Presentation on theme: "IDIOPATHIC NEPHROTIC SYNDROME IN CHILDREN"— Presentation transcript:
1IDIOPATHIC NEPHROTIC SYNDROME IN CHILDREN Dr. Hala Wannouspediatric nephrologistdamascus universityfaculty of medicinechildren’s hospital.
2Introduction Definition of NS Etiology of NS Pathology of NS Pathophysiology of NSClinical Manifestations of NSComplications of NSLaboratory DataDiagnosisTreatment
3DefinitionNephrotic syndrome (NS) results from increased permeability of Glomeulrar basement membrane (GBM) to plasma protein. It is clinical and laboratory syndrome characterized by massive proteinuria, which lead to hypoproteinemia ( hypo-albuminemia), hyperlipidemia and pitting edema.
4Nephrotic Criteria: *Massive proteinuria : qualitative proteinuria: persistent 3+ or 4+ urinalysis forprotein, Or, urinary protein (mg)/urinary creatinine (mg)ratio in a spot sample >2quantitative proteinuria : 24 hr urine collection forprotein: ≥40 mg/m2/hr , or ≥ 50 mg/kg/24 hr*Hypoalbuminemia :serum albumin : < 2.5 g/dl.*Hyperlipidemia :serum cholesterol : > 5.7 mmol/L (>200 mg/dl)*Edema: pitting edema in different degree, often massivegeneralized oedema
5Etiology of NS (Classification): A- Idiopathic NS (INS): majorityINS is defined by the combination of a nephrotic syndromeand non-specific histological abnormalities of the kidney.The cause is still unclear up to now. Recent 10 years,increasing evidence has suggested that INS may resultfrom a primary disorder of T– cell function.Accounting for 90% of NS in child. mainly discussed .B-Secondary NS:NS resulted from systemic diseases, such as anaphylactoidpurpura, systemic lupus erythematosus, HBV infection.C-Congenital NS: rareFirst 3 months or first year of life, only treatment renaltransplantation.
7Idiopathic NS (INS): Pathology Minimal Change Nephrotic Syndrome (MCNS): about 85%The glomeruli appear normal basically, or show a minimal increase in mesangial cells and matrix under light microscopy. Findings on immunofluorescence microscopy are typically negative. Under Electron microscopy : fusion of the foot processes of the podocytesMesangial proliferative glomerulonephritis: about 5%Focal segmental glomerulosclerosis (FSGS): 7-10%
19NB:*Nephrotic syndrome is 15 times more common inchildren than in adults.*Most cases of idiopathic nephrotic syndrome are in children and are due to minimal-change disease. The age at onset varies with the type of nephroticsyndrome.
20Proteinuria Pathophysiology: Idiopathic nephrotic syndrome is associated withcomplex disturbances in the immune system,especially T cell–mediated immunity.The Main Trigger Of Idiopathic Nephrotic Syndrome and Fundamental and highly important change of pathophysiology :Proteinuria
21Pathogenesis of Proteinuria: Increased permeability of the glomerular capillary wall for proteins due to loss of negative charged glycoprotein.On biopsy, the extensive effacement of podocyte foot processes (the hallmark of idiopathic nephrotic syndrome) suggests a pivotal role for the podocyte.Type of proteinuria:-A-Selective proteinuria: where proteins of low molecular weight(LMW), such as albumin, are excreted more readily than protein of high molecular weight(HMW) .B-Non selective :LMW+HMW are lost in urine
22Pathogenesis of hypoalbuminemia: *Due to hyperproteinuria----- Loss of plasma protein in urine mainly the albumin. *Increased catabolism of protein during acute phase.
23Pathogenesis of hyperlipidemia: *Response to Hypoalbuminemia → reflex to liver --→ synthesis of generalize protein ( including lipoprotein ) and lipid in the liver ,the lipoprotein (high molecular weight) not loss in urine → hyperlipidemia*Diminished catabolism of lipoprotein: loss of lipase in urine.
