Minimal Change Disease, Pediatric · peritonitis Acute kidney injury Historical Background The underlying histopathology MCD (also known as “Nil disease”) became known shortly

Minimal Change Disease, Pediatric

Raed Bou Matar and Katherine M. Dell

ContentsHistorical Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Definitions and Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Laboratory Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Decision to Obtain a Renal Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Classic Minimal Change Disease (MCD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6MCD Variants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Primary Focal Segmental Glomerulosclerosis (FSGS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Primary Membranous nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Secondary Nephrotic Syndrome/Podocytopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9General Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Control of Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Treatment (Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Prevention and Treatment of Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

R. Bou Matar (*) • K.M. DellDepartment of Pediatrics, Cleveland Clinic Lerner Collegeof Medicine at Case Western Reserve University,Cleveland, OH, USA

Center for Pediatric Nephrology, Cleveland Clinic,Cleveland, OH, USAe-mail: [email protected]; [email protected];[email protected]

# Springer International Publishing AG 2018H. Trachtman et al. (eds.), Glomerulonephritis,https://doi.org/10.1007/978-3-319-27334-1_8-1

1

AbstractMinimal change disease (MCD) is the mostcommon glomerular disease encountered inchildren and one of the most commonlyencountered kidney diseases in this agegroup. The disease commonly presents withthe classic tetrad that characterizes nephroticsyndrome (NS): generalized edema, high-grade proteinuria, hypoalbuminemia, anddyslipidemia. Increased risk of thrombosisand infection are uncommon, but potentiallylife-threatening associated features. The mani-festations of MCD are thought to be the resultof the impaired glomerular permselectivity,leading to urinary losses of albumin and otherpeptides. Although the majority of childrenwith MCD respond well to currently offeredtherapies and have an excellent long-termprognosis, some children, especially thosewith frequently relapsing or steroid-dependentnephrotic syndrome, may encounter major chal-lenges related to corticosteroid and other med-ication-related side effects and impairedquality of life.

KeywordsNephrotic syndrome Minimal change diseaseFocal segmental glomerulosclerosis PodocyteEdema Immunosuppression CorticosteroidsCyclophosphamide Tacrolimus CyclosporinePlasma exchange Spontaneous bacterialperitonitis Acute kidney injury

Historical Background

The underlying histopathology MCD (alsoknown as “Nil disease”) became known shortlyafter the introduction of the renal biopsy by Brun,Iversen, and Muerhke in the early 1950s. In theinitial half of the twentieth century, NS was con-sidered fatal in approximately two-thirds of indi-viduals, mainly due to infectious complications.The discovery of antibiotics in the 1940s led to adramatic reduction in mortality, which was furtherreduced by the introduction of steroids in the1950s to approximately 9% (Farnsworth 1950;Muehrcke et al. 1955; Iversen and Brun 1951;

Arneil and Lam 1966). The natural course of NSin children and rate of response to therapy waswell described in the International Study of Kid-ney Diseases in Childhood (ISKDC) prospectiveobservational study published in 1978 thatincluded 521 newly diagnosed children withnephrotic syndrome (Anonymous 1978). Newer,large multicenter studies of primary nephroticsyndrome in adults and children, such as the NEP-TUNE study (clinicaltrials.gov NCT01209000),have the potential to provide additional insightsintoMCD pathogenesis, especially with respect tothe role of genetic factors (Gipson et al. 2016;Gadegbeku et al. 2013).

Definitions and Nomenclature

• Nephrotic syndrome (NS): the combinationof edema, high-grade proteinuria (>40 mg/m2/h or a urine protein to creatinine ratio>2.0 mg/mg), hypoalbuminemia (<2.5 g/dl),and dyslipidemia (Anonymous 1981b, Clarkand Barrat 1998).

• Complete remission: a spot urine proteinto creatinine ratio of less than 0.2 mg/mg,or urine albumin dipstick readings thatare negative or trace for three consecutivedays in children with a previous diagnosis ofsteroid-sensitive nephrotic syndrome (Gipsonet al. 2009).

• Partial remission: Greater than 50% reductionin proteinuria but without full criteria for com-plete remission. The clinical significance ofpartial remission of the disease has not beenwell defined.

• Relapse: A spot urine protein to creatinineratio �2.0 mg/mg, or urine albumin dipstickreadings exceeding 300 mg/dl (3+ or more)(Lombel et al. 2013).

• Steroid-sensitive nephrotic syndrome (SSNS):A remission following a 4–8-week treatmentcourse of daily corticosteroids (Gipson et al.2009).

• Steroid-dependent nephrotic syndrome(SDNS): Steroid sensitive NS patients whodevelop a relapse during the tapering phase ofthe medication or within 2 weeks after the

2 R. Bou Matar and K.M. Dell

corticosteroid is discontinued (Clark andBarrat 1998; Gipson et al. 2009).

• Frequently relapsing nephrotic syndrome(FRNS). Steroid-sensitive NS patients whohave two or more relapses within a 6-monthperiod following the initial course of therapy,or four or more relapses within any 12-monthperiod (Gipson et al. 2009).

• Steroid-resistant nephrotic syndrome (SRNS):Persistent high-grade proteinuria following a4-week treatment course of daily corticoste-roids (Gipson et al. 2009).

Epidemiology

MCD carries an incidence of 2–7 per 100,000children annually worldwide and has a cumulativeprevalence of 16 per 100,000 children (Clark andBarrat 1998; Nash et al. 1992; Srivastava et al.1999; Hogg et al. 2000; McEnery and Strife1982). The disease incidence peaks at age2–3 years, and the disease has a male preponder-ance in young children, with a ratio of 2:1 (Clarkand Barrat 1998; Nash et al. 1992). In childrenwho are less than 10 years of age who presentwith NS, the underlying histopathologic lesion isestimated to be MCD in 90% of cases. Suchestimate is closer to 50% or less in children age10 years or older. Beyond the first few yearsof life, the likelihood of MCD histology andresponse to corticosteroids gradually decreaseswith age (Anonymous 1978). MCD appears tobe more common in Asian children and is rela-tively uncommon in Africans (Bhimma et al.1997; Sharples et al. 1985). In contrast, childrenof African ancestry presenting with NS carry amuch higher risk of steroid-resistance, with focalsegmental glomerulosclerosis (FSGS) as the pre-dominant underlying histology (Bonilla-Felix etal. 1999; Kopp et al. 2008) (See “▶ Focal Seg-mental Glomerulosclerosis, Pediatric”).

Pathogenesis

MCD is thought to result from a disruption ofthe glomerular filtration barrier (GFB), a

complex structure composed of the capillaryendothelial cells, the glomerular basement mem-brane (GBM), and the podocytes. Podocytes, alsoknown as the glomerular epithelial cells, arehighly specialized terminal epithelial cells, char-acterized by major processes and minor (foot)processes. The foot processes interdigitate withothers from neighboring podocytes and are linkedby a special cell-cell junction, known as the slitdiaphragm (Karnovsky and Ainsworth 1972). TheGFB allows for the filtration of aqueous plasmawhile retaining larger biological molecules, suchas albumin and other proteins, in the circulation.This retention of macromolecules is maintainedthrough both size selectivity (molecules largerthan 42 Å in diameter) and electric charge (nega-tively charged molecules are less likely to pene-trate the GFB) (Brenner et al. 1978) (See“▶Mechanisms of Glomerular Disease”).

ProteinuriaPodocyte injury, leading to the loss of charge and/or size selectivity of the GFB, is considered respon-sible for the high-grade albuminuria seen in MCDas well as in other proteinuric diseases (Taylor et al.1997; Kitano et al. 1993; Carrie et al. 1981; van denBorn et al. 1992; Sorensson et al. 1998; Ciarimboliet al. 1999). The triggering events for such aninjury have not been fully elucidated but bothimmunologic and nonimmunologic factors arebelieved to be involved (Shankland 2006).Dysregulation of both humoral and cell-mediatedimmunity probably contributes to the pathogenesisof the disease (Yokoyama et al. 1987; Fodor et al.1982; Yang et al. 2008; Yan et al. 1998; Sasdelli etal. 1981, Shalhoub 1974). Abnormalities of theimmune response may explain why viral infectionsfrequently trigger relapses of MCD See “▶Mech-anisms of Glomerular Disease”. In addition, chil-dren with a history of atopy or certain malignancies(e.g., Hodgkin’s lymphoma) are more likely todevelop the disease (Audard et al. 2006; Shalhoub1974; Abdel-Hafez et al. 2009). MCD responds tosteroidal and nonsteroidal immunomodulators,such as calcineurin inhibitors, mycophenolatemofetil, or rituximab, which are known to suppressthe cell-mediated and/or humoral immuneresponse (Yang et al. 2008; Anonymous 1978).

Minimal Change Disease, Pediatric 3

Although mutations in several genes have beenimplicated in the pathogenesis of other forms ofprimary NS (notably FSGS), specific gene defectshave been infrequently described, to date, inpatients with primary MCD (Gbadegesin et al.2015; Gee et al. 2014). Similarly, a putative circu-lating permeability factor, well described in FSGS,has been implicated in only rare cases of MCNS(Ali et al. 1994; Aggarwal et al. 2007).

EdemaMCD and other causes of NS are associated withavid sodium and water retention, which is thoughtto be mediated by two mechanisms. The first,termed the “underflow” hypothesis, identifieshypoalbuminemia as the primary factor. Theresulting decreased oncotic pressure contributesto decreased effective arterial blood volume and,thereby, triggers compensatory mechanisms thatare typically seen with volume depletion (e.g.,increased proximal tubule sodium reabsorptionand activation of ADH). The second, termed the“overflow” hypothesis, postulates that there is aprimary abnormality of sodium retention, which issuggested by evidence that sodium and waterretention are seen before the serum albumindrops to the level at which oncotic pressure issignificantly decreased. Although the mechanismremains poorly defined, it is thought to be relatedto abnormal collecting tubule sodium handling,likely involving corin-mediated activation of epi-thelial sodium channels (Teoh et al. 2015).

DyslipidemiaActive MCD is commonly associated with signif-icant dyslipidemia. Total cholesterol, low-densitylipoprotein (LDL), very low-density lipoprotein(VLDL), triglycerides, and lipoprotein A [Lp (a)]are elevated while high-density lipoprotein (HDL)is low (Querfeld 1999; Querfeld et al. 1993).Evidence suggests that dyslipidemia in NS isassociated with a combination of increased pro-duction and diminished cellular uptake of variouslipoproteins. However, the precise underlyingmechanisms behind such changes remain elusive(Wang et al. 2012).

