Most children with chronic kidney disease (CKD) present with variable degree of linear growth impairment at the time of transplantation (1). In addition to universal growth determinants (e.g., ethnical characteristics and target height), growth deficit in children with CKD depends on the individual influence of (i) patient's background (e.g., intrauterine growth retardation often associated with congenital diseases); (ii) age at onset of CKD; (iii) caloric intake during infancy; (iv) primary renal disease (e.g., tubular impairment with chronic dehydration and metabolic acidosis); and (v) CKD staging (growth hormone [GH] resistance and bone disease occur when glomerular filtration rate [GFR] is <60 mL/min/1.73 m2).
Growth retardation persists in renal allograft recipients despite successful transplantation. Indeed, the mean z-score of American patients having reached adult height is −1.5 standard deviation score (SDS), with 25% of them having a z-score of −2.3 SDS and 10% with a z-score inferior to −3.3 SDS (2). Most articles on growth in children posttransplant are short-term studies, but final height is the only available endpoint for patients. During the last decade, height of American children at the time of transplantation has increased by 1.0 SDS, and final height of European children on renal replacement therapy has improved by a mean of 1.8 SDS, reflecting substantial improvement in renal care (1–4).
Improvements in growth pretransplant management have led to better height attainment at transplantation, which is one of the most important factors in final height achievement (4, 5). The current average height deficit at the time of transplantation is approximately 1.8 SDS (1, 2). Therefore, measures for improving pretransplant growth, such as nutrition, should be regarded as a priority.
The timing of transplantation should take care of vulnerable phases of life when growth velocity in healthy children is at its maximum, i.e., during early infancy and during puberty. Therefore, subjects between 2 and 5 years of age have greater height deficit at transplantation, but they exhibit remarkable catch-up growth, whereas school-age children and adolescents demonstrate limited growth improvement (1, 2). On such bases, kidney transplantation should be sometimes postponed to an optimal growth period, according to local expertise.
As in children with CKD, GFR is a major determinant, and a long duration with a GFR <50 mL/min/1.73 m2 has a negative effect on final height (5). In addition, prepubertal catch-up growth and total pubertal height gain correlate positively with GFR (6). Indeed, long-term GFR is better in patients with adequate nephron mass, perfect control of blood pressure, limited exposure to calcineurin inhibitors, good human leukocyte antigen matching, short ischemia time, and optimal drug compliance.
Growth depression is a side effect of glucocorticoid therapy and is partially mediated by alterations in the somatotropic hormone axis. Indeed, dexamethasone has been shown to impair the GH-induced stimulation of local secretion and paracrine action of insulin-like growth factor-I and GHR expression. Immunosuppression strategies allowing at steroid avoidance/withdrawal do not increase mortality or graft loss in adults (7). Only few randomized trials in children have demonstrated evidence of catch-up growth under steroid-sparing strategies: alternate-day prednisone therapy (5); early steroid withdrawal (discontinued at day 4) under tacrolimus, mycophenolate mofetil, and daclizumab induction (8); and late steroid withdrawal (i.e., ≥1-year posttransplant) under cyclosporine microemulsion and mycophenolate mofetil (9). These are 6 to 12-month results and need further confirmation of better final height without decreased GFR or graft survival in the long term. However, recent immunosuppressive strategies have allowed limited long-term steroid exposure in low immunologic risk pediatric recipients. In addition, steroid sparing is accompanied by significant better lipid and glucose metabolism profiles, lower body mass index, and better blood pressure control (8, 9).
Calcineurin inhibitors have no significant effect on human growth, but they may be responsible for nephrotoxicity, decreased GFR, and further growth retardation. Sirolimus may also impair growth velocity because of its antiproliferative and antiangiogenic properties (10).
Recombinant human GH (rhGH) has been used in growth-retarded children with CKD and in renal replacement therapy, with better final height in patients on conservative treatment and hemodialysis than in transplant patients (11); in addition, it has been shown that rhGH may reverse the catabolic and growth-depressing effects of glucocorticoids (1). Most randomized controlled studies in transplant patients are based on short-term small series. They all confirm increased height velocity without any acceleration in bone maturation or change in GFR, but they also lead to conflicting results regarding final height and the risk of acute rejection (4, 12, 13). The largest multicenter experience comes from the NAPRTCS and concludes that rhGH is safe and effective on growth velocity (+0.49±0.10 SDS in the treatment group vs. −0.10±0.08 SDS in the control group, P<0.001), without associated increase in adverse events, including rejection episodes (14). In a long-term study of 48 renal transplant patients, height SDS before rhGH was −3.2±1.1 and adult height was −2.2±1.2 SDS compared with −3.0±0.9 and −1.8±0.9 on conservative treatment, respectively (11). However, the use of rhGH in short transplant children has not been approved by North American or European drug regulatory agencies, but it may be proposed to selected patients at a dose of 1.4 mg/m2 (0.05 mg/kg) per day, which provides a significant increase in growth velocity at least for the first 2 years of treatment (1, 15).
Donor source and antihypertensive medication may be predictive of height changes (2). Indeed, recipients of living donor organs have a better height gain than those from deceased donors. Subjects not receiving antihypertensive treatment during the first posttransplantation month have better growth than those using antihypertensive drugs (0.38 vs. 0.13 SDS, respectively; P<0.001).
Finally, there is no evidence for any significant proper influence of gender, race, and parathyroid hormone level.
In conclusion, optimal final height is a major issue regarding posttransplantation quality of life and self-esteem; furthermore, growth retardation is associated with excessive mortality rate in children (16, 17). Recent strategies, including steroid-sparing/avoidance regimens, could further improve longitudinal growth in renal transplant children.
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