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肾病综合征 Nephrotic Syndrome. 武汉大学第一临床学院 刘红燕. Definition. Nephrotic syndrome (NS) is defined by the presence of following: Heavy proteinuria (>3.5g/d) Hypoalbuminemia (serum albumin <30g/L) Peripheral edema Hyperlipidemia / hypercholesterolemia. Major causes of NS (primary or idiopathic).

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nephrotic syndrome

肾病综合征Nephrotic Syndrome

武汉大学第一临床学院 刘红燕

definition
Definition

Nephrotic syndrome (NS) is defined by the presence of following:

  • Heavy proteinuria (>3.5g/d)
  • Hypoalbuminemia (serum albumin <30g/L)
  • Peripheral edema
  • Hyperlipidemia / hypercholesterolemia
major causes of ns primary or idiopathic
Major causes of NS (primary or idiopathic)
  • Minimal change disease (微小病变型)
  • Mesangial proliferative glomerulonephritis (系膜增生性肾小球肾炎)
  • Focal segmental glomerulonephritis (局灶节段硬化性肾小球肾炎)
  • Membranous glomerulonephritis (膜性肾病)
  • Membranoproliferative glomerulonephritis (膜增殖性肾小球肾炎/系膜毛细血管性肾小球肾炎)
major causes of ns secondary or systemic
Major causes of NS (secondary or systemic)
  • Antoimmune: systemic lupus erythematosus (SLE)
  • Endocrine: diabetic nephropathy
  • Infections: Hepatitis B, C, HIV
  • Allergenic: Henoch-Schonlen purpura
  • Neoplastic: Hodgkin’s and non-Hodgkin’s lymphomas, multiple myeloma
  • Others: Amyloidosis, Hereditary nephritis, medications
pathophysiology
Pathophysiology
  • Heavy protinuria
  • Hypoalbuminemia
  • Edema
  • Hyperlipidemia
heavy proteinuria
Heavy proteinuria
  • Damage to the charge-selective barrier of GMB →ultrafiltration of negatively charged albumin
  • Damage to the size-selective barrier of GMB →passsage of lager molecular proteins
  • Protein filtration > reabsorption capacity of tubules
  • Heperperfusion/Hyperfiltration factors (hypertension, protein-rich diet) →proteinuria increase
consequence of urinary loss of plasma proteins
Consequence of urinary loss of plasma proteins
  • Serum protein ↓or hypoalbuminemia
  • IgG/Complement ↓→infection
  • Coagulation component alternation (anticoagulants ↓)→thrombosis
  • Hormone-binding proteins ↓/metal-binding proteins ↓→endocrine or metabolic abnormalities
  • Lager proteins may increase
hypoalbuminemia
Hypoalbuminemia
  • Urinary loss
  • albumin catabolism ↑ by tubules
  • Malnutrition due to GI changes
edema
Edema
  • Reduced plasma oncotic pressure (colloid osmotic pressure)
  • Hypovolemia →renin-angiotensin-aldosteron ↑ ; Sympathetic nervouse and vasopression systems ↑
  • Primary renal Na+ retension (non-plasma Hormone effects on the kidney)
hyperlipidemia
Hyperlipidemia
  • One of the sentinel features of NS with numerous alterations in lipids profiles (hypercholesterolemia, hypertriglyceridemia, LDL and VLDL ↑)
  • Overproduction by the liver of lipoproteins
  • Decreased catabolism of lipoproteins and triglyceride
minimal changes nephropathy mcd
Minimal changes nephropathy(MCD, 微小病变型肾病)

Overview and Terminology

  • First described in 1913 by Monk as “lipoid nephrosis”
  • other terms “nil disease” and “idiopathic nephrotic syndrome”
pathogenesis
Pathogenesis
  • Unclear
  • Most likely a consequence of T cell abnormalities (glomerular permembility factor)
  • Other potential mechanisms (circulating immune complexes)
histopathology
Histopathology

Light microscope (LM)

  • Lack alteration in glomerular structure
  • Some lipid droplets in tubule cells

Immunoflurescent microscopy( IM)

  • No change

Electron microscopy (EM)

  • Fusion of epithelial foot processes
clinical presentation
Clinical presentation
  • Most common in children; accouting for 10%-15% of NS in adults with male predominance
  • Typical feature of NS
  • Uncommon with nephritic features (hematuria, hypertension)
  • Renal function (normal or dereasesd transiterily)
diagonosis
Diagonosis
  • Children and prealdolescent children presenting with NS will have MCD (about 80%-85%)
  • Children with NS sensitive to steroid treatment
  • Secondary MCD kept in mind when adult or old patients presents with MCD
  • Renal biopsy
treatment 1
Treatment (1)

