Documentos de Académico
Documentos de Profesional
Documentos de Cultura
S y n d ro m e in th e N e w b o r n
Michelle N. Rheault, MD
KEYWORDS
Proteinuria Hematuria Congenital nephrotic syndrome
Diffuse mesangial sclerosis Nephritis Hemolytic uremic syndrome
Neonatal lupus
KEY POINTS
Congenital nephrotic syndrome (CNS) presents within the first 3 months of life with
massive proteinuria, hypoalbuminemia, and edema.
Elevated maternal serum a-fetoprotein, enlarged placenta (>25% of birth weight), and
prematurity are suggestive of CNS.
CNS is most often caused by single gene mutations affecting kidney podocyte structural
or signaling proteins.
Infants with CNS are at risk for infection and thromboembolism, which may be the initial
clinical manifestation.
Nephritic syndrome in the newborn is rare, and presenting features may include hematuria,
proteinuria, hypertension, acute kidney injury, oliguria, and edema.
INTRODUCTION
Glomerular disorders in infancy are rare, and can include both nephrotic and nephritic
syndromes. These syndromes can be idiopathic, or due to primary genetic disorders,
congenital infections, or maternal antibody transfer. Regardless of etiology, dysfunc-
tion of the glomerular filtration barrier is evident in these conditions. The kidney glomer-
ular filtration barrier is a size-selective and charge-selective filter that prevents the
passage of red blood cells and plasma proteins into the urine while allowing the
passage of water and small solutes. It is composed of 3 layers: an endothelium, a
glomerular basement membrane (GBM), and epithelial cells, also known as podocytes.
Podocytes are highly differentiated cells that have a complex cellular architecture con-
sisting of a cell body, major processes, and foot processes. Adjacent foot processes
are connected by a slit diaphragm, which comprises the main size-selective filtration
Disclosure: None.
Division of Pediatric Nephrology, University of Minnesota Childrens Hospital, 2450 Riverside
Avenue, MB680, Minneapolis, MN 55454, USA
E-mail address: rheau002@umn.edu
barrier in the kidney (Fig. 1).13 Dysfunction in any of the 3 components of the glomer-
ular filtration barrier can lead to loss of red blood cells and plasma proteins in the urine,
and clinical nephrotic or nephritic syndromes. The presence of these syndromes in the
neonate can cause significant morbidity and mortality; therefore, urgent diagnosis and
treatment are necessary.
Nephrotic syndrome (NS) is defined as massive leakage of plasma proteins into the
urine caused by dysfunction of the glomerular filtration barrier, leading to hypoalbumi-
nemia and edema. NS can be further classified by age at presentation as congenital
NS (CNS, age at presentation <3 months), infantile NS (age at presentation 3
12 months), or childhood NS (age at presentation >1 year). As the genetics of NS
have started to be unraveled over the past 15 years, it has become clear that different
mutations in the same gene can manifest at various ages, making the classification by
age somewhat arbitrary (NPHS1- and NPHS2-related disease can present in infancy,
childhood, or rarely in adulthood, for example).4,5 Nonetheless, the designation of
congenital nephrotic syndrome still guides diagnosis, management, and prognosis,
and this terminology has been retained by the pediatric nephrology community.
Prenatal diagnosis of CNS is suggested by elevated maternal serum a-fetoprotein
(MSAFP) obtained in routine second-trimester screening. Fetal serum contains high
concentrations of a-fetoprotein (AFP) that is lost into the urine/amniotic fluid during
the nephrotic state. Elevated MSAFP is common and is found in approximately 1%
of all pregnancies using a cutoff of greater than 2.5 multiples of the mean (MoM).
Elevated MSAFP can be seen in pregnancies complicated by neural tube defects,
gastroschisis, or chromosomal abnormalities as well as CNS.6,7 CNS is a rare cause
of elevated MSAFP, with one retrospective study identifying only 5 infants with CNS
among 658 women with elevated MSAFP (<1%).7 Most patients with pregnancies
affected by CNS have persistently elevated MSAFP on follow up screens in addition
to elevated AFP in amniotic fluid obtained by amniocentesis.7 Median MSAFP concen-
trations were 8.3 MoM in pregnancies affected with CNS attributable to NPHS1
Fig. 1. The glomerular filtration barrier. Cross section of a glomerular capillary (left) and elec-
tron microscopy image of a normal capillary wall (right). WT1 is a transcription factor important
for podocyte function. Nephrin is a major component of the slit diaphragm (SD) connecting
podocyte foot processes. Podocin is an adapter protein located intracellularly in the SD area.
