Membranous nephropathy, a common immune-mediated glomerular disease, is the leading cause of nephrotic syndrome (NS) in Caucasian adults.1 While the disease progresses relatively slowly in most patients, about 40% go on to develop end-stage renal disease (ESRD).2 Because of the condition's frequency, it is the second- or third-leading cause of ESRD from a primary glomerulopathy.3
Patients with membranous nephropathy who remain nephrotic are at an increased risk for thromboembolic4 and cardiovascular events.5,6 Current immunosuppressive therapies, including the use of corticosteroids with alkylating agents and calcineurin inhibitors, are not always successful in inducing proteinuria remission in membranous nephropathy, and they can be associated with significant adverse effects and a high relapse rate. Thus, new therapies have been sought.
Berg and colleagues were the first to report that adrenocorticotropic hormone (ACTH) lowered albumin excretion and improved glomerular filtration rate (GFR) in patients with membranous nephropathy,7,8 in steroid-treated patients with renal disease,9 and in patients on hemodialysis.10
Almost all participants in these studies had a reduction in serum low–density lipoprotein (LDL) cholesterol and lipoprotein(a), whereas the influence of the agent on triglyceride metabolism was less consistent. Subsequent case series strengthened these observations.11,12
GFR Up, Albumin Excretion Down
Fourteen patients with membranous nephropathy received ACTH intramuscularly at increasing doses for 56 days.11,13 ACTH treatment, at the estimated optimal dose of 1 mg twice weekly, was then continued in five patients with severe steroid-resistant nephrotic syndrome. In these five patients, the total treatment period was 12 months, and the follow-up time after discontinuing treatment was 18 months.
At that dose, serum concentrations of cholesterol, triglycerides, apolipoprotein B, and lipoprotein(a) declined by 30% to 60%, whereas the serum concentrations of high-density lipoprotein cholesterol and apolipoprotein A-I increased by 30% to 40%. In addition, urinary albumin excretion rate decreased by 90%, and glomerular filtration rate went up 25%.
All patients who had ACTH treatment discontinued after 56 days showed deterioration in condition. However, the five patients in whom ACTH therapy was resumed were still in remission 18 months after treatment discontinuation.13
Similarly, Picardi et al treated seven patients with membranous nephropathy with the same schedule of ACTH.14 While five patients had complete remission of proteinuria within six months of treatment, two patients had to interrupt ACTH because of side effects.
More recently, Ponticelli et al conducted a randomized pilot study of 32 patients with idiopathic membranous nephropathy that compared methyl-prednisolone plus chlorambucil or cyclophosphamide (Group A, 16 patients) versus synthetic adrenocorticotropic hormone (Group B, 16 patients).15 ACTH was administered by one intramuscular injection (1 mg) every other week, with the frequency increased to two injections per week for a total treatment period of one year.
Data were reported according to an intention-to-treat analysis. Complete or partial remission as a first event was reached by 93% of patients in Group A (5 complete remissions and 10 partial remissions) and 87% in Group B (10 complete remissions and 4 partial remissions), which was not a significant difference.
These studies suggest that prolonged synthetic ACTH therapy may represent an effective treatment for patients with idiopathic membranous nephropathy. Reported side effects include dizziness, alertness, disturbed night sleep, fluid retention, glucose intolerance, diarrhea, risk of infection (pneumonia, folliculitis), low serum potassium, and the development of bronze-colored skin. With the exception of pneumonia, which required antibiotic therapy, all side effects resolved after the end of ACTH therapy.13,15
ACTH Gel: Retrospective Case Series
These studies used a synthetic version of ACTH (Synacthen, which is not available in the United States), but a retrospective case series of patients with nephrotic syndrome using a natural, highly purified, full-sequence ACTH1-39 gel formulation (H.P. Acthar Gel), currently approved in the United States for remission of proteinuria in the nephrotic syndrome, reported similar encouraging results.16
In this study, Bomback et al reviewed data on 21 patients identified as receiving treatment with ACTH gel for idiopathic nephrotic syndrome, including 11 patients with membranous nephropathy. The majority of these patients received ACTH as second-, third-, or fourth-line therapy for resistant nephrotic syndrome.
Dosing intervals varied from two to three times weekly, with all but six patients treated for at least six months. The longest treatment period was 14 months.
Overall, 11 of 21 subjects (52%) reached a complete or partial remission, including nine who had membranous nephropathy and had already tried a mean of 2.4 unsuccessful immunosuppressive therapies. A total of four patients (19%) had a complete remission, and no severe infections were reported in the entire cohort.
A multicenter, randomized, double-blind, four-arm, placebo-controlled study using ACTH gel in treatment-resistant patients with membranous nephropathy and nephrotic syndrome is currently under way (ClinicalTrials.gov, NCT01386554).