Corticosteroid therapy

  • Exquisitely sensitive
  • Dose of prednisone
  • Caution with the side-effects of steroid
dose of prednisone
Dose of prednisone
  • Initial

(full)

  • Tapering(slowly)
  • Maintainece

(longer)

Children

  • 2mg/kg/d<60mg/d×8-12w
  • 10%reduction/1-2w
  • Effetively minimal dose(10mg/d)×6-12m

Adult

  • 1 mg/kg/d×8-12w
  • 10%reduction/1-2w
  • Effetively minimal dose(10mg/d)×6-12m
treatment 2
Treatment (2)

Cytotoxic therapy

  • For patients with more relapses, steroid-dependant or steroid-resistant
  • Cyclophosphamide

2mg.kg-1.d-1; total dose 6-8g; side-effects

  • Chlorambucil (苯丁酸氮芥)

0.1-0.2mg/kg/d for 8 weeks

treatment 3
Treatment(3)

Cyclosporine

  • Selectively inhibits Th, Tc
  • As the second line medication to treat patients with steroid-resistant, frequently relapsing/steroid-dependent MCD
  • 5 mg .kg-1.d-1 for 8-12 weeks, then tapering
  • Side effects
treatment 4
Treatment (4)
  • Other medications: MMF
  • General therapy
  • Symptomatic treatment
  • Chinese medicine
mesangial proliferative glomerulonephritis mspgn
Mesangial proliferative glomerulonephritis(MsPGN, 系膜增生性肾小球肾炎)
overview and terminology
Overview and Terminology
  • MsPGN is a morphlogic entity and characterized by glomerular mesangial hypercellularity
  • This morphologic definition includes many well-characterized GNs (IgA nephropathy, Henoch-Schonlein purpura nephritis, lupus nephritis and others)
  • When these well-defined entities are diagnosed and excluded, the resuliting are known as MsPGN or non-IgA MsPGN
pathogenesis1
Pathogenesis
  • Unclear
  • Possibly due to immune complex depositon and complement fixation
  • Altered mesangial function may play an active role
clinic presentation
Clinic presentation
  • More in adolescents and young adults, more male patients
  • 50% of patients with a pre-episode of upper respiratory tract infection
  • 70% of patients with hematuria
  • Some patients with mild hypertension, azotemia
  • Accounting for 20-25% of renal biopsed patients and 30% of primary NS
histopathology1
Histopathology
  • LM

Varying degrees of mesangial hypercellularity with an increase in mesangial matrix

  • IM

IgG, IgM, C3deposition in mesangial region and/or in capillary wall in granular pattern

  • EM

Elctron-dense deposits in the mesangium

differential diagnosis
Differential diagnosis
  • Clinical presentation
  • Renal biopsy
  • Exclusion of the secondary GN and other primary glomerulopathies (IgA nephropathy)
treatment
Treatment
  • Therapy for MsPGN not-defined
  • Efficacy of steroid or cytotoxic therapy depends on the degree of pathologic injury
  • Other medications (ACEI /ARB /Chinese medicine)
membranous nephropathy mn
Membranous Nephropathy(MN, 膜性肾病)

Overview and Terminology

  • Most common pattern of idiopathic NS in adults, less common than MCD in children
  • 15-25% of MN adult patients with no associated systemic illnesses
  • Up to 30% of MN patients with associated systemic illnesses(SLE,HBV,tumors)
pathogenesis2
Pathogenesis
  • Immune complex formation in situ at the subepithelial capillary wall
  • Deposition of circulating immune complexes
  • Complement activation →proteinuria
clinical presentation1
Clinical presentation
  • Heavy proteinuria in more than 80% of patients with full expression of NS
  • 30% of patients with microscopic hematuria
  • More male patients and more severe
  • 80%-90% of patients old than 30 years at diagnosis
  • The older the patients, the greater possibility of malignancy
  • Most common pattern of NS associated with venous thromboses
histopathology2
Histopathology

Usually classified as four stages

LM: capillary walls thickened with subepithelial projections (Spikes)

IM: strong granular capillary wall staining for IgG, C3

EM: subepithelial electron-dense deposits all along the capillary walls

diagnosis 1
Diagnosis(1)
  • Based on histological findings in patients whose history, physical examination and appropriated laboratory tests exclue the likelihood of a secondary cause
diagnosis 2
Diagnosis(2)

Following lab tests negtive or normal

  • Antinuclear Ab
  • Anti-DNA Ab
  • Rheumatoid factor
  • Glycosylated HB
  • Hepatitis Ag or Ab
  • Carcinoembryonic Ag
  • cryoglobulins
treatment 11
Treatment (1)

