velocity[24]. Furthermore, pyrimidine synthesis inhibitors (e.g., mycophenolate mofetil) and mammalian target of rapamycin (mTOR) inhibitors are also widely used in paediatric settings. However, definitive evidence of their negative impact on growth remains lacking. Due to concerns over side effects, mTOR inhibitors are employed with greater caution[25,26]. Moreover, the influence of genetic polymorphisms [such as cytochrome P450 3A5 (CYP3A5) and UDP-glucuronosyltransferase 1A9 (UGT1A9)] on the metabolism of tacrolimus and mycophenolate mofetil underscores the importance of individualised immunosuppressant dose adjustment, which may indirectly mitigate potential growth effects[27].

In summary, the mechanisms by which immunosuppressants affect growth following paediatric kidney transplantation primarily involve corticosteroids’ suppression of skeletal growth and interference with sex hormone secretion, while other immunosuppressants exert relatively minor effects. Current clinical management tends towards corticosteroid minimisation strategies to promote paediatric growth and development while maintaining immunoprotection of the transplanted kidney. Future research should focus on individualised application of immunosuppressants and growth monitoring to optimise immunosuppression regimens, thereby minimising adverse effects on paediatric development[22-24].

CLINICAL FACTORS AFFECTING POSTOPERATIVE GROWTH AND DEVELOPMENT IN PAEDIATRIC KIDNEY TRANSPLANTATION

Transplant age and growth and development

The extent of growth improvement following paediatric kidney transplantation is closely correlated with the age at transplantation. Multiple studies indicate that younger transplantation age correlates with a greater likelihood of postoperative growth catch-up, with the most pronounced effect observed in children under three years of age. This phenomenon primarily arises because the skeletal and endocrine systems of young children remain in a highly active developmental phase. The restoration of renal function more effectively corrects metabolic disturbances caused by chronic renal insufficiency, thereby promoting rapid height gain.

For instance, a single-centre cohort study in China conducted long-term follow-up on 101 paediatric kidney transplant recipients. Results demonstrated a significant improvement in height-for-age z-score from -2.27 at transplantation to -0.76 during the postoperative stabilisation phase, indicating markedly enhanced growth post-surgery. The study further indicated that transplant age and pre-transplant height significantly influence final stature, emphasising that early transplantation maximises growth potential. Additionally, it underscored the critical importance of maintaining optimal graft function for improving growth retardation and sexual development[4].

Another retrospective study analysing 60 paediatric kidney transplant recipients aged 16 years or younger found that approximately 38.3% experienced catch-up growth within two years post-transplant. Advanced age and episodes of rejection were identified as significant factors influencing the loss of catch-up growth. This study explicitly stated that the likelihood of post-transplant catch-up growth diminishes with increasing age, suggesting that early transplantation, particularly during early childhood, is advantageous for postoperative growth recovery[28].

Furthermore, analysis of the American OPTN database revealed that for children weighing ≤ 15 kg, those receiving kidney transplants between 1 and 2 years of age demonstrated higher kidney graft survival and patient survival rates. Moreover, younger transplant age correlated with improved long-term postoperative outcomes. This ‘optimal age window’ indicates that 1 year to 2 years of age represents the golden period for kidney transplantation, maximising children’s growth potential[29].

Regarding the mechanisms by which transplant timing influences growth and development, early transplantation reduces dialysis duration, thereby avoiding dialysis-related malnutrition and metabolic disorders that negatively impact skeletal growth. Shortening dialysis periods and performing early kidney transplantation minimises the accumulation of growth-inhibiting factors, facilitating the restoration of the GH axis and normal skeletal development[30]. Concurrently, early transplantation aids in normalising sex hormone levels, facilitating unimpeded pubertal progression and further height gain[4].

Notably, the use of kidneys from donors with acute kidney injury (AKI) is increasingly discussed in paediatric transplantation. Current literature suggests that transplantation using such donors can yield acceptable outcomes, although delayed graft function (DGF) may be more frequent and the evidence base remains limited. The earlier wording that these grafts have superior recovery capacity compared with adult donors was too broad; a more accurate interpretation is that selected reports describe favourable recovery or utilisation outcomes in carefully chosen paediatric settings, but these findings should not be generalised beyond the available data.

In summary, existing research consistently supports performing kidney transplantation at the youngest possible age, particularly in children under three years old, to achieve optimal postoperative growth catch-up and ultimate height. Early transplantation not only ameliorates growth retardation but also facilitates sexual maturation and social adaptation, thereby enhancing long-term quality of life. Clinically, efforts should focus on minimising waiting times to facilitate early transplantation, maximising children’s growth potential and overall prognosis[4,28-30].

Preoperative and postoperative renal function status

Renal function status plays a pivotal role in the prognosis and restoration of growth and development following paediatric kidney transplantation. Optimal graft function, particularly estimated glomerular filtration rate (eGFR), has been demonstrated to correlate positively with postoperative growth velocity. Multiple studies indicate that favourable postoperative eGFR recovery not only reflects sound graft function but also portends improvements in the GH axis and nutritional metabolism status of paediatric patients, thereby promoting normal height and weight development[31-33]. Furthermore, stable renal function helps reduce the toxic side effects of immunosuppressants, thereby enhancing patients’ quality of life.

However, chronic graft injury represents a significant factor limiting growth recovery, with interstitial fibrosis and chronic rejection being the primary pathological manifestations. Interstitial fibrosis causes irreversible damage to renal structure and function, subsequently impairing both filtration and endocrine capabilities, thereby hindering normal childhood growth. Non-invasive imaging techniques such as T1-mapping enable early quantitative assessment of renal tissue microstructural alterations, indicating fibrosis progression and active immune-inflammatory states. This technology reveals that elevated postoperative T1 values correlate with increased serum inflammatory markers (e.g., interleukin-6 and TNF-α), suggesting a close association between immune-inflammatory responses and renal impairment[34]. Therefore, monitoring postoperative renal function changes to detect chronic injury early is crucial for optimising treatment strategies and promoting growth and development.

Preoperative renal function status also influences postoperative recovery. Studies indicate that patients with lower preoperative eGFRs face increased risk of DGF postoperatively, which in turn impacts long-term growth and development[35,36]. DGF is associated not only with preoperative inflammatory status but also with intraoperative haemodynamic management. For instance, maintaining adequate mean arterial pressure and ensuring sufficient red blood cell transfusion during surgery improves graft perfusion, reduces postoperative renal insufficiency, and promotes rapid renal recovery[37]. The incidence of chronic graft injury following paediatric kidney transplantation is relatively high, and is associated with recurrent acute rejection episodes, infections, and the pharmacological effects of immunosuppressive agents[38,39]. Therefore, thorough preoperative assessment of renal function and rigorous postoperative monitoring of renal status are crucial for minimising chronic injury and ensuring long-term graft stability.

