CJASN ePress. Published on December 23, 2016 as doi: 10.2215/CJN.

05000516

Minimal Change Disease

Marina Vivarelli,* Laura Massella,* Barbara Ruggiero,† and Francesco Emma*

Abstract
Minimal change disease (MCD) is a major cause of idiopathic nephrotic syndrome (NS), characterized by intense
proteinuria leading to edema and intravascular volume depletion. In adults, it accounts for approximately 15%
of patients with idiopathic NS, reaching a much higher percentage at younger ages, up to 70%–90% in children >1
year of age. In the pediatric setting, a renal biopsy is usually not performed if presentation is typical and the patient *Division of
responds to therapy with oral prednisone at conventional doses. Therefore, in this setting steroid-sensitive NS Nephrology and
can be considered synonymous with MCD. The pathologic hallmark of disease is absence of visible alterations by Dialysis, Bambino
light microscopy and effacement of foot processes by electron microscopy. Although the cause is unknown and it is Gesù Children’s
likely that different subgroups of disease recognize a different pathogenesis, immunologic dysregulation and Hospital, IRCCS,
Rome, Italy; and
modifications of the podocyte are thought to synergize in altering the integrity of the glomerular basement †
Clinical Research
membrane and therefore determining proteinuria. The mainstay of therapy is prednisone, but steroid-sensitive Center for Rare
forms frequently relapse and this leads to a percentage of patients requiring second-line steroid-sparing immu- Diseases “Aldo e Cele
nosuppression. The outcome is variable, but forms of MCD that respond to steroids usually do not lead to chronic Daccò”, IRCCS –
Istituto di Ricerche
renal damage, whereas forms that are unresponsive to steroids may subsequently reveal themselves as FSGS. Farmacologiche Mario
However, in a substantial number of patients the disease is recurrent and requires long-term immunosuppression, Negri, Ranica,
with significant morbidity because of side effects. Recent therapeutic advances, such as the use of anti-CD20 Bergamo, Italy
antibodies, have provided long-term remission off-therapy and suggest new hypotheses for disease pathogenesis.
Clin J Am Soc Nephrol 12: ccc–ccc, 2016. doi: 10.2215/CJN.05000516 Correspondence:
Dr. Marina Vivarelli,
Division of
Nephrology and
Introduction Therefore, the terms steroid-sensitive NS on the basis Dialysis, Ospedale
In adults, minimal change disease (MCD) represents Pediatrico Bambino
of clinical features and MCD on the basis of histo-
Gesù–IRCCS, Piazza
approximately 10%–15% of patients with idiopathic logic picture are not entirely equal. In clinical practice, S. Onofrio 4, 00165
nephrotic syndrome (Figure 1) (1,2). In children .1 year however, especially in children who do not systemat- Rome, Italy. Email:
of age, MCD is the most common cause of nephrotic ically undergo a renal biopsy, these terms are often marina.vivarelli@
syndrome, accounting for 70%–90% of patients; used as synonyms. In this review, the term MCD will opbg.net
around puberty, this proportion decreases signifi- include all children with classic clinical features of
cantly as other glomerular diseases, such as membra- steroid-sensitive NS in which a renal biopsy was not
nous nephropathy, become more frequent (Figure 1) performed, and all adults with the histologic pattern of
(3,4). The histologic picture of MCD is identical in MCD regardless of response to therapy.
adults and children. Because most children respond
to steroid treatment, the disease is termed “steroid-
sensitive nephrotic syndrome” (steroid-sensitive NS) Definitions and Epidemiology
on the basis of clinical features, and renal biopsy is The reported incidence of MCD in children varies
not performed unless steroid resistance is observed. If between two and seven new cases per 100,000 chil-
performed, it usually shows the absence of significant dren (3,7). The exact prevalence is not known, but on
changes by light microscopy (LM), a finding that has the basis of disease evolution and average age of
puzzled physicians for decades. When ultrastructural onset, it can be estimated at approximately 10–50 cases
analyses were first performed in the 1950s, extensive per 100,000 children. The disease is slightly more com-
fusion of podocyte foot processes was observed (5). mon in Asia and has a male predominance (approxi-
Soon after, the term “lipoid nephrosis,” introduced mately 2:1) in young children that disappears in
in the early 1900s to describe the presence of micro- adolescents and adults (3,8). MCD is much less fre-
scopic lipid droplets in urine and tubular cells, was quent in adults, but the exact incidence in this popula-
replaced by MCD, to highlight the existence of mini- tion is less well documented.
mal alterations of the glomerulus by LM. However, a Defining steroid sensitivity represents a first critical
minority of patients that have FSGS lesions on their aspect for prognosis, as forms that respond do not evolve
renal biopsy do respond to steroids and, conversely, toward chronic renal failure. In MCD, unlike other
patients with steroid-resistant nephrotic syndrome glomerular diseases, steroid response when present
(steroid-resistant NS) may have MCD at disease onset, is often complete, with total disappearance of protein-
before developing FSGS lesions later in the course of uria. However, time to remission is very different in
their disease (6). children compared with adults. As shown in Figure 2,

www.cjasn.org Vol 12 February, 2016 Copyright © 2016 by the American Society of Nephrology 1
2 Clinical Journal of the American Society of Nephrology

