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Nephrotic Syndrome

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  • 1. Nephrotic Syndrome In Children 肾 病 综 合 征 华中科技大学同济医学院 附属同济医院儿科教研室 刘 铜 林
  • 2. Idiopathic nephrotic syndrome (INS) Simple nephrosis , nephr i tic nephrosis Minimal change nephropathy (MCN) Non-minimal change nephropathy (non-MCN) Massive (heavy , excessive) proteinuria Hypo-proteinemia , hypo-albuminemia Hyper-lipidemia , hyper-cholesterolemia Pitting edema , non- pitting edema Anasarca , ascites , pleural effusion Corticosteroid , prednisone , methylprednisolone Key words
  • 3. Definition Classification Etiology Pathology Pathophysiology Clinical Manifestation Complication Laboratory Data Diagnosis Treatment Main Contents
  • 4. Male patient, 4 years old, Complaint of : edema , oliguria and proteinuria for 7 days.
  • 5. Nephrotic syndrome (NS) results from increased permeability of glomerular basement membrane ( GBM ) to plasma protein. It is a syndrome characterized by massive proteinuria, hypo-albuminemia, hyper-cholesterolemia , Hypercoagulable state and pitting edema. (4-increase, 1-decrease). Definition
  • 6. Nephrotic Criteria
    • Massive proteinuria:
    • qualitative proteinuria: 3+ or 4+,
    • quantitative proteinuria : ≥50mg/kg.d
    • Hypo-albuminemia:
    • serum albumin : < 30g/L
    • Hyper-cholesterolemia:
    • serum cholesterol : > 5.7mmol/L
    • Hypercoagulable state : ND
    • Edema: pitting edema in different degree
  • 7. Nephr i tic Criteria
    • Hematuria: RBC in urine: ≥2+ (≥10 /HPF)
    • Hypertension:
        • ≥ 130/90 mmHg in school-age children
        • ≥ 120/80 mmHg in preschool-age children
        • ≥ 110/70 mmHg in infant and toddler’s children
    • Azotemia ( renal insufficiency ) :
    • Increased level of serum BUN 、 Cr
    • Hypo-complementemia:
    • Decreased level of serum c 3
  • 8.
    • 除具有上述四大基本特征外,还具以下四项中一项
    • 或多项者:
      • 2 周内分别 3 次以上离心尿镜检, RBC≥10 个 /HP ,并证实为肾小球性血尿者
      • 反复或持续高血压,学龄前儿童≥ 120/80 mm Hg ,学龄儿童≥ 130/90mmHg ,并除外激素等所致者
      • 肾功能不全,并除外由于血容量不足等所致者。
      • 血补体 (C 3 ) 反复或持续降低者
    肾炎型 NS (Nephritic-type NS)
  • 9. Clinical Classification of NS
    • Simple nephrosis : ( > 80% )
    • Only nephrotic criteria (4-increase, 1-decrease)
    • without nephr i tic criteria.
    • Nephr i tic nephrosis : ( < 20% )
    • Besides nephrotic criteria with at least
    • one or more nephr i tic criteria.
  • 10. Etiology
    • Idiopathic NS (INS): majority
    • The cause is still unclear up to now. Recent 10 years ,
    • increasing evidence has suggested that INS may
    • result from a primary disorder of T– cell function.
    • Accounting for 90% of NS in child. mainly discussed.
    • Secondary NS:
    • NS resulted from systemic diseases, such as anaphylactoid
    • purpura , systemic lupus erythematosus, HBV infection.
    • Congenital NS: rare
  • 11. Secondary NS : DIAMOND
    • I nfection : APSGN, HBV, HIV,shunt nephropathy, reflux nephropathy, leprosy, syphilis, schistosomiasis, hydatid disease
    • D rug,Toxic,Allegy : mercury, snake venom, vaccine, pellicillamine, Heroin,gold, NSAID, captopril, probenecid, volatile hydrocarbons
    • N eoplasma : Hodgkin’s disease, carcinoma ( renal cell, lung, neuroblastoma, breast, and etc)
    • A utoimmune or collagen-vascular diseases : SLE, Hashimoto’s thyroiditis, EMC, HSP, Vasculitis
    • Genetic D isease : Alport syn., Fabry syn., Nail-patella syn., Sickle cell disease, Amyloidosis, Congenital nephropathy
    • M etabolic disease : Diabetes mellitus
    • O thers : Chronic transplant rejection, congenital nephrosclerosis
  • 12.