Notably, the use of kidneys from donors with AKI is increasingly common in paediatric transplantation. Studies indicate that although DGF occurs more frequently in the short term after transplantation from AKI donors, long-term renal function recovery is favourable. Some studies even demonstrate superior recovery capacity compared to adult donors[40,41]. This offers new possibilities for expanding donor sources, reducing waiting times, and improving growth and development in paediatric patients.

In summary, pre- and postoperative renal function statuses are critical determinants of growth and development following paediatric kidney transplantation. Maintaining favourable graft function (high eGFR) promotes growth and development, whereas chronic graft injury such as interstitial fibrosis limits growth recovery. Comprehensive preoperative assessment, meticulous intraoperative management, and dynamic postoperative monitoring of renal function and immune status can effectively reduce chronic injury incidence and optimise long-term growth and developmental outcomes in paediatric patients. Future research should further focus on renal function protection mechanisms and non-invasive monitoring techniques for early injury detection to advance personalised clinical management.

Immunosuppressive regimens and corticosteroid use

The mechanism of rhGH treatment should also be described with greater caution. rhGH primarily promotes linear growth through effects on the GH-IGF-1 axis and skeletal growth plates. Some studies additionally report associations between rhGH-treated cohorts and more favourable inflammatory, anaemia-related, or graft-function profiles; however, these observations do not establish that rhGH directly improves renal function, suppresses inflammation, or corrects anaemia independent of broader clinical care. In the present context, the most defensible conclusion is that rhGH can improve anthropometric outcomes in selected children, particularly when combined with optimisation of graft function, steroid exposure, and nutritional status[18,42,43].

Corticosteroid avoidance or withdrawal protocols have been demonstrated to improve growth parameters in paediatric kidney transplant recipients. In recent years, with the widespread adoption of newer immunosuppressive agents such as tacrolimus and mycophenolate mofetil, some studies have attempted to progressively reduce or even completely discontinue corticosteroids to mitigate their adverse effects. A systematic review indicated that, within the context of modern immunosuppression (including induction therapy and the combination of tacrolimus with mycophenolate mofetil), paediatric patients utilising corticosteroid avoidance or withdrawal protocols did not exhibit a significant increase in acute rejection rates. Moreover, marked improvements were observed in growth parameters, BMI, blood pressure, and lipid profiles[23]. Moreover, corticosteroid withdrawal reduces risks associated with diabetes and hypertension, enhancing patients’ quality of life[44]. However, despite data supporting its safety and benefits, considerable controversy persists in clinical practice, with some centres refraining from widespread adoption due to concerns over rejection risk[23].

Notably, individualised adjustment of immunosuppression regimens is particularly crucial. The immune status of paediatric kidney transplant recipients is complex and dynamic, making reliance solely on drug concentration monitoring insufficient for comprehensively assessing immunosuppression intensity. Emerging immunomonitoring methods, such as plasma torsion virus (TTV) load measurement and virus-specific T-cell monitoring, provide more precise tools for adjusting immunosuppressant dosages. This facilitates maintaining immune tolerance while reducing corticosteroid usage, thereby lowering the risks of rejection and infection[45-47]. Furthermore, genetic polymorphisms such as variations in CYP3A5 and UGT1A9 influence the pharmacokinetics of tacrolimus and mycophenolate mofetil, suggesting that future optimisation of immunosuppression regimens should incorporate pharmacogenomics to achieve precision medication[27].

In summary, prolonged corticosteroid use constitutes a significant factor contributing to growth restriction following paediatric kidney transplantation. Implementing corticosteroid avoidance or tapering regimens, combined with modern immunosuppressive agents and personalised immune monitoring strategies, can effectively improve growth parameters while reducing metabolic and endocrine complications. Future clinical research should prioritise optimising immunosuppression protocols to balance rejection prevention with growth preservation, thereby enhancing the long-term quality of life for paediatric kidney transplant recipients.

Application and efficacy of GH therapy

The application of rhGH in paediatric CKD and kidney transplant patients has been extensively studied, demonstrating significant efficacy in promoting pre- and postoperative growth and development. A prospective study conducted by two paediatric nephrology centres in Germany involving 146 CKD patients under eight years of age revealed that those receiving rhGH treatment prior to surgery exhibited comparable height z-scores at the time of kidney transplantation to untreated patients, despite having undergone longer dialysis periods and receiving fewer living-related kidney transplants. Post-transplantation, the rhGH-treated cohort exhibited markedly reduced steroid exposure and significantly greater increases in height-related parameters (including sitting height and leg length z-scores) compared to the untreated group. Notably, patients without preoperative rhGH demonstrated poorer outcomes post-transplant, including accelerated graft decline, lower haemoglobin levels, and elevated C-reactive protein levels—factors all associated with growth restriction. After adjusting for these confounding factors, the rhGH treatment remained statistically significant in improving seated height z-scores, indicating rhGH’s positive role in promoting skeletal development and improving body proportions[48].

The mechanism of rhGH treatment extends beyond direct height promotion, encompassing renal function improvement, inflammatory response suppression, and anaemia alleviation. Growth retardation in CKD arises multifactorially from malnutrition, metabolic disorders, and hormonal imbalances. rhGH accelerates skeletal growth by promoting bone cell division and cartilage formation. Concurrently, it improves renal metabolic conditions and reduces inflammatory cytokine release, thereby indirectly protecting transplanted kidney function and lowering inflammation levels. Furthermore, rhGH stimulates erythropoiesis, aiding anaemia correction—a critical factor for children’s overall growth and development[18,48].

In clinical practice, rhGH application strategies must comprehensively consider patient age, CKD stage, and dialysis status. Research indicates that early initiation of rhGH therapy, particularly prior to kidney transplantation, more effectively promotes postoperative growth catch-up. Italian experts noted that despite clear international guidelines defining rhGH indications, significant variations exist in its clinical utilisation across centres, with most patients not receiving post-transplant rhGH treatment. Experts emphasise that multidisciplinary collaboration is crucial for optimising rhGH treatment outcomes, requiring individualised assessment to formulate appropriate therapeutic regimens[20,49].

Furthermore, the safety profile of rhGH therapy has been confirmed in multiple studies. While close monitoring for potential adverse effects such as increased intracranial pressure and glucose metabolism abnormalities is necessary during treatment, overall risks remain manageable. Long-term follow-up data indicate that rhGH treatment favourably influences final adult height in paediatric kidney transplant recipients, with particularly pronounced effects when administered against a background of reduced steroid use. Studies further demonstrate that combining rhGH with minimised postoperative steroid exposure significantly enhances both the velocity and quality of height gain[43,49].

