Article Published in the Author Account of

Andrew S Bomback

Treatment of Nephrotic Syndrome with Adrenocorticotropic Hormone (ACTH)

Abstract: Over the last two decades, adrenocorticotropic hormone (ACTH) has re-emerged as a potentially effective therapy for nephrotic syndrome, particularly for patients who have failed more conventional immunosuppressive therapies. The initial experience in Europe using synthetic ACTH in membranous nephropathy led to a randomized trial in which ACTH performed comparably to a combined regimen of steroids and alkylating agents. Observational data from American patients treated with natural ACTH gel for resistant nephrotic syndrome have also been promising. While we await larger clinical trials of ACTH in the nephrotic patient population, we still also await a more precise understanding of how the therapy achieves remission of proteinuria. We discuss a number of possible mechanisms for ACTH's beneficial effects on the inflammation and injury that occurs in nephrotic syndrome.



Introduction

Patients with idiopathic nephrotic syndrome often require immunosuppression to achieve remission, yet many patients either relapse after remission or are resistant to therapy. For example, while up to 90% of adults with minimal change disease (MCD) will respond to initial therapy with prednisone, approximately one third of these same patients will relapse within 6 months and require further immunosuppression (Palmer et al., 2008; Waldman et al., 2007). With diseases such as idiopathic membranous nephropathy (iMN) and focal segmental glomerulosclerosis (FSGS), for which first-line therapies have substantially lower response rates than for MCD, physicians are often compelled to use second-, third-, and even fourth-line therapies to achieve remission (Cattran et al., 2007; 1999; 2001; 2004; Ponticelli et al., 1993; Segarra et al., 2009). New therapies for these diseases are thus always being sought. In this review, we explore the currently available data for one such novel therapy, adrenocorticotropic hormone (ACTH), currently being used and investigated as treatment for nephrotic syndrome.

European Synthetic ACTH Experience

Technically speaking, ACTH is not a particularly new therapy for nephrotic syndrome. Indeed, ACTH injections were one of the first therapies used for nephrotic syndrome but promptly fell out of use when oral prednisone became a cheap, easy to implement, and equally effective option. Nonetheless, ACTH remains one of the only medications approved by the Food and Drug Administration (FDA) for treating nephrotic syndrome (the approval stems from its initial use), alongside steroids and cyclophosphamide.

The story of how ACTH re-emerged as a “novel” nephrotic syndrome therapy is one of serendipity. Berg and colleagues in Sweden were originally interested in using ACTH as a lipid-lowering therapy. In their studies, they employed tetracosactide, a synthetic, depot formulation of ACTH (Synacthen®, Novartis Pharmaceuticals, Basel, Switzerland). Their earliest publications, in 1996 (Berg and Nilsson-Ehle, 1996) and 1997 (Arnadottir et al., 1997), reported principally on reductions in serum lipid concentrations in chronic kidney disease patients previously treated with steroids and hemodialysis patients, respectively. Given that patients with nephrotic syndrome typically have very elevated cholesterol levels, Berg and colleagues began to study ACTH in patients with iMN, the leading cause of idiopathic nephrotic syndrome in European adults. In 1999, they reported again that ACTH yielded impressive reductions in serum lipid values but, more importantly, also led to profound reductions in proteinuria and serum creatinine (with concomitant rises in serum albumin and estimated glomerular filtration rate) in 14 patients with iMN. When ACTH was discontinued after a treatment duration of 56 days, all 14 patients promptly relapsed (Berg et al., 1999).

Within five years, this group had created a treatment regimen (1 mg twice a week for 2-11 months, continued until the patient demonstrated a sustained remission of proteinuria) and reported on their series of 23 patients with various etiologies of nephrotic range proteinuria, including MCD, iMN, FSGS, membranoproliferative glomerulonephritis (MPGN), and diabetic nephropathy, all of whom demonstrated significant and prolonged remissions with ACTH therapy (Berg and Arnadottir, 2004). Subsequently, a randomized, controlled study by Ponticelli et al. (2006) reported similar remission rates in 32 patients with iMN randomized to ACTH (n=16) or to therapy with alternating months of steroids and cyclophosphamide (n=16), the gold standard for treating iMN. After a median follow-up of 24 months, there were 4 complete and 8 partial remissions in the steroid/cytotoxic therapy group versus 8 complete and 6 partial remissions in the ACTH group. There have been two additional, small case series of ACTH in iMN, a 4-patient study from Germany (Rauen et al., 2009) and 5 additional patients from Sweden reported in the first half of a basic science article (Lindskog et al., 2010).

