Nephrotic Syndrome

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Nephrotic Syndrome

  1. 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. 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. 3. Definition Classification Etiology Pathology Pathophysiology Clinical Manifestation Complication Laboratory Data Diagnosis Treatment Main Contents
  4. 4. Male patient, 4 years old, Complaint of : edema , oliguria and proteinuria for 7 days.
  5. 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. 6. Nephrotic Criteria <ul><li>Massive proteinuria: </li></ul><ul><li>qualitative proteinuria: 3+ or 4+, </li></ul><ul><li>quantitative proteinuria : ≥50mg/kg.d </li></ul><ul><li>Hypo-albuminemia: </li></ul><ul><li>serum albumin : < 30g/L </li></ul><ul><li>Hyper-cholesterolemia: </li></ul><ul><li>serum cholesterol : > 5.7mmol/L </li></ul><ul><li>Hypercoagulable state : ND </li></ul><ul><li>Edema: pitting edema in different degree </li></ul>
  7. 7. Nephr i tic Criteria <ul><li>Hematuria: RBC in urine: ≥2+ (≥10 /HPF) </li></ul><ul><li>Hypertension: </li></ul><ul><ul><ul><li>≥ 130/90 mmHg in school-age children </li></ul></ul></ul><ul><ul><ul><li>≥ 120/80 mmHg in preschool-age children </li></ul></ul></ul><ul><ul><ul><li>≥ 110/70 mmHg in infant and toddler’s children </li></ul></ul></ul><ul><li>Azotemia ( renal insufficiency ) : </li></ul><ul><li>Increased level of serum BUN 、 Cr </li></ul><ul><li>Hypo-complementemia: </li></ul><ul><li>Decreased level of serum c 3 </li></ul>
  8. 8. <ul><li>除具有上述四大基本特征外,还具以下四项中一项 </li></ul><ul><li>或多项者: </li></ul><ul><ul><li>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 </li></ul></ul><ul><ul><li>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 </li></ul></ul><ul><ul><li>肾功能不全,并除外由于血容量不足等所致者。 </li></ul></ul><ul><ul><li>血补体 (C 3 ) 反复或持续降低者 </li></ul></ul>肾炎型 NS (Nephritic-type NS)
  9. 9. Clinical Classification of NS <ul><li>Simple nephrosis : ( > 80% ) </li></ul><ul><li>Only nephrotic criteria (4-increase, 1-decrease) </li></ul><ul><li>without nephr i tic criteria. </li></ul><ul><li>Nephr i tic nephrosis : ( < 20% ) </li></ul><ul><li>Besides nephrotic criteria with at least </li></ul><ul><li>one or more nephr i tic criteria. </li></ul>
  10. 10. Etiology <ul><li>Idiopathic NS (INS): majority </li></ul><ul><li>The cause is still unclear up to now. Recent 10 years , </li></ul><ul><li>increasing evidence has suggested that INS may </li></ul><ul><li>result from a primary disorder of T– cell function. </li></ul><ul><li>Accounting for 90% of NS in child. mainly discussed. </li></ul><ul><li>Secondary NS: </li></ul><ul><li>NS resulted from systemic diseases, such as anaphylactoid </li></ul><ul><li>purpura , systemic lupus erythematosus, HBV infection. </li></ul><ul><li>Congenital NS: rare </li></ul>
