Nephrotic syndrome

Nephrotic syndrome is a clinical state characterized by : Massive proteinuria ( > 40 mg /m²/hour), Hypoalbuminaemia ( 250 mg /dl). 60%-80% present before 6 years. MCNS most commonest type of nephrotic syndrome , about 85% of idiopathic nephrotic syndrome.

1. WELCOME
TO
SEMINAR

2. NEPHROTIC
SYNDROME
PRESENTED BY-
DR. SYED KAMRUL HASAN
IMO, DEPARTMENT OF PAEDIATRICS,
JRRMCH, SYLHET

3. What is Nephrotic syndrome ?
Nephroticsyndrome is a clinical state characterized by :
Massive proteinuria ( > 40 mg /m²/hour)
Hypoalbuminaemia( < 2.5 gm/dl)
Generalized edema
Hyperlipidemia ( S. cholesterol >250 mg /dl)

4. EPIDEMIOLOGY :
2-7/lac, <16 years
In Asia, 7-16/lac, < 16 years
60%-80% present before 6 years
MCNS –M:F 2:1,
Median age 2 and half years
FSGS-M:F 1.3:1

5. PATHOPHYSIOLOGY

6. Mechanism of proteinuria :
Proteinuria results from an increase in glomerular
capillary wall permeability. The cause of the
increased permeability is not well understood.
It may be due to :
T cell dysfunction
Plasma Permeability factor
Mutation of genes

7. T cell dysfunction
Alteration of cytokines
Increase IL4 & IL13
Podocytesexpress receptors for IL4 & IL13
& become Activated
Disruption of Glomerular physiology
Loss of negatively charged glycoproteins within the glomerular
capillary wall

8. Plasma Permeability factors
Permeability factors are present in circulations and they
increase glomerular permeability in MCD and FSGS.
Important permeability factors are –Vascular endothelial
growth factor (VEGF) and Heparanase.
VEGF-produced by glomerular podocytesand receptors for
these factors are located on glomerular endothelial cell and
mesangialcells

10. Mechanism of edema formation :
Massive urinary protein loss
Hypoalbuminaemia
Decrease plasma oncotic pressure
Transudation of fluid
from intravascular space
to interstitial space
Oedema
Because of the low plasma oncotic
pressure , reabsorbed Na+ & water
Are lost into the interstitial space
Decrease intravascular
Volume
ADH release
Reabsorption of
water in collecting
ducts
Decrease
intrvascular volume
↓ Renal perfusion
Activation of renin
angiotensin
aldosterone system
Distal tubular
reabsorption of Na+
and H2O

11. Mechanism of hyperlipidemia :
The hypoproteinaemiastimulates generalized protein
synthesis in the liver including lipoproteins.
Lipid catabolism is diminished due to decrease plasma
lipoprotein lipase which is lost through urine.

12. Mechanism of hypercoagulability :
A. Increase prothromboticfactor :
Haemoconcentrationdue to hypovolumia, abuse of diuretics,
dehydration
Increase fibrinogen
Impaired fibrinogenolysis
Thrombocytosis
Relative immobilization
B. Decrease fibrinolyticfactor :
Increase urinary loss of protienC,S, antithrombinIII

13. ETIOLOGY

14. Idiopathic Nephrotic Syndrome: (90%)
a. Minimal change nephrotic syndrome (85%)
b. Focal segmental glomerulo-sclerosis (10%)
c. Mesangial proliferation (5%)

15. Secondary NephroticSyndrome : (10%)
Infection : Hepatitis B & C, HIV, malaria, syphilis,
toxoplasmosis, cytomegalovirus(CMV), bacterial
endocarditis
Drugs : Penicillamine, Gold, NSAIDS, Interferone,
Lithium, Captopril, Mercury, Phenidione.
Allergic Disorder : Bee sting, Food allergens
Malignant Disease : Chronic lymphocytic
leukaemia, Hodgkin’s lymphoma
Systemic disease :SLE, HSP, Amyloidosis,
Polyarteritis, Diabetes mellitus

16. Congenital Nephrotic Syndrome : Rare
Finnish Type
Denys Drash Syndrome

17. MINIMALCHANGENEPHROTICSYNDROME

18. •Most commonest type of nephrotic syndrome ,
about 85% of idiopathic nephrotic syndrome.
•Common in male than female (2:1).
•Common in between 2-6 years of age.
•Usually present with mild oedema, initially noted
around the eyes with times oedema become
generalized with development of ascites, pleural
effusion & genital oedema.
•Anorexia, irritability, abdominal pain & diarrhoea are
common.
•Hypertension & gross haematuria are uncommon.
•Bed side heat coagulation test +++/++++

19. •In light microscopy: No appreciable glomerular
pathology is noted.
•Immunofluroscencemicroscopy : Typically negative.
•In electron microscopy: Effacement of foot processes
of podocytesin glomerular basement membrane.
•More than 95% response to steroid but high
tendency to relapse.

