1、Nephrotic Syndrome Capital Institutes of Pediatrics Chen Chaoying Purpose and Requirement Master the definition of NS Master the clinical types of NS Master the treatment principles of NS Nephrotic Syndrome Definition: 1. Massive proteinuria 2. Hypoalbuminemia With or without 3. Hypercholesterolemia
2、 4. Edema -50 mg / kg / d or 3.5 gm/day) -+,2周周3次次 -尿蛋白尿蛋白/肌酐肌酐2.0 5.72mmol/L Nephrotic Syndrome 1. Primary 2. Secondary 3. Congenital Nephrotic Syndrome 90 % - primary glomerular abnormality (Idiopathic) Rest part of renal involvement in different diseases Nephrotic Syndrome Incidence of Idiopathic
3、 Form 2 to 7 / 100,000 Male-to-female 2-4:1 in children 1:1 in adolescents and adults MCNS : 2 and 5 years of age 92% remission Adolescents : aggressive Classification 1.Clinical Simple Nephritic Hematuria Hypertension Azotemia Complement decrease Classification 2. Pathological 1. Minimal Change NS
4、2. Mesangial Proliferation Glomeruer Nephritis 3. Focal Segmental Glomerulosclerosis 4. Membranous nephropathy (1%) 5. Membranous Proliferative Glomeruer Nephritis Pathological Types MCNS Nephrotic Syndrome 76% MCNS No glomerular abnormalities in light microscope Effacement of foot processes in elec
5、tron microscopy Minimal deposition of mesangial matrix Serum complement (C3) normal Circulating immune complexes absent Pathogenesis of NS In MCNS : T Cell dysfunction leads to alteration of cytokines which causes a loss of negatively charged glycoproteins within capillary wall In FSGS: A plasma fac
6、tor produced by lymphocytes responsible Mutations in podocyte proteins (podocin, a actinin 4) In Steroid resistant NS: Mutations in NPHS 1(nephrin) & 2(podocin) and WT1 or ACTN4 (-actinin) genes Increased permeability of glomerular capillary wall, which leads to massive proteinuria and hypoalbuminem
7、ia. Massive Proteinuria - Mechanism Loss of negatively charged sialoproteins and glycoproteins Increased size of pores Loss of foot processes Increased excretion or decreased absorption Protein Loss Albumin Thyroxine-binding protein Cholecalciferol-binding protein Transferrin Metal binding proteins
8、Anti Thrombin III, Proteins C & S Hypoproteinemia - Mechanism Increased loss Inadequate synthesis Increased catabolism Hyperlipidemia - Mechanism Loss of lipoprotein lipase enzyme in urine synthesis of lipoproteins Oedema - Mechanism Massive proteinuria hypoalbuminemia - plasma oncotic pressure - tr
9、ansudation of fluid from intravascular compartment to interstitial space. Primary retention of water and sodium Clinical Features Age of onset : 85 - 90% 3.5 gm or 50 mg/kg Urine protein / creatinine ratio : 2.0 Urine protein selectivity Hyaline casts Microscopic hematuria in 20% Hyaline Cast in uri
10、ne Blood S.Cholesterol S.Albumin S. A/G ratio - reversal S.Creatinine Bl. Urea S . C3 and C4 levels Diagnosis 4 characteristics Renal Biopsy - indications Age of onset 15 yrs. Features suggestive of disease other than MCNS macroscopic hematuria, HTN, Low C 3, renal failure Steroid non-responder Freq
11、uent relapses Steroid dependency Secondary steroid resistance Prior cytotoxic therapy DD Protein losing enteropathy Hepatic failure CHF Acute or chronic GN PEM Secondary Nephrotic Syndrome Vasculitides SLE, Sarcoidosis, HSP, Rheumatoid arthritis, Wageners granulomatosis Goofpasteur syndrome Metaboli
12、c Amyloidosis, Myxoedema, DM Infections Syphilis, Shunt nephritis, Hepatitis B and C, CMV, HIV Parasitic Plasmodium malariae, Toxoplasma, Syphilis Drugs Gold, Mercury, Penicillamine, Lithium, Ethosuccimide, NSAIDS Malignancies Lymphomas, Carcinomas Congenital / Inherited Alport syndrome, Nail - Pate
13、lla syndrome MINIMAL CHANGE NEPHROTIC SYNDROME FOCAL SEGMENTAL GLOMERULOSCLER OSIS MEMBRANOU S NEPHROPAT HY MEMBRANOPROLI FERATIVE GLOMERULONEPH RITIS Type I Type II FREQUENCY Children 75% 10% 30% calories from fats Avoid saturated fats Reduction in salt intake (1-2 g/d) for those with persistent ed
14、ema Calcium and Vitamin D supplementation Ensure physical activity? Diuretic Therapy Treatment of Initial Episode Steroid Therapy Prednisalone 2mg / kg / d in 2-3 divided doses for 4-8 weeks the most dosage 60 mg / d After 4-8 wks, reduce dose 2 mg/kg/d as a single dose every other day morning slowl
15、y tapering in 2-3 months/ 6 mons/ 9 Then discontinue Shorter duration of initial therapy is not recommended. ISKDC Terminology Remission Urine albumin : Nil or Traces or 3 relapses in 1 year ISKDC Terminology Steroid Dependent Relapse while on alternate day steroid therapy or within 14 days of stopp
16、ing prednisone therapy, and response to more steroid . Steroid Resistant: do not respond to the initial treatment with prednisone within 4 weeks of therapy 2mg/kg/d (FSGS= 80%, MPG = 20%, MCNS rarely) Treatment of Relapse Relapse often precipitated by URI Prednisone 2 mg/kg/d until the urine is prot
17、ein free for 3 consecutive days Thereafter 1.5 mg/kg/d on alternate days for 4 wks and stop. (Total duration of therapy = 5 to 6 wks.) Management of Frequent Relapses, Steroid Dependence, Steroid resistance 1. Long term alternate day prednisone: 0.5 to 0.75 mg/kg/d as a single morning dose on altern
18、ate days for 9 18 months Management of Frequent Relapses, Steroid Dependence, Steroid resistance 2. Levamisole 2.0 to 2.5 mg/kg on alternate days for 1-2 years Co-treatment with prednisone at 1.5 mg/kg/d on alt. days for 2-4 weeks gradually reducing the dose to 0.15 0.25 mg/kg for 6 or more months.
