1

CHAPTER I
INTRODUCTION
1.1

Background
Congenital nephrotic syndrome (CNS) is a rare kidney disorder
characterized by heavy proteinuria, hypoalbuminemia, and edema starting
soon after birth. The majority of cases are caused by genetic defects in the
components of the glomerular filtration barrier, especially nephrin and
podocin. CNS may also be a part of a more generalized syndrome or
caused by a perinatal infection. Immunosuppressive medication is not
helpful in the genetic forms of CNS, and kidney transplantation is the only
curative therapy. Before the operation, management of these infants
largely depends on the magnitude of proteinuria. In severe cases, daily
albumin infusions are required to prevent life-threatening edema. The
therapy also includes hypercaloric diet, thyroxin and mineral substitution,
prevention of thrombotic episodes, and prompt management of infectious
complications. The outcome of CNS patients without major extrarenal
manifestations is comparable with other patient groups after kidney
transplantation.

1.2

Objective
The aim of this study is to explore more about the theoretical on
Congenital Nephrotic Syndrome. It is also to integrate the theory and
application of pediatric management in children with Congenital
Nephrotic Syndrome.

CHAPTER II
LITERATURE REVIEW
2.1

Definition
The nephrotic syndrome (NS) is characterised by a triad of massive

proteinuria (>40mg/m per hour or 50mg/kg per day), hypoalbuminemia

(2.5mg/dL), and hyperlipidemia (serum cholesterol >200mg/dL or 6.5mmol/L).
Other supporting characteristics may include the presence of edema and a raised
2 globulin on serum electrophoresis, although these are not essential for the
diagnosis. In physicians managing young children in whom 24 hour urine
collections are difficult, the Children's Nephrotic Syndrome Study Group
Consensus Conference recommended the use of the protein: creatinine ratio on a
spot early morning sample of urine with a urine protein: creatinine (Up/Ucr) ratio
2.0.
NS may be classified according to etiology (primary or secondary), age of
onset (congenital, infantile, acquired or late onset NS), or histopathology (e.g.
minimal

change

disease,

mesangial

hypercellularity,

focal

segmental

glomerulosclerosis [FSGS], membranous, membranoproliferative). However the

most useful classification for management purposes is to define the disease
according to its response to steroids (steroid sensitive or resistant with steroid
sensitive disease being further classified into frequent relapses and steroid
dependent NS) as patients who are steroid sensitive have an excellent prognosis
with preservation of kidney function whilst those that are steroid resistant are
more prone to complications with a high risk of having deterioration of kidney
function and progression to end-stage kidney disease needing renal replacement
therapy. More recently single gene mutations affecting podocyte differentiation
and function have been described in steroid resistant disease, predicting
unresponsiveness to immunosuppressive therapy.
Congenital nephrotic syndrome (CNS) is a rare form of NS that presents at
birth or within the first three months of life. NS presenting after three months up

to one year of age is called infantile NS. The precise diagnosis of the glomerular
lesion is based on clinical, laboratory and histological criteria.
2.2.

Epidemiology
Nephrotic syndrome can affect any age, although it is mainly found in

adults with a ratio of adults to children of 26 to 1. The syndrome presents in

different ways in the two groups, the most frequent glomerulopathy in children is
minimal change disease (66% of cases), followed by focal and segmental
glomerulosclerosis (8%) and mesangiocapillary glomerulonephritis (6%). In
adults the most common disease is mesangiocapillary glomerulonephritis (3040%), followed by focal and segmental glomeruloesclerosis (15-25%) and
minimal change disease (20%). The latter usually presents as secondary and not
primary as occurs in children. Its main cause is diabetic nephropathy. It is usually
present in a patients in their 40s or 50s. From the glomerulonephritis cases
approximately 60% to 80% are primary, while the remainder are secondary.
There are also differences in epidemiology between the sex, the disease is
more common in men than in women by a ratio of 2 to 1. The epidemiological
data also reveals information regarding the most common way that symptoms
develop in patients with nephrotic syndrome, spontaneous remission occurs in up
to 20% or 30% of cases during the first year of the illness. However, this
improvement is not definitive as some 50% to 60% of patients die and/or develop
chronic renal failure 6-14 years after this remission. On the other hand, between
10% and 20% of patients have continuous episodes of remissions and relapses
without dying or jeopardizing their kidney. The main causes of death are
cardiovascular, as a result of the chronicity of the syndrome, and thromboembolic
accidents.

2.3

Etiology

Nephrotic syndrome is clinically divided into 2 groups, namely:

1.

Primary

Nephrotic

Syndrome

(Idiopathic)

It is said that primary nephrotic syndrome is primarily caused by

abnormalities in the glomerular itself without any other cause. This group is most
often found in children. Congenital Nephrotic Syndrome is included in the
primary nephrotic syndrome, a type of nephrotic syndrome where it is usually
discovered

since

the

child

was

born

or

under

year

of

age.