In summary, rhGH application in paediatric kidney transplant recipients not only promotes pre- and postoperative growth but also significantly optimises growth outcomes through multiple mechanisms, including improved renal function, reduced inflammation, and correction of anaemia. Future efforts should focus on strengthening multidisciplinary collaboration, refining treatment guidelines, and standardising the timing and dosage of rhGH administration to maximise its positive impact on growth and development in paediatric kidney transplant patients[18,31,48].

Nutritional status and metabolic factors

Nutritional support plays a crucial role in the recovery of growth and development following paediatric kidney transplantation. Given that children who undergo kidney transplantation often suffer from CKD and its associated complications, appropriate nutritional management not only promotes growth and development but also improves the patient’s overall metabolic status and reduces cardiovascular risk. Recent studies indicate a high prevalence of obesity and metabolic syndrome among paediatric kidney transplant recipients, with approximately 36.5% of patients being overweight or obese. Metabolic disorders such as hypertension, dyslipidaemia, and hyperglycaemia are prevalent, and 19.2% of patients meet diagnostic criteria for metabolic syndrome[50]. These metabolic abnormalities not only heighten cardiovascular disease risk but may also compromise graft function. Although studies indicate no significant association between metabolic syndrome and graft filtration rate, the incidence of left ventricular hypertrophy is markedly elevated in patients with metabolic syndrome, suggesting potential structural cardiac effects from metabolic factors[50]. The objectives of nutritional support are to correct deficiencies in energy and protein intake, prevent malnutrition, and control body weight to avoid obesity and its associated complications. The Paediatric Renal Nutrition Taskforce has proposed clinical practice recommendations for nutritional management in children with CKD and kidney transplant recipients. These emphasise comprehensive management of obesity and metabolic syndrome risk through dietary adjustments, increased physical activity, and behavioural interventions, thereby promoting growth and development and improving metabolic health[13,51]. Furthermore, nutritional support must address stage-specific requirements, such as growth retardation in infancy and rapid adolescent growth, which demand higher energy and micronutrient intakes. Individualised nutritional strategies are essential to meet these developmental needs[13].

Metabolic acidosis is a common metabolic abnormality in children with CKD. Theoretically, its correction may improve bone metabolism and growth outcomes. However, clinical evidence indicates that correcting metabolic acidosis alone has limited effect on growth velocity, suggesting the need for additional therapeutic measures such as optimising nutrition and controlling inflammatory states[52]. Iron metabolism abnormalities and chronic inflammatory states are also prevalent in paediatric kidney transplant recipients, impairing erythropoiesis and potentially leading to anaemia and growth retardation. Chronic inflammation inhibits erythropoiesis and skeletal growth through multiple mechanisms, while disrupted iron metabolism regulation reduces iron utilisation efficiency, thereby affecting tissue oxygen supply and metabolic function[52]. Therefore, interventions targeting iron metabolism abnormalities and inflammatory states are equally crucial for promoting favourable growth and development following paediatric kidney transplantation.

In summary, improving post-transplant growth and development in paediatric kidney recipients requires comprehensive management of multiple factors. Adequate nutritional support forms the foundation, necessitating prevention of both malnutrition and the development of obesity and metabolic syndrome; correction of metabolic acidosis, while not the primary means of restoring growth, remains essential; interventions targeting iron metabolism abnormalities and inflammatory states can promote erythropoiesis and skeletal health. Future clinical management should involve multidisciplinary teams developing personalised intervention plans tailored to individual metabolic characteristics, thereby maximising postoperative growth potential and enhancing quality of life[13,50-52].

MONITORING AND PREDICTION OF GROWTH AND DEVELOPMENT FOLLOWING PAEDIATRIC KIDNEY TRANSPLANTATION

Growth indicators and assessment methods

In studies examining postoperative growth and development following paediatric kidney transplantation, the accurate assessment of growth indicators constitutes a critical component of clinical management and efficacy evaluation. The SDS, as a commonly employed statistical method, is widely utilised for evaluating changes in children’s height, weight, and BMI. The SDS normalises growth indicators relative to an individual’s age and sex, facilitating comparisons of growth status across different time points and between patients. For instance, in a study involving 59 paediatric kidney transplant recipients, age-adjusted haemoglobin SDS was employed to evaluate anaemia severity. Results demonstrated a positive correlation between haemoglobin SDS and renal function (eGFR), alongside significant associations with erythropoietin and fibroblast growth factor 23 (FGF23), indicating that SDS possesses high sensitivity and specificity in reflecting post-transplant physiological status in paediatric kidney recipients[53]. Furthermore, the application of SDS extends beyond haematological parameters, playing a crucial role in the dynamic monitoring of height and weight. This facilitates clinicians’ assessment of growth curve trends and the efficacy of therapeutic interventions[54].

Accurate assessment of renal function is paramount for understanding the mechanisms underlying post-transplant growth and development in paediatric patients. Traditionally, glomerular filtration rate is often estimated after adjustment for body surface area (BSA). However, in growing children, changes in BSA may lead to inaccurate glomerular filtration rate adjustments, affecting the true reflection of renal function. Research indicates that absolute measured glomerular filtration rate (mGFR) is more suitable than BSA-adjusted values for assessing renal function in growing children. For children experiencing rapid changes in weight and height, employing absolute mGFR more accurately reflects the kidneys’ actual filtration capacity, avoiding biases introduced by BSA adjustments. For instance, in paediatric transplant recipients with low body weight, studies indicate that renal function assessment should integrate absolute mGFR with the size and compatibility of the transplanted kidney to guide clinical decision-making and prognosis evaluation[29,55]. This optimised assessment method holds significant importance for guiding immunosuppressant dose adjustments and the individualised design of nutritional and hormonal therapies.

Collectively, the dynamic monitoring of height, weight, and BMI using SDS, combined with renal function assessment via absolute mGFR, provides a scientifically rigorous and precise evaluation framework for post-transplant growth and development in paediatric kidney recipients. This not only facilitates the timely identification of growth disorders but also promotes the formulation and adjustment of personalised treatment plans, ultimately improving growth outcomes and quality of life for paediatric patients. Future research should further refine the application of SDS, integrating multiple biomarkers and imaging techniques to comprehensively evaluate growth and renal function status in paediatric transplant recipients, thereby advancing clinical management standards[53,55].

The growth and development of paediatric patients following kidney transplantation are influenced by multiple factors, and this complexity has prompted interest in combining genetic information with clinical variables. However, the current literature should be interpreted carefully: Most transplant pharmacogenomic studies focus on drug exposure, rejection risk, or graft outcomes rather than on validated longitudinal growth endpoints. Thus, genetic polymorphisms such as CYP3A5, ABCB1, and related variants are best viewed as tools that may help individualise immunosuppressive therapy and indirectly protect growth by reducing rejection or toxicity, rather than as stand-alone predictors of height outcomes[56-61].