20. Minimal Change
Nephrotic Syndrome

22. FOCALSEGMENTAL GLOMERULOSCLEROSIS

23. •About 10% of idiopathic nephrotic syndrome.
•Occurs in older children.
•Male female ratio 1.3:1.
•The clinical profile is similar to MCNS, though
microscopic hematuria & hypertension may be
present.
•Only 20% response to steroid.

24. •On light microscopy : shows mesangial
proliferation & segmental scarring.
•On immunofluroscence microscopy : shows IgM
& C3 staining in the area of segmental sclerosis.
•On electron microscopy : shows segmental
scarring of glomerulus tuft with the obliteration of
the glomerular capillary lumen.

25. MESENGIALPROLIFERATION

26. oUsually occurs in older children.
oMale & female are equally affected.
oThe clinical profile is similar to MCNS with
haematuria & hypertension.
oAbout 50 % response to steroid.

27. oOn light microscopy : shows diffuse increase in
mesangial cell & matrix.
oImmunofluroscence microscopy : shows slight
deposition of IgM in mesengial cell.
oElectron microscopy : shows increse number of
mesengial cells & matrix as well as effacement of
the epithelial cell foot process.

28. CONGENITAL NEPHROTIC SYNDROME

29. Nephrotic syndrome is present at birth or appears
within three months of life.
Renal biopsy should be performed in all cases.
The commonest form is the autosomal recessive
Finnish nephrotic syndrome due to defective
production of Nephrin.
There is no specific therapy, appropriate supportive
care is instituted.

30. Causes of congenital nephroticsyndrome:
Classic' Finnish 'type.
Diffuse mesangialsclerosis -
*with pseudohermaphroditism(Denys-Drash
syndrome).
*with microcephaly ,development delay and hiatal
hernia(Galloway-Mowatsyndrome).
*idiopathic.
Primary focal segmental glomerulosclerosis
Congenital infections : cytomegalovirus, syphilis,
rubella, toxoplasma, hepatitis B.

31. FINNISHTYPECONGENITAL
NEPHROTICSYNDROME

32. The Finnish type congenital nephroticsyndrome is
an autosomal recessive disease.
Infants with the Finnish type of congenital nephrotic
syndrome are born prematurely, often with large
placenta.
Nephroticsyndrome is present at or soon after birth.

33. Clinical presentation:
Failure to thrive,
Repeated infection,
Delayed development,
Ascites,
Spontaneous vascular thrombosis.
Biopsyshows cortical microcysts, representing
dilated proximal convoluted tubules, glomeruli may
show mesangialproliferation and increased
mesangialmatrix.

34. Relation of edema with hypoalbuminaemia :
Serumalbumin Oedema
20 -25 gm/l Periorbitaloedema
18 -<20 gm/l Dependent oedema
15 -< 18 gm/l Ascites
< 15 gm/l Genital oedema

35. Heat Coagulation Test

36. Interpretation of HCT :
Keep the tube in front of newspaper
Readnewspaper Amountof protein
mg/dl
Clearlyread Trace 10-20
Canread but with
difficulty
+ 30-100
Can’t read , only
see writing
++ 100-300
Only paper is seen +++ 300-1000
Nothing is seen ++++ >10000

38. Terminology Related To
Nephrotic Syndrome

39. Remission:
Protein free urine (urinary protein excretion <4mg /
m² /hror urine protein negative/trace) for 3
consecutive days.
Relapse :
Proteinuria (urinary protein excretion > 40 mg/ m² /hr
or urine protein +++ or more) for 3 consecutive days
( plus edema), in a patient having previously in
remission .

40. Frequent relapse :
When relapses ≥ 4 times in a 12 months period (who
respond previously with prednisolone therapy).
Infrequent relapse :
When ≤ 3 relapses in a 12 months period (who
respond previously with prednisolone therapy).

41. Steroid dependent :
Patient relapse while on alternate day steroid therapy
or within 28 days of completing a successful course
of prednisolone therapy.
Steroid resistant :
Children who failed to respond to prednisolone
therapy within 8 weeks of therapy are termed steroid
resistant.

42. Late responder :
Patient with initial resistance who responds
later.
Late resistance :
Initial responder who subsequently fails to
respond to steroid therapy.