  11. 11. Secondary NS : DIAMOND <ul><li>I nfection : APSGN, HBV, HIV,shunt nephropathy, reflux nephropathy, leprosy, syphilis, schistosomiasis, hydatid disease </li></ul><ul><li>D rug,Toxic,Allegy : mercury, snake venom, vaccine, pellicillamine, Heroin,gold, NSAID, captopril, probenecid, volatile hydrocarbons </li></ul><ul><li>N eoplasma : Hodgkin’s disease, carcinoma ( renal cell, lung, neuroblastoma, breast, and etc) </li></ul><ul><li>A utoimmune or collagen-vascular diseases : SLE, Hashimoto’s thyroiditis, EMC, HSP, Vasculitis </li></ul><ul><li>Genetic D isease : Alport syn., Fabry syn., Nail-patella syn., Sickle cell disease, Amyloidosis, Congenital nephropathy </li></ul><ul><li>M etabolic disease : Diabetes mellitus </li></ul><ul><li>O thers : Chronic transplant rejection, congenital nephrosclerosis </li></ul>
  12. 12. <ul><li>Minimal Change Nephropathy (MCN): > 80% </li></ul><ul><li>The glomeruli appear normal basically, the foot process of epithelial (podocyte) appears fused . </li></ul><ul><li>(2) Non—MCN : < 20% </li></ul><ul><ul><li>Mesangial proliferative glomerulonephritis </li></ul></ul><ul><li>(MsPGN): about 10% </li></ul><ul><ul><li>Focal segmental glomerulosclerosis (FSGS): 5% </li></ul></ul><ul><ul><li>Membranous Nephropathy (MN) : 2% </li></ul></ul><ul><ul><li>Membrane proliferative glomerulonephritis </li></ul></ul><ul><ul><ul><li>(MPGN) : 1% </li></ul></ul></ul><ul><ul><li>Others : rare , Cresent glomerulonephritis </li></ul></ul>Pathology
  13. 13. Pathology: Minimal Change Nephropathy <ul><li>Little or no lesion </li></ul><ul><li>under light microscopy (LM) </li></ul><ul><li>Absence of immune complex </li></ul><ul><li>under fluorescent microscopy (FM) </li></ul><ul><li>Fusion of foot process of epithelial </li></ul><ul><li>under electric microscopy (EM) </li></ul>
  14. 14. MCN: normal glomerulus in LM
  15. 16. MCN: fusion of foot process of epithelial in EM
  16. 17. MsPGN: Mesangial proliferation and expansion IgG and C3 deposits in mesangial
  17. 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
  18. 19. Pathophysiology : pathogenesis of proteinuria
  19. 20. Pathophysiology : pathogenesis of proteinuria <ul><li>Massive proteinuria is the most important characteristics of NS. </li></ul><ul><li>Protein loss from urine exceeds 50mg/kg.d generally and it is composed primarily of albumin in NS . </li></ul><ul><li>NS results from increased permeability of glomerular basement membrane ( GBM ) to plasma protein. </li></ul>
  20. 21. Pathophysiology : pathogenesis of proteinuria <ul><li>The mechanism of proteinuria may be related </li></ul><ul><li>to 2 aspects: </li></ul><ul><li>Molecular barrier injury: holes on GBM become </li></ul><ul><li>larger, plasma protein can pass through the GBM </li></ul><ul><li>into the urine ; </li></ul><ul><li>Charge barrier injury : loss of negative charge (glycoprotein) within GBM, plasma protein </li></ul><ul><li>(with negative charge) can pass through the GBM </li></ul><ul><li>into the urine. </li></ul>
  21. 22. Pathophysiology : pathogenesis of proteinuria <ul><li>Lymphocytes ->29 kd peptide -> glomerular negtive charge ( polyanion ) ↓ -> proteinuria </li></ul><ul><li>lymphocytes -> 60 ~ 160kd GPF -> proteinuria </li></ul><ul><li>lymphocytes -> 13 ~ 18kd SIRS -> proteinuria </li></ul><ul><li>GPF: glomerular permeability factor </li></ul><ul><li>SIRS: soluble immune response suppressor </li></ul>MCN may be associated with a primary disorder of T–cell lymphocyte function.