Laminin is a major structural protein of the glomerular basement membrane (GBM). Genetic
mutations in these proteins lead to congenital nephrotic syndrome. (From Jalanko H. Con-
genital nephrotic syndrome. Pediatr Nephrol 2009; 24(11):21218.)
Nephrotic and Nephritic Syndrome in Newborns 3
mutations while median AFP concentrations in amniotic fluid were even higher, at 33.4
MoM.8 Of importance, heterozygous carriers of NPHS1 mutations also demonstrate
elevated MSAFP and amniotic fluid AFP levels that overlap with values in homozygous
affected infants.8 This situation is hypothesized to be due to temporary dysfunction in
the glomerular filtration barrier during glomerulogenesis in NPHS1 heterozygotes that
improves with time.9 Thus, elevated MSAFP cannot be used to distinguish CNS car-
riers from affected infants.
A universal finding in children with CNS is elevated urine protein excretion. Normal
urine protein excretion varies by age, with the highest values in preterm infants and
decreasing values throughout childhood. In one study, healthy premature infants in
the first month of life demonstrated urine protein concentration of 88 to 845 mg/L
(mean 182 mg/m2/d) in a 24-hour urine collection, whereas term infants excreted
slightly less, between 95 and 455 mg/L (mean 145 mg/m2/d).10 By contrast, children
aged 10 to 16 years excreted between 45 and 391 mg/L (mean 63 mg/m2/d). Urine
protein-to-creatinine ratios have also been used to estimate protein excretion, owing
to the technical difficulties in obtaining a 24-hour urine collection in a neonate. For chil-
dren younger than 2 years, a normal urine protein-to-creatinine ratio is less than
0.5 mg/mg, but normal values in neonates have not been well described.11
Urine protein excretion in children with CNS is generally massive, and greater than
2000 mg/L in most affected infants.12,13 Urine protein loss leads to low serum albumin
levels less than 2.5 g/dL, with presenting values often less than 1.5 g/dL. In infants with
extremely low serum albumin levels, the magnitude of proteinuria may not be apparent
until serum albumin levels are restored with albumin infusions. Hematuria and leukocy-
turia are often present as well.12 In addition to albumin, several other proteins are lost in
the urine, including immunoglobulins, transferrin, antithrombin III, ceruloplasmin,
vitamin Dbinding protein, and thyroid-binding protein.14 Hypoalbuminemia and the
resultant decreased plasma oncotic pressure leads to leakage of fluid from the intra-
vascular to the interstitial space, causing hypovolemia, renal hypoperfusion, and sec-
ondary renal sodium and fluid retention with clinical edema.15 Massive edema (ie,
anasarca) can lead to serious complications, including respiratory distress from pulmo-
nary edema and/or pleural effusions in addition to severe ascites and scrotal edema.
The differential diagnosis of CNS is broad, and includes several primary genetic dis-
orders and congenital infections (Table 1). Most children with CNS have a monogenic
cause for their disease with mutations in proteins that regulate the glomerular filtration
barrier, particularly proteins important in formation of and signaling from the podocyte
slit diaphragm. Two large studies have demonstrated that more than 80% of infants
with CNS have a mutation identified in 1 of 5 genes: NPHS1 (39%61%), NPHS2
(15%39%), LAMB2 (2%4%), WT1 (w2%), or PLCE1 (w2%).16,17
CNS of the Finnish Type (CNF) is the most common cause of CNS and is named
because of its high incidence in Finland of 1:8200 live births, owing to the effect of
founder mutations.18 There is also a very high concentration of disease among Old
Order Mennonites in Lancaster County, Pennsylvania, with an incidence of 1 in 500
live births.19 CNF is inherited in an autosomal recessive manner and is caused by
mutations in nephrin (NPHS1), the major structural component of the glomerular slit
diaphragm (see Fig. 1).20 Absence of the slit diaphragm and its size-selective barrier
properties leads to massive loss of plasma proteins into the urine that begins in utero.
Infants with CNF do not have associated major extrarenal findings, as NPHS1 is
expressed almost exclusively in the kidney podocyte.21
4 Rheault
Table 1
Causes of congenital nephrotic syndrome
Abbreviations: DMS, diffuse mesangial sclerosis; GBM, glomerular basement membrane; GDP, gua-
nosine diphosphate; HIV, human immunodeficiency virus; NS, nephrotic syndrome; SLE, systemic
lupus erythematosus.