Approximately 90% of children with nephrotic syndrome is an idiopathic

nephrotic syndrome. Idiopathic nephrotic syndrome consists of 3 histological
types: minimal change nephrotic syndrome, proliferative glomerulonephritis
(mesangial proliferation), and focal segmental glomerulosclerosis. All three of
these disorders can represent three distinct diseases with similar clinical
manifestations; in other words, all three of these disorders represent a spectrum of
a single disease.
Primary CNS :
Nephrin gene mutations

Podocin gene mutations (NPHS2)

WT1 gene mutations (Denys-Drash, isolated CNS)

LamB2 gene mutations (Pierson syndrome, isolated CNS)

PLCE1 gene mutations

LMX1B mutations (nail-patella syndrome)

Lam B3 gene mutations (Herlitz junctional epidemolysis bullosa,

mitochondrial myopathies)

CNS with or without brain and other malformations (no gene defect
identified as yet)

Pathology
Minimal Change Nephrotic Syndrome (MCSN) (85% of cases of nephrotic
syndrome in children), the glomeruli appear normal or show minimal increase in

mesangial cells and matrix. The discovery in immunofluorescence microscopy is

usually negative, and electron microscopy shows only the loss of epithelial cell
foot processes (Podocyte) in the glomerulus. More than 95% of children with
SNKM respond to corticosteroid therapy.
Proliferative Glomerulonephritis (Mesangial Proliferation) (5% of total cases
SN) is characterized by an increase in the diffuse mesangial cells and matrix on a
regular microscope examination. Immunofluoroscence microscope can show
traces 1+ mesangial IgM and / or IgA. Electron microscopy showed an increase of
mesangial cells and matrix followed by the disappearance of Podosit cells.
Approximately 50% of patients with this histological lesions respond to
corticosteroid therapy.
Focal Segmental Glomerulosclerosis (FSGS) (10% of cases SN) glomeruli
showed mesangial proliferation and scarring segmental examination with a regular
microscope.Immunofluorescence microscopy showed IgM and C3 in the area are
experiencing sclerosis.On examination with an electron microscope, visible
scarring segmental glomerular tuft is accompanied by damage to the glomerular
capillary lumen. Similar lesions can be seen also on HIC infection, vesicoureteral
reflux, and intravenous heroin abuse. Only 20% of patients with FSGS who
respond to prednisone therapy. The disease is usually progressive, ultimately
involving all glomeruli, leading to end-stage renal disease in most patients.
2. Secondary Nephrotic Syndrome:
It is arising as a result of a systemic disease or as a result of various causes
such as drugs side effects. Common causes are:

Metabolic or congenital diseases: diabetes mellitus, amyloidosis, Alport

syndrome, myxoedema

Infections: hepatitis B, malaria, schistosomiasis, leprosy, syphilis,

streptococcal, AIDS

Toxins and allergens: heavy metals (Hg), penisillamin, probenecid,

insect venom, snake venom

Systemic immunologic disease: systemic lupus erythematosus, HenochSchinlein, sarkoidosis

2.4

Neoplasma: lung tumors, Hodgkin's disease, gastrointestinal tumors

Pathophysiology

Genetic forms of Congenital Nephrotic syndrome

Nephrin gene (NPHS1) mutations: Nephrin gene codes for nephrin, a
1241-residue

trans-membrane

adhesion

protein

of

the

immunoglobulin

superfamily and is synthesized almost exclusively by glomerular podocytes. The

protein is a key component of the podocyte slit diaphragm. NPHS1 mutations
account for most (nearly 90%) patients responsible for the Finnish-type of
congenital NS. In Finland two founder mutations (Fin-major and Fin-minor) are
detected in almost all cases of CNS. Close to 100 mutations in the NPHS1 gene
have been identified and has been described in various ethnic groups throughout
the world. Since nephrin is specifically located at the slit diaphragm of the
glomerular podocytes, this could explain the absence of slit diaphragms and foot
processes in patients with NPHS1 mutations. Although NPHS1 mutations account
for the majority of Finnish type CNS, no abnormalities were found in seven
affected individuals from Europe and North America (including the five flanking
region). It is postulated that these patients may have mutations elsewhere in the
promoter or in the intron areas or in a gene encoding another protein that interacts
with nephrin. Also two siblings with a mild form of CNS of the Finnish type with
intermittent proteinuria were found to be compound heterozygotes for two novel
non-conserved misuse mutations.
Children with CNS due to NPHS1 mutations show little phenotype
variation. There is often a history of premature birth with a low birth weight for
gestational age. The placenta in almost all cases is over 25% of the newborn
weight. Fetal distress with meconium stained liquor is common but major
respiratory problems are rare. Extra-renal malformations include:

Widely separated cranial sutures due to delayed ossification

Small nose and low set ears

Flexion deformities of the hips, knees, and elbows secondary to the large
placenta

Minor functional disorders such as muscular hypertrophy and cardiac

hypertrophy
Proteinuria begins in utero and is detectable in the first urine sample at

birth. Heavy proteinuria (up to 100g/L) results in oliguria and severe edema if
not treated. Hematuria is uncommon but may develop in some cases. Severe
urinary protein losses are accompanied by severe hypogammaglobulinaemia.
As a result of this these patients have severe malnutrition, poor statural growth
and are highly susceptible to bacterial infections (peritonitis, respiration
infections, etc.). Hypothyroidism from loss of thyroxin binding protein in the
urine develops as the disease progresses. These patients are also prone to
thromboembolic complications due to the severity of the NS.
Laboratory findings of hypoalbuminaemia, hypogammaglobulinaemia,
and hyperlipidemia with massive proteinuria are typical. The blood urea and
serum creatinine are initially normal or low corrected for gestational age due
to the state of inanition. Sonography shows enlarged kidneys with increased
echogenicity and loss of cortico-medullary differentiation.
Podocin gene: Podocin gene (NPHS2) mutations are more common in
childhood steroid resistant NS [autosomal recessive focal segmental
glomerulosclerosis (FSGS)] but also found in some cases of CNS.
NPHS2 encodes an integral membrane protein called podocin that is found
exclusively in glomerular podocytes. Since podocin is a podocyte-adapter
protein required for proper targeting of nephrin in the slit diaphragms, nephrin
expression may also be distorted in CNS due to NPHS2 mutations.
A triallelic abnormality with NPHS1, and NPHS2 mutations (homozygotes
mutations in one gene and heterozygous mutations in the other) has also been
reported in some patients with CNS. (17,24,25) These findings demonstrate

the genetic heterogeneity of CNS and the absence of clear genotype/phenotype

correlations.