43. INVESTIGATION

44. For diagnosis :
-Urine R/M/E ( 3+ or 4+ proteinuria , granular &
hyaline casts)
-Spot urine protein creatinine ratio (>2.0)
-24 hours urinary total protein (>1gm/m2/day )
-Serum albumin (<2.5 gm/dl)
-Serum cholesterol (> 250mg/dl )

45. For infection screening :
-CBC
-Blood culture
-Urine culture
-Chest X -ray
-HBsAg
-MT

46. To exclude secondary nephroticsyndrome :
-Serum creatinine
-Serum C3, C4
-Serum electrolyte
-For cause identificatin:
HBsAg, Anti HCV
ANA, Anti ds DNA
HIV screening
VDRL
Renal USG
Renal biopsy

47. Renal biopsy
Indication :
Age of onsent < 1 year or >12 years
Haematuria
Sustained hypertension
Renal failure
Persistent ↓C3 ,C4
Steroid resistance nephrotic syndrome
Suspected secondary cause of nephotic
syndrome
Before cyclosporine or tacrolimus therapy

48. MANAGEMENT

49. Criteria for hospital admission :
First attack ( for counseling)
With complications
Need for renal biopsy
Doubtful compliance

50. Aim of management :
Achieve remission
Prevention of relapse
Avoidance of complications & side effects
of drugs

51. Treatment of Nephrotic Syndrome
Supportive & Symptomatic management
Specific management
Prevention and treatment of complications

52. Supportive & symptomatic treatment:
Dietary management & daily activities
Control of oedema
Prevention and treatment of infections
Counseling of parents and psychosocial support.

53. Dietary Management
A balance diet, adequate in protein and calories
Protein : An adequate protein intake (1.5-2
gram/kg/day)
Patient with persistent proteinuria should
receive 2-2.5gm /kg/day.
Fat : <30% of the diet
Supplements vitamins and minerals
Salt intake restricted up to remission

54. DAILYACTIVITIES
Physical activity as tolerated
May attend school

55. Management of Oedema:
Mild to moderate oedema:
Salt restriction up to remission
No fluid restriction no diuretics

56. Massive oedema:
Salt restriction
Fluid restriction
Diuretics :
Oral frusemide(1-3mg/kg) in 1-3 divided
doses or iv 4-10 mg/kg /day.
Spironolactone (1-3mg/kg/day) added in
case of higher or prolonged duration of
treatment.

57. Hydrochlorthiazide(1-3 mg/kg/day) or
metolazone(0.1-0.5 mg/kg/day) may be
added with frusemidein severe case.
I/V 20 % human albumin (0.5-1 gm/kg
/dose over 1-2 hours) when fluid restriction
& diuretics are not effective.

58. Indication of albumin infusion in NS :
Serum albumin < 1.5 gm/dl
Oedemanot improve even after maximum
dose of diuretics
Child with signs of hypovolumia
Severe complication of diuretic therapy

59. Prevention & treatment of infection by
appropriate antibiotics

60. SpecificManagement for
First Attack
Relapse
Steroid dependent nephroticsyndrome
Steroid resistant nephroticsyndrome
Frequent relapse
Infrequent relapse

61. First attack
Prednisolone :
60mg/m
2
/day (max. 80mg) 2-3 divided doses
for 6 weeks. Then
40mg/m
2
/every alternate day –single morning for
dose for 4 weeks. Then slowly tapered &
discontinued over the next 4-8 weeks.

62. Relapse
Prednisolone :
60mg/m
2
/day -till urine become protein free for 3
consecutive days.
Followed by 40mg/m
2
/every alternate day single
morning for dose for 4 weeks & gradually
tapered over 4-8 weeks

63. Alternative drugs used in Nephrotic
Syndrome :
oLevamisole
oCyclophosphamide & chlorambucil
oCyclosporine
oMycophenolatemofetil
oTacrolimus
oMethyl prednisolone

64. Frequent relapses /
Steroid dependennce
Prednisolone–60 mg /m²/ day till remission then
Alternate day prednisolone to maintain remission
Steroid threshold
<0.5 mg/kg on
alternate day
Alternate day
prednisolone
for 9-18 months
Threshold >0.5 mg/kg on
alternate day or
Severe complication, or
steroid toxicity
Levamisole,
Cyclophosphamide,
Tacrolimus,
CyclosporinA,
Mycophenolatemofetil

65. Frequent relapses & Steroid dependence :
Following treatment of a relapse, prednisolone is
gradually tapered to maintain the patient in remission
on alternate day dose of 0.5 mg/kg, which is
administered for 9-18 months. If the prednisolone
threshold to maintain remission is higher or if
features of steroid toxicity are seen, additional use of
the following immunomodulators are suggested :

66. Levamisole :
2-2.5 mg /kg on alternate days for 12-24 months.
Prednisolone 1.5 mg/kg on alternate days for 2-4
weeks.
Gradually reduced by 0.15-0.25 mg/kg every 4 weeks
to a maintenance dose of 0.25-0.5 mg/kg that is
continued for 6 or more months.