Treatment of idiopathic MN remains controversial and should be individualized

Steroids+Cytotoxic (ponticelli protocol)

ponticelli protocol
Ponticelli protocol
  • Months 2, 4, 6 chlorambucil 0.2mg/kg/d
  • Months 1, 3, 5 methylprednisone 1.0 iv qd×3d
  • then methylprednisone 0.4mg/kg/d×27d
treatment 21
Treatment (2)
  • Immune inhibition agents(MMF,骁悉)
  • ACEI/ARB
  • Other therapies (anticoagulation)
focal segmental glomerulosclerosis fsgs
Focal segmental glomerulosclerosis(FSGS, 局灶节段性肾小球硬化)
terminology
Terminology

Focal vs diffuse

  • Some glomeruli involved (focal)
  • All glomoruli involved (diffuse)

Segmental vs global (dealing with individual glomerulus)

  • Only part of the glomerulus involved (segmental)
  • Whole golmerulus involved (global)
overview
Overview
  • Accounting for less than 15% of cases of idiopathic NS in children, but more in adults
  • Hematuria,hypertension and GFR↓often found in patients at presentation
pathogenesis3
Pathogenesis
  • Loss of renal mass( compensatory theory)
  • GEC injury
  • RAS activation
  • Cytokine overproduction(TGF-β)
clinical presentaion
Clinical presentaion
  • Most patients with idiopathic FSGS present with asymptomatic proteinuria or full NS
  • Detection of asympotomatic cases occurs often at physicals
  • Patients with NS present with edema
histopathology3
Histopathology
  • LM: focal segmental distribution of sclerosis (mesangial matrix ↑,capillary lumen obliteration, adhesion to Bowman’s capsule)
  • IM: IgM and C3 deposition in focal areas(团块状沉积)
  • EM: some or extensive effacement of foot process
diagnosis
Diagnosis
  • Renal biopsy required
  • Few glomerular sampling may not find the sclerotic glomerulus
  • Finding of tubular fibrosis in such biopsy may suggest the possibility of unobserved sclerosis glomeruli
  • Patients thought to have MCD with a poor response to steroids or cytotoxic may have FSGS
treatment1
Treatment

FSGS with normal renal function

  • More intensive and more prolonged immunosuppressive therapy(6-12months, steroid, cytotoxic, cyclosporine, MMF)
  • ACEI/ARB

FSGS with GFR decrease

  • Follow the therapies for chronic renal failure
membranoproliferative glomerulonephritis mpgn
Membranoproliferative glomerulonephritis(MPGN,膜增殖性肾小球肾炎)
overview and terminology1
Overview and Terminology
  • Other terms as “mesangiocapillary GN(系膜毛细血管性肾小球肾炎)”“Lobular GN(分叶性肾小球肾炎)”“Hypocmplementemic GN(低补体性肾炎)”
  • Secondary conditions are more common than the idiopathic forms
pathogenesis4
Pathogenesis
  • Immune complex deposition in the mesangial and capillary wall →C activation(for MPGN type Ⅰ)
  • MPGN type Ⅱdoes not appear to involve immune complex, but rather utilize some other mechanism for C activation
clinical presentation2
Clinical presentation
  • Less common entity of NS, but if it occurs, most in children and young adults
  • Patients present with Nephrotic (type Ⅰ, 2/3 slow progression), Nephritic(type Ⅱ, 5%, aggressive) or in combination features
  • Preceding upper respiratory infection and persistent proteinuria, hematuria, hypocomplementemic, anemia indicate an incidence of MPGN
histopathology4
Histopathology
  • LM: marked mesangial proliferation and thickening of GBM, glomrular lobularity, double contours(tram-tracks)
  • IM: IgG and C3 granular deposits in mesangium and capillary walls
  • EM: subendothelial and mesangial electron-dense deposits
diagnosis1
Diagnosis
  • Clinical features
  • Persistent hypocomplementemia, anemia not compatible with renal damage, nephrotic with hemoturia, early hypertension and GFR↓
  • Renal biopsy with exclusion of secondary MPGN
treatment and prognosis
Treatment and prognosis
  • Effective therapy needed
  • Steroid and cytotoxic maybe effective on some younger age patients
  • Symptomatic therapies( anticoagulation)
  • Renal function protecting therapies
  • Poor prognosis, 50%of patients following 10 year course progress to ESRD
slide62
小 结

