Nephrotic Syndrome

Dept. of pediatrics, Tongji Hospital, HUST 1

Nephrotic SyndromeNephrotic SyndromeIn ChildrenIn Children

肾病综合征

Nephrotic SyndromeNephrotic SyndromeIn ChildrenIn 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

刘铜林刘铜林


Idiopathic nephrotic syndrome (INS)

Simple nephrosis ， nephritic 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

Idiopathic nephrotic syndrome (INS)

Simple nephrosis ， nephritic 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 Key words


DefinitionClassificationEtiologyPathologyPathophysiology Clinical Manifestation ComplicationLaboratory DataDiagnosisTreatment

DefinitionClassificationEtiologyPathologyPathophysiology Clinical Manifestation ComplicationLaboratory DataDiagnosisTreatment

Main ContentsMain Contents Main ContentsMain Contents


Male patient,

4 years old,

Complaint of :

edema , oliguria

and proteinuria

for 7 days.


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).

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).

DefinitionDefinition DefinitionDefinition


Nephrotic CriteriaNephrotic 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


NephrNephriitic Criteriatic 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 、 CrHypo-complementemia: Decreased level of serum c3


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≥ 120/80mmHg ，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 (C3) 反复或持续降低者

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≥ 120/80mmHg ，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 (C3) 反复或持续降低者

肾炎型 NS (Nephritic-type NS) 肾炎型 NS (Nephritic-type NS)


Clinical Classification of NSClinical Classification of NS

Simple nephrosis: （＞ 80% ） Only nephrotic criteria (4-increase, 1-decrease)

without nephritic criteria.Nephritic nephrosis: （＜ 20% ） Besides nephrotic criteria with at least

one or more nephritic criteria.


EtiologyEtiology

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


Secondary NS : Secondary NS : DIAMONDDIAMONDInfection: APSGN, HBV, HIV,shunt nephropathy, reflux nephropathy, leprosy, syphilis, schistosomiasis, hydatid disease

Drug,Toxic,Allegy: mercury, snake venom, vaccine, pellicillamine, Heroin,gold, NSAID, captopril, probenecid, volatile hydrocarbons

Neoplasma: Hodgkin’s disease, carcinoma ( renal cell, lung, neuroblastoma, breast, and etc)

Autoimmune or collagen-vascular diseases: SLE, Hashimoto’s thyroiditis, EMC, HSP, Vasculitis

Genetic Disease: Alport syn., Fabry syn., Nail-patella syn., Sickle cell disease, Amyloidosis, Congenital nephropathy

Metabolic disease: Diabetes mellitus

Others: Chronic transplant rejection, congenital nephrosclerosis


(1)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

(1)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

PathologyPathology PathologyPathology


Pathology: Minimal Change NephropathyPathology: 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)


MCN: normal glomerulus in LM



MCN: fusion of foot process of epithelial in EM


MsPGN: Mesangial proliferation and expansion

IgG and C3 deposits in mesangial


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

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INS 的病因与发病机制


PathophysiologyPathophysiology : pathogenesis of proteinuria: pathogenesis of proteinuria PathophysiologyPathophysiology : pathogenesis of proteinuria: pathogenesis of proteinuria


PathophysiologyPathophysiology : pathogenesis of proteinuria: pathogenesis of proteinuria

Massive proteinuria is the most important Massive proteinuria is the most important characteristics ofcharacteristics of NS.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.


PathophysiologyPathophysiology : pathogenesis of proteinuria: pathogenesis of proteinuria

The mechanism of proteinuria may be relatedThe mechanism of proteinuria may be related to 2 aspects:to 2 aspects: Molecular barrier injury:Molecular barrier injury: holes on GBM become holes on GBM become

larger, plasma protein can pass through the GBM larger, plasma protein can pass through the GBM

into the urine ;into the urine ;Charge barrier injury :Charge barrier injury : loss of negative charge loss of negative charge

(glycoprotein) within GBM, plasma protein(glycoprotein) within GBM, plasma protein

(with negative charge) can pass through the GBM (with negative charge) can pass through the GBM

into the urine.into the urine.


Pathophysiology : pathogenesis of proteinuriaPathophysiology : pathogenesis of proteinuria

Lymphocytes→29kd 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.


PathophysiologyPathophysiology : : pathogenesis of proteinuria pathogenesis of proteinuria

If the damage of glomeruli is mild and the permeability If the damage of glomeruli is mild and the permeability is not so high , only lower molecular weight protein is not so high , only lower molecular weight protein ( such as albumin, transferrin) can pass through the ( such as albumin, transferrin) can pass through the GBM, which is called GBM, which is called selective proteinuriaselective proteinuria;;

If the damage of glomeruli is severe , both small and If the damage of glomeruli is severe , both small and large proteinslarge proteins （（ such as IgG, IgAsuch as IgG, IgA ）） can all pass through can all pass through the GBM, which is called the GBM, which is called non-selective proteinurianon-selective proteinuria..


