A pilot study to determine the dose and effectiveness of adrenocorticotrophic hormone (H.P. Acthar® Gel) in nephrotic syndrome due to idiopathic membranous nephropathy

Abstract

Background: H.P. Acthar(®) Gel is currently the only Food and Drug Administration therapy approved for the treatment of nephrotic syndrome. Active drug ingredients include structurally related melanocortin peptides that bind to cell surface G-protein-coupled receptors known as melanocortin receptors, which are expressed in glomerular podocytes. In animal models of membranous nephropathy, stimulation has been demonstrated to reduce podocyte injury and loss. We hypothesized that H.P. Acthar(®) Gel would improve symptoms of the nephrotic syndrome in patients with idiopathic membranous nephropathy.

Methods: Twenty patients received a subcutaneous dose of 40 or 80 IU twice weekly. Changes in proteinuria, albumin, cholesterol profile, estimated glomerular filtration rate and serum anti-PLA2R antibodies were assessed at baseline and in response to treatment along with tolerance and safety.

Results: Baseline characteristics included mean proteinuria (9.1 ± 3.4 g/day), albumin (2.7 ± 0.8 g/dL), estimated glomerular filtration rate (77 ± 30 mL/min) along with elevated total and low-density lipoprotein (LDL) cholesterol. By 12 months of follow-up, there was a significant improvement in proteinuria in the entire cohort, decreasing to 3.87 ± 4.24 g/day (P < 0.001) with significant improvements in serum albumin, total and LDL cholesterol. A >50% decrease in proteinuria was noted in 65% of the patients with a trend toward better outcomes among patients who received greater cumulative doses. No significant adverse effects were documented. Clearing of serum anti-PLA2R antibodies prior to or in parallel with proteinuria improvement was noted in some, but not all patients.

Conclusions: H.P. Acthar(®) Gel is a potential therapy for nephrotic syndrome secondary to idiopathic membranous nephropathy that deserves further study.

Keywords: ACTH (H.P. Acthar® Gel); membranous nephropathy; nephrotic syndrome.

FIGURE 1:

Proteinuria response to treatment. The proteinuria response over time is graphed with (A) depicting the patients initiated at 40 IU and (B), those initiated at 80 IU. The patients wherein the dose was escalated from 40 to 80 IU are shown in gray.

FIGURE 2:

Proteinuria and cumulative ACTH dose. Proteinuria was inversely related to cumulative ACTH dose and the trend of this relationship was statistically significant (R = 0.53, P < 0.05).

FIGURE 3:

Association between proteinuria and anti-PLA₂R antibody. In antibody-positive patients, the association between proteinuria (black squares) and the anti-PLA₂R antibody (gray circles) versus time is plotted. (A) Patients wherein a response was noted. (B) Patients who did not respond either clinically or immunologically to ACTH therapy.

FIGURE 4:

Correlation between proteinuria and anti-PLA₂R antibody. There was a statistically significant correlation between the percentage change in anti-PLA₂R antibodies (% Δ anti-PLA₂R antibody) and improvement in proteinuria (% Δ proteinuria) after completion of the ACTH therapy (R² = 0.29; P = 0.04, A) and after 1 year (R² = 0.67; P < 0.001, B).

FIGURE 5:

The pharmacological response to ACTH. The serum (A) and urine cortisol (B) response to therapy is plotted against time where black represents the patients treated with the 80 IU dose and gray the patients treated with 40 IU.