Figure 1. | Etiology of nephrotic syndrome according to age from 1 year onwards. (A) Minimal change disease. (B) Focal segmental glo-
merulosclerosis. (C) Membranous nephropathy. Data are approximated from Nachman et al. (1) and Cameron (2).
Clin J Am Soc Nephrol 12: ccc–ccc, February, 2016
Figure 2. | Time-to-response to prednisone is much shorter in children than in adults with minimal change disease. Data are extrapolated from
references Waldman et al. (12) and Vivarelli et al. (82) for children (A and B), from references (83) and Chen et al. (84) for adults (C and D).
after a first episode, approximately 50% of children achieve re-
mission within 8 days of steroid treatment and most patients
who are going to respond to steroids do so within 4 weeks.
In contrast, in adults the median time to remission exceeds
2 months. In both populations, MCD has a high tendency to
relapse, and relapses tend to be more rapid in children.
In Table 1, a further classification of MCD in clinical
subgroups on the basis of response to therapy, separating
children and adults, is reviewed. This classification for
children was initially proposed by the International Study
of Kidney Disease in Children (ISKDC) (9) and has been
adapted over the years (10).
Pathology
MCD accounts for the vast majority of idiopathic NS in
children, particularly for the steroid-sensitive forms (3,11).
In adults the picture is much more varied, with MCD be-
ing the third cause of idiopathic NS, after FSGS and mem-
branous nephropathy (1,2,4). Thus, whereas in adults early
kidney biopsy is crucial in driving the therapeutic ap-
proach (12), the indications for renal biopsy in children
are limited to features that may suggest alternative diag-
noses: at onset, age ,1 or .12 years, gross hematuria, low
serum C3, marked hypertension, renal failure without
severe hypovolemia, and positive history for secondary
cause; subsequently, steroid resistance or therapy with cal-
cineurin inhibitors. By LM, no glomerular lesions or only
mild focal mesangial prominence not exceeding three or
four cells per segment are seen. The presence of more than
four mesangial cells per mesangial region affecting at least
80% of the glomeruli defines the diffuse mesangial hyper-
cellularity variant of MCD. These patients can present
with hematuria and hypertension, unlike children with
classic MCD (13). Immunofluorescence is usually negative.
However, low-intensity mesangial IgM (sometimes accom-
panied by C3 or C1q) staining can be found (14) and MCD
is occasionally accompanied by glomerular IgA deposits, a
Minimal Change Disease, Vivarelli et al. 3
histologic picture that has been defined as IgA nephro-
pathy with MCD (15). Focal segmental distribution of IgM
and C3 staining should strongly suggest FSGS even when
no sclerotic lesions are captured by LM, whereas more
than trace amounts of IgG and IgA suggest alternative di-
agnoses. By electron microscopy, foot process effacement
is the only morphologic feature of MCD. Other pathologic
features automatically exclude the diagnosis of MCD,
which is therefore a diagnosis of exclusion.
Clinical Features
Rarely, nephrotic-range proteinuria is discovered on a
routine urinalysis, but most frequently the presenting
symptom of MCD is nephrotic syndrome, characterized by
edema, periorbital (often misinterpreted as allergic), of the
scrotum or labia, and of the lower extremities (11). Anasarca
may develop with ascites and pleural and pericardial effu-
sion, leading to abdominal pain because of hypoperfusion
and/or thrombosis, dyspnea (rarely), and cold extremities
with low BP (11). Especially in children, severe infections
such as sepsis, pneumonia, and peritonitis may be present at
disease onset or during disease course because of Ig de-
pletion and altered T cell function (16). Moreover, onset is
frequently preceded by upper respiratory tract infection.
Intravascular volume depletion and oliguria are also pres-
ent, and concomitant factors (sepsis, diarrhea, diuretics) can
lead to AKI, which is more frequently seen in adults (12),
although it occurs in about half of children hospitalized for
nephrotic syndrome (17). Rarely, AKI with gross hematuria
followed by anuria can also be secondary to bilateral renal
vein thrombosis. Gross hematuria is rare, occurring in 3% of
patients (11).
Laboratory analyses begin with urinalysis, with urinary
dipstick showing 31/41 proteinuria (corresponding to
$300 mg/dl on urinalysis) and, in about 20% of pa-
tients, microhematuria, which may resolve during remission
of proteinuria. Urine collection shows nephrotic-range
4 Clinical Journal of the American Society of Nephrology

Table 1. Definitions on the basis of references (9,10,64) and on the authors’ clinical experience

Nephrotic Syndrome
Edema
Massive proteinuria (.40 mg/m2 per h in children, .3.5 g/d in adults)
Hypoalbuminemia (,2.5 g/dl)
Remission
Resolution of edema
Normalization of serum albumin ($3.5 g/dl)
Marked reduction in proteinuria
Complete remission (,4 mg/m2 per h or negative dipstick in children, ,0.3 g/d in adults)
Partial remission (,2 g/1.73 m2 per d, decreased by 50% and serum albumin $2.5 g/dl in children, ,3.5 g/d and
decreased by 50% in adults)
Relapse
Recurrence of massive proteinuria (.40 mg/m2 per h in children, .3.5 g/d in adults)
Positive urine dipstick ($31 for 3 d or positive for 7 d, usually applicable to children)
6Edema
Steroid-Sensitive Nephrotic Syndrome
Response to PDN 60 mg/m2 per d within 4–6 wk 6MPD boluses in children
Response to PDN 1 mg/kg per d or 2 mg/kg every other d, within 16 wk in adults
Nonrelapsing Nephrotic Syndrome
No relapses for .2 yr after the end of therapy for the first episode of nephrotic syndrome (applicable to children, not
yet defined in adults)
Infrequently Relapsing Nephrotic Syndrome
,2 relapses per 6 mo (or ,4 relapses per 12 mo)
Frequently Relapsing Nephrotic Syndrome
$2 relapses per 6 mo (or $4 relapses per 12 mo)
Steroid-Dependent Nephrotic Syndrome
Relapse during steroid therapy or within 15 d of discontinuation
Steroid-Resistant Nephrotic Syndrome
No response to PDN 60 mg/m2 per d within 4 wk 6MPD boluses in children
No response to PDN 1 mg/kg per d or 2 mg/kg every other d, within 16 wk in adults
Multidrug-Resistant Nephrotic Syndrome
Poorly defined as absence of partial remission after 6 mo OR absence of complete remission after 2 yr
Treatment often consists of MPD boluses 1 oral prednisone for 6 mo 1 CsA and, in some cases, rituximab. Other
protocols are also used

