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Nephrotic Syndrome In ChildrenWhen not to refer? : 

Nephrotic Syndrome In ChildrenWhen not to refer? Dr Geetha.S Asst.Professor, Dept of Pediatrics Medical College, Trivandrum

Introduction : 

Introduction Chronic disease in children Mostly managed by Pediatricians Familiar with treatment Different courses Long-term management of some children will need a joint effort with nephrologist

Definition : 

Definition Heavy Proteinuria Hypoalbuminemia <2.5 gm/dl Hyperlipidemia- S.cholesterol>200mg/dl Edema

Nephrotic Syndrome (NS): Types : 

Nephrotic Syndrome (NS): Types Minimal change nephrotic syndrome (MCNS) Focal segmental glomerulosclerosis (FSGS) Membranoproliferative glomerulonephritis (MPGN) Membranous glomerulonephritis (MGN). Congenital nephrosis

Minimal Change Glomerulopathy : 

Minimal Change Glomerulopathy Glomerular diseases that cause NS Pathology No glomerular lesions by light microscopy No staining with antisera specific for immunoglobulins or complement components. Effacement of visceral epithelial cell foot processes

Epidemiology : 

Epidemiology Prevalence is 2-5 cases per 100,000 children and the cumulative prevalence rate is 15.5/100,000. Age MCNS 2.5 years median age FSGS 6 years median age Sex 3:2 Boys:Girls in children <6 yrs Equal ratio in those older

Epidemiology : 

Epidemiology Familial incidence European survey 63 of 1877 nephrotic children had affected siblings Familial NS similar with respect to histopathology and steroid response

Nephrotic Syndrome : 

Nephrotic Syndrome Generally has a glomerular cause Types: primary and secondary Secondary NS : anaphylactoid purpura, SLE, diabetes mellitus, sickle cell disease,Syphilis,Malaria,Hepatitis B

Proteinuria : 

Proteinuria Early morning urine protein is 3+/4+ (ondipstick or boiling test), Spot protein/creatinine ratio >2 mg/mg, or Urine albumin excretion >40 mg/m2 per hr (on a timed-sample)

Edema : 

Edema Lower colloid osmotic pressure? 15mmHg H2O colloid osmotic pressure 26 mmHg

Clinical Features- Edema : 

Clinical Features- Edema Intravascular volume depletion Sodium retention Renin-aldosterone activation

Scoring System for Oedema : 

Scoring System for Oedema Ankle Oedema (+) Ankle & Leg Oedema but not to knee (++) Ankle & Leg Oedema to knee (+++) Oedema to thighs Oedema to thighs with ascitis and/or sacral fluid Oedema to thighs with ascitis and pleural effusion.

Hypoproteinemia : 

Hypoproteinemia Albumin Immunoglobulins Metal binding proteins Erythropoietin urinary loss Transferrin Complement deficiency Coagulation components

Hyperlipidemia : 

Hyperlipidemia Hypercholesterolemia Hypertriglyceridemia Low-density lipoproteins (LDL) Increased Very low- density lipoproteins (VLDL) Increased

Mechanisms of Hyperlipidemia : 

Mechanisms of Hyperlipidemia Increased hepatic synthesis of LDL, VLDL and lipoprotein (a) in response to hypoalbuminemia Urinary loss of HDL Enzymatic changes with abnormal lipid biosythesis and degradation(urinary loss of lipoprotein lipase)

Clinical Features- Infection : 

Clinical Features- Infection Bacterial infections Prone to bacterial sepsis Cellulitis Viral Infections Relapse preceded by viral infection Measles may induce remission in NS

Clinical Features- Thrombosis : 

Clinical Features- Thrombosis Serious risk of thrombosis Increased fibrinogen concentration Antithrombin III concentration reduced Platelets hyperaggregable Increased blood viscosity

Initial evaluation : 

Initial evaluation Height, Weight Blood pressure Physical examination-infections and underlying systemic disorder

Laboratory : 

Laboratory Urinalysis Complete blood count, S. Albumin, cholesterol, urea & creatinine S. Sodium ASO & C3(with gross or persistent microscopic hematuria Chest X-ray and tuberculin test Hepatitis B surface antigen, antinuclear antibodies. Urine culture ( routinely not necessary)

Laboratory- Plasma Protein : 

Laboratory- Plasma Protein Albumin Hypoalbuminemia due to loss via the kidney Immunoglobulins IgG levels reduced IgM levels elevated IgM-IgG-Switching