The

clinical

findings

in

patients

with

CNS

due

to NPHS2 mutations are more variable than those with NPHS1 mutations.
Some individuals have milder disease and only presents in adolescents or
young adulthood. Patients presenting with CNS develop end-stage kidney
disease after a few years.(23) These patients do not have major extra-renal
manifestations although minor cardiac abnormalities have been reported. (5)
The histopathological findings are usually that of FSGS.
Proteinuria
Proteinuria is a basic disorder of nephrotic syndrome. Proteinuria mostly
from leakage glomerular (glomerular proteinuria) and only a small portion is
derived from tubular secretion (tubular proteinuria). Changes in glomerular
basement membrane integrity causes increased glomerular permeability to plasma
proteins and the major protein excreted in the urine is albumin. Under normal
circumstances the glomerular basement membrane(GBM) has a barrier
mechanism to prevent leakage of protein. The first barrier mechanism based on
molecular size (size barrier) and the second based on electric charge (charge
barrier). In the second nephrotic syndrome barrier mechanism is disrupted.
Besides the configuration of protein molecules also determine whether or not the
protein passes through the GBM. Proteinuria can be divided into selective and
non-selective based on the molecular size of protein lost in the urine. Selective
proteinuria if the exit is composed of small molecules such as albumin. While
non-selective if the protein out consisting of large molecules such as
immunoglobulins. Proteinuria selectivity is determined by the structural integrity
GBM.
Hypoalbuminemia
Hypoalbuminemia caused by the loss of albumin in urine and increased
catabolism of albumin in the kidney. Protein synthesis in the liver is usually
elevated (but not sufficient to replace the loss of albumin in the urine), but may be
normal or decreased.

Edema
Edema in nephrotic syndrome can be explained by the theory of underfill
and overfill. Underfill theory explains that hypoalbuminemia is a key factor in the
occurrence of edema in nephrotic syndrome. Hypoalbuminemia cause a decrease
in plasma oncotic pressure so that the fluid shift from the intravascular to the
tissue interstitium and causes edema. Due to a decrease in plasma oncotic pressure
and plasma fluid shifts occur hypovolemia, and kidneys compensate by increasing
the retention of sodium and water. The compensation mechanism will improve
intravascular volume but will also exacerbate the occurrence of hypoalbuminemia
thus edema increasingly continue.
Overfill theory explains that sodium retention is the primary renal defect.
Retention of sodium by the kidneys lead to increased extracellular fluid, causing
edema. Reduced glomerular filtration rate due to kidney damage will increase
sodium retention and edema due to the activation of the renin-angiotensinaldosterone system, especially the increase in the concentration of the hormone
aldosterone which would affect the renal tubular cells to absorb sodium ions so
that ion excretion of sodium (natriuresis) decreases. There was also an increase in
sympathetic nerve activation and catecholamine concentrations that lead to arrest
or glomerular vascular resistance increased, this resulted in a decrease in GFR and
increase in capillary starling insistence peritubuler resulting in a decrease in
sodium excretion.
Hyperlipidemia
Serum cholesterol, very low density lipoprotein (VLDL), low density
lipoprotein (LDL), triglycerides increased, while high density lipoprotein (HDL)
can be increased, normal or decreased. This is due to increased synthesis of lipids
in the liver and decreased catabolism in peripheral (decrease lipoprotein, VLDL,
chylomicrons

and

intermediate

density

lipoproteins

from

the

blood).

Increased lipoprotein lipid synthesis is stimulated by a decrease in serum albumin

and decrease in oncotic pressure.

10

2.5

Signs and Symptoms

Swelling (edema) is the most common symptom. It may occur:

In the face and around the eyes (facial swelling)
In the arms and legs, especially in the feet and ankles
In the belly area (swollen abdomen)
Other symptoms include:
Foamy appearance of the urine
Weight gain (unintentional) from fluid retention
Respiratory tract infection - A history of a respiratory tract infection
immediately preceding the onset of nephrotic syndrome is frequent
Allergy - Approximately 30% of children with nephrotic syndrome have a
history of allergy
Symptoms of infection - Such as fever, lethargy, irritability, or abdominal
pain due to sepsis or peritonitis
Hypotension and signs of shock - Can be present in children presenting
with sepsis
Respiratory distress - Due to either massive ascites and thoracic
compression or frank pulmonary edema, effusions, or both
Tachypnea - To compensate for mechanical restriction to breathing
Seizure - Due to cerebral thrombosis
Anorexia
Irritability
Fatigue
Abdominal discomfort
Diarrhea
Hypertension

11

2.6

Diagnosis
1) Blood analysis often shows high cholesterol levels and low albumin.
BUN and creatinine may or may not be elevated. If BUN and creatinine
are elevated the patients has renal failure and the prognosis is worse.
2) Urinalysis. Evaluation of the urine by a simple urine dipstick in the office
can give preliminary information on the amount of protein in the urine.
However, this test is a qualitative test. In order to determine the actual
amount of protein in the urine, a 24-hour quantitative test must be done,
which indicates levels of protein and creatinine in the urine.Often, a
comparison of protein to creatinine based on a single sample is used to
determine 24-hour protein loss. This is helpful for quicker results or when
the patients cannot collect urine over 24 hours.
3)

Kidney biopsy may be used to determine the underlying cause and

extent of disease with the exception of the following cases:

Children with NS most often have minimal change disease and respond
well to a short course of steroids. A biopsy should only be considered if
they do not show a favorable response to the steroids with 6-8 weeks.

