Nephrotic Syndrome

1. Dept. of pediatrics, Tongji Hospital, HUST 1
Nephrotic SyndromeNephrotic Syndrome
In 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

刘铜林

2. Dept. of pediatrics, Tongji Hospital, HUST 2
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

3. Dept. of pediatrics, Tongji Hospital, HUST 3
Definition
Classification
Etiology
Pathology
Pathophysiology
Clinical Manifestation
Complication
Laboratory Data
Diagnosis
Treatment
Main ContentsMain Contents

4. Dept. of pediatrics, Tongji Hospital, HUST 4
Male patient,
4 years old,
Complaint of :
edema , oliguria
and proteinuria
for 7 days.

5. Dept. of pediatrics, Tongji Hospital, HUST 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).
DefinitionDefinition

6. Dept. of pediatrics, Tongji Hospital, HUST 6
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

7. Dept. of pediatrics, Tongji Hospital, HUST 7
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 、Cr
Hypo-complementemia:
Decreased level of serum c3

8. Dept. of pediatrics, Tongji Hospital, HUST 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
≥120/80mmHg，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(C
3)反复或持续降低者
肾炎型NS (Nephritic-type NS)

9. Dept. of pediatrics, Tongji Hospital, HUST 9
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.

10. Dept. of pediatrics, Tongji Hospital, HUST 10
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

11. Dept. of pediatrics, Tongji Hospital, HUST 11
Secondary NS : Secondary NS : DIAMONDDIAMOND
Infection: 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

12. Dept. of pediatrics, Tongji Hospital, HUST 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
PathologyPathology

13. Dept. of pediatrics, Tongji Hospital, HUST 13
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)

14. Dept. of pediatrics, Tongji Hospital, HUST 14
MCN: normal glomerulus in LM

15. Dept. of pediatrics, Tongji Hospital, HUST 15

16. Dept. of pediatrics, Tongji Hospital, HUST 16
MCN: fusion of foot process of epithelial in EM

17. Dept. of pediatrics, Tongji Hospital, HUST 17
MsPGN: Mesangial proliferation and expansion
IgG and C3 deposits in mesangial

18. Dept. of pediatrics, Tongji Hospital, HUST 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. Dept. of pediatrics, Tongji Hospital, HUST 19
PathophysiologyPathophysiology : pathogenesis of proteinuria: pathogenesis of proteinuria

20. Dept. of pediatrics, Tongji Hospital, HUST 20
PathophysiologyPathophysiology : pathogenesis of proteinuria: pathogenesis of proteinuria
Massive proteinuria is the most important Massive proteinuria is the most important
characteristics of NS.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. Dept. of pediatrics, Tongji Hospital, HUST 21
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.

22. Dept. of pediatrics, Tongji Hospital, HUST 22
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.

23. Dept. of pediatrics, Tongji Hospital, HUST 23
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..

24. Dept. of pediatrics, Tongji Hospital, HUST 24
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

25. Dept. of pediatrics, Tongji Hospital, HUST 25
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

26. Dept. of pediatrics, Tongji Hospital, HUST 26
•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

27. Dept. of pediatrics, Tongji Hospital, HUST 27
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

28. Dept. of pediatrics, Tongji Hospital, HUST 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. Dept. of pediatrics, Tongji Hospital, HUST 29
Clinical ManifestationClinical 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. Dept. of pediatrics, Tongji Hospital, HUST 30
Ascites andAscites and abdomen distention abdomen distention
Edema in scrotum Edema in scrotum
and penisand penis

31. Dept. of pediatrics, Tongji Hospital, HUST 31
Clinical ManifestationClinical Manifestation
Edema in scrotum and penisEdema in scrotum and penis

32. Dept. of pediatrics, Tongji Hospital, HUST 32
Clinical ManifestationClinical Manifestation
Pitting edema and abdomen distentionPitting edema and abdomen distention

33. Dept. of pediatrics, Tongji Hospital, HUST 33
ComplicationsComplications
Infection: URI, UTI, peritonitis, cellulitis
– IgG¯, IgA¯, Complement ¯
– WBC function ¯
– Lack of Zinc and other trace elements
thrombosis：
– Higher concentration of , ,
ⅠⅡ
, , ,
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

34. Dept. of pediatrics, Tongji Hospital, HUST 34
ComplicationsComplications
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. Dept. of pediatrics, Tongji Hospital, HUST 35
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.

36. Dept. of pediatrics, Tongji Hospital, HUST 36
Laboratory DataLaboratory 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. Dept. of pediatrics, Tongji Hospital, HUST 37
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 biopsy
Complication？

The pathway of diagnosisThe pathway of diagnosis：：

38. Dept. of pediatrics, Tongji Hospital, HUST 38
TreatmentTreatment
General (non-specific ) and Symptomatic
therapy
Anticoagulation therapy
Corticosteroid therapy
Immunosuppressive agent therapy
Chinese traditional medicine therapy

39. Dept. of pediatrics, Tongji Hospital, HUST 39
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 .

40. Dept. of pediatrics, Tongji Hospital, HUST 40
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.

41. Dept. of pediatrics, Tongji Hospital, HUST 41
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

42. Dept. of pediatrics, Tongji Hospital, HUST 42
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

43. Dept. of pediatrics, Tongji Hospital, HUST 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. Dept. of pediatrics, Tongji Hospital, HUST 44
Immunosuppressive agent therapyImmunosuppressive agent therapy
Frequent relapse
Steroid dependent
Steroid resistant
Severe steroid toxicity
Indication:

45. Dept. of pediatrics, Tongji Hospital, HUST 45
Immunosuppressive agent therapyImmunosuppressive 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. Dept. of pediatrics, Tongji Hospital, HUST 46
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

47. Dept. of pediatrics, Tongji Hospital, HUST 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