24Pathogenesis of edema: *Reduction in plasma colloid osmotic pressure↓ secondary to hypoalbuminemia Edema and hypovolemia*Intravascular volume↓antidiuretic hormone(ADH) and aldosterone(ALD) water and sodium retention Edema*Intravascular volume↓ glomerular filtration rate(GFR)↓ water and sodium retention EdemaIntrarenal factors: (Nephrotic kidney retains sodium), may be involved in the formation of edema in some patients with increased intravascular volume with diminished plasma levels of renin and aldosterone.
25How many pathological types causes nephrotic syndrome?
26Clinical Manifestations: In MCNS , The male preponderance of 2:11.Main manifestations:Edema (varying degrees) is the common symptomLocal edema: edema in face , around eyes( Periorbital swelling) ,in lower extremities.Generalized edema (anasarca), ascites, pleural effusion, edema in penis and scrotum.2-Non-specific symptoms:Fatigue and lethargy , loss of appetite, nausea and vomiting , abdominal pain , diarrheabody weight increase, urine output decreasepleural effusion (respiratory distress)
29Investigations: 1-Urine analysis: a-Proteinuria: or 4 + SELECTIVE. Or, urinary protein (mg)/urinary creatinine (mg) ratio in a spot sample >2b-24 hr urine collection for protein:≥40 mg/m2/hr , or ≥ 50 mg/kg/24hrc- volume: oliguria (during stage of edema formation)d-Microscopically:Macroscopic hematuria is rare, occurring in 3% of patients.Microscopic hematuria is present in 20% of cases.Fat bodies, large number of hyaline casts
30Investigations: 2-Blood: A-serum protein: decrease ＜ 5.5 g/dL , Albumin levelsare low (＜2.5 g/dL).B-Serum cholesterol and triglycerides: high, Cholesterol ＞5.7 mmol/L (＞ 200mg/dl).C- Hemoglobin levels and hematocrit are increased inpatients with plasma volume contraction.D-Serum complement: Vary with clinical type.E-Renal function : Blood urea nitrogen and creatinine concentrations are usually within the normal range, or slightly increased in relation to a modest reductionin the glomerular filtration rate (GFR).
31Initial episode of Nephrotic syndrome C3, C4, CH50, ANA, Anti DNA Antibodies, ANCAPT, PTT, Fibrinogen, ATIII, Protein C, Protein SScreen for tuberculosis: x-ray chest, mantoux testScreen for urinary tract infection; urine culture and colony count.HbsAg test, HCV Antibodies, HCV PCR, HIV Antibodies.Steroid therapy is started after the infection is cleared (forTB, after 3-4 weeks of 2 anti TB drugs).
32Kidney Biopsy: Considered in: 1- Children less than 1 year, or more than 11 years of age2- Macorscopic Hematuria3- Persistent Hypertension4- Persistent renal failure (raised BUN, Creatinine) withouthypovolemia5- Low serum C3 levels (Secondary NS)6- Steroid resistant NS7- Frequent relapsing NS, before considering alternativetherapy, namely anticalcineurin agents.
33Differential Diagnosis of NS: D.D of generalized edema:-1- Protein –losing enteropathy2- Hepatic Failure.3- Protein energy malnutrition4- Acute and chronic GN5- urticaria? Angio edema
34Complications of NS: 1-Infections: Infections is a major complication in children with NS.It frequently trigger relapses.Nephrotic patients are liable to infection because :A- loss of immunoglobins in urine, and an impaired synthesis.B- Impaired T lymphocyte function.C- The edema fluid act as a culture medium.D- Use corticosteroids and immunosuppressive agents.E- MalnutritionThe common infection : URI, peritonitis, cellulitis, and UTI may be seen.Organisms: encapsulated (Pneumococci, H.influenzae), Gram negative (e.g E.coli), and Viral infections (Chickenpox).
35Complications … Vaccines in NS: polyvalent pneumococcal vaccine (if not previouslyimmunized) at disease onset, or when the child is in remissionand off daily prednisone therapy.Children with a negative varicella antibodies titer should begiven varicella vaccine.Varicella vaccination is safe and effective if the child is inremission even if he is on low-dose alternate day steroids.
