ACKD

Glomerular Diseases in Children

Scott E. Wenderfer and Joseph P. Gaut

Unique challenges exist in the diagnosis and treatment of glomerular diseases with their onset during childhood. Mounting
evidence supports the notion that earlier onset cases occur due to larger numbers of genetic risk alleles. Nearly all causes of
adult-onset glomerulonephritis, nephrotic syndrome, and thrombotic microangiopathy have also been described in children,
although the prevalence of specific causes differs. Postinfectious glomerulonephritis, Henoch-Scho € nlein purpura nephritis,
and minimal change disease remain the most common causes of glomerular disease in younger children in the United States
and can be diagnosed clinically without need for biopsy. IgA nephropathy is the most common pediatric glomerular disease
diagnosed by kidney biopsy and is considered the most common chronic glomerulopathy worldwide. In both developing
and developed countries, there is a strong relationship between infectious diseases and nephritis onset or relapse. Although
research has led to a better understanding of how to classify and manage glomerular diseases in children, the need for
disease-specific biomarkers of activity and chronicity remains a hurdle. The strength of the immune system and the growth
and maturation that occurs during adolescence are unique and require age-specific approaches to disease management.
Q 2017 by the National Kidney Foundation, Inc. All rights reserved.
Key Words: Glomerulonephritis, Hematuria, Proteinuria, Nephrotic syndrome, Pediatric

INTRODUCTION APPROACH TO CLASSIFICATION

In children as in adults, glomerular diseases present clini-
cally in several different ways. Depending on both the
nature and severity of the primary disease and the extent
to which the normal physiological functions of the glomer-
ulus are perturbed,1 children may be identified inciden-
tally or may become critically ill with oligoanuric rapidly
progressive kidney injury in need of urgent dialysis. A
few glomerular diseases are inherited, but most forms
are acquired and are generally considered to be immuno-
logically mediated. There are 3 classical clinical syndromes
that develop from glomerular injury: acute and chronic
glomerulonephritis (GN), defined by the triad of hematu-
ria, hypertension, and acute kidney injury (AKI); nephrotic
syndrome (NS), defined by proteinuria and hypoalbumi-
nemia; and hemolytic uremic syndrome (HUS), defined
by microangiopathic hemolytic anemia, thrombocyto-
penia, and AKI.
In GN, glomerular proliferation and inflammation lead
to decreased glomerular perfusion, resulting in compro-
mised kidney function and retention of salt and water
with potential development of hypertension and edema.
In isolated NS, glomerular injury occurs in the absence of
inflammation and often proliferation, and an increase in
the permeability of the glomerular capillary loops drives
a sequence of events leading to the classical clinical
features: proteinuria, hypoalbuminemia, decreased
plasma oncotic pressure, and edema. However, NS can
also occur secondarily to GN in many cases.
From Baylor College of Medicine, Department of Pediatrics, and Texas Chil-
dren’s Hospital, Renal Section, Houston, TX; and Washington University
School of Medicine, Department of Pathology and Immunology, and Depart-
ment of Medicine, St. Louis, MO.
Financial Disclosure: The authors declare that they have no relevant finan-
cial interests.
Address correspondence to Scott E. Wenderfer, Texas Children’s Hospital,
1102 Bates Avenue, Ste. 245, Houston, TX 77030. E-mail: wenderfe@bcm.edu
Ó 2017 by the National Kidney Foundation, Inc. All rights reserved.
1548-5595/$36.00
https://doi.org/10.1053/j.ackd.2017.09.005
The patient with glomerular disease presents clinically
with a constellation of features that may include hematu-
ria, proteinuria, edema, hypertension, and AKI.2 In GN,
the urinary sediment is characterized as active when
dysmorphic erythrocytes and cellular casts are present.
A series of questions guide the initial diagnostic and
management plan (Table 1). NS is not a diagnosis but a
constellation of clinical findings. By definition, in children,
it comprises proteinuria greater than 50 mg/kg per 24 hour
(or .40 mg/m2 per hour or a urinary protein-to-creatinine
ratio greater than 2.0 mg/mg), hypoalbuminemia (serum
albumin , 3.0 g/dL), and hyperlipidemia. NS may mani-
fest in any of the proliferative glomerular diseases, but in
children, it more commonly occurs as in isolation without
nephritis. Table 2 guides the initial diagnostic and manage-
ment plan for isolated NS.
Various classification systems have been proposed to
understand and manage glomerular diseases. As advances
in kidney research have revealed more about the molecu-
lar and cellular pathways,3-6 disease classification has
evolved to reflect these findings (Table 3).1 GN classifica-
tion starts by establishing whether disease is kidney
limited or systematic, followed by pathologic classification
and genetic evaluation in appropriate cases. Most acute
GN episodes in children are postinfectious, isolated to
the kidney, and prone to spontaneous resolution.7 A his-
tory of antecedent illness with hypocomplementemia
precludes the need for kidney biopsy and intensive phar-
macologic therapy. Diagnosing pulmonary edema and
hypertension secondary to oliguria and volume overload
is important to distinguish from the pulmonary-kidney
syndrome as seen in vasculitis, lupus, or Goodpasture
syndrome.8,9
Evaluation of the urine sediment is the key to distin-
guishing between GN and primarily proteinuric diseases.
In the absence of red blood cell casts and proliferative
urinary sediment, suspicion should shift away from GN.
Diagnosis of proteinuric kidney diseases proceeds with
ruling out secondary causes (Table 4). Only then should
kidney biopsy or genetic testing be considered to identify

