How did adrenocorticotropic hormone (ACTH) historically help in the treatment of minimal change disease?

Historical Use of ACTH in Minimal Change Disease

ACTH Was Not Recommended for Minimal Change Disease in Children

The KDIGO 2013 guidelines explicitly stated that ACTH (adrenocorticotropic hormone; corticotropin) should not be used as a steroid-like option in children with steroid-sensitive nephrotic syndrome (SSNS) or steroid-resistant nephrotic syndrome (SRNS) because it was very expensive and had not been studied in this population. 1

This recommendation reflected the lack of pediatric evidence at that time, despite ACTH having historical use in adult glomerular diseases.

Historical Mechanism and Rationale in Adults

While not recommended in children, ACTH was explored historically in adult minimal change disease based on several proposed mechanisms:

Steroidogenic Effects

• ACTH stimulates endogenous cortisol production from the adrenal cortex, providing an alternative route to achieve glucocorticoid effects without exogenous steroid administration 2, 3
• This mechanism was thought to potentially reduce some steroid-related side effects while maintaining immunosuppressive benefits 3

Direct Melanocortin Receptor Effects

• ACTH binds to melanocortin receptors (MC1R, MC3R, MC5R) expressed on podocytes and other glomerular cells, potentially exerting direct anti-proteinuric effects independent of steroidogenesis 4, 5
• These direct effects on the glomerular filtration barrier were hypothesized to restore podocyte function and reduce proteinuria 4

Immunomodulatory Properties

• ACTH was thought to have immunomodulatory effects beyond simple glucocorticoid production, potentially affecting T-cell function and cytokine profiles 4
• These effects could theoretically address the underlying immune dysregulation in minimal change disease 4

Limited Historical Evidence Base

The historical use of ACTH in minimal change disease was largely empirical and anecdotal:

• No randomized controlled trials specifically evaluated ACTH in minimal change disease during the historical period 1
• Most evidence came from case series and retrospective observations rather than rigorous prospective studies 2, 3
• The 2013 KDIGO commentary explicitly noted the absence of studies in children with SSNS or SRNS, which limited any recommendation for its use 1

Modern Prospective Data (Post-Historical Period)

More recent prospective studies have provided some evidence for ACTH efficacy:

• A 2012 prospective trial included 2 patients with resistant minimal change disease treated with ACTH gel 80 units subcutaneously twice weekly for 6 months—one achieved partial remission but relapsed within 4 weeks of stopping ACTH 2
• A 2015 single-center pilot study using low-dose synthetic ACTH (tetracosactide 1 mg IM weekly for 12 months) included 3 patients with minimal change disease, achieving a 55.5% overall responder rate across all nephrotic conditions studied 3
• A 2016 case series reported 3 patients with minimal change disease who received ACTH as second-line or later therapy—all responded with one complete remission and two partial remissions, with good tolerability 5

Critical Limitations and Concerns

Cost Barrier

• ACTH was prohibitively expensive, making it impractical for routine use even when some efficacy was observed 1
• This cost factor was a major reason for the explicit recommendation against its use in the 2013 KDIGO guidelines 1

Steroid-Like Adverse Effects

• Despite theoretical advantages, ACTH still produced significant steroid-like side effects including weight gain, hyperglycemia, and fluid retention in a substantial proportion of patients 2, 3, 5
• In the 2012 prospective trial, 3 of 15 subjects (20%) reported significant steroid-like adverse effects prompting early termination 2

Relapse Risk

• The durability of response was questionable, with documented relapses occurring within weeks of stopping therapy 2, 5
• This raised concerns about whether ACTH provided any sustained benefit over conventional glucocorticoids 2

Historical Context: Why ACTH Was Explored

ACTH was investigated historically because:

• Minimal change disease is typically steroid-sensitive, but many patients experience frequent relapses or become steroid-dependent, requiring alternative approaches 1, 4
• Chronic glucocorticoid use causes cumulative toxicity including growth retardation in children, osteoporosis, diabetes, and cardiovascular complications 1
• Alkylating agents (cyclophosphamide, chlorambucil) carry risks of permanent gonadal toxicity and malignancy, making them undesirable for repeated courses 1
• Calcineurin inhibitors require long-term use and carry nephrotoxicity risks 1

ACTH was explored as a potential steroid-sparing agent that might achieve remission through alternative mechanisms while avoiding some conventional immunosuppressive toxicities. 4, 5

Current Status

Modern guidelines now recognize other steroid-sparing options as preferred alternatives:

• Rituximab has emerged as a valid option for frequently relapsing or steroid-dependent nephrotic syndrome, though optimal dosing requires further clarification 1
• Mycophenolate mofetil is considered a valid second-line option due to widespread availability, ease of administration, and favorable side-effect profile compared to alkylating agents or calcineurin inhibitors 1
• Levamisole (when available) and calcineurin inhibitors remain established alternatives 1

The historical exploration of ACTH in minimal change disease reflected desperation for steroid-sparing alternatives in a disease characterized by frequent relapses and steroid toxicity, but the lack of rigorous evidence, prohibitive cost, and persistent steroid-like side effects prevented it from becoming a recommended therapy. 1, 2, 3