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Home , Glomerulonephritis, Minimal change disease

BRIEF REVIEW www.jasn.org

The Treatment of in Adults

Jonathan Hogan and Jai Radhakrishnan

Division of , 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 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 activation. common, and some patients become -resistant (SR), steroid-dependent CD80 is also present in the (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 .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 that shows rats, which leads to the production of pared with MCD in remission or no glomerular lesions on light 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 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 ), causeMCDisthecauseof90%ofcasesof the glomerular . 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 , 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 without histologic augmentation or supplementation of Published online ahead of print. Publication date available at www.jasn.org. evidence of MCD, a 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 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 (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 . 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- , 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 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 . 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 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 , 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 .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. The time to complete remission is Therapy and amount of proteinuria. Renal biop- longer than the time observed in chil- The effects of initial therapy with intra- sies were performed on 22 patients dren, with 50% of patients responding by venous compared

J Am Soc Nephrol 24: 702–711, 2013 Adult Minimal Change Disease 703 BRIEF REVIEW www.jasn.org

Daily Versus Alternate-Day Steroid Therapy Alternate-day corticosteroid regimens for NS were first described in the 1950s,35 and they have been associated with less adrenal suppression, less effect on growth, and similar efficacy in chil- dren. However, no randomized or pro- spective trials comparing daily with alternate-day dosing have been per- formed in adults. Observational studies have shown similar remission rates.18,36 In the largest series examining daily versus alternate-day steroid regimens, Waldman et al.18 conducted a retrospec- tive analysis of 95 MCD patients over 17 years of age treated at a single center in the United States; 88 of 95 patients were treated with prednisone for an average of Figure 1. Percentage of MCD patients with more than 1 g of proteinuria treated with pred- 26.6 weeks. The initial dosing regimens nisone versus no steroid treatment (control). Patients in the steroid group were treated with at were 1 mg/kg per day in 65 patients and fi least 20 mg/d for at least 6 months. Modi ed from reference 25, with permission. 2 mg/kg every other day in 23 patients followed by a taper. There was no signi- with oral prednisone in adult MCD intravenous methylprednisolone for 3 ficant difference in rate of complete re- have been studied in two randomized days (20 mg/kg per day) followed by mission between the groups, time to trials. The work by Yeung et al.33 com- low-dose prednisone for 6 months (start- remission, rate of relapse time to first re- pared the efficacy of intravenous meth- ing dose of 0.5 mg/kg per day in adults for lapse, or adverse events between treat- ylprednisolone (20 mg/kg per day for 3 4 weeks followed by taper over 5 months). ment groups (Figure 2). days followed by a 2-week steroid-free The control group received high-dose period and oral prednisolone at 0.5 prednisone (1 mg/kg per day in adults) Duration and Taper of Steroid mg/kg) with oral prednisolone (1 mg/kg for 4 weeks followed by low-dose predni- Therapy per day for 4–6 weeks followed by a sone for 5 months. In the adult cohort, The optimal duration of corticosteroid taper) in 18 adults with MCD.33 At 2 remission (decrease of proteinuria to therapy is unknown in adults. In chil- weeks, 3 of 10 (33%) patients treated ,100 mg/d) occurred in 8 of 11 (73%) dren, 6 months of corticosteroid treat- with intravenous methylprednisolone study patients compared with 11 of 11 ment were associated with lower relapse had attained remission compared with (100%) control patients. No differences rates compared with 3 months of ther- 5 of 7 (71%) of patients with oral pred- were observed in time to response to treat- apy.31 In the retrospective case series by nisolone. The nonresponders in the ment, number of relapses, or relapse-free Waldman et al.,18 the majority (.80%) methylprednisolone group then received event rate at 1 year of follow-up in the of patients had attained remission by 16 oral prednisolone (1 mg/kg per day), and adult cohort. More patients in the control weeks. Given this time to response and five of seven patients achieved remission. group experienced adverse events (obesity the increased risk of adverse events with At 1 month, all patients in the predniso- and Cushingoid facies) compared with prolonged courses of high-dose steroid lone group had achieved remission. the study group, but a subgroup analysis treatment, it is currently recommended However, this study was limited by small on adverse events in adults versus children that a trial of steroids for 16 weeks be enrollment, and it did not include mea- was not performed. used before declaring a patient a failure surements of proteinuria, renal func- Similar to the study by Yeung et al.33, of steroid treatment (Table 1).37 tion, serum albumin, or BP. Moreover, the trial by Imbasciati et al.33 was limited The optimal corticosteroid taper pro- methylprednisolone therapy was consid- by small enrollment and did not report tocol in adults is also not known. In ered to have failed if remission was not important clinical and laboratory data. children, data support that slow steroid achieved 2 weeks after therapy, with no However, given the higher remission tapers may lead to less steroid depen- oral steroid use during this time. rates observed in the oral prednisone dence and relapse compared with rapid Imbasciati et al.34 performed a mul- groups combined with the ease of ad- tapers. The work by Ueda et al.38 stud- ticenter, randomized, prospective trial ministration of an oral versus intrave- ied 46 incident children diagnosed with in 89 patients with MCD, 22 of whom nous medication, oral steroid therapy is steroid-sensitive NS after treatment were adults. The study group received recommended. with high-dose steroids (60 mg/m2)for

