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 (NS), characterized by intense leading to 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 and can be considered synonymous with MCD. The pathologic hallmark of disease is absence of visible alterations by Dialysis, Bambino light and effacement of foot processes by electron microscopy. Although the cause is unknown and it is Gesu` Children’s likely that different subgroups of disease recognize a different pathogenesis, immunologic dysregulation and Hospital, IRCCS, Rome, Italy; and modifications of the 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 Dacco`”, IRCCS – renal damage, whereas forms that are unresponsive to steroids may subsequently reveal themselves as FSGS. Istituto di Ricerche Farmacologiche Mario However, in a substantial number of patients the disease is recurrent and requires long-term , Negri, Ranica, with significant morbidity because of side effects. Recent therapeutic advances, such as the use of anti-CD20 Bergamo, Italy , 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 of clinical features and MCD on the basis of histo- Pediatrico Bambino – Gesu`–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 .1year 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 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 - 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 Minimal Change Disease, Vivarelli et al. 3

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- histologic picture that has been defined as IgA nephro- mission within 8 days of steroid treatment and most patients pathy with MCD (15). Focal segmental distribution of IgM who are going to respond to steroids do so within 4 weeks. and C3 staining should strongly suggest FSGS even when In contrast, in adults the median time to remission exceeds no sclerotic lesions are captured by LM, whereas more 2 months. In both populations, MCD has a high tendency to than trace amounts of IgG and IgA suggest alternative di- relapse, and relapses tend to be more rapid in children. agnoses. By electron microscopy, foot process effacement In Table 1, a further classification of MCD in clinical is the only morphologic feature of MCD. Other pathologic subgroups on the basis of response to therapy, separating features automatically exclude the diagnosis of MCD, children and adults, is reviewed. This classification for which is therefore a diagnosis of exclusion. children was initially proposed by the International Study of Disease in Children (ISKDC) (9) and has been adapted over the years (10). Clinical Features Rarely, nephrotic-range proteinuria is discovered on a routine urinalysis, but most frequently the presenting Pathology symptom of MCD is nephrotic syndrome, characterized by MCD accounts for the vast majority of idiopathic NS in edema, periorbital (often misinterpreted as allergic), of the children, particularly for the steroid-sensitive forms (3,11). scrotum or labia, and of the lower extremities (11). In adults the picture is much more varied, with MCD be- may develop with and pleural and pericardial effu- ing the third cause of idiopathic NS, after FSGS and mem- sion, leading to abdominal pain because of hypoperfusion branous nephropathy (1,2,4). Thus, whereas in adults early and/or thrombosis, dyspnea (rarely), and cold extremities kidney biopsy is crucial in driving the therapeutic ap- with low BP (11). Especially in children, severe infections proach (12), the indications for renal biopsy in children such as sepsis, pneumonia, and peritonitis may be present at are limited to features that may suggest alternative diag- disease onset or during disease course because of Ig de- noses: at onset, age ,1or.12 years, gross , low pletion and altered function (16). Moreover, onset is serum C3, marked , renal failure without frequently preceded by upper respiratory tract infection. severe hypovolemia, and positive history for secondary Intravascular volume depletion and oliguria are also pres- cause; subsequently, steroid resistance or therapy with cal- ent, and concomitant factors (sepsis, diarrhea, diuretics) can cineurin inhibitors. By LM, no glomerular lesions or only lead to AKI, which is more frequently seen in adults (12), mild focal mesangial prominence not exceeding three or although it occurs in about half of children hospitalized for four cells per segment are seen. The presence of more than nephrotic syndrome (17). Rarely, AKI with gross hematuria four mesangial cells per mesangial region affecting at least followed by anuria can also be secondary to bilateral renal 80% of the glomeruli defines the diffuse mesangial hyper- vein thrombosis. Gross hematuria is rare, occurring in 3% of cellularity variant of MCD. These patients can present patients (11). with hematuria and hypertension, unlike children with Laboratory analyses begin with urinalysis, with urinary classic MCD (13). Immunofluorescence is usually negative. dipstick showing 31/41 proteinuria (corresponding to However, low-intensity mesangial IgM (sometimes accom- $300 mg/dl on urinalysis) and, in about 20% of pa- panied by C3 or C1q) staining can be found (14) and MCD tients, , which may resolve during remission is occasionally accompanied by glomerular IgA deposits, a 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) (,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 (,2g/1.73m2 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 4–6wk6MPD 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, . Other protocols are also used

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

proteinuria (urine .40 mg/h per m2 or urine and protein C, leading to a state of hypercoagulability and protein-to-creatinine ratio .200 mg/mmol in children (11) therefore to an increased risk of thrombosis, usually (97% of and urine proteins .3.5 g/d in adults [12]). Blood chem- patients) venous thrombosis (18). Added risk factors for istry shows a reduction in serum total protein and serum thromboembolic disease are infection, the presence of a albumin, frequently ,2 g/dl, with an increased a2-globulin central venous line, immobilization, and underlying genetic and a reduced g-globulin fraction. The reduction in serum thrombophilia (11). 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, Pathogenesis and IgE is normal or increased. Hyperlipidemia is pres- It is as yet debated whether MCD and FSGS represent ent, and is a consequence of (1) an increased hepatic syn- a disease continuum with a common pathogenesis or two thesis of cholesterol, triglycerides, and lipoproteins; (2) separate disease entities. Excluding secondary forms of a decreased catabolism of lipoproteins because of a de- MCD (Table 2), the vast majority of cases arise in other- creased activity of lipoprotein lipase which transforms wise healthy individuals. Because the main histologic VLDL to LDL; and (3)adecreasedLDLreceptoractivity feature is foot process effacement, visible by electron mi- and an increased urinary loss of HDL and proteins with croscopy, studies have concentrated on finding what anticoagulant properties, such as antithrombin III. Regard- disrupts the integrity of the glomerular filtration barrier. ing hematologic parameters, hemoconcentration leads to Figure 3 shows a sketch of this disruption and of some of increased hemoglobin and hematocrit levels, and thrombo- the mechanisms that may contribute to determining it. The cytosis is frequently observed (11). This array of alter- existence of one or more circulating factors capable of in- ations (hypovolemia, hyperdyslipidemia, urinary loss of creasing its permeability, thus resulting in proteinuria, anticoagulants, and thrombocytosis) is worsened by was first hypothesized on the