Laboratory- Hyperlipidemia : 

Laboratory- Hyperlipidemia Increased synthesis of cholesterol, triglycerides and lipoproteins Decreased catabolism of lipoproteins Decreased activity of lipoprotein lipase Decreased LDL receptor activity Increased urinary loss of HDL

Laboratory- Urinalysis : 

Laboratory- Urinalysis Broad, waxy casts Lipid droplets Hematuria (22.7 % of MCNS ) Low urine sodium High osomolality

Selectivity Index : 

Selectivity Index Clearance of IgG/ Clearance of Transferrin MCD 53% < 0.10 13 % > 0.20 FSGS 15% < 0.10 57% > 0.20

Appropriate therapy of first episode : 

Appropriate therapy of first episode Dose and Duration of corticosteroids Doesn’t affect response rate (Hodson EM, Willis NS, Craig JC. Corticosteroidtherapy for nephrotic syndrome in children.Cochrane Database System Rev 2007; CD001533)

Steroid-Prednisolone : 

Steroid-Prednisolone Duration - minimum of 12 weeks. Sustained remission and reduction in relapse rates are superior if AD treatment is not stopped abruptly but tapered over the next 2-4 months.(Cochrane group) Dose 2 mg/kg per day (maximum 60 mg in single or divided doses) for 6 weeks, followed by 1.5 mg/kg (maximum 40 mg) as a single morning dose on alternate days for the next 6 weeks( IAP)

Course-Remission : 

Course-Remission Urinary protein excretion <4 mg/m²/h; nil or trace by dipstick on spot sample for 3 consecutive early morning specimens

Relapse : 

Relapse Urinary protein excretion >40 mg/m²/h; > 3+ by dipstick for 3 consecutive morning specimens having been in remission previously Edema is not essential

Frequent relapses : 

Frequent relapses Two or more relapses in 6 months of initial response; 3 or more relapses in any 12 month period

Steroid resistance : 

Steroid resistance Failure to achieve remission after 4 wk of daily therapy with oral prednisolone at a dose of 2 mg/kg/day

Steroid dependence : 

Steroid dependence Occurrence of 2 consecutive relapses during alternate steroid therapy or within 2 wk of its cessation 28 days(Nelson)

Treatment -Relapse : 

Treatment -Relapse Prednisolone 2 mg/kg/day (single or divided doses) until urine protein is trace or nil for three consecutive days. Single morning dose of 1.5 mg/kg on alternate days for 4 weeks, and then discontinued. Duration of treatment is 5-6 weeks. Prolongation of therapy is not necessary for patients with infrequent relapses

Relapse : 

Relapse No predictors of relapse Relapses as responsive to steroids 25% spontaneously remit Treatment may be deferred till 5 days Intensification of relapse treatment has little effect on subsequent relapse rate

Frequent relapser : 

Frequent relapser prednisolone is gradually tapered to maintain the patient in remission on alternate day dose of 0.5-0.7 mg/kg, Duration for 9- 18 months. Monitor growth and blood pressure, features of steroid toxicity.

Indications for Alternative Therapy-SSNS : 

Indications for Alternative Therapy-SSNS Relapse on Prednisone Dosage <0.5-0.7 mg/kg/alt day plus: Severe steroid side effects High risk of toxicity- diabetes Unusually severe relapses Relapses on Prednisone Dosage >0.5-0.7 mg/kg/alt day

Drugs : 

Drugs Levamisole 2-2.5 mg/kg on alternate days for 12-24months with prednisolone 1.5 mg/kg on alternate days is given for 2-4 weeks; and Dose of PDN is gradually reduced by 0.15-0.25 mg/kg every 4 weeks to a maintenance dose of 0.25-0.5 mg/kg that is continued for six or more months. PDN can be discontinue rarely

Levamisole- SSNS : 

Levamisole- SSNS British association for Pediatric Nephrology 1991 ,61 children Levamisole vs placebo same dose Steroids stopped at 56 days 14/31 in levmisole group in complete remission at 112 days 4/30 in placebo group in complete remission

Levamisole – Side effects : 

Levamisole – Side effects Leukopenia; Flu-like symptoms, Liver toxicity, Convulsions Skin rash The leukocyte count should be monitored 12-16 weeks interval

Alternate drugs : 

Alternate drugs Cyclophosphamide, Tacrolimus, Mycophenolate mofetil, Cyclosporine

ACE Inhibition : 

