NEPHROTIC

SYNDROME
By w. Simwanza
 DEFINITION
A non-inflammatory condition of glomerular
dysfunction characterized by

• Significant proteinuria (over

1g/m2 body surface/d), in children it is defined as protein excretion of
more than 40 mg/m2/h.
• Hypoalbuminemia (< 20g/l),
• Oedema
• Hypercholesterolemia
 ETIOLOGY
Often unknown, but some potential causes include:
Primary causes due to primary renal disease
• MCNS (minimal change nephrotic syndrome): 80% in children
• Different forms of glomerulonephritis (focal segmental, membranous,
membranoproliferative glomerulonephritis, mesangial capillary)
• Secondary causes due to systemic disease :
• Idiopathic
• Obstructive uropathy,
• Sickle cell disease
• Drugs: NSAIDs etc,
• Syphilis
• Viral infections e.g hepatitis B, c and other chronic bacterial (TB) or viral infection (HIV)
• Diabetes mellitus
• Lupus erythematosus
• Amyloidosis and paraproteinemias

• Congenital nephrotic syndrome (rare)

• The glomerular structural changes that may cause
proteinuria are damage to the endothelial surface,
the glomerular basement membrane, or the
podocytes. One or more of these mechanisms may
be seen in any one type of nephrotic syndrome.
Albuminuria alone may occur, or, with greater
injury, leakage of all plasma proteins, (ie,
proteinuria) may take place.
 CLINICAL FEATURES

• Edema
• Periorbital edema is commonly the 1st
abnormality
• Other locations of edema may be present at
extremities, scrotum/labia, abdomen (ascites),
lungs (pleural effusion)
• Tiredness
• Paleur
• Metabolic consequences of the nephrotic
syndrome include the following:
• Infection
• Hyperlipidemia and atherosclerosis
• Hypocalcemia and bone abnormalities
• Hypercoagulability
• Hypovolemia
• Acute renal failure may indicate an underlying
glomerulonephritis but is more often precipitated
by hypovolemia or sepsis. Edema of the kidneys
that causes a pressure-mediated reduction in the
GFR has also been hypothesized.
• Hypertension related to fluid retention and reduced
kidney function may occur.
• Failure to thrive may develop in patients with
chronic edema, including ascites and pleural
effusion. Failure to thrive may be caused by
anorexia, hypoproteinemia, increased protein
catabolism, or frequent infectious complications.
Edema of the gut may cause defective absorption,
leading to chronic malnutrition.
• Infection
• Infection is a major concern in nephrotic syndrome; patients have an increased susceptibility
to infection with Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, and
other gram-negative organisms. Varicella infection is also common. The most common
infectious complications are bacterial sepsis, cellulitis, pneumonia, and peritonitis.
• Proposed explanations include the following:
• Urinary immunoglobulin losses
• Edema fluid acting as a culture medium
• Protein deficiency
• Decreased bactericidal activity of the leukocytes
• Immunosuppressive therapy
• Decreased perfusion of the spleen caused by hypovolemia
• Urinary loss of a complement factor (properdin factor B) that opsonizes certain bacteria
• Hypercoagulability
• Venous thrombosis and pulmonary embolism are well-known complications
of the nephrotic syndrome. Hypercoagulability in these cases appears to
derive from urinary loss of anticoagulant proteins, such as antithrombin III
and plasminogen, along with the simultaneous increase in clotting factors,
especially factors I, VII, VIII, and X.
• A study by Mahmoodi et al of almost 300 patients with nephrotic syndrome
confirmed that venous thromboembolism (VTE) was almost 10 times higher
in these persons than in the normal population (1% vs 0.1-0.2%). [13] This high
incidence may justify the routine use of preventive anticoagulation treatment
during the first 6 months of a persistent nephrotic syndrome.
• Therefore femoral vein punctures are contraindicated. May cause Renal Vein
thrombosis
• Hypocalcemia
• Hypocalcemia is common in the nephrotic syndrome, but
rather than being a true hypocalcemia, it is usually caused
by a low serum albumin level.
• Nonetheless, low bone density and abnormal bone
histology are reported in association with nephrotic
syndrome. This could be caused by urinary losses of
vitamin D–binding proteins, with consequent
hypovitaminosis D and, as a result, reduced intestinal
calcium absorption
• Hyperlipidemia and atherosclerosis
• Hyperlipidemia may be considered a typical feature of the
nephrotic syndrome, rather than a mere complication.
• It is related to the hypoproteinemia and low serum oncotic
pressure of nephrotic syndrome, which then leads to reactive
hepatic protein synthesis, including of lipoproteins.
• In addition, reduced plasma levels of lipoprotein lipase results in
diminution of lipid catabolism. Some of the elevated serum
lipoproteins are filtered at the glomerulus, leading to lipiduria and
the classical findings of oval fat bodies and fatty casts in the urine
sediment.
 Complications
• Generalized edema (anasarca) (pathology of oedema)
• Circulatory collapse due to hypovolaemia (reduced blood volume
pre-renal failure, shock
• Bacterial peritonitis (infected ascites) (increased susceptibility to
infections)
• Pneumococcal sepsis and other infections
• Renal vein Thrombosis – increased hypercoaguability (increased
platelet aggregation, loss of urinary antithrombin III, increased
blood viscosity)
• Protein malnutrition -Growth impairment, poor wound healing
 INVESTIGATIONS

Urinalysis:
• 3 to 4+ proteinuria (protein excretion of 50mg/kg/day)
• +/- microscopic hematuria (but gross hematuria is rare)
• Fraction