basisofobservationsof an increase in circulating fibrinogen, factors V and VIII, 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 profile in patients (25), which is mirrored by the Fungi Bee sting spontaneous model of idiopathic nephrotic syndrome in fi Cat fur the Buffalo/Mna rat (26). These observations twiththe 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 , IL13 overexpression has been shown to induce Non- 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 fi Drugs (29). Con rming 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 , in different forms of nephrotic syndrome has Lithium suggested a role for B cells as drivers of disease. Looking Tyrosine-kinase inhibitors Infections back, multiple lines of evidence implicate B cells in the 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)unlikeother 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 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 pathogenesis of MCD is hemopexin, a plasma protein that MCD and FSGS, as well as in experimental models of the binds sialoglycoproteins in podocytes, leading to proteinuria diseases, has been excluded and the efficacy of recombinant and foot process effacement in rats and cytoskeletal re- CTLA4-Ig (abatacept and belatacept, which downregulate arrangement in human cultured podocytes (37). A key pro- CD80) in reducing proteinuria was not confirmed (36). These tein found to be upregulated in both MCD and FSGS is c-mip results suggest caution and the need for thorough valida- (reviewed in Ollero and Sahali [38]). Transgenic mice tion of preclinical results before passing from bench to bed- overexpressing c-mip in podocytes develop heavy proteinuria side. Another mediator that has been implicated in the without any inflammatory lesions or cell infiltration. c-mip lnJA o eho 12: Nephrol Soc Am J Clin

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 ccc 2 2 – –

1.5 mg/kg every other d 1.5 mg/kg every 60 mg/m every other d per d), 4 6wk 40 mg/m every other d, ccc 6 wk, no taper other d 8 wk, taper 40 mg/m2 every other d (or 6wk eray 06MnmlCag ies,Vvrlie l 7 al. et Vivarelli Disease, Change Minimal 2016 February, , 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 (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 4wk taper 1.5 mg/kg every other d), No taper 4wk 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 $3mo 2mo Continue for 9–18 moevery 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.1yr SDNS: CsA/TAC MMF 1–2 yr MMF CsA/TAC.1yr MMF MMF.1yr CPA Rituximab

KDIGO, 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, ; Lev, levamisole; MMF, mofetil mycophenolate; CsA, cyclosporine A; TAC, . 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 1–2yr(evidencelevel2C) 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. aDuring first episode, for hypercholesterolemia and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers for proteinuria in normotensive subjects are not indicated. bTaper by 5–10 mg/wk (it is preferable not to exceed a total maximum steroid exposure of 24 mo). cIn 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- most with an increase in total dose of steroids but some toskeletal disorganization and foot processes effacement. Re- used a matching cumulative dose spread over two periods cent studies have found that changes in the podocyte of different length. In the regimens where the total dose of expression of angiopoietin-like 4 are able to induce protein- steroid was increased, the probability of relapse after 12 or uria, foot process effacement, and dyslipidemia, another key 24 months was lower, but not all of these studies were clinical feature of MCD (39). 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). Treatment Over the past 3 years, however, the results of three pro- Pathologic features of MCD may be found even in renal spective controlled studies have, to some extent, modi- biopsies of patients with primary steroid resistance. In the fied our point of view on the optimal therapeutic approach vast majority of these cases, however, it can be safely as- at onset. In summary, as evidenced in the most recent sumed that the pathology will shift over time to FSGS (6). Cochrane review (44), extending the treatment regimen for Therefore, for the purpose of this review we will consider .12 weeks total or giving higher doses does not signifi- MCD equivalent to steroid-sensitive NS. Treatment of cantly modify the onset of frequent relapses. steroid-resistant forms is therefore excluded from this review. Even greater uncertainty exists in the treatment of relapses. In acute management, salt and fluid intake restriction is It is known that 80%–90% of children with steroid-sensitive mandatory to improve clinical manifestations (edema) (40). NS have at least one relapse in their history of the disease. Steroid treatment with prednisone or prednisolone, its active The most difficult patients to treat are those with frequently metabolite, are the primary drugs used at disease onset. There relapsing NS or steroid-dependent NS. KDIGO recommen- is no definitive consensus on the optimal dose and duration dations on the treatment of relapses are, in fact, made on the of therapy, which combines maximum remission duration basis of levels of evidence that are never more than grade C with minimal side effects including stunted growth in children, or D (43). Despite the lack of controlled studies, the use of obesity, osteopenia, cataracts, glucose intolerance, hyperten- low-dose steroids on alternate days is recommended for fre- sion, and behavioral disorders (41). Therefore, in Tables 3 quent relapses (45). Interestingly, because of the extreme fre- and 4 we have summarized different attempts to an evidence- quency of minor infectious episodes triggering relapse, three based standardized approach in children and adults. 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 Children low-grade proteinuria is frequently sufficient in preventing In 1979, the ISKDC led to indications for optimal treatment a full-blown relapse (reviewed in Hahn et al. [44]). regimen at onset of pediatric nephrotic syndrome (predni- sone 60 mg/m2 per day for 4 weeks and 40 mg/m2 3daysa Nonsteroidal Immunosuppressive Drugs week for another 4 weeks [42]). Subsequent studies com- Children with MCD who develop frequently relapsing pared different therapeutic regimens of longer duration, NS or steroid-dependent NS need steroid-sparing agents Clin J Am Soc Nephrol 12: ccc–ccc, February, 2016 Minimal Change Disease, Vivarelli et al. 9

to reduce the secondary side effects of prolonged pred- plasma level of MMF (area under the curve .50 mg) was nisone. Currently used agents are levamisole, alkylating very similar to CsA (53). As for calcineurin inhibitors, the agents, calcineurin inhibitors, antiproliferatives, and rituximab. probability of relapse is very high after withdrawal. Apart , vincristine, mizobirine, and fusidic acid have from effects on the gastrointestinal system and bone mar- also been used, though they are not currently recommended. row, which are very dose–dependent, the main advantage The Cochrane review, updated in 2013 (46), provides a clear of MMF compared with CsA is that it is not nephrotoxic. overview of studies assessing the drugs in use over the This has made it the first choice in treating steroid-dependent greatest number of years. NS, where a long history of disease is expected. Levamisole, an immunostimulatory drug with an an- The drug that has aroused the most interest over the last thelmintic effect in animals, is reported to increase time to decade is rituximab. Rituximab is a chimeric monoclonal relapse in frequently relapsing NS compared with