    • Minimal Change Nephropathy (MCN): > 80%
    • The glomeruli appear normal basically, the foot process of epithelial (podocyte) appears fused .
    • (2) Non—MCN : < 20%
      • Mesangial proliferative glomerulonephritis
    • (MsPGN): about 10%
      • Focal segmental glomerulosclerosis (FSGS): 5%
      • Membranous Nephropathy (MN) : 2%
      • Membrane proliferative glomerulonephritis
        • (MPGN) : 1%
      • Others : rare , Cresent glomerulonephritis
    Pathology
  • 13. Pathology: Minimal Change Nephropathy
    • Little or no lesion
    • under light microscopy (LM)
    • Absence of immune complex
    • under fluorescent microscopy (FM)
    • Fusion of foot process of epithelial
    • under electric microscopy (EM)
  • 14. MCN: normal glomerulus in LM
  • 15.  
  • 16. MCN: fusion of foot process of epithelial in EM
  • 17. MsPGN: Mesangial proliferation and expansion IgG and C3 deposits in mesangial
  • 18. 2.INS 的发病机制: 肾小球毛细血管滤过屏障结构 电荷屏障与分子屏障 INS 的病因与发病机制
  • 19. Pathophysiology : pathogenesis of proteinuria
  • 20. Pathophysiology : pathogenesis of proteinuria
    • Massive proteinuria is the most important characteristics of NS.
    • Protein loss from urine exceeds 50mg/kg.d generally and it is composed primarily of albumin in NS .
    • NS results from increased permeability of glomerular basement membrane ( GBM ) to plasma protein.
  • 21. Pathophysiology : pathogenesis of proteinuria
    • The mechanism of proteinuria may be related
    • to 2 aspects:
    • Molecular barrier injury: holes on GBM become
    • larger, plasma protein can pass through the GBM
    • into the urine ;
    • Charge barrier injury : loss of negative charge (glycoprotein) within GBM, plasma protein
    • (with negative charge) can pass through the GBM
    • into the urine.
  • 22. Pathophysiology : pathogenesis of proteinuria
    • Lymphocytes ->29 kd peptide -> glomerular negtive charge ( polyanion ) ↓ -> proteinuria
    • lymphocytes -> 60 ~ 160kd GPF -> proteinuria
    • lymphocytes -> 13 ~ 18kd SIRS -> proteinuria
    • GPF: glomerular permeability factor
    • SIRS: soluble immune response suppressor
    MCN may be associated with a primary disorder of T–cell lymphocyte function.
  • 23. Pathophysiology : pathogenesis of proteinuria
    • If the damage of glomeruli is mild and the permeability is not so high , only lower molecular weight protein ( such as albumin, transferrin) can pass through the GBM, which is called selective proteinuria ;
    • If the damage of glomeruli is severe , both small and large proteins ( such as IgG, IgA ) can all pass through the GBM, which is called non-selective proteinuria .
  • 24. Pathophysiology : pathogenesis of hypoalbuminemia
    • Loss of plasma protein from urine
    • Loss of extrarenal , such as from intestine
    • Increased catabolism of protein in renal tubules
  • 25. Pathophysiology : pathogenesis of hyperlipidemia
    • Hypoalbuminemia -> synthesis of generalized
    • protein ( including lipoprotein ) and lipid in
    • the liver -> hyperlipidemia
    • Lipoprotein levels and all serum lipid (including cholesterol , triglycerides ) are increased
  • 26.