364 Adv Chronic Kidney Dis. 2017;24(6):364-371

 Glomerular Diseases 365

primary podocytopathies10 or idiopathic forms of minimal more commonly show thickened glomerular capillary loops
change disease (MCD),11 focal segmental glomerulosclero- with associated spike formation on the silver stain, patients
sis (FSGS),12 or membranous glomerulopathy.13 In the with Ehrenreich and Churg stage I disease may show only
near future, our understanding of genetics, autoimmunity, minimal changes.17 Further staining for target antigens for
and infectious diseases will most certainly necessitate membranous glomerulopathy, such as phospholipase A2
further refinements. receptor 1 (PLA2R) and thrombospondin type 1 domain-
Finally, the clinical triad of glomerular disease, thrombo- containing 7A, can be helpful in discriminating primary
cytopenia, and microangiopathic hemolytic anemia points vs secondary causes.18,19 In a pediatric study, positive
toward the thrombotic microangiopathies (TMAs).14 PLA2R staining was detected in 2 patients’ ages of 11 and
Whereas diarrhea-positive hemolytic uremic syndrome 12 years from a cohort of 34 with idiopathic membranous
(D1 HUS) remains the most common TMA in children glomerulopathy.20 In adults, thrombospondin type 1
and Shiga toxin-producing E. coli (STEC-HUS) the most domain-containing 7A membranous patients have a higher
common cause of D 1 HUS cases, there is increasing recog- incidence of malignancy.18 In neonates, membranous glo-
nition and diagnosis of many atypical causes for HUS merulopathy may have developed from maternal transfer
(Table 5). Again, further classification involves ruling out of antineutral endopeptidase antibodies,21 and antibodies
secondary causes before embarking on complement directed against cationic bovine serum albumin have also
profiling and genetic testing. been implicated in children.22
If the patient presents with hematuria and shows min-
APPROACH TO PATHOLOGIC EXAMINATION imal changes on light microscopy, the differential diag-
Examination of the biopsy material should include light, nosis includes IgA nephropathy, lupus nephritis, thin
immunofluorescence, and electron microscopy performed basement membrane nephropathy, and Alport syn-
using standard techniques. Routine stains performed for drome. Whereas IgA nephropathy and lupus may be
light microscopy include hematoxylin and eosin, periodic readily distinguished by immunostaining, electron mi-
acid-Schiff, Jones’ methena- croscopy is required to di-
mine silver, and Masson’s tri- agnose thin basement
chrome. Immunofluores- CLINICAL SUMMARY membrane nephropathy
cence staining for IgG, IgA, and Alport syndrome.
IgM, C3, and C1q (and at
Diagnosis of glomerular diseases in children should Various cutoffs of glomer-
some centers for C4, fibrin- incorporate relevant genetic information and tissue ular basement membrane
ogen, albumin, kappa light histopathology, in addition to serologic and urine analyses. (GBM) thickness have been
chain, and lambda light
Care is warranted to distinguish between a primary proposed to qualify as thin
chain) is performed for all pediatric disorder and acquired glomerulonephritis. (between 200 and 270 nm
native biopsies. Kidney path- or between 1.5 and 2 stan-