predni- antibody that binds to the CD20 antigen expressed on B sone alone, but in the absence of clear data from controlled cells, thus inducing B cell depletion. Although there have studies, it is rarely used. However, a randomized controlled been few randomized controlled studies, rituximab reduces multicenter study (European Clinical Trials Database iden- drug dependency, allowing interruption of all therapy, tifier 2005–005745–18) was recently completed, coordinated though often only temporarily, as recently reviewed (54). In by the Dutch, on its effect in both frequently relapsing NS 2013, Boyer and Niaudet hypothesized that rituximab may and steroid-dependent NS compared with placebo. These change the dependence of nephrotic syndrome on steroids findings, once published, should indicate the ideal patients or CsA to dependence on rituximab itself, often requiring to treat with this drug. In our experience, levamisole can multiple infusions (55). Though its overall safety profile is be a safe and effective steroid-sparing option in relatively reassuring (56), rituximab use in children is not without rare mild forms of frequently relapsing NS. Alkylating agents serious side effects: fulminant myocarditis, pulmonary fibro- such as cyclophosphamide (47) or chlorambucil (48), as well sis, fatal Pneumocystis jirovecii infections, severe ulcerative as levamisole, were some of the first steroid-sparing drugs to colitis, and severe allergic reactions (reviewed in Avner be used in this disease. In current clinical practice, chloram- et al. [11]). We have shown that, in children with frequently bucil is infrequently or no longer used. Many studies show relapsing NS or steroid-dependent NS, rituximab infusion that they reduce the number of relapses compared with determines a prolonged depletion of memory B cells (33), prednisone alone, and that cyclophosphamide induces and have observed long-term hypogammaglobulinemia more prolonged remission in patients with frequently relaps- in a few patients. Therefore, prospective long-term studies ing NS compared with those with steroid-dependent NS. are necessary to evaluate the effect of repeated infusions In the 1990s, cyclosporin A (CsA) was introduced. It in- on immune competence in the pediatric setting. A new fully hibits calcineurin (like tacrolimus; TAC) and thus blocks humanized anti-CD20 monoclonal antibody, ofatumumab, the activation of T cells, modifying the immune re- is available, which appears effective in some patients with sponse. The first comparative studies published on this multidrug resistance (34). drug involved alkylating agents, showing no superiority of Of note, live vaccines are contraindicated in patients CsA versus chlorambucil (46) or versus cyclophosphamide receiving steroid-sparing agents and in patients receiving (46). The fact that CsA is easier to handle (no need for high-dose steroids; inactivated vaccines should be admin- frequent check of the blood count and no gonadal toxicity) istered, keeping in mind that suboptimal response re- and that alkylating agents seemed to be more effective in quiring a repeated dose may be an issue (40,57). frequently relapsing NS than steroid-dependent NS, led to a preference for CsA, especially in steroid-dependent Steroid-Resistant Forms NS. Moreover, calcineurin inhibitors also act through a va- In children, steroid resistance is defined as lack of re- soactive mechanism and by modifying podocyte perm- mission despite therapy with oral prednisone at adequate selectivity, which also makes them effective in reducing dosage (see Table 3) for a number of weeks that is still proteinuria in some steroid-resistant forms (49). CsA is controversial. However, because of the finding that 95% effective in controlling the disease over time, allow- of children with steroid-sensitive NS respond to pred- ing prednisone discontinuation in many patients with nisone within 4 weeks (9), most centers declare steroid re- steroid-dependent NS. Unfortunately, it has disadvantages, sistance after 4 weeks of treatment. At this point, in as many patients relapse after interruption and prolonged addition to requesting genetic screening for genetic forms use leads to significant nephrotoxicity (50). TAC acts in a of nephrotic syndrome and performing a renal biopsy, similar way but there are no studies on whether it is better three intravenous methylprednisolone boluses followed than CsA (51). However, published and personal experi- by the introduction of a calcineurin inhibitor, most fre- ence suggest that TAC can be a good alternative to CsA in quently CsA, are recommended (10). Oral prednisone is adolescents, especially girls, as it does not induce hyper- usually reduced to alternate days and gradually tapered trichosis or gingival hypertrophy, side effects to which until discontinuation within 6 months (10). Response to these patients are very sensitive, thus improving thera- CsA, when present, is gradual, and has been observed peutic compliance. An oral glucose tolerance test before even many months after the introduction of CsA in about starting is prudential (52). 80% of patients (58). In about 30% of children, the presence More recently, mycophenolate mofetil (MMF) has been of a genetic mutation determines the course of the disease used in MCD. It has an antiproliferative effect on both B (59), and in this case the chances of response to treatment and T cells. There are no superiority studies with regard are extremely low. Children that respond to CsA in sub- to CsA, however, a post hoc analysis by Gellermann et al. sequent relapses become steroid-sensitive (secondary ste- showed that the disease control in patients with a higher roid sensitivity). Some of these patients display prolonged 10 Clinical Journal of the American Society of Nephrology

remission with calcineurin inhibitors and can therefore with frequently relapsing NS and steroid-dependent NS be gradually shifted to therapy with MMF (60). In children (31 were MCD), long-term outcome was better with cyclo- who do not respond to CsA in 6–12 months, the use of phosphamide versus CsA, with 63% patients maintaining TAC can be attempted in the absence of known genetic remission after 2 years compared with 25% with CsA (68). causes (61). Other therapeutic approaches have been at- On the other hand, adding CsA to steroids was found to tempted but response is uncertain. The use of rituximab induce remission more rapidly than steroids alone at first is still controversial, appearing successful in some reports relapse (69). The optimal CsA dose is not established, how- and one study (62), which was not confirmed in a subse- ever, KDIGO guidelines suggest a 3–5 mg/kg per day range quent open-label randomized trial (63). Other anecdotal on the basis of dosages used in these studies. Some patients therapeutic successes with ofatumumab are yet to be con- may relapse once CsA is discontinued. Only one study firmed (34). Plasmapheresis and immunoadsorption may has been conducted in frequently relapsing NS or steroid- also be beneficial in some patients. 