Growth hormone therapy in pediatric kidney transplantation—the long-term clinical benefits beyond improvement of growth after withdrawal of pre-transplant therapy

Abstract

Growth retardation is one of the significant complications of chronic kidney disease (CKD) in children. The pathogenesis is multifactorial and includes genetic factors (the parental height and syndromic pattern of a specific primary kidney disease), birth-related factors (like prematurity/small for gestational age), age at onset of CKD, a nutritional deficiency and protein-energy wasting, hormonal disturbances, inadequate metabolic control, anemia, and poor efficacy of kidney replacement therapy. Once the potentially manageable clinical risk factors are addressed in children with CKD, however they still present height between the 3rd and 10th percentile and low height velocity (< the 25th percentile persisting > 3 months in infants and > 6 months in children)— growth hormone (GH) therapy should be considered. GH therapy is recommended in all stages of CKD beyond stage 2, including patients on dialysis and after kidney transplantation [1]. The improvement of growth velocity is always a primary outcome measure of GH therapy; however, administration of this hormone is associated with several other clinical effects. Impact of GH therapy on kidney function was evaluated in different studies. Experimental studies revealed that the administration of GH in CKD may induce hyperfiltration, followed by the decrease of GFR (as a consequence); however, this association was not confirmed in clinical studies, including children with CKD and treated with GH [2–6]. Pediatric kidney recipients are the group of special attention in terms of selection of an optimal approach to improve the growth deficit. Meta-analysis of randomized-controlled trials (RCTs) aimed at improving growth after transplantation has evidenced that steroid minimization by itself is an effective approach in pre-pubertal children; however, several patients still require GH therapy, if the reduced exposure to steroids is not a satisfactory measure [7, 8]. The data from these early reports have raised a concern that GH administered after transplantation may induce acute rejection [9, 10]. It was suggested that the presence of specific GH and IGF-1 receptors on lymphocytes and macrophages is of clinical importance [11]; however, the impact of GH therapy on subsets of lymphocytes relevant to the risk of acute rejection was denied in a prospective study [12]. Analysis of the potential impact of GH on T-helper cell phenotypes in pediatric kidney transplant recipients showed a temporary and clinically non-relevant increase in production of interleukins -2, -4 and -13, which returned to baseline values after 16 weeks of follow-up [13]. The augmentation of proliferative and cytotoxic responses to promote the anti-alloantigen reaction in mixed leucocyte culture was reported during GH administration, however with no clinical relevance [14]. The higher incidence of acute rejection in patients treated with GH after kidney transplantation (compared with non-treated transplant recipients) was not confirmed in several studies, a relevant meta-analysis of randomized controlled trials and by registry data [8, 15, 16]. In one of these trials, the absence of an association between GH therapy and a higher incidence of rejection was confirmed by protocol biopsies of the kidney graft; however, this study indicated caution in recruiting immunologically unstable patients with a history of previous acute rejection episodes to post-transplant therapy with GH [17]. There were no data on a decline of kidney graft function specifically related to GH therapy conducted after kidney transplantation [18]. The meta-analysisof RCTs * Ryszard Grenda [email protected]