Nephrotic and Nephritic Syndrome in Newborns 5
The diagnosis of CNF can often be made on a clinical basis (Table 2). More than
80% of infants with CNF are born prematurely, and most are appropriate for gesta-
tional age.12 The placenta is typically larger than normal, weighing more than 25%
of the infants birth weight. Approximately 80% of affected infants present with edema
and NS within the first week of life, with the remainder presenting within 3 months.12
The initial urinalysis demonstrates proteinuria, hematuria, and leukocyturia with a
negative urine culture.12 Severe hypoalbuminemia is present with the serum albumin
concentration generally less than 1.5 mg/dL. Renal function is initially normal, with
decline in kidney function observed over several years. Over the first several months
of life, hypothyroidism develops from loss of thyroid-binding globulin in the urine, and
responds to thyroxine therapy.22 In the first 2 months of life, kidneys are enlarged (12
standard deviations above the mean) and hyperechoic on ultrasonography with
preserved corticomedullary differentiation.23 By 12 months of age, corticomedullary
differentiation is lost and kidneys remain hyperechoic.
Kidney biopsy in CNF is rarely necessary for diagnosis. When performed, light
microscopy demonstrates a mild increase in mesangial matrix and increased mesan-
gial hypercellularity at early stages, with glomerular sclerosis and interstitial fibrosis
evident with advancing age.24 Microcystic dilatation of proximal and distal tubules
can be observed.12 On electron microscopy there is retraction and broadening of
podocyte foot processes, classically described as effacement. In infants with severe
NPHS1 mutations, slit diaphragms may be completely absent.12
Diagnosis of CNF can be confirmed by detection of mutations in NPHS1. Genetic
testing is commercially available. More than 100 mutations in NPHS1 have been iden-
tified in affected patients. Mutations have been found throughout all 29 exons.25,26 In
Finland, greater than 90% of affected individuals have 1 of 2 mutations (nt121delCT or
R1109X) that lead to premature stop codons and the absence of detectable protein at
the slit diaphragm.12
Table 2
Diagnosis of congenital nephrotic syndrome of the Finnish type (NPHS1)
Abbreviations: MoM, multiples of the median; MSAFP, maternal serum a-fetoprotein; SD, standard
deviation.
6 Rheault
WT1 encodes a zinc-finger transcription factor involved in kidney and gonadal devel-
opment. The WT1 protein is highly expressed in podocytes, and controls the expres-
sion of slit diaphragm proteins such as nephrin as well as several growth factors and
transcription factors (see Fig. 1).29 Heterozygous mutations in WT1 can cause either
isolated diffuse mesangial sclerosis (DMS) or Denys-Drash syndrome. DMS is a
distinct pathologic appearance of the kidney with diffuse increase in mesangial matrix
with no mesangial cellular proliferation by light microscopy, with eventual contraction
and obliteration of the glomerular tuft. Denys-Drash syndrome is characterized by
early onset of NS, male pseudohermaphroditism, DMS on renal biopsy, rapid progres-
sion to end-stage kidney disease, and Wilms tumor, although incomplete forms of the
syndrome have been described (Box 1).30 NS typically begins at a few months of age,
but Wilms tumor may be the first manifestation of the disease.31 Genotypic male
patients (46XY) display either ambiguous genitalia or female phenotype. Genotypic
female patients (46XX) have normal female genitalia and normal puberty. WT1 muta-
tions are also found in older children causing Frasier syndrome, WAGR syndrome, or
isolated NS.30,32
Children with WT1 mutations require close ultrasonographic surveillance for devel-
opment of Wilms tumor. Removal of native kidneys should be performed to prevent
the development of Wilms tumor. Phenotypic females with DMS should have karyo-
types performed.
Pierson syndrome was originally described as CNS with DMS on renal biopsy and
complex ocular anomalies.33,34 The most common ocular finding is microcoria, but
abnormalities of the lens, cornea, and retina have also been reported.35 Pierson syn-
drome is caused by mutations in LAMB2 encoding laminin-b2, a component of the
Box 1
Diagnosis of Denys-Drash syndrome
Congenital nephrotic syndrome (CNS) with diffuse mesangial sclerosis on kidney biopsy
Male pseudohermaphroditism or ambiguous genitalia
Wilms tumor
Nephrotic and Nephritic Syndrome in Newborns 7
GBM responsible for cell adhesion (see Fig. 1). Laminin-b2 is also expressed in the
nervous system, leading to neurologic deficits in affected children.36
Several congenital infections have been reported to cause CNS, particularly in devel-
oping countries.50 The observed proteinuria and hypoalbuminemia is generally less
severe than in genetic forms of CNS. Congenital syphilis may manifest in the
newborn, but most often presents between 1 and 4 months of age. Early treatment
with penicillin can be curative.51 Renal pathology commonly demonstrates a mem-
branous nephropathy. Cytomegalovirus (CMV)-associated CNS has also been
described, and responds to treatment with gancyclovir.52,53 Renal pathology in
CMV-associated CNS usually shows DMS. Rare infants with CNS associated with
congenital rubella and toxoplasmosis have also been described.54,55 NS arising
from infections with hepatitis B or human immunodeficiency virus have been reported
in older children but not infants; nevertheless, this remains a diagnostic consideration
in this population.56,57
All infants diagnosed with CNS should undergo a thorough family and birth history
(Table 3). In addition, a complete physical examination including formal eye examina-
tion should be performed to uncover any associated syndromes. Renal ultrasonogra-
phy should be performed to exclude other congenital anomalies of the kidney and
urinary tract. Confirmation of NS is made through urine and blood testing. Screening
examinations for congenital infections should be performed by either TORCH titer or
polymerase chain reaction if available. Finally, genetic testing should be performed as
indicated.