PDN, prednisone; MPD, methylprednisolone; CsA, cyclosporine A.

proteinuria (urine proteins .40 mg/h per m2 or urine
protein-to-creatinine ratio .200 mg/mmol in children (11)
and urine proteins .3.5 g/d in adults [12]). Blood chem-
istry shows a reduction in serum total protein and serum
albumin, frequently ,2 g/dl, with an increased a2-globulin
and a reduced g-globulin fraction. The reduction in serum
protein leads to a reduced total serum calcium, with ion-
ized calcium usually within the normal range. IgG is mark-
edly decreased, IgA is slightly reduced, IgM is increased,
and IgE is normal or increased. Hyperlipidemia is pres-
ent, and is a consequence of (1) an increased hepatic syn-
thesis of cholesterol, triglycerides, and lipoproteins; (2)
a decreased catabolism of lipoproteins because of a de-
creased activity of lipoprotein lipase which transforms
VLDL to LDL; and (3) a decreased LDL receptor activity
and an increased urinary loss of HDL and proteins with
anticoagulant properties, such as antithrombin III. Regard-
ing hematologic parameters, hemoconcentration leads to
increased hemoglobin and hematocrit levels, and thrombo-
cytosis is frequently observed (11). This array of alter-
ations (hypovolemia, hyperdyslipidemia, urinary loss of
anticoagulants, and thrombocytosis) is worsened by
an increase in circulating fibrinogen, factors V and VIII,
and protein C, leading to a state of hypercoagulability and
therefore to an increased risk of thrombosis, usually (97% of
patients) venous thrombosis (18). Added risk factors for
thromboembolic disease are infection, the presence of a
central venous line, immobilization, and underlying genetic
thrombophilia (11).
Pathogenesis
It is as yet debated whether MCD and FSGS represent
a disease continuum with a common pathogenesis or two
separate disease entities. Excluding secondary forms of
MCD (Table 2), the vast majority of cases arise in other-
wise healthy individuals. Because the main histologic
feature is foot process effacement, visible by electron mi-
croscopy, studies have concentrated on finding what
disrupts the integrity of the glomerular filtration barrier.
Figure 3 shows a sketch of this disruption and of some of
the mechanisms that may contribute to determining it. The
existence of one or more circulating factors capable of in-
creasing its permeability, thus resulting in proteinuria,
was first hypothesized on the basis of observations of
the capability of plasma taken from nephrotic subjects to
Clin J Am Soc Nephrol 12: ccc–ccc, February, 2016 Minimal Change Disease, Vivarelli et al. 5

shown an imbalance in T cell subpopulations during active

Table 2. Secondary causes of minimal change disease (1,11) phase of disease, with a prevalence of circulating CD81
T suppressor cells that aggravate renal damage in mouse
Allergy models of nephrotic syndrome (24) and a prevalence of a
Pollen type 2 T helper cell (Th2; IL4, IL5, IL9, IL10, and IL13)
Dust
cytokine profile in patients (25), which is mirrored by the
Fungi
Bee sting spontaneous model of idiopathic nephrotic syndrome in
Cat fur the Buffalo/Mna rat (26). These observations fit with the
Food allergens (cow’s milk, egg) clinical observation of an association between MCD and
Malignancies atopy, as allergies are driven by Th2 responses. Of all Th2
Hodgkin disease cytokines, IL13 overexpression has been shown to induce
Non-Hodgkin lymphoma foot process effacement and proteinuria in rats (27). Certainly,
Leukemia no single cytokine can be considered pathogenic per se in
Multiple myeloma MCD, but rather may play a role in the context of a complex
Thymoma network with multiple cellular and circulating players (28).
Bronchogenic cancer
Moreover, different lines of evidence suggest a reduced
Colon cancer
Eosinophilic lymphoid granuloma (Kimura disease) function of regulatory T cells in MCD in adult patients
Drugs (29). Confirming this, MCD has been observed in immune
Nonsteroidal anti-inflammatory drugs dysregulation, polyendocrinopathy, enteropathy, X-linked
Salazopyrin syndrome, a congenital immunodeficiency with severe T
D-penicillamine regulatory cell hypofunction (30).
Mercury In the last few years, clinical evidence of the effectiveness
Gold of B cell depletion via rituximab, an anti-CD20 monoclonal
Tiopronin antibody, in different forms of nephrotic syndrome has
Lithium suggested a role for B cells as drivers of disease. Looking
Tyrosine-kinase inhibitors
back, multiple lines of evidence implicate B cells in the
Infections
Viral pathogenesis of nephrotic syndrome (reviewed in Elie
Parasitic et al. [20]): (1) total IgG and IgG subclasses display pro-
Mycoplasma pneumoniae tracted alterations in nephrotic patients during remission;
Autoimmune disorders (2) MCD has been observed in diseases associated with
SLE monoclonal light chains, implicating altered Igs in disease
Diabetes mellitus pathogenesis; (3) plasma soluble CD23, a classic parameter
Myasthenia gravis of B cell activation, is increased during relapse; (4) measles
Autoimmune pancreatitis virus also has an inhibitory effect on Ig synthesis; and (5)
Celiac disease the immunosuppressors employed in the treatment of
Allogeneic stem cell transplantation
Immunizations MCD have an antiproliferative effect on B cells, as well
as on T cells. However, there are also lines of evidence
against a direct role of B cells in MCD pathogenesis. First
of all, by definition in MCD there is little or no Ig deposi-
induce proteinuria in previously non-nephrotic subjects, tion on renal biopsy. In vitro, rituximab has been proven to
and a vast body of literature in both human and mouse bind directly to podocyte SMPDL3b and it has been sug-
models has been accrued regarding FSGS (19). In MCD gested that its antiproteinuric effect may be independent
there is less clinical evidence of this, but the existence of B cell depletion (31). Moreover, after rituximab infusion,
of a circulating mediator produced by abnormal T cells some patients maintain prolonged remission despite re-
was postulated as far back as 1974 by Shalhoub, on the constitution of B cells (32). Regarding this aspect, we
basis of the following observations: (1) remission may fol- have recently shown that after rituximab-induced B cell
low measles infection, which causes cell-mediated immu- depletion in children with frequently relapsing nephrotic
nosuppression; (2) MCD may occur in Hodgkin disease, syndrome or steroid-dependent nephrotic syndrome, the
a lymphoid neoplasia; (3) MCD responds to drugs that reconstitution of memory B cells predicts relapse (33). Tar-
suppress cell-mediated immunity; and (4) unlike other geting B cells may affect costimulatory pathways involved
glomerular disorders, there is an absence of humoral (Ig in T cell activation, and this may well be one of the mech-
and complement) deposition in glomeruli (16,20). This hy- anisms involved in the effectiveness of CD20-depleting
pothesis was strengthened by studies showing that super- agents, such as rituximab and the newer humanized
natants of T cell hybridoma lines produced from patients anti-CD20 monoclonal antibody, ofatumumab (34).
with MCD were able to induce foot process effacement In the last decade, studies have focused on the role of
and proteinuria in rats (21). Subsequently, a vast body of podocytes in determining proteinuria in MCD. A variety of
evidence has emerged implicating different aspects of interesting studies have investigated this aspect of MCD
T cell regulation and function in driving podocyte injury pathogenesis. One potential target of T cells on the podocyte
in MCD (20). These are reinforced by the therapeutic ef- is CD80 (also known as B7–1), a T cell costimulatory mole-
fectiveness of immunosuppression, both with prednisone cule expressed on antigen-presenting cells and B cells, which
and second-line steroid-sparing agents, as will be dis- has been found in the urine of patients with MCD during
cussed below. In summary, these results (22,23) have disease relapse (35). Recently, however, the presence of
6 Clinical Journal of the American Society of Nephrology