  22. 23. Pathophysiology : pathogenesis of proteinuria <ul><li>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 ; </li></ul><ul><li>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 . </li></ul>
  23. 24. Pathophysiology : pathogenesis of hypoalbuminemia <ul><li>Loss of plasma protein from urine </li></ul><ul><li>Loss of extrarenal , such as from intestine </li></ul><ul><li>Increased catabolism of protein in renal tubules </li></ul>
  24. 25. Pathophysiology : pathogenesis of hyperlipidemia <ul><li>Hypoalbuminemia -> synthesis of generalized </li></ul><ul><li>protein ( including lipoprotein ) and lipid in </li></ul><ul><li>the liver -> hyperlipidemia </li></ul><ul><li>Lipoprotein levels and all serum lipid (including cholesterol , triglycerides ) are increased </li></ul>
  25. 26. <ul><ul><li>Higher concentration of I, Ⅱ , Ⅴ,Ⅶ,Ⅷ,Ⅹ </li></ul></ul><ul><ul><li>Lower level of anticoagulant substance: antithrombin Ⅲ , protein S, protein C </li></ul></ul><ul><ul><li>Overvigorous diuresis, blood inspissation </li></ul></ul><ul><ul><li>Higher blood viscosity </li></ul></ul><ul><ul><li>Increased platelet aggregation </li></ul></ul><ul><ul><li>Role of corticosteroid </li></ul></ul>Pathophysiology : pathogenesis of Hypercoagulable state
  26. 27. Pathophysiology : pathogenesis of edema <ul><li>Hypoalbuminemia  plasma colloid osmotic pressure↓ ( 25mmHg->6 ~ 8mmHg )  </li></ul><ul><li>fluid extravasation (intravascular->interstitial) </li></ul><ul><li> Edema </li></ul><ul><li>Intravascular volume↓  antidiuretic hormone (ADH ) and aldosterone(ALD)  water and sodium retension  Edema </li></ul><ul><li>Intravascular volume↓  glomerular filtration rate </li></ul><ul><li>(GFR)↓  water and sodium retension  Edema </li></ul>
  27. 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
  28. 29. Clinical Manifestation <ul><li>Non-specific symptoms: </li></ul><ul><ul><ul><li>fatigue , inertia and lethargy </li></ul></ul></ul><ul><ul><ul><li>loss of appetite, nausea and vomiting, </li></ul></ul></ul><ul><ul><ul><li>abdominal pain , diarrhea </li></ul></ul></ul><ul><ul><ul><li>body weight increase, urine output decrease </li></ul></ul></ul><ul><li>Pitting edema in different degree : </li></ul><ul><ul><ul><li>Local edema: edema in face , around eyes, in lower extremities. </li></ul></ul></ul><ul><ul><ul><li>Generalized edema (anasarca): edema in penis and scrotum. </li></ul></ul></ul><ul><ul><ul><li>Celom effusion : ascites, pleural effusion </li></ul></ul></ul><ul><li>, </li></ul>
  29. 30. Ascites and abdomen distention Edema in scrotum and penis
  30. 31. Clinical Manifestation Edema in scrotum and penis
  31. 32. Clinical Manifestation Pitting edema and abdomen distention
  32. 33. Complications <ul><ul><ul><li>Infection: URI, UTI, peritonitis, cellulitis </li></ul></ul></ul><ul><ul><ul><ul><li>IgG  , IgA  , Complement  </li></ul></ul></ul></ul><ul><ul><ul><ul><li>WBC function  </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Lack of Zinc and other trace elements </li></ul></ul></ul></ul><ul><ul><ul><li>thrombosis : </li></ul></ul></ul><ul><ul><ul><ul><li>Higher concentration of Ⅰ,Ⅱ, Ⅴ,Ⅶ,Ⅷ,Ⅹ </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Lower level of anticoagulant