Other than 2 children reported in the literature with PLCE1 mutations, immunosup-
pressive medications are not useful in the treatment of CNS. Treatment is generally
8 Rheault
Table 3
Evaluation of an infant with suspected congenital nephrotic syndrome
Abbreviations: BUN, blood urea nitrogen; MSAFP, maternal serum a-fetoprotein; OFC, occipital-
frontal circumference; PCR, polymerase chain reaction; SLE, systemic lupus erythematosus.
supportive, with the ultimate goal of kidney transplantation. Intravenous albumin infu-
sions with loop diuretics are required on a chronic basis to manage edema, and may
require placement of an indwelling catheter. Infants with CNS require close moni-
toring of growth and need a hypercaloric diet (w130 kcal/kg/d) with added protein
(w4 g/kg/d). Nasogastric or gastrostomy tubes are often required to ensure adequate
nutrition. Some infants will demonstrate an improvement in proteinuria with treatment
with captopril or indomethacin, but infants with severe nephrin (NPHS1) mutations
often do not respond.58 Bilateral nephrectomies are performed when children are
nearing end-stage kidney disease or if the NS cannot be managed by medical means.
Kidney transplantation often takes place between 1 and 3 years of age.
Children with NS are at risk for infection, owing to losses of components of the alter-
native complement pathway into their urine.59 This process results in increased
susceptibility to infection with encapsulated organisms such as Streptococcus pneu-
moniae, Haemophilus influenzae, and Escherichia coli. Common infections include
pneumonia, cellulitis, peritonitis, urinary tract infection, and sepsis.60 A high degree
of suspicion for infection is warranted in infants with CNS and fever, and broad-
spectrum antibiotics should be initiated pending culture results. Prophylactic anti-
biotics or intravenous immunoglobulin infusions do not seem to influence the
incidence of infection in this population, and are not recommended.61
Thromboembolism is a potentially serious complication of NS, and may be the pre-
senting sign. The most common types of thrombosis include deep vein thrombosis,
pulmonary embolism, renal vein thrombosis, and central sinus thrombosis.62
Nephrotic and Nephritic Syndrome in Newborns 9
Nephrotic infants are at risk for thromboembolism for several reasons. First, there is
urinary loss of factors that inhibit clot formation, such as antithrombin III. Second,
there is increased production of procoagulant factors by the liver. Intravascular vol-
ume depletion attributable to NS itself or diuretic therapy can also increase the risk
of thromboembolism. Some centers treat all infants with CNS prophylactically with
warfarin to prevent thrombosis, particularly if there is an indwelling catheter.63
Nephritic syndrome in the newborn is rare and presents with hematuria, proteinuria,
hypertension, acute kidney injury, oliguria, and edema (Box 2). Causes may overlap
with those of congenital NS and include primary glomerulonephritis in addition to
systemic disease, infections, and passive transplacental transfer of certain maternal
antibodies (Table 4).
Box 2
Diagnosis of nephritic syndrome in the neonate
Hematuria
Proteinuria
Acute kidney injury
Oliguria
Hypertension
Edema
10 Rheault
Table 4
Causes of nephritic syndrome in the neonate
LUPUS NEPHRITIS
Infants with nephritic syndromes should have an evaluation similar to that for infants
with CNS (see Table 3). Maternal and family history of lupus should be explored. In
addition, a complete blood count should be performed to evaluate for anemia or
thrombocytopenia. Hypocomplementemia and elevated double-stranded DNA anti-
bodies may suggest primary lupus. Kidney biopsy may be required to make a defini-
tive diagnosis.
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