Management should involve ongoing monitoring for
ologic findings may be pediatric-specific measures of therapeutic responsiveness,
dard deviations below the
grouped by the pathologic including systemic and kidney-specific assessment of both
mean thickness for age
patterns observed on light disease activity and damage. and gender).23,24 Thinning
microscopy. Since the kidney of the GBM may also be
responds to injury in a limited seen in heterozygous
number of ways, incorpora- women with Alport
tion of the pathologic pattern of injury with the clinical pre- syndrome. Given the significant overlap between thin
sentation is critical to arrive at an accurate diagnosis. basement nephropathy and Alport syndrome, genetic
Scoring of histopathology can also be of great utility. testing for variants in the COL4A3, COL4A4, and
Determination of activity and chronicity indices in patients COL4A5 genes may be indicated.24
with lupus nephritis can be performed on permanent
sections.8,15 Similarly, applying the recently revised Mesangial Hypercellularity
Oxford classification for IgA nephropathy may assist in Mesangial hypercellularity is a common finding in pediat-
personalized management of these patients.16 ric kidney biopsies and is typically encountered in the
clinical setting of hematuria (Fig. 1B). The differential diag-
Minimal Changes nosis is IgA nephropathy and class II lupus nephritis.15
It is not uncommon to observe minimal glomerular findings The Oxford classification of IgA nephropathy has been
on a pediatric kidney biopsy (Fig. 1A). The differential diag- demonstrated to predict kidney outcome.16 Since IgA ne-
nosis depends on the adequacy of the sample: if , 10 phropathy may have variable pathology,25 similar to lupus
glomeruli are present and the corticomedullary junction is nephritis, the various pathologic lesions are enumerated
not available, a diagnosis of FSGS cannot be excluded and used to determine an overall score (MEST-C). The le-
with confidence. Both FSGS and MCD will show diffuse sions include mesangial hypercellularity (M), endocapil-
podocyte foot process effacement in nonsclerotic glomeruli lary proliferation (E), segmental glomerulosclerosis (S),
in the absence of immune-complex deposits. In contrast, tubular atrophy/interstitial fibrosis (T), and crescents (C).
patients with membranous glomerulopathy will show sub- The MEST-C score is generated and may provide addi-
epithelial IgG deposits with or without codeposition of C3. tional information to the clinician useful for predicting
Although patients with membranous glomerulopathy will the clinical course of disease.