19、Adverse Effects : Leucopenia Flu like symptoms Liver toxicity Convulsions Skin rashes Management of Frequent Relapses, Steroid Dependence, Steroid resistance 3. Cytotoxic drugs Cyclophosphamide (following remission) 2-3 mg/kg/d for 8-12 week regimen with along with prednisone (1-1.5 mg/kg/d) Adverse
20、 Effects : Leucopenia Hemorrhagic cystitis Alopecia Gonadal toxicity Nausea & vomiting Management of Frequent Relapses, Steroid Dependence, Steroid resistance Cyclosporine : 3-6 mg/kg/d in q 12 h doses (100-150 mg/m2/d) combined initially with alt. day prednisone for 12-24 months Adverse Effects : N
21、ephrotoxicity Hypertension Hypercholesterolemia Elevated transaminases Management of Frequent Relapses, Steroid Dependence, Steroid resistance Micophenlate mofetil (MMF) : 800 - 1200 mg / m2 along with tapering dose of prednisone for 12- 24 months Adverse Effects : GI discomfort Diarrhoea Leucopenia
22、 Management of NS Other Drugs Used ACE Inhibitors : to prevent proteinuria Act by alteration of capillary permeability and reduction in glomerular hydrostatic pressure HMG coenzyme-A reductase inhibitors to reduce s. cholesterol Albumin Infusion : controversial Hypotension Severe Oliguria Management
23、 of NS Immunization Patients on prednisone therapy are considered immunosuppressed avoid live attenuated vaccines All patients should receive pneumococcal vaccine Initial Steroid Resistance Mesangial proliferative GN Focal segmental glomerulosclerosis (FSGS) Membrano-proliferaive GN (MPGN) Type 1 :
24、with intact BM Type 2: (30%) with dense deposits, -persistent low serum C3, abundant immunonglobulin & C3 deposits Membranous nephropathy Initial Steroid Resistance Trial of pulse methylprednisone (15-30 mg/kg) First 6 doses given every other day followed by tapering for periods up to 18 months Cycl
25、osporin A IVIG Mycophenolate mofetil Outcome of MCNS Most stop getting relapses by 11 to 15 yrs Full recovery Very small proportion develop late steroid resistance Mortality : 1-4 % sec. to infections & hypovolemia Prognosis Related to pathological type and response to steroid 90%MCNS 30% non-relaps
26、e 20%FSGS responsive 40% 1-2 relapse 50%MsPGN 30% frequent relapse 小结小结 肾小球肾小球 大量血浆大量血浆 原发性原发性 滤过膜滤过膜 白蛋白白蛋白 临床综合征临床综合征 继发性继发性 通透性通透性 从尿中丢失从尿中丢失 先天性先天性 大量蛋白尿大量蛋白尿 尿蛋白尿蛋白3+3+- -4+4+、50mg/kg/d、3.5g/d 低白蛋白血症低白蛋白血症 30g/L 高胆固醇血症高胆固醇血症 5.7mmol/L 不同程度水肿不同程度水肿 治疗治疗 Nephrotic Features Nephritic Features Mini
27、mal change glomerulopathy + Membranous glomerulopathy + + Focal segmental glomerulosclerosis + + Fibrillary glomerulonephritis + + Mesangioproliferative glomerulopathy* + + Membranoproliferative glomerulonephritis + + Proliferative glomerulonephritis* + + Acute diffuse proliferative glomerulonephrit
28、is + + Crescentic glomerulonephritis + + TABLE 30-1 - Manifestations of Nephrotic and Nephritic Features by Glomerular Disease Hematuria Proteinuria 1 Creatinine 1.5 Hematuria Proteinuria 13 Creatinine 3 No abnormality 30% 2% 0% Thin basement nephropathy 26% 4% 0% IgA nephropathy 28% 24% 8% Glomerul
29、onephritis without crescents* 9% 26% 23% Glomerulonephritis with crescents* 2% 24% 44% Other renal disease 5% 20% 25% Total 100% n = 43 100% n = 123 100% n = 255 TABLE 30-2 - Renal Disease in Patients with Hematuria Undergoing Renal Biopsy Brenner and Rectors The Kidney Nelson Textbook of Pediatrics - 18Ed Oxford Textbook of Clinical Nephrology(3rd Ed) Reference IgA肾病 紫癜性肾 炎 思考题 肾脏病理与临床的关系