Clinical Features

Clinical Presentation

Children with MCD often present with painlessgeneralized pitting edema. The swelling is mostprominent in gravity-dependent areas, such asthe lower extremities in ambulatory children andthe sacral region in infants or recumbent children.Periorbital swelling may be most pronouncedin the morning and gradually improve as thechild ambulates during the day. Often, there isa history of an antecedent viral infections (e. g.,upper respiratory infection or gastrointestinalsymptoms), although some MCD patients maypresent without such history. Very commonly,localized periorbital swelling is initially mistakenfor allergic symptoms. Patients may have receiveda course of antihistamines or other allergic thera-pies without improvement. Since both allergiesand MCD often respond dramatically to cortico-steroids, maintaining a high index of suspicionfor NS should prompt the clinician to collecta urine sample in any child who presents withperiorbital edema, prior to initiation of systemiccorticosteroids therapy, thereby avoiding anunintended delay in the diagnosis. Other cutane-ous areas with weak underlying fasciae thatare more prone to edema include the scrotumand labia. Parents may also note abdominalswelling. Gross hematuria, dysuria, fever, weightloss, and/or lymphadenopathy are not typicalof MCD and should prompt a thorough evalua-tion for alternative etiologies.

Physical Examination

The physical examination of a child withsuspected MCD aims at evaluating the extent ofthe edema, monitoring for complications of thedisease, and excluding alternative etiologies. Acarefully measured weight should be obtainedand compared to a recent value (if available).The difference between the two weights is usedto reliably estimate the percentage weight gain asa quantitative assessment of the child’s volumeoverload. A blood pressure measurement should

4 R. Bou Matar and K.M. Dell

also be obtained, preferably manually from theright arm utilizing an appropriate sized cuff. Theblood pressure is usually normal in children withMCD. Sustained hypertension, therefore, favorsother underlying histologies, such as FSGS.

Evaluation of gravity-dependent regions forpitting edema is performed by applying ade-quate thumb pressure against the underlyingbone, best elicited at the tibial shaft in ambula-tory children, or the sacral/occipital bones inrecumbent infants. Careful examination of theskin should be performed, screening for signs ofbreakdown or cellulitis. Particular attentionshould be given to the genital inspection to eval-uate for scrotal or labial edema and to excludeoccult skin breakdown. Chest percussion and/orauscultation may detect pleural effusion, a rela-tively common finding in children with activeMCD that usually remains asymptomatic andwithout clinical consequence. Moderate tosevere ascites may be detected by eliciting anabdominal fluid wave. Abdominal rebound ten-derness should raise concern for spontaneousbacterial peritonitis, an uncommon but seriouscomplication of MCD.

Diagnosis

The diagnosis of MCD is typically made based onclinical criteria, including history, physical exam,and laboratory findings. As noted below, renalbiopsy is performed in a minority of patients.

Laboratory Evaluation

A urine dipstick, preferably with microscopy,should be obtained in all children who presentwith generalized edema. In untreated childrenwith MCD, the urine dipstick reveals high-gradeproteinuria, defined as 3þ (&gt;300 mg/dL) or 4þ(&gt;2000 mg/dL). This is usually followed by aquantitative assessment of urine protein in theform of a spot urine protein to creatinine ratioin the nephrotic range (normal <0.2 mg/mg;nephrotic range >2.0 mg/mg). A 24 h urine col-lection of protein, commonly performed in adults

with proteinuria, is less commonly requested inchildren due to the known challenges associatedwith obtaining an accurate 24 h urine collection.In addition, collection of a random urine sample,or preferably a first morning urine sample, forprotein-to-creatinine ratio appears to correlatewell with 24 h urine protein quantitation in chil-dren (Abitbol et al. 1990). The urinalysis may alsoreveal microscopic hematuria in 1 out of 5 chil-dren who present with MCD. However, as previ-ously mentioned, gross hematuria is rare in MCDand should prompt further evaluation for an alter-native diagnosis (Anonymous 1978). In additionto high-grade proteinuria, the diagnosis is furthersupported by the presence of severe hypo-albuminemia (Serum albumin <2.5 g/dl) and ele-vated serum cholesterol and/or triglycerides onblood chemistries.

Table 1 Secondary causes of nephrotic syndrome (See“▶Overview of Current Approaches to Glomerular Dis-ease Classification”)

Autoimmune diseases

Henoch-Schönlein purpura

Systemic lupus erythematosus

Diabetes mellitus

Sarcoidosis

Infections

Hepatitis B

Hepatitis C

HIV

Drugs

Nonsteroidal anti-inflammatory drugs (MCNS)

Gold

Captopril

Penicillamine/ bucillamine

Anti-TNF agents (infliximab and etanercept)

Anabolic steroids

Malignancies

Leukemia

Lymphoma (Hodgkin disease usually associated withMCNS)

Other

Sickle cell disease

Insect stings (Bees and ants)

Food allergies

Preeclampsia

Mitochondrial disorders

Minimal Change Disease, Pediatric 5

Laboratory evaluation for MCD also includesrenal function tests (BUN and serum creatinine),serum electrolytes, a complete blood count, andcomplement levels (C3/C4). Mild hyponatremiais commonly encountered in children with activenephrotic syndrome, attributed to excessive waterretention in response to reduced effective intra-vascular blood volume associated with hypo-albuminemia. BUN may also be elevated, dueto avid proximal tubule sodium retention bythe same mechanism. However, serum creatinineis expected to be normal, or even low, except in asmall subset of MCD patients who may havecoexistent acute kidney injury (AKI). Hemo-concentration, reflected by elevated hemoglobinand hematocrit, is commonly seen as a reflectionof relative intravascular volume depletion in chil-dren with severe edema. For unknown reasons,thrombocytosis is also commonly seen in childrenwith MCD and may further exacerbate the risk ofthrombosis (See “▶Diagnostic Testing in Glo-merular Disease”).

Complement levels in MCD are invariablynormal. Therefore, the finding of low C3, C4,or both suggests alternative diagnoses (Table 1).The finding of isolated C3 hypocomplementemiacould be due to membranoproliferative glo-merulonephritis, C3 glomerulonephritis, or post-infectious nephritis. Combined C3 and C4hypocomplementemia should raise concerns forlupus nephritis. Since sexually transmitted virusesmay be associated with secondary causes of NS,Hepatitis B, Hepatitis C, and human immunodefi-ciency virus screening may be indicated inadolescents, especially those with a history ofunprotected intercourse or other high risk behav-iors (See “▶Glomerular Diseases Associatedwith Hepatitis B and C Infection, Pediatric”, and“▶HIVAN, Pediatric”).

A screening test for latent tuberculosis shouldbe considered prior to the initiation of corticoste-roids therapy. Screening for latent tuberculosismay be performed utilizing the purified proteinderivative (PPD) or the QuantiFERON®-TB test.Note that the QuantiFERON®-TB test is currentlyconsidered the preferred method of testing onlyfor children age 5 years and older (Nicol et al.2009; Lighter et al. 2009).

Decision to Obtain a Renal Biopsy

Prepubertal children (>1 year of age) who presentwith typical features of NS with normal bloodpressure, no history of gross hematuria, normalserum creatinine, and normal complement levelsare highly likely to haveMCD. A kidney biopsy isnot considered necessary in children who fulfillthese criteria and they may be empirically treatedwith corticosteroids without histological confir-mation of the disease (Gipson et al. 2009). Epide-miological studies showed that >90% of childrenwho fulfill these criteria have steroid-responsivedisease (White et al. 1970, Anonymous 1981b,1978). However, a kidney biopsy should beperformed in children who initially fulfill thecriteria for MCD but do not show an appropriateresponse to 4 weeks of therapy with high-dosecorticosteroids (with goodmedication adherence),as steroid nonresponders have a high risk of hav-ing other etiologies for NS (e.g., FSGS) (See“▶ Focal Segmental Glomerulosclerosis,Pediatric”).

For pubertal children who present with NS,a kidney biopsy should be considered (Gipson etal. 2009). In addition, a renal biopsy is also indi-cated for children with clinical features suggestiveof non-MCD etiologies, such as arthritis, severehypertension, low complement levels, grosshematuria, or a sustained elevation of serum cre-atinine. It is important to note, however, that a fewchildren who satisfy the definition of SRNS maystill respond to a more prolonged treatment courseof glucocorticoids. Therefore, corticosteroidsshould be continued for an additional 4 weekseven as a biopsy is being arranged.

Pathology

Classic Minimal Change Disease (MCD)

As the name implies, classic MCD is character-ized by minimal or no abnormalities on lightmicroscopy (Fig. 1) and absent immune stainingfor immunoglobulins, C3, or C1q. Glomeruli onbiopsy specimens should be screened carefully onlight microscopy for any signs of segmental

6 R. Bou Matar and K.M. Dell

glomerulosclerosis, which, if present, exclude thediagnosis of MCD (and suggests FSGS). On theother hand, occasional global sclerosis or mildmesangial hypercellularity may be occasionallyobserved in children with MCD (Churg et al.1970). In untreated children with MCD, EM usu-ally reveals diffuse effacement of the podocyte

foot processes (Fig. 2). Effacement of the footprocesses may be absent or focal in distributionin children with MCD who were previouslytreated with corticosteroids, particularly those inpartial or complete remission of the disease (See“▶Histopathology of Glomerular Diseases”).

Fig. 1 Light microscopy in MCD. The glomerulusshown illustrates the typical light microscopy appearanceof MCD, including the normocellular appearance withpatent glomerular capillaries and glomerular basement

membranes of normal thickness and contour. Thepodocytes in Bowman’s space appear mildly swollen, acommon histologic finding in MCD (Jones methenaminesilver staining, 400 � magnification)

Fig. 2 Electron microscopy in MCD. Electron micros-copy shows a glomerular capillary with the typical appear-ance of diffuse podocyte foot process effacement seen in

MCD. No immune type deposits or other abnormalities arepresent, another defining feature of MCD (6000� originalmagnification)

Minimal Change Disease, Pediatric 7

MCD Variants

Several histological variants of MCD havebeen described that share many of the clinicaland histological characteristics of classic MCD.Observational studies suggest that such variantsmay be associated with reduced responsivenessto steroids or increased frequency of relapses(Markowitz et al. 2003; Border 1988; Myllymakiet al. 2003).