The primary objective of the study is to assess the proportion of treatment-resistant subjects who have a complete or partial remission of proteinuria after 24 weeks of treatment. If successful, it will provide physicians with an important therapeutic option for patients with membranous nephropathy who are treatment resistant and have a low probability of spontaneous remission.
The exact mechanism by which ACTH mediates its effects on proteinuria is not completely understood but is likely independent of its induction of cortisol production, as production remains low and there is concomitant evidence that steroids alone do not affect disease outcome.17
Ponticelli et al hypothesize that by modifying apolipoprotein metabolism, ACTH might restore glomerular expression of apolipoprotein J (also called clusterin), which is reduced in patients with membranous nephropathy.15,18
More recently, it was suggested that ACTH may mediate its effects via the alpha-melanocyte-stimulating hormone (α-MSH). Both ACTH and α-MSH are derived from the pro-opiomelanocortin (POMC) precursor.
In a recent study, treatment with α-MSH or MS05, a specific MC1R agonist, showed similar and significant reductions in proteinuria in rats with passive Heymann nephritis, while ACTH had a tendency to reduce the level of proteinuria that did not reach statistical significance.19 These results suggest that ACTH mediates its effects via α-MSH interaction on MC1R on podocytes and may explain why patients who are resistant to previous immunosuppressive therapies respond to ACTH.
ACTH also may work by modulating autoantibody production. More than 70% of patients with membranous nephropathy are positive for autoantibodies to the phospholipase A2 receptor (PLA2R),20 and the presence of these antibodies correlates with clinical disease activity.21
We recently analyzed anti-PLA2R in patients treated with ACTH gel (H.P. Acthar Gel) to better understand its potential mechanism of action.22 Samples were collected from 14 patients in two pilot studies (Mayo Clinic, n=9; Columbia, n=5) that treated membranous nephropathy patients with ACTH gel for six months.
Twelve patients (86%) were anti-PLA2R positive at baseline, and all 12 experienced a reduction in anti-PLA2R (17% to 100%) by six months, with the disappearance of anti-PLA2R in five cases.
There were five partial remissions at six months—three in patients who cleared their anti-PLA2R and two in those lacking baseline anti-PLA2R. Another patient later achieved a 96% reduction in anti-PLA2R without further treatment, while two others fully cleared their anti-PLA2R after receiving rituximab for perceived failure of ACTH gel.
With 12- to 18-month follow-up of those with undetectable anti-PLA2R at baseline or after ACTH gel (with or without rituximab), there were four complete and two partial remissions, one nonresponder, and a final patient who achieved partial remission but relapsed coincident with a return of anti-PLA2R. Two other patients also showed an increase in anti-PLA2R after discontinuing treatment with ACTH gel.
Thus, measurement of anti-PLA2R provides useful information relating immunological and clinical disease activity in membranous nephropathy patients treated with new agents such as ACTH gel. This study suggests that ACTH gel may work in part by suppressing autoantibody production, although the duration and degree of this response need further study.
Major breakthroughs have been made in the field of membranous nephropathy. We now know that autoimmunity accounts for 70% to 80% of cases, and new autoantibodies are being discovered.
Promising new therapies in membranous nephropathy are being evaluated by two important ongoing clinical trials: one examining the use of ACTH gel in patients who are treatment resistant, as previously discussed, and one comparing rituximab with cyclosporine in treatment-naïve or relapsing membranous nephropathy patients (ClinicalTrials.gov, NCT01180036).
When commercially available, quantification of antibodies (e.g., anti-PLA2R) may help monitor disease activity and therapeutic response more efficiently than proteinuria alone. Soon, we should be able to reach the goal of personalized therapy in patients with membranous nephropathy. •
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17. Cattran DC, Delmore T, Roscoe J, et al. A randomized controlled trial of prednisone in patients with idiopathic membranous nephropathy. N Engl J Med
18. Ghiggeri GM, Bruschi M, Candiano G, et al. Depletion of clusterin in renal diseases causing nephrotic syndrome. Kidney Int
19. Lindskog A, Ebefors K, Johansson ME, et al. Melanocortin 1 receptor agonists reduce proteinuria. J Am Soc Nephrol
20. Beck LH Jr., Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med
21. Beck LH Jr., Fervenza FC, Beck DM, et al. Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. J Am Soc Nephrol
22. Beck LH, Fervenza FC, Bomback AS, et al. Response of anti-PLA2R to adrenocorticotropic hormone (ACTH) gel in membranous nephropathy. Abstract presented at: American Society of Nephrology Kidney Week 2011; Nov. 10, 2011; Philadelphia, PA.