Machine-learning methods are similarly promising but remain preliminary in this field. Existing paediatric transplant models more commonly predict DGF, post-transplant renal function, or graft failure than linear growth itself. Their clinical value for growth-focused care will depend on external validation, transparent reporting of discrimination and calibration, and incorporation of growth-specific longitudinal variables such as height SDS, pubertal stage, cumulative steroid exposure, and nutritional trajectories.

Accordingly, predictive analytics should currently be framed as an emerging research direction rather than a mature clinical tool for personalising growth management after paediatric kidney transplantation. Future models will be more clinically persuasive if they integrate pharmacogenomics, graft-function metrics, inflammatory burden, nutritional data, and endocrine variables within multicentre longitudinal cohorts.

On the other hand, blood testing of the ratio of regulatory T cells to effector T cells (Teff) provides an immunological perspective for assessing chronic transplant nephritis status. Studies reveal that the ratio of activated regulatory T cells to Teff is significantly higher in non-inflammatory patients, suggesting its potential as a biomarker for chronic rejection[62]. Furthermore, emerging urinary biomarkers such as urinary vitronectin demonstrate potential for non-invasive monitoring of fibrosis[63]. FGF23, a hormone regulating mineral metabolism, is closely associated with iron metabolism and anaemia, significantly impacting growth and development in paediatric kidney transplant recipients. Studies indicate that abnormal FGF23 expression correlates with renal insufficiency, anaemia, and bone metabolism disorders, suggesting its potential as a biomarker for assessing post-transplant growth, development, and metabolic status[64,65]. Furthermore, factors related to iron metabolism, particularly in anaemia management, play a crucial role, indirectly influencing children’s growth curves and developmental outcomes[66].

In summary, emerging biomarkers derived from blood and urine not only enable early, dynamic, and non-invasive monitoring of rejection responses but also provide effective tools for the comprehensive management of post-transplant growth and development in paediatric kidney recipients. Future large-scale, multicentre clinical studies are required to validate the clinical utility of these markers within treatment pathways, advance the establishment of multi-parameter monitoring models, and thereby facilitate precise, individualised immunomodulation and growth support strategies. This approach aims to optimise long-term outcomes and developmental quality in paediatric kidney transplantation.

Genetic polymorphism and machine learning predictive models

The growth and development of paediatric patients following kidney transplantation are influenced by multiple factors. The integration of genetic polymorphisms with clinical variables offers novel insights for constructing precise growth prediction models. Single nucleotide polymorphisms (SNPs), as the primary form of genetic variation, reflect individual differences in the metabolism of immunosuppressive agents. This, in turn, affects drug concentrations and therapeutic efficacy, thereby significantly influencing post-transplant growth outcomes. For instance, CYP3A5 gene polymorphisms have been extensively studied. The enzyme encoded by this gene participates in the metabolism of immunosuppressants such as tacrolimus, and differing genotypes result in significant variations in drug plasma concentrations and dosage requirements, thereby influencing rejection responses and graft survival rates[67,68]. Furthermore, polymorphisms in CYP3A5 alongside genes such as ABCB1 and SXR have been demonstrated to correlate with acute rejection risk, providing a genetic backdrop for growth prediction[69]. Integrating these highly relevant SNPs with clinical variables (e.g., immunosuppressant plasma concentrations, patient age, and surgical parameters) to construct growth prediction models offers a more comprehensive reflection of individual biological and clinical characteristics.

Machine learning methods demonstrate significant advantages in predicting post-transplant growth and development. Traditional statistical models are often constrained by assumptions of linear relationships between variables and the subjectivity of feature selection, making them ill-suited for handling large-scale, multidimensional, and complex clinical genomic data. In contrast, machine learning can leverage vast datasets to automatically extract key features, enabling modelling of nonlinear and complex relationships. For instance, random forests, gradient-boosted machines, and deep learning models have demonstrated superior performance in predicting post-transplant renal function in children, DGF, and chronic rejection[70-72]. These models not only enhance predictive accuracy but also reveal key prognostic factors through feature importance analysis, providing robust support for clinical decision-making. Furthermore, machine learning models can integrate genetic polymorphisms, immunosuppressant dose adjustments, and clinical indicators to enable personalised treatment planning, advancing precision medicine[73,74].

In summary, the integration of genetic polymorphisms with machine learning prediction models provides a robust foundation for the precise assessment of post-transplant growth and development in paediatric kidney recipients. The combined application of genotype information—such as SNPs in CYP3A5, ABCB1, and SXR—with clinical variables can optimise immunosuppressant dosing and enhance the precision of rejection prevention. Concurrently, predictive models constructed using machine learning techniques not only enhance the accuracy of growth and development forecasting but also assist in formulating personalised treatment plans, significantly improving patients’ long-term prognosis. This research direction represents a future trend in post-renal transplant growth management, necessitating further large-scale, multicentre studies to validate its clinical application value.

CLINICAL INTERVENTION STRATEGIES FOR GROWTH AND DEVELOPMENT FOLLOWING PAEDIATRIC KIDNEY TRANSPLANTATION

Optimisation of immunosuppressive regimens

Optimising immunosuppression regimens following paediatric kidney transplantation is crucial for ensuring graft survival and promoting postoperative growth and development. While corticosteroids in conventional immunosuppression protocols effectively prevent rejection, their inhibitory effect on paediatric growth has drawn increasing attention in recent years. Research indicates that corticosteroid avoidance or withdrawal strategies can significantly mitigate these adverse effects on growth while maintaining immunosuppressive efficacy. For instance, in early studies employing cyclosporine A and azathioprine, corticosteroid withdrawal groups exhibited increased rates of acute rejection but no significant rise in graft loss or mortality[23]. In contemporary immunosuppression regimens, corticosteroid withdrawal or avoidance protocols combining induction therapy with tacrolimus and mycophenolate mofetil similarly demonstrated no significant increase in rejection risk. These approaches further facilitated improvements in paediatric growth, BMI, blood pressure, and lipid profiles[23,44]. Consequently, early withdrawal or avoidance of corticosteroids represents a safe and beneficial strategy for children at low immunological risk.

Beyond corticosteroid adjustment, individualised optimisation of immunosuppressive agent dosing constitutes a crucial aspect of regimen refinement. Significant inter-individual variability in paediatric drug metabolism exists, with genetic polymorphisms notably influencing the metabolism of tacrolimus and mycophenolate mofetil. For instance, CYP3A5 and UGT1A9 genetic polymorphisms are closely associated with therapeutic drug concentrations and dosage requirements for immunosuppressants. Patients with the CYP3A53/3 genotype exhibit markedly higher trough concentrations and dose ratios for tacrolimus compared to those carrying wild-type alleles, indicating greater drug exposure and necessitating dose adjustments to prevent toxic reactions[27]. Such genetic testing facilitates precision dosing, mitigating risks from excessive or inadequate immunosuppression.