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366 Wenderfer and Gaut
Table 1. Questions to Guide the Initial Diagnostic and Management
Plan of Childhood-Onset Glomerulonephritis
1. Is the process acute or chronic? Chronic GN can be
asymptomatic until disease is advanced. Clues of chronicity
include significant anemia, kidney osteodystrophy, or small
echogenic kidneys on ultrasound. Acute onset of severe
hypertension can cause headaches and seizures, while long-
standing hypertension may be asymptomatic but cause left
ventricular hypertrophy.
2. Is the kidney disease isolated? Can be primary (acquired) or
secondary, due to multisystem disease. Relevant extrarenal
involvement, such as involvement of the lung or sinuses, or a
history of concurrent or proceeding infection may provide
clues.
3. Is there hypocomplementemia? A low serum level of
complement component C3 indicates 1 of 5 diseases in
children: PIGN, LN, C3G, aHUS, or GN associated with
chronic infections (subacute bacterial endocarditis or shunt
nephritis). A low C4 level can distinguish between diseases
primarily of the classical pathway from those with primarily
alternative pathway involvement.
4. Is the onset rapidly progressive? RPGN is suggestive of a
crescentic GN. More rarely, AKI may result from acute GN
with superimposed acute tubular necrosis.
5. Is nephrotic syndrome present? Suggests a more high-risk
glomerular histopathology, more likely to require
immunosuppression before inflammation resolves.
Abbreviations: AKI, acute kidney injury; aHUS, atypical hemolytic
uremic syndrome; C3G, C3 glomerulopathy; GN, glomerulone-
phritis; LN, lupus nephritis; PIGN, postinfectious glomerulone-
phritis; RPGN, rapidly progressive GN.
In the setting of proteinuria in addition to hematuria, the
differential diagnosis includes an unsampled FSGS and
diffuse mesangial hypercellularity (DMH). DMH, present
in approximately 3% of pediatric idiopathic NS patients, is
believed to be in the spectrum of MCD as they both share
the feature of diffuse podocyte foot process effacement.
Although DMH is less steroid-responsive relative to
MCD, the long-term prognosis is similar.26
Focal Segmental Glomerulosclerosis
Segmental glomerulosclerosis is defined as partial obliter-
ation of the glomerular tuft by increased matrix (Fig. 1C).
In the pediatric population, FSGS accounts for approxi-
mately 20% of cases of NS.27 Patients typically present
with steroid-resistant NS, the most common cause of pedi-
atric CKD.28 In the pediatric population, genetic causes of
FSGS are more common.29,30 Identification of a genetic
cause provides a definitive diagnosis, helps predict
disease course, enables for family planning, avoids
unnecessary tests and treatments, may identify
extrarenal manifestations for early treatment, and lead to
targeted therapies in patients with coenzyme Q10
synthesis mutations.31 Patients with genetic FSGS have a
more rapid progression to ESRD and are less likely to
have disease recurrence following transplantation.32
Currently, there are 53 genes associated with steroid-
resistant NS.32-38 A recent study of 187 cases enrolled in
the United Kingdom national registry of children with
NS identified putative disease causing variants in 26% of
