Nephrotic Syndrome
Abadi Leul (MD)
Nephrotic Syndrome
• Nephrotic syndrome is characterized by
– Edema
– Heavy proteinuria (>3.5 g/24 hr in adults or 40
mg/m2/hr in children)
– hypoalbuminemia (<2.5 g/dL) and
– hyperlipidemia
• Nephrotic syndrome is primarily a pediatric disorder and
is 15 times more common in children than adults.
• The incidence is 2-3/100,000 children per year
• The majority of affected children will have steroid-
sensitive minimal change disease
Etiology
• 90% of the cases with nephrotic syndrome are idiopathic
nephrotic syndrome.
• Causes of idiopathic nephrotic syndrome include
– Minimal change disease (85%)
• The glomeruli appear normal or show a minimal
increase in mesangial cells and matrix.
• Findings on immunofluorescence microscopy are
typically negative,
– Mesangial proliferation (5%)
• Diffuse increase in mesangial cells and matrix on
light microscopy
• Immunofluorescence microscopy may reveal trace
– Focal segmental glomerulosclerosis (10%).
• Glomeruli show mesangial proliferation and
segmental scarring on light microscopy
• Immunofluorescence microscopy shows IgM
and C3 staining in the areas of segmental
sclerosis
• The remaining 10% of children with nephrotic
syndrome have secondary nephrotic syndrome
– Membranous nephropathy or
– Membranoproliferative GN.
Pathophysiology
• An increase in permeability of the glomerular capillary wall
– Leads to massive proteinuria and hypoalbuminemia.
– Hypoalbuminemia in turn leads to a reduction in the plasma oncotic
pressure and transudation of fluid from the intravascular compartment
to the interstitial space.
– Decreases renal perfusion pressure, activating the renin-angiotensin-
aldosterone system, which stimulates tubular reabsorption of sodium.
– The reduced intravascular volume also stimulates the release of
antidiuretic hormone, which enhances the reabsorption of water in the
collecting duct.
– Hypoalbuminemia stimulates generalized hepatic protein synthesis,
including synthesis of lipoproteins resulting in increased lipid level
– Lipid catabolism is diminished, as a result of reduced plasma levels of
lipoprotein lipase, related to increased urinary losses of this enzyme.
Clinical Manifestations
• The idiopathic nephrotic syndrome is more common in males
than in females
• Most commonly appears between the ages of 2 and 6 yr.
• MCNS is present in 85–90% of patients <6 yr of age.
• 20 to 30% of adolescents have MCNS.
• Children usually present with mild edema, which is initially
noted around the eyes and in the lower extremities.
• With time, the edema becomes generalized, resulting in ascites,
pleural effusions, and genital edema.
• Anorexia, irritability, abdominal pain, and diarrhea are common
• hypertension and gross hematuria are uncommon.
• A diagnosis other than MCNS should be considered in the
following conditions
– Age <1 yr,
– Family history,
– Extra renal findings - arthritis, rash, anemia
– Hypertension or pulmonary edema,
– Acute or chronic renal insufficiency, and
– Hematuria.
• DDX of marked edema includes
– Protein-losing enteropathy,
– Hepatic failure,
– Congestive heart failure,
– Acute or chronic glomerulonephritis, and
– Protein malnutrition.
Diagnosis
• Urinalysis
– proteinuria of 3+ or 4+
– 24 hour urine protein
• Exceeds 3.5 g/24 hr in adults and 40 mg/m2/hr in
children.
– The serum albumin level is generally <2.5 g/dL, and
– The serum cholesterol and triglyceride levels are elevated.
– C3 and C4 levels are normal.
– The serum creatinine value is usually normal,
• may be increased because of diminished renal perfusion
resulting from contraction of the intravascular volume
Treatment
• Children with severe symptomatic edema, including large pleural
effusions, ascites, or severe genital edema, should be hospitalized
• sodium and fluid restriction may be necessary if the child is
hyponatremic
• A swollen scrotum should be elevated with pillows
• Duiresis
– Chlorothiazide 10 mg/kg/dose IV every 12 hr.
– Furosemide 1–2 mg/kg/dose IV q 12 hr.
