BRIEF REVIEW www.jasn.org The Treatment of Minimal Change Disease in Adults Jonathan Hogan and Jai Radhakrishnan Division of Nephrology, Columbia University Medical Center, New York, New York ABSTRACT Minimal change disease (MCD) is the etiology of 10%–25% of cases of nephrotic CD80 (also known as B7–1) is a trans- syndrome in adults. The mainstay of treatment for adult MCD, oral gucocorticoids, is membrane protein that is present on based on two randomized controlled trials and extensive observational data in antigen-presenting cells and acts as a adults, and this treatment leads to remission in over 80% of cases. Relapses are costimulatory signal for T cell activation. common, and some patients become steroid-resistant (SR), steroid-dependent CD80 is also present in the podocytes (SD), or frequently relapsing (FR). The data guiding the treatment of these patients of mice in MCD models and is necessary are limited. Here, we review MCD in adults with particular focus on the evidence for for resulting proteinuria.7–9 Soluble uri- immunosuppressive therapy in these patients. nary CD80 levels are elevated in children and adolescents with MCD in relapse J Am Soc Nephrol 24: 702–711, 2013. doi: 10.1681/ASN.2012070734 compared with those individuals in re- mission, patients with other glomerular disease, and control subjects.10 Further- Minimal change disease (MCD) is charac- most closely resembles MCD is puromy- more, urinary CD80/creatinine ratios terized clinically by the nephrotic syn- cin aminonucleoside nephrosis (PAN) in are increased in MCD in relapse com- drome (NS) and a renal biopsy that shows rats, which leads to the production of pared with MCD in remission or no glomerular lesions on light microscopy reaction oxygen species and direct DNA FSGS.10 Thus, although only explored (or only minimal mesangial prominence), damage. Histologically, PAN results in so far in research settings, CD80 may negative staining on immunoflouores- alteration of the podocyte actin cytoskel- be a useful biomarker in MCD. cence microscopy (or low-level staining eton, foot process effacement, and de- Angptl4 is a secreted glycoprotein that for C3 and IgM), and foot process efface- tachment from the glomerular basement is upregulated in the glomeruli of several ment but no electron-dense deposits on membrane. Clinically, these changes re- models of podocyte injury in rats, in- electron microscopy.1 MCD may also be sult in proteinuria.2 cluding PAN.11 This upregulation is spe- suspected clinically in the absence of a bi- In the 1970s, Shalhoub3 proposed cific to models of steroid-sensitive NS opsy by exhibiting responsiveness to corti- that the cause of lipoid nephrosis compared with models of membranous costeroid treatment, and it is sometimes (a pseudonym for MCD) is a T cell- nephropathy (passive heyman nephri- called steroid-sensitive NS. In children, be- secreted circulating factor that damages tis), mesangial injury (Thy1.1 nephritis), causeMCDisthecauseof90%ofcasesof the glomerular basement membrane. and collapsing FSGS (injection of rats idiopathic NS and usually exquisitely re- Although this circulating factor has with serum from patients with collaps- sponsive to steroids, corticosteroid treat- not been identified, recent studies high- ing FSGS). Moreover, a transgenic ment is often initiated without a biopsy, light a role of immune dysregulation mouse model showed that upregulation unless clinical and laboratory evidence in MCD. T-regulatory (Treg) cells, which of podocyte Angptl4 results in protein- points to an alternative diagnosis. The cau- attenuate immune responses by sup- uria and histologic changes similar to sesofNSinadultsaremorevaried,and pression of T-effector cells, are dysfunc- although some physicians may choose a tional in humans with MCD,4,5 and trial of corticosteroids without histologic augmentation or supplementation of Published online ahead of print. Publication date available at www.jasn.org. evidence of MCD, a kidney biopsy is usu- Treg cell function has led to decreased ally warranted to establish the etiology. proteinuria in a rat model of the idio- Correspondence: Dr. Jai Radhakrishnan, Columbia pathic NS.6 University Medical Center—Internal Medicine, Di- vision of Nephrology, 622 West 168th Street, PH PATHOPHYSIOLOGY In addition to Treg cell dysfunction, 4-124, New York, NY 10025. Email: jr55@columbia. the roles of two podocyte proteins have edu The pathophysiology of MCD is not been explored in MCD: CD80 and Copyright © 2013 by the American Society of well understood. The animal model that angiopoietin-like protein 4 (Angptl4). Nephrology 702 ISSN : 1046-6673/2404-702 J Am Soc Nephrol 24: 702–711, 2013 www.jasn.org BRIEF REVIEW those changes seen in MCD. To date, no during an AKI episode and showed het- 4 weeks and 10%–25%ofpatientsre- Angptl4 studies have been conducted in erogeneous findings: arteriosclerosis quiring 12–16 weeks of therapy. More- humans with MCD. (68%), acute tubular injury (64%), in- over, although alternate-day (every other Most recently, the upregulation of NF- terstitial inflammation (59%), mild tu- day) therapy may have a more favorable related kB has been shown in the nuclei of bular atrophy with interstitial fibrosis effect on growth rates in children, the T and B cells of patients with MCD in re- (59%), and interstitial edema (41%). advantages of this regimen in adults lapse compared with patients with MCD Six patients did not have any of the above have not been proven.18,19 in remission, control patients, and pa- injury patterns on renal biopsy. In this tients with membranous nephropathy.12 series, AKI was associated with higher Controlled Trials of Corticosteroid This finding implies that NF-related kB serum creatinine at last follow-up visit. Use in Adults with MCD is involved in chromatin remodeling, The correlation of AKI with older age, There are two randomized trials that have which enhances transcription factor bind- hypertension, more severe hypoalbu- explored the use of corticosteroids in adults ing in relapsing MCD. minemia and proteinuria, and arterio- with MCD. In 1970, Black et al.25 sclerosis on renal biopsy had been noted published a multicenter controlled study in a prior case control series.21 comparing prednisone (at least 20 mg/d for CLINICAL PRESENTATION CKD or end stage kidney disease is not at least 6 months) with no steroid treat- typically seen in adult MCD on presen- ment in 125 adults with NS, 31 of whom Adults with MCD present with NS: tation, and it should prompt the search had MCD. The steroid group showed a edema, nephrotic-range proteinuria, hy- for other diseases. MCD patients will rapid decrease in proteinuria and improve- poalbuminemia, and hyperlipidemia. typically experience relapses, and up to ment in edema within the first month of MCD is the etiology of NS in 10%–25% one third of patients may frequently treatment compared with control. Impor- of adults.13–15 On urinalysis, micro- relapse (FR) or become corticosteroid- tantly, by 2 years, a significant number of scopic hematuria is present in 10%– dependent (SD).17,18,22,23 Relapses are patients in the control group had 30% of adults with MCD16–19 and may alsoseenin40%ofadultswhohad experienced a spontaneous remission, lead- resolve with disease remission. Most ca- MCD during childhood.24 ing ultimately to similar outcomes with ses are idiopathic, but secondary etiolo- As discussed below, the few controlled respect to proteinuria, serum albumin, gies must be considered in adults. These studiesthathavebeenperformedin and edema in the two groups (Figure 1). latter conditions include malignancies MCD patients show similar long-term Similarresultswereshowninthe (Hodgkin’s lymphoma and thymoma), remission rates between treated and only placebo-controlled trial of steroid drugs (nonsteroidal anti-inflammatory nontreated patients.25,26 Given the risk treatment in adult MCD. The work drugs and lithium), infections (strongy- of adverse events caused by current by Coggins26 compared alternate-day loides), atopy, and other superimposed treatment modalities, one may ask prednisone (average dose=125 mg/d) renal disease.20 whether MCD patients should be treated for 2 months with placebo in 28 adult Although MCD in children usually or not. However, the significant comor- MCD patients. As observed in the work remits within a few weeks of starting bidities associated with NS (hyperlipid- by Black et al.,25 steroid-treated patients corticosteroids, adult MCD responds less emia,27 infections,16,28 skin breakdown remitted more rapidly, with 12 of 14 rapidly, taking up to 3–4 months of ste- from edema, risk of thromboembolic treated patients in complete remission roid therapy to induce remission. Addi- events,29,30 AKI,andworsenedquality before 2 months compared with 6 of 14 tionally, 10%–30% of adults may fail to of life) prompt most physicians to rec- controls. However, there was no differ- respond to steroid therapy, with a signif- ommend treatment for MCD patients. ence in overall remission rates over 77 icant proportion of nonresponders Importantly, drug-related adverse events months of follow-up. Adverse events showing interstitial fibrosis on the initial become more common in FR and SD were observed in four patients who biopsy and lesions of FSGS on subse- patients because of prolonged and re- were treated with more than one course quent biopsies.18 peated exposure to corticosteroids. of steroids. Adults with MCD present with AKI in Beyond these trials, most experience 20%–25%ofcases.18,19 The work by with the use of corticosteroids for adults Waldman et al.18 retrospectively exam- TREATMENT OF INITIAL EPISODE with MCD is extrapolated from large ined 95 adults with MCD, 24 (25.2%) OF MCD WITH CORTICOSTEROIDS prospective randomized controlled tri- of whom met criteria for AKI during ei- als in children31,32 and observational ther initial presentation (n=17) or re- Efficacy studies in children and adults.18,19,22,23 lapse (n=7). Factors associated with Corticosteroid therapy leads to complete AKI were older age, male sex, presence remission in over 80% of adults with Intravenous Versus Oral Steroid of hypertension, lower serum albumin, MCD.