Furthermore, while clinical practice relies predominantly on plasma concentration monitoring for immunosuppressant adjustment, this approach alone may not comprehensively reflect immune status. Emerging immunomonitoring tools such as TTV load, QuantiFERON Monitor^®, and immune function assays (ImmuKnow^®) have demonstrated potential in supplementing the assessment of immunosuppression levels. Notably, TTV load correlates with infection and rejection risk, offering novel biomarkers for individualised adjustment of immunosuppressive dosing[45-47]. These approaches hold promise when combined with conventional drug monitoring to optimise immunosuppression regimens, balancing rejection prevention with growth preservation.

Regarding immunosuppressant selection, although mTOR inhibitors (e.g., sirolimus and everolimus) demonstrate certain advantages in adults, their use remains limited in paediatric settings due to increased side effects and lack of clear superiority over calcineurin inhibitors[25,26]. The current recommendation prioritises the combination of tacrolimus with mycophenolate mofetil, while minimising or avoiding long-term corticosteroid use. Induction immunosuppression typically employs anti-thymocyte globulin or basiliximab, with selection tailored to individual immune risk profiles[75,76].

It is important to note that dose adjustments of immunosuppressants must balance the prevention of rejection with the avoidance of infection and drug toxicity. Many paediatric kidney transplant recipients experience opportunistic infections, and even repeated hospitalisations, due to immunosuppression. However, studies indicate that this immunosuppressed state is not entirely determined by blood drug concentrations or drug type, highlighting the necessity of immune monitoring[45]. Clinically, reducing mycophenolate mofetil dosage is common, primarily due to side effects such as leukopenia and gastrointestinal symptoms. However, such dose reduction does not significantly increase antibody production or rejection risk[42].

In summary, optimising postoperative immunosuppression regimens in paediatric kidney transplant recipients should prioritise corticosteroid avoidance or early withdrawal strategies to mitigate growth suppression. Concurrently, individualised dose adjustments of immunosuppressants should be achieved based on genetic polymorphisms and immune function monitoring. By comprehensively balancing drug efficacy, adverse effects, and patient immune status, an equilibrium can be attained between preventing graft rejection and promoting paediatric growth and development, thereby providing safer and more effective immune management protocols for paediatric kidney transplant patients.

Appropriate use of GH therapy

rhGH therapy plays a significant role in managing growth and development following paediatric kidney transplantation, particularly for children with severe growth restriction both pre- and postoperatively. Research indicates that initiating rhGH treatment at an appropriate preoperative stage can markedly improve growth outcomes after kidney transplantation. A prospective study conducted at two German paediatric nephrology centres involving 146 children under eight years of age with CKD demonstrated that those receiving preoperative rhGH treatment exhibited significantly greater increases in post-transplant height, sitting height, and limb length z-scores compared to the non-rhGH group. Furthermore, postoperative steroid usage was lower in the rhGH cohort, and this was closely associated with improved graft function, reduced C-reactive protein levels, and ameliorated anaemia, suggesting that rhGH therapy not only promotes growth but may also enhance graft function and inflammatory status[48]. Furthermore, rhGH treatment facilitates early postoperative GH responsiveness and development, particularly in children with severe pre-transplant growth retardation, thereby promoting better physical development.

Appropriate application of rhGH therapy requires attention to initiation timing and continuous monitoring of treatment efficacy and potential adverse effects. Current consensus recommends considering rhGH therapy for paediatric CKD patients at stage 3 or above, or dialysis patients with persistent growth impairment. For those who have undergone kidney transplantation but continue to experience growth restriction, rhGH therapy should be initiated promptly if spontaneous growth catch-up fails to occur within one year post-transplant and a steroid-free immunosuppression regimen is unfeasible[18]. In clinical practice, prescribing practices for rhGH exhibit variability, with endocrinologists and nephrologists holding differing views on the optimal initiation timing and indications. Nevertheless, multidisciplinary collaboration remains paramount for the rational application of rhGH therapy[20].

Regarding safety monitoring, while rhGH therapy has demonstrated acceptable safety in paediatric CKD patients, vigilant surveillance for potential adverse effects remains essential, including intracranial hypertension, glucose metabolism abnormalities, and tumour risk. Regular assessments of growth velocity, bone age, renal function, and immunosuppressive agent usage are required throughout treatment to ensure the safety and efficacy of GH therapy[49]. Furthermore, reducing steroid use postoperatively positively influences growth promotion. Studies indicate that early discontinuation or reduction of steroids significantly improves postoperative height z-scores and final adult height, suggesting that combining rhGH therapy with optimised immunosuppression maximises postoperative growth in children[43].

In summary, the rational application of GH therapy following paediatric kidney transplantation should be based on individualised assessment, with particular emphasis on the importance of initiating rhGH treatment preoperatively. This should be combined with continuous postoperative growth monitoring and side effect management. Multicentre, multidisciplinary collaboration and the implementation of evidence-based guidelines will help improve the prognosis for postoperative growth failure, enhancing the quality of life and long-term health outcomes for these young patients[31,77].

Nutrition and metabolic management

Following paediatric kidney transplantation, nutritional and metabolic management constitutes a critical component in safeguarding the patient’s growth and development alongside the stability of the transplanted kidney function. First, enhanced postoperative nutritional support is paramount for correcting anaemia and maintaining an optimal metabolic state. Children with CKD frequently present with malnutrition, and postoperative nutritional deficiencies can lead to growth retardation and compromised immune function, subsequently impacting graft survival rates and the patient’s overall prognosis. The Paediatric Renal Nutrition Taskforce emphasises that children with kidney disease, particularly post-transplant recipients, require individualised nutritional assessment and management. This encompasses appropriate energy intake, protein supply, and micronutrient supplementation, while concurrently addressing risks of obesity and metabolic syndrome[13,51]. Anaemia, a common complication of renal disease, should be corrected postoperatively using erythropoietin and other agents to improve tissue oxygenation, thereby promoting growth and enhancing quality of life[78]. Furthermore, nutritional support must include appropriate supplementation of vitamins and minerals, avoiding both deficiency and excess, particularly water-soluble vitamins and trace elements such as magnesium and zinc, whose deficiencies are closely associated with growth impairment[79,80].