ACE Inhibition 50% decrease in proteinuria without a decrease in GFR in patients Enalapril(0.1-0.2mg/day)

Diet-balanced : 

Diet-balanced Protein (1.5-2 g/ kg) In persistent proteinuria high (2-2.5 g/kg ) Good quality protein < 30% calories should be derived from fat Reduction of salt intake (1-2 g per day) in persistent edema. PDN stimulates appetite Preventing excessive weight gain

Edema : 

Edema PDN produces diuresis within 5-10 days, Diuretics Contraindicated -diarrhea, vomiting or hypovolemia. Indication- persistent edema and weight gain of 7-10% (oral frusemide (1-3 mg/kg/day), <1week Potassium sparing diuretics -Higher doses and prolonged duration of frusemide, e.g., spironolactone (2-4 mg/kg daily). Blood pressure should be monitored frequently.

Edema unresponsive : 

Edema unresponsive Loop and thiazide diuretic, and/or a potassium sparing agent Refractory edema-Albumin (20%) infusion at 0.5-1 g/kg over 2-4hr, followed by administration of frusemide (1-2 mg/kg IV) Albumin Hypovolemia Oliguria Renal insufficiency Abdominal pain Hypotension

Action of albumin : 

Action of albumin Increased urine output( the effect is not sustained). Caution- patients with renal failure, pneumonia or pulmonary edema Monitor for respiratory distress, hypertension and CCF. Paracentesis- resp distress,skin breaks

Treatment- Antibiotics : 

Treatment- Antibiotics IV Cry Penicillin with ascites(role of prophylactic antibiotics is controversial) Gram negative coverage for peritonitis

Vaccines & Relapse : 

Vaccines & Relapse Precipitation of relapse- hepatitisB,MMR or meningococcal vaccines

Course : 

Course Morbidity 1/4 of patients have a single relapse 1/4 relapse occasionally 1/2 become steroid dependent Steroid toxicity pre-renal azotemia Dyslipidemia Most remit at puberty 2-7% will continue to relapse Renal survival near 100% in MCNS

Course : 

Course Mortality 1940’s- 40% 1 year mortality but Now 1-2% Main cause of death is Infection & Thrombosis Late outcome of 152 patients followed 14-19 years 7.2% mortality

Predictors of course : 

Predictors of course Remission of proteinuria is better predictor than histology

Probability of no renal failure : 

Probability of no renal failure

Complications -Peritonitis : 

Complications -Peritonitis Asymptomatic CF- Abdominal pain, tenderness, distension, diarrhea, vomiting Organisms-S. pneumoniae, S. pyogenes, E. coli Drugs-Cefotaxime or ceftriaxone for 7-10 days; ampicillin+genta 7-10days ascitic fluid >100 leukocytes/mm3; >50% neutrophils

Pneumonia : 

Pneumonia CF-Fever, cough, tachypnea, intercostal recessions, crepitations Organisms S. pneumoniae,H. influenzae, S. aureus Drugs-Oral: amoxicillin, co-amoxiclav, erythromycin Parenteral: ampicillin and aminoglycoside; or cefotaxime/ceftriaxone Duration 7-10 days

Cellulitis : 

Cellulitis Cutaneous erythema, induration, tenderness Staphylococci, Group A streptococci, H. influenzae Co-amoxiclav, Cloxacillin and ceftriaxone for 7-10 days

Fungal : 

Fungal Pulmonary infiltrates, persistent infections fever unresponsive to antibiotics, sputum/urine showing septate hyphae Candida, Aspergillus spp. Skin, mucosa: fluconazole for 10 days Systemic Amphotericin for 14-21 days

Thrombosis : 

Thrombosis Risk factors Arterial&venous Sites- renal with oligoanuria,hematuria or flank pain, especially following an episode of dehydration. Femoral and mesenteric arterial thrombosis Saggital sinus and cortical venous thrombosis after diarrhea and present with convulsions, vomiting, altered sensorium and neurological deficits.