Adult patients with a history of diabetes who have tested negative to other
disorders such as myeloma, infections, and collagen vascular disease. It is
presumed the cause of the proteinuria is diabetic nephropathy and a kidney
biopsy is not necessary. If the duration of diabetes has been short or the
severity of the NS is profound, a kidney biopsy is considered.

Elderly patients, patients who are not expected to live long, or those for
whom immunosuppressive drug therapy is not advisable are typically not
candidates for biopsy.

In severe forms of CNS, generalized edema, urinary protein > 20 g/L, and
serum albumin level <10 g/L can be detected in the newborn period. The amount
of proteinuria, however, varies in different entities, and the clinical signs may not
be evident during the first weeks of life. Also, the true magnitude of proteinuria

12

may be detectable only after partial correction of hypoproteinemia by albumin

infusions. Small amounts of red blood cells and leucocytes are often present in
urine. Serum creatinine and urea levels are variable. Renal function remains quite
normal for the first months in NPHS1, but in other forms, kidney failure may
develop faster. Blood pressure values can be low due to hypoproteinemia or
elevated if renal failure is already present.
In newborns, the placental weight >25% of birth weight is present in NPHS1
but may be seen in other forms of CNS [14]. The kidneys may be of normal size
or larger than normal in ultrasound scanning, and the renal cortex is often
hyperechogenic. Search for possible nonrenal malformations is important,
especially since they may give clues to the etiologic diagnosis. These include
genital abnormalities (WT1), eye defects (LAMB2), and neurological disorders
(MowatGalloway). Cardiac evaluation often reveals ventricular hypertrophy but
no structural defects.
Renal biopsy does not reveal the etiology of CNS. As pointed out, the genetic
defects may cause several types of glomerular lesions, such as mesangial
expansion, FSGS, MCNS, and DMS, and the findings overlap in different entities.
Also, the nonglomerular findings, such as tubular dilatations and interstitial
fibrosis and inflammation, can be seen in all forms of proteinuric diseases. Thus,
the indications for renal biopsy are not quite clear. The knowledge of severity of
glomerular sclerosis and interstitial fibrosis may help in the assessment of
treatment strategies. On the other hand, the lesions are focal, and the biopsy
findings may be misleading. If immunohistochemistry for nephrin and podocin is
available, analysis of their expression in a biopsy sample is useful. Total lack of
either protein speaks for a severe disorder not responding to antiproteinuric
therapy.
Genetic analysis is the method of choice for precise CNS diagnosis. The
knowledge of etiology helps in assessing management and prognosis, in follow-up
for possible associated symptoms, and in genetic counseling of the family.
Analysis of NPHS1 and NPHS2 mutations is warranted in all CNS patients. These

13

analyses

are

commercially

available

in

Athena

Diagnostics

(www.athenadiagnostics.com). If no mutations are detected in these genes or if

clinical findings speak for mutations in WT1 or LAMB2 gene, analysis of these
genes can be obtained at research laboratories.
Prenatal diagnosis in families with a known risk for CNS should be based on
genetic testing whenever possible. The results can be obtained fast if the
mutations are known in advance. In case of no family history or if the mutations
in the affected child were not identified, prenatal genetic testing is a challenge,
since sequencing theNPHS1 (29 exons) and NPHS2 (eight exons) genes is time
consuming and usually not possible within the short time frame available. NPHS1
especially can still be suspected prenatally based on elevated alpha-fetoprotein
(AFP) levels in maternal serum and amniotic fluid. If the AFP concentration in
amniotic fluid is very high and the ultrasound examination does not reveal fetal
anencephaly or other malformations, NPHS1 is a probable diagnosis. However,
heterozygous fetal carriers of NPHS1 gene mutations may have temporarily
elevated AFP levels in amniotic fluid and maternal serum, and repeated
measurement of amniotic fluid AFP before the 20th week of pregnancy is
recommended in cases with high AFP levels.
2.7

Differential Diagnoses

Minimal-Change Nephropathy

Focal Segmental Glomerulosclerosis

Membranous Glomerulonephritis

Diabetic Nephropathy

Primary Glomerular Diseases (e.g., IgA nephropathy)

Fibrillary Glomerulopathies (the most common being amyloidosis)

Lupus Nephritis

Multiple Myeloma (e.g., light-chain deposition diseases)

14

2.8 Treatment
CNS management of infants with heavy proteinuria
Protein substitution parenterally (20% albumin infusions, 3-4 g/kg per day of
albumin)
Nutrition

Hypercaloric diet (130 kcal/kg per day)

Protein Supplementation (Rapeseed/sun flower oil)

A, D, E and water soluble vitamins

Calcium and magnesium supplementation

Medication

Anti-proteinuric drugs (angiotensin converting enzyme inhibitors,

indomethacin)

Thyroxin supplementation

Anticoagulation (warfarin, aspirin, anti-thrombin III-infusion)

Parenteral antibodies when bacterial infection suspected

Control Edema
Symptomatic control of edema is achieved by parental albumin infusions
using 20% albumin (5-20 mg/kg/day) given over 6 hours with intravenous
furosemide (0.5 - 1 mg/kg given half way through and at the end of the
albumin infusion) is helpful to control life threatening edema, protein
malnutrition, reduced growth, and secondary complications such as
thrombosis. (5) Thiazide diuretics and aldosterone antagonists are used as
adjunctive for control of edema. Reduction of protein excretion includes
administration

of

angiotensin

converting

enzymes

inhibitors

and

indomethacin. Patients with severe NPHS1 and NPHS2 mutations inhibiting

nephrin and podocin expression (stop codons, deletions, missense mutations)
do not respond to this treatment.