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- Adults ously treated with prednisone at onset (70). MMF use has In adults, most indications for the treatment of MCD are been reported only in small patient cohorts, showing efficacy derived from clinical trials in children and from obser- in about 60%–70% of patients (71,72). KDIGO guidelines (64) vational studies performed in patients of various ages. suggest to use cyclophosphamide as a first-line therapy for Despite two small-sized placebo-controlled trials show- frequently relapsing NS or steroid-dependent NS, or alter- ing no significant advantage with prednisone in inducing natively CsA, to preserve fertility and MMF only in patients complete or partial remission in adult MCD, even in the intolerant to the other drugs (Table 3). Also, rituximab has long-term, KDIGO guidelines recommend oral prednisone proven to be effective in adults (73), and data from another at onset (evidence level 1C), since patients treated with frequent cause of nephrotic syndrome in adults, membra- steroids go more rapidly into remission than controls (64). nous nephropathy, in which rituximab is used as single In these very old studies, steroids were given orally but agent, are encouraging even considering the long-term safety doses and schedules varied widely, ranging from an aver- (74). A current evidence-based approach to MCD therapy age of 25 mg daily dose in one study to 125 mg on alter- in adults is shown in Table 3 and reviewed in Hogan and nate days in the other. No subsequent, well designed, and Radhakrishnan (65) and Canetta and Radhakrishnan (75). adequately sized controlled trials were conducted with oral steroids in inducing remission of the nephrotic syn- drome. Therefore, the currently accepted induction regimen Steroid-Resistant Forms of 1 mg/kg per day (maximum 80 mg/d) or 2 mg/kg every About 10%–20% of cases of adult MCD are steroid- other day (maximum 120 mg/d) for 16 weeks (minimum resistant, defined as no response to 16 weeks of oral pred- 4 weeks if remission is promptly achieved; evidence level nisone daily or alternate days, and in these patients a second 2C) is extrapolated from pediatric randomized controlled renal biopsy may reveal FSGS. Treatment of steroid-resistant trials and observational studies in adults (12). Previous MCD should follow KDIGO guidelines for steroid-resistant studies failed to show a significant benefit of intravenous FSGS (64). Genetic forms are much rarer than in chil- methylprednisolone (20 mg/kg per day for 3 days) fol- dren, but should be investigated in young adults and in lowed by reduced-dose oral steroids (prednisone 0.5 mg/kg thepresenceofpositivefamilyhistory,particularlyre- per day) versus full-dose oral steroids alone (prednisone garding ACTN4 mutations (76). The mainstay of therapy 1 mg/kg per day). In adults, there are no controlled studies in these patients are calcineurin inhibitors, but cyclophos- defining the best regimen for tapering the prednisone after phamide, both oral and intravenous, has also been used the initial response, and this remains one of the most con- and proved effective in some patients (reviewed in Hogan troversial issue for therapy since slow tapering may increase and Radhakrishnan [65]). An open-label trial compar- cumulative steroid doses, but rapid tapering may expose ing TAC versus intravenous cyclophosphamide showed patients to the risk of relapses (reviewed in Hogan and an effective and more rapid induction of remission by Radhakrishnan [65]). A reasonable compromise may be to TAC (77). MMF, chlorambucil, azathioprine, ACTH, and taper prednisone by 5–10 mg/wk after remission over rituximab have been used only in the setting of small case 8 weeks for a total 24-week period of exposure to pred- series with variable results. nisone (12). Many questions on treatment efficacy and safety remain unanswered regarding the optimal dose and duration of Outcome steroids and steroid-sparing agents on subsequent relapses In children, after remission of the first episode of nephro- in frequently relapsing NS and steroid-dependent NS sis, about 30% do not suffer relapses for 18–24 months, and (64–66). The use of alkylating agents or calcineurin inhib- this usually indicates that the risk of future relapses is neg- itors in frequently relapsing NS or steroid-dependent NS is ligible. Approximately 20%–30% progress to infrequent relapses determined on the basis of clinical studies in children or and rarely experience more than three or four episodes in small observational studies in adults. In adults, cyclophos- total, managed by therapy with prednisone alone. The remain- phamide was shown to be better than CsA in steroid- ing 40%–50%, more frequently children ,5 years of age, will dependent NS, and even more in frequently relapsing have a frequently relapsing or steroid-dependent course, NS, in maintaining remission (67). In a randomized con- with relapses during steroid tapering or soon after discon- trolled trial by Ponticelli et al. on 75 adults and children tinuation, requiring second-line steroid-sparing therapy Clin J Am Soc Nephrol 12: ccc–ccc, February, 2016 Minimal Change Disease, Vivarelli et al. 11

(3,12). Rarely, children with initially steroid-sensitive disease terms of both time to remission and response rate between will develop secondary steroid resistance. This clinical fea- children and adults. Children have a shorter time to remis- ture is highly predictive of post-transplant recurrence (78). sion, usually within days or weeks from treatment initia- In adults, relapses are frequent, occurring in about 56%–76% tion, whereas adults require months to achieve proteinuria of patients (12,79). In all patients with MCD, the occurrence reduction (Figure 2) (12,82–84). Therefore, therapeutic pro- of chronic renal failure is exceptional, providing the disease tocols with steroids at onset differ in children versus adults, maintains its response to steroids. Usually, no relapses for at as reported above, and consequently the definition of steroid- least 2 years from discontinuation of all therapy indicates resistant NS differs, as children are considered resistant permanent remission. Occasionally, patients can relapse sev- after 4 weeks of full-dose steroids (Table 1) whereas in eral years after they have been declared cured. Long-term adults, 16 weeks of prednisone (1 mg/kg per day) are re- outcome studies of large cohorts of childhood onset MCD quired to define patients as steroid-resistant NS. This oc- followed into adulthood show about 3% developing chronic curs in adults in approximately 10%–30% of cases, mostly renal failure and 16%–42% recurring in adulthood. The main because of evolution to FSGS (12). Timing of relapses also risk factor for adult relapses is frequent relapses in child- differs, with children relapsing more frequently and sooner hood (41,80). The main morbidity of MCD at all ages there- compared with adults. fore derives from the side effects of therapy discussed above, Interestingly, some children demonstrate initial resistance primarily immunosuppression and, regarding prednisone, to oral prednisone but respond to additional therapies, such inhibition of linear growth, worsened by urinary loss of thy- as methylprednisolone boluses or CsA. After discontinua- roid hormones and IGF1–1 (11,41,81). Importantly, subjects tion of therapy, these patients do not always relapse (9). with childhood-onset MCD who maintain frequently relaps- Conversely, patients with onset of MCD during early child- ing NS or steroid-dependent NS during adulthood are at hood who maintain active disease in adulthood continue to major risk for long-term toxicity, not exactly quantified be- present a relapsing nephrotic syndrome with the character- cause of the lack of long-term observational studies, including istics of childhood onset MCD. These observations suggest sterility associated with cytotoxic agents, nephrotoxicity with that MCD is not a homogeneous disease and that children calcineurin inhibitors, diabetes, hypertension, obesity, osteo- and adults present different forms of the disease. A subset porosis, and cataracts related to steroids, and solid or blood of children with a longer time to remission at disease onset neoplasia because of prolonged immunosuppression (41,80). may represent a subgroup with childhood onset adult MCD.