Figure 3. | Pathogenesis of minimal change disease: hypotheses. In the presence of a normal glomerular basement membrane (shown at the
center), with healthy podocyte foot processes (light blue), serum proteins, mainly albumin, remain within the glomerular capillary lumen.
Mechanisms, that are as yet not fully elucidated but are partly intrinsic to the podocyte and partly due to the presence of soluble mediators
released by a disregulated immune system (see top of the figure and text), modify this integrity. Therefore (red arrow), the actin cytoskeleton of
the podocyte and the glomerular basement membrane are disrupted, and albumin and other serum proteins filter out of the bloodstream and
into the urinary space. This leads to the intense proteinuria seen in nephrotic syndrome.

CD80 on human podocytes during renal disease, including
MCD and FSGS, as well as in experimental models of the
diseases, has been excluded and the efficacy of recombinant
CTLA4-Ig (abatacept and belatacept, which downregulate
CD80) in reducing proteinuria was not confirmed (36). These
results suggest caution and the need for thorough valida-
tion of preclinical results before passing from bench to bed-
side. Another mediator that has been implicated in the
pathogenesis of MCD is hemopexin, a plasma protein that
binds sialoglycoproteins in podocytes, leading to proteinuria
and foot process effacement in rats and cytoskeletal re-
arrangement in human cultured podocytes (37). A key pro-
tein found to be upregulated in both MCD and FSGS is c-mip
(reviewed in Ollero and Sahali [38]). Transgenic mice
overexpressing c-mip in podocytes develop heavy proteinuria
without any inflammatory lesions or cell infiltration. c-mip
Table 3. Therapy procedures for children, modified by KDIGO 2012 (43), Prof. Arvind Bagga, and authors’ clinical experience

Italy 2016 (SINePe

Therapy United States 2009 India 2008 France 2008 KDIGO 2012 Recommendations in
Preparation)

PDN at onset 2 mg/kg per d, 6 wk 2 mg/kg per d, 6 wk 60 mg/m2 per d, 4 wk 60 mg/m2 per d (or 2 mg/kg 60 mg/m2 per d, 6 wk
1.5 mg/kg every other d 1.5 mg/kg every 60 mg/m2 every other d per d), 4–6 wk 40 mg/m2 every other d,
6 wk, no taper other d 8 wk, taper 40 mg/m2 every other d (or 6 wk
Duration 12 wk 6 wk, no taper Duration 18 wk 1.5 mg/kg every other d), No taper
Duration 12 wk 2–5 mo, taper Duration 12 wk
Minimum duration 12 wk
PDN in relapse 2 mg/kg per d until 2 mg/kg per d until 60 mg/m2 per d until 60 mg/m2 per d (or 2 mg/kg 60 mg/m2 per d until
Clin J Am Soc Nephrol 12: ccc–ccc, February, 2016

(first relapses, 3 d after remission; 3 d after remission 6 d after remission per d) until 3 d after 5 d after remission
NRNS) 1.5mg/kgeveryotherd 1.5 mg/kg every 60 mg/m2 every other remission 40 mg/m2 every other d,
4 wk, no taper other d, 4 wk, no d, 4 wk, taper 40 mg/m2 every other d (or 4 wk
taper 1.5 mg/kg every other d), No taper
4 wk
No taper
Long-term 2 mg/kg per d until 2 mg/kg per d until 60 mg/m2 per d until 60 mg/m2 per d (or 2 mg/kg Not yet available
PDN (FRNS 3 d after remission 3 d after remission 6 d after remission per d) until 3 d after
or SDNS) 1.2 mg/kg every other 1.2 mg/kg every 60 mg/m2 every other remission
d, 4 wk other d, 4 wk d, 4 wk 40 mg/m2 every other d (or
Taper by 0.5 mg/kg Taper by 0.5–0.7 mg/ Taper by 15 mg/m2 1.5 mg/kg every other d)
every other d over kg every other d every other d, Taper over $3 mo
2 mo Continue for 9–18 mo every 2 wk up to Lowest every other d or
15 mg/m2 every daily dose to maintain
other d, continue for remission
12–18 mo
Steroid-sparing FRNS: CPA 12 wk Lev 1–2 yr Lev CPA 8–12 wk Not yet available
agents (FRNS MMF 1–2 yr CPA 12 wk CPA Chlorambucil 8 wk
or SDNS) CsA/TAC 2–5 yr CsA/TAC 1–2 yr CsA Lev.1 yr
SDNS: CsA/TAC MMF 1–2 yr MMF CsA/TAC.1 yr
MMF MMF.1 yr
CPA Rituximab