• IgM nephropathyThis variant is characterized by isolated

IgM staining of the glomerular mesangiumby immunofluorescence and electron-densemesangial immune deposits by EM (Border1988). Increased risk of resistance to cortico-steroid therapy or progression to a steroid-dependent course has been associated withthis entity (Myllymaki et al. 2003; Swartz etal. 2009).

• Mesangial proliferative glomerulonephritisAlso known as the mesangial hyper-

cellularity variant of MCD, this entity is char-acterized by mesangial proliferation (Waldherret al. 1978; Anonymous 1983, 1981a). Chil-dren with mesangial proliferative glomerulo-nephritis often present with history of grosshematuria and/or systemic hypertension, bothfeatures that are uncommon in classic MCD.Resistance to corticosteroids has beendescribed in 40% of children with this entity(Anonymous 1983).

• C1q nephropathyGlomerular C1q deposition is most com-

monly recognized as a manifestation of lupusnephritis. However, the histological entity“C1q nephropathy” is used to describe pre-dominant C1q mesangial deposition detectedon IF in patients who present with no otherserological or clinical features of systemiclupus erythematosus. Such IF pattern may beobserved in association with minimal changeson LM (thus, as an MCD variant) or withFSGS. This clinical significance of C1q depo-sition in MCD remains uncertain. Increasedrisk of steroid dependence, steroid resistance,and progression to ESRD was suggested in

small studies (Hisano et al. 2008; KersnikLevart et al. 2005; Markowitz et al. 2003;Vizjak et al. 2008).

Differential Diagnosis

Primary Focal SegmentalGlomerulosclerosis (FSGS)

The hallmark of primary FSGS is the presence offocal (involving some glomeruli) and segmental(involving only certain segments of each involvedglomerulus) sclerotic lesions on light microscopy.MCD and FSGS share many similarities in termsof underlying pathophysiology and clinical pre-sentation. Both disorders are believed to be theresult of a major insult to the podocytes, reflectedby diffuse effacement of the podocyte foot pro-cesses on EM. However, FSGS is characterizedby its classic histopathology of segmental glomer-ular scarring. Clinically, both disorders presentwith an insidious onset of the NS. In addition,children with FSGS may present with isolatedhigh-grade proteinuria detected on a routine uri-nalysis, commonly associated with systemichypertension, but without overt nephrotic syn-drome. Classic MCD almost never presents asasymptomatic proteinuria. Responsiveness totherapy and prognosis also differ between MCDand FSGS, with the latter being much less likely torespond to corticosteroids therapy and carrying anincreased risk of progression to ESRD (Anony-mous 1978). Sampling error and/or a relativelylate development of glomerulosclerosis in thecourse of FSGS may explain why some childrenwith this disease may initially have histologicalfeatures indistinguishable from MCD (or one ofits variants) on an early kidney biopsy (See“▶ Focal Segmental Glomerulosclerosis,Pediatric”).

Primary Membranous nephropathy

Primary membranous nephropathy (MN) is a veryuncommon cause of NS in children. Details aboutthe clinical features, pathophysiology, diagnosis,

8 R. Bou Matar and K.M. Dell

and treatment of MN are covered elsewhere in thetext (See “▶Anti-PL-PLA2R/ Anti-Thrombo-spondin Type 1 Domain Containing 7A Membra-nous Nephropathy”).

Secondary Nephrotic Syndrome/Podocytopathies

Various autoimmune diseases, infectious agents,metabolic disorders, toxins, medications, andmalignancies have been associated with second-ary podocyte injury, leading to NS. Such etiolo-gies are far less common that primary MCD andare usually differentiated by the history and asso-ciated systemic manifestations (Table 1). Muta-tions in multiple genes have also been linked tothe development of NS, which may or may not beassociated with syndromic features. As notedabove, however, no significant associations ofMCD with specific gene mutations have beenreported, to date (See “▶Overview of CurrentApproaches to Glomerular DiseaseClassification”).

Management

General Approach

The initial management approach for childrenwith suspected MCD is directed at control ofsymptoms, induction of immunological remis-sion, prevention of complications, and minimiz-ing treatment-associated side effects. Aspreviously discussed, children who fulfill certainclinical criteria for MCD are empirically treatedwith corticosteroids without histological confir-mation with a kidney biopsy (see “Diagnosis”)(Gipson et al. 2009). The initial response to corti-costeroids and frequency/timing of subsequentrelapses of the disease are used to dictate subse-quent therapeutic options. All children presentingwith NS benefit from supportive non-pharmacologic measures (see below), particularlyduring the active illness.

Control of Symptoms

Children of NS often present with moderate tosevere generalized edema that may interfere withambulation and place them at risk for skin break-down. Dietary salt restriction and elevation of thefeet should be initially implemented to controlthe symptoms. Fluid restriction is also commonlyimplemented but is unlikely to be effective if notcoupled with strict restriction of dietary sodium.Oral diuretics, such as furosemide, may be addedin more resistant cases. However, the use of oraldiuretics in children with NS carries a significantrisk electrolyte disturbances (hyponatremia,hypokalemia, and metabolic alkalosis) and deple-tion of effective blood volume, which, in turn,may increase the risk of acute kidney injury orthromboembolism. Periodic monitoring of elec-trolytes and renal function is essential in childrenwith active NS, particularly those receivingdiuretics.

In hospitalized children, salt-poor 25% humanalbumin infusions (0.5–1.0 g/kg infused over4–6 h) with or without concurrent use of loopdiuretics (furosemide 1–2 mg/kg IV given mid-way during or immediately following the albumininfusion) is an effective strategy that is reservedfor those with severe anasarca. The use of IValbumin and diuretics serves to expand the intra-vascular volume while concurrently inducingbrisk diuresis. In one study, each infusion ofalbumin and furosemide resulted in an averageweight loss of 0.4 kg or 1.2% body weight(Haws and Baum 1993). However, the effect isusually transient and such regimen carries a smallbut significant risk of hypertension, volume over-load, and pulmonary edema. Thus, such regimenshould be reserved for the treatment of substantialanasarca, especially if associated with major dis-comfort, difficulty with ambulation, severe scrotaledema, or detectable skin breakdown. Intravenousalbumin should be avoided in children with mod-erate to severe hypertension, left ventricular dys-function (suspected or confirmed), or advancedoliguric acute kidney injury (Hogg et al. 2000).Similar to children on oral diuretics, serum elec-trolytes should be monitored at least daily in

Minimal Change Disease, Pediatric 9

patients receiving infusions of human albuminwith or without concurrent furosemide therapy.

Treatment (Table 2)

Corticosteroids• Initial course of corticosteroids:

Children age 1–12 years of age who presentinitially with a clinical picture suggestiveof MCD are treated with a 4–6-week courseof daily prednisone 2 mg/kg/day or 60 mg/m2

(maximum 60 mg per day) followed by anadditional 4–6 weeks of alternate day therapyat 1.5 mg/kg/dose (maximum 40 mg per dose)(Gipson et al. 2009). Alternatively, alternateday therapy may be given for up to 5 monthsand tapered over a period of 2–5 months,although this is a less common approach(Hodson et al. 2007; Lombel et al. 2013).Shorter initial treatment courses of cortico-steroids, including previously recommended8 week course of initial treatment (Anonymous1981b), are no longer advised due to a potentialincreased risk of future relapses (Brodehl1991; Hodson et al. 2000; Bagga et al. 1999;Anonymous 1988; Hodson et al. 2007). Tworandomized controlled studies (RCT) showedno additional clinical benefit when comparingthe current standard 3-month course of steroidswith more prolonged courses of 5–6 months(Sinha et al. 2015; Teeninga et al. 2013). More-over, one RCT showed no differences in thetime to remission between children who

received prednisone as a once daily dosewhen compared to divided doses twice daily(Hodson et al. 2007). BSA-based dosing maybe preferred in younger children (weight<30 kg) (Saadeh et al. 2011; Feber et al.2009). The likelihood of achieving completeremission of the disease utilizing the aboveregimen is estimated to be more than 90%,with most steroid-sensitive patients (94%)responding within the first 4 weeks of treat-ment (median 7 days) (Vivarelli et al. 2010;Anonymous 1981b).

• RelapsesChildren with MCD who develop their first

relapse of the disease are treated for each epi-sode with a course of prednisone similar to thatdescribed for initial therapy, but with a morerapid transition to alternate day dosing and ashorter overall course. Once the relapse is con-firmed (protein �300 mg/dL on dipstick on 3consecutive days), prednisone is restarted at2 mg/kg/day, to be continued until remissionis achieved (negative or trace for protein ondipstick for 3 consecutive days), then reducedto 1.5 mg/kg/dose given on alternate days.Alternate day dosing of prednisone is contin-ued for 4 weeks then discontinued (Gipson etal. 2009). If subsequent relapses develop andare infrequent (<2 relapses per 6 month periodand <4 relapses per year), they can be treatedin a similar manner as the first relapse.

• Frequent relapses and steroid dependencyChildren with known or presumed MCD

who develop �2 relapses per 6 month period

Table 2 Immunosuppressive treatment of idiopathic nephrotic syndrome in children

Initial course 2 mg/kg/day (max 60 mg) daily for 4–6 weeks followed by 1.5 mg/kg/dose (max 40 mg)every other day for 4–6 weeks

Infrequent relapses 2mg/kg/day (max 60mg) daily until remission is confirmed followed by 1.5 mg/kg/dose(max 40 mg) every other day for 4 weeks

Frequent relapses or steroid-dependent

2 mg/kg/day (max 60 mg) daily until remission followed by 1.5 mg/kg/dose (max40 mg) every other day for 4 weeks followed by taper dose slowly over 2 months

Steroid-sparingmedicationsa

Mycophenolate mofetil 400–600 mg/m2/dose (maximum 1 g) twice dailyCyclosporine 3–5 mg/kg/day divided twice daily (target 12 h trough 100–200 ng/mL)Tacrolimus 0.1 mg/kg/day divided twice daily (target 12 h trough 4–6 ng/ml)Oral cyclophosphamide 2 mg/kg/day for 12 weeksIV cyclophosphamide (pulse) 500 mg/m2/dose monthly for 6 monthsRituximab 375 mg/m2/infusion, 1–4 infusions separated by 2 weeks

aChoice depends on tolerance of a specific agent, physician, and family preference

10 R. Bou Matar and K.M. Dell

or �4 relapses per year are considered to havefrequently relapsing NS (FRNS). Frequentrelapses are typically treated in a similar fash-ion as less frequent episodes (i.e., prednisone2 mg/kg/day until the urine dipstick is trace ornegative for 3 days, followed by 1.5 mg/kg/dose given on alternate days for an additionalduration of 4 weeks). However, children withFRNS generally receive an additional gradualprednisone wean rather than abrupt discontin-uation, which is usually given over 2 monthsuntil discontinued (Gipson et al. 2009).

