Rationale: Poor growth is one of the major complications of chronic kidney disease (CKD) and can persist following kidney transplantation (kTx). Since growth delay can have a negative impact on psychological well-being, social development, self-esteem, and quality of life, achieving an acceptable adult height is a crucial issue for Ktx recipients (Qvist et al., 2004). Although a successful kTx corrects many of the metabolic abnormalities from the pre-transplant CKD period, post-transplant catch-up growth is generally insufficient to correct a pre-existing growth deficit and is usually more pronounced in young prepubertal children (Silverstein, 2018). Final adult height after kTx is closely related to the pre-transplant height and target adult height range based on parental height is attained only in 42–75% of paediatric CKD patients (Jung et al., 2013). Growth in infancy, childhood and puberty is determined by specific age-related key factors being nutrition, somatotrophin axis and sex hormones, respectively (Waller, 2011). In addition, specifically in paediatric KTx recipients statural growth is affected by three major factors: age at kTx, allograft function, and corticosteroid dose and therapy duration (Fine, Martz, & Stablein, 2010) (Haffner, 2020) (Grenda et al., 2010) (Tourlamain et al., 2023).

Our understanding of the impact of deranged CKD-MBD parameters on statural growth is mainly based on pretransplant CKD. Given the multifactorial aetiology of growth impairment, the reported evidence in the association of CKD-MBD parameters and statural growth is rather weak (Haffner, 2020). In a study including 890 children and adolescents reported to the International Pediatric Peritoneal Dialysis Network Registry, parathyroid hormone (PTH) levels above 300 pg/ml were associated with radiological symptoms of CKD-MBD, whereas only time-averaged PTH concentrations above 500 pg/ml were associated with impaired longitudinal growth (Borzych et al., 2010). Recently Brown et al. reported that low (≤ 22 mmol/L) and very low (≤ 18 mmol/L) serum bicarbonate levels were associated with worse height Z-scores in children with CKD due to nonglomerular disease but not in glomerular disease (Brown et al., 2022). Furthermore, among children ≤13 years of age, treatment with alkali was positively associated with improved growth. In contrast, in 704 children in the Cardiovascular Comorbidity in Children with CKD Study, a prospective cohort of paediatric patients with CKD stages 3-5, no association was found between time-varying metabolic acidosis and longitudinal growth (Harambat et al., 2017). Another modifiable parameter associated with pre-transplant growth restriction is anaemia: improved growth has been reported in children with higher haemoglobin (Hb) levels and early erythropoietin prescription (Boehm et al., 2007).

Little is known on the association between CKD-MBD parameters and statural growth after paediatric KTx. A German study including 389 paediatric KTx recipients reported an inverse association between the degree of metabolic acidosis and anaemia with linear body dimension length (Franke et al., 2015). Anaemia and hypertension were also associated with height SD scores in a study from the ESPN/ERA-EDTA Registry analysing growth in 3492 children who underwent KTx between 1990 and 2012 (Bonthuis et al., 2020). Although derangements in CKD-MBD parameters such as hyperparathyroidism, hypo- and hypercalcemia and hypo- and hyperphosphatemia are common in paediatric KTx recipients, to the best of our knowledge there are no reports on their association with statural growth. Given the significance of other patient- and transplant characteristics (allograft function and corticosteroid use), such studies would require sufficient numbers of patients to detect associations between CKD-MBD parameters and growth.

Methods:The Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) Registry provides detailed anthropometric and biochemical data on paediatric KTx recipients. As of January 2023 there were 3548 patients

registered in the CERTAIN Registry, of whom 2414 with data at least at 3 months post Ktx. Data are registered prior to kidney transplantation, at month 1, 3, 6, 9 and 12 posttransplant and in 6 months intervals thereafter. Specific case report forms collect detailed and accurate information on relevant data and events of paediatric kidney transplantation in the peri- and posttransplant course. The CERTAIN web application has an automatic and manual data validation functionality and only data passing this quality verification process are incorporated into the research database. Using data from the CERTAIN Registry allows a robust analysis of the association of CKD-MBD parameters and statural growth in a largest European cohort so far, taking into account the  relevant patient and transplant characteristics.

Statistical analysis will be performed in collaboration with prof. Els Goetghebeur, Department of Applied Mathematics, Computer Science and Statistics at Ghent University.

Primary analysis: The primary outcome measure is the difference in height Z-scores at baseline and year 1, 3, 5 and 10 from KTx;  the covariates will include well-known factors associated with statural growth such as age at transplantation, donor source, disease – and dialysis vintage, time-varying parameters glucocorticoid dose, systolic hypertension and allograft function as well as time-varying CKD-MBD parameters Ca, P, PTH, Hb and bicarbonate. Previous studies in children with CKD have shown that worsening GFR is associated with worsening of CKD-MBD parameters. To account for the effect of eGFR change, structural marginal models will be applied and compared with the conventional Cox PH models. Also, a sensitivity analysis will be performed excluding patients with syndromic short stature.

Secondary analyses: Association between the difference in height Z-scores at baseline and year 1, 3, 5 and 10 from KTx and the use of calcium and phosphate supplements, calcium-containing phosphate binders, nutritional vitamin D, activated vitamin D analogues, calcimimetics, alkali supplementation, iron supplements, erythropoetin and pre- and post-KTx use of rhGH