KDIGO, Kidney Disease Improving Global Outcomes; SINePe, Società Italiana Nefrologia Pediatrica; PDN, prednisone; NRNS, nonrelapsing nephrotic syndrome; FRNS, frequently relapsing
nephrotic syndrome; SDNS, steroid-dependent nephrotic syndrome; CPA, cyclophosphamide; Lev, levamisole; MMF, mofetil mycophenolate; CsA, cyclosporine A; TAC, tacrolimus.
Minimal Change Disease, Vivarelli et al.
7
8 Clinical Journal of the American Society of Nephrology

Table 4. Therapy procedures for adults (64,66,75)

First Episode of Nephrotic Syndromea

PDN 1 mg/kg per d or 2 mg/kg every other d (maximum 80 mg/d or 120 mg every other d) for 4–16 wk (evidence
level 2C)
Taper slowly over a total period of up to 6 mo after achieving remissionb (evidence level 2D)
Infrequent relapses
PDN 1 mg/kg per d or 2 mg/kg every other d (maximum 80 mg/d or 120 mg every other d) for 4–16 wk (evidence
level 2C)
Taper slowly over a total period of up to 6 mo after achieving remissionb (evidence level 2D)
Frequent relapses and steroid dependencyc
CPA 2–2.5 mg/kg per d for 8 wk (single course) (evidence level 2C)
If relapse occurs despite CPA or to preserve fertility:
CsA 3–5 mg/kg per d in two divided doses for 1–2 yr (evidence level 2C)
Or TAC 0.05–0.1 mg/kg per d in two divided doses until 3 mo after remission, then tapered to the minimum efficient dose for 1–
2 yr (evidence level 2C)
If intolerant to PDN, CPA, and CsA or TAC:
MMF 500–1000 mg twice daily for 1–2 yr (evidence level 2D)

PDN, prednisone; CPA, cyclophosphamide; CsA, cyclosporine A; TAC, tacrolimus; MMF, mofetil mycophenolate.
a
During first episode, statins for hypercholesterolemia and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers
for proteinuria in normotensive subjects are not indicated.
b
Taper by 5–10 mg/wk (it is preferable not to exceed a total maximum steroid exposure of 24 mo).
c
In patients with frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome who develop steroid-related side
effects (evidence level 1B).

