Nephrotic syndrome

Nephrotic syndrome, or nephrosis, is defined by the presence of nephrotic-range

proteinuria, edema, hyperlipidemia, and hypoalbuminemia. While nephrotic-range
proteinuria in adults is characterized by protein excretion of 3.5 g or more per day, in
children it is defined as protein excretion of more than 40 mg/m2/h or a first-morning urine
protein/creatinine of 2-3 mg/mg creatinine or greater.
One of the most exciting developments in recent years in understanding the
pathophysiology of nephrotic syndrome has occurred in the area of podocyte biology

Signs and

symptoms

Pitting edema
symptom in
children with
syndrome. It
in the lower
and
regions,
and abdomen

is the presenting
about 95% of
nephrotic
is typically found
extremities, face
periorbital
scrotum or labia,
(ascites).

Other
nephrotic syndrome may include the following:

signs and
symptoms of

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 [3]
Macrohematuria
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

Diagnosis
In order to establish the presence of nephrotic syndrome, laboratory tests should confirm the
existence of (1) nephrotic-range proteinuria, (2) hypoalbuminemia, and (3) hyperlipidemia.
Therefore, initial laboratory testing should include the following:

Urinalysis
Urine protein quantification
Serum albumin
Lipid panel
The following tests should be performed to determine whether the nephrotic
syndrome is idiopathic or secondary and, if INS has been determined, whether signs
of chronic kidney disease, kidney insufficiency, or other signs exclude the possibility
of minimal change nephrotic syndrome (MCNS):

Complete blood count (CBC)

Metabolic panel - levels of serum electrolytes, calcium, phosphorus, and ionized
calcium, as well as of blood urea nitrogen (BUN) and creatinine
Testing for HIV
Testing for hepatitis B and C
Complement studies (C3, C4)
Antinuclear antibody (ANA), antidouble-stranded DNA antibody (in selected patients)
Genetic studies
Kidney ultrasonography
Chest radiography
Mantoux test
Kidney biopsy

Management
Corticosteroids
If kidney biopsy is not initially indicated, a trial of corticosteroids is the first step in
the treatment of INS.
Diuretics
Loop diuretics, such as furosemide (starting at 1-2 mg/kg/d), may improve edema.
Metolazone may be beneficial in combination with furosemide for resistant edema.
Antihypertensive agents
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers
(ARBs) can reduce hypertension and may also contribute to reducing proteinuria. However,
ACE inhibitors and ARBs can cause birth defects, so adolescent women who are taking these
agents must be counseled regarding use of birth control, and pregnancy testing should be
considered before starting these agents.
Calcium channel blockers and beta blockers may also be used as first-line agents for
hypertension.
Alkylating agents
Alkylating agents (eg, cyclophosphamide [CYP], chlorambucil, nitrogen mustard) offer
the benefit of possible sustained remission after a defined course of treatment, although
with the possible risk of infertility and other side effects.

Calcineurin inhibitors
Calcineurin inhibitors (eg, cyclosporin A [CSA], tacrolimus [TAC]) are steroid-sparing
agents that can also be used in children who fail to respond to, or who subsequently relapse
after, treatment with CYP, or in children whose families object to the use of CYP.
Home monitoring
Home monitoring of urine protein and fluid status is an important aspect of
management. All patients and parents should be trained to monitor first morning urine
proteins at home with urine dipstick. Urine testing at home is also useful in monitoring
response (or nonresponse) to steroid treatment.