Blood analysis
• Serum albumin: ↓ usually < 2g/dL
• Serum cholesterol: ↑
• PTT ↓
• Platelets: ↑
• Total serum calcium: ↓ due to decreased albumin-bound
 INVESTIGATIONS
• If a particular etiology is suspected, additional labs
should be ordered (hepatitis serologies, rapid HIV
test/ELISA, sickle screen, renal ultrasound)

• Renal biopsy is indicated for patients:

• outside the typical age range ( < 1 year old, > 10 years
old  increased risk for FSGN)
• who do not respond to steroids
• with hypertension at presentation
• with a persistently elevated creatinine (evidence of
renal insufficiency)
 MANAGEMENT

Goals

• Establish the cause

• Treat the cause if possible

• Treat the symptoms

• Prevent complications
 General Guidelines
• From a therapeutic perspective, nephrotic syndrome may be classified as
steroid sensitive, steroid resistant, steroid dependent, or frequently
relapsing.
• Corticosteroids (prednisone), cyclophosphamide, and cyclosporine are
used to induce remission in nephrotic syndrome. Diuretics are used to
reduce edema. Angiotensin-converting enzyme (ACE) inhibitors and
angiotensin II receptor blockers are administered to reduce proteinuria.

• Treat primary cause if known

• Avoid immobilization (thrombosis)
• Moderate fluid restriction
• Regular urine for protein
• Low-salt, high protein diet
• Treat any infection if suspected
• Daily weight
 Medications
Prednisone
• Start only after the diagnosis is confirmed,
• Either daily or twice daily dosing may be used
• Phase 1: Start with prednisone at 60 mg/m2/24 hr OR 2
mg/kg/24 hr (maximum daily dose 60 mg) daily (or
twice daily) for 4-6 weeks
• Phase 2: Decrease the dose to 40 mg/m² every other
day for 6 weeks (to maintain remission, avoid relapses
while decreasing the cumulative toxicity of daily steroids)
• Sufficient recovery of pituitary-adrenal axis
function after alternate-day therapy in most
cases.
• But it remains a minimal risk for adrenal
insufficiency with abrupt prednisone
withdrawal.
• Therefore a more prolonged steroid wean is
recommended thereafter.
• For up to 1 yr after completing prednisone
therapy, the child will require corticosteroid
supplementation for severe illness or surgery
 Side effects of long time corticosteroid therapy
• Reduced immunity (TB!)
• Frequent and severe infections (varicella)
• Moon face (Cushing syndrome)
• Weight increase
• Hyperglycemia, diabetes
• Hypertension
• Peptic ulcer
• Growth restriction
• Euphoria, insomnia
• Shock if discontinued abruptly
• Time needed to respond to prednisone
~ 2 weeks (response = urine free of
protein).
• If ≥ 2+ proteinuria continues after 1
mo of continuous, BD prednisone, the
nephrosis is termed steroid resistant .
Diuretics:
USE ONLY IN SEVERE CASE. USE CAUTIOUSLY :
• Hemoconcentration is risk factor for thrombo-embolic
complications.
• Mild to moderate edema can be managed at home with
chlorothiazide, 10–40 mg/kg/24 hr, in two divided
doses (maximum 1000 mg/day)
• If hypokalemia develops, an oral potassium chloride
supplement or spironolactone (aldactone) 3–5 mg/kg/24
hr divided into four doses may be added
• In severe cases, furosemide (lasix) may be given, 0.5-1
mg/kg/day
 RELAPSE

• Definition: the recurrence of edema and not

simply of proteinuria

• Many children will have intermittent proteinuria

that resolves spontaneously
 RELAPSE
• Each relapse should be treated in a similar manner.

• If proteinuria resolves for 3 consecutive days

during a relapse, change to phase 2 (give every
other day prednisone rather than daily)

• A small number of patients will have relapses

shortly after switching to or after terminating
alternate-day therapy (these patients are termed
“steroid dependent”)
 Repeated relapses
• If there are repeated relapses or the child suffers
severe corticosteroid toxicity cyclophosphamide
therapy should be considered

• Cyclophosphamide
• 3mg/kg/24 hr as a single dose x 12 weeks
• Continue alternate-day prednisone
• Need to monitor WBC
• Side effects: leucopenia, hemorrhagic cystitis, alopecia,
sterility
 Summary of new treatment
guidelines
• guidelines that address
The Kidney Disease: Improving Global Outcomes (KDIGO) group released new
management of steroid-sensitive nephrotic syndrome in children aged 1–18 years
• Highlights of these new guidelines include:
• Initial treatment: Oral prednisone, starting as a daily dose of 60 mg/m 2/day or 2 mg/kg/day
(maximum, 60 mg/day) for 4–6 weeks. After 4–6 weeks, switch to 40 mg/m 2 or 1.5 mg/kg
(maximum, 40 mg) on alternate days for 2–5 months with tapering, with a minimum total
duration of treatment of 12 weeks.
• Treatment of infrequent relapse (1 relapse in 6 months or 1–3 relapses in 12 months):
Administer initial treatment dose (60 mg/m 2/day or 2 mg/kg/day) until urinary protein is
negative for 3 days. After urine is negative for protein for 3 days, change prednisone to 40
mg/m2 or 1.5 mg/kg (maximum, 40 mg) on alternate days for 4 weeks, then stop or taper
dose.
• Treatment of frequent relapse (2 relapses in 6 months or ≥4 relapses in 12 months): Continue
infrequent relapse treatment for 3 months at lowest dose to maintain remission or use
corticosteroid-sparing agents, including alkylating agents, levamisole, ciclosporin,
mycophenolate mofetil.
 PROGNOSIS
• Some children with steroid-responsive nephrosis
may have repeated relapses until the disease
resolves spontaneously

• MCNS: No residual renal dysfunction

• To minimize the psychologic effects of the

nephrosis, emphasize that when in remission the
child is normal and may have unrestricted diet
and activity