Adults versus Children Conclusions MCD is a typical disease of childhood, accounting for the MCD is a histologic picture than does not correspond to a vast majority of primary NS cases in children and for about single disease entity. It can be found in very different clinical 10%–15% in adults (1,3). Features common to all ages of on- settings, and at different ages in life. Therefore, recognition setaretherenalpathology,thehighprevalenceofsteroid- of distinct subgroups of patients with common clinical and responsiveness compared with most other nephropathies laboratory features is essential in determining disease prog- and overall the favorable outcome. However, some rele- nosis and in tailoring optimal therapeutic strategies. vant differences exist between children and adults. First, clinical features at onset: whereas in children and Acknowledgments young adults, edema is the main clinical symptom inducing The authors wish to thank Dr. Andrea Pasini and Prof. Arvind parents to seek health care, adults .60 years may frequently Bagga for their thoughtful contribution. present with impaired renal function and hypertension (12). This work has been funded by the Associazione per la Cura del Patients with reversible acute renal failure, probably linked Bambino Nefropatico, which supports M.V. and L.M. with higher proteinuria levels, are more frequent in adults than in children (12), although a recent paper shows that Disclosures AKI is frequently seen in children with nephrotic syndrome None. seeking hospitalization (17). In addition, thrombotic com- plications because of a combination of hypercoagulability, References increased blood lipids, and hemoconcentration occur in a 1. Nachman PH, Jennette JC, Falk RJ: Primary glomerular disease. small percentage of children (2.7%) and in a much more In: The Kidney, 8th Ed., edited by Brenner BM, Philadelphia, consistent proportion of adults (24.1%), most frequently at Saunders Elsevier, 2008, pp 987–1066 2. Cameron JS: The nephrotic syndrome and its complications. disease onset (18). Second, a male preponderance has been Am J Kidney Dis 10: 157–171, 1987 described in children (11), whereas a female preponderance 3. Eddy AA, Symons JM: Nephrotic syndrome in childhood. Lancet has been described in adults (12). Third, in children the 362: 629–639, 2003 disease is usually idiopathic, excluding the trigger of infec- 4. Floege J, Amann K: Primary glomerulonephritides. Lancet 387: tion, whereas secondary forms (Table 2) are more frequent 2036–2048, 2016 fi 5. Farquhar MG, Vernier RL, Good RA: An electron microscope in adults (1,11). Fourth, focal areas of interstitial brosis or study of the glomerulus in nephrosis, , and tubular atrophy without the finding of sclerotic glomeruli lupus erythematosus. J Exp Med 106: 649–660, 1957 do not exclude MCD in adults and frequently associate 6. D’Agati VD, Kaskel FJ, Falk RJ: Focal segmental glomerulo- with chronic hypertension, particularly in the elderly, sclerosis. N Engl J Med 365: 2398–2411, 2011 7. Hogg RJ, Portman RJ, Milliner D, Lemley KV, Eddy A, Ingelfinger J: whereas in children these lesions strongly suggest the pos- Evaluation and management of proteinuria and nephrotic syn- sibility of a FSGS that was not correctly sampled at biopsy. drome in children: recommendations from a pediatric nephrology Fifth, the timing of treatment response is quite different in panel established at the National Kidney Foundation conference on 12 Clinical Journal of the American Society of Nephrology

proteinuria, albuminuria, risk, assessment, detection, and elimi- 28. Bertelli R, Bonanni A, Di Donato A, Cioni M, Ravani P, Ghiggeri nation (PARADE). Pediatrics 105: 1242–1249, 2000 GM: Regulatory T cells and minimal change nephropathy: In the 8. Gdadegesin R, Smoyer WE: Nephrotic syndrome. In: Compre- midst of a complex network. Clin Exp Immunol 183: 166–174, hensive Pediatric Nephrology, edited by Geary DF, Scaefer F, 2016 Philadelphia, Mosby Elsevier, 2008, pp 205–218 29. Liu LL, Qin Y, Cai JF, Wang HY, Tao JL, Li H, Chen LM, Li MX, 9. The primary nephrotic syndrome in children. Identification Li XM, Li XW: Th17/Treg imbalance in adult patients with of patients with minimal change nephrotic syndrome from minimal change nephrotic syndrome. Clin Immunol 139: initial response to prednisone. A report of the International 314–320, 2011 Study of Kidney Disease in Children. JPediatr98: 561–564, 30. Hashimura Y, Nozu K, Kanegane H, Miyawaki T, Hayakawa A, 1981 Yoshikawa N, Nakanishi K, Takemoto M, Iijima K, Matsuo M: 10. Ehrich JH, Geerlings C, Zivicnjak M, Franke D, Geerlings H, Minimal change nephrotic syndrome associated with immune Gellermann J: Steroid-resistant idiopathic childhood nephrosis: dysregulation, polyendocrinopathy, enteropathy, X-linked syn- Overdiagnosed and undertreated. Nephrol Dial Transplant 22: drome. Pediatr Nephrol 24: 1181–1186, 2009 2183–2193, 2007 31. Fornoni A, Sageshima J, Wei C, Merscher-Gomez S, Aguillon- 11. Avner ED, Harmon WE, Niaudet P, Yoshikawa N, Emma F, Prada R, Jauregui AN, Li J, Mattiazzi A, Ciancio G, Chen L, Goldstein SL: Idiopathic Nephrotic Syndrome in Children: Zilleruelo G, Abitbol C, Chandar J, Seeherunvong W, Ricordi C, Clinical Aspects. Pediatric