Background
Pediatric nephrotic syndrome, also known as nephrosis, is defined by the presence of
nephrotic-range proteinuria, edema, hyperlipidemia, and hypoalbuminemia. Nephrotic-range
proteinuria in adults is characterized by protein excretion of 3.5 g or more per day. However,
because of the great range of body sizes in children, the pediatric definition of nephroticrange proteinuria is more cumbersome.
Nephrotic-range proteinuria in children is protein excretion of more than 40 mg/m 2/h.
Because 24-hour urine collections are potentially unreliable and burdensome, especially in
young children, many pediatric nephrologists instead rely on a single, first-morning urine
sample to quantify protein excretion by the ratio of protein to creatinine. [4]
The use of a first-morning urine sample eliminates the contribution of potentially
nonpathological orthostatic proteinuria, which might otherwise falsely elevate the protein
level in a urine sample collected while a patient is active during the day. A urine
protein/creatinine value of more than 2-3 mg/mg indicates nephrotic range proteinuria and
correlates with results from 24-hour urine collection.
Nephrotic syndrome is a constellation of clinical findings that is the result of massive renal
losses of protein. Thus, nephrotic syndrome is not a disease itself, but the manifestation of
many different glomerular diseases. These diseases might be acute and transient, such
as postinfectious glomerulonephritis, or chronic and progressive, such as focal segmental
glomerulosclerosis (FSGS). Still other diseases might be relapsing and remitting, such as
minimal change nephrotic syndrome (MCNS).
The glomerular diseases that cause nephrotic syndrome generally can be divided into
primary and secondary etiologies. Primary nephrotic syndrome (PNS), also known as
idiopathic nephrotic syndrome (INS), is associated with glomerular diseases intrinsic to the
kidney and not related to systemic causes. The subcategories of INS are based on
histological descriptions, but clinical-pathological correlations have been made.
A wide variety of glomerular lesions can be seen in INS. These include MCNS, focal
segmental glomerulosclerosis (FSGS), membranous nephropathy (MN),
membranoproliferative glomerulonephritis (MPGN), C3 glomerulonephritis (C3GN), IgA
nephropathy, diffuse mesangial proliferation, and others.
By definition, secondary nephrotic syndrome refers to an etiology extrinsic to the kidney.
Secondary causes of nephrotic syndrome include (1) autoimmune and vasculitic diseases,
such as Henoch-Schnlein purpura (HSP), systemic lupus erythematosus, and antineutrophil
cytoplasmic antibody (ANCA)associated vasculitis; (2) infectious diseases, such as
congenital syphilis, malaria, human immunodeficiency virus (HIV), and hepatitis B and C; (3)

malignancy; (4) environmental and drug exposure, such as heroin and mercury; and (5)
systemic diseases such as diabetes mellitus, among many other causes (see Etiology).
Nephrotic syndrome may also be caused by genetic abnormalities. Infantile NS (presenting
before age 3 mo) and congenital NS (presenting at age 4-12 mo) have been associated with
defects in the nephrin gene (NPHS1), phospholipase C epsilon 1 gene (PLCE1), and the
Wilms tumor suppressor gene (WT1). Mutations in the podocin gene (NPHS2) are associated
with a familial, autosomal-recessive form of FSGS. Mutations in the -actinin-4 gene (ACTN4)
and the gene TRPC6are associated with autosomal-dominant forms of familial
FSGS.Additionally, other genetic syndromes have been associated with nephrotic syndrome,
such as nail-patella syndrome, Pierson syndrome, Schimke immuno-osseous dysplasia, and
others.
INS is divided into steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome (SRNS)
because response to steroids has a high correlation with histological subtype and prognosis.
The landmark study of nephrotic syndrome in children, the International Study of Kidney
Disease in Children (ISKDC), found that the vast majority of preadolescent children with INS
had MCNS on kidney biopsy.[5, 6] Whereas 90% of children with MCNS responded to
corticosteroid treatment with remission of their nephrotic syndrome, only 20% of children
with FSGS responded to steroids.

Pathophysiology
Proteinuria and hypoalbuminemia
The hallmark of INS is massive proteinuria, leading to decreased circulating albumin
levels. The initiating event that produces proteinuria remains unknown. However, strong
evidence suggests that INS, at least in part, has an immune pathogenesis.
The effect of glucocorticoids on inducing remission in INS implicates the immune
system, and particularly T-lymphocytes, in the pathogenesis of the condition.
Glucocorticoids, primarily acting through the nuclear factor kappaB (NF-B) transcription
pathway, have a variety of effects, including inhibiting cytokine production and inhibiting Tcell production and proliferation.
Edema
The classical explanation for edema formation is a decrease in plasma oncotic
pressure, as a consequence of low serum albumin levels, causing an extravasation of plasma
water into the interstitial space. The resulting contraction in plasma volume (PV) leads to
stimulation of the renin-angiotensin-aldosterone axis and antidiuretic hormone. The resultant
retention of sodium and water by the renal tubules contributes to the extension and
maintenance of edema.
Hyperlipidemia
INS is accompanied by disordered lipid metabolism. Apolipoprotein (apo)-B
containing lipoproteins are elevated, including very-low-density lipoprotein (VLDL),
intermediate-density lipoprotein (IDL), low-density lipoproteins (LDL), and lipoprotein(a), with
resultant increases in total cholesterol and LDL-cholesterol. The level of high-density

