Nephrotic syndrome
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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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肾病综合征 Nephrotic Syndrome

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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


Nephrotic syndrome

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


Nephrotic syndrome

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)


Nephrotic syndrome

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


Nephrotic syndrome

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↓


Nephrotic syndrome

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%


Nephrotic syndrome

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


Nephrotic syndrome

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


Nephrotic syndrome

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


Nephrotic syndrome

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


Nephrotic syndrome

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


Nephrotic syndrome

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


Nephrotic syndrome

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


Nephrotic syndrome

  • 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


Nephrotic syndrome

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


Nephrotic syndrome

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?


Nephrotic syndrome

  • These picture are from the renal biopsy of a 60-year-old man who presented with nephrotic syndrome. What is the diagnosis?


Nephrotic syndrome

  • How to treat minimal change disease patients with steroid?


Nephrotic syndrome

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