Patients who develop a relapse during thetapering of prednisone or shortly after discon-tinuation (within 2 weeks) are considered to besteroid-dependent. Frequent prednisone treat-ment courses may be necessary for suchpatients leading to an increased risk of growthfailure and other prednisone-related sideeffects. Two strategies have been suggestedby experts in an attempt to minimize the riskof toxicity from corticosteroids (Lombel et al.2013): one involves a tailored adjustment ofprednisone dosing and the other involves initi-ation of alternative “steroid sparing” immuno-suppression as discussed below. With the firstapproach, prednisone is tapered to the lowestdose that had previously proven to maintainremission in the same patient. In addition,low dose of prednisone either daily or on alter-nate day dosing can be given for a prolongedduration (months to years) to maintain remis-sion while closely monitoring for signs of lin-ear growth delay or other side effects.However, the long-term safety and effective-ness of such clinical regimens have not beenwell studied. In children with FRNS or SDNS,relapses are often triggered by viral infections.Hence, a short (<2 weeks) course of daily lowdose of prednisone has been suggested to beadministered during episodes of upper respira-tory or gastrointestinal infections to minimizethe risk of relapses, particularly in childrenwith MCD who are maintained on an alternateday regimen of low-dose prednisone (Gulati etal. 2011; Srivastava et al. 1992; Mattoo andMahmoud 2000).

Steroid-Sparing MedicationsA second treatment strategy for SDNS or FRNSencompasses initiation of immunomodulatory ste-roid-sparing mediations to allow for completediscontinuation or significant reduction of predni-sone. As the term implies, steroid-sparing regi-mens aim to maintain a prolonged remissionof MCD, possibly through immunomodulatorymechanisms, thereby minimizing the long-termcumulative exposure to corticosteroids.

Mycophenolate mofetil, calcineurin inhibitors(cyclosporine or tacrolimus), cyclophosphamide,and rituximab are the most commonly used ste-roid-sparing medications in this setting. This sec-ond strategy is preferred in children with MCDwho require relatively high doses of prednisone tomaintain remission (>0.2 mg/kg/day) and in chil-dren who manifest behavioral changes, growthretardation, or other significant long-term sideeffects attributed to prednisone (Gipson et al.2009). Several medications, as discussed below,are considered to be safe and effective in promot-ing long-term remission. Each has specific short-and long-term toxicities, but none has proven tobe clearly superior in clinical studies. The choiceof therapy, therefore, is generally based on toler-ance of a specific agent, and physician and familypreference (Gipson et al. 2009).

• Mycophenolate mofetil (MMF)MMF is a noncompetitive inhibitor of ino-

sine monophosphate dehydrogenase. T- and B-lymphocytes are inhibited, both of which aredependent on this enzyme to generateguanosine triphosphate and deoxyguanosinetriphosphate (Eugui et al. 1991). MMF isstarted at a dose of 400–600 mg/m2/dose(maximum 1 g) twice daily (Gipson et al.2009). During continuous use, MMF mayreduce the frequency of relapses and allow fordecreased long-term need for corticosteroids(Hogg et al. 2006; Afzal et al. 2007; Fujinagaet al. 2007; Novak et al. 2005; Bagga et al.2003). Many children who were previouslysteroid-dependent may be able to reduce thedose or discontinue prednisone (Banerjee et al.2013). MMF is also considered an attractivechoice for the management of MCD in view of

Minimal Change Disease, Pediatric 11

its favorable side-effects profile, particularlyin terms of avoiding the long-term potentialfor nephrotoxicity associated with calcineurininhibitors or malignancy and infertility risksof cyclophosphamide. However, the effect ofMMF does not appear to be sustained after themedication is discontinued. The majority ofchildren with MCD (75%) are expected todevelop a relapse after stopping MMF (Hogget al. 2006). MMF is generally well tolerated inthe majority of children with MCD. The mostcommon adverse reactions associated withMMF, some of which may require reductionor discontinuation of the medication, includediarrhea, vomiting, leukopenia, and anemia(Butani et al. 1999; Bunchman et al. 2001).MMF is also currently available in an entericcoated formulation, which may be a viableoption to minimize the risk of nausea or diar-rhea for older children who are able to taketablets (Pape et al. 2008; Vilalta Casas et al.2006). Since most children with MCD requireliquid suspensions, the use of enteric coatedmycophenolic acid has limited use in pediatricMCD. Serial monitoring of complete bloodcounts to detect anemia and/or leukopeniaand a metabolic profile to detect liver injuryis recommended in all children who aremaintained on MMF.

• Calcineurin inhibitors (CNIs)Cyclosporine A and Tacrolimus (FK506)

inhibit a calcium-dependent phosphataseenzyme known as calcineurin. Calcineurin isa major T-cell activator and promoter of IL2production (Borel 1991). CNIs were initiallythought to be effective in NS, including MCD,primarily due to their immunosuppressantproperties. More recent data suggest thatthese agents have a second, nonimmune-medi-ate effect by which they stabilize the podocytecytoskeleton directly to induce remission.However, the precise mechanism behind thiseffect has not been uncovered to date (Faul etal. 2008). Cyclosporine, started at a dose of3–5 mg/kg per day divided twice daily, hasbeen shown to be safe and effective in thetreatment of MCD, even in children with ste-roid-dependent or steroid-resistant disease

(Niaudet and Habib 1994; Niaudet et al.1991; Kano et al. 1999; Habib and Niaudet1994; Mahmoud et al. 2005; Gipson et al.2009). Following initiation of therapy, cyclo-sporine dose is titrated to maintain 12 h troughserum levels of 100–200 ng/mL. Tacrolimusappears to have a similar effect based on rela-tively smaller clinical trials, started at a dose of0.1 mg/kg per day divided twice daily (Sinha etal. 2006), with levels typically targeted atapproximately 4-6 ng/ml. Lower levels ofeach drug, however, can be targeted if theyallow for discontinuation of corticosteroidswhile maintaining remission. Similar toMMF, many children who are maintained onCNIs develop a relapse of the disease after thetreatment is discontinued (Ishikura et al. 2012;Niaudet 1992; Ponticelli et al. 1993).

Adverse effects associated with CNIsare dependent on the dose and duration oftherapy. Hypertension, hyperkalemia, hyper-glycemia, tremor, and seizures have beenreported. Cosmetic side effects, particularlygingival hyperplasia and hypertrichosis, havebeen associated with cyclosporine, but nottacrolimus. Hyperglycemia, occasionally pro-gressing to permanent diabetes mellitus andneurotoxicity (tremors, seizures), are more fre-quently encountered with tacrolimus thancyclosporine A (Dittrich et al. 2006; Trompeteret al. 2002; Anonymous 1994a, b). Chronicnephrotoxicity, manifested as tubulointerstitialscarring, is not uncommonly seen with bothcyclosporine A and tacrolimus, particularlyafter 2 years of continuous therapy (Iijima etal. 2002). The role of serial kidney biopsies toassess tubulointerstitial fibrosis is a subject ofongoing investigation (See “▶Medication-Associated Glomerular Disease”).

• CyclophosphamidePrior to the introduction of other steroid-

sparing agents, alkylating agents such as cyclo-phosphamide were considered as first-linetherapy for SDNS or FRNS. However, in thepresence of potentially safer and effectivealternatives, these agents have been utilizedless frequently in recent years for the preven-tion of relapses in SDNS or FRNS.

12 R. Bou Matar and K.M. Dell

Nevertheless, cyclophosphamide remains aneffective option for children with known con-traindications or MMF and Tacrolimus(Zagury et al. 2011). The typical course oftherapy is oral cyclophosphamide given at adose of 2 mg/kg/day given for 12 weeks.Monthly intravenous “pulse” cyclophospha-mide regimens (500 mg/ m2/dose for 6 months)are also considered safe and effective (Prasadet al. 2004; Gulati et al. 2001) and may beparticularly useful for children who cannot tol-erate oral medications or are nonadherent tooral therapies. Adverse effects commonlyassociated with alkylating agents include leu-kopenia, bacterial infections, and alopecia(Latta et al. 2001). Accordingly, monitoringof the complete blood counts is mandatoryduring therapy. Less common side effectsinclude alopecia, hemorrhagic cystitis, andincreased risk of malignancy or infertility.The latter two adverse effects are rare in NSpatients who typically do not receive the highcumulative doses of alkylating agents(>200 mg/kg) that are used for oncologic indi-cations (Guesry et al. 1978, Watson et al.1985). However, the risk of malignancy andinfertility are very concerning for patients andparents, and are likely major factors influenc-ing both physician and patient/parent prefer-ences for treatment.

• LevamisoleLevamisole is an antihelminthic agent that

also has immunosuppressant activity. It hasdemonstrated efficacy as a steroid-sparingagent in SDNS and FRNS. Unfortunately, itis unavailable in many countries including theUSA.

• RituximabRituximab, a monoclonal Anti-CD20 anti-

body, is emerging as a promising therapeuticoption in children with FRNS/SDNS. Cur-rently, it is commonly used in children whofail to respond to conventional steroid-sparingtherapies. Rituximab (1–4 infusions separatedby 2 weeks, 375 mg/m2 each) results in pro-longed depletion of B-cells lasting approxi-mately 6 months with complete recovery ofB-cells anticipated 12 months after therapy

(Sanz et al. 2007; Maloney et al. 1997).Rituximab therapy appears to induce in asustained steroid-sparing benefit in childrenwith MCD that lasts at least 6 months(Sellier-Leclerc et al. 2010, 2012; Fujinaga etal. 2010; Guigonis et al. 2008; Ravani et al.2011). Relapses are anticipated in many, butnot all patients, after the recovery of B-cells(Kamei et al. 2009). MMF may be used asmaintenance therapy after Rituximab infusionsto prevent future relapse (Ito et al. 2011).Although generally tolerated by most children,Rituximab has significant potential side effectsincluding infusion-associated anaphylaxis/acute cytokine release (10% of patients) andincreased risk of bacterial infections. Leukope-nia is an infrequent complication and, there-fore, monthly complete blood counts areadvisable until the B-cell population isreconstituted. Hypogammaglobulinemia canoccur in a small percentage of patients, whomay require intravenous immunoglobulin ther-apy. In addition, rare cases of a progressiveneurologic disorder called progressive multi-focal leukoencephalopathy (PML) have beenreported in patients receiving rituximab,although these were primarily patients withlymphoproliferative or rheumatologic disor-ders who were receiving multiple immunemodulating medications.

