This document provides an overview of nephrotic syndrome, including its pathogenesis, clinical manifestations, investigations, and management. Some key points: - Nephrotic syndrome is characterized by massive proteinuria, hypoalbuminemia, edema, and hyperlipidemia. It is mostly seen in children aged 2-6 years. - The podocyte plays a crucial role in the glomerular filtration barrier and podocyte injury can lead to nephrotic syndrome. - Clinical consequences include edema, hyperlipidemia, increased infection risk, and hypercoagulability. - Corticosteroids are the main treatment for minimal change nephrotic syndrome, with relapses requiring high-

1. NEPHROTIC SYNDROME•

2. INTRODUCTION
 Common renal disorder.
massive proteinuria
hypoalbuminemia edema.
 Hypercholesterolemia is always present.
 Affects 1-3 per 100,000 children <16 yr of age.
 80% of children with nephrotic syndrome respond
to corticosteroid therapy.

3. Main causes of nephrotic
syndrome
 Idiopathic nephrotic syndrome
 Genetic disorders associated with proteinuria or
nephrotic syndrome
 Secondary causes of nephrotic syndrome

4. PATHOGENESIS
Role of the Podocyte
 The podocyte plays a crucial role in the
development of proteinuria and
progression of glomerulosclerosis.
The podocyte is a highly differentiated
epithelial cell located on the outside of
the glomerular capillary loop .

6. CONT....
 The podocyte functions as structural support
of the capillary loop, is a major component
of the glomerular filtration barrier to
proteins, and is involved in synthesis and
repair of the glomerular basement
membrane.
 The foot processes of a podocyte
interdigitate with those from adjacent
podocytes and are connected by a slit
called the slit diaphragm.
 The slit diaphragm play an important role in
podocyte function

7. CONT..
 Important component proteins of the slit diaphragm
include nephrin, podocin, CD2AP, and α-actinin 4.
 Podocyte injury or genetic mutations of genes
producing podocyte proteins may cause nephrotic-
range proteinuria.
 In idiopathic, hereditary, and secondary forms of
nephrotic syndrome, there are immune and
nonimmune insults which decrease in number of
functional podocytes, and altered slit diaphragm
integrity. The end result is increased protein
“leakiness” across the glomerular capillary wall into
the urinary space.

8. CLINICAL CONSEQUENCES
OF NEPHROTIC SYNDROME
EDEMA-
The most common presenting
symptom in children.
2 opposing theories, underfill
hypothesis and the overfill
hypothesis

11.  The overfill hypothesis ,nephrotic syndrome is
associated with primary sodium retention, with
subsequent volume expansion and leakage of
excess fluid into the interstitium.
 There is accumulating evidence that the epithelial
sodium channel in the distal tubule may play a key
role in sodium reabsorption in nephrotic syndrome.

12. The goal of therapy should be a
gradual reduction of edema with
judicious use of diuretics, sodium
restriction, and cautious use of
intravenous albumin infusions, if
indicated.

13.  HYPERLIPIDEMIA-
 Hyperlipidemia is thought to be the result of
increased synthesis as well as decreased
catabolism of lipids.
 Several alterations in the lipid profile in children with
nephrotic syndrome, including an increase in
cholesterol, triglycerides, low-density lipoprotein,
and very-low-density lipoproteins.
 The high density lipoprotein level remains