36Complications….. 2-Hypercoagulability (Thrombosis): Hypercoagulability of the blood leading to venous or arterial thrombosis.Hypercoagulability in Nephrotic syndrome caused by:1- Higher concentration of I, II, V,VII, VIII, X, XIII, andfibrinogen2- Lower level of anticoagulant substance:antithrombin III, protein C, protein S.3- decrease fibrinolysis.4- Higher blood viscosity (Hypovolemia)5- Increased platelet aggregation6- Overaggressive diuresis7- Infection
37Complications….. 3- Acute Renal Failure : pre-renal and renal. 4- cardiovascular disease :Hyperlipidemia, may be a risk factor forcardiovascular disease.5- Hypovolemic shock6- Others: growth retardation, malnutrition,adrenal cortical insufficiency.
38Management of NS:General (non-specific )*Corticosteroid therapy
39General therapy: Hospitalization: Diet : for initial work-up and evaluation of treatment.Diet :Protein intake of around 130–140% of the recommendeddaily allowance for age.Low salt diet: only during period of edema or hypertension.Salt-free diet: in cases of massive edema.Restricting fluid intake: in severe edema and hyponatremia(plasma sodium concentration less than 125 meq/l).Reduction of saturated fat is recommended.Carbohydrates should be given preferentially as starch ordextrin-maltose, avoiding sucrose which increases lipidabnormalities.
40General therapy: Activity: usually no restriction , except massive edema, heavy hypertension, and infection.Avoiding infection: very important.Diuretics :Diuretics should only be used in cases of severeedema, after hypovolemia has been corrected.Furosemide is administered at a dose of 1–2 mg/kg.Furosemide with Hydrochlorothiazide (HCT): 2 mg/kg/daySpironolactone : 5–10 mg/kgPatients with severe edema may be treated with furosemideplus albumin to increase the rate of diuretic delivery to thekidney (loop diuretics are highly protein bound).Refractory edema with serious effusions may require drainage of ascites and/or pleural effusions.
41Indication of albumin infusion therapy Albumin : Intravenous 20% albumin infusion at a dose of1 g/kg/dose, given over 3–4 hours.Indication:1- Severe edema2- Ascites3- Pleural effusion4- Genital edema5- HypovolemiaFollowed immediately by furosemide (1–2 mg/kg/dose), after exclude hypovolemia.
42General therapy: Anticoagulant : Prophylactic warfarin therapy may be given to high riskpatients with :Plasma albumin concentration below 20 g/l, with:fibrinogen level over 6 g/l, or an antithrombin III levelbelow 70% of normal.Patients at risk may also be treated with low dose aspirinand dipyridamole.Treatment of Hyperlipidemia: Statins are effective.Anti Hypertension Drugs: An angiotensin converting enzymeinhibitor is preferred.VaccinationPreventive treatment with vitamin D and Calcium supplements.
43Corticosteroid—prednisone therapy: The standard regimen : Prednisone at a dose of 60 mg/m2/day (maximum 80 mg/day), divided into 2 doses for 4 consecutive weeks . After complete absence of proteinuria (remission), prednisone dose should be tapered to 40 mg/m2 given every other day as a single morning dose for 4 weeks [ International Study of Kidney Disease in Children (ISKDC) ]. There is emerging evidence that children who receive 3 months or more steroid therapy at disease presentation appear to have a significantly higher relapse-free rate at 12 months post- presentation than those who receive the standard regimen. Thus, the alternate-day dose is slowly tapered and discontinued over the next 2-3 months.
44Treatment of relapse in NS: Many children with nephrotic syndrome(50-70%) will experience one or more relapses: (proteinuria>50 mg/kg/day or Albustix +++ for 3 consecutive days after having been in remission). Treatment: Prednisone at a dose of 60 mg/m2/day (maximum 80 mg/day), divided into 2 doses until the child enters remission (proteinuria˂5 mg/kg/day or urine trace or negative for protein for 3 consecutive days). The prednisone dose is then changed to alternate- day dosing and tapered over 1-2 months.
