Minimal Change Disease: A Changing Perspective

Dr. Zachary Appelbaum, is a Nephrology fellow in the Renal -Electrolyte and Hypertension Division at the Hospital of the University of Pennsylvania. He matriculated from the University of Miami Leonard M. Miller School of Medicine and completed Internal Medicine residency at George Washington University Hospital. His main academic interests include Nephrology and healthcare policy.


Dr. Ralph Nader, @Ralph__Nader, is an Assistant Professor at the Perelman School of Medicine and a nephrologist in the Renal-Electrolyte and Hypertension Division at the Hospital of the University of Pennsylvania. As part of the Penn Glomerular Center, his main clinical and research interests revolve around glomerular diseases and onconephrology with a special interest in amyloidosis and gammopathies of renal significance.

Minimal change disease (MCD) is a primary podocytopathy that accounts for approximately 80% and 15% of nephrotic syndrome (NS) in the pediatric and adult populations respectively. A kidney biopsy is necessary in adults, whereas the diagnosis is presumed in children based on clinical presentation. MCD is characterized by normal histology on light microscopy, absence of significant staining by immunofluorescence (IF), and foot process effacement on electron microscopy. Corticosteroids are typically utilized as first line agents in the management of MCD, however other immunosuppressive treatments, including antimetabolites, calcineurin inhibitors, and B cell depleting agents, are used in patients intolerant to corticosteroids or in patients with poorly controlled MCD.

The pathogenesis of MCD likely involves both T and B cell mediated processes. One current hypothesis is that MCD is caused by one or more circulating factors that alter the glomerular filtration barrier’s permeability. While initially this factor was thought to be produced by T cells, based on response to cell-mediated immunity suppression and the absence of antibody deposition found on IF, further research suggests a role for B cells based on the effectiveness of the anti-CD20 agent rituximab and an increase in plasma soluble CD23 during MCD relapses. Recent literature has described a role for anti-nephrin antibodies in the pathogenesis of MCD. Nephrin is a structural component of the slit diaphragm and administration of anti-nephrin antibodies has produced proteinuria in animal models.

In an important study by Watts et al, a subset of MCD patients with active disease developed elevated levels of nephrin autoantibodies, which decreased during periods of remission. Kidney biopsies from these patients demonstrated delicate punctate IgG that colocalized specifically with nephrin, possibly representing in situ binding of nephrin autoantibodies. The evidence supporting a pathogenic role for both T and B cells underscores their essential cross-talk and the role that T cells play in orchestrating, maintaining, and amplifying the humoral immune response. In particular, there is polarization of Th2 immune cells that favors propagation of a humoral immune response and may be implicated in MCD relapses. As in other autoimmune conditions, MCD has been associated with a reduced number and function of regulatory T cells – the biology of which continues to be an active area of research.

Because MCD accounts for 80% of NS cases in children, pediatric patients are often treated empirically with corticosteroids without undergoing kidney biopsy. A recent study published in AJKD by Chen et al analyzed the clinical course of childhood and adult-onset MCD from the CureGN cohort. The difference in performing a biopsy can be noted from the time of disease onset until kidney biopsy. Specifically, children and adults were biopsied at approximately 238 and 36 days after disease onset respectively – clearly demonstrating the need for an early tissue diagnosis in adults in whom a workup is indicated to rule out other causes of NS. Moreover, this study comments on the generalizability of the findings noted in the pediatric cohort as those patients underwent a kidney biopsy for a reason. For example, the most common disease classification at enrollment in the childhood-onset group was frequent relapsing/glucocorticoid-dependent disease; this may not necessarily represent the entire spectrum of pediatric MCD cases.

In both children and adults, MCD remission can typically be obtained with a course of corticosteroids. However, approximately 20% of adult patients exhibit steroid resistance. Steroid-sparing agents – calcineurin inhibitors, mycophenolate, and rituximab – are used in subsequent relapses and in patients defined as frequent relapsers, steroid dependent, and steroid resistant. Table 1 summarizes some of the pertinent characteristics of the different immunosuppressive regimens.

Medication Dosing Efficacy Adverse Effects
Corticosteroids Adults: induction regimen consists of prednisone 1 mg/kg daily or 2 mg/kg every other day for 16 weeks.

Children: 2 mg/kg daily or 1.5 mg/kg every other day for 2 months

95% remission rate by 8 weeks.
Adults: 75-95% remission rate at 16 weeks
Obesity, osteopenia, cataracts, glucose intolerance,
hypertension, and behavioral disturbances
Calcineurin Inhibitors (CNI) (Cyclosporine or Tacrolimus) Cyclosporine: 3-5 mg/kg daily in divided doses

Tacrolimus: 0.05-0.3 mg/kg daily in divided doses

CNI are utilized in steroid resistant forms of MCD.