67. Cyclophosphamide :
2-2.5 mg/kg for 12 weeks
Prednisolone 1.5 mg/kg on alternate days for 4 wks.
Followed by 1mg/kg for next 8 weeks.
Steroid therapy tapered & stopped over the next 2-3
months.

68. Cyclosporine (CsA) :
4-5 mg/kg daily for 12-24 months
Prednisolone 1.5 mg/kg on alternate days for 2-4
weeks .
Gradually reduced by 0.15-0.25 mg/kg every 4 weeks
to a maintenance dose of 0.25-0.5 mg/kg that is
continued for 6 or more months.

69. Tacrolimus :
0.1-0.2 mg/kg daily for 12 –24 months.
Mycophenolate mofetil (MMF) :
20-25 mg/kg/day 12 hourly for 12-24 months
tapering doses of prednisolone for 12 -24 months.

70. Adjunct therapy :
ACE inhibitor
Angiotensin II blocker
These drugs causing efferent arteriolar dilation &
reducing glomerular filtration pressure & thus
reducing proteinuria in steroid resistant nephrotic
syndrome.

71. Rituximab:
Is an anti CD-20 monoclonal antibody
1-2 dose Rituximab significantly reduces relapse
rate in FRNS and SDNS
Dose : 375 mg/m2 i.v infusion

72. Steroid Resistance Nephrotic Syndrome :
The choice of therapy in steroid resistant nephrotic
syndrome include:
calcineurin inhibitors with alternate day prednisolone,
IV methylprednisolone followed by cyclophosphamide
or cyclosporine.
Angiotensin converting enzyme inhibitors and
angiotensin receptor blockers reduce the intensity of
proteinuria.
Hypertension should be controlled, aiming to achieve
reduction of blood pressure to the 50th percentile.
Statins are used to control hyperlipidaemia

73. Treatment protocol of steroid
resistant NS of BSMMU
Failure to remission after 8weeks of prednisolone
therapy(60mg/m2)
Do renal biopsy and if it is MCNS with steroid resistant
Oral cyclosporin(100mg/m2/day) or
Tacrolimus(50-70mg/day) plus
alternate day prednisolone(1.5mg/kg/day) for 1-2 years.

74. Another protocol-
Pulse methylprednisolone (20-30mg/kg)alternate
day for 5-6 days followed by tapering dose of oral
prednisolone (1.5mg/kg) every alternate day for 1-
2 years.
For other than MCNS with steroid resistant
Injection cyclophosphamide (500mg/m2/month) for
6 months plus alternate day prednisolone
(1.5mg/kg) for 1-2 years.

75. CONGENITALNEPHROTICSYNDROME
•There is no specific treatment
•The disease is resistant to corticosteroid &
cytotoxic drugs.
Nephrectomy
Dialysis up to weight 10 kg or 1 year of age
Renal transplantation

76. COMPLICATIONS OF
NEPHROTIC SYNDROME

77. Complication related to disease:
1.Infections:
UTI
Pneumonia
Spontaneous bacterial peritonitis
Cellulitis
Septicemia
Meningitis
Bone & joint infection
Flair up of tuberculosis
Varicella, Measles

78. 2. Thromboembolism :
Deep vein thrombosis
Renal vein thrombosis
Pulmonary vein thrombosis
Cerebral venous sinus thrombosis
3. Hypovolumia& shock
4. Hypocalcaemia
5. Diarrhea & vomiting
6. Acute renal failure
7. Anaemia

79. 8. Abdominal pain due to :-
Peritonitis,
Mesenteric ischaemia,
UTI,
Renal vein thrombosis,
Steroid induced gastritis

80. COMMON ORGANISM CAUSING INFECTION IN
NEPHROTIC SYNDROME
Bacterial :
Streptococcus pneumoniae
Haemophilusinfluenzae
E.coli
Klebsiella
Pseudomonas
Mycobacterium tuberculosis
Virus :
Measles
Varicella

81. Prevention of infection
Immunization:
Administration of live vaccines measles,
mumps, rubella, oral polio, varicella is avoided
until steroid therapy discontinued for 4 weeks.
Other vaccinespneumococcal, Hib, Hepatitis
B may be given.
Patient in remission should receive the
varicella vaccine.