      • Higher concentration of I, Ⅱ , Ⅴ,Ⅶ,Ⅷ,Ⅹ
      • Lower level of anticoagulant substance: antithrombin Ⅲ , protein S, protein C
      • Overvigorous diuresis, blood inspissation
      • Higher blood viscosity
      • Increased platelet aggregation
      • Role of corticosteroid
    Pathophysiology : pathogenesis of Hypercoagulable state
  • 27. Pathophysiology : pathogenesis of edema
    • Hypoalbuminemia  plasma colloid osmotic pressure↓ ( 25mmHg->6 ~ 8mmHg ) 
    • fluid extravasation (intravascular->interstitial)
    •  Edema
    • Intravascular volume↓  antidiuretic hormone (ADH ) and aldosterone(ALD)  water and sodium retension  Edema
    • Intravascular volume↓  glomerular filtration rate
    • (GFR)↓  water and sodium retension  Edema
  • 28. INS 的病理生理 致病因素 高脂血症 ↓ ↑ 肾小球损伤 脂蛋白合成↑ ↓ ↑ 通透性↑— 大量蛋白尿 — 低蛋白血症 ↓ 低血容量 低血浆胶体渗透压 ↓ ADH ↑ 、 RAAS ↑ 、心钠素↓ 体液进入间质或体腔 ↓ 肾炎型 INS 时 水钠潴留 GFR ↓ 凹陷性水肿
  • 29. Clinical Manifestation
    • Non-specific symptoms:
        • fatigue , inertia and lethargy
        • loss of appetite, nausea and vomiting,
        • abdominal pain , diarrhea
        • body weight increase, urine output decrease
    • Pitting edema in different degree :
        • Local edema: edema in face , around eyes, in lower extremities.
        • Generalized edema (anasarca): edema in penis and scrotum.
        • Celom effusion : ascites, pleural effusion
    • ,
  • 30. Ascites and abdomen distention Edema in scrotum and penis
  • 31. Clinical Manifestation Edema in scrotum and penis
  • 32. Clinical Manifestation Pitting edema and abdomen distention
  • 33. Complications
        • Infection: URI, UTI, peritonitis, cellulitis
          • IgG  , IgA  , Complement 
          • WBC function 
          • Lack of Zinc and other trace elements
        • thrombosis :
          • Higher concentration of Ⅰ,Ⅱ, Ⅴ,Ⅶ,Ⅷ,Ⅹ
          • Lower level of anticoagulant substance: antithrombin Ⅲ
          • Overvigorous diuresis, blood inspissation
          • Higher blood viscosity
          • Increased platelet aggregation
          • Role of corticosteroid
          • Inducement : infection and vascular puncture
  • 34. Complications
        • Electrolyte imbalance :
        • hyponatrimia, hypokalemia, hypocalcemia
          • Lower salt diet
          • Overvigorous(excessive) diuresis
          • Extra-renal loss
          • Steroid induced hypocalcemia
        • ARF: pre-renal and renal
        • Hypovolemic shock
        • Others : growth retardation, malnutrition,
        • adrenal cortical insufficiency
  • 35. Laboratory Data
        • Qualitative proteinuria: 3 + or 4 +
        • 24-hour urine total protein
        • (quantitative proteinuria ): ≥50mg/kg.d
        • Urine protein pattern:
          • simple nephrosis  albumin  selective pro.
          • nephr i tic nephrosis  albumin, IgG , IgA and
          • other proteins  non-selective proteinuria.
  • 36. Laboratory Data
        • Serum biochemistry:
        • TP  , ALB  , CHOL 
        • Serum electrolyte:
        • Natrium  , Kalium  , Calcium 
        • Coagulable state : PT, KPTT , FIB, D-D
        • Renal function: ( BUN, Cr ) usually normal
        • Serum immunoglobulin and C3:
      • IgG  , IgA  , IgM  , IgE  ; C3 :  , N, 
        • Serum preotein electrophoresis :
        • r↓, a2↑, β↑
  • 37. Diagnosis and differential diagnosis
    • How can we recognize a child who has NS?
    • Simple or nephr i tic NS?
    • Refractory NS ?
    • Idiopathic or secondary NS?
    • MCN or non-MCN?
    • deduction ; renal biopsy
    • Complication ?
    The pathway of diagnosis :
  • 38. Treatment
    • General (non-specific ) and Symptomatic therapy
    • Anticoagulation therapy
    • Corticosteroid therapy
    • Immunosuppressive agent therapy
    • Chinese traditional medicine therapy
  • 39. General therapy
    • Activity: usually no restriction , except
    • massive edema , heavy hypertension and infection.
    • Diet: Lower salt diet (2g/d) only during period of edema,
    • normal or appropriate protein intake (2 ~ 3g/kg.d).
    • Avoiding infection: very important.