Additional TherapiesChildren who do not achieve full remissiondespite the above interventions are at highrisk for progression to ESRD as well as futuredevelopment of cardiovascular disease. Use ofangiotensin-converting enzyme inhibitors (ACEI),angiotensin receptor blockers (ARBs), and/orhydroxymethylglutaryl CoA (HMG CoA) reduc-tase inhibitors may help delay or prevent suchlong-term complications in the small subset ofMCD patients who do not respond to immuno-suppressive therapies.

ACEI or ARBs are infrequently needed inchildren with MCD because most do not develophypertension and the proteinuria resolvespromptly with successful immunosuppressivetherapy. However, MCD children who develop

Minimal Change Disease, Pediatric 13

hypertension, particularly those with steroid-resistant disease, may benefit from ACEI fortheir antiproteinuric and long-term renoprotectiveproperties (Bagga et al. 2004; Ellis et al. 2003;Montane et al. 2003).

Similar to other causes of nephrotic syndrome,active MCD commonly results in significantdyslipidemia, including elevated levels of totalcholesterol, low-density lipoprotein (LDL), verylow-density lipoprotein (VLDL), triglycerides,and lipoprotein A [Lp (a)]. Low levels of high-density lipoprotein (HDL) are also frequentlyencountered during active relapses (Querfeld1999; Querfeld et al. 1993). Such changes inlipoproteins have been considered unfavorable inadults and correlated with increased long-termrisk of cardiovascular complications as well asprogression of chronic kidney disease (Veverkaand Jolly 2004; Moorhead et al. 1989; Keane1994; Samuelsson et al. 1997; Taal 2004). How-ever, dyslipidemia in most children with MCD ismost often transient since the majority respondwell to corticosteroids and/or other immunosup-pressive therapy. Accordingly, treatment withHMG CoA reductase inhibitors is seldom neededin MCD but has been advocated in older children(�8 years of age) with refractory steroid-resistantdisease (Prescott et al. 2004; Sanjad et al. 1997;Coleman and Watson 1996).

Prevention and Treatment ofComplications

Medication-Related Side EffectsChildren who receive standard therapy for MCDare frequently exposed to prolonged and relativelyhigh doses of corticosteroids. Clinical providersshould carefully monitor for short- and long-termside effects of corticosteroids. Parents shouldbe educated regarding both common side effectsof corticosteroids as well as other rare but seriouscomplications. Not uncommonly, the treatmentregimen may need to be adjusted, shortened,or discontinued based on clinical judgment ofunacceptable toxicity. Common acute adverseeffects associated with corticosteroids includehyperglycemia, hypertension and behavioral

changes, acne, weight gain, and cushingoid facies.Longer-term adverse effects include growthimpairment, obesity, posterior subcapsular cata-racts, and osteonecrosis/fractures (Jones 1985;Solomon 1981; Limaye et al. 1988; Hayasaka etal. 2006; Brocklebank et al. 1982; Bachmann et al.1977; Ng et al. 2001; Leroy et al. 2009; Rees et al.1988; Emma et al. 2003; Donatti et al. 2003).Alternate-day regimens are generally thought tocarry a reduced risk of growth impairment (Politoet al. 1986). Thus, one goal of therapy for FRNSor SDNS is transition to alternate day dosing assoon as possible. In addition, alternate day dosingprovided as a single dose in the morning issuggested to minimize effects on growth hormonesecretion.

Infection PreventionChildren with MCD are at risk for variousinfectious complications, including cellulitis,spontaneous bacterial peritonitis pneumonia, bac-teremia/sepsis, and UTI (Rheault et al. 2014).Maintaining a high index of suspicion, repo-sitioning of immobilized patients, and frequentmonitoring of the skin for areas of cellulitis orskin breakdown are essential. Antibiotics shouldbe initiated if clinical signs of cellulitis aredetected, but preventive antibiotics are not gener-ally recommended in this setting. Some infectiouscomplications of NS are preventable in this era ofwide-spread vaccinations. Despite rare reports ofnephrotic relapses temporally related to vaccines(Abeyagunawardena et al. 2003), the long-termbenefits of immunizations far outweigh the slightshort-term risk of relapse. Therefore, childrenwho are not fully immunized should receive theage-appropriate vaccinations based upon guide-lines released by the American Academy of Pedi-atrics (AAP). In addition, children with MCDshould receive the 23-valent polysaccharide pneu-mococcal vaccine (PPSV23) and the conjugatedpneumococcal vaccine (PCV13), if the PCV13series has not been previously given (Gipson etal. 2009). The AAP recommends that all livevaccines, including the varicella vaccine, bedelayed if the child is receiving prednisone at adose greater than the equivalent of 2 mg/kg/day or20 mg per day, or equivalent dosing of other

14 R. Bou Matar and K.M. Dell

corticosteroids, for more than 14 days. In suchchildren receiving a relatively high dose of corti-costeroids, the live vaccines may be administeredstarting 1 month after discontinuation of the cor-ticosteroids. If the duration of high-dose cortico-steroids is less than 14 days, the live vaccinesshould be given without further delay as soon asthe corticosteroids are discontinued (Anonymous2012). However, children who are receiving anyof the steroid-sparing agents (e.g., CNIs, MMF)should not receive live immunizations whilethey are being treated with those agents. Childrenwith MCD and their household contacts shouldalso receive the annual inactivated seasonal influ-enza vaccine.

Thrombosis PreventionEarly ambulation, maintaining physical activity,and avoidance of prolonged bed rest shouldbe implemented to reduce the risk of deep veinthrombosis (DVT), particularly during an activerelapse of the NS. Compression stockingsshould also be used to reduce the risk of DVT.Asymmetric edema of the lower extremity may besometimes positional but if persistent should alsoraise concerns for deep vein thrombosis (Hawsand Baum 1993). Management of establishedthrombosis requires initiation of systemic anti-coagulation and/or thrombolytic therapy underthe guidance of an experienced pediatric hematol-ogist (Lilova et al. 2000). To date, the role, if any,of prophylactic anticoagulation and/or aspirintherapy in children with active NS has not beenestablished (Andrew et al. 1998).

Prognosis

Responsiveness to corticosteroids is consideredthe most important prognostic factor in childrenwith NS, including MCD; therefore, those whoare steroid resistant (or become resistant) have ahigh risk of progression to end-stage kidney dis-ease (ESKD) regardless of their underlying renalhistopathology. Although most children withMCD (70%) who respond to the initial course ofcorticosteroids are expected to develop at leastone subsequent relapse of their disease, the

likelihood of relapse declines over time, withmost children (80%) entering a prolonged remis-sion 8 years following the initial diagnosis (Tar-shish et al. 1997). However, at least 40% ofchildren with MCD continue to develop relapsesinto adulthood. Not surprisingly, children withfrequent relapses during childhood who requiresteroid-sparing medications are more likely tohave one or more relapses during adulthood(Ruth et al. 2005). Hypertension, obesity, cata-racts, and osteoporosis are common in adultswith history of prolonged exposure to corticoste-roids during childhood (Fakhouri et al. 2003;Kyrieleis et al. 2009), although there is someevidence that children receiving intermittent highdoses (i.e., during relapses) may not show bonemineral density abnormalities long-term (Leonardet al. 2004).

The current mortality rate in children withMCD is not known. The most recent estimationwas reported in the early 1980s to be 2.6% overup to 15 years of follow-up. Such estimationwas in dramatic contrast to the two-thirds mortal-ity rate in children with NS observed in theearly twentieth century, prior to the discovery ofantibiotics (1940s) and corticosteroids (1950s)(Anonymous 1984).

Acknowledgments We would like to thank Dr. LealHerlitz for her contribution of all pathology imagesincluded in this chapter.

References

Abdel-Hafez M, Shimada M, Lee PY et al (2009)Idiopathic nephrotic syndrome and atopy: is there acommon link? Am J Kidney Dis 54(5):945–953.https://doi.org/10.1053/j.ajkd.2009.03.019

Abeyagunawardena AS, Goldblatt D, Andrews N et al(2003) Risk of relapse after meningococcal C conjugatevaccine in nephrotic syndrome. Lancet 362(9382):449–450

Abitbol C, Zilleruelo G, Freundlich M et al (1990) Quan-titation of proteinuria with urinary protein/creatinineratios and random testing with dipsticks in nephroticchildren. J Pediatr 116(2):243–247

Afzal K, Bagga A, Menon S et al (2007) Treatment withmycophenolate mofetil and prednisolone for steroid-dependent nephrotic syndrome. Pediatr Nephrol

Minimal Change Disease, Pediatric 15

22(12):2059–2065. https://doi.org/10.1007/s00467-007-0617-9

Aggarwal N, Batwara R, McCarthy ET et al (2007) Serumpermeability activity in steroid-resistant minimalchange nephrotic syndrome is abolished by treatmentof Hodgkin disease. Am J Kidney Dis 50(5):826–829.https://doi.org/10.1053/j.ajkd.2007.06.021

Ali AA, Wilson E, Moorhead JF et al (1994) Minimal-change glomerular nephritis. Normal kidneys in anabnormal environment? Transplantation 58(7):849–852

Andrew M, Michelson AD, Bovill E et al (1998) Guide-lines for antithrombotic therapy in pediatric patients.J Pediatr 132(4):575–588. https://doi.org/10.1016/S0022-3476(98)70343-9

Anonymous (1978) Nephrotic syndrome in children: pre-diction of histopathology from clinical and laboratorycharacteristics at time of diagnosis. A report of theInternational Study of Kidney Disease in Children.Kidney Int 13(2):159–165

Anonymous (1981a) Primary nephrotic syndrome in chil-dren: clinical significance of histopathologic variantsof minimal change and of diffuse mesangial hyper-cellularity. A Report of the International Study of Kid-ney Disease in Children. Kidney Int 20(6):765–771.doi:S0085-2538(15)32626-0 [pii]

Anonymous (1981b) The primary nephrotic syndrome inchildren. Identification of patients with minimal changenephrotic syndrome from initial response to predni-sone. A report of the International Study of KidneyDisease in Children. J Pediatr 98(4):561–564

Anonymous (1983) Childhood nephrotic syndrome asso-ciated with diffuse mesangial hypercellularity. A reportof the Southwest Pediatric Nephrology Study Group.Kidney Int 24(1):87–94

Anonymous (1984) Minimal change nephrotic syndromein children: deaths during the first 5 to 15 years’ obser-vation. Report of the International Study of KidneyDisease in Children. Pediatrics 73(4):497–501

Anonymous (1988) Short versus standard prednisonetherapy for initial treatment of idiopathic nephroticsyndrome in children. Arbeitsgemeinschaft furPadiatrische Nephrologie. Lancet 1(8582):380–383

Anonymous (1994a) A comparison of tacrolimus (FK 506)and cyclosporine for immunosuppression in liver trans-plantation. The U.S. Multicenter FK506 Liver StudyGroup. N Engl J Med 331(17):1110–1115. https://doi.org/10.1056/NEJM199410273311702

Anonymous (1994b) Randomised trial comparingtacrolimus (FK506) and cyclosporin in prevention ofliver allograft rejection. European FK506 MulticentreLiver Study Group. Lancet 344(8920):423–428

Anonymous (2012) Red book. In: Pickering LK (ed)Immunocompromised children American Academy ofPediatrics. pp 74–90.

