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Idiopathic Nephrotic Syndrome Dr.Fahad Gadi, MD Pediatrics Demonstrator King Abdulaziz University Rabigh Medical School Nephrotic Syndrome Generally has a glomerular cause Types: primary and secondary Secondary NS : anaphylactoid purpura, systemic lupus erythematosus, diabetes mellitus, sickle cell disease, syphilis, NS: Types Minimal change nephrotic syndrome (MCNS) Focal segmental glomerulosclerosis (FSGS) Congenital nephrosis Membranoproliferative glomerulonephritis (MPGN) Membranous glomerulonephritis (MGN). FSGS Second most common histologic subtype FSGS is always a histopathologic diagnosis FSGS may manifest in a fashion that is indistinguishable from MCNS, but it may also be found only after years of clinical nephrotic syndrome when earlier biopsies have been interpreted as MCNS. FSGS is a known consequence of hyperfiltration and is regularly seen in patients with reflux nephropathy and in some patients with a single kidney whose other has been lost because of conditions such as multicystic dysplastic kidney disease Congenital NS Congenital nephrotic syndrome becomes a consideration when nephrosis appears during the first year of life and particularly in those instances in which the clinical syndrome starts in the first few months MPGN In older children and adolescents. Clinical picture is more closely associated with a nephritic picture, but on occasion it may appear similar to MCNS or FSGS. Membranous glomerulonephritis (MGN) accounts for less than 1% of the cases of NS in childhood and adolescence Often associated with hepatitis or other viral disease. Mortality MCNS: reported cumulative mortality rate (at 20 y postonset) of less than 15% (range in various studies, 5-15%). FSGS: cumulative mortality rate is greater than 50% Morbidity Hospitalization, in some instances A prolonged period of treatment Frequent monitoring both by parents and by physician Administration of medications associated with significant adverse events A high rate of recurrence (ie, relapses in >60% of patients) The potential for progression to chronic renal failure (CRF) Definitions Nephrotic Syndrome (NS)- Edema, Albumin < 2.5 mg/dL, proteinuria > 40 mg/m2*hr Remission- Urinary protein < 4 mg/ m2*hr or Albustix = 0/Trace for 3 consecutive days Steroid Responsive- Remission with steroids alone Definitions Relapse- Urinary protein > 40 mg/m2*hr or Albustix > 2+ for 3 consecutive days Frequent Relapses- Two or more relapses within 6 months of initial response or 4 or more relapses within any 12 month period Definitions Steroid Dependence- Two consecutive relapses occurring during corticosteroid treatment or within 14 days of its cessation Steroid Resistance- Failure to achieve response in spite of 4 weeks of prednisone 60 mg/m2*day Pathogenesis: not clear Believed to have an immune pathogenesis Despite the regular finding of elevated levels of IgE and an association with atopy in steroid-responsive NS, current data merely suggest a common immune activation rather than a direct association Glomerular capillary permeability to albumin is selectively increased Epidemiology Incidence Incidence 2-7 new cases per 10,000 Prevalence 15.7 cases per 10,000 Age MCD 2.5 years median age FSGS 6 years median age Sex 3:2 Boys; Girls in children <6 yo Equal ratio in those older Epidemiology Familial incidence European survey 63 of 1877 nephrotic children had affected siblings Familial NS similar with respect to histopathology and steroid response Epidemiology Bonilla-Felix has noted a lower incidence of MCD and higher incidence of FSGS than previously reported Gulati in 1999 reported a doubling of the incidence of FSGS over historical controls Associated Disorders Atopy has been found in 34-60% of children with MCD Meadow reported plasma IgE levels elevated in 10 of 84 with MCD Malignancy Hodgkin’s disease T cell lymphomas Thymoma/ myasthenia gravis Diabetes Mellitus Clinical Features- Edema Physical exam Accumulates in gravity dependent tissues Puffiness around eyes Genital edema is generally painful Clinical Features- Edema Pathogenesis 80% of oncotic pressure due to albumin Below 2 g/dL edema accumulates Intravascular volume depletion Renin-aldosterone activation Plasma volume (PV) has not always been found to be decreased and, in fact, in most adults, measurements of PV have shown it to be increased. Only in young children with MCNS have most (but not all) studies demonstrated a reduced PV. Additionally, most studies have failed to document elevated levels of renin, angiotensin, or aldosterone, even during times of avid sodium retention. Active sodium reabsorption also continues despite actions that should suppress renin effects Hematuria Frequency of macrohematuria depends on the histologic subtype of NS. More common in those patients with MPGN In MCNS has been reported to be as high