    • Diuresis: Hydrochlorothiazide (HCT) : 2mg/kg.d
    • Antisterone : 2 ~ 4mg/kg.d
    • Dextran : 10 ~ 15ml/kg , after 30 ~ 60m,
    • followed by Furosemide (Lasix) at 2mg/kg .
  • 40. Anticoagulation therapy
    • Dipyridamole: 5mg/kg.d
    • Heparin : 1.0 ~ 1.5mg/kg.d , ×7 ~ 10d
    • Warfarin: Initial dose: 2.5mg , Tid×3 ~ 5d
    • Subsequent dosage : 2.5 ~ 5mg/d
    • Regulation of dosage
    • according to coagulable state.
  • 41. Corticosteroid—prednisone therapy
    • Short course: 2mg/kg.d -> pro(-) , 2mg/kg.qod×4w
    • -> no taper , termination, total course : 8 ~ 12 w,
    • Relapse rate (1y) ≈ 81%
    • Medium (Standard) course: 2mg/kg.d×4w ->
    • 2mg/kg.qod×4w -> taper, total Course : about 6 m,
    • Relapse rate (1y) ≈ 61%
    • Long course: 2mg/kg.d×4 ~ 6w ->
    • 2mg/kg.qod×4 ~ 6w -> taper, total Course: 9 ~ 12m,
    • Relapse rate (1y) ≈31%
    Induction phase and maintanence phase
  • 42. Response to Steroid therapy
    • steroid-responsive NS : ≤ 8w->proteinuria (-)
    • steroid-dependent NS : steroid-responsive ,
    • but require maintenance of prednisone
    • at high dosage .
    • steroid-resistant NS : 8w->proteinuria remains
    • (+++/++++)
    • relapse: proteinuria (-)->(++ or up) for over 2w ;
    • frequent relapse: relapse twice/6m or trice/1y.
    According to response to prednisone therapy
  • 43. (1) 激素敏感型 INS (steroid-responsive NS) : 以口服泼尼松足量治疗≤ 8 周,尿蛋白转阴者 (2) 激素耐药型 INS (steroid-resistant NS) : 以口服泼尼松足量治疗满 8 周,尿蛋白仍阳性者 (3) 激素依赖型 INS (steroid-dependent NS) : 对泼尼松敏感,但减量或停药 1 个月内复发,且重复 2 次以上者。 (4) 复发( relapse ) 与频复发( frequent relapse ) : 尿蛋白由阴性转为阳性,持续在 2 周以上者为复发。 病程中半年内复发≥ 2 次, 1 年内复发≥ 3 次者为频复发 INS 的治疗方法 根据激素疗效对 INS 分型 :
  • 44. Immunosuppressive agent therapy
    • Frequent relapse
    • Steroid dependent
    • Steroid resistant
    • Severe steroid toxicity
    Indication:
  • 45. Immunosuppressive agent therapy
    • Cyclophosphamide ( CTX ) : 2 ~ 2.5mg/kg.d
    • ×8 ~ 12w, total maxium cumulative dose :
    • ≤ 200mg/kg , oral administration
    • Chlorambucil: 0.2mg/kg.d×8 ~ 12w, total maxium cumulative dose : 12 ~ 16mg/kg
    • Cyclosporin A: 5 ~ 6mg/kg.d ×6m or more, keep blood concentration between 50 ~ 150ng/ml
    • azathioprine: 1 ~ 2mg/kg.d ×8 ~ 12w
    • Mycophenolate mofetil (MMF):
  • 46. Pulse therapy
    • Methylprednisolone(MP):
    • 15 ~ 30mg/kg×3d
    • Cyclophosphamide(CTX):
    • 500 ~ 750mg/ ㎡, once/m , for 6m or more,
    • total cumulative dose : 150 ~ 200mg/kg 。
    • Indication:
    • Refractory nephrosis,
    • Lupus nephritis,
    • purpura nephritis
    • RPGN
    • Others
  • 47. 1.What is nephrotic syndrome ? 2.What are the main clinical types of INS ? 3.What is the diagnostic criteria of INS ? 4.What are the pathological types of INS ? 5.What are the common complications of INS ? 6.How do you treat INS (general principles) ? 7.How do you evaluate the response of steroid therapy ? Questions

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