Nephrology, 7th Ed., Berlin, Springer, Ikehata M, Rastaldi MP, Reiser J, Burke GW III: Rituximab targets 2016, pp 2730 podocytes in recurrent focal segmental glomerulosclerosis. Sci 12. Waldman M, Crew RJ, Valeri A, Busch J, Stokes B, Markowitz G, Transl Med 3: 85ra46, 2011 D’Agati V, Appel G: Adult minimal-change disease: Clinical 32. Sellier-Leclerc AL, Baudouin V, Kwon T, Macher MA, Gue´rin V, characteristics, treatment, and outcomes. Clin J Am Soc Nephrol Lapillonne H, Descheˆnes G, Ulinski T: Rituximab in steroid- 2: 445–453, 2007 dependent idiopathic nephrotic syndrome in childhood– 13. Ranganathan S: Pathology of podocytopathies causing nephrotic follow-up after CD19 recovery. Nephrol Dial Transplant 27: syndrome in children. Front Pediatr 4: 32, 2016 1083–1089, 2012 14. Pardo V, Riesgo I, Zilleruelo G, Strauss J: The clinical significance 33. Colucci M, Carsetti R, Cascioli S, Casiraghi F, Perna A, Rava` L, of mesangial IgM deposits and mesangial hypercellularity in Ruggiero B, Emma F, Vivarelli M: B Cell reconstitution after rit- minimal change nephrotic syndrome. Am J Kidney Dis 3: uximab treatment in idiopathic nephrotic syndrome. JAmSoc 264–269, 1984 Nephrol 27: 1811–1822, 2015 15. Herlitz LC, Bomback AS, Stokes MB, Radhakrishnan J, D’Agati 34. Basu B: Ofatumumab for rituximab-resistant nephrotic syn- VD, Markowitz GS: IgA nephropathy with minimal change dis- drome. N Engl J Med 370: 1268–1270, 2014 ease. Clin J Am Soc Nephrol 9: 1033–1039, 2014 35. Garin EH, Mu W, Arthur JM, Rivard CJ, Araya CE, Shimada M, 16. Shalhoub RJ: Pathogenesis of lipoid nephrosis: A disorder of Johnson RJ: Urinary CD80 is elevated in minimal change disease T-cell function. Lancet 2: 556–560, 1974 but not in focal segmental glomerulosclerosis. Kidney Int 78: 17. Rheault MN, Zhang L, Selewski DT, Kallash M, Tran CL, Seamon 296–302, 2010 M, Katsoufis C, Ashoor I, Hernandez J, Supe-Markovina K, 36. Delville M, Baye E, Durrbach A, Audard V, Kofman T, Braun L, D’Alessandri-Silva C, DeJesus-Gonzalez N, Vasylyeva TL, Olagne J, Nguyen C, Descheˆnes G, Moulin B, Delahousse M, FormeckC,WollC,GbadegesinR,GeierP,DevarajanP, Kesler-Roussey G, Beaudreuil S, Martinez F, Rabant M, Carpenter SL, Kerlin BA, Smoyer WE; Midwest Pediatric Grimbert P, Gallazzini M, Terzi F, Legendre C, Canaud G: Nephrology Consortium: AKI in children hospitalized with B7-1 blockade does not improve post-transplant nephrotic nephrotic syndrome. Clin J Am Soc Nephrol 10: 2110–2118, syndrome caused by recurrent FSGS. J Am Soc Nephro 27: 2015 2520–2527, 2015 18. Kerlin BA, Ayoob R, Smoyer WE: Epidemiology and pathophys- 37. Lennon R, Singh A, Welsh GI, Coward RJ, Satchell S, Ni L, iology of nephrotic syndrome-associated thromboembolic dis- Mathieson PW, Bakker WW, Saleem MA: Hemopexin induces ease. Clin J Am Soc Nephrol 7: 513–520, 2012 nephrin-dependent reorganization of the actin cytoskeleton in 19. Maas RJ, Deegens JK, Wetzels JF: Permeability factors in idio- podocytes. J Am Soc Nephrol 19: 2140–2149, 2008 pathic nephrotic syndrome: Historical perspectives and lessons 38. Ollero M, Sahali D: Inhibition of the VEGF signalling pathway for the future. Nephrol Dial Transplant 29: 2207–2216, 2014 and glomerular disorders. Nephrol Dial Transplant 30: 1449– 20. Elie V, Fakhoury M, Descheˆnes G, Jacqz-Aigrain E: Physiopa- 1455, 2015 thology of idiopathic nephrotic syndrome: Lessons from gluco- 39. Clement LC, Avila-Casado C, Mace´ C, Soria E, Bakker WW, corticoids and epigenetic perspectives. Pediatr Nephrol 27: Kersten S, Chugh SS: Podocyte-secreted angiopoietin-like-4 1249–1256, 2012 mediates proteinuria in glucocorticoid-sensitive nephrotic 21. Koyama A, Fujisaki M, Kobayashi M, Igarashi M, Narita M: A syndrome. Nat Med 17: 117–122, 2011 glomerular permeability factor produced by human T cell 40. McCaffrey J, Lennon R, Webb NJ: The non-immunosuppressive hybridomas. Kidney Int 40: 453–460, 1991 management of childhood nephrotic syndrome. Pediatr Nephrol 22. Pereira WF, Brito-Melo GE, Guimara˜es FT, Carvalho TG, Mateo 31: 1383–1402, 2016 EC, Simo˜es e Silva AC: The role of the immune system in idio- 41. Ru¨th EM, Kemper MJ, Leumann EP, Laube GF, Neuhaus TJ: pathic nephrotic syndrome: A review of clinical and experi- Children with steroid-sensitive nephrotic syndrome come of age: mental studies. Inflamm Res 63: 1–12, 2014 long-term outcome. J Pediatr 147: 202–207, 2005 23. Sahali D, Sendeyo K, Mangier M, Audard V, Zhang SY, Lang P, 42. Nephrotic syndrome in children: a randomized trial comparing Ollero M, Pawlak A: Immunopathogenesis of idiopathic ne- two prednisone regimens in steroid-responsive patients who re- phrotic syndrome with relapse. Semin Immunopathol 36: lapse early. Report of the international study of kidney disease in 421–429, 2014 children. J Pediatr 95: 239–243, 1979 24. Wang Y, Wang YP, Tay YC, Harris DC: Role of CD8(1) cells in the 43. Lombel RM, Gipson DS, Hodson EM; Kidney Disease: Improving progression of murine adriamycin nephropathy. Kidney Int 59: Global Outcomes: Treatment of steroid-sensitive nephrotic 941–949, 2001 syndrome: new guidelines from KDIGO. Pediatr Nephrol 28: 25. van den Berg JG, Weening JJ: Role of the immune system in the 415–426, 2013 pathogenesis of