15

As this disease progresses, loss of thyroxin binding globulin and thyroxin lead
to a rise in thyroid-stimulating hormone. This necessitates thyroxin
substitution stating with 6.25 - 12.5 ug/kg, the dose adjusted according to
thyroid stimulation hormone levels.
Anti-coagulation therapy using aspirin and dipyridamole is indicated as urinary
protein losses result in imbalance of plasma coagulation factor levels,
predisposing to hypercoagulability and risk for thrombosis. Finnish patients with
NPHS1 mutations have also been successfully treated with warfarin from 3-4
weeks of age. Before surgical or vascular procedures, warfarin is stopped, and
antithrombin III (50 iu/kg) is given to temporarily correct the deficiency.
Urinary losses of gammaglobulins and complement predispose patients with
CNS to bacterial infections. Prophylactic antibodies treatment has not shown to be
helpful and may induce resistant bacterial strains. (5) A high index of suspicion
for infections is needed as symptoms are vague and often masked by signs of
focal infection occurring at the same time. Parenteral antibodies should be
commenced promptly if sepsis is suspected providing broad spectrum cover.
Prophylactic use of immunoglobulin infusions does not reduce the incidence of
bacterial infections but has been used as adjunctive treatment with antibodies to
control sepsis. Response to treatment is favorable in most cases if commenced
early.
Nutrition
A high energy (130 kcal/kg per day) and high protein (3-4 g/kg per day) diet is
indicated. Breast milk and milk formulas are first used with excess protein given
as casein based protein products. Glucose polymers are given to increase energy
intake, and a mixture of rapeseed and sunflower oil is given to balance lipid
levels.
Vitamin D supplementation is used starting with 400 iu/day) and adjusted to

16

maintain 25-OH vitamin D levels between 30-100 ng/L. Alphacalcidol is

indicated for secondary hyperparathyroidism to present renal osteodystrophy.
Multivitamin preparations are given according to recommended dietary
allowances for healthy children of the same age. Supplemental magnesium (50
mg/day) and calcium (500-1000 mg/day) may be required to maintain normal
serum levels. Fluid intake is adjusted to 100-130 mls/kg per day. Most patients
may require supplemental feeding via a nasogastric tube or stomach peg to ensure
adequate energy intake.
Kidney transplantation
Renal transplantation has become an established mode of therapy for most
children with CNS. The fact that CNS children are often transplanted at 12 years
of age using adult-size kidneys may sometimes be surgically demanding and
increase the risk for thrombotic and ureteral complications compared with older
recipients. Postoperatively, abundant hydration of the recipient (3,000 ml/m2) is
necessary to maintain optimum aortic and renal artery blood flow and avoid lowflow states that could damage the graft. The use of immunosuppressive
medication should be balanced in order to prevent rejection episodes, which may
be clinically subtle, and on the other hand, avoid the many side effects associated
with these drugs. Recurrence of NS in the graft is rare but has occurred in some
NPHS1 children who developed antinephrin antibodies after transplantation.
Treatment of the recurrence with cyclophosphamide and plasmapheresis often
leads to remission.
Overall, the results of kidney transplantation in CNS are quite good and
similar to those obtained in other etiologies. Patient survival at 5 years is over
90% and graft survival over 80% in registry databases and in single centers.
Chronic allograft nephropathy, however, is a major problem also in these patients,
and a second transplantation is inevitable when the patients become young adults.
Treatment of Initial Presentation of Nephrotic Syndrome

17

Prednisolone: When the diagnosis of nephrotic syndrome has been made,

prednisolone can be started in children with typical features; for children with
atypical features, they should be referred to pediatric nephrology for consideration
of renal biopsy. There is increasing evidence that longer initial course of
prednisolone are associated with a lower incidence of relapse, and therefore a 12
weeks initial course is recommended. The dosage of prednisolone is based on the
surface area.

60 mg/m/day for 4 weeks (maximum 80 mg)

40 mg/m/on alternate days for 4 weeks (maximum 60 mg)

Reduce dose by 5 to 10 mg/m each week for another 4 weeks then stop.
Prednisolone can be given as a single dose in the morning with food, or as

divided doses during the day, and patients have to be issued a steroid warning.
Albumin: Is indicated in clinical hypovolemia and symptomatic edema. A low
serum albumin is not an indication for intravenous albumin. If there is evidence of
hypovolemia, give 1 gm/kg 20% albumin (5 ml/kg) over 4 to 6 hours. Give 2
mg/kg of IV furosemide midinfusion. If clinically shocked, give 10 ml/kg 4.5%
albumin. Children should be closely monitored during albumin infusions, and
where possible should be administered during working hours.
Penicillin prophylaxis : Penicillin V can be given during proteinuria and
discontinued when the child goes into remission. Grossly edematous children are
at risk of cellulitis and may benefit from antibiotic prophylaxis.
Dose: Under 5 years125 mg bid and for above 5 years 250 mg bid.
Salt/Fluid restriction: A low salt diet is used to prevent further fluid retention and
also edema. Fluid restriction may also be helpful.
Vaccination: Pneumococcal vaccination is recommended for children with
nephrotic syndrome. Varicella vaccination is only available on a named patient
basis.
Treatment of Relapse Nephrotic Syndrome
Upto 60 to 70% of children with nephrotic syndrome may have one or more
relapse. These are diagnosed if there is +++ or ++++ proteinuria for 3 or more