Complete remission rates of up to 80%

CNI can be utilized in combination with corticosteroids in older patients to avoid the adverse effects of corticosteroids.

Tremor, nephrotoxicity, alopecia (tacrolimus), and gingival hyperplasia (cyclosporine)
Mycophenolate mofetil (MMF) Children: 24-36 mg/kg/day

Adults: 1-1.5 grams twice daily

50% reduction in relapse rate Leukopenia, gastrointestinal symptoms
Rituximab 375 mg/m2 IV x 1-4 doses

1 g IV per dose for 2 doses (2 weeks apart)

Results in remission in about approximately 60%
Infection, Infusion reactions, Cost
Cyclophosphamide 2 mg/kg daily for 8 – 12 weeks About 80% remission rate and 10% relapse rate
at one year.
Infertility, leukopenia, and malignancy
Table 1 created by Appelbaum and Nader

In the recent Chen et al study, which analyzed the clinical course of 554 patients – mostly childhood and adult-onset disease – with biopsy proven MCD, childhood-onset MCD exhibited faster times to remission and more frequent relapses compared to adult-onset MCD. Additionally, patients with childhood-onset disease were more likely to enter remission after rituximab initiation as compared to adolescents or adults. This noted difference following rituximab therapy may suggest more responsive lesions and fewer chronic changes in pediatric patients. Given the spectrum of response to treatment and the noted differences in sustained control of NS, important questions arise regarding the possibility of distinct MCD phenotypes, variations in response to treatment at different times in the disease course, and the ongoing need to identify predictive risk factors for remission or relapse.

Furthermore, the authors noted a higher rate of remission in the steroid-sensitive group than the steroid-resistant group after rituximab therapy suggesting that while there is no biomarker available to predict the effect of B cell depletion, response or resistance to previous immunosuppressive agents, such as corticosteroid therapy, can guide the decision to administer rituximab.

The Chen et al study reiterates that the prognosis of MCD remains favorable. In fact, 4% of childhood-onset MCD patients developed ESKD compared to 3% of adult-onset patients. These findings are similar to other studies that suggest less than 5% of adult-onset patients progress to ESKD .

The study by Chen et al illustrates the variety of MCD phenotypes based on response to treatment and subsequent risk of relapse. Certain phenotypes, particularly those found in childhood-onset disease, are initially easier to treat but exhibit higher relapse rates.

Because patients receiving rituximab therapy had higher remission rates amongst the steroid-sensitive cohort as opposed to the steroid-resistant group, pertinent questions arise regarding this specific patient population and their response to B cell depletion. Are these patients being treated earlier before substantial sclerosis has occurred? Is this a subset of patients in whom the humoral immune response is the more predominant driver in the pathogenesis of their disease? Is it possible that these patients have higher anti-nephrin antibodies, or other – yet to be discovered – antibody titers at presentation?

While it may be too early to tell, it seems like the story of MCD is reminiscent of the one re-written for membranous nephropathy in 2009 with the discovery of PLA2R  and the other antigens identified afterward, opening the door to precision medicine in the treatment of glomerular disease.

In their elegant 2022 study, Watts et al identified nephrin auto-antibodies in a subset of patients with MCD, and the paper from Chen et al seems to describe patients with MCD having different phenotypes. As such, given this variety in MCD phenotypes and the heterogeneity in response to treatment, questions arise as to the prevalence of anti-nephrin in this cohort, its possible role in the differences seen in disease phenotypes, and the possibility of other yet-to-be-discovered antigens which may explain the variety seen in MCD.

– Post prepared by Zachary Appelbaum and Ralph Nader @Ralph__Nader


To view Chen et al (subscription required)please visit
Title: Age of Onset and Disease Course in Biopsy-Proven Minimal Change Disease: An Analysis From the Cure Glomerulonephropathy Network
Authors: Dhruti P. Chen, Margaret E. Helmuth, Abigail R. Smith, Pietro A. Canetta, Isabelle Ayoub, Krzysztof Mucha, Mahmoud Kallash, Jeffrey B. Kopp, Rasheed Gbadegesin, Brenda W. Gillespie, Larry A. Greenbaum, Rulan S. Parekh, Tracy E. Hunley, C. John Sperati, David T. Selewski, Jason Kidd, Aftab Chishti, Kimberly Reidy, Amy K. Mottl, Debbie S. Gipson, Tarak Srivastava, Katherine E. Twombley on behalf of the CureGN Consortium
DOI: 10.1053/j.ajkd.2022.11.012


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