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3次 尿蛋白/肌酐2.0,25-30g/L,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,Minimal Change NS 2. M
4、esangial 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 electron
5、 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 factor
6、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 hypoalbuminemia.,
7、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 An
8、ti 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 - tran
9、sudation of fluid from intravascular compartment to interstitial space. Primary retention of water and sodium,Clinical Features, Age of onset : 85 - 90% 6 yrs yrs 30% adolescents may have MCNS Onset : insidious Initial episode & subsequent relapses may follow minor infections or insect bites, bee st
10、ings, poison ivy, etc.,Clinical Features,COMMON: Anorexia, irritability, abdominal pain, diarrhoea and genital edema Frothy urine (high concentrations of protein) Edema may cause dyspnea (pleural effusion or laryngeal edema), Chest discomfort (pericardial effusion), arthralgia (hydrarthrosis), or ab
11、dominal pain (ascites or, in children, mesenteric edema). Edema may obscure signs of muscle wasting and cause parallel white lines in fingernail beds (Muehrckes lines). UNCOMMON: Hypertension, Gross hematuria,COMPLICATIONS,A. Due to Disease B. Due to Treatment,A. Complications Due to Disease,Infecti
12、ons: S.pneumonia, H. influenza VPDs Disturbance of electrolytes Thrombotic complications Acute renal failure Iron, copper, zinc, and vitamin D deficiencies Laryngeal edema - rarely PEM due to protein loss,1. 感染 类型 呼吸道感染 皮肤 腹膜炎 泌尿系感染 病原 -细菌：肺炎球菌 大肠杆菌 -病毒 原因： -免疫球蛋白、补体丢失，免疫功能低下 -蛋白营养不良 -皮质激素治疗 -局部水肿引致
13、易发感染 处理： -不主张预防用药 -感染者积极治疗,2.电解质紊乱,不恰当禁盐或低盐饮食 利尿剂及激素应用 吐泻丢失感染应激 低蛋白及VitD缺乏,低钠 脑水肿惊厥 低钾 乏力、心律失常 低钙 手足搐搦,3. 高凝状态血管栓塞,栓塞部位 肾静脉栓塞 发热、腰痛、血尿（非肾小球源性） 肾衰 股动脉栓塞 脑栓塞 瘫痪等 肺栓塞 胸痛、咯血,4 肾上腺危相 发病因素 不恰当长期应用激素 对垂体-肾上腺皮质轴的反馈抑制 未合理减药,感染诱发 主要表现 皮肤湿冷及大理石花纹、肢端凉、精神 差或烦燥 治疗 静点激素、静点白蛋白及生理盐水扩容,5 急性肾衰,低血容量所致肾前性 肾小球病变 肾间质水肿 间质
14、性肾炎,诱因,肾血流 感染,水肿 药物,B. Complications Due to Treatment,Steroids Cushingoid syndrome Hypertension due to salt retention Osteoporosis Susceptibility to infections Growth failure Cateracts Glaucoma Gastritis Peptic ulcer Hypokalemia Behavioural changes Crisis of adrenal gland,Cyclophosphami Alopecia Leu
15、copenia Infertility Hemorrhagic cystitis,INVESTIGATIONS,Urine,Routine exam. : 3+ or 4 + proteinuria 24 hour urine protein 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 urine,Blood,S.Cholesterol S.Albumin
16、 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 Frequent relapses Steroid dependency
17、 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 Metabolic Amyloidosis, Myxoedema, DM In
18、fections 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 - Patella syndrome,Management - Princ
19、iples,Admission For establishment of diagnosis For exclusion of infection To wait for spontaneous remission Treat infections Supportive therapy Steroid therapy,Supportive Care,Diet : Balanced adequate protein (1.5 2 gm/kg) Not 30% calories from fats Avoid saturated fats Reduction in salt intake (1-2
20、 g/d) for those with persistent edema 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 6 weeks the most dosage 80 mg / d After 4-8 wks, reduce dose 1.5 mg/kg/d as a single
21、dose every other day morning slowly 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 4mg / m2 /hr for 3 consecutive early morning specimen Response Urine free of protein in 4 wks. (
22、Steroid sensitive) Late Response A response beyond 4 weeks,ISKDC Terminology,Relapse Proteinuria 2+ plus edema for 3 consecutive early morning specimen (having been in remission previously) Early Relapse Initial early responders who relapse during 8 wks of therapy Frequent Relapse Two or more relaps
23、es in 6 mo. Or 3 relapses in 1 year,ISKDC Terminology,Steroid Dependent Relapse while on alternate day steroid therapy or within 14 days of stopping prednisone therapy, and response to more steroid . Steroid Resistant: do not respond to the initial treatment with prednisone within 4 weeks of therapy
24、 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 protein 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 Freque
25、nt Relapses, Steroid Dependence, Steroid resistance,1. Long term alternate day prednisone: 0.5 to 0.25 mg/kg/d as a single morning dose on alternate 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 y
26、ears 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. Adverse Effects : Leucopenia Flu like symptoms Liver toxicity Convulsions Skin rashes,Management of Frequent Relapses, Steroid Dependence, Steroid resistan
27、ce,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 Effects : Leucopenia Hemorrhagic cystitis Alopecia Gonadal toxicity Nausea & vomiting,Management of Frequent Relapses, Steroid Dependence, Steroid resista
28、nce,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 : Nephrotoxicity Hypertension Hypercholesterolemia Elevated transaminases,Management of Frequent Relapses, Steroid Dependence, Steroid resistance,Micophenlate
29、 mofetil (MMF) : 800 - 1200 mg / m2 along with tapering dose of prednisone for 12-24 months Adverse Effects : GI discomfort Diarrhoea Leucopenia,Management of NS Other Drugs Used,ACE Inhibitors : to prevent proteinuria Act by alteration of capillary permeability and reduction in glomerular hydrostat
30、ic pressure HMG coenzyme-A reductase inhibitors to reduce s. cholesterol Albumin Infusion : controversial Hypotension Severe Oliguria Heperin,Management of NS Immunization,Patients on prednisone therapy are considered immunosuppressed avoid live attenuated vaccines All patients should receive pneumo
31、coccal vaccine,Initial Steroid Resistance,Mesangial proliferative GN Focal segmental glomerulosclerosis (FSGS) Membrano-proliferaive GN (MPGN) Type 1 : with intact BM Type 2: (30%) with dense deposits, -persistent low serum C3, abundant immunonglobulin & C3 deposits Membranous nephropathy,Initial St
32、eroid Resistance,Trial of pulse methylprednisone (15-30 mg/kg) CTX Cyclosporin A Mycophenolate mofetil,PROGNOSIS,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
33、,Related to pathological type and response to steroid 90%MCNS 30% non-relapse 20%FSGS responsive 40% 1-2 relapse 50%MsPGN 30% frequent relapse,小结,肾小球 大量血浆 原发性 滤过膜 白蛋白 临床综合征 继发性 通透性 从尿中丢失 先天性,大量蛋白尿 尿蛋白3+-4+、50mg/kg/d、3.5g/d,低白蛋白血症 30g/L,高胆固醇血症 5.7mmol/L,不同程度水肿,治疗,TABLE 30-1 - Manifestations of Nephrotic and Nephritic Features by Glomerular Disease,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,