18

days. Urine should be checked initially twice weekly, then weekly after the first
episode, and the families should be instructed to get in contact in case a relapse of
proteinuria occur, or if there is ++ for more than 1 week.
Prednisolone: Should be restarted once a relapse has been diagnosed:

2 mg/kg daily (maximum 80 mg) until the urine is negative or trace for 3
days.

40 mg/m/on alternate days for 4 weeks (maximum 60 mg) then stop or

taper the dose over 4 to 8 weeks.

Albumin: The indications are similar as for initial presentation.

Salt/Fluid restriction: During proteinuria, no salt diet is advised.
Penicillin prophylaxis: During proteinuria, penicillin can be given.
Vaccination: Consider giving varicella vaccine between relapses in children who
are varicella seronegative.
Referral to pediatric nephrology in cases of:

Frequent relapsers

Steroid dependency

Steroid toxicity

Diagnosis and Treatment of Frequent Relapses

Frequent relapses are diagnosed if there is:

2 or more relapses within the first 6 months of presentation

4 or more relapses within any 12-month period.

This becomes steroid dependency. If the relapses are occurring during

steroid tapering, varicella status should be repeated 6 monthly in those who are
nonimmune.
Low dose alternate day prednisolone: In the dose of 10 to 15 mg/alternate days
may prevent relapses.
Levamisole: Levamisole may be beneficial for children who have occasional
relapses. It is less useful for children who are steroid dependent. The dose is 2.5

19

mg/kg on alternate days for 6 months to a year. Reversible neutropenia is rare but
occurs sometimes, and a FBC should be checked monthly for the first 3 months.
Cyclophosphamide: Can be given in the dose of 3 mg/kg/ day for 8 weeks.
Cyclosporin: At a dose of 2.5 mg/kg bid usually for 1 year may be useful as a
steroid sparing agent. Levels should be checked after 1 to 2 weeks. For children
under 5 years, tid dosing may be necessary. Monitor BP and renal function.
Mycophenolate mofetil (MMF): Can be given to children showing signs of
cyclosporin toxicity. Doses of 600/m/bid have been used. FBC should be
monitored for leukopenia.
2.9

Complications
1. Thrombosis
Venous thrombosis is more common in patients with nephrotic syndrome

compared with arterial thrombosis; thrombosis, when present, may occur in the
renal vein, sagittal sinus, or pulmonary artery. Thrombosis in this patient
population is multifactorial. Patients may have a hereditary risk factor (such as
Factor V Leiden mutation) that predisposes them to clot formation. They may be
intravascularly depleted as a result of nephrotic syndrome that may be exacerbated
by diuretic use to control edema. When combined with the urinary loss of
coagulation cascade regulators (such as antithrombin III) and an increase in
hepatic production of procoagulant factors (such as fibrinogen, factor V, and
factor VIII), conditions that favor thrombus formation result. Thrombocytosis and
platelet aggregation also occur in nephrotic syndrome and may play a role in
thrombosis.
2. Infections
In addition to urinary loss of hematologic factors, there is also loss of
immunoglobulins. This loss of circulating antibodies puts nephrotic children at
risk for bacterial infections, particularly those with encapsulated bacteria (eg,
Streptococcus pneumoniae, Haemophilus influenzae, and Group B streptococcus).
Peritonitis caused by S pneumoniae is a well-described infection in children with
nephrotic syndrome. Patients may also experience serious infections like cellulitis

20

and pneumonia, and can develop sepsis. These children must be vaccinated
against these bacteria because of waning immunity over time as a result of their
underlying diagnosis. Current recommendations call for administration of the 23valent pneumococcal polysaccharide vaccine for all children older than 2 years
with nephrotic syndrome. The vaccine should be administered at least 8 weeks
after the last dose of the 13-valent pneumococcal conjugate vaccine, with an
additional dose of the 23-valent pneumococcal polysaccharide vaccine 5 years
after the first dose in patients who have ongoing disease. Patients undergoing
treatment for nephrotic syndrome with immunosuppressants are also at continued
risk of infections, and febrile illnesses in this population require close follow-up.
3. Vitamin D deficiency and Hypothyroidism
Beyond the urinary loss of albumin and immunoglobulins, nephrotic
syndrome also causes the loss of other important proteins, including vitamin D
binding protein and thyroid-binding globulin. This loss may cause vitamin D
deficiency and increase the potential for metabolic bone disease. Although
hypothyroidism is more of a frequent problem in patients with CNS, in whom
proteinuria is heavy and long-standing, general practitioners should recognize this
as a potential issue in children who are resistant to corticosteroids or who have
frequent relapses.
4. Renal Dysfunction
Renal dysfunction can occur in the setting of nephrotic syndrome,
especially with patients presenting with hypovolemia. Preceding illness,
aggressive diuretic use, or sepsis with hypotension may result in decreased renal
blood flow, causing a decrease in the glomerular filtration rate. Acute kidney
injury in most of these cases is reversible with remission of the nephrotic
syndrome and adequate volume repletion.
2.10