45According to response to prednisone therapy: 1- Steroid Sensitive2- Steroid Dependent3- Steroid ResistantSteroid Sensitive : complete remission achieved with steroidtherapy (More than 95% of children with minimal changedisease, and less than 20% of patients with FSGS).Steroid Dependent: ≥ 2 consecutive relapses duringcorticosteroid therapy, or within 14 days after cessation oftherapy.Steroid resistant: failure to achieve remission following 4 weeksprednisone 60 mg/m2/day, followed by 3 pulses ofmethylprednisolone.Frequent relapsing: 2 or more relapses within the first 6 monthsafter the initial remission, or 4 or more relapses withina period of 1 year.
46Side Effects With Long Term Use of Steroids (Steroid toxicity): .hyperglycemiamyopathypeptic ulcerpoor healing of wound.Hirsutism, striae, acneThromboembolismHypertensionSusceptibility to infectionsobesityStunted growthCataractsPseudo tumor cerebralPsychosisOsteoporosisavascular necrosis of boneCushingoid featuresAdrenal gland suppression
47Major therapeutic challenges in NS are: Frequent relapses/ steroid - dependent cases First 2-3 relapses are treated with short courses of oral prednisone 60 mg/m2/day, till remission occurs followed by alternate days single dose for 4 weeks. Since repeated courses of high dose steroids cause more steroid toxicity than alternate day regimes given for 6-12 months, thus after the 3rd relapse within 6 months (frequent relapser), or steroid - dependent cases are subsequently treated with oral prednisone used in as low dose as possible on alternate days to maintain sustained remission without major side effects. Most children tolerate 0.5 mg/kg of prednisone on alternate days without side effects and maintain protein free urine.
48Alternative agent: When can be used: Cyclophosphamide Plus steroids Steroid-dependent patients, frequent relapsers, and steroid-resistant patients.Cyclophosphamide Plus steroidsCyclosporin ATacrolimusMycophenolate mofetile (MMF)
49Indications for Alternative Therapy in a steroid responsive NS: Relapse occurs on prednisone dosage >0.5 mg/kg / on alternate days plus one or more of the following : A- Unacceptable side effects of corticosteroid therapy B- High risk of toxicity: boys approaching puberty, ordiabetes. C- Unusually severe relapses with hypovolemia, thrombosis,severe sepsis, or acute renal failure. D- Inadequate facilities for follow-up or concern aboutcompliance.Relapse on prednisone dose > 1 mg/kg on alternate days.Drugs used for alternative therapy are introduced after inducing remission with oral prednisone therapy whilst tapering steroids. the details for dosage, duration and side – effects of these drugs is given in the following table :
50Drug dosage and duration MonitoringSide EffectsDrug dosage and durationClinical: CBC, Urinalysis (every two weeks). Sperm count after puberty.Reversible: alopecia, Hemorrhagic cystitis, Bone Marrow suppression, Infections. Long term: gonadal toxicity, sterility and malignancy.Cyclophosphamide 2 mg/kg/day PO x 8 – 12 weeks MAX cumulative dose: mg/kgAfter puberty EEGSame as above Focal seizuresChlorambucil 0.2 mg/kg/day PO X 8 – 12 weeks Max cumulative dose: mg/kgCBC monthly.Skin rash, abdominal pain, vomiting and neutropenia, vasculitis, hyperactivity and seizuresLevamisole 2.5 mg/kg/alternate day x 6 – 24 monthsCBC weekly.Diarrhea-vomiting-abdominal pain, bone marrow depressionCellceptMycophenolate mofetil600 mg/m2/dose, twice daily(maximum dose of 1000 mg bid)Or 15 mg/kg/day x 12 – 24 monthsDrug monitoring monthly (Trough Level 100 – 150 ng/ml),S. Creatinine monthly. Kidney biopsy yearlyHypertension, gingival hyperplasia, hirsutism, hyperkalemia, infections, nephrotoxicity.Cyclosporin A 4-6 mg/kg/day BID for 6 –12 months.