idiopathic nephrotic syndrome. Clin Sci (Lond) 44. Hahn D, Hodson EM, Willis NS, Craig JC: Corticosteroid therapy 107: 125–136, 2004 for nephrotic syndrome in children. Cochrane Database Syst Rev 26. Le Berre L, Herve´ C, Buzelin F, Usal C, Soulillou JP, Dantal J: 3: CD001533, 2015 Renal macrophage activation and Th2 polarization precedes the 45. Alternate-day versus intermittent prednisone in frequently re- development of nephrotic syndrome in Buffalo/Mna rats. Kidney lapsing nephrotic syndrome. A report of “Arbetsgemeinschaft fu¨r Int 68: 2079–2090, 2005 Pa¨diatrische Nephrologie”. Lancet 1: 401–403, 1979 27. Lai KW, Wei CL, Tan LK, Tan PH, Chiang GS, Lee CG, Jordan SC, 46. Pravitsitthikul N, Willis NS, Hodson EM, Craig JC: Non-cortico- Yap HK: Overexpression of interleukin-13 induces minimal- steroid immunosuppressive medications for steroid-sensitive change-like nephropathy in rats. J Am Soc Nephrol 18: nephrotic syndrome in children. Cochrane Database Syst Rev 10: 1476–1485, 2007 CD002290, 2013 Clin J Am Soc Nephrol 12: ccc–ccc, February, 2016 Minimal Change Disease, Vivarelli et al. 13

47. Webb H, Jaureguiberry G, Dufek S, Tullus K, Bockenhauer D: 64. Kidney Disease Improving Global Outcomes Glomerulone- Cyclophosphamide and rituximab in frequently relapsing/ phritis Work Group: KDIGO clinical practice guideline for glo- steroid-dependent nephrotic syndrome. Pediatr Nephrol 31: merulonephritis. Kidney Int 2[Suppl. 2]: 139–274, 2012 589–594, 2016 65. Hogan J, Radhakrishnan J: The treatment of minimal change 48. Das U, Dakshinamurty KV, Prasad N: Ponticelli regimen in disease in adults. J Am Soc Nephrol 24: 702–711, 2013 idiopathic nephrotic syndrome. Indian J Nephrol 19: 48–52, 66. Palmer SC, Nand K, Strippoli GF: Interventions for minimal 2009 change disease in adults with nephrotic syndrome. Cochrane 49. Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Database Syst Rev (1): CD001537, 2008 Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, Reiser J, 67. Mak SK, Short CD, Mallick NP: Long-term outcome of adult- Mundel P: The actin cytoskeleton of kidney podocytes is a direct onset minimal-change nephropathy. Nephrol Dial Transplant 11: target of the antiproteinuric effect of cyclosporine A. Nat Med 14: 2192–2201, 1996 931–938, 2008 68. Ponticelli C, Edefonti A, Ghio L, Rizzoni G, Rinaldi S, Gusmano 50. Kengne-Wafo S, Massella L, Diomedi-Camassei F, Gianviti A, R, Lama G, Zacchello G, Confalonieri R, Altieri P, Bettinelli A, Vivarelli M, Greco M, Stringini GR, Emma F: Risk factors for Maschio G, Cinotti GA, Fuiano G, Schena FP, Castellani A, Delia cyclosporin A nephrotoxicity in children with steroid- Casa-Alberighi O: Cyclosporin versus cyclophosphamide for dependant nephrotic syndrome. Clin J Am Soc Nephrol 4: patients with steroid-dependent and frequently relapsing idio- 1409–1416, 2009 pathic nephrotic syndrome: A multicentre randomized controlled 51. Wang W, Xia Y, Mao J, Chen Y, Wang D, Shen H, Fu H, Du L, Liu trial. Nephrol Dial Transplant 8: 1326–1332, 1993 A: Treatment of tacrolimus or cyclosporine A in children with 69. Eguchi A, Takei T, Yoshida T, Tsuchiya K, Nitta K: Combined idiopathic nephrotic syndrome. Pediatr Nephrol 27: 2073–2079, cyclosporine and prednisolone therapy in adult patients with the 2012 first relapse of minimal-change nephrotic syndrome. Nephrol 52. Palepu S, Prasad GV: New-onset diabetes mellitus after kidney Dial Transplant 25: 124–129, 2010 transplantation: Current status and future directions. World J 70. Li X, Li H, Chen J, He Q, Lv R, Lin W, Li Q, He X, Qu L, Suya W: Diabetes 6: 445–455, 2015 Tacrolimus as a steroid-sparing agent for adults with steroid- 53. Gellermann J, Weber L, Pape L, To¨nshoff B, Hoyer P, Querfeld U; dependent minimal change nephrotic syndrome. Nephrol Dial Gesellschaft fu¨rPa¨diatrische Nephrologie (GPN): Mycophenolate Transplant 23: 1919–1925, 2008 mofetil versus cyclosporin A in children with frequently 71. Pesavento TE, Bay WH, Agarwal G, Hernandez RA Jr, Hebert LA: relapsing nephrotic syndrome. JAmSocNephrol24: 1689– Mycophenolate therapy in frequently relapsing minimal change 1697, 2013 disease that has failed cyclophosphamide therapy. Am J Kidney 54. Ravani P, Bonanni A, Rossi R, Caridi G, Ghiggeri GM: Anti-CD20 Dis 43: e3–e6, 2004 antibodies for idiopathic nephrotic syndrome in children. Clin J 72. Siu YP, Tong MK, Leung K, Kwan TH, Au TC: The use of enteric- Am Soc Nephrol 11: 710–720, 2016 coated mycophenolate sodium in the treatment of relapsing and 55. Boyer O, Niaudet P: Nephrotic syndrome: Rituximab in child- steroid-dependent minimal change disease. J Nephrol 21: 127– hood steroid-dependent nephrotic syndrome. Nat Rev Nephrol 131, 2008 9: 562–563, 2013 73. Ruggenenti P, Ruggiero B, Cravedi P, Vivarelli M, Massella L, 56. Tellier S, Brochard K, Garnier A, Bandin F, Llanas B, Guigonis V, Marasa` M, Chianca A, Rubis N, Ene-Iordache B, Rudnicki M, Cailliez M, Pietrement C, Dunand O, Nathanson S, Bertholet- Pollastro RM, Capasso G, Pisani A, Pennesi M, Emma F, Remuzzi Thomas A, Ichay L, Decramer S: Long-term outcome of children G; Rituximab in Nephrotic Syndrome of Steroid-Dependent or treated with rituximab for idiopathic nephrotic syndrome. Pe- Frequently Relapsing Minimal Change Disease Or Focal Seg- diatr Nephrol 28: 911–918, 2013 mental Glomerulosclerosis (NEMO) Study Group: Rituximab in 57. Banerjee S, Dissanayake PV, Abeyagunawardena AS: Vaccina- steroid-dependent or frequently relapsing idiopathic nephrotic tions in children on immunosuppressive medications for renal syndrome. J Am Soc Nephrol 25: 850–863, 2014 disease. Pediatr Nephrol 31: 1437–1448, 2016 74. Ruggenenti P, Debiec H, Ruggiero B, Chianca A, Pelle´ T, Gaspari 58. Bu¨scher AK, Beck BB, Melk A, Hoefele J, Kranz B, Bamborschke F, Suardi F, Gagliardini E, Orisio S, Benigni A, Ronco P, Remuzzi D, Baig S, Lange-Sperandio B, Jungraithmayr T, Weber LT, G: Anti-phospholipase A2 receptor antibody titer predicts post- Kemper MJ, To¨nshoff B, Hoyer PF, Konrad M, Weber S; German rituximab outcome of membranous nephropathy. JAmSoc Pediatric Nephrology Association (GPN): Rapid response to cy- Nephrol 26: 2545–2558, 2015 closporin A and favorable renal outcome in nongenetic versus 75. Canetta PA, Radhakrishnan J: The evidence-based approach to genetic steroid-resistant nephrotic syndrome. Clin J Am Soc adult-onset idiopathic nephrotic syndrome. Front Pediatr 3: 78, Nephrol 11: 245–253, 2016 2015 59. Sadowski CE, Lovric S, Ashraf S, Pabst WL, Gee HY, Kohl S, 76. Lipska BS, Iatropoulos P, Maranta R, Caridi G, Ozaltin F, Anarat Engelmann S, Vega-Warner V, Fang H, Halbritter J, Somers MJ, A, Balat A, Gellermann J, Trautmann A, Erdogan O, Saeed B, Tan W, Shril S, Fessi I, Lifton RP, Bockenhauer D, El-Desoky S, Emre S, Bogdanovic R, Azocar M, Balasz-Chmielewska I, Benetti Kari JA, Zenker M, Kemper MJ, Mueller D, Fathy HM, Soliman E, Caliskan S, Mir S, Melk A, Ertan P, Baskin E, Jardim H, Davitaia NA, Hildebrandt F; SRNS Study Group: A single-gene cause in T, Wasilewska A, Drozdz D, Szczepanska M, Jankauskiene A, 29.5% of cases of steroid-resistant nephrotic syndrome. JAmSoc Higuita LM, Ardissino G, Ozkaya O, Kuzma-Mroczkowska E, Nephrol 26: 1279–1289, 2015 Soylemezoglu O, Ranchin B, Medynska A, Tkaczyk M, Peco- 60. Gellermann J, Ehrich JH, Querfeld U: Sequential maintenance Antic A, Akil I, Jarmolinski T, Firszt-Adamczyk A, Dusek J, therapy with cyclosporin A and mycophenolate mofetil for Simonetti GD, Gok F, Gheissari A, Emma F, Krmar RT, Fischbach sustained remission of childhood steroid-resistant nephrotic M, Printza N, Simkova E, Mele C, Ghiggeri GM, Schaefer F; syndrome. Nephrol Dial Transplant 27: 1970–1978, 2012 PodoNet Consortium: Genetic screening in adolescents with 61. Choudhry S, Bagga A, Hari P, Sharma S, Kalaivani M, Dinda A: steroid-resistant nephrotic syndrome. Kidney Int 84: 206–213, 2013 Efficacy and safety of tacrolimus versus cyclosporine in children 77. Li H, Shi X, Shen H, Li X, Wang H, Li H, Xu G, Chen J: Tacrolimus with steroid-resistant nephrotic syndrome: A randomized con- versus intravenous pulse cyclophosphamide therapy in Chinese trolled trial. Am J Kidney Dis 53: 760–769, 2009 adults with steroid-resistant idiopathic minimal change ne- 62. Gulati A, Sinha A, Jordan SC, Hari P, Dinda AK, Sharma S, phropathy: A multicenter, open-label, nonrandomized cohort Srivastava RN, Moudgil A, Bagga A: Efficacy and safety of treat- trial. Clin Ther 34: 1112–1120, 2012 ment with rituximab for difficult steroid-resistant and -dependent 78. Ding WY, Koziell A, McCarthy HJ, Bierzynska A, Bhagavatula nephrotic syndrome: Multicentric report. Clin J Am Soc Nephrol MK, Dudley JA, Inward CD, Coward RJ, Tizard J, Reid C, Antignac 5: 2207–2212, 2010 C, Boyer O, Saleem MA: Initial steroid sensitivity in children with 63. Magnasco A, Ravani P,Edefonti A, Murer L, Ghio L, Belingheri M, steroid-resistant nephrotic syndrome predicts post-transplant Benetti E, Murtas C, Messina G, Massella L, Porcellini MG, recurrence. J Am Soc Nephrol 25: 1342–1348, 2014 Montagna M, Regazzi M, Scolari F, Ghiggeri GM: Rituximab in 79. Nolasco F, Cameron JS, Heywood EF, Hicks J, Ogg C, Williams children with resistant idiopathic nephrotic syndrome. JAmSoc DG: Adult-onset minimal change nephrotic syndrome: A long- Nephrol 23: 1117–1124, 2012 term follow-up. Kidney Int 29: 1215–1223, 1986 14 Clinical Journal of the American Society of Nephrology

80. Fakhouri F,Bocquet N, Taupin P,Presne C, Gagnadoux MF,Landais 83. Short versus standard prednisone therapy for initial treatment of P, Lesavre P, Chauveau D, Knebelmann B, Broyer M, Gru¨nfeld JP, idiopathic nephrotic syndrome in children. Arbeitsgemeinschaft Niaudet P: Steroid-sensitive nephrotic syndrome: from childhood to fu¨rPa¨diatrische Nephrologie. Lancet 1: 380–383, 1988 adulthood. Am J Kidney Dis 41: 550–557, 2003 84. Chen CL, Fang HC, Chou KJ, Lee JC, Lee PT, Chung HM, Wang JS: 81. Emma F, Sesto A, Rizzoni G: Long-term linear growth of children Increased endothelin 1 expression in adult-onset minimal with severe steroid-responsive nephrotic syndrome. Pediatr change nephropathy with acute renal failure. Am J Kidney Dis 45: Nephrol 18: 783–788, 2003 818–825, 2005 82. Vivarelli M, Moscaritolo E, Tsalkidis A, Massella L, Emma F: Time for initial response to steroids is a major prognostic factor in Published online ahead of print. Publication date available at www. idiopathic nephrotic syndrome. J Pediatr 156: 965–971, 2010 cjasn.org.