Table 2. Questions to Guide the Initial Diagnostic and Management
Plan of Childhood-Onset Nephrotic Syndrome
1. Is the process congenital/infantile? Cases are caused either
by podocyte gene mutation, especially nephrin and podocin,
or by a perinatal infection.
2. Is kidney disease isolated or are additional organ systems
involved? Only 10-15% of children have an identifiable
secondary cause for their NS, and the treatment is targeted to
the primary underlying cause. Mutations in at least 50 genes
have been identified in either inherited or sporadic primary
NS.
3. Does child have SSNS (steroid-sensitive NS)?
Corticosteroids will induce a remission in the vast majority of
children with NS. Therefore, for those with a typical clinical
presentation, a kidney biopsy is not indicated prior to
initiating steroids. These patients have the best prognosis.
4. Does child have FRNS (frequently relapsing NS)? FRNS is
defined as $ 2 relapses within 6 months or $ 4 within any 12-
month period. At this point, the potential adverse effects of
cumulative steroid doses required to achieve remission
begin to exceed the presumed benefits of maintaining NS
remission. The possibility of medication nonadherence or
occult infection (dental infections or sinusitis) should be
considered. If performed, kidney biopsy nearly always shows
MCD. Steroid dose can be tapered to a “threshold dose,”
below which relapses occur and/or steroid sparing agent can
be introduced.
5. Does child have SDNS (steroid-dependent NS)? SDNS is
defined as 2 consecutive relapses during steroid therapy or
relapses within 14 days of its cessation. The potential adverse
effects of cumulative steroid doses required to maintain
remission exceeds presumed benefits of achieving NS
remission and here too threshold dosing or steroid sparing
agents are beneficial. Prognosis remains good for these
patients.
6. Does child have SRNS (steroid-resistant NS)? SRNS is
defined as a failure to achieve remission after 6-8 weeks of
full-dose daily prednisone. Biopsy is more likely to identify
histopathology other than MCD, and genetic testing is more
likely to identify a causative podocyte gene mutation.
Patients may or may not respond to immunosuppression,
and refractory disease carries the worst prognosis.
Abbreviations: MCD, minimal change disease; NS, nephrotic syn-
drome.
patients.32 The majority (.60%) of genetic FSGS cases
may be attributed to pathogenic variants in 3 genes:
WT1, NPHS1, and NPHS2.32,33
Proliferative Glomerulonephritis and Crescents
Crescents, defined as a glomerular extracapillary prolifer-
ation greater than or equal to 2 cell layers in thickness
(Fig. 1D), are commonly associated with rapidly progres-
sive GN. Crescents are formed following rupture of the
glomerular capillary loops with subsequent inflammation,
fibrinoid necrosis, and cellular proliferation. Crescents
may be observed in a variety of disorders including lupus,
IgA nephropathy, pauci-immune GN, and anti-GBM dis-
ease. Distinguishing these from one another relies heavily
on immunofluorescence findings, most notably with linear
(as opposed to granular) glomerular capillary loop
staining for IgG in anti-GBM disease. Pauci-immune GN,
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 Glomerular Diseases 367

