Does What Goes Around Always Come Around?

• Minimal change disease
• children
• Nephrosis
• Lipoid
• Adrenocorticotropic Hormone
• Adrenal Cortex Hormones
• Immunosuppressive Agents
• Steroids
• Anti-Infective Agents

In the ongoing search for drugs to treat disease, the emphasis is on new. Occasionally, an old abandoned drug will make a comeback and be reintroduced into clinical practice. Infectious disease specialists encounter this more often than practitioners in other disciplines, and there is literature on how to evaluate older drugs in light of knowledge that has been gained about newer antimicrobial agents (1). Is adrenocorticotropic hormone a candidate for comeback of the year in nephrology?

Minimal change disease in childhood is Rodney Dangerfield’s illness—it gets no respect. If the patient responds to steroids, the empirical diagnostic criterion, then the disease is considered to be no big deal, and it is assumed that everything will eventually turn out well. However, for the majority of affected children, life is not so simple. They will follow a relapsing course, will receive numerous courses of corticosteroids, and may require second-line immunosuppressive therapy to maintain remission. In other words, minimal change disease is not trivial (2).

Because the threat of ESKD in children with FSGS looms so large, it dominates the nephrotic syndrome research agenda. Moreover, minimal change disease is the victim of therapeutic success. After the introduction of corticosteroids in the early 1950s and the clear demonstration of efficacy, childhood nephrotic syndrome seemed to be solved. It has been hard to compete with corticosteroids and supplant them as first-line treatment, despite the litany of adverse effects associated with their use.

Interestingly, adrenocorticotropic hormone was known to be effective in achieving remission in childhood nephrotic syndrome before corticosteroids became available. Lieberman and Pavlova-Wolf (3) summarized 14 reports published between 1945 and 1965 involving 419 pediatric patients with nephrotic syndrome treated with adrenocorticotropic hormone. Studies were divided into two groups: nine prescribed short-term adrenocorticotropic hormone use (≤28 days), and five prescribed long-term (>5 weeks, with a period of daily treatment followed by long-term intermittent administration) adrenocorticotropic hormone use. An initial response, defined as a diuresis, occurred in 74% of patients who received short-term adrenocorticotropic hormone therapy, and a proteinuria response occurred in 56% of patients/treatment courses with available data. In the long-term studies, 71% of patients had a proteinuria response that was sustained up to 4.7 years after adrenocorticotropic hormone treatment. However, despite these favorable data, adrenocorticotropic hormone was unceremoniously replaced in the nephrology pharmacy by prednisone, which was easier to manufacture and administer.

Adrenocorticotropic hormone seemed poised to make a comeback in the 21st century when a purer formulation was synthesized and marketed as a useful, more stable alternative to corticosteroids. In small patient series, administration of adrenocorticotropic hormone resulted in reduction in proteinuria in adults with membranous nephropathy and resistant FSGS (4). The melanocortin receptor is detectable on the podocyte cell membrane in experimental models of membranous nephropathy, and it was activated by adrenocorticotropic hormone (5). This finding raised the possibility that adrenocorticotropic hormone has direct effects on the glomerular barrier to reduce proteinuria independent of actions via the cytoplasmic steroid receptor and might be a useful treatment for glomerular disease. Leaving the economics aside, the obvious question is whether Acthar represents a real advance in the treatment of childhood nephrotic syndrome.

A study in this issue of the Clinical Journal of the American Society of Nephrology describes a randomized clinical trial conducted by the Midwest Pediatric Nephrology Consortium (6). It evaluated the efficacy of adrenocorticotropic hormone in 31 children with frequently relapsing or steroid-dependent nephrotic syndrome. Patients were assigned to receive adrenocorticotropic hormone 80 U/1.73 m² for 6 months followed by 40 U/1.73 m² for 6 months or no relapse-preventing treatment. The study was well designed, the patient cohort was generally representative of children being treated for steroid-responsive nephrotic syndrome in the United States, and the two arms were comparable. Finally, the protocol reflects the current approach to adrenocorticotropic hormone use. The results were unequivocal and negative. There was no benefit of adrenocorticotropic hormone therapy in modulating disease activity. However, there were three children who did achieve a sustained remission in response to adrenocorticotropic hormone. I will get back to them momentarily. The failure of adrenocorticotropic hormone to show consistent benefit in children with frequently relapsing or steroid-dependent minimal change disease, despite a putative podocyte target, underscores the notion that, although minimal change disease is a podocytopathy, multiple pathways lead to podocyte dysfunction. Single therapies directed at this cell are unlikely to be effective in all children with minimal change disease. Recent data linking minimal change disease to genetic variation in HLA antigens imply that engaging immune targets may be more productive in improving outcomes in children with hard to manage minimal change disease (7,8). Much work remains to be done to translate the genetic linkages to molecular pathways that can be targeted by drugs.