• When fluid restriction and parentral diuretics are not effective
– 25% albumine 0.5 gm/kg/dose q 6–12 hr administered over 1–2
hr and
– Furosemide 1–2 mg/kg/dose IV
– Pts on this therapy need close monitoring for the development
• Prednisone 60 mg/m2/day (maximum daily dose, 80 mg divided
into 2–3 doses) for at least 4 consecutive weeks.
• 80 to 90% of children will respond to steroid therapy
– urine trace or negative for protein for 3 consecutive days by 2
wk.
• The vast majority of children who will respond to prednisone
therapy will do so within the first 4 wk of treatment.
• After the initial 6-wk course, the prednisone dose should be
tapered to 40 mg/m2/day given every other day as a single
morning dose and then tapered and discontinued over the next 2–3
mo.
• Children who continue to have proteinuria (2+ or greater) after 8
wk of steroid therapy are considered steroid resistant, and a
diagnostic renal biopsy should be performed.
• Other indications for renal Biopsy include
– Hematuria, hypertension, renal insufficiency,
hypocomplementemia, age <1 yr or >8 yr
• Children with NS are said to have relapse when
– Proteinuria of 3+ - 4+ with Edema
• The relapse rate in children treated with longer initial steroid courses
may be as low as 30–40%.
• Relapses is treated with daily divided-dose prednisone at the usual
doses until the child enters remission (urine trace or negative for
protein for 3 consecutive days).
• When a patient relapses while on alternate-day steroid therapy or
within 28 days of stopping prednisone therapy, it is termed steroid
dependent.
• Patients who respond well to prednisone therapy but relapse ≥4 times
in a 12-mo period are termed frequent relapsers.
• Children who fail to respond to prednisone therapy within 8 wk are
termed steroid resistant.
• Steroid-resistant nephrotic syndrome is usually FSGS (80%), MCNS
(20%), and rarely mesangial proliferative.
• Cyclophosmide can be used as an alternative drug in
– severe corticosteroid toxicity (cushingoid appearance,
hypertension, cataracts, and/or growth failure).
• Cyclophosphamide is 2–3 mg/kg/24 hr given as a single oral dose,
for a total duration of 8–12 wk. Alternate-day prednisone therapy is
often continued during the course of cyclophosphamide
administration.
• Cyclosporine 3–6 mg/kg/24 hr divided q 12 hr) or
• Tacrolimus 0.15 mg/kg/24 hr divided q 12 hr are also effective in
maintaining prolonged remissions in children with nephrotic
syndrome and are useful as steroid-sparing agents
Complication
• Infection is the major complication of nephrotic syndrome.
– urinary losses of immunoglobulins and properdin factor B,
– defective cell-mediated immunity,
– immunosuppressive therapy,
– malnutrition, and edema/ascites acting as a potential “culture medium.”
– Spontaneous bacterial peritonitis is the most frequent type of infection,
– Others include sepsis, pneumonia, cellulitis, and urinary tract infections
– Streptococcus pneumoniae is the most common organism causing
peritonitis,
– But gram-negative bacteria such as Escherichia coli may also be
encountered.
• Thromboembolic events occur in 2 to 5% of children with NS
• Both arterial and venous thromboses may be seen, including
renal vein thrombosis, pulmonary embolus, sagittal sinus
thrombosis.
• The risk of thrombosis is related to increased prothrombotic
factors (fibrinogen, thrombocytosis, hemoconcentration,
relative immobilization) and
• Decreased fibrinolytic factors (urinary losses of antithrombin
III, proteins C and S).
Prognosis
• MCNS has the best prognosis
• Majority of steroid responsive children have repeated relapses
– Decreases in frequency as the child grows older
• those children who respond to steroids rapidly and those who
have no relapses during the first 6 mo after diagnosis are likely
to follow an infrequently relapsing course.
• Steroid-resistant nephrotic syndrome, most often caused by
FSGS, generally have a much poorer prognosis.
• These children develop progressive renal insufficiency,- end
stage renal disease requiring dialysis or renal transplantation.
• Recurrent nephrotic syndrome develops in 30–50% of
transplant recipients with FSGS.
