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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 B71) 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.79 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: cccccc, 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 immunoouores- 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, Shalhoub 3 proposed cic 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),
cause MCD is the cause of 90% of cases of 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 identied, 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
ses of NS in adults are more varied, 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
evidence of MCD, a kidney biopsy is usu- Treg cell function has led to decreased available at www.jasn.org.

ally warranted to establish the etiology. proteinuria in a rat model of the idio- Correspondence: Dr. Jai Radhakrishnan, Columbia
pathic NS.6 University Medical CenterInternal 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

J Am Soc Nephrol 24: cccccc, 2013 ISSN : 1046-6673/2404-ccc 1


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those changes seen in MCD. To date, no during an AKI episode and showed het- 4 weeks and 10%25% of patients re-
Angptl4 studies have been conducted in erogeneous ndings: arteriosclerosis quiring 1216 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 inammation (59%), mild tu- day) therapy may have a more favorable
related kB has been shown in the nuclei of bular atrophy with interstitial brosis 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 nding 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 rst month of
MCD is the etiology of NS in 10%25% one third of patients may frequently treatment compared with control. Impor-
of adults. 1315 On urinalysis, micro- relapse (FR) or become corticosteroid- tantly, by 2 years, a signicant 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 MCD1619 and may also seen in 40% of adults who had 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 studies that have been performed in and edema in the two groups (Figure 1).
latter conditions include malignancies MCD patients show similar long-term Similar results were shown in the
(Hodgkins lymphoma and thymoma), remission rates between treated and only placebo-controlled trial of steroid
drugs (nonsteroidal anti-inammatory 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 signicant 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 34 months of ste- from edema, risk of thromboembolic treated patients in complete remission
roid therapy to induce remission. Addi- events,29,30 AKI, and worsened quality 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 brosis 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% of cases. 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 children 31,32 and observational
ther initial presentation (n=17) or re- Efcacy 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 methylprednisolone compared

2 Journal of the American Society of Nephrology J Am Soc Nephrol 24: cccccc, 2013
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Daily Versus Alternate-Day Steroid


Therapy
Alternate-day corticosteroid regimens
for NS were rst described in the
1950s,35 and they have been associated
with less adrenal suppression, less effect
on growth, and similar efcacy 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
least 20 mg/d for at least 6 months. Modied 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 cant 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 rst re-
pared the efcacy 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 46 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
ve 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

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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 510 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 rst remission in MCD adults treated with daily versus alternate-day unwilling to take steroids. Cyclophos-
steroids. QD, daily; QOD, every other day. Modied from reference 18, with permission. phamide 23,3942 and cyclosporine 43
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 dened
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 22.5 mg/kg per d38 wk 75%
Cyclosporine 35 mg/kg per d in divided doses312 yr 75%
Tacrolimus 0.050.1 mg/kg per d in divided doses312 yr Unknown
Infrequent relapse
Same as initial medication Same as initial regimen Unknownthought to be
similar to initial remission rate

4 Journal of the American Society of Nephrology J Am Soc Nephrol 24: cccccc, 2013
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treatment as outlined above. Approxi- patients may be treated with a course patients, and shorter time to remission
mately 10%20% of adults with MCD 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 22.5
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 rst 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 ve 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 rst re- ve (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 rst 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- cyclophosphamide (CYC) leads to re- this cohort was 55% (n=11), with a mean
therapy (1 mg/kg per day). Remission mission in a signicant 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.
et 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 rst 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 efcacy 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 classied 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 denitions used here are the deni- 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 rst
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 benet in these MCD to receive tacrolimus (n=12; dosed

Table 2. Denitions of steroid-resistant, steroid dependent, and frequently relapsing MCD


Denition
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
a
Adapted from adult FSGS guidelines in reference 37.
b
No formal denition exists in adults; adapted from the denition 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; 22.5 mg/kg per 50%80% 50%80% 50%80% 50% 25%56% 25%56%
one RCT in adults d38 wk
iv CYC Two small RCTs in adults 750 mg/m2 per 50% 77% NA 14% 40% NA
mo36 mo + steroids
Cyclosporine 6 Large observational 35 mg/kg per d in 45%92% 45%92% 45%92% NA 62%75% 62%75%
prednisone series data; one small divided dose312 yr
RCT in children and
one RCT in adults
Tacrolimus 6 Small observational 0.050.1 mg/kg per d in 79%100% 91%100% NA 40% 50% NA
prednisone series; two small divided dose312 yr
RCTs in adults
Mycophenolate Small observational 12 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.
a
In steroid-resistant cases, review of the initial biopsy and a repeat biopsy may be considered to evaluate for FSGS.

to achieve trough level of 48 ng/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/m 2 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 trial 49 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=510 ng/ml) or intravenous CYC registry data of cyclosporine use in 150 (range=29 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) achieved complete remission in 74% 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.

6 Journal of the American Society of Nephrology J Am Soc Nephrol 24: cccccc, 2013
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Prolonged treatment in 36 adults (10 pa- patients was variable at 318 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 315 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 azathioprine (2 mg/kg per day for 2 hypoalbuminemia.
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 sufcient 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-aldosterone sys-
year remission rates of 79%91% and Other Immunomodulatory tem or statin 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 efcacy in case used in children with MCD, has not been cardiovascular disease, implying that long-
reports 57 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 rm 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 statins 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 immunosuppression regimens in CONCLUSION
has shown efcacy in case reports and adults and children with SR and SD
small case series,18,6068 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-
Rituximab highlighted in case reports in difcult- costeroids (with daily or alternate-day
The use of rituximab in adults with FR to-treat patients.87,88 dosing) continue to be rst-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.6979 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 become FR, SD, or SR. The availability of
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. cated and resistant patients to be tailored
MCD is not well documented. Histor- As discussed above, risk factors for AKI in individually based on the adverse event
ically, azathioprine was not used in MCD include older age, hypertension, proles of these medications. Preclinical
difcult-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 (22.5 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.

J Am Soc Nephrol 24: cccccc, 2013 Adult Minimal Change Disease 7


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