Prognosis
The prognosis for nephrotic syndrome under treatment is generally good

although this depends on the underlying cause, the age of the patient and their

21

response to treatment. It is usually good in children, because minimal change

disease responds very well to steroids and does not cause chronic renal failure.
However, children under the age of 5 generally have a poorer prognosis than
prepuberscents, as do adults older than 30 years of age as they have a greater risk
of kidney failure. Any relapses that occur become less frequent over time the
opposite occurs with mesangiocapillary glomerulonephritis, in which the kidney
fails within three years of the disease developing, making dialysis necessary and
subsequent kidney transplant.
Other causes such as focal segmental glomerulosclerosis frequently lead to
end stage renal disease. Factors associated with a poorer prognosis in these cases
includes the level of proteinuria, blood pressure control and kidney function
(GFR).
Without treatment, nephrotic syndrome has a very bad prognosis
especially rapidly progressing glomerulonephritis, which leads to acute kidney
failure after a few months.

22

CHAPTER III
CASE REPORT
3.1

Objective
The objective of this paper is to report a case of a 4 month old boy with a

diagnosis of Congenital Nephrotic Syndrome.

3.2

Case
MA, a boy, 4 months old, with 3.6 kg of BW and 52 cm of BH, came to

RSUP Haji Adam Malik Medan on 28th July at 19.30. The main complaint was
swelling on his whole body.
History of disease:
MA, a boy, 4 months old, with 3.6 kg of BW and 52 cm of BH, came to
RSUP Haji Adam Malik Medan on 29th August at 19.30 . The chief complaint
was swelling on his whole body. It has been experienced by the patient since 1
week ago. Swelling begins in the legs and pervade to the whole body. Patient also
looked pale for about 2 days. The patients frequency of urine is also little and
sometimes patient does not even urinate. Foamy and sandy urine was not found.
History of fever, cough, flu, seizure and bleeding was not found. Defecate in the
normal range.
History of medication: History of family: None
History of parents medication: Unclear
History of pregnancy: The gestation age was 38 weeks. No history of
complication, neonate and maternal problem.
History of birth: Birth assisted by midwife spontaneously. The baby was born
paravaginal and he cried immediately. Bluish was not found.

23

Body weight was 2400 gram, body length 48 cm, and head
circumference was unclear.
History of feeding: 4 months of breast feeding
History of immunization: Hepatitis B 1x, BCG 1x, Polio 1x, DPT 1x
History of growth and development: Patients mother explained that he was
growing according to his age.
Physical Examination:

Present status: Level of consciousness: compos mentis with GCS 15

(E4V6M5). Body temperature: 36,8C, HR: 130 bpm, RR: 38 x/i, BW: 3.8
kg, BH: 52 cm, BW/A: BL/A: 100%, BW/BL: 147.1%, anemic (-), icteric
(-), dyspnea (-), cyanosis (-), edema (+).

Localized status:

Head: Face: edema (+)

Eyes: superior and inferior palpebra edema (+), light reflex +/+,
isochoric pupil, conjunctiva palpebra inferior pale (-/-)
Ears: within normal range
Nose: within normal range
Mouth : within normal range

Neck : Lymph node enlargement (-)

Thorax : Symmetrical fusiform, retraction (-)

HR: 130 bpm, regular, murmur (-)
RR: 38 x/i, regular, ronchi (-/-)

Abdomen: enlarged, symmetric, normal peristaltic, liver and

spleen: undeterminable, undulation (+)

Extremities : pulse 130 bpm regular, adequate p/v,warm, CRT < 3,

pitting edema (+)

Laboratory finding
Complete blood analysis (29 th July 2015 / 20:25)
Test
Hemoglobin
Erythrocyte

Result
5,70
2,34

Unit
g%
106/mm3

Referral
10,7-17,1
3,75-4,95

24

Leucocyte
Thrombocyte
Hematocrite
Eosinophil
Basophil
Neutrophil
Lymphocyte
Monocyte
MCV
MCH
MCHC

103/mm3
103/mm3
%
%
%
%
%
%
fL
pg
g%

6,0-17,5
217-497
38-52
1-6
0-1
37-80
20-40
2-8
81-95
29-35
28-34

Result

Unit

Referral

2,0

g/dl

3.8-5,4

131.70

mg/dL

40-60

11,40
0,34

mg/dL
mg/dL

<50
0,17-0,42

128
6,1
4,6
109

mEq/L

135-155

mEq/L
mEq/L

3,6-5,5
96-106

20,85
304
16,30
0,20
0,100
67,60
24,00
8,10
69,70
24,40
35,00

Clinical Chemistry
Test
Liver
Albumin
Carbohydrate Metabolism
Blood Glucose
Renal Function
Ureum
Creatinine
Electrolite
Natrium
Calcium
Kalium
Cloride
Urine Dipstick
Leu
-

Nit
-

Uro
-

Pro
+1

pH
5.0

Differential Diagnosis

Blo
-

SG
1.030

Ket
+

Bil
+

Glu
-

: Congenital Nephrotic Syndrome

Kwashiorkor

Working Diagnosis

: Congenital Nephrotic Syndrome + Suspicion

of Sepsis

Management:
- O2 1-2L/I via nasal canule
- IVFD D5% NaCl 0.45% 4gtt/I micro
- Inj.Ceftriaxone 80mg/12hrs/IV
- Furosemide 2x4mg