Table 3. Classification of Glomerulonephritis in Children Table 4. Classification of Proteinuric Kidney Diseases in Children
Congenital Diseases Cytomegalovirus, Human Category Disease Category Etiology
Immunodeficiency Virus,
Syphilis, Toxoplasmosis Primary Idiopathic MCD, FSGS, MN
Monogenic diseases Thin basement membrane Inherited Podocytopathies, CNS
nephropathy (COL4A3, Secondary Associated with T1DM, T2DM, MODY/
COL4A4)* diabetes HNF1 mutation
Alport syndrome, X-linked Neoplasia Leukemia, lymphoma,
(COL4A5) Kimura disease
Alport syndrome, autosomal Drugs Antibiotics (cefixime,
(COL4A3, COL4A4) norfloxacin,
Denys-Drash syndrome (WT1) rifampin), NSAIDs,
Frasier syndrome (WT1) lithium, interferon
Nail patella syndrome (LMX1B) Infections Herpes viruses (CMV,
Pierson syndrome (LAMB2) EBV, HHV7, VZV),
Schimke immuno-osseous HIV, influenza,
dysplasia (SMARCAL1) parvovirus B19
Primary acquired diseases Acute postinfectious Associated with Guillain-Barre,
glomerulonephritis autoimmune myasthenia gravis,
Membranoproliferative disorders sarcoidosis, thyroid
glomerulonephritis (MPGN) disease
C3 glomerulopathy (C3G)
Abbreviations: CMV, cytomegalovirus; CNS, congenital nephrotic
IgA nephropathy
syndrome; EBV, Epstein–Barr virus; FSGS, focal segmental glomer-
Anti–glomerular basement ulosclerosis; HNF1b, hepatocyte nuclear factor 1beta; HHV7, human
membrane (GBM) disease herpes virus 7; HIV, human immunodeficiency virus; MCD, minimal
Systemic diseases with GN Infectious glomerulopathies change disease; MN, membranous nephropathy; MODY, maturity
(acute or chronic) onset diabetes of the young; NSAIDS, nonsteroidal anti-
Systemic lupus erythematosus inflammatory drugs; T1DM, type 1 diabetes mellitus; T2DM, type 2
Henoch Scho € nlein purpura diabetes mellitus; VZV, varicella zoster virus.
Antineutrophil cytoplasmic
antibody-associated pathway as well as serologic testing for complement
vasculitis (EGPA, GPA, MPA) factors and anticomplement autoantibodies.40 Patients
Goodpasture syndrome with immune complexes should be evaluated for infec-
tious and autoimmune disorders.
Abbreviations: EGPA, eosinophilic granulomatosis with polyangii-
tis; GN, glomerulonephritis; GPA, granulomatosis with polyangiitis;
MPA, microscopic polyangiitis. Thrombotic Microangiopathy
*Gene names: COL4A3 ¼ procollagen IV alpha 3, Glomerular and arteriolar fibrin thrombi appear as eosino-
COL4A4 ¼ procollagen IV alpha 4, COL4A5 ¼ procollagen IV alpha philic granular material distending glomerular capillary
5, LAMB2 ¼ Laminin beta 2, SMARCAL1 ¼ SWI/SNF-related, loops and lodged within arterioles, particularly at the
matrix-associated, actin-dependent regulator of chromatin like 1,
WT1 ¼ Wilm’s tumor 1. vascular pole of the glomeruli (Fig. 1F). Other findings
observed in acute TMA include glomerular mesangiolysis
and arteriolar mucoid intimal edema. Fragmented red
with little to no immunostaining, is associated with circu- blood cells may be seen both within glomeruli and in
lating antineutrophil cytoplasmic antibodies (ANCA) and vascular walls. Chronic TMA will show features similar to
encompasses the clinical entities of granulomatosis with membranoproliferative glomerulonephritis with duplica-
polyangiitis, eosinophilic granulomatosis with polyangii- tion of the glomerular capillary loops. Patients presenting
tis, and microscopic polyangiitis.9 with TMA in the absence of Shiga toxin-producing infection
Membranoproliferative glomerulonephritis shows should be strongly considered for further genetic evaluation
lobular accentuation, endocapillary proliferation and to evaluate for abnormalities within the alternative comple-
duplication of the glomerular capillary loops (Fig. 1E). ment pathway (Table 5). While studies of carefully curated
Patients may present with GN, NS, or asymptomatic atypical HUS populations have identified pathogenic vari-
hematuria and proteinuria. Patients presenting with GN ants in 43-61% of patients,41-43 the diagnostic yield in
are more likely to harbor proliferative lesions on the bi- routine clinical practice, applying the American College of
opsy.39 Historically classified as types I, II, and III, recent Medical Genetics and Genomics/American Molecular
studies provide evidence for a pathophysiologic classifica- Pathology Association guidelines for variant classification,
tion as either immune complex or complement-mediated identified likely pathogenic variants in 12% of cases.
disease39 These are distinguished from one another based When CFHR3-CFHR1 deletions are included, the overall
on the immunofluorescence findings. Both entities will yield increases to 25%.44
show electron dense deposits. It is important to exclude
an infectious etiology in cases with isolated C3 deposits APPROACH TO THERAPY
where prognosis differs substantially.40 A diagnosis of Rapidly progressive GN is an emergency that needs ur-
C3GN warrants further investigation into genetic etiol- gent histological diagnosis. Most of these patients have
ogies involving variants in the alternative complement aggressive diseases that are successfully treated only