Arneil GC, Lam CN (1966) Long-term assessmentof steroid therapy in childhood nephrosis. Lancet2(7468):819–821

Audard V, Larousserie F, Grimbert P et al (2006) Minimalchange nephrotic syndrome and classical Hodgkin’slymphoma: report of 21 cases and review of the

literature. Kidney Int 69(12):2251–2260. https://doi.org/10.1038/sj.ki.5000341

Bachmann HJ, Schildberg P, Olbing H et al (1977) Corti-sone cataract in children with nephrotic syndrome. EurJ Pediatr 124(4):277–283

Bagga A, Hari P, Srivastava RN (1999) Prolonged versusstandard prednisolone therapy for initial episode ofnephrotic syndrome. Pediatr Nephrol 13(9):824–827

Bagga A, Hari P, Moudgil A et al (2003) Mycophenolatemofetil and prednisolone therapy in children with ste-roid-dependent nephrotic syndrome. Am J Kidney Dis42(6):1114–1120

Bagga A, Mudigoudar BD, Hari P et al (2004) Enalaprildosage in steroid-resistant nephrotic syndrome. PediatrNephrol 19(1):45–50. https://doi.org/10.1007/s00467-003-1314-y

Banerjee S, Pahari A, Sengupta J et al (2013) Outcome ofsevere steroid-dependent nephrotic syndrome treatedwith mycophenolate mofetil. Pediatr Nephrol 28(1):93–97. https://doi.org/10.1007/s00467-012-2278-6

Bhimma R, Coovadia HM, Adhikari M (1997) Nephroticsyndrome in South African children: changing perspec-tives over 20 years. Pediatr Nephrol 11(4):429–434

Bonilla-Felix M, Parra C, Dajani T et al (1999) Changingpatterns in the histopathology of idiopathic nephroticsyndrome in children. Kidney Int 55(5):1885–1890.https://doi.org/10.1046/j.1523-1755.1999.00408.x

Border WA (1988) Distinguishing minimal-change diseasefrom mesangial disorders. Kidney Int 34(3):419–434

Borel JF (1991) Mechanism of action of cyclosporin A andrationale for use in nephrotic syndrome. Clin Nephrol35(Suppl 1):S23–S30

Brenner BM, Hostetter TH, Humes HD (1978) Glomerularpermselectivity: barrier function based on discrimina-tion of molecular size and charge. Am J Phys 234(6):F455–F460

Brocklebank JT, Harcourt RB, Meadow SR (1982) Corti-costeroid-induced cataracts in idiopathic nephrotic syn-drome. Arch Dis Child 57(1):30–34

Brodehl J (1991) The treatment of minimal changenephrotic syndrome: lessons learned from multicentreco-operative studies. Eur J Pediatr 150(6):380–387

Bunchman T, Navarro M, Broyer M et al (2001) The use ofmycophenolate mofetil suspension in pediatric renalallograft recipients. Pediatr Nephrol 16(12):978–984.https://doi.org/10.1007/s004670100006

Butani L, Palmer J, Baluarte HJ et al (1999) Adverseeffects of mycophenolate mofetil in pediatric renaltransplant recipients with presumed chronic rejection.Transplantation 68(1):83–86

Carrie BJ, Salyer WR, Myers BD (1981) Minimal changenephropathy: an electrochemical disorder of the glo-merular membrane. Am J Med 70(2):262–268

Churg J, Habib R, White RH (1970) Pathology of thenephrotic syndrome in children: a report for the Inter-national Study of Kidney Disease in Children. Lancet760(1):1299–1302

Ciarimboli G, Schurek HJ, Zeh M et al (1999) Roleof albumin and glomerular capillary wall charge distri-bution on glomerular permselectivity: studies on the

16 R. Bou Matar and K.M. Dell

perfused-fixed rat kidney model. Pflugers Arch438(6):883–891

Clark A, Barrat T (1998) Steroid-responsive nephroticsyndrome. In: Barrat T, Avner E, Harmon W (eds)Pediatric Nephrology. Lippincott, Williams andWilkins, Baltimore, p 731

Coleman JE, Watson AR (1996) Hyperlipidaemia, diet andsimvastatin therapy in steroid-resistant nephrotic syn-drome of childhood. Pediatr Nephrol 10(2):171–174

Dittrich K, Knerr I, Rascher W et al (2006) Transientinsulin-dependent diabetes mellitus in children withsteroid-dependent idiopathic nephrotic syndrome dur-ing tacrolimus treatment. Pediatr Nephrol 21(7):958–961. https://doi.org/10.1007/s00467-006-0102-x

Donatti TL, Koch VH, Fujimura MD et al (2003) Growthin steroid-responsive nephrotic syndrome: a study of 85pediatric patients. Pediatr Nephrol 18(8):789–795.https://doi.org/10.1007/s00467-003-1142-0

Ellis D, Vats A, Moritz ML et al (2003) Long-termantiproteinuric and renoprotective efficacy andsafety of losartan in children with proteinuria. JPediatr 143(1):89–97. https://doi.org/10.1016/S0022-3476(03)00279-8

Emma F, Sesto A, Rizzoni G (2003) Long-term lineargrowth of children with severe steroid-responsivenephrotic syndrome. Pediatr Nephrol 18(8):783–788.https://doi.org/10.1007/s00467-003-1176-3

Eugui EM, Almquist SJ, Muller CD et al (1991) Lympho-cyte-selective cytostatic and immunosuppressiveeffects of mycophenolic acid in vitro: role ofdeoxyguanosine nucleotide depletion. Scand JImmunol 33(2):161–173

Fakhouri F, Bocquet N, Taupin P et al (2003) Steroid-sensitive nephrotic syndrome: from childhood to adult-hood. Am J Kidney Dis 41(3):550–557. https://doi.org/10.1053/ajkd.2003.50116

Farnsworth EB (1950) Acute and subacute glomerulone-phritis modified by adrenocorticotropin. Proc Soc ExpBiol Med 74(1):57–59

Faul C, Donnelly M, Merscher-Gomez S et al (2008) Theactin cytoskeleton of kidney podocytes is a direct targetof the antiproteinuric effect of cyclosporine A. Nat Med14(9):931–938. https://doi.org/10.1038/nm.1857

Feber J, Al-Matrafi J, Farhadi E et al (2009) Prednisonedosing per body weight or body surface area in childrenwith nephrotic syndrome: is it equivalent? PediatrNephrol 24(5):1027–1031. https://doi.org/10.1007/s00467-008-1089-2

Fodor P, Saitua MT, Rodriguez E et al (1982) T-cell dys-function in minimal-change nephrotic syndrome ofchildhood. Am J Dis Child 136(8):713–717

Fujinaga S, OhtomoY, Umino D et al (2007) A prospectivestudy on the use of mycophenolate mofetil in childrenwith cyclosporine-dependent nephrotic syndrome.Pediatr Nephrol 22(1):71–76. https://doi.org/10.1007/s00467-006-0294-0

Fujinaga S, Hirano D, Nishizaki N et al (2010) Singleinfusion of rituximab for persistent steroid-dependentminimal-change nephrotic syndrome after long-termcyclosporine. Pediatr Nephrol 25(3):539–544. https://doi.org/10.1007/s00467-009-1377-5

Gadegbeku CA, Gipson DS, Holzman LB et al (2013)Design of the Nephrotic Syndrome Study Network(NEPTUNE) to evaluate primary glomerular nephrop-athy by a multidisciplinary approach. Kidney Int83(4):749–756. https://doi.org/10.1038/ki.2012.428

Gbadegesin RA, Adeyemo A, Webb NJ et al (2015) HLA-DQA1 and PLCG2 Are candidate risk loci for child-hood-onset steroid-sensitive nephrotic syndrome. J AmSoc Nephrol 26(7):1701–1710. https://doi.org/10.1681/ASN.2014030247

Gee HY, Ashraf S, Wan X et al (2014) Mutations in EMP2cause childhood-onset nephrotic syndrome. Am J HumGenet 94(6):884–890. https://doi.org/10.1016/j.ajhg.2014.04.010

Gipson DS,Massengill SF, Yao L et al (2009)Managementof childhood onset nephrotic syndrome. Pediatrics124(2):747–757. https://doi.org/10.1542/peds.2008-1559

Gipson DS, Troost JP, Lafayette RA et al (2016) Completeremission in the Nephrotic Syndrome Study Network.Clin J Am Soc Nephrol 11(1):81–89. https://doi.org/10.2215/CJN.02560315

Guesry P, Lenoir G, Broyer M (1978) Gonadal effects ofchlorambucil given to prepubertal and pubertal boys fornephrotic syndrome. J Pediatr 92(2):299–303

Guigonis V, Dallocchio A, Baudouin V et al (2008)Rituximab treatment for severe steroid- or cyclospor-ine-dependent nephrotic syndrome: a multicentricseries of 22 cases. Pediatr Nephrol 23(8):1269–1279.https://doi.org/10.1007/s00467-008-0814-1

Gulati S, Pokhariyal S, Sharma RK et al (2001) Pulsecyclophosphamide therapy in frequently relapsingnephrotic syndrome. Nephrol Dial Transplant 16(10):2013–2017