lipoprotein (HDL) cholesterol is normal or low. Elevations in triglyceride levels occur with
severe hypoalbuminemia.
The traditional explanation for hyperlipidemia in INS was the increased synthesis of
lipoproteins that accompany increased hepatic albumin synthesis due to hypoalbuminemia.
However, serum cholesterol levels have been shown to be independent of albumin synthesis
rates.
Decreased plasma oncotic pressure may play a role in increased hepatic lipoprotein
synthesis, as demonstrated by the reduction of hyperlipidemia in patients with INS receiving
either albumin or dextran infusions. Also contributing to the dyslipidemia of INS are
abnormalities in regulatory enzymes, such as lecithin-cholesterol acyltransferase, lipoprotein
lipase, and cholesterol ester transfer protein.
Thrombosis
Patients with nephrotic syndrome are at increased risk for thrombosis. The incidence
rate of thromboembolic complications (TEC) is about 25% in adults with nephrotic syndrome.
The risk of TEC varies with the underlying disease. Infants with congenital nephrotic
syndrome have an incidence of TEC of about 10%. The risk of thrombosis increases
throughout childhood, and adolescents are at higher risk than younger children after the first
year of life. The risk of TEC also is greater in secondary compared with primary nephrotic
syndrome. Children with membranous nephropathy and nephrotic syndrome are at high risk
of TEC, with an incidence of approximately 25%.[23] One study found the subclinical rate of
pulmonary embolism in children with nephrotic syndrome to be 28% using scintigraphic
pulmonary ventilation and perfusion studies.
Infection
Patients with INS are at increased risk of infection. Peritonitis and sepsis are the most
common and serious infections. Peritonitis occurs at a rate of approximately 2-6% and may
be accompanied by sepsis or bacteremia. The predominant bacterial causes
are Streptococcus pneumoniae and Gram-negative enteric organisms such as Escherichia
coli.[28]
Various infections can also occur, including meningitis, cellulitis, viral infections, and
others. Varicella is a particular concern in immunosuppressed patients and can be lethal.
Prompt recognition and treatment with acyclovir (or postexposure prophylaxis with varicellazoster immune globulin [VZIG]) is essential. Routine childhood varicella immunization has
alleviated some of the concern regarding this complication.
Acute kidney failure
Acute kidney failure (AKF) is a rare complication of INS, occurring in about 0.8% of cases.
[29]
Causes include the following :

Rapid progression of underlying disease (nephrotic syndrome other than MCNS,

secondary nephrotic syndrome)
Bilateral renal vein thrombosis

Acute interstitial nephritis (AIN) due to drug therapy (eg, antibiotics, nonsteroidal antiinflammatory agents [NSAIDs], diuretics)
Acute tubular necrosis (ATN) due to hypovolemia or sepsis

General complications
Complications are discussed in detail in previous sections (see Pathophysiology and History).
Complications of INS include:

Edema
Hyperlipidemia
Thrombosis (renal vein thrombosis, deep vein thrombosis, and pulmonary embolism
are the most frequently encountered TEC in children. Other venous sites of
thrombosis include the superior sagittal sinus, other cerebral venous sites, and the
inferior vena cava.)
Infection (spontaneous bacterial peritonitis, sepsis, cellulitis)
Acute kidney failure
Medication adverse effects (steroids, diuretics, albumin, steroid-sparing
agentsPatient Education

Soon after nephrotic syndrome is diagnosed, the patient and family should be educated
about the disease, its management, and its expected course. The family should participate
in therapeutic decisions and should be encouraged to adhere to the medical regimen.
As with all chronic illnesses, many psychosocial issues may need to be addressed, including
(but not limited to) the following:

Behavior
Adherence to medication
Adequate parental/caretaker supervision
Medical insurance
Missed work and school due to hospitalizations and outpatient visits

Exams and Tests

Albumin blood test

Blood chemistry tests such as basic metabolic panel or comprehensive metabolic panel

Blood urea nitrogen (BUN)

Creatinine - blood test

Creatinine clearance - urine test

Urinalysis

ERIKA JOYCE C. MANUBAY

BSN 3-2