704 Journal of the American Society of Nephrology J Am Soc Nephrol 24: 702–711, 2013 www.jasn.org BRIEF REVIEW

groups. These data suggest that higher dose and longer taper of steroids lead to improved outcomes in children with MCD. In adults, no studies comparing rapid versus slow steroid taper exist. Based on case series reports, steroids are usually tapered by 5–10 mg/wk after remission has been achieved for a total period of corticosteroid exposure of at least 24 weeks.16, 18,19

ALTERNATIVE REGIMENS FOR THE INITIAL EPISODE

The data for the use of steroid-sparing regimens in the treatment of the initial MCD episode are limited to case reports and case series. These treatments are reserved for patients who have relative contraindications (severe hyperglycemia or steroid-induced psychosis) or are Figure 2. Time to first remission in MCD adults treated with daily versus alternate-day unwilling to take steroids. Cyclophos- steroids. QD, daily; QOD, every other day. Modified from reference 18, with permission. phamide23,39–42 and cyclosporine43 have been used with response rates of approximately 75% with this limited 4 weeks. They were then randomized to slow-taper group at both 6 months experience (Table 1). either rapid taper (prednisolone=40 (51.7% versus 17.6%) and last follow- mg/m2 for 3 consecutive days per week up (mean follow-up=46 months, for 4 weeks) or slow taper (prednis- 34.5% versus 5.9%). The slow-taper CORTICOSTEROID-RESISTANT olone=40 mg/m2 every other day for 4 group initially received a 35% higher ste- MCD weeks followed by a slow taper over 5 roid dose than the rapid-taper group, months). There was a higher incidence but the total cumulative steroid dose at Steroid-resistant (SR) MCD is defined of FR and/or SD in the rapid- versus last follow-up was similar between as failing 16 weeks of corticosteroid

Table 1. Available treatment regimens and published response rates for the initial episode and infrequent relapse of adult MCD Medication Regimen Remission Rates (Complete + Partial) Initial episode without contraindication to steroids Prednisone Dose: 1 mg/kg per day (maximum 80%–90% 80 mg/day) or 2 mg/kg every other day (maxium 120 mg every other day), for a minimum of 4 weeks, and a maximum of 16 wks (as tolerated). After remission, taper over a total period of corticosteroid exposure of at least 24 weeks. Initial episode with contraindication to steroids Oral CYC 2–2.5 mg/kg per d38 wk 75% Cyclosporine 3–5 mg/kg per d in divided doses31–2 yr 75% 0.05–0.1 mg/kg per d in divided doses31–2 yr Unknown Infrequent relapse Same as initial medication Same as initial regimen Unknown—thought to be similar to initial remission rate