Thrombosis : 

Thrombosis Investigations Ultrasonography, Doppler studies and cranial MRI Treatment- Of dehydration, use of heparin (IV) or low-molecular-weight heparin (subcutaneously) initially, followed by oral anti-coagulants on the long-term No role for prophylactic treatment with anticoagulants

Hypertension : 

Hypertension The onset of nephrotic syndrome or later due to steroid toxicity. Drugs-ACE inhibitors, calcium channel blockers or β adrenergic antagonists Aim-keep the blood pressure at less than the 90th centile

Hypovolemic shock : 

Hypovolemic shock Risk factors Clinical features abdominal pain, hypotension, tachycardia, cold extremities and poor capillary refill; Lab:hematocrit , urea and uric acid are elevated. Management :rapid infusion of normal saline at a dose of 15-20 mL/kg over 20-30 minutes;this is repeated once more Infusion of 5% albumin (10-15 mL/kg) or 20% albumin (0.5-1 g/kg)

Can you Predict a Relapse? : 

Can you Predict a Relapse? early onset of nephrotic syndrome, frequently relapsing course, and treatment with alkylating agents or CsA

Steroid Toxicity : 

Steroid Toxicity Cushingoid habitus Obesity Striae Hirsutism Acne Growth failure Avascular necrosis Osteoporosis

Steroid Toxicity : 

Steroid Toxicity Peptic ulceration Pancreatitis Posterior lens opacities Myopathy Increased ICP Susceptibility to infection

Monitor : 

Monitor blood pressure six-monthly record of height and weight and yearly evaluation for cataract.

Diagnosis : 

Diagnosis Diagnosis: NS? Primary or secondary? Complications?

Differential diagnosis : 

Differential diagnosis Primary Secondary Children minimal change HSP Teenager mesangial proliferative FSGS nephritis Middle age mesengial capillary SLE, LN nephritis old age membranous myeloma, nephropathy amyloidosis

Treatment : 

Treatment Minimal changes: sensitive to steroids; single drug; reuse when relapse; combined with cytotoxic drugs when resistant or dependent on steroids Membranous GN: combine steroid with cytotoxic drugs or cyclosporin

Treatment : 

Treatment FSGS: sensitive to steroids in 30-50% of patients; slow response to therapy; steroids therapy (onset) for 3-4 months; if not response until 6 month (resistant), then try cyclosporine. Mesangial proliferative GN: no evidence show that adults will response to steroids; aspirin

Long term management : 

Long term management Parental motivation and involvement provide information on expected course and risk of complications Urine albumin check- frequency( relapse, during intercurrent infections, mild periorbital puffiness)

Slide 67: 

Daily urine protein examination, medications received and intercurrent infections. Ensure normal activity and school attendance Appropriate immunization and other measures for protection.

Other drugs : 

Other drugs symptoms of upper gastrointestinal discomfort-ranitidine Long-term calcium supplementation prolonged (>3 months) treatment with steroids should receive supplements of oral calcium (250-500 mgdaily) and vitamin D (125-250 IU) hyperlipidemia, lipids normalize following remission.

Other steroids : 

Other steroids Deflazacort-under evaluation Methyl prednisolone –pulses in resistant NS

Steroids & immunisation : 

Steroids & immunisation 2 mg/ kg/day or greater, or total 20 mg/day or greater (for patients weighing >10 kg) for more than 14 days are considered immunocompromised No live vaccines Live vaccines -Off steroids for least 4 weeks or alternate day less than 0.5 mg/kg. No oral polio for siblings

Immunizations : 

Immunizations Varicella VZIG if exposed within 96 hr of exposure a single dose of intravenous immunoglobulin (400 mg/kg) may be used instead (Pickering LK, Baker CJ, Long SS,McMillan JA. Red Book: 2006 Report of theCommittee on Infectious Diseases, 27th edn. Elk Grove Village, IL: American Academy of Pediatrics; 2006. p. 711-725.)

After remission-Pneumocooccal vaccine : 

After remission-Pneumocooccal vaccine 2-4 doses of the heptavalent conjugate pneumococcal vaccine for children below 2 yr of age. unimmunized children between 2-5 yr, a priming dose of the conjugate vaccine should be followed 8 weeks later, by a dose of the 23-valent polysaccharide vaccine. Children older than 5 yr -single dose of the polysaccharide vaccine. Revaccination after 5 yr is considered for children (<10-yr-old) with active nephrotic syndrome.

