For medical students

1. NEPHROTIC
SYNDROME
By w. Simwanza

2. 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

3. 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)

4. • 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.

6. 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

7. • Metabolic consequences of the nephrotic
syndrome include the following:
• Infection
• Hyperlipidemia and atherosclerosis
• Hypocalcemia and bone abnormalities
• Hypercoagulability
• Hypovolemia

8. • 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.

9. • 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.

10. • 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

11. • 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

12. • 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

13. • 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.

14. 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

15. 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

16. 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)

17. MANAGEMENT
Goals
• Establish the cause
• Treat the cause if possible
• Treat the symptoms
• Prevent complications

18. 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

19. 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)
Medications

20. • 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

21. 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

22. • 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 .

23. 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

24. RELAPSE
• Definition: the recurrence of edema and not
simply of proteinuria
• Many children will have intermittent proteinuria that
resolves spontaneously

25. 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”)

26. 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

27. Summary of new treatment
guidelines
• The Kidney Disease: Improving Global Outcomes (KDIGO) group released new guidelines that address
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/m2/day or 2 mg/kg/day
(maximum, 60 mg/day) for 4–6 weeks. After 4–6 weeks, switch to 40 mg/m2 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/m2/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.

28. 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