J Am Soc Nephrol 24: 702–711, 2013 Adult Minimal Change Disease 705 BRIEF REVIEW www.jasn.org treatment as outlined above. Approxi- patients may be treated with a course patients, and shorter time to remission mately 10%–20%ofadultswithMCD of corticosteroids identical to their pre- with initial steroid treatment was associ- are resistant, and a repeat renal biopsy in vious regimen when relapse occurs. FR ated with shorter time to remission with these patients may show FSGS. This result patients are those patients who have had CYC. is associated with a worse prognosis, and two or more relapses within 6 months of Mak et al.19 used oral CYC at 2–2.5 treatment regimens should follow the initial response or four or more relapses mg/kg per day for 8 weeks in 22 MCD recommendations for steroid-resistant in any 12-month period. SD patients are patients who were SR (n=2), were SD FSGS.37 Available treatment regimens for those patients who have had two relapses (n=9), were FR (n=5), had steroid psy- SR MCD are further described below. during or within 2 weeks of completing chosis (n=1), or were having a first re- a course of corticosteroids. Up to 33% lapse after corticosteroid treatment of patients will become FR (11%–29%) (n=5). The cumulative remission rates RELAPSE OF MCD or SD (14%–30%) patients.17,18,22,23 in this group were 86%, 74%, and 63% FR and SD patients tend to be younger at 1, 3, and 5 years of follow-up com- Relapse rates in adult MCD are high, than infrequent relapsers or non-SD pared with 50%, 35%, and 26% for cor- with case series data showing that 56%– patients, and these patients require al- ticosteroid therapy. Within this group, 76% of patients experience at least one ternate treatment regimens for future the five FR patients had a high rate of relapse after steroid-induced remis- relapses and long-term maintenance sustained remission (80% at 9.1 years sion.17,18,22,23,44 Relapses are also seen therapy. With a repeated course of mean follow-up) compared with the in 40% of adults who had MCD during steroids, some patients may also be- SD group, of whom four (44%) patients childhood.24 A course of corticosteroids come SR. experienced sustained remission and is usually administered for the first re- five (56%) patients experienced addi- lapse, although there are no trials to sup- tional relapses. port this practice. TREATMENT OF FR, SD, AND In a retrospective case series, Waldman Eguchi et al.45 randomized 52 MCD STEROID-RESISTANT MCD et al.18 reported the use of oral CYC adults with their first relapse to cyclo- (mean oral dose=123.6 mg/d, mean du- sporine (area under the curve=1700– Alkylating Agents ration of therapy=11.5 weeks) in 20 pa- 2000 ng/ml) plus prednisolone (0.8 In retrospective reports (Table 3), oral tients. The cumulative remission rate in mg/kg per day) or prednisolone mono- (CYC) leads to re- this cohort was 55% (n=11), with a mean therapy (1 mg/kg per day). Remission mission in a significant number of FR time to remission of 6.4 weeks. Remis- was achieved sooner in the cyclosporine or SD adults with MCD.18,19,23,41 The sion occurred in 80% of SD (n=5) com- group, with the possible additional ben- relapse-free interval seems to be longer pared with 50% of SR (n=4) patients. efit of lower exposure to steroids. It than with cyclosporine (see below). Seven patients experienced subsequent should be noted that these patients had The work by Nolasco et al.23 de- relapses. quiescent courses after their first episode scribed the use of oral CYC in 36 patients There are two open-label, random- of MCD, with a time from remission to with MCD: CYC was used by 2 patients as ized prospective trials that describe the relapse of greater than 2 years. primary therapy, 11 patients were SR, 10 efficacy of intravenous CYC compared After an initial relapse episode, MCD patients were SD, and 11 patients were with oral tacrolimus in adults with patients are classified as infrequent re- FR. The remission rates were 58% and MCD.46,47 Intravenous CYC was chosen lapsing, FR, SD, or SR (Table 2). These 69% at 8 and 16 weeks, respectively. because of the higher rates of remission, categories are somewhat arbitrary, and The rate of sustained remission in this lower incidence of adverse events, and the definitions used here are the defini- group was 66% at 4 years. Moreover, lower cumulative medication dose of in- tions recently published in the Kidney the total relapse rate was 40% in the travenous CYC compared with oral CYC Disease Improving Global Outcomes CYC group compared with 76% in the in children with SR-MCD.48,49 The first Clinical Practice Guideline for Glomer- steroid group. The addition of predni- study randomized 26 adults with SD ulonephritis.37 Infrequent-relapsing sone to CYC did not add benefit in these MCD to receive tacrolimus (n=12; dosed

Table 2. Definitions of steroid-resistant, steroid dependent, and frequently relapsing MCD Definition Steroid resistanta Failed to achieve remission with 16 wk of daily or alternate-day steroids Steroid dependenta Two or more relapses during steroid taper or within 2 wk of discontinuing steroid therapy Frequently relapsingb Two or more relapses within 6 mo or four or more relapses within 1 yr of achieving remission aAdapted from adult FSGS guidelines in reference 37. bNo formal definition exists in adults; adapted from the definition for children with FR MCD from reference 37.

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Table 3. Published experience for the treatment of steroid-resistant, SD, and FR MCD in adults Remission Rates Relapse Rates Medication Evidence Regimen SRa SD FR SRa SD FR Oral CYC Observational series; 2–2.5 mg/kg per 50%–80% 50%–80% 50%–80% 50% 25%–56% 25%–56% one RCT in adults d38wk iv CYC Two small RCTs in adults 750 mg/m2 per 50% 77% NA 14% 40% NA mo36 mo + steroids Cyclosporine 6 Large observational 3–5 mg/kg per d in 45%–92% 45%–92% 45%–92% NA 62%–75% 62%–75% prednisone series data; one small divided dose31–2yr RCT in children and one RCT in adults Tacrolimus 6 Small observational 0.05–0.1 mg/kg per d in 79%–100% 91%–100% NA 40% 50% NA prednisone series; two small divided dose31–2yr RCTs in adults Mycophenolate Small observational 1–2 g/d in divided dose 25% 80%–100% 58% NA 20%–50% 20%–50% mofetil series; one small RCT in children In many studies, the outcomes for these groups are combined. NA, data not available; RCT, randomized controlled trial. aIn steroid-resistant cases, review of the initial biopsy and a repeat biopsy may be considered to evaluate for FSGS.