Experience with ACTH Gel in the United States

The preparation of ACTH used for these European patients was tetracosactide, a synthetic, depot formulation of ACTH (Synacthen) that is not currently available for use in the United States. However, a natural, highly-purified ACTH gel formulation (H.P. Acthar gel, repository corticotropin injection, Questcor Pharmaceuticals, California, USA) is available in the United States and FDA-approved for treating nephrotic syndrome. The data on this ACTH gel treatment regimen are far smaller than the published European data using synthetic ACTH.

We and others recently published the first modern experience using ACTH gel for nephrotic syndrome in an American patient population (Bomback et al., 2011). In a retrospective case series, we reported all known cases of idiopathic nephrotic syndrome treated with ACTH gel outside of research settings (i.e., by prescription) with initiation of therapy by December 31, 2009, allowing a minimum of 6 months of follow-up at the time of manuscript preparation. Full data were available for 21 patients with the following diagnoses: iMN (n=11), MPGN (n=4), FSGS (n=1), MCD (n=1), IgA nephropathy (n=1), class V SLE glomerulonephritis (n=1), monoclonal diffuse proliferative glomerulonephritis (n=1), and unbiopsied nephrotic syndrome (n=1).

Figure 1. Changes in proteinuria with ACTH gel therapy in 11 patients with nephrotic syndrome due to membranous nephropathy. Data from Bomback et al., 2011.

Figure 1. Changes in proteinuria with ACTH gel therapy in 11 patients with nephrotic syndrome due to membranous nephropathy. Data from Bomback et al., 2011.

Eighteen of the 21 patients were considered to have resistant nephrotic syndrome, having failed a mean 2.3 immunosuppressive regimens prior to ACTH gel therapy (9 patients had failed at least 3 prior therapies). Most patients had impaired baseline renal function (eGFR range 11 to >60 ml/min/1.73m2), with 12 patients demonstrating stage 4 or 5 chronic kidney disease (eGFR <30 ml/min/1.73m2). Overall, 11 of 21 patients (52%) achieved a complete or partial remission, with 4 (19%) in complete remission. Of the 11 patients who achieved complete or partial remission, 9 had iMN, 1 had FSGS, and 1 had IgA nephropathy. Of the 11 patients with iMN (Figure 1), 3 achieved complete remission and 6 achieved partial remission despite having previously failed a mean 2.4 therapies. Of the 10 patients with nephrotic syndrome diagnoses other than iMN, 1 patient with IgA nephropathy achieved complete remission, 1 patient with FSGS achieved partial remission, and 1 patient with MPGN had a limited response to therapy.

Thus, the initial experience with ACTH gel in non-research settings demonstrated that iMN was the leading diagnosis among treated patients and showed the greatest benefit of therapy. Based on this observation, we and others recently presented in abstract form a cohort consisting solely of patients with iMN: 17 patients treated at two centers (Columbia University and Mayo Clinic) on a standardized regimen of ACTH gel (median treatment time of 6 months, range of 3-12 months). Seven of these patients received therapy as part of investigator-initiated research studies. Fourteen of the 17 patients had failed a mean 2.5 previous immunosuppressive therapies. At the end of follow-up, which ranged from 6 to 13 months, 10 of the 17 patients were in complete (n=3) or partial (n=7) remission.

A number of small, investigator-initiated studies examining the effects of ACTH gel on nephrotic syndrome are currently underway at various centers around the United States. These studies are using ACTH therapy for patients with a range of etiologies of nephrotic syndrome, including iMN, FSGS, MCD, IgA nephropathy, systemic lupus erythematosus, and diabetic nephropathy. Results from these trials are expected to be reported in 2012.

Potential Mechanisms of ACTH Therapy

Although the data are still premature, the observations of ACTH therapy’s effects on nephrotic syndrome in the United States (using a natural gel formulation) are essentially in agreement with the previously published reports from Europe (using a synthetic ACTH analogue). Still, none of these data reviewed above provide any further understanding of the mechanism of action by which ACTH ameliorates proteinuria in the nephrotic syndrome. Speculatively, its better performance in iMN than other causes of nephrotic syndrome might point to a target of action — e.g., antibodies against the M-type phospholipase A2 receptor (PLA2R), the target antigen of that disease (Beck et al., 2009). However, clearly a gap exists in our understanding of how this agent works, and widespread adoption of the therapy will likely not occur until we have a better grasp of this treatment mechanism.

Figure 2. ACTH acts via the MC2R in the adrenal gland to stimulate steroid production.

Figure 2. ACTH acts via the MC2R in the adrenal gland to stimulate steroid production.