as 34% of cases. Higher percentage of patients with FSGS have microhematuria than those with MCNS, but this is not helpful in differentiating between types of NS in the individual patient. Hematuria: microscopic Microscopic hematuria is present at the onset of the disease in 20-30% of patients with MCNS, but it disappears thereafter. By contrast, microscopic hematuria is consistently present in 80-100% of patients with MPGN and in 60% of patients with MN. Patients with FSGS have hematuria more often than patients with MCNS, but the presence of hematuria cannot be used to distinguish between the 2 conditions. Clinical Features- Edema Evidence against Analbuminemia Steroid induced diuresis Increased intravascular volume Low renin/aldosterone levels Clinical Features- Hypovolemia Classic teaching Not all patients are hypovolemic Clinical Features- Infection Bacterial infections Prone to bacterial sepsis Cellulitis IgG levels low Lymphocyte function impaired Viral Infections Measles may induce remission in NS Relapse preceded by viral infection Clinical Features- Thrombosis Serious risk of thrombosis Increased fibrinogen concentration Antithrombin III concentration reduced NS patients resistant to heparin Platelets hyperaggregable Increased blood viscosity Laboratory Features Hct may be elevated Hyponatremia is common Plasma creatinine is elevated in 33% of patients Laboratory- Plasma Protein Albumin Hypoalbuminemia due to loss via the kidney Immunoglobulins IgG levels reduced IgM levels elevated IgM-IgG-Switching 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 Broad, waxy casts Lipid droplets Hematuria 22.7% of MCNS Low urine sodium High osomolality Laboratory- Proteinuria > 40 mg/hour * m2 Urine protein/creatinine ratio > 2 Unusual to see tubular proteinuria Selectivity Index Clearance of IgG/ Clearance of Transferrin MCD 53% < 0.10 13 % > 0.20 FSGS 15% < 0.10 57% > 0.20 Indications for Biopsy Pretreatment Recommended Onset age < 6 months Macroscopic hematuria Microscopic hematuria and HTN Low C3 Renal failure Discretionary Onset between 6-12 months or > 12 years Persistent HTN or hematuria Indications for Biopsy Post treatment Steroid resistance Frequent relapsers Steroid Sensitive Nephrotic Syndrome- SSNS Natural history 1 year mortality 2.5% Late outcome of 152 patients followed 14-19 years 7.2% mortality 1/4 of patients have a single relapse 1/3 relapse occasionally 1/2 become steroid dependent Most remit at puberty 2-7% will continue to relapse Renal survival near 100% Diuretic Therapy loop diuretics (furosemide) given orally in usual amounts (~1-2 mg/kg/d) are safe and moderately effective If the edema is sufficiently intense that intravenous diuretic therapy seems indicated, then salt-poor albumin should be infused (usually at 1 gram/kg body weight given IV over 2-4 hours) Diuretics other than loop diuretics (eg, thiazides, spironolactone, metolazone) are generally not potent enough alone diuresis but may give an added effect when combined with furosemide. Metolazone (with or without spironolactone) may be beneficial in combination with furosemide for resistant edema. Treatment- Diet Low protein Decreases albuminuria Malnutrition Salt restriction During edema Treatment- Antibiotics/ Immunizations Prophylactic Penicillin with ascites Gram negative coverage for peritonitis Streptococcal immunization Varicella VZIG if exposed Immunizations No live viruses while on daily steroids No oral polio for siblings Treatment- Albumin Controversial Indication- Hypovolemia Abdominal pain Hypotension Oliguria Renal insufficiency Complications Mortality 1940’s- 40% 1 year mortality Now 1-2% Main cause of death Infection Thrombosis Steroid: Initial therapy Higher dosages or longer courses of daily steroids do not significantly change the response rate in MCNS 90% of patients with MCNS respond to this therapy with complete clearing of proteinuria, but only about 20% of children with FSGS and <5% of those with MPGN experience a clinical remission (defined as a diuresis without complete clearing of proteinuria). The majority of children with MCNS will respond between the 10th and 14th days of such therapy, but a full course of at least 4 weeks of daily therapy is still recommended. Children who do not respond (ie, complete clearing of proteinuria) should be referred to a pediatric nephrologistfor percutaneous renal biopsy and consideration be given to an alternative plan of treatment. Corticosteroids Initiation High dose steroids 2 mg/kg/day (max 80 mg) 60 mg/m2 (max 80 mg) 3 accepted protocols 80% respond within 2 weeks Corticosteroids Initiation Course Long Standard Short Days of Prednisone 2 mg/m BSA Daily Alt Day 42 42 28 28 14 + 6 16 + 8 Corticosteroids Initiation Higher dosages or longer courses of daily steroids do not significantly change the response rate in MCNS The intensity and duration of the initial