to achieve trough level of 4–8ng/ml)or Although a small case series in chil- (5 mg/kg per day) for 9 months followed intravenous CYC (n=14; CYC dose=750 dren showed the use of chlorambucil in by a 3-month taper to withdrawal. At 9 mg/m2 monthly) for 24 weeks. Both MCD,50 its use in adult MCD is limited months, 64% (18/28) of patients on CYC groups received oral prednisone until re- to case reports.51 and 74% (26/35) of patients on cyclo- mission. At 24 weeks of follow-up, com- sporine maintained remission (P = plete remission was achieved in 91% of Calcineurin Inhibitors NS). However, at 2 years, 25% of patients the tacrolimus group compared with The data on the use of cyclosporine in SD assigned to cyclosporine versus 63% of 77% of the intravenous CYC group. Sim- and steroid-responsive adults with MCD patients assigned to CYC were still in re- ilar remission rates at 48 weeks (50% in are heterogeneous, with many patients mission. the tacrolimus group and 60% in the receiving additional immunosuppressive In the retrospective case series by CYC group) and rates of relapse (40% therapies. Meyrier et al.52 conducted a Waldman et al.,18 cyclosporine (mean in the CYC group versus 50% in the prospective, open-label trial on the use dose=220 mg/d, target trough=150– tacrolimus group) were observed, and of cyclosporine monotherapy and cyclo- 200 ng/ml) was used in 39 patients the percentage of patients who were able sporine plus steroids (prednisone=12– (including n=8 SD patients and n=20 to become steroid-free was also similar. 15 mg/kg per day) in SD/SR NS patients, steroid-resistant patients) for a mean The second trial49 randomized 37 52 of whom had MCD. SD MCD pa- duration of 49.5 weeks. Remission was adults with SR MCD to receive steroids tients had a remission rate of 71% on achieved in 61% of these patients, plus either tacrolimus (n=21; trough cyclosporine. Meyrier53 also reported with a mean time to remission of 5 weeks level=5–10 ng/ml) or intravenous CYC registry data of cyclosporine use in 150 (range=2–9 weeks). A trend to higher (n=16; administered monthly for 6 adults with SD or SR NS, 82 of whom remission rates was observed in the SD months and then every other month had MCD.53 Cyclosporine treatment (75%) compared with the SR (45%) for 6 months, total dose=10 g/1.73 m2) achievedcompleteremissionin74% group; 41% of patients relapsed after cy- for 1 year; 6-month and 2-year cumula- and partial remission in 11% of these closporine discontinuation. tive remission rates were again higher in patients. Remission rates were higher The optimal dose, trough level, and the tacrolimus group (tacrolimus: 78.9% in patients with SD compared with SR duration of cyclosporine therapy are and 62% versus CYC: 50% and 37.5%). disease. Pooled data from open trials unknown and may be guided by the Relapses were more common in the similarly showed 60% complete and above studies. Meyrier et al.56 found the tacrolimus group in this trial. In both 10% partial remission rates in 146 adults cutoff dose for avoiding renal toxicity on trials, the CYC treatment group was and children with SR/SD MCD.54 long-term follow-up of adults with SD older than the tacrolimus group, time Ponticelli et al.55 randomized 73 pa- or SR NS to be 5.5 mg/kg per day. Similar to remission was shorter in the tacrolimus tients (11 adults and 62 children) with to steroid therapy, slower withdrawal of group, and there were similar rates of FR/SD NS (31 patients with MCD and therapy may decrease relapse rates, and adverse events between treatment 42 patients with FSGS) to CYC (2.5 mg/ abrupt cessation is associated with the groups. kg per day) for 8 weeks or cyclosporine possibility of cyclosporine dependency.