Pathophysiology : Pathophysiology : pathogenesis of hypoalbuminemia pathogenesis of hypoalbuminemia

Loss of plasma protein from urine

Loss of extrarenal , such as from intestine

Increased catabolism of protein in renal tubules


Pathophysiology : Pathophysiology : pathogenesis of hyperlipidemia 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


• Higher concentration of I, ,Ⅱ , , ,ⅤⅦⅧⅩ

• Lower level of anticoagulant substance: antithrombin Ⅲ ， protein S, protein C

• Overvigorous diuresis, blood inspissation

• Higher blood viscosity

• Increased platelet aggregation

• Role of corticosteroid

• Higher concentration of I, ,Ⅱ , , ,ⅤⅦⅧⅩ

• 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 : Pathophysiology : pathogenesis of pathogenesis of Hypercoagulable state Pathophysiology : Pathophysiology : pathogenesis of pathogenesis of Hypercoagulable state


Pathophysiology :Pathophysiology : pathogenesis of edema 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


INS 的病理生理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 ↓

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


Clinical ManifestationClinical Manifestation

Non-specific symptoms: fatigue ， inertia and lethargyloss of appetite, nausea and vomiting, abdominal pain , diarrheabody 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

,


Ascites andAscites and abdomen distention abdomen distention

Edema in scrotum Edema in scrotum andand penispenis



Edema in scrotum andEdema in scrotum and penispenis



Pitting edema and abdomen distentionPitting edema and abdomen distention


ComplicationsComplicationsInfection: URI, UTI, peritonitis, cellulitis

– IgG, IgA, Complement – WBC function – Lack of Zinc and other trace elements

thrombosis ：– Higher concentration of , ,Ⅰ Ⅱ , , ,ⅤⅦⅧⅩ– 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


ComplicationsComplications

Electrolyte imbalance:

hyponatrimia, hypokalemia, hypocalcemia

– Lower salt diet

– Overvigorous(excessive) diuresis

– Extra-renal loss

– Steroid induced hypocalcemia

ARF: pre-renal and renal

Hypovolemic shockOthers: growth retardation, malnutrition,

adrenal cortical insufficiency


Laboratory DataLaboratory Data

Qualitative proteinuria: 3+ or 4+

24-hour urine total protein

(quantitative proteinuria ): ≥50mg/kg.d

Urine protein pattern: – simple nephrosis albumin selective pro.– nephritic nephrosis albumin, IgG , IgA and

other proteins non-selective proteinuria.


Laboratory DataLaboratory Data

Serum biochemistry: TP , ALB , CHOL Serum electrolyte: Natrium , Kalium , Calcium Coagulable state ： PT, KPTT , FIB, D-DRenal function: （ BUN, Cr ） usually normalSerum immunoglobulin and C3:

IgG ， IgA ， IgM ， IgE ； C3 ： , N, Serum preotein electrophoresis ： r↓, a2↑, β↑


Diagnosis and differential diagnosisDiagnosis and differential diagnosis

How can we recognize a child who has NS?Simple or nephritic NS?Refractory NS ？ Idiopathic or secondary NS?MCN or non-MCN? deduction ； renal biopsyComplication ？

The pathway of diagnosisThe pathway of diagnosis ：：


TreatmentTreatment

General (non-specific ) and Symptomatic therapy

Anticoagulation therapyCorticosteroid therapyImmunosuppressive agent therapyChinese traditional medicine therapy


General therapy 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 .


AnticoagulationAnticoagulation therapytherapy

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.


Corticosteroid—prednisone therapyCorticosteroid—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 phaseInduction phase and maintanence phase


ResponseResponse to Steroid therapy 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


(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

(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INS 的治疗方法

根据激素疗效对 INS 分型 :


Immunosuppressive agent therapyImmunosuppressive agent therapy

Frequent relapseSteroid dependentSteroid resistantSevere steroid toxicity

Indication:


Immunosuppressive agent therapyImmunosuppressive agent therapy

Cyclophosphamide （ CTX ） : 2 ～ 2.5mg/kg.d

×8 ～ 12w, total maxium cumulative dose :

≤200mg/kg , oral administrationChlorambucil: 0.2mg/kg.d×8 ～ 12w, total

maxium cumulative dose ： 12 ～ 16mg/kgCyclosporin A: 5 ～ 6mg/kg.d ×6m or more, keep

blood concentration between 50 ～ 150ng/ml azathioprine: 1 ～ 2mg/kg.d ×8 ～ 12wMycophenolate mofetil (MMF):


Pulse therapyPulse 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


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 ？

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 ？

QuestionsQuestions

Health & Medicine

Nephrotic Syndrome