Gulati A, Sinha A, Sreenivas V et al (2011) Daily cortico-steroids reduce infection-associated relapses in fre-quently relapsing nephrotic syndrome: a randomizedcontrolled trial. Clin J Am Soc Nephrol 6(1):63–69.https://doi.org/10.2215/CJN.01850310

Habib R, Niaudet P (1994) Comparison between pre- andposttreatment renal biopsies in children receivingciclosporine for idiopathic nephrosis. Clin Nephrol42(3):141–146

Haws RM, Baum M (1993) Efficacy of albumin anddiuretic therapy in children with nephrotic syndrome.Pediatrics 91(6):1142–1146

Hayasaka Y, Hayasaka S, Matsukura H (2006) Ocularfindings in Japanese children with nephrotic syndromereceiving prolonged corticosteroid therapy.Ophthalmologica 220(3):181–185. https://doi.org/10.1159/000091762

Hisano S, Fukuma Y, Segawa Y et al (2008) Clinicopath-ologic correlation and outcome of C1q nephropathy.Clin J Am Soc Nephrol 3(6):1637–1643. https://doi.org/10.2215/CJN.00830208

Hodson EM, Knight JF, Willis NS et al (2000) Corticoste-roid therapy in nephrotic syndrome: a meta-analysisof randomised controlled trials. Arch Dis Child83(1):45–51

Minimal Change Disease, Pediatric 17

Hodson EM, Willis NS, Craig JC (2007) Corticosteroidtherapy for nephrotic syndrome in children. CochraneDatabase Syst Rev 17(4):CD001533. https://doi.org/10.1002/14651858.CD001533.pub4

Hogg RJ, Portman RJ, Milliner D et al (2000) Evaluationand management of proteinuria and nephrotic syn-drome in children: recommendations from a pediatricnephrology panel established at the NationalKidney Foundation conference on proteinuria, albu-minuria, risk, assessment, detection, and elimination(PARADE). Pediatrics 105(6):1242–1249

Hogg RJ, Fitzgibbons L, Bruick J et al (2006)Mycophenolate mofetil in children with frequentlyrelapsing nephrotic syndrome: a report from theSouthwest Pediatric Nephrology Study Group. Clin JAm Soc Nephrol 1(6):1173–1178. https://doi.org/10.2215/CJN.00550206

Iijima K, Hamahira K, Tanaka R et al (2002) Risk factorsfor cyclosporine-induced tubulointerstitial lesions inchildren with minimal change nephrotic syndrome.Kidney Int 61(5):1801–1805. https://doi.org/10.1046/j.1523-1755.2002.00303.x

Ishikura K, Yoshikawa N, Nakazato H et al (2012) Two-year follow-up of a prospective clinical trial of cyclo-sporine for frequently relapsing nephrotic syndrome inchildren. Clin J Am Soc Nephrol 7(10):1576–1583.https://doi.org/10.2215/CJN.00110112

Ito S, Kamei K, Ogura M et al (2011) Maintenance therapywith mycophenolate mofetil after rituximab in pediatricpatients with steroid-dependent nephrotic syndrome.Pediatr Nephrol 26(10):1823–1828. https://doi.org/10.1007/s00467-011-1886-x

Iversen P, Brun C (1951) Aspiration biopsy of the kidney.Am J Med 11(3):324–330

Jones JP Jr (1985) Fat embolism and osteonecrosis. OrthopClin North Am 16(4):595–633

Kamei K, Ito S, Nozu K et al (2009) Single doseof rituximab for refractory steroid-dependentnephrotic syndrome in children. Pediatr Nephrol24(7):1321–1328. https://doi.org/10.1007/s00467-009-1191-0

Kano K, Kyo K, Yamada Y et al (1999) Comparisonbetween pre- and posttreatment clinical and renal biop-sies in children receiving low dose ciclosporine-A for 2years for steroid-dependent nephrotic syndrome. ClinNephrol 52(1):19–24

Karnovsky MJ, Ainsworth SK (1972) The structural basisof glomerular filtration. Adv Nephrol Necker Hosp2:35–60

Keane WF (1994) Lipids and the kidney. Kidney Int46(3):910–920

Kersnik Levart T, Kenda RB, Avgustin Cavic M et al(2005) C1Q nephropathy in children. Pediatr Nephrol20(12):1756–1761. https://doi.org/10.1007/s00467-005-2040-4

Kitano Y, Yoshikawa N, Nakamura H (1993) Glomerularanionic sites in minimal change nephrotic syndromeand focal segmental glomerulosclerosis. Clin Nephrol40(4):199–204

Kopp JB, Smith MW, Nelson GW et al (2008) MYH9 is amajor-effect risk gene for focal segmental glomerulo-sclerosis. Nat Genet 40(10):1175–1184. https://doi.org/10.1038/ng.226

Kyrieleis HA, Lowik MM, Pronk I et al (2009) Long-termoutcome of biopsy-proven, frequently relapsing mini-mal-change nephrotic syndrome in children. Clin J AmSoc Nephrol 4(10):1593–1600. https://doi.org/10.2215/CJN.05691108

Latta K, von Schnakenburg C, Ehrich JH (2001) A meta-analysis of cytotoxic treatment for frequently relapsingnephrotic syndrome in children. Pediatr Nephrol 16(3):271–282

Leonard MB, Feldman HI, Shults J et al (2004) Long-term,high-dose glucocorticoids and bone mineral contentin childhood glucocorticoid-sensitive nephrotic syn-drome. N Engl J Med 351(9):868–875. https://doi.org/10.1056/NEJMoa040367

Leroy V, Baudouin V, Alberti C et al (2009) Growth inboys with idiopathic nephrotic syndrome on long-termcyclosporin and steroid treatment. Pediatr Nephrol 24(12):2393–2400. https://doi.org/10.1007/s00467-009-1266-y

Lighter J, Rigaud M, Eduardo R et al (2009) Latenttuberculosis diagnosis in children by using theQuantiFERON-TB Gold In-Tube test. Pediatrics123(1):30–37. https://doi.org/10.1542/peds.2007-3618

Lilova MI, Velkovski IG, Topalov IB (2000) Thromboem-bolic complications in children with nephroticsyndrome in Bulgaria (1974–1996). Pediatr Nephrol15(1–2):74–78

Limaye SR, Pillai S, Tina LU (1988) Relationship of ste-roid dose to degree of posterior subcapsular cataracts innephrotic syndrome. Ann Ophthalmol 20(6):225–227

Lombel RM, Gipson DS, Hodson EM et al (2013) Treat-ment of steroid-sensitive nephrotic syndrome: newguidelines from KDIGO. Pediatr Nephrol 28(3):415–426. https://doi.org/10.1007/s00467-012-2310-x

Mahmoud I, Basuni F, Sabry A et al (2005) Single-centreexperience with cyclosporin in 106 children with idio-pathic focal segmental glomerulosclerosis. NephrolDial Transplant 20(4):735–742. https://doi.org/10.1093/ndt/gfh766

Maloney DG, Grillo-Lopez AJ, White CA et al (1997)IDEC-C2B8 (Rituximab) anti-CD20 monoclonal anti-body therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 90(6):2188–2195

Markowitz GS, Schwimmer JA, Stokes MB et al (2003)C1q nephropathy: a variant of focal segmentalglomerulosclerosis. Kidney Int 64(4):1232–1240.https://doi.org/10.1046/j.1523-1755.2003.00218.x

Mattoo TK, Mahmoud MA (2000) Increased maintenancecorticosteroids during upper respiratory infectiondecrease the risk of relapse in nephrotic syndrome.Nephron 85(4):343–345. https://doi.org/10.1159/000045684

McEnery PT, Strife CF (1982) Nephrotic syndrome inchildhood. Management and treatment in patientswith minimal change disease, mesangial proliferation,

18 R. Bou Matar and K.M. Dell

or focal glomerulosclerosis. Pediatr Clin N Am 29(4):875–894

Montane B, Abitbol C, Chandar J et al (2003)Novel therapy of focal glomerulosclerosis withmycophenolate and angiotensin blockade. PediatrNephrol 18(8):772–777. https://doi.org/10.1007/s00467-003-1174-5

Moorhead JF, Wheeler DC, Varghese Z (1989) Glomerularstructures and lipids in progressive renal disease. Am JMed 87(5N):12N–20N

Muehrcke RC, Kark RM, Pirani CL (1955) Biopsy of thekidney in the diagnosis and management of renal dis-ease. N Engl J Med 253(13):537–546. https://doi.org/10.1056/NEJM195509292531301

Myllymaki J, Saha H, Mustonen J et al (2003) IgMnephropathy: clinical picture and long-term prognosis.Am J Kidney Dis 41(2):343–350. https://doi.org/10.1053/ajkd.2003.50042

Nash M, Edelman C, Bernstein J (1992) The nephroticsyndrome. In: Edelman C (ed) Pediatric kidney disease.Little, Brown and Company, Boston, p 1247

Ng JS, Wong W, Law RW et al (2001) Ocular complica-tions of paediatric patients with nephrotic syndrome.Clin Exp Ophthalmol 29(4):239–243

Niaudet P (1992) Comparison of cyclosporin andchlorambucil in the treatment of steroid-dependent idi-opathic nephrotic syndrome: a multicentre randomizedcontrolled trial. The French Society of PaediatricNephrology. Pediatr Nephrol 6(1):1–3

Niaudet P, Habib R (1994) Cyclosporine in the treatmentof idiopathic nephrosis. J Am Soc Nephrol 5(4):1049–1056

Niaudet P, Broyer M, Habib R (1991) Treatment of idio-pathic nephrotic syndrome with cyclosporin A in chil-dren. Clin Nephrol 35(Suppl 1):S31–S36

Nicol MP, DaviesMA,Wood K et al (2009) Comparison ofT-SPOT.TB assay and tuberculin skin test for the eval-uation of young children at high risk for tuberculosis ina community setting. Pediatrics 123(1):38–43. https://doi.org/10.1542/peds.2008-0611

Novak I, Frank R, Vento S et al (2005) Efficacy ofmycophenolate mofetil in pediatric patients with ste-roid-dependent nephrotic syndrome. Pediatr Nephrol20(9):1265–1268. https://doi.org/10.1007/s00467-005-1957-y

Pape L, Ahlenstiel T, Kreuzer M et al (2008) Improvedgastrointestinal symptom burden after conversionfrom mycophenolate mofetil to enteric-coatedmycophenolate sodium in kidney transplanted chil-dren. Pediatr Transplant 12(6):640–642