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Prolonged treatment in 36 adults (10 pa- patients was variable at 3–18 months, therapy with corticosteroids are sugges- tients with MCD and 26 patients with and all patients continued to be in re- ted. Albumin infusion may be considered FSGS) for a mean of 26 months followed mission 3–15 years after discontinuation if there is evidence of severe intravas- by slow withdrawal led to sustained of therapy.82 Another case series showed cular volume depletion with severe remissions without steroids in 11 of that (2 mg/kg per day for 2 . 14 patients and sustained remissions years) decreased the number of relapses with low doses of corticosteroids in 3 and prednisolone requirements in seven Nonimmunomodulatory Therapies patients. In 20% of patients who re- FR/SD patients with a mean age of 13.5 for MCD mained cyclosporine-dependent, doses years who had also failed CYC therapy Because proteinuria and hyperlipidemia in of ,3 mg/kg pr day were sufficient to during childhood.83 Other than these MCD typically improve with disease re- maintain remission. The cumulative case series, few reports exist of the use mission, the success of corticosteroid ther- rate of remission peaked at 6 months.54,56 of azathioprine in adult MCD.41 apy usually obviates the need for inhibitors Tacrolimus achieved 6-month and 2- of the renin-angiotensin- sys- year remission rates of 79%–91% and Other Immunomodulatory tem or therapy during initial MCD 50%–62% in SD/SR MCD patients as Treatments for FR, SD, or episodes or infrequent relapses. One study noted above,46,47 and it may allow for Steroid-Responsive Disease of 40 adults who had relapsing NS as chil- the discontinuation of steroids. Tacroli- The use of levimasole, which has been dren did not show a higher incidence of mus has also shown efficacy in case used in children with MCD, has not been cardiovascular disease, implying that long- reports57 and case series,18,58,59 with reported in adults. Adrenocorticotropin term cardiovascular risk was not increased remission rates of 64%–100% in this hormone (ACTH) gel use was reported by intermittent hyperlipidemia during ne- limited experience. Moreover, as ob- without success in one patient who had phrotic relapses in childhood, although served with cyclosporine, relapse after previously failed or relapsed after steroid, this study was small and no firm conclu- tacrolimus discontinuation compared MMF, and calcineurin inhibitor ther- sion can be derived from the data.89 The with CYC favors a slow taper off this apy,84 and ACTH led to partial remission use of renin-angiotensin-aldosterone medication.47 in one of two resistant MCD patients in blockers and may be considered another case series; this patient relapsed on a case-by-case basis in MCD adults, par- Mycophenolate Mofetil 4 weeks after discontinuing ACTH ther- ticularly those patients with hypertension. In children with MCD, mycophenolate apy.85 A pilot study recently showed that mofetil has been used as a steroid-sparing adding the protease inhibitor saqauinavir agent. In adults, mycophenolate mofetil to regimens in CONCLUSION has shown efficacy in case reports and adults and children with SR and SD small case series,18,60–68 with remission MCD may decrease proteinuria and Adults with NS caused by MCD con- rates of 60%–80% in this limited experience. steroid requirements in these patients.86 tinue to pose a challenge to clinicians. Plasma exchange therapy has also been Unless a contraindication exists, corti- highlighted in case reports in difficult- costeroids (with daily or alternate-day The use of rituximab in adults with FR to-treat patients.87,88 dosing) continue to be first-line therapy and immunosuppression-dependent for MCD in adults, with longer treat- MCD has been reported in case reports ment duration and slower tapers re- and small uncontrolled case series with OTHER TREATMENT quired compared with children to attain some success.69–79 These studies indicate CONSIDERATIONS IN MCD remission and minimize relapses. Re- that response to treatment is associated lapse is common, and many patients will with peripheral B cell depletion. Treatment of MCD with becomeFR,SD,orSR. The availabilityof Concomitant AKI nonsteroidal immunomodulatory ther- Azathioprine AKI can occur in patients with MCD and apies allows the treatment of compli- The use of azathioprine in adults with may be severe enough to require dialysis. catedandresistantpatientstobetailored MCD is not well documented. Histor- Asdiscussedabove, risk factors for AKIin individually based on the adverse event ically, azathioprine was not used in MCD include older age, hypertension, profiles of these medications. Preclinical difficult-to-treat MCD because of studies severe NS, and arteriosclerosis on renal and patient-based research studies con- in children with FR MCD where azathi- biopsy.18,21 Kidney function typically tinue to shed light on this poorly un- oprine was not effective.80,81 One retro- recovers even in the most severely af- derstood disease. spective series described 13 patients with fected patients, although patients who SR MCD, 5 of whom (on biopsy review) have experienced AKI may have residual had FSGS, who were treated with azathi- chronic renal impairment.18 Careful oprine (2–2.5 mg/kg per day) for 4 years. attention to patients’ volume status, sup- DISCLOSURES The time to remission in the MCD portive therapy for AKI, and continued None.

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