25

- Spironolactone 2x4mg
- Bicnat 4x1/3 tab
- Diet ASI/PASI
Planning Assesment:

Urinalysis
Lipid Profile
ASTO

Follow Up
S
O

30th August - 31st August

Swelling throughout the body
Sensorium: Compos Mentis, Temp: 36,5oC, BB:3,8Kg, TB: 52cm,
BSA: 0.9 m, BP:110/70 mmHg (N:91-109/54-68)
Head :- Face: edema (+)
Eyes: superior and inferior palpebra edema (+), light reflex (+/+),
isochoric pupil, pale inferior conjunctiva palpebra (-/-)
Ear : within normal range
Nose : within normal range
Mouth : within normal range
Thorax : symmetrical fusiform, retraction (-),
HR: 124 bpm, regular, murmur (-)
RR : 32 x/i, regular, ronchi (-/-)
Abdomen : supple, peristaltic (+)N, Liver and Spleen : undeterminable,
undulation (+)
Extremities : pulse 124 bpm, regular, adequate p/v, felt warm, CRT < 3 ,
edema pretibial (+)
DD/ Congenital Nephrotic Syndrome + Anemia
Suspicion of Sepsis

O2 1-2L/I via nasal canule

IVFD D5% NaCl 0.45% 4gtt/I micro
Inj.Ceftriaxone 80mg/12hrs/IV
Furosemide 2x4mg
Spironolactone 2x4mg

Results
Test
Urinalysis
No urine
was taken

Result
sample

Unit

References

26

Lipid
Total Cholesterol
Triglyceride
HDL
LDL
Immunoserology
ASTO
Urine Dipstick
Leu
-

S
O

A
P

Nit
-

Uro
-

88
108
22
49

mg/dL
mg/dL
mg/dl
mg/dl

< 200
40 200
>65
<150

<200
Pro
++

pH
5.0

Blo
-

SG
1.030

Ket
+

Bil
-

Glu
-

1st September 2015

Swelling throughout the body
Sensorium: Compos Mentis, Temp: 37,1oC, BB: 4Kg;
Head :- Face: edema (+)
Eyes: superior and inferior palpebra edema (+), light reflex (+/+),
isochoric pupil, pale inferior conjunctiva palpebra (-/-)
Ear : within normal range
Nose : within normal range
Mouth : within normal range
Thorax : symmetrical fusiform, retraction (-),
HR: 110 bpm, regular, murmur (-)
RR : 30 x/i, regular, ronchi (-/-)
Abdomen : supple, peristaltic (+)N, Liver and Spleen : undeterminable,
undulation (+)
Extremities : pulse 110 bpm, regular, adequate p/v, felt warm, CRT < 3 ,
edema pretibial (+)
Congenital Nephrotic Syndrome
- O2 1-2L/I via nasal canule
- IVFD D5% NaCl 0.45% 4gtt/I micro
- Inj.Ceftriaxone 80mg/12hrs/IV
- Furosemide 2x4mg
- Spironolactone 2x4mg
Pemberian prednisone full dose 60mg/m dalam 3 dosis (3-3-2 tab)
Captopril 2 x 6,25mg
Spironolactone 2 x 25mg

27

Urinalysis
Keterangan
Warna
Glukosa
Keton
Protein
Sedimen
Lekosit
Eritrosit
Epitel
Bilirubin
Urobilinogen
Nitrit
pH

Hasil
Kuning Jernih
Negatif
Negatif
Negatif
0-1
0-1
0-1
Negatif
8,0

Nilai Normal
Kuning
Negatif
Negatif
Negatif
<6
<3
Negatif
Negatif
Negatif
5,0-8,0

Urine Dipstick
Leu
-

Nit
-

Uro
-

2nd September 2015

OUTPATIENT

Pro
++

pH
5.0

Blo
-

SG
1.030

Ket
+

Bil
-

Glu
-

28

CHAPTER IV
DISCUSSION AND SUMMARY
4.1.

Discussion
The main clinical manifestation in this patient is edema, which is seen in

about 95% of children with nephrotic syndrome. In the early phase, edema often
seems to be intermittent, usually first appear in areas that have low tissue
resistance (periorbital area and pretibia). Interstital edema is a common clinical
expression of nephrotic syndrome. Expansion of the interstital compartment is
secondary to the accumulation of sodium in the extracellular compartment, due to
an imbalance between oral or parenteral sodium intake and urinary sodium
output, along with alterations of fluid transfer across the capillary walls.
Patient was diagnosed with nephrotic syndrome due to hypoalbuminemia.
Hypoalbuminemia is a low level of albumin (a protein) in the blood due to
proteinuria. Low albumin in the blood causes fluid to move from the blood into
the tissue, causing swelling. The kidney perceives the decrease of fluid in the
blood and aggressively retains as much fluid and salt as it can. This contributes to
the body's fluid-overload state.
4.2.

Summary
- MA, a boy, 4 months old, came to RSUP Haji Adam Malik Medan on 29 th
July 2015, with a chief complaint of swelling on the whole body. Based on
anamnesis, physical examination, and laboratory assessment, he was
diagnosed with congenital nephrotic syndrome and was given treatment of the

29

followings:

Inj.Ceftriaxone

80mg/12hrs/IV,

Furosemide

2x4mg,

Spironolactone 2x4mg, Bicnat 4x1/3 tab and diet ASI/PASI.

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Nephrotic

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Nephrotic

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