ACTH, along with α-, β-, and γ-MSH, are a group of small peptide hormones, called melanocortins, derived from the common precursor pro-opiomelanocortin (POMC). While all melanocortins share an invariant His-Phe-Arg-Trp (HFRW) core sequence, they differ in their affinity for the five melanocortin receptors distributed throughout the body (MC1R-MC5R) (Mountjoy et al., 1992). In trying to elucidate the therapeutic mechanism of ACTH, it is important to note that ACTH is cleaved to α-MSH, but these two peptides have divergent binding properties. Only ACTH binds to the MC2R, the melanocortin receptor found in the adrenal cortex and responsible for initiating steroidogenesis. Indeed, one proposed mechanism of ACTH’s effects on nephrotic syndrome is by stimulating endogenous steroid production (Figure 2). Some cases of nephrotic syndrome undergo spontaneous remission (Schieppati et al., 1993), which theoretically could be due to an ACTH surge triggered by the stress of illness leading to an endogenous steroid load. The flaw with this mechanism, however, is that steroids alone have not been shown to be an effective therapy for membranous nephropathy (Hogan et al., 1995), whereas ACTH has shown its best results in this disease.

Figure 3. ACTH and α-MSH bind to MC1R targets in B-cells, T-cells, and antigen presenting cells (APCs) to quell inflammation.

Figure 3. ACTH and α-MSH bind to MC1R targets in B-cells, T-cells, and antigen presenting cells (APCs) to quell inflammation.

The MC1R is located on various cells, including melanocytes, keratinocytes, and glial cells. Of note, these receptors have also been localized to B cells, T cells, and antigen presenting cells (Figure 3), the key players in virtually all inflammatory reactions (from either an external or internal source). B and T cells are the prime targets of most immunosuppressive therapies used for nephrotic syndrome. A potential mechanism of ACTH’s effects on proteinuria, therefore, is via its actions on the MC1R in these cell lines. In this case, α-MSH, which is felt to have a greater affinity than ACTH for the MC1R, may be the active therapeutic peptide. Conversely, ACTH may have a stronger affinity for the MC3R, which is located in macrophages and also implicated in inflammatory reactions, than α-MSH.

ACTH and α-MSH both have the potential to induce a potent, anti-inflammatory and immune-modulating response, which is why both agents have been used or investigated in various diseases characterized by hyperactive immunity and inflammation, including multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, and gout (Catania et al., 2004; 2010). α-MSH has been shown to protect against acute kidney injury in a rodent model of ischemia-reperfusion by reducing inflammatory cell recruitment and infiltration into injury sights, presumably via its actions at the MC1R. Chiao et al. (1997) demonstrated that α-MSH, given either during the period of ischemia or up to 6 hours after resolution of ischemia (in their model, removal of bilateral renal pedicle cross-clamps), not only significantly reduced elevations in blood urea nitrogen (BUN) and creatinine but also, on histopathology, markedly reduced percentage of tubular cell necrosis and neutrophil infiltration into the sight of injury compared to sham-treated animals.

Figure 4. ACTH and α-MSH may also bind to MC1R targets located on the podocyte, stabilizing glomerular architecture and ameliorating proteinuria.

Figure 4. ACTH and α-MSH may also bind to MC1R targets located on the podocyte, stabilizing glomerular architecture and ameliorating proteinuria.

This anti-inflammatory effect of ACTH (and α-MSH), however, is not particularly unique to the peptide(s) and does not fully explain why these drugs can induce remission of nephrotic syndrome after other agents with similar anti-inflammatory mechanisms, including corticosteroids, B cell depleting agents (e.g., rituximab), and T cell targeted therapies (e.g., cyclophosphamide) have failed. The explanation may lie, again, in the MC1R, albeit in a newly recognized location: the podocyte (Figure 4). Lindskog et al. (2010), in a recent study using rats with passive Heyman nephritis, an animal model of membranous nephropathy, proposed that ACTH may work at the MC1R in podocytes to reduce proteinuria, improve glomerular morphology, and reduce oxidative stress. In the first part of their investigation, they localized MC1R in the kidney of normal and iMN-afflicted humans to the podocyte by showing co-localization with staining for synaptopodin, a podocyte specific protein. Next, they treated mice with Heyman nephritis with ACTH, α-MSH, and MS05, a specific agonist for the MC1R. After 4 weeks, MS05 showed similar reductions in proteinuria as ACTH and α-MSH, along with significantly less podocyte effacement and absence of “spike” formation in the glomerular basement membrane, the hallmark finding in membranous nephropathy. Their results, which point to a specific effect of ACTH (likely via α-MSH) on the MC1R in podocytes, may explain why patients resistant to other immunosuppressive therapies respond to ACTH therapy. However, the reason for the therapy’s relative lack of efficacy in podocytopathies such as MCD and FSGS, compared to iMN, is not known.