substance: antithrombin Ⅲ </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Overvigorous diuresis, blood inspissation </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Higher blood viscosity </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Increased platelet aggregation </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Role of corticosteroid </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Inducement : infection and vascular puncture </li></ul></ul></ul></ul>
  33. 34. Complications <ul><ul><ul><li>Electrolyte imbalance : </li></ul></ul></ul><ul><ul><ul><li>hyponatrimia, hypokalemia, hypocalcemia </li></ul></ul></ul><ul><ul><ul><ul><li>Lower salt diet </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Overvigorous(excessive) diuresis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Extra-renal loss </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Steroid induced hypocalcemia </li></ul></ul></ul></ul><ul><ul><ul><li>ARF: pre-renal and renal </li></ul></ul></ul><ul><ul><ul><li>Hypovolemic shock </li></ul></ul></ul><ul><ul><ul><li>Others : growth retardation, malnutrition, </li></ul></ul></ul><ul><ul><ul><li>adrenal cortical insufficiency </li></ul></ul></ul>
  34. 35. Laboratory Data <ul><ul><ul><li>Qualitative proteinuria: 3 + or 4 + </li></ul></ul></ul><ul><ul><ul><li>24-hour urine total protein </li></ul></ul></ul><ul><ul><ul><li>(quantitative proteinuria ): ≥50mg/kg.d </li></ul></ul></ul><ul><ul><ul><li>Urine protein pattern: </li></ul></ul></ul><ul><ul><ul><ul><li>simple nephrosis  albumin  selective pro. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>nephr i tic nephrosis  albumin, IgG , IgA and </li></ul></ul></ul></ul><ul><ul><ul><ul><li>other proteins  non-selective proteinuria. </li></ul></ul></ul></ul>
  35. 36. Laboratory Data <ul><ul><ul><li>Serum biochemistry: </li></ul></ul></ul><ul><ul><ul><li>TP  , ALB  , CHOL  </li></ul></ul></ul><ul><ul><ul><li>Serum electrolyte: </li></ul></ul></ul><ul><ul><ul><li>Natrium  , Kalium  , Calcium  </li></ul></ul></ul><ul><ul><ul><li>Coagulable state : PT, KPTT , FIB, D-D </li></ul></ul></ul><ul><ul><ul><li>Renal function: ( BUN, Cr ) usually normal </li></ul></ul></ul><ul><ul><ul><li>Serum immunoglobulin and C3: </li></ul></ul></ul><ul><ul><li>IgG  , IgA  , IgM  , IgE  ; C3 :  , N,  </li></ul></ul><ul><ul><ul><li>Serum preotein electrophoresis : </li></ul></ul></ul><ul><ul><ul><li>r↓, a2↑, β↑ </li></ul></ul></ul>
  36. 37. Diagnosis and differential diagnosis <ul><li>How can we recognize a child who has NS? </li></ul><ul><li>Simple or nephr i tic NS? </li></ul><ul><li>Refractory NS ? </li></ul><ul><li>Idiopathic or secondary NS? </li></ul><ul><li>MCN or non-MCN? </li></ul><ul><li>deduction ; renal biopsy </li></ul><ul><li>Complication ? </li></ul>The pathway of diagnosis :
  37. 38. Treatment <ul><li>General (non-specific ) and Symptomatic therapy </li></ul><ul><li>Anticoagulation therapy </li></ul><ul><li>Corticosteroid therapy </li></ul><ul><li>Immunosuppressive agent therapy </li></ul><ul><li>Chinese traditional medicine therapy </li></ul>