corticosteroid regime influences the rate of relapse of NS Cochrane metaanlysis: steroid In children in their first episode of SSNS, treatment with prednisone for at least three months results in fewer children relapsing by 12 to 24 months with an increase in benefit being demonstrated for up to seven months of treatment compared with two months therapy. In a population with a baseline risk for relapse of 60% with two months of prednisone, daily prednisone for four weeks followed by alternate-day therapy for six months would be expected to reduce the number of children experiencing a relapse by about 33%. In comparison with three months of therapy, six months of therapy results in a reduced risk for relapse without increase in adverse effects. The reduction in risk for relapse is associated with both an increase in duration and an increase in dose. During daily therapy, prednisone is as effective when administered as a single daily dose compared with divided doses. Alternate-day therapy is more effective than intermittent therapy (three consecutive days of seven days) in maintaining remission. In relapsing SSNS, long duration of alternate-day prednisone is more effective than the standard duration therapy for relapse originally recommended by the ISKDC Corticosteroids- Maintenance Individualized for each patient Usually tapered over 6 months- 1 year Steroid 4 weeks: intensive (daily) treatment 8 weeks: 1.5 mg/kg/d (one dose every other morning) 8 weeks: 1.0 mg/kg/d (one dose every other morning) 8 weeks: 0.5 mg/kg/d (one dose every other morning) Relapse No predictors of relapse Relapses as responsive 25% spontaneously remit Treatment deferred 5 days Intensification of relapse treatment has little effect on subsequent relapse rate Corticosteroids- Relapse 60 mg/m2/day until remission Change to alternate day Taper over 1-3 months Steroid Toxicity Cushingoid habitus Obesity Striae Hirsutism Acne Growth failure Avascular necrosis Osteoporosis Steroid Toxicity Peptic ulceration Pancreatitis Posterior lens opacities Myopathy Increased ICP Susceptibility to infection Indications for Alternative Therapy-SSNS Relapse on Prednisone Dosage >0.5 mg/kg/alt day plus: Severe steroid side effects High risk of toxicity- diabetes Unusually severe relapses Relapses on Prednisone Dosage >1.0 mg/kg/alt day Options for Alternative TherapySSNS Alkylating Agents Nitrogen mustard Cyclophosphamide Chlorambucil Levamisole Cyclosporine Cyclophosphamide- SSNS 8 weeks of 3 mg/kg/day 69% of children with SRNS remain in remission for 1 year 44% for 5 years Younger children do worse Steroid dependent children do worse 2 mg/kg/day may or may not have any benefit Chlorambucil- SSNS 0.2 mg/kg/day for 8 weeks Jones 1988 5 patients with SSNS 1 course induced remission for 7.4 months 2 course induced remission for 22 months Bailey 1989 5 patients with SSNS All remitted with 1 course Elzouki 1990 16 patients with SSNS 56% complete remission (39 month follow) Relapse rate cut in half Levamisole- SSNS Antihelmithic with immunomodulating properties 2.5 mg/kg/qOD for 2 months Tenbrock 1998 5 patients SSNS 5/5 complete remission 24 month followup 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 Cyclosporine- SSNS 5 mg/kg/day Used with steroids Patients usually respond well Cyclosporine dependence is common Long term side effects unknown Steroid Resistant Nephrotic Syndrome (SRNS) Natural history 40% ESRD by 5 years ISKDC Tejani 70% ESRD by 2 years 12% of all transplants are performed for the diagnosis FSGS 12-24% of pediatric ESRD patients have FSGS as diagnosis Heavy proteinuria, hypertension and interstitial fibrosis are risk factors for rapid loss of renal function Progression to ESRD in 2 years SRNS- Mendoza Protocol Week 1-2 3-10 11-18 Methyprednisolone Dose 30 mg/kg 3x/week 1x/week 1x every 2weeks Number Pulses 6 8 4 19-50 51-82 1x every 4 weeks 1x every 8 weeks 8 4 Prednisone 0 2 mg/kg qOD With or without taper Slow taper Slow taper Alkylating agent added if complete or partial remission not achieved by 2 weeks, or if Urine protein/creatinine ratio > 2 at 10 weeks Cyclophosphamide 2-2.5 mg/kg/day for 8-12 weeks Chlorambucil 0.18-0.22 mg/kg/day for 8-12 weeks SRNS- Mendoza Protocol Remission, Normal CrCl Proteinuria Urine p/c ratio 0.2-0.5 Urine p/c ratio 0.5-1.9 Urine p/c ratio >2.0 Renal Function Proteinuria, normal CrCl Decreased CrCl ESRD Number 21/32 % 66 3/32 2/32 6/32 9 6 19 3/32 5/32 3/32 9 16 9 SRNS- Cyclophosphamide ISKDC Trial of SRNS (FSGS) Prednisone 40 mg/m2 qOD x 12 months Cyclophosphamide 2.5 mg/kg/day x 3 months plus the same prednisone dose Control 28% complete remission Treatment group 25% complete remission Geary- 12/29 patients full or partial response Tejani reported 0/10 responded SRNS- ACE Inhibition Milliner reported a 50% decrease in proteinuria without a decrease in GFR in patients with SRNS treated with ACE I