There are some concerns about the study that need to be acknowledged. The sample size is limited, especially for a multicenter study involving this well established network of high-quality sites. With 16 participating sites and a 3.5-year study duration, only 0.5 patients were entered annually at each site. This is likely well below the number of patients with this condition who were treated at each institution. Thus, the enrolled participants may have differed from the bulk of patients who opted not to join the study. They may not have considered adrenocorticotropic hormone to be a worthwhile alternative to corticosteroid therapy, and this may be related to the study design, in which patients had to discontinue ongoing therapy before assignment to adrenocorticotropic hormone or placebo. This requirement may have been troubling to parents and patients, and it may have been perceived as a threat to their tenuous coexistence with nephrotic syndrome. This limitation is supported by the CONSORT diagram, which indicates that 30 patients declined participation. Testing adrenocorticotropic hormone as add-on therapy to their ongoing treatment might have been more palatable and may have resulted in a more efficient recruitment. Such pragmatic issues need to be emphasized more in the design of trials of chronic kidney conditions, such as minimal change disease (9). Alternatively, investigator enthusiasm for this study, an unappreciated and neglected factor in clinical trial feasibility, may have been limited.

That being said, might there be an approach to enhance the utility of adrenocorticotropic hormone in childhood minimal change disease? There may be some children for whom adrenocorticotropic hormone is a useful drug, evidenced by the three participants in the ATLANTIS trial who remained in remission on the drug. The challenge is how to pick out these particular patients in a crowded nephrotic syndrome clinic. There is a temptation to ask whether the effect of adrenocorticotropic hormone might differ in children with frequently relapsing versus steroid-dependent disease. However, years of experience have proven to most pediatric nephrologists how hard it is to predict the relapsing course for an individual child with nephrotic syndrome. In addition, this clinical categorization has little value in guiding selection of the optimal drug to treat an individual child with minimal change disease.

With the arrival of precision medicine in nephrology, the rules of the game are changing, and the operating principle is to define subgroups of patients with nephrotic syndrome who are more likely to respond and benefit from a novel therapy. This principle requires the delineation of a disease-causing pathway and hopefully, a noninvasive biomarker profile to identify the targeted subgroup of patients. In most patients, this plan would be on the basis of gene activation profiles and downstream protein networks. This type of analysis has borne fruit in FSGS, and it has highlighted the contribution of activation of the discrete pathways in discrete patient subsets (10). There is much less work being done in minimal change disease. Moreover, adrenocorticotropic hormone does not activate a discrete signaling pathway, and a genomic-proteomic profile may not be the ideal approach to identify patients likely to benefit from the agent. Instead, metabolomic profiling of kidney tissue and/or urine may be required to tease out a group of patients in whom adrenocorticotropic hormone is participating in the pathogenesis of the nephrotic syndrome and for whom it represents a viable approach to treatment. These are exciting times, and many studies worldwide are ongoing to determine mechanisms and pathways leading to nephrotic syndrome as a rational guide to precision medicine–based therapeutics.

The Nephrotic Syndrome Study Network (NEPTUNE), an National Institute of Diabetes and Digestive and Kidney Diseases/NCATS-funded observational cohort study of patients, young and old, with nephrotic syndrome undergoing diagnostic kidney biopsy, is an example of an active effort to answer these questions and escort nephrotic syndrome into the precision medicine age (11). A pediatric cohort has been added that is enrolling children with new-onset nephrotic syndrome without a kidney biopsy, reflecting standard clinical practice in pediatric nephrology. Since the initiation of the CNEPTUNE 5 years ago, 127 participants have been entered. This project will build on the biopsied cohort, expand the focus to include both minimal change disease and FSGS, and hopefully, provide clinically meaningful answers to the questions parents have when told that their child has nephrotic syndrome. How active will his disease be? Will she lose kidney function? What is the best treatment?

Wang et al. (6) are to be commended for performing a trial that will be useful in clinical practice for pediatric nephrologists. At the end of the day, adrenocorticotropic hormone has not fully come around again to be used in the treatment of childhood nephrotic syndrome. However, even in this negative outcome, there is a glimmer of light, and the three children who benefited from this study should point the way forward for precision medicine in nephrology. In this way, we can hope to fulfill the promise that each patient with nephrotic syndrome will get the right therapy at the right dose at the right time—maybe even adrenocorticotropic hormone.

• Copyright © 2018 by the American Society of Nephrology