  38. 39. General therapy <ul><li>Activity: usually no restriction , except </li></ul><ul><li>massive edema , heavy hypertension and infection. </li></ul><ul><li>Diet: Lower salt diet (2g/d) only during period of edema, </li></ul><ul><li>normal or appropriate protein intake (2 ~ 3g/kg.d). </li></ul><ul><li>Avoiding infection: very important. </li></ul><ul><li>Diuresis: Hydrochlorothiazide (HCT) : 2mg/kg.d </li></ul><ul><li>Antisterone : 2 ~ 4mg/kg.d </li></ul><ul><li>Dextran : 10 ~ 15ml/kg , after 30 ~ 60m, </li></ul><ul><li>followed by Furosemide (Lasix) at 2mg/kg . </li></ul>
  39. 40. Anticoagulation therapy <ul><li>Dipyridamole: 5mg/kg.d </li></ul><ul><li>Heparin : 1.0 ~ 1.5mg/kg.d , ×7 ~ 10d </li></ul><ul><li>Warfarin: Initial dose: 2.5mg , Tid×3 ~ 5d </li></ul><ul><li>Subsequent dosage : 2.5 ~ 5mg/d </li></ul><ul><li>Regulation of dosage </li></ul><ul><li>according to coagulable state. </li></ul>
  40. 41. Corticosteroid—prednisone therapy <ul><li>Short course: 2mg/kg.d -> pro(-) , 2mg/kg.qod×4w </li></ul><ul><li>-> no taper , termination, total course : 8 ~ 12 w, </li></ul><ul><li>Relapse rate (1y) ≈ 81% </li></ul><ul><li>Medium (Standard) course: 2mg/kg.d×4w -> </li></ul><ul><li>2mg/kg.qod×4w -> taper, total Course : about 6 m, </li></ul><ul><li>Relapse rate (1y) ≈ 61% </li></ul><ul><li>Long course: 2mg/kg.d×4 ~ 6w -> </li></ul><ul><li>2mg/kg.qod×4 ~ 6w -> taper, total Course: 9 ~ 12m, </li></ul><ul><li>Relapse rate (1y) ≈31% </li></ul>Induction phase and maintanence phase
  41. 42. Response to Steroid therapy <ul><li>steroid-responsive NS : ≤ 8w->proteinuria (-) </li></ul><ul><li>steroid-dependent NS : steroid-responsive , </li></ul><ul><li>but require maintenance of prednisone </li></ul><ul><li>at high dosage . </li></ul><ul><li>steroid-resistant NS : 8w->proteinuria remains </li></ul><ul><li>(+++/++++) </li></ul><ul><li>relapse: proteinuria (-)->(++ or up) for over 2w ; </li></ul><ul><li>frequent relapse: relapse twice/6m or trice/1y. </li></ul>According to response to prednisone therapy
  42. 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 :
  43. 44. Immunosuppressive agent therapy <ul><li>Frequent relapse </li></ul><ul><li>Steroid dependent </li></ul><ul><li>Steroid resistant </li></ul><ul><li>Severe steroid toxicity </li></ul>Indication:
  44. 45. Immunosuppressive agent therapy <ul><li>Cyclophosphamide ( CTX ) : 2 ~ 2.5mg/kg.d </li></ul><ul><li>×8 ~ 12w, total maxium cumulative dose : </li></ul><ul><li>≤ 200mg/kg , oral administration </li></ul><ul><li>Chlorambucil: 0.2mg/kg.d×8 ~ 12w, total maxium cumulative dose : 12 ~ 16mg/kg </li></ul><ul><li>Cyclosporin A: 5 ~ 6mg/kg.d ×6m or more, keep blood concentration between 50 ~ 150ng/ml </li></ul><ul><li>azathioprine: 1 ~ 2mg/kg.d ×8 ~ 12w </li></ul><ul><li>Mycophenolate mofetil (MMF): </li></ul>
  45. 46. Pulse therapy <ul><li>Methylprednisolone(MP): </li></ul><ul><li>15 ~ 30mg/kg×3d </li></ul><ul><li>Cyclophosphamide(CTX): </li></ul><ul><li>500 ~ 750mg/ ㎡, once/m , for 6m or more, </li></ul><ul><li>total cumulative dose : 150 ~ 200mg/kg 。 </li></ul><ul><li>Indication: </li></ul><ul><li>Refractory nephrosis, </li></ul><ul><li>Lupus nephritis, </li></ul><ul><li>purpura nephritis </li></ul><ul><li>RPGN </li></ul><ul><li>Others </li></ul>
  46. 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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