Varicella vaccine : 

Varicella vaccine One dose is recommended for children between 12 months and 12 yr of age, and 2 doses separated by an interval of at least 4 weeks for children 13 yr or older

Varicella : 

Varicella intravenous acyclovir (1500 mg/m2/day in 3 doses)or oral acyclovir (80 mg/kg/day in 4 doses) for 7-10 days The dose of prednisolone should be tapered to 0.5 mg/kg/day or lower

TB : 

TB Mantoux positive but show no evidence of tuberculosis should receive prophylaxis with INH for six months. Those showing evidence of active tuberculosis should receive standard therapy

Stress : 

Stress high-dose steroids for more than 2 weeks in the past year supplementation of steroids during surgery, anesthesia or serious infections IV hydrocortisone of 2-4 mg/kg/day, followed by oral prednisolone at 0.3-1 mg/kg/day. Rapid tapering

Pediatrician can manage successfully : 

Pediatrician can manage successfully Idiopathic nephrotic syndrome Its complications Frequent relapses or steroid dependence

Even then… a referral is needed : 

Even then… a referral is needed Onset below 1-year of age, Family history of nephrotic syndrome. Hypertension, Gross/persistent microscopic hematuria, Impaired renal function, Extrarenal features (e.g., arthritis, serositis, rash). Complications: refractory edema, thrombosis, severe infections, steroid toxicity. Resistance to steroid therapy. Frequently relapsing or steroid dependent nephrotic syndrome

Renal Biopsy : 

Renal Biopsy At Onset Age of onset <1 year. Gross hematuria, persistent microscopic hematuria low serum C3 Sustained hypertension. Renal failure not attributable to hypovolemia. Suspected secondary causes of nephrotic syndrome. After Initial Treatment Proteinuria persisting despite 4-weeks of daily corticosteroid therapy. Before treatment with cyclosporin A or tacrolimus

Treatment is … : 

Treatment is … Individualized Effort of Pediatrician and pediatric nephrologist. As new evidence comes some may change

Case1Jyothish 3yrs : 

Case1Jyothish 3yrs History of URI for 1 week Periorbital edema B/L progressively increasing , more in morning, Gradually edema of legs, abdominal distention Reduced urine out put for 3 days O/E weight 18Kg, gen edema,ascites BP 96/68

Slide 82: 

Urine alb 3+ Urine p/c ratio 6 S albumin -1.8 mg/dl T protein-3.1 mg/dl S cholesterol-458 mg/dl Mantoux 2mm Chest Xray normal

Case-2Alan 4yr 9months 13.10.09 : 

Case-2Alan 4yr 9months 13.10.09 periorbital Oedema -2 days Cough and dyspnoea 5 days no oliguria Past h/O nephrotic syndrome daily 29.6.09-11.08.09 and AD till 24.09.09 Urine alb 2+ for 3 days S cholesterol 685 S alb1.6 Protein 3.4 Urine pc ratio 5.25 Cxr pleural effusion mild

Slide 84: 

First Relapse Within 2 weeks Treat pred 2mg/kg till alb nil for 3 days then AD (1.5mg/kg)for 4 weeks Taper and stop over 1-2 month

Slide 85: 

Relapse within 2 weeks of stopping initial Chance for frequent relapse Steroid dependence Look for occult infections Look for exposure to infections

Case 3 Jiya 5 and half years12.09.09 : 

Case 3 Jiya 5 and half years12.09.09 Oedema 1 week Started at 2 years with edema,oliguria,cola colored urine Started on steroids at local hospital -NS Treated with Pred full dose (no details) tapered within 1 month of initial treatment (1)Relapsed at 5 mg/day dose Full treatment(2) at 5 mg/day. And 5-6 episodes since then.

Slide 87: 

Last in August referred to us on 20 mg/day daily fever No oliguria Alb3+ Chols 303 alb1.5 Protein-3.7 s calcium 5.8 Urine PC ratio 10.8

Freq Relapse : 

Freq Relapse Mantoux CXR USS Abd Urine C & S ANA,Ds DNA Retreated predn relapse AD 2mg/kg

References : 

References Management of Steroid Sensitive Nephrotic Syndrome Revised Guidelines VOLUME 45 MARCH 17, 2008 Indian Pediatrics Consensus Statement on Management and Audit Potential for Steroid Responsive Nephrotic Syndrome. Report of a Workshop by the British Association for Paediatric Nephrology andResearch Unit, Royal College of Physicians. Arch Dis Child 1994; 70: 151-157. Hodson EM, Willis NS, Craig JC. Corticosteroidtherapy for nephrotic syndrome in children.Cochrane Database System Rev 2007; CD001533. Primary nephrotic syndrome in children: clinicalsignificance of histopathologic variants of minimalchange and of diffuse mesangial hypercellularity. AReport of the International Study of Kidney Disease in Children. Kidney Int 1981; 20: 765-771.

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