Metabolic disturbances constitute a significant factor affecting post-transplant growth in paediatric kidney recipients, with maintenance of acid-base equilibrium being particularly crucial. Although correction of metabolic acidosis has limited direct impact on growth, overall metabolic stability positively influences renal function preservation and optimisation of the growth environment[81]. Research indicates that post-transplant serum bicarbonate levels show no significant correlation with height gain, and alkaline therapy does not markedly improve growth. Nevertheless, maintaining normal metabolic status helps reduce other complications[81]. Consequently, metabolic management should holistically consider the patient’s electrolyte balance, mineral metabolism, and bone metabolic status, with timely adjustments to the treatment plan. Furthermore, post-transplant patients frequently exhibit metabolic syndrome manifestations such as dyslipidaemia and impaired glucose metabolism. These require management through appropriate dietary interventions, suitable exercise, and pharmacological interventions to reduce cardiovascular risk and promote healthy growth[21,82].

In summary, postoperative nutritional and metabolic management in paediatric kidney transplantation necessitates multidisciplinary collaboration. This approach, integrating individualised nutritional support, anaemia correction, and maintenance of metabolic equilibrium, is essential for effectively promoting postoperative growth and development while enhancing long-term graft survival. Future efforts should focus on strengthening evidence-based research into nutritional interventions and refining clinical guidelines to ensure that paediatric kidney transplant recipients receive optimal nutritional and metabolic support.

Early transplantation and reduced dialysis duration

Improvements in post-transplant growth and development in paediatric kidney recipients are closely linked to the timing of transplantation and duration of dialysis. Shortening the interval between dialysis initiation and transplantation is a key strategy for optimising growth outcomes. During dialysis, children often face multiple physiological and metabolic burdens, such as malnutrition, chronic inflammation, and bone metabolism abnormalities, all of which can contribute to growth retardation. Multiple studies confirm that prolonged dialysis duration exacerbates growth impairment and impacts final adult height[28]. For instance, a retrospective cohort study demonstrated a negative correlation between dialysis duration and pre-transplant height SDSs, with longer dialysis periods associated with more severe growth suppression[28]. Furthermore, prolonged dialysis duration is linked to diminished post-transplant growth catch-up, particularly evident in older children or those experiencing rejection episodes[28].

Early kidney transplantation (i.e., prophylactic transplantation or transplantation aimed at minimising dialysis duration) has been demonstrated to significantly improve post-transplant growth and renal function survival. A French renal replacement therapy registry study analysing 1911 paediatric primary kidney transplants found that prophylactic recipients exhibited a 55% reduced risk of graft loss post-transplantation (hazard ratio: 0.45, 95% confidence interval: 0.33-0.62) compared to those transplanted after dialysis. This advantage persisted across all dialysis duration groups, indicating prophylactic transplantation as the preferred treatment for paediatric end-stage renal disease[83]. Another study in children under six years old found no significant differences between the prophylactic and non-prophylactic groups in patient and graft survival, renal function, or height gain. However, the prophylactic group exhibited a lower incidence of cytomegalovirus infection, suggesting that early transplantation may reduce infection risk[84].

Promoting living donor kidney transplantation is an effective approach to achieving early transplantation and reducing dialysis duration. Living donor transplantation not only shortens waiting times and minimises cold ischaemia time but also facilitates faster graft function recovery, thereby aiding early post-transplant renal function improvement and promoting growth and development. Data indicate that living donor transplantation is increasingly prevalent in paediatric kidney transplantation, correlating with superior long-term survival rates and lower complication incidence[39,85]. Moreover, living donor transplantation demonstrates superior success rates and renal function recovery compared to deceased donor transplantation, particularly in younger children with lower body weights[86,87].

Reducing dialysis duration, alongside early transplantation, positively impacts postoperative height and sexual maturation in children. A single-centre Chinese study indicates that transplantation age and height at transplantation are key determinants of final adult height, while prolonged dialysis, though not directly affecting near-final height, exacerbates growth impairment[4]. Furthermore, early transplantation facilitates restoration of normal endocrine function, promotes pubertal development, and reduces delayed sexual maturation[4,88].

In summary, shortening dialysis duration and facilitating early kidney transplantation—particularly by promoting living donor transplantation—constitute key measures to mitigate dialysis’s adverse effects on paediatric growth and development. Achieving this requires enhanced early assessment and transplant preparation for children with end-stage renal disease, optimised organ allocation processes, and strengthened promotion of living donor transplantation. Furthermore, proactive management of immunosuppressive medications post-surgery to prevent rejection and infection contributes to preserving graft function, thereby further promoting paediatric growth and development alongside optimised long-term outcomes[43,83].

Psychosocial support and long-term follow-up

The psychological well-being and social adaptation of paediatric kidney transplant recipients are crucial safeguards for their comprehensive growth and development. Transplantation is not only a major physiological procedure; patients also face long-term psychological stress and social adjustment challenges postoperatively, factors that directly impact their quality of life and developmental progress. Research indicates that psychological disorders, poor medication adherence, and low educational attainment are closely associated with long-term adverse outcomes in transplant recipients. For instance, a retrospective cohort study of paediatric liver transplant patients revealed that those with psychiatric disorders or substance use disorders exhibited significantly increased mortality risk in adulthood. Patients who failed to complete secondary education were more likely to be lost to follow-up and demonstrated markedly elevated mortality rates[89]. These findings underscore the critical importance of prioritising psychosocial support in renal transplant management. Active intervention to address mental health concerns, facilitate social functional recovery, and enhance educational attainment provides robust support for patients’ long-term health and developmental outcomes.

Furthermore, establishing a standardised long-term follow-up system is crucial for dynamically adjusting treatment plans and promptly identifying and intervening in potential risk factors. Paediatric kidney transplant recipients require continuous professional medical supervision and psychosocial support from the early postoperative period through adulthood. Long-term follow-up should not only encompass monitoring physiological indicators and immunosuppressive medications but also include regular assessments of mental health and social adaptation. Through multidisciplinary team collaboration that integrates resources from nephrology, psychology, social work, and education departments, individualised, dynamically adjusted follow-up plans can be developed, effectively reducing mortality rates and loss-to-follow-up, and enhancing transplant success rates and quality of life[89]. Consequently, the refinement of psychosocial support and long-term follow-up systems constitutes a key strategy for safeguarding the healthy development and quality of life of paediatric kidney transplant recipients.

CHALLENGES AND FUTURE DIRECTIONS IN RESEARCH ON POSTOPERATIVE GROWTH AND DEVELOPMENT FOLLOWING PAEDIATRIC KIDNEY TRANSPLANTATION

Research limitations and data deficiencies

Research into post-transplant growth and development in paediatric kidney recipients exhibits significant limitations, primarily concerning study design and data resources. First, the vast majority of existing studies are single-centre, retrospective analyses, lacking support from large-scale, multicentre, prospective data with long-term follow-up. This design constrains the generalisability and reliability of conclusions. For instance, an international survey indicates that even in countries with specialised paediatric kidney transplant centres, the annual number of paediatric kidney transplant cases remains limited. This results in small study sample sizes and significant variations in perioperative anaesthesia and intensive care management, making it difficult to establish uniform management protocols[90]. Furthermore, existing predictive models for paediatric kidney transplantation—such as machine learning-based delayed graft dysfunction (DGF) prediction models—while improving predictive accuracy to some extent, remain constrained by sample size and data completeness, making it challenging to fully reflect the complex clinical reality[70].

