Done by Dr. Ali Abdul-Razak Nephrotic syndrome Done by Dr. Ali Abdul-Razak

Normal urinary protein excretion is ≤100 mg/m²/day or ≤ 150 mg/day Proteinuria Normal urinary protein excretion is ≤100 mg/m²/day or ≤ 150 mg/day Normal A/G ratio is 1 First –morning sample of urine protein/creatinine value of more than 2-3 mg/mg indicates nephrotic range proteinuria and correlates with results from 24-hour urine collection.

TSP=5.5-9.9 g 3.5-5.5g Albumin Globulin 2-3.5 g

The dipstick is reported as Negative Trace (10-20 mg/dL) 1+ (30 mg/dL) 2+ (100 mg/dL) 3+ (300 mg/dL) 4+ (1000-2000 mg/dL).

Causes of proteinuria: Transient proteinuria: fever, exercise, dehydration, cold exposure, congestive HF, seizure and stress. Orthostatic(postural) proteinuria.

Glomerular disease: (previous causes of glomerular hematuria) plus diabetic nephropathy. Tubular disease: here the proteinuria is less than 1g/day like in cystinosis, Wilsons disease, galactosemia, heavy metal poisoning, acute tubular necrosis, reflux nephropathy.

Nephrotic syndrome It is primarily a pediatric disorder and it is 15 times more common in children than adults. It is characterized by heavy proteinuria (more than 2g/day or> 40mg/m²/hr), hypoalbuminemia (less than 2.5g/dl), edema, and hyperlipidemia.

Mesangial proliferation 5% Idiopathic NS 90% Minimum change disease 85% Mesangial proliferation 5% Focal segmental glomerulosclerosis 10%

The remaining 10% have NS due to membranous nephropathy or membranoproliferative GN

Pathophysiology: By light microscopy :In minimum change disease the glomeruli appear normal or show minimum increase in the mesangial cells and matrix. By electron microscopy reveal effacement of epithelial cell foot processes. The underlying abnormality in NS is an increase in the permeability of the glomerular capillary wall (due to loss of negative charges), which leads to massive proteinuria and hypoalbuminemia.

fusion of foot process of epithelial in EM

Pathophysiology Edema appears when albumin less than 2.5 g/dl decreased oncotic pressure transudation of fluid to interstitial space decreases intravascular volume increased reabsorption of salt and water via the renin-angiotensin-aldosterone system and ADH, respectively

Pathophysiology : Hyperlipidemia elevated serum lipids (cholesterol and triglycerides) and lipoprotein levels via: hypoalbuminemia generalized increase in hepatic protein synthesis(including lipoprotein) reduced levels of lipoprotein lipase(loss in urine) diminished lipid catabolism

Clinical features It more common in male than female ratio is 2:1 It is most common in children 2-6 years of age initial episode and subsequent relapses may follow an upper respiratory tract infection

Hypertension and gross hematuria are uncommon 1. Proteinuria symptomatic pitting edema Usual initial feature eyes, lower extremities - generalized - ascites, pleural effusion - weight gain with decreased urine output fluid accumulates in dependent areas and may shift from face & back to abdomen, perineum, and legs as the day progresses Hypertension and gross hematuria are uncommon

Edema in scrotum and penis Ascites and abdomen distention

2. Other Manifestations: abdominal pain, anorexia, diarrhea 3. complications: 1. Infections: child with NS liable for infection for different reasons: Urinary loss of immunoglobulin(IgG, IgA, Complement  and properdin factor B) Defective cell mediated immunity Immunosuppressive therapy (steroids & cytotoxic drugs) Malnutrition Edema act as a good culture media for bacteria

Spontaneous bacterial peritonitis is the most frequent type of infection (streptococcal pneumoniae, gram negative like E.coli) Also sepsis, pneumonia, cellulitis and UTI. s/s of infection may be minimal if on steroid therapy all patients should receive a single injection of polyvalent pneumococcal vaccine while in remission Influenza vaccine should be given on yearly basis.