This direct podocyte effect may turn out to be similar to that of calcineurin inhibitors like cyclosporine and tacrolimus on nephrotic syndrome. The immunosuppressive action of calcineurin inhibitors is via inhibition of nuclear factor of activated T cells (NFAT) signaling in T cells. When these drugs emerged as an effective second-line therapy for steroid-resistant nephrotic syndrome, their beneficial effect was assumed to be due to immunosuppression, specifically by inhibiting T cell involvement in glomerular injury. However, Faul et al. (2008) induced heavy proteinuria in mice afflicted with severe combined immunodeficiency (SCID) that are devoid of T and B cells and then demonstrated significant reductions in proteinuria with cyclosporine therapy. Hence, the anti-proteinuric effect was T cell independent and instead resulted from stabilization of the actin cytoskeleton in podocytes. Cyclosporine, by blocking the calcineurin-mediated dephosphorylation of synaptopodin, protects synaptopodin from degradation and thus preserves podocyte (and by extension, glomerular) architecture.

ACTH may have a similar architectural effect on the podocyte. Binding of ACTH and α-MSH on the MC1R decreases NF-κB activation (Catania et al., 2004). NF-κB is a transcription factor activated by cell surface receptor signaling to meet stress and inflammatory responses; inactive NF-κB is sequestered in the cytoplasm, whereas active NF-κB translocates to the nucleus and induces an extensive array of target genes that promote inflammation and fibrosis (Wiggins et al., 2010). Nephrin is a protein that is crucial for podocyte integrity; this protein is deficient in congenital nephrotic syndromes and is markedly downregulated in cases of idiopathic nephrotic syndrome. Nephrin normally serves as an endogenous inhibitor to NF-κB, keeping the transcription factor sequestered in its inactive cytoplasmic form. Nephrin deficiency leads to NF-κB activation (i.e., NF-κB is able to translocate to the nucleus) and subsequently results in glomerular damage mediated by NF-κB-dependent pathways (Hussain et al., 2009). Thus, MC1R activation can essentially substitute for nephrin, decreasing NF-κB activity, and preserving podocyte integrity.

Conceivably, the explanation for ACTH’s effects on proteinuria and the nephrotic syndrome will not be singular but rather incorporate many of the above proposed etiologies (Figures 2-4) and other, yet-to-be delineated mechanisms. Indeed, the reported benefits with ACTH tend to argue against a unifying theory of its workings. For instance, Beck et al. (2009) reported (in abstract form) that ACTH-induced reductions in proteinuria were accompanied by concomitant reductions in antibody titers for the M-type phospholipase A2 receptor (PLA2R), the major target antigen of iMN. These results could be interpreted as a B-cell mediated effect: ACTH reduced B-cell production of these pathologic antibodies. These results, however, could also be interpreted as a direct podocyte effect: the PLA2R is present on all podocytes, and therefore the underlying defect of iMN may be antigen presentation more so than antibody production, with ACTH’s podocyte activity normalizing antigen presentation. Or, quite possibly, ACTH affects both antibody production (via the MC1R in B cells) and antigen presentation (via the MC1R in podocytes).

Conclusion

In Europe and the United States, early data suggest that ACTH (in either a synthetic, depot form or a natural, highly-purified gel) can be an effective therapy for nephrotic syndrome. The best results have been seen in iMN, with an especially impressive record in patients who have previously failed other immunosuppressive therapies. The mechanism by which ACTH works to reduce proteinuria and induce a remission of nephrotic syndrome still is undefined, however. ACTH, either alone or via its breakdown product α-MSH, may induce a potent anti-inflammatory effect by reducing B- and T-cell activity and may also have a direct, podocyte-sparing effect within the glomerulus. Future research into this potential therapy will need to not only further define its role in clinical medicine, but also continue to explore the route by which this therapy achieves its promising results.

Disclosures

Dr. Bomback has received research support and honoraria from Questcor Pharmaceuticals. Dr. Radhakrishnan has no disclosures.

Corresponding Author

Andrew S. Bomback, M.D., M.P.H., Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, 622 West 168th Street, PH 4-124, New York, New York 10032, USA.

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[Discovery Medicine; ISSN: 1539-6509; Discov Med 12(63):91-96, August 2011. Copyright © Discovery Medicine. All rights reserved.]

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