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368 Wenderfer and Gaut
Table 5. Classification of Atypical Hemolytic-Uremic Syndrome
Category Examples
Infection induced Hemophilus influenza,
Streptococcus pneumonia
Non–Shiga toxin-producing
diarrheal illnesses
(Campylobacter,
Clostriduim difficile)
Viruses (CMV, Coxsackie,
Dengue, EBV, HBV, HCV,
HHV6, HIV, influenza,
norovirus, parvovirus, VZV)
Plasmodium falciparum
Inherited complement loss- CFH (24-27%), CFH-related
of-function mutations genes (3-10%), CFI (4-8%),
CD46 (MCP) (5-9%),
thrombomodulin (5%)
Inherited complement gain- Complement component C3
of-function mutations (2-8%), CFB (1-4%)
Other inherited disorders DGKE mutation (,1%)
Autoimmune disorders SLE, anti-ADAMTS13, CFH,
CFI, cardiolipin antibodies
Drug induced Antimicrobials (ciprofloxacin,
interferons, valacyclovir),
anti-VEGF antibodies,
calcineurin inhibitors (CsA,
TAC), chemotherapy
(bleomycin, cisplatin,
gemcitabine, mitomycin),
drugs of abuse (cocaine,
ecstasy, heroin)
Other Stem cell transplant-
associated (TA-TMA)
Cobalamin (B12) deficiency
Malignant hypertension
Radiation nephropathy
Pregnancy/postpartum AKI
Disseminated carcinoma
Abbreviations: AKI, acute kidney injury; CFH, complement factor H,
CFI, complement factor I; CMV, cytomegalovirus; CsA, cyclosporine
A; DGKE, diacylglycerol kinase epsilon; EBV, Epstein–Barr virus;
HBV, hepatitis B virus; HCV, hepatitis C virus; HHV6, human Herpes
virus 6; HIV, human immunodeficiency virus; SLE, systemic lupus
erythematosus; TA, transplant associated; TAC, tacrolimus; TMA,
thrombotic microangiopathy; VEGF, vascular endothelial growth
factor; VZV, varicella zoster virus.
with immunosuppressive therapy initiated early and in
high doses. In patients with anti-GBM nephritis or severe
vasculitis, early plasmapheresis may be lifesaving.
Although D1 HUS can cause severe multisystem organ
failure, the treatment remains conservative. However,
early intervention in the therapy of atypical HUS with
plasma infusions and/or anti-C5 antibody therapy is also
critical.45
There are many excellent reviews on the approach to immu-
nosuppression of different glomerular diseases.8-14,25,46
Evidence-based guidelines exist for guiding therapy, although
pediatric-specific guidelines are less common. Care should be
taken to identify and begin to treat comorbid infections. Most
infection-associated glomerular diseases will resolve without
immunosuppressive therapy. Chronic indolent infections
like tuberculosis, human immunodeficiency virus, or chronic
sinusitis can be exacerbated by immunosuppression if not
adequately addressed. Hepatitis C virus is a very rare cause
of glomerular diseases in the pediatric age group, and with
proper vaccination, the incidence of hepatitis B virus–associ-
ated glomerular diseases is decreasing dramatically.47 Based
on available evidence, with the exception of Alport
syndrome, identification of a genetic diagnosis should not pre-
clude a trial of immunosuppression in idiopathic glomerular
diseases.31
There is limited evidence supporting the use of antipro-
teinuric therapies in immune-mediated kidney diseases.48
However, there is strong evidence supporting inhibition of
the renin, angiotensin, and aldosterone system (RAAS) in
diabetic kidney diseases and in patients with CKD.49
Therefore, the use of these agents in children with chronic
glomerular diseases is common, especially in patients who
are refractory to other therapies. When treating hyperten-
sion, unless contraindicated, the use of RAAS inhibitors
should be considered first line for their added potential
antiproteinuric effect. It remains unclear in nonhyperten-
sive patients with proteinuria whether RAAS inhibitors
should be started at onset of disease or reserved for use
for persistent proteinuria nonresponsive to immunosup-
pression.
Management of edema in NS depends upon whether the
patient has increased kidney sodium reabsorption (the
“underfill” scenario) or sodium retention (the “overfill”
scenario). The latter patient often appears with hyperten-
sion in the absence of oliguria and will respond to diuretics
alone. However, “underfill” patients tend to be oliguric,
hyponatremic, and intravascularly depleted, despite total
body fluid overload. Diuretics alone will exacerbate these
patients’ kidney hypoperfusion and may lead to AKI.
Intravenous albumin-assisted diuresis will better liberate
edema fluid in “underfill” patients and can improve the
hyponatremia, oliguria, and pre-kidney azotemia. In
some “overfill” patients, albumin infusions only exacer-
bate total body sodium overload and hypertension
without measurable benefit toward diuresis. Most pediat-
ric patients with idiopathic NS present with the “underfill”
scenario, although the “overfill” scenario can occur in
older adolescents.
MONITORING DISEASE ACTIVITY
There is a tremendous need to define disease activity in
glomerular diseases. Rheumatologists have long debated
how to apply specific algorithms for distinguishing be-
tween disease activity and parenchymal damage in sys-
temic lupus erythematosus (SLE)50 and vasculitis.51
Scarring of the kidney will not respond to additional
immunosuppression. In the absence of repeat kidney
biopsy, it is often challenging to determine the degree of
disease activity in proteinuric kidney diseases. Similarly,
microscopic hematuria can persist long after kidney
inflammation has subsided.
The discovery of disease activity biomarkers may even-
tually aid in addressing this clinical need.8 Diagnostic
biomarkers would be selected to determine the presence
or absence of disease regardless of high or low disease
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 Glomerular Diseases 369

