NEPHROTIC SYNDROME-3.pptx

For medical students

1. NEPHROTIC SYNDROME By w. Simwanza

2. DEFINITION A non-inflammatory condition of glomerular dysfunction characterized by Significant proteinuria (over 1g/m 2 body surface/d), in children it is defined as protein excretion of more than 40 mg/m 2 /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, m embranous, m embranoproliferative 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.

5. CLINICAL FEATURES Edema Periorbital edema is commonly the 1 st abnormality Other locations of edema may be present at extremities, scrotum/labia, abdomen ( ascites ), lungs (pleural effusion) Tiredness Paleur

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

7. 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.

8. 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.

9. 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

10. 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

11. 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

12. 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.

13. Complications Generalized edema ( anasarca ) (pathology of oedema ) C irculatory 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

14. 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 Renal function: usually normal

15. 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 )  

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

17. 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

18. Prednisone Start only a fter 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) d aily (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

19. 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

20. 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

21. 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 .

22. 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

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

24. 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 ”)

25. 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

26. 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/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/m 2 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 .

27. 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