interferes with podocyte signaling, potentially leading to cy-
toskeletal disorganization and foot processes effacement. Re-
cent studies have found that changes in the podocyte
expression of angiopoietin-like 4 are able to induce protein-
uria, foot process effacement, and dyslipidemia, another key
clinical feature of MCD (39).
Treatment
Pathologic features of MCD may be found even in renal
biopsies of patients with primary steroid resistance. In the
vast majority of these cases, however, it can be safely as-
sumed that the pathology will shift over time to FSGS (6).
Therefore, for the purpose of this review we will consider
MCD equivalent to steroid-sensitive NS. Treatment of
steroid-resistant forms is therefore excluded from this review.
In acute management, salt and fluid intake restriction is
mandatory to improve clinical manifestations (edema) (40).
Steroid treatment with prednisone or prednisolone, its active
metabolite, are the primary drugs used at disease onset. There
is no definitive consensus on the optimal dose and duration
of therapy, which combines maximum remission duration
with minimal side effects including stunted growth in children,
obesity, osteopenia, cataracts, glucose intolerance, hyperten-
sion, and behavioral disorders (41). Therefore, in Tables 3
and 4 we have summarized different attempts to an evidence-
based standardized approach in children and adults.
Children
In 1979, the ISKDC led to indications for optimal treatment
regimen at onset of pediatric nephrotic syndrome (predni-
sone 60 mg/m2 per day for 4 weeks and 40 mg/m2 3 days a
week for another 4 weeks [42]). Subsequent studies com-
pared different therapeutic regimens of longer duration,
most with an increase in total dose of steroids but some
used a matching cumulative dose spread over two periods
of different length. In the regimens where the total dose of
steroid was increased, the probability of relapse after 12 or
24 months was lower, but not all of these studies were
randomized and were often retrospective. On the basis of
these results, the 2012 Kidney Disease Improving Global
Outcomes (KDIGO) guidelines were issued (Table 2) (43).
Over the past 3 years, however, the results of three pro-
spective controlled studies have, to some extent, modi-
fied our point of view on the optimal therapeutic approach
at onset. In summary, as evidenced in the most recent
Cochrane review (44), extending the treatment regimen for
.12 weeks total or giving higher doses does not signifi-
cantly modify the onset of frequent relapses.
Even greater uncertainty exists in the treatment of relapses.
It is known that 80%–90% of children with steroid-sensitive
NS have at least one relapse in their history of the disease.
The most difficult patients to treat are those with frequently
relapsing NS or steroid-dependent NS. KDIGO recommen-
dations on the treatment of relapses are, in fact, made on the
basis of levels of evidence that are never more than grade C
or D (43). Despite the lack of controlled studies, the use of
low-dose steroids on alternate days is recommended for fre-
quent relapses (45). Interestingly, because of the extreme fre-
quency of minor infectious episodes triggering relapse, three
recent studies have been published confirming the clinical
experience that in the pediatric setting, a low dose of pred-
nisone switched from alternate days to daily at the onset of
low-grade proteinuria is frequently sufficient in preventing
a full-blown relapse (reviewed in Hahn et al. [44]).
Nonsteroidal Immunosuppressive Drugs
Children with MCD who develop frequently relapsing
NS or steroid-dependent NS need steroid-sparing agents
Clin J Am Soc Nephrol 12: ccc–ccc, February, 2016
to reduce the secondary side effects of prolonged pred-
nisone. Currently used agents are levamisole, alkylating
agents, calcineurin inhibitors, antiproliferatives, and rituximab.
Azathioprine, vincristine, mizobirine, and fusidic acid have
also been used, though they are not currently recommended.
The Cochrane review, updated in 2013 (46), provides a clear
overview of studies assessing the drugs in use over the
greatest number of years.
Levamisole, an immunostimulatory drug with an an-
thelmintic effect in animals, is reported to increase time to
relapse in frequently relapsing NS compared with predni-
sone alone, but in the absence of clear data from controlled
studies, it is rarely used. However, a randomized controlled
multicenter study (European Clinical Trials Database iden-
tifier 2005–005745–18) was recently completed, coordinated
by the Dutch, on its effect in both frequently relapsing NS
and steroid-dependent NS compared with placebo. These
findings, once published, should indicate the ideal patients
to treat with this drug. In our experience, levamisole can
be a safe and effective steroid-sparing option in relatively
mild forms of frequently relapsing NS. Alkylating agents
such as cyclophosphamide (47) or chlorambucil (48), as well
as levamisole, were some of the first steroid-sparing drugs to
be used in this disease. In current clinical practice, chloram-
bucil is infrequently or no longer used. Many studies show
that they reduce the number of relapses compared with
prednisone alone, and that cyclophosphamide induces
more prolonged remission in patients with frequently relaps-
ing NS compared with those with steroid-dependent NS.
In the 1990s, cyclosporin A (CsA) was introduced. It in-
hibits calcineurin (like tacrolimus; TAC) and thus blocks
the activation of T cells, modifying the immune re-
sponse. The first comparative studies published on this
drug involved alkylating agents, showing no superiority of
CsA versus chlorambucil (46) or versus cyclophosphamide
(46). The fact that CsA is easier to handle (no need for
frequent check of the blood count and no gonadal toxicity)
and that alkylating agents seemed to be more effective in
frequently relapsing NS than steroid-dependent NS, led
to a preference for CsA, especially in steroid-dependent
NS. Moreover, calcineurin inhibitors also act through a va-
soactive mechanism and by modifying podocyte perm-
selectivity, which also makes them effective in reducing
proteinuria in some steroid-resistant forms (49). CsA is
effective in controlling the disease over time, allow-
ing prednisone discontinuation in many patients with
steroid-dependent NS. Unfortunately, it has disadvantages,
as many patients relapse after interruption and prolonged
use leads to significant nephrotoxicity (50). TAC acts in a
similar way but there are no studies on whether it is better
than CsA (51). However, published and personal experi-
ence suggest that TAC can be a good alternative to CsA in
adolescents, especially girls, as it does not induce hyper-
trichosis or gingival hypertrophy, side effects to which
these patients are very sensitive, thus improving thera-
peutic compliance. An oral glucose tolerance test before
starting is prudential (52).
More recently, mycophenolate mofetil (MMF) has been
used in MCD. It has an antiproliferative effect on both B
and T cells. There are no superiority studies with regard
to CsA, however, a post hoc analysis by Gellermann et al.
showed that the disease control in patients with a higher
Minimal Change Disease, Vivarelli et al. 9
plasma level of MMF (area under the curve .50 mg) was
very similar to CsA (53). As for calcineurin inhibitors, the
probability of relapse is very high after withdrawal. Apart
from effects on the gastrointestinal system and bone mar-
row, which are very dose–dependent, the main advantage
of MMF compared with CsA is that it is not nephrotoxic.
This has made it the first choice in treating steroid-dependent
NS, where a long history of disease is expected.