Figure 1. A, Normal appearing glomerulus (PAS, 6003). B, Mesangial hypercellularity (H&E, 4003). C, Segmental glomerulo-
sclerosis of no special type (H&E, 6003). D, Necrotizing cellular crescent with glomerular capillary loop rupture (Jones’ silver,
4003). E, Endocapillary proliferation (PAS, 4003). F, Glomerular microthrombi (H&E, 4003). Abbreviations: H&E, hematox-
ylin and eosin; PAS, periodic acid-Schiff.

activity.52 Diagnostic biomarkers should be highly sensi-
tive and specific for a specific disease, as measured by a
high area under the curve by receiver operating curve
analysis. Prognostic biomarkers would be selected for abil-
ity to predict disease course or response to therapy, regard-
less of specificity for a specific disease.53 In contrast,
disease activity biomarkers by definition should change
over time in individual patients. These biomarkers would
be worthless for screening asymptomatic patients for a
specific glomerular disease. However, after the diagnosis
of glomerular disease is established, they would be funda-
mental for monitoring response to therapy and/or risk of
relapse.
The APOL1 risk allele has been identified as both a valid
prognostic biomarker for kidney disease in human immu-
nodeficiency virus–infected patients and for ESRD in
patients with primary FSGS.12 For lupus nephritis, antinu-
clear antibody titer is a reasonable diagnostic biomarker
due to its high sensitivity, but its utility is limited due to
a low specificity. In contrast, anti–double-stranded DNA
antibodies are highly specific for SLE but limited by a
low sensitivity.52 However, anti–double-stranded DNA
antibody titers vary over time and do correlate with lupus
nephritis disease activity. Along with serum levels of com-
plement components C3 and C4, the titer of double-
stranded DNA antibodies and the erythrocyte sedimenta-
tion rate represent the best clinically available serologies
for monitoring nephritis in SLE.8 Antimyeloperoxidase
and antiproteinase 3 antibody titers have modest utility
for diagnosis or disease activity monitoring in kidney
vasculitis.9 Putative biomarkers anti-PLA2R antibodies
(for membranous)13 and antihypogalactosylated IgA1 an-
tibodies (for IgA nephropathy)25 await further study in pe-
diatric cohorts. No putative age-specific biomarkers have
yet been identified for childhood-onset GN.
MONITORING KIDNEY DAMAGE
The goal of treating children with glomerular disease is to
preserve kidney function and prevent CKD. In the acute
setting, determining the presence of a definitive cure is
the priority. For chronic glomerular diseases, however,
the objective shifts to disease management. For most

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370 Wenderfer and Gaut
chronic diseases, the ability to achieve remission is para-
mount to optimizing long-term outcomes. In the absence
of complete remission, however, there is also usually prog-
nostic implications for achieving some degree of partial
remission. Similarly, distinguishing between nonrespon-
sive disease and progressive disease is crucial. This
“treat-to-target” approach allows for maximizing treat-
ment efficacy while minimizing adverse effects.54 Deci-
sions to escalate or wean therapy should also depend
upon patient-reported outcomes.55
Defining what constitutes a partial or complete
response to therapy in glomerular diseases has not been
easy. Even in cases where definitions have been devel-
oped based on high-quality evidence, the evidence tends
to come from studies of primarily adult-onset disease pa-
tients. In some cases, children were even excluded from
the clinical trials used to define outcome measures. There-
fore, it is imperative that pediatric physician scientists
first determine whether pediatric outcome definitions
are required.
In lupus nephritis and vasculitis, disease damage scales
have been developed in an attempt to distinguish irrevers-
ible scarring from treatable disease activity. However, the
SLE International Clinical Consortium/American College
of Rheumatology damage index50 and the vasculitis dam-
age index56 are complicated algorithms required for clin-
ical trials and not suited for routine clinical use.
Ultimately, clinicians will need to find surrogate damage
biomarkers to predict scarring in their patients with
glomerular disease. On kidney biopsy, IFTA scoring and
numeration of fibrous crescents or global glomerulosclero-
sis are all useful but require repeat percutaneous biopsy.
Decline in estimated or measured GFR has many limita-
tions. Ongoing research by prospective observational
cohort studies will be important for the collection of bio-
samples paired with disease outcomes.57 NEPTUNE, the
Nephrotic Syndrome Study Network, a North American
multicenter collaborative, is one such study enrolling
children and adults with MCD, FSGS, and membranous
glomerulopathy.58 CureGN, the Cure Glomerulonephrop-
athy Network, is another, with plans for enrollment of
2400 children and adults within 5 years of first diagnostic
kidney biopsy (www.CureGN.org). CARRA, the Child-
hood Arthritis and Rheumatology Research Alliance, is
prospectively enrolling North American children with
SLE with and without nephritis in their registry (https://
carragroup.org/research). These studies and others will
be instrumental for identification and validation of dam-
age biomarkers in childhood-onset GN.
CONCLUSIONS
Now, it is an exciting time to be caring for children with
glomerular disease. Advances in genetics and systems
biology have led to the reclassification of disease based
on pathogenesis and molecular disease mechanisms.
Comparative effectiveness research and novel clinical trial
designs are allowing for better study of rare diseases.
Collaborative networks have now developed the needed
infrastructure to study kidney diseases in children.
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