Second, the paediatric-specific mechanisms of growth and development remain incompletely elucidated. Growth and development in paediatric kidney transplant recipients are influenced by multiple factors, including the inhibitory effects of CKD on skeletal growth, side effects of immunosuppressive medications, nutritional status, endocrine function, and psychosocial factors[4,22]. However, current research predominantly consists of cross-sectional or short-term observational studies, lacking in-depth understanding of the dynamic interactions and combined effects of these factors on paediatric growth and development. Particularly concerning immunosuppressive therapy, while studies indicate adverse effects of corticosteroids on paediatric growth and sexual development, the precise molecular mechanisms and long-term consequences remain unclear[22]. Furthermore, despite clinical guidelines and expert consensus on GH therapy in paediatric CKD and post-transplant care, actual treatment decisions vary considerably across regions, centres, and physician experience. High-quality evidence regarding optimal timing and dosage remains lacking[20,91].

Application prospects of biomarkers and precision medicine

Precision monitoring and individualised treatment represent key directions for enhancing postoperative growth and development management in paediatric kidney transplantation. Currently, biomarkers demonstrate broad application prospects in non-invasive monitoring of rejection reactions and assessment of growth status. Although eGFR, traditionally calculated from serum creatinine, remains the gold standard for monitoring rejection, its sensitivity and specificity are inadequate, particularly in paediatric and long-term transplant settings. This leads to many ‘clinically stable’ patients actually experiencing subclinical acute rejection, highlighting the limitations of creatinine monitoring[56]. Consequently, developing more precise non-invasive biomarkers has become a research priority. Multiple studies highlight the diagnostic and predictive value of diverse emerging biomarkers in blood and urine. For instance, donor-derived circulating cell-free DNA has been demonstrated as a sensitive non-invasive indicator highly correlated with renal transplant rejection. Its integration with standard clinical monitoring significantly enhances predictive accuracy for rejection events[57]. Moreover, multi-omics analyses of urinary mRNA, microRNA, and metabolites have demonstrated potential for identifying acute rejection and monitoring graft injury[92-94]. These biomarkers not only reduce reliance on invasive biopsies but also provide reproducible monitoring tools for long-term follow-up.

The application of precision medicine in paediatric kidney transplantation relies on integrating advanced technologies such as genomics and machine learning. Combined analysis of whole-exome sequencing and donor-derived circulating cell-free DNA has demonstrated preliminary capabilities in assessing donor-recipient matching risks and predicting transplant-related complications, providing scientific grounds for individualised follow-up and treatment[95]. Machine learning methods have achieved breakthroughs in clinically phenotyping inflammation induced by cardiopulmonary bypass, suggesting that similar strategies may be applied to analyse immune response heterogeneity in paediatric kidney transplant recipients, thereby aiding the formulation of precision immunosuppression regimens[96].

Furthermore, dynamic monitoring of immune biomarkers—including immune-related gene polymorphisms and the ratio of regulatory T cells to Teff—offers novel perspectives for assessing immune tolerance status and inflammatory activity, potentially serving as a basis for personalised immunotherapy[62,97,98]. Pharmacogenomics research has identified common actionable genotypes in transplant recipients, suggesting that integrating pharmacogenomic information into clinical prescribing guidance may optimise immunosuppressant dose adjustment and safety management[99,100].

In summary, research on postoperative biomarkers in paediatric kidney transplantation is progressively shifting from traditional biochemical indicators towards multi-omics data integration and precision medicine. In the future, combining multi-level data from genomics, metabolomics, and immunological biomarkers, supplemented by artificial intelligence analysis, will enable more sensitive, specific, and personalised monitoring of transplant rejection and growth development. This will provide robust scientific support for optimising clinical management, propelling paediatric kidney transplantation into a new era of precision medicine[101-106].

Multidisciplinary collaboration and comprehensive care

The management of growth and development following paediatric kidney transplantation involves multiple factors, and the efforts of a single discipline alone cannot comprehensively address the complex needs of patients. Consequently, establishing a multidisciplinary collaboration and integrated management model is particularly crucial. Such multidisciplinary teams typically encompass specialists in paediatric nephrology, endocrinology, nutrition, psychology, and social work, aiming to provide patients with comprehensive support and individualised treatment plans across both medical and psychosocial dimensions.

First, establishing a multidisciplinary team encompassing paediatric nephrology, endocrinology, nutrition, and psychology effectively integrates expertise and resources across specialities. This enables the formulation of scientifically sound and appropriate interventions for growth and development issues following paediatric kidney transplantation. Nephrologists oversee post-transplant renal function maintenance and immunosuppression management, endocrinologists address GH therapy and sexual development concerns, dietitians provide guidance on nutritional status and dietary adjustments, while psychologists assess the psychological state of patients and families, assisting in coping with disease-related stress and anxiety. This team model not only optimises medical treatment but also enhances the quality of life for patients and families, improving treatment adherence and satisfaction[107,108].

Second, developing individualised, dynamically adjusted comprehensive management plans forms the core of multidisciplinary team collaboration. Given variations in each child’s transplant background, disease status, age, and psychological development stage, management strategies must be flexibly tailored to specific circumstances. For instance, GH application requires dynamic assessment and adjustment based on the patient’s growth rate, renal function status, and immunosuppressive medication use; nutritional interventions necessitate personalised design according to weight, height, metabolic requirements, and complications; psychological support should also be modified in response to changes in the patient’s psychological development and social environment[20,109]. Furthermore, as patients age, particularly during adolescence, the demands of growth and development become more complex. The team must closely monitor and promptly address any potential developmental delays or psychological issues[19].

The successful implementation of a multidisciplinary integrated management model relies on close communication and collaboration among team members. Regular multidisciplinary consultations, case discussions, and shared patient information ensure timely interdisciplinary communication and treatment consistency. Furthermore, active patient and family involvement is crucial; education and psychological support enhance their understanding of the disease and treatment process, promoting active cooperation and long-term follow-up[109,110]. Post-transplant growth in paediatric kidney recipients is determined by the interaction of baseline CKD-related growth impairment, age at transplantation, graft function, cumulative steroid exposure, nutritional and metabolic status, and the selective use of rhGH. The most consistent evidence supports early transplantation when feasible, protection of graft function, and steroid-sparing immunosuppression in appropriately selected children. rhGH has an important but targeted role in persistent growth failure after optimisation of modifiable factors, rather than serving as a universal intervention.

