Adrenocorticotropic hormone therapy for the treatment of idiopathic nephrotic syndrome in children and young adults: a systematic review of early clinical studies with contemporary relevance

Abstract

Adrenocorticotropic hormone (ACTH) as a treatment for proteinuria due to nephrotic syndrome (NS) has re-emerged over the last decade. Current clinical data are primarily limited to adults with treatment-resistant NS. Largely unknown to today’s clinicians is the existence of early clinical studies, following ACTH’s introduction in the late 1940s, showing sustained proteinuria response in idiopathic NS in predominantly pediatric, treatment-naïve patients. Before ACTH, patients suffered severe edema and high mortality rates with no reliable or safe treatment. ACTH dramatically altered NS management, initially through recognition of diuresis effects and then through sustained proteinuria remission. This review synthesizes early clinical literature to inform current NS patient management. We undertook a MEDLINE search using MeSH terms “adrenocorticotropic hormone” and “nephrotic syndrome,” with limits 1945–1965 and English. Sixty papers totaling 1137 patients were found; 14 studies (9 short-term, five long-term, N = 419 patients) met inclusion criteria. Studies were divided into two groups: short-term (≤28 days) and long-term (>5 weeks; short-term initial daily treatment followed by long-term intermittent)ACTH therapy and results were aggregated. An initial response, defined as a diuresis, occurred in 74 % of patients/treatment courses across nine short-term ACTH studies. Analyzed in eight of these studies, proteinuria response occurred in 56 % of patients/treatment courses. Across five long-term ACTH studies, proteinuria response was shown in 71 % of patients and was sustained up to 4.7 years following treatment. The inventory and re-evaluation of early clinical data broadens the evidence base of clinical experiences with ACTH for implementation of current treatment strategies and aiding the design of future studies.Electronic supplementary materialThe online version of this article (doi:10.1007/s40620-016-0308-3) contains supplementary material, which is available to authorized users.

Adrenocorticotropic Hormone for Childhood Nephrotic Syndrome

“…ACTH formulations were different in the 1950s compared with the highly purified, long-acting repository corticotropin injection used in this study. It is not possible to quantitatively compare the dosing used in the 1950s with the ACTH formulation available today; no pharmacokinetic data exist in children (13). In our study, we chose 80 U/1.73 m 2 administered twice weekly on the basis of adult experiences (17), but this dosing had not been verified in children with nephrotic syndrome for the treatment goal of relapse prevention.…”

“…On the basis of a systemic review of early studies showing that 71% of patients responded to ACTH maintenance therapy (13), goal enrollment was determined to be 60 participants (30 participants in each arm) to provide 90% statistical power to detect a 40% difference in the 6-month relapse rate (70% versus 30%), with a two-sided z test, the a-spending function by Lan and DeMets (21,22), and a type 1 error rate of 5%. Two analyses at 50% and 100% enrollment (with 6 months of follow-up) were planned.…”

“…Adrenocorticotropic hormone (ACTH) was widely used in the 1950s as a first-line treatment of nephrotic syndrome, and was shown to induce disease remission and improve patient survival (8)(9)(10)(11)(12). However, by the 1960s, ACTH was replaced by oral prednisone for its ease of administration and the belief that ACTH acts via stimulation of corticosteroid production (8,13,14). More recently, several case series of patients with steroid-and multidrug-resistant nephrotic syndrome reported ACTH to be efficacious in inducing and sustaining disease remission and improving GFR, which suggests that ACTH has effects beyond steroidogenesis (13,(15)(16)(17)(18).…”

“…However, by the 1960s, ACTH was replaced by oral prednisone for its ease of administration and the belief that ACTH acts via stimulation of corticosteroid production (8,13,14). More recently, several case series of patients with steroid-and multidrug-resistant nephrotic syndrome reported ACTH to be efficacious in inducing and sustaining disease remission and improving GFR, which suggests that ACTH has effects beyond steroidogenesis (13,(15)(16)(17)(18). In addition, one randomized trial demonstrated similar efficacy when comparing ACTH with methylprednisolone and a cytotoxic agent in membranous nephropathy, renewing interest in ACTH for nephrotic syndrome treatment (19).…”

“…Furthermore, published experience in Due to the number of contributing authors, the affiliations are listed at the end of this article. children is limited, and clinicians rely on anecdotal evidence to guide patient treatment (13). Hence, we conducted a multisite, open-label, randomized, clinical trial to evaluate the efficacy and safety of 12 months of ACTH in children with frequently relapsing or steroid-dependent nephrotic syndrome.…”