The drug that has aroused the most interest over the last
decade is rituximab. Rituximab is a chimeric monoclonal
antibody that binds to the CD20 antigen expressed on B
cells, thus inducing B cell depletion. Although there have
been few randomized controlled studies, rituximab reduces
drug dependency, allowing interruption of all therapy,
though often only temporarily, as recently reviewed (54). In
2013, Boyer and Niaudet hypothesized that rituximab may
change the dependence of nephrotic syndrome on steroids
or CsA to dependence on rituximab itself, often requiring
multiple infusions (55). Though its overall safety profile is
reassuring (56), rituximab use in children is not without rare
serious side effects: fulminant myocarditis, pulmonary fibro-
sis, fatal Pneumocystis jirovecii infections, severe ulcerative
colitis, and severe allergic reactions (reviewed in Avner
et al. [11]). We have shown that, in children with frequently
relapsing NS or steroid-dependent NS, rituximab infusion
determines a prolonged depletion of memory B cells (33),
and have observed long-term hypogammaglobulinemia
in a few patients. Therefore, prospective long-term studies
are necessary to evaluate the effect of repeated infusions
on immune competence in the pediatric setting. A new fully
humanized anti-CD20 monoclonal antibody, ofatumumab,
is available, which appears effective in some patients with
multidrug resistance (34).
Of note, live vaccines are contraindicated in patients
receiving steroid-sparing agents and in patients receiving
high-dose steroids; inactivated vaccines should be admin-
istered, keeping in mind that suboptimal response re-
quiring a repeated dose may be an issue (40,57).
Steroid-Resistant Forms
In children, steroid resistance is defined as lack of re-
mission despite therapy with oral prednisone at adequate
dosage (see Table 3) for a number of weeks that is still
controversial. However, because of the finding that 95%
of children with steroid-sensitive NS respond to pred-
nisone within 4 weeks (9), most centers declare steroid re-
sistance after 4 weeks of treatment. At this point, in
addition to requesting genetic screening for genetic forms
of nephrotic syndrome and performing a renal biopsy,
three intravenous methylprednisolone boluses followed
by the introduction of a calcineurin inhibitor, most fre-
quently CsA, are recommended (10). Oral prednisone is
usually reduced to alternate days and gradually tapered
until discontinuation within 6 months (10). Response to
CsA, when present, is gradual, and has been observed
even many months after the introduction of CsA in about
80% of patients (58). In about 30% of children, the presence
of a genetic mutation determines the course of the disease
(59), and in this case the chances of response to treatment
are extremely low. Children that respond to CsA in sub-
sequent relapses become steroid-sensitive (secondary ste-
roid sensitivity). Some of these patients display prolonged
10 Clinical Journal of the American Society of Nephrology
remission with calcineurin inhibitors and can therefore
be gradually shifted to therapy with MMF (60). In children
who do not respond to CsA in 6–12 months, the use of
TAC can be attempted in the absence of known genetic
causes (61). Other therapeutic approaches have been at-
tempted but response is uncertain. The use of rituximab
is still controversial, appearing successful in some reports
and one study (62), which was not confirmed in a subse-
quent open-label randomized trial (63). Other anecdotal
therapeutic successes with ofatumumab are yet to be con-
firmed (34). Plasmapheresis and immunoadsorption may
also be beneficial in some patients.
Adults
In adults, most indications for the treatment of MCD are
derived from clinical trials in children and from obser-
vational studies performed in patients of various ages.
Despite two small-sized placebo-controlled trials show-
ing no significant advantage with prednisone in inducing
complete or partial remission in adult MCD, even in the
long-term, KDIGO guidelines recommend oral prednisone
at onset (evidence level 1C), since patients treated with
steroids go more rapidly into remission than controls (64).
In these very old studies, steroids were given orally but
doses and schedules varied widely, ranging from an aver-
age of 25 mg daily dose in one study to 125 mg on alter-
nate days in the other. No subsequent, well designed, and
adequately sized controlled trials were conducted with
oral steroids in inducing remission of the nephrotic syn-
drome. Therefore, the currently accepted induction regimen
of 1 mg/kg per day (maximum 80 mg/d) or 2 mg/kg every
other day (maximum 120 mg/d) for 16 weeks (minimum
4 weeks if remission is promptly achieved; evidence level
2C) is extrapolated from pediatric randomized controlled
trials and observational studies in adults (12). Previous
studies failed to show a significant benefit of intravenous
methylprednisolone (20 mg/kg per day for 3 days) fol-
lowed by reduced-dose oral steroids (prednisone 0.5 mg/kg
per day) versus full-dose oral steroids alone (prednisone
1 mg/kg per day). In adults, there are no controlled studies
defining the best regimen for tapering the prednisone after
the initial response, and this remains one of the most con-
troversial issue for therapy since slow tapering may increase
cumulative steroid doses, but rapid tapering may expose
patients to the risk of relapses (reviewed in Hogan and
Radhakrishnan [65]). A reasonable compromise may be to
taper prednisone by 5–10 mg/wk after remission over
8 weeks for a total 24-week period of exposure to pred-
nisone (12).
Many questions on treatment efficacy and safety remain
unanswered regarding the optimal dose and duration of
steroids and steroid-sparing agents on subsequent relapses
in frequently relapsing NS and steroid-dependent NS
(64–66). The use of alkylating agents or calcineurin inhib-
itors in frequently relapsing NS or steroid-dependent NS is
determined on the basis of clinical studies in children or
small observational studies in adults. In adults, cyclophos-
phamide was shown to be better than CsA in steroid-
dependent NS, and even more in frequently relapsing
NS, in maintaining remission (67). In a randomized con-
trolled trial by Ponticelli et al. on 75 adults and children
with frequently relapsing NS and steroid-dependent NS
(31 were MCD), long-term outcome was better with cyclo-
phosphamide versus CsA, with 63% patients maintaining
remission after 2 years compared with 25% with CsA (68).
On the other hand, adding CsA to steroids was found to
induce remission more rapidly than steroids alone at first
relapse (69). The optimal CsA dose is not established, how-
ever, KDIGO guidelines suggest a 3–5 mg/kg per day range
on the basis of dosages used in these studies. Some patients
may relapse once CsA is discontinued. Only one study
has been conducted in frequently relapsing NS or steroid-
dependent NS, showing that TAC was equally effective to
intravenous cyclophosphamide in inducing and maintain-
ing remission at 2 years in 26 adults who had been previ-
ously treated with prednisone at onset (70). MMF use has
been reported only in small patient cohorts, showing efficacy
in about 60%–70% of patients (71,72). KDIGO guidelines (64)
suggest to use cyclophosphamide as a first-line therapy for
frequently relapsing NS or steroid-dependent NS, or alter-
natively CsA, to preserve fertility and MMF only in patients
intolerant to the other drugs (Table 3). Also, rituximab has
proven to be effective in adults (73), and data from another
frequent cause of nephrotic syndrome in adults, membra-
nous nephropathy, in which rituximab is used as single