肾病综合征诊断标准

  • 尿蛋白>3.5g/d
  • 血浆白蛋白低于30g/L
  • 水肿
  • 血脂升高

1,2为诊断NS所必需

slide63
肾综分类和常见病因

原发性

  • 微小病变性肾病(MCD)
  • 系膜增生性肾小球肾炎(MsPGN)
  • 膜性肾病(MN)
  • 局灶节段性肾小球硬化(FSGS)
  • 膜增生性肾小球肾炎(MPGN)
slide64
继发性
  • 过敏性紫癜性肾炎
  • 系统性红斑狼疮性肾炎
  • 糖尿病肾病
  • 乙肝相关性肾炎
  • 肾淀粉样变性
  • 骨髓瘤性肾病
slide65
病理生理
  • 大量蛋白尿:电荷屏障、分子屏障受损
  • 血浆蛋白低:尿中丢失、肾小管代谢↑、营养不良
  • 水肿:血浆胶体渗透压↓、低血容量→RAS活力↑、继发性水钠潴留
  • 高脂血症:肝脏合成↑,脂蛋白分解和利用↓
slide66
微小病变型肾病
  • 临床特点:儿童多见,成人发病低,典型肾综
  • 病理特点:LM正常,IM(-),EM见足突广泛融合
  • 治疗及预后:90%病例对糖皮质激素敏感,但复发率高达60%
slide67
系膜增生性肾小球肾炎

临床特点:发病率高,占肾病综合征50%,好发于青少年,前驱感染史,可并血尿

病理特点:LM 系膜及基质增生,IM系膜区IgG,IgM,C3颗粒样沉积,EM系膜区电子致密物

治疗及预后:激素及细胞毒药物治疗反应与病理轻重有关

slide68
膜性肾病

临床特点:好发于中老年人,隐匿起病,极易发生血栓形成,排除继发性原因

病理特点:LM 上皮下钉突形成,GBM增厚; IM IgG,C3呈颗粒样沉积; EM GBM上皮侧电子致密物,足突融合

治疗及预后:早期可由激素和细胞毒药物治疗缓解 (ponticelli方案); 病变缓慢进展,约20-35%患者临床表现可自行缓解

slide69
局灶节段性肾小球硬化

临床特点:好发于青少年男性、常伴有血尿、高血压、GFR↓

病理特点:LM 局灶节段硬化;IM IgM,C3呈团块状沉积,EM 足细胞足突广泛融合

治疗及预后:对激素及细胞毒药物反应差,逐渐发展成肾衰

slide70
膜增生性肾小球肾炎

临床特点:好发于青少年,常伴血尿,高血压,与肾损害不相称的贫血,低补体血症

病理特点:LM 系膜及基质弥漫增生,系膜插入现象,双轨征;IM IgG,C3颗粒样系膜区及毛细血管壁沉积;EM 系膜区内皮下电子致密物沉积

治疗及预后:治疗困难,对症治疗,保护肾功能,病变进展快,预后差

slide71
肾综常见并发症
  • 感染:由于营养不良,免疫功能紊乱,应用激素
  • 血栓和栓塞:由于血液浓缩、高脂血症、抗凝和纤溶系统失衡
  • 急性肾衰竭:由于血容量不足或肾间质水肿压迫肾小管→肾小管阻塞
  • 蛋白质及脂肪代谢紊乱
slide72
诊断
  • 确诊NS
  • 病因诊断、除外继发和遗传性疾病
  • 判断有无并发症
slide73
鉴别诊断

常见继发性肾综原因

  • 紫癜性肾损害:青少年,典型皮疹,腹痛和关节痛,血尿蛋白尿在皮疹后
  • 狼疮性肾炎:女性多发,多系统受累,自身抗体(+)
  • DN:糖尿病史,眼底病变
slide74
肾淀粉样变性:好发于中老年,其它器官受累(心、神经、消化),肾活检肾淀粉样变性:好发于中老年,其它器官受累(心、神经、消化),肾活检
  • 骨髓瘤肾病:中老年男性多见,骨痛,血清单克隆球蛋白↑,尿蛋白电泳M带,尿本周氏蛋白阳性
  • 其它肿瘤性疾病
slide75
治 疗
  • 一般治疗原则
  • 一般治疗
  • 利尿消肿
  • 免疫抑制治疗
  • 调脂治疗
  • 抗凝治疗
  • 各种病理类型原发性肾病综合征的治疗
slide76
治疗
  • 糖皮质激素
  • 细胞毒药物
  • CTX
  • MMF
  • CsA、FK506
  • 来氟米特(爱诺华)
  • 中药:雷公藤
questions
Questions
  • This 5-year-old boy has 4+ protein in his urine on stick testing. His serum albumin is 21g/L. What is the most likely diagnosis?
slide78
These picture are from the renal biopsy of a 60-year-old man who presented with nephrotic syndrome. What is the diagnosis?