Future progress will depend on rigorous multicentre longitudinal studies that use standardised growth endpoints, clarify the long-term safety and indications of rhGH, and determine how biomarkers, pharmacogenomics, and predictive models can be translated into clinically meaningful, growth-focused care. In parallel, multidisciplinary follow-up that integrates nephrology, endocrinology, nutrition, psychology, and family education remains essential for improving both height outcomes and broader developmental well-being in paediatric kidney transplant recipients.

Enhancing patient and family education and adherence

Improving patient and family education is closely linked to treatment adherence and constitutes a critical factor in ensuring children’s growth and development following kidney transplantation, as well as securing favourable long-term outcomes. Primarily, strengthening awareness among patients and families regarding the significance of growth and development is paramount. Research indicates that issues such as growth retardation and delayed sexual maturation remain prevalent after paediatric kidney transplantation, adversely affecting patients’ quality of life and psychosocial well-being[22,111]. Therefore, systematic educational programmes should encompass knowledge on growth and development, assisting families in understanding the importance of postoperative growth support and its long-term implications. Furthermore, disseminating nutritional knowledge to promote balanced dietary intake among children remains vital. Research indicates that some parents lack adequate understanding of nutritional requirements and exhibit irregular dietary habits, necessitating targeted nutritional guidance from healthcare institutions[112]. During exceptional periods such as the coronavirus disease 2019 pandemic, patient and family education must remain robust, with timely dissemination of the latest infection control measures and medication information to prevent anxiety and reduced adherence arising from information gaps[113,114].

Second, enhancing treatment adherence is central to achieving favourable postoperative growth and outcomes. The literature extensively documents high rates of immunosuppressant non-adherence among paediatric and adolescent kidney transplant recipients. Non-adherence not only increases the risk of acute rejection but also severely impacts graft survival rates[115,116]. Consequently, interventions targeting adherence should be multi-faceted. Strategies employed in clinical practice include utilising patient self-reporting tools, electronic monitoring devices, and pharmacokinetic variability indices to assess adherence[117,118]. Compliance improvement programmes emphasise personalised support, such as employing gamified education to enhance adolescents’ medication knowledge and motivation[119], while encouraging family involvement to jointly supervise and support patients[120,121]. Additionally, healthcare teams should routinely assess compliance barriers, promptly providing psychological support and social resource connections to help patients overcome common issues like medication forgetfulness and concerns about side effects[122,123].

The continuity and tailored nature of patient and family education are also paramount. Research indicates that education should not be viewed as a single event but should span the entire transplant journey, with content and delivery methods adapted to different developmental stages to foster dynamic communication[124,125]. Simultaneously, considering patient individuality and cultural backgrounds, educational materials and communication approaches must be diversified to enhance information comprehensibility and acceptance[126,127]. For instance, social media and large language models may assist in delivering accessible, credible information, though clinical oversight remains essential to prevent misinformation-induced confusion[126,128,129]. Furthermore, specialised education and psychological support for family members—particularly guardians—can alleviate caregiving burdens while enhancing the household’s overall coping capacity and quality of life[130,131].

In summary, enhancing patient and family education and adherence requires a four-pronged approach: Strengthening the dissemination of growth, development, and nutrition knowledge; conducting precise assessments and interventions for adherence barriers; delivering continuous, personalised educational support; and reinforcing family support systems. Through multidisciplinary collaboration that integrates innovative educational methods and social resources, we can effectively promote postoperative growth and development in paediatric kidney transplant recipients, improve patients’ quality of life and long-term prognosis, and ultimately maximise transplant success.

The complexity of postoperative growth and development in paediatric kidney transplantation reflects the interplay of multiple factors, encompassing transplant age, renal function status, choice of immunosuppression regimen, and GH therapy. The authors contend that while current research has achieved significant advances in respective fields, the key to future progress lies in organically integrating these findings to form a scientific and systematic management strategy. Early kidney transplantation is widely regarded as a fundamental measure for promoting growth recovery. Clinical data indicate that younger recipients exhibit greater growth potential, closely linked to the cumulative impact of pre-transplant disease on physical development. However, early transplantation also presents challenges regarding immune tolerance and postoperative management, making optimisation of immunosuppression regimens particularly crucial. Current strategies to reduce corticosteroid usage have demonstrated positive effects in mitigating drug-related growth suppression across multiple studies. Nevertheless, individual variations in response to immunosuppressive agents necessitate clinicians to balance efficacy and safety, avoiding rejection episodes due to inadequate immunosuppression. GH therapy, employed as an adjunctive measure, has been demonstrated to effectively improve postoperative growth retardation, particularly in early kidney transplant recipients. Nevertheless, no uniform standards currently exist regarding its optimal initiation timing, dose adjustment, or long-term safety. The principle of individualised assessment thus becomes paramount. Tailoring GH regimens to each patient’s specific renal function, nutritional status, and immune profile maximises therapeutic efficacy while minimising potential risks. In recent years, the emergence of biomarkers and genetic prediction models has opened new perspectives for managing growth and development following paediatric kidney transplantation. These emerging tools not only aid in the early identification of high-risk patients but also provide scientific grounds for precisely adjusting immunosuppression and GH therapy. Although related research remains in its infancy, its potential is undeniable. Future large-scale, multicentre validation studies will be pivotal in advancing its clinical application.

In summary, the future of growth and development management following paediatric kidney transplantation relies on close multidisciplinary collaboration that integrates expertise from nephrology, endocrinology, nutrition, and genetics to drive a shift from monotherapy to comprehensive management. Concurrently, conducting large-scale, long-term, prospective clinical studies will not only clarify the specific influences of various factors but also provide robust evidence for developing standardised, individualised treatment guidelines. Through these endeavours, the ultimate goal is to significantly enhance the growth and development outcomes and overall quality of life for paediatric kidney transplant recipients, achieving a deep integration of medical technology and clinical practice to secure a brighter future for these young patients.

CONCLUSION

Growth and development after paediatric kidney transplantation reflect the interplay of transplant timing, graft function, immunosuppressive exposure, nutritional and metabolic status, endocrine therapy, and psychosocial support. Early transplantation, preservation of graft function, and steroid-sparing immunosuppression are among the most consistently supported strategies for improving growth outcomes. rhGH can be effective in selected children with persistent growth failure, but its timing, dosing, and long-term safety require individualised assessment and further study. Emerging biomarkers, pharmacogenomics, and predictive models may eventually help identify high-risk patients and guide precision therapy, although their growth-focused clinical utility remains to be validated. Future progress will depend on large, prospective multicentre studies and close collaboration among nephrology, endocrinology, nutrition, psychology, genetics, and family-support teams. Through such integrated care, paediatric kidney transplantation can more effectively support linear growth, developmental well-being, and long-term quality of life.