agent, are encouraging even considering the long-term safety
(74). A current evidence-based approach to MCD therapy
in adults is shown in Table 3 and reviewed in Hogan and
Radhakrishnan (65) and Canetta and Radhakrishnan (75).
Steroid-Resistant Forms
About 10%–20% of cases of adult MCD are steroid-
resistant, defined as no response to 16 weeks of oral pred-
nisone daily or alternate days, and in these patients a second
renal biopsy may reveal FSGS. Treatment of steroid-resistant
MCD should follow KDIGO guidelines for steroid-resistant
FSGS (64). Genetic forms are much rarer than in chil-
dren, but should be investigated in young adults and in
the presence of positive family history, particularly re-
garding ACTN4 mutations (76). The mainstay of therapy
in these patients are calcineurin inhibitors, but cyclophos-
phamide, both oral and intravenous, has also been used
and proved effective in some patients (reviewed in Hogan
and Radhakrishnan [65]). An open-label trial compar-
ing TAC versus intravenous cyclophosphamide showed
an effective and more rapid induction of remission by
TAC (77). MMF, chlorambucil, azathioprine, ACTH, and
rituximab have been used only in the setting of small case
series with variable results.
Outcome
In children, after remission of the first episode of nephro-
sis, about 30% do not suffer relapses for 18–24 months, and
this usually indicates that the risk of future relapses is neg-
ligible. Approximately 20%–30% progress to infrequent relapses
and rarely experience more than three or four episodes in
total, managed by therapy with prednisone alone. The remain-
ing 40%–50%, more frequently children ,5 years of age, will
have a frequently relapsing or steroid-dependent course,
with relapses during steroid tapering or soon after discon-
tinuation, requiring second-line steroid-sparing therapy
Clin J Am Soc Nephrol 12: ccc–ccc, February, 2016
(3,12). Rarely, children with initially steroid-sensitive disease
will develop secondary steroid resistance. This clinical fea-
ture is highly predictive of post-transplant recurrence (78).
In adults, relapses are frequent, occurring in about 56%–76%
of patients (12,79). In all patients with MCD, the occurrence
of chronic renal failure is exceptional, providing the disease
maintains its response to steroids. Usually, no relapses for at
least 2 years from discontinuation of all therapy indicates
permanent remission. Occasionally, patients can relapse sev-
eral years after they have been declared cured. Long-term
outcome studies of large cohorts of childhood onset MCD
followed into adulthood show about 3% developing chronic
renal failure and 16%–42% recurring in adulthood. The main
risk factor for adult relapses is frequent relapses in child-
hood (41,80). The main morbidity of MCD at all ages there-
fore derives from the side effects of therapy discussed above,
primarily immunosuppression and, regarding prednisone,
inhibition of linear growth, worsened by urinary loss of thy-
roid hormones and IGF1–1 (11,41,81). Importantly, subjects
with childhood-onset MCD who maintain frequently relaps-
ing NS or steroid-dependent NS during adulthood are at
major risk for long-term toxicity, not exactly quantified be-
cause of the lack of long-term observational studies, including
sterility associated with cytotoxic agents, nephrotoxicity with
calcineurin inhibitors, diabetes, hypertension, obesity, osteo-
porosis, and cataracts related to steroids, and solid or blood
neoplasia because of prolonged immunosuppression (41,80).
Adults versus Children
MCD is a typical disease of childhood, accounting for the
vast majority of primary NS cases in children and for about
10%–15% in adults (1,3). Features common to all ages of on-
set are the renal pathology, the high prevalence of steroid-
responsiveness compared with most other nephropathies
and overall the favorable outcome. However, some rele-
vant differences exist between children and adults.
First, clinical features at onset: whereas in children and
young adults, edema is the main clinical symptom inducing
parents to seek health care, adults .60 years may frequently
present with impaired renal function and hypertension (12).
Patients with reversible acute renal failure, probably linked
with higher proteinuria levels, are more frequent in adults
than in children (12), although a recent paper shows that
AKI is frequently seen in children with nephrotic syndrome
seeking hospitalization (17). In addition, thrombotic com-
plications because of a combination of hypercoagulability,
increased blood lipids, and hemoconcentration occur in a
small percentage of children (2.7%) and in a much more
consistent proportion of adults (24.1%), most frequently at
disease onset (18). Second, a male preponderance has been
described in children (11), whereas a female preponderance
has been described in adults (12). Third, in children the
disease is usually idiopathic, excluding the trigger of infec-
tion, whereas secondary forms (Table 2) are more frequent
in adults (1,11). Fourth, focal areas of interstitial fibrosis or
tubular atrophy without the finding of sclerotic glomeruli
do not exclude MCD in adults and frequently associate
with chronic hypertension, particularly in the elderly,
whereas in children these lesions strongly suggest the pos-
sibility of a FSGS that was not correctly sampled at biopsy.
Fifth, the timing of treatment response is quite different in
Minimal Change Disease, Vivarelli et al. 11
terms of both time to remission and response rate between
children and adults. Children have a shorter time to remis-
sion, usually within days or weeks from treatment initia-
tion, whereas adults require months to achieve proteinuria
reduction (Figure 2) (12,82–84). Therefore, therapeutic pro-
tocols with steroids at onset differ in children versus adults,
as reported above, and consequently the definition of steroid-
resistant NS differs, as children are considered resistant
after 4 weeks of full-dose steroids (Table 1) whereas in
adults, 16 weeks of prednisone (1 mg/kg per day) are re-
quired to define patients as steroid-resistant NS. This oc-
curs in adults in approximately 10%–30% of cases, mostly
because of evolution to FSGS (12). Timing of relapses also
differs, with children relapsing more frequently and sooner
compared with adults.
Interestingly, some children demonstrate initial resistance
to oral prednisone but respond to additional therapies, such
as methylprednisolone boluses or CsA. After discontinua-
tion of therapy, these patients do not always relapse (9).
Conversely, patients with onset of MCD during early child-
hood who maintain active disease in adulthood continue to
present a relapsing nephrotic syndrome with the character-
istics of childhood onset MCD. These observations suggest
that MCD is not a homogeneous disease and that children
and adults present different forms of the disease. A subset
of children with a longer time to remission at disease onset
may represent a subgroup with childhood onset adult MCD.
Conclusions
MCD is a histologic picture than does not correspond to a
single disease entity. It can be found in very different clinical
settings, and at different ages in life. Therefore, recognition
of distinct subgroups of patients with common clinical and
laboratory features is essential in determining disease prog-
nosis and in tailoring optimal therapeutic strategies.
Acknowledgments
The authors wish to thank Dr. Andrea Pasini and Prof. Arvind
Bagga for their thoughtful contribution.
This work has been funded by the Associazione per la Cura del
Bambino Nefropatico, which supports M.V. and L.M.
Disclosures
None.
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