82. If the child with nephrotic syndrome is on
continuous immunosuppression , siblings
should receive the inactivated polio vaccine
instead of OPV.
Siblings can safely receive the MMR &
varicella vaccines without a risk of
exposing the patient to the attenuated
viruses.

83. Complication due to drug

84. STEROID
Cushingoid face
Obesity
Cataract
Buffalo hump
Hypertension
Avascular necrosis
GF
More chance to develop infection
Osteoporosis
Hyperglycaemia
Peptic ulcer

85. Low hair line
Cataract
Facial Plethora
Buffalo Hum
Gynaecomashia
Stria
Hypertension
Abdominal fat

86. WHATTODO?
Stop steroid when toxicity develop
Go for Alternative drug
Counseling the parents

87. CYCLOPHOSPHAMIDE
Side effect:
Neutropenia
Disseminated varicella
Reversible alopecia
Hemorrhagic cystitis
Sterility
Risk of future malignancy

88. What to do?
-Blood count –weekly during the first 4 weeks
of treatment than 2 weekly.
-If TC of WBC <5000/ cmm –drug is withheld
till normal
-Maintain high urine output to prevent
hemorrhagic cystitis and use MESNA ( sodium 2-
mercaptoethane sulfanate ) if iv cyclophosphamide
given.

89. CYCLOSPORINE
Side effect:
Hypertension
Nephrotoxicity
Hirsutism
Tremor
Gum hypertrophy
What to do?
Blood level of urea creatinineshould be measured
every 4-6 weeks.

90. LEVAMISOLE
Side effect:
GIT upset
Influenza like symptoms
Skin rash may associated with leukocytoclastic
vasculitis
Neutropenia
Liver toxicity
Convulsion

91. What to do?
Monitor blood leucocyte count for every 2-
4 month
All the side effect diminishes after drug
withdraw

92. Tacrolimus :
Side effect :
Septicemia
Cardiac damage
Hypertension
Hepatotoxicity
Nephrotoxicity
Electrolyte imbalance
Hyperglycemia
What to do ?
Blood level of creatinine & glucose should estimated
every 2-3 months

93. SOMESPECIALSITUATION
NS WITH TB:
Clinical feature
low grade fever
persisting cough
Investigation:
Chest X-Ray
MT
Treatment:
At first start anti tubercular drugs , after 2 weeks
start prednisolone therapy.

94. NS WITH VARICELA
Treatment:
oral acyclovir 80 mg/kg daily in 4 divided dose for 7-
10 days.
Patient exposed to varicella:
VZIG 125 unit/10 kg body weight ( minimum
125unit , maximum 625unit) should be given within
96 hours of significant exposure.
Intravenous immunoglobulin 400mg/kg may be
used.

95. NS WITH HEPATITIS B
Lamivudin 2 week before steroid given &
continue 6 weeks to 6 month after the end
of the treatment.
Interferon should also be given.

96. NS WITH MEASLES
Measles causes a serious danger to
patients receiving steroid & cytotoxic drug.
NS less than <1 year is uncommon , so
most patients are already vaccinated
before they get NS.
After 2 weeks start prednisolone therapy.

97. COUNSELING
Should be trained how to test urine for albumin &
maintain a diary.
Parents should be explained about the naturel
history of the disease.
Should be provided with a booklet covering all
information about the condition.
Normal activity & schooling
Parents compliance & co operation is essential.

98. Prognosis :
Depends on whether the patient is steroid
responsive or resistant.
In Steroid sensitive Nephrotic Syndrome:
The final outcome is excellent . Most of the patient
stop getting relapses between the age of 14-20 years
without any residual renal dysfunction. The
subsequent course of steroid responsive NS are-
25-40% have infrequent relapse
40% have frequent relapse
20% steroid dependence

99. In Steroid resistant NephroticSyndrome :
Generally have much poorer prognosis.
Develop ESRD over 10 years requiring dialysis
& or transplantation.

100. FOLLOW UP
During hospital admission:
Daily-Vital signs,
-Weight
-Fluid intake
-Urine out put
-Abdominal girth
-Edema
-Any sign of infection
.

101. During discharge:
Mother should know when to return
If the child develop edema with any sign of
infection such as fever, cough, diarrhea,
vomiting then mother should test urine for
albumin.
If the urine for albumin 3+ or more for 3
consecutive days then she must return to
the hospital.

102. BADPROGNOSTIC SIGNSOFNS
Very young (<1 yr) & (>10yr)
Persistent heavy hematuria
Hypocomplementemia
Hypertension
Renal failure
No Response within 28 days of adequate
prednisolone regimen