2. Arterial and Venous Thrombosis due to an increase in: certain coagulation factors I, Ⅱ,Ⅴ,Ⅶ,Ⅷ,Ⅹ inhibitors of fibrinolysis platelet aggregation - (decreased antithrombin III) Partial immobilization hemoconcentration

3. Others deficiencies of coagulation factors IX, XI, & XII reduced levels of vitamin D. growth retardation, malnutrition 4. Electrolyte imbalance: hyponatremia, hypokalemia, hypocalcaemia 5. ARF: pre-renal and renal( rare with minimal change NS) 6. Hypovolemic shock.

Diagnosis 1. Urinalysis: proteinuria 3+ to 4+ ,urinary protein exceed 40mg/m²/hour in children Microscopic hematuria in 20% of cases. 2. Serum albumin level less than 2.5g/dl (with reversed ratio of albumin/globulin). 3. Decreased calcium due to decreased albumin.

4. Serum cholesterol and triglyceride are elevated. 5. Normal C3 level 6. Renal function usually normal 6. Renal biopsy is not required in most cases.°

Treatment 1. Edema 1. Moderate salt-free diet chlorothiazide 10-40 mg/kg/d po bid with KCl supplement or spironolactone 3-5 mg/kg/d po qid NB. Be careful of hypovolemia and shock

Treatment 2. Severe salt-free diet fluid restriction elevate swollen scrotum with pillows 25% albumin 1 gm/kg/d IV followed by lasix 1-2 mg/kg/d po qid or metolazone 0.2-0.4 mg/kg/d po bid

60 mg/m2/d po single daily dose (max. dose of 80 mg/d), 2. Proteinuria 1. Prednisone 1. Initial Therapy 60 mg/m2/d po single daily dose (max. dose of 80 mg/d), Or 1-2mg/kg/day for 4-6 weeks or until urine is negative of albumin response time: 50% of cases respond within 8 days 80% of cases respond within 1 month - (a majority respond within 2 weeks)

protein-free urine for 3 consecutive days Treatment goals: protein-free urine for 3 consecutive days normalization of albumin (complete remission) steroid-responsive: 95% of those with minimal-change 55% of those with mesangial proliferative 20% of those with focal sclerosis

After 6 weeks daily dose give: 2. 'Weaning' Therapy After 6 weeks daily dose give: 40 mg/m2/d po single morning dose on alternate days For at least 4 weeks slowly tapered for 1-2mo Relapse , is the recurrence of proteinuria+edema 3. Relapse therapy 60 mg/m2/d po tid until proteinuria resolves for 3 consecutive days then 40 mg/m2/d po alternate day for 4 weeks

Steroid dependent NS: relapse shortly after switching to or after terminating alternate-day therapy . Steroid resistant NS: those patients who continue to have proteinuria after 8 weeks of steroid therapy (renal biopsy indicated) Therapy of steroid dependent and resistant NS: cyclophosphamide 2-3 mg/kg/d po d for 8-12 weeks may be given with alternate day steroid therapy

Side effects of cyclophosphamide: leukopenia (monitor WBC count weekly & if <5,000, discontinue cyclophosphamide) disseminated varicella infection hemorrhagic cystitis alopecia sterility

Other options: for complicated NS High dose pulse methylprednisolone 30mg/kg bolus , first 6 doses given every other day followed by tapering regimen for up to 18 mo Cyclosporine 3-6mg/kg/day bid Angiotensin converting enzyme inhibitors may be helpful adjunct therapy to reduce proteinuria.

Prognosis Majority with steroid-dependent variety will have repeated relapses until spontaneous resolution of the disease toward the end of the 2nd decade . Steroid resistant NS most often caused by focal segmental glomerulosclerosis have a poorer prognosis end stage RF

Prognosis poor prognostic factors : hematuria hypertension hypocomplementemia Age < 1year and > 7years All these are indications for renal biopsy

Congenital nephrotic syndrome It refers to infants who develop NS during the first 3mo of life The most common cause is the Finnish type, AR disorder (Scandinavian descent) Usually presented with massive proteinuria, large placenta and marked edema recurrent infections progressive RF death by the age of 5 years.

Congenital nephrotic syndrome Steroids and immunosuppressives are of no value. Final treatment bilateral nephrectomy, frequent dialysis and kidney transplant . Antenatal diagnosis : increase α fetoprotein in amniotic fluid.

Congenital nephrotic syndrome Other causes of congenital NS include --Congenital infections like syphilis, toxoplasmosis, rubella and CMV. --Treatment of the underlying infection may improve or resolve the nephrotic state.