Polito C, Oporto MR, Totino SF et al (1986) Normalgrowth of nephrotic children during long-term alter-nate-day prednisone therapy. Acta Paediatr Scand75(2):245–250

Ponticelli C, Edefonti A, Ghio L et al (1993) Cyclosporinversus cyclophosphamide for patients with steroid-dependent and frequently relapsing idiopathicnephrotic syndrome: a multicentre randomized con-trolled trial. Nephrol Dial Transplant 8(12):1326–1332

Prasad N, Gulati S, Sharma RK et al (2004) Pulse cyclo-phosphamide therapy in steroid-dependent nephroticsyndrome. Pediatr Nephrol 19(5):494–498. https://doi.org/10.1007/s00467-003-1404-x

Prescott WA Jr, Streetman DA, Streetman DS (2004) Thepotential role of HMG-CoA reductase inhibitorsin pediatric nephrotic syndrome. Ann Pharmacother38(12):2105–2114. https://doi.org/10.1345/aph.1D587

Querfeld U (1999) Should hyperlipidemia in children withthe nephrotic syndrome be treated? Pediatr Nephrol13(1):77–84

Querfeld U, Lang M, Friedrich JB et al (1993) Lipoprotein(a) serum levels and apolipoprotein(a) phenotypesin children with chronic renal disease. Pediatr Res34(6):772–776. https://doi.org/10.1203/00006450-199312000-00015

Ravani P, Magnasco A, Edefonti A et al (2011) Short-termeffects of rituximab in children with steroid- andcalcineurin-dependent nephrotic syndrome: a random-ized controlled trial. Clin J Am Soc Nephrol 6(6):1308–1315. https://doi.org/10.2215/CJN.09421010

Rees L, Greene SA, Adlard P et al (1988) Growth andendocrine function in steroid sensitive nephrotic syn-drome. Arch Dis Child 63(5):484–490

Rheault MN, Wei CC, Hains DS et al (2014) Increasingfrequency of acute kidney injury amongst childrenhospitalized with nephrotic syndrome. Pediatr Nephrol29(1):139–147. https://doi.org/10.1007/s00467-013-2607-4

Ruth EM, Kemper MJ, Leumann EP et al (2005) Childrenwith steroid-sensitive nephrotic syndrome come of age:long-term outcome. J Pediatr 147(2):202–207. https://doi.org/10.1016/j.jpeds.2005.03.050

Saadeh SA, Baracco R, Jain A et al (2011) Weight or bodysurface area dosing of steroids in nephrotic syndrome:is there an outcome difference? Pediatr Nephrol 26(12):2167–2171. https://doi.org/10.1007/s00467-011-1961-3

Samuelsson O, Mulec H, Knight-Gibson C et al (1997)Lipoprotein abnormalities are associated with increasedrate of progression of human chronic renal insuffi-ciency. Nephrol Dial Transplant 12(9):1908–1915

Sanjad SA, al-Abbad A, al-Shorafa S (1997) Managementof hyperlipidemia in children with refractory nephroticsyndrome: the effect of statin therapy. J Pediatr 130(3):470–474

Sanz I, Anolik JH, Looney RJ (2007) B cell depletiontherapy in autoimmune diseases. Front Biosci12:2546–2567

Sasdelli M, Cagnoli L, Candi P et al (1981) Cell mediatedimmunity in idiopathic glomerulonephritis. Clin ExpImmunol 46(1):27–34

Sellier-Leclerc AL, Macher MA, Loirat C et al (2010)Rituximab efficiency in children with steroid-depen-dent nephrotic syndrome. Pediatr Nephrol25(6):1109–1115. https://doi.org/10.1007/s00467-010-1465-6

Sellier-Leclerc AL, Baudouin V, Kwon T et al (2012)Rituximab in steroid-dependent idiopathic nephrotic

Minimal Change Disease, Pediatric 19

syndrome in childhood – follow-up after CD19 recov-ery. Nephrol Dial Transplant 27(3):1083–1089. https://doi.org/10.1093/ndt/gfr405

Shalhoub RJ (1974) Pathogenesis of lipoid nephrosis: adisorder of T-cell function. Lancet 2(7880):556–560

Shankland SJ (2006) The podocyte’s response to injury:role in proteinuria and glomerulosclerosis. KidneyInt 69(12):2131–2147. https://doi.org/10.1038/sj.ki.5000410

Sharples PM, Poulton J, White RH (1985) Steroid respon-sive nephrotic syndrome is more common in Asians.Arch Dis Child 60(11):1014–1017

Sinha MD, MacLeod R, Rigby E et al (2006) Treatment ofsevere steroid-dependent nephrotic syndrome (SDNS)in children with tacrolimus. Nephrol Dial Transplant 21(7):1848–1854. https://doi.org/10.1093/ndt/gfi274

Sinha A, Saha A, Kumar M et al (2015) Extending initialprednisolone treatment in a randomized control trialfrom 3 to 6 months did not significantly influence thecourse of illness in children with steroid-sensitivenephrotic syndrome. Kidney Int 87(1):217–224.https://doi.org/10.1038/ki.2014.240

Solomon L (1981) Idiopathic necrosis of the femoral head:pathogenesis and treatment. Can J Surg 24(6):573–578

Sorensson J, Ohlson M, Lindstrom K et al (1998) Glomer-ular charge selectivity for horseradish peroxidase andalbumin at low and normal ionic strengths. ActaPhysiol Scand 163(1):83–91. https://doi.org/10.1046/j.1365-201x.1998.00315.x

Srivastava RN, Vasudev AS, Bagga A et al (1992) Long-term, low-dose prednisolone therapy in frequentlyrelapsing nephrotic syndrome. Pediatr Nephrol 6(3):247–250

Srivastava T, Simon SD, Alon US (1999) High incidenceof focal segmental glomerulosclerosis in nephrotic syn-drome of childhood. Pediatr Nephrol 13(1):13–18

Swartz SJ, Eldin KW, Hicks MJ et al (2009) Minimalchange disease with IgMþ immunofluorescence: asubtype of nephrotic syndrome. Pediatr Nephrol24(6):1187–1192. https://doi.org/10.1007/s00467-009-1130-0

Taal MW (2004) Slowing the progression of adult chronickidney disease: therapeutic advances. Drugs 64(20):2273–2289

Tarshish P, Tobin JN, Bernstein J et al (1997) Prognosticsignificance of the early course of minimal changenephrotic syndrome: report of the International Studyof Kidney Disease in Children. J Am Soc Nephrol8(5):769–776

Taylor GM, Neuhaus TJ, Shah V et al (1997) Charge andsize selectivity of proteinuria in children with idio-pathic nephrotic syndrome. Pediatr Nephrol 11(4):404–410

Teeninga N, Kist-van Holthe JE, van Rijswijk N et al(2013) Extending prednisolone treatment does notreduce relapses in childhood nephrotic syndrome. JAm Soc Nephrol 24(1):149–159. https://doi.org/10.1681/ASN.2012070646

Teoh CW, Robinson LA, Noone D (2015) Perspectives onedema in childhood nephrotic syndrome. Am J Physiol

Ren Physiol 309(7):F575–F582. https://doi.org/10.1152/ajprenal.00229.2015

Trompeter R, Filler G, Webb NJ et al (2002) Randomizedtrial of tacrolimus versus cyclosporin microemulsion inrenal transplantation. Pediatr Nephrol 17(3):141–149.https://doi.org/10.1007/s00467-001-0795-9

van den Born J, van den Heuvel LP, Bakker MA et al(1992) A monoclonal antibody against GBM heparansulfate induces an acute selective proteinuria in rats.Kidney Int 41(1):115–123

Veverka A, Jolly JL (2004) Recent advances in the second-ary prevention of coronary heart disease. Expert RevCardiovasc Ther 2(6):877–889. https://doi.org/10.1586/14779072.2.6.877

Vilalta Casas R, Vila Lopez A, Nieto Rey JL et al (2006)Mycophenolic Acid reaches therapeutic levels whereasmycophenolate mofetil does not. Transplant Proc38(8):2400–2401. https://doi.org/10.1016/j.transproceed.2006.08.062

Vivarelli M, Moscaritolo E, Tsalkidis A et al (2010) Timefor initial response to steroids is a major prognosticfactor in idiopathic nephrotic syndrome. J Pediatr156(6):965–971. https://doi.org/10.1016/j.jpeds.2009.12.020

Vizjak A, Ferluga D, Rozic M et al (2008) Pathology,clinical presentations, and outcomes of C1q nephropa-thy. J Am Soc Nephrol 19(11):2237–2244. https://doi.org/10.1681/ASN.2007080929

Waldherr R, Gubler MC, Levy M et al (1978) Thesignificance of pure diffuse mesangial proliferation inidiopathic nephrotic syndrome. Clin Nephrol 10(5):171–179

Wang L, Shearer GC, Budamagunta MS et al (2012) Pro-teinuria decreases tissue lipoprotein receptor levelsresulting in altered lipoprotein structure and increasinglipid levels. Kidney Int 82(9):990–999. https://doi.org/10.1038/ki.2012.244

Watson AR, Rance CP, Bain J (1985) Long term effects ofcyclophosphamide on testicular function. Br Med J(Clin Res Ed) 291(6507):1457–1460

White RH, Glasgow EF, Mills RJ (1970) Clinicopatholog-ical study of nephrotic syndrome in childhood. Lancet 1(7661):1353–1359

Yan K, Nakahara K, Awa S et al (1998) The increase ofmemory T cell subsets in children with idiopathicnephrotic syndrome. Nephron 79(3):274–278

Yang T, Nast CC, Vo A et al (2008) Rapid remission ofsteroid and mycophenolate mofetil (mmf)-resistantminimal change nephrotic syndrome after rituximabtherapy. Nephrol Dial Transplant 23(1):377–380.https://doi.org/10.1093/ndt/gfm592

Yokoyama H, Kida H, Abe T et al (1987) Impaired immu-noglobulin G production in minimal change nephroticsyndrome in adults. Clin Exp Immunol 70(1):110–115

Zagury A, de Oliveira AL, de Moraes CA et al (2011)Long-term follow-up after cyclophosphamide therapyin steroid-dependent nephrotic syndrome. PediatrNephrol 26(6):915–920. https://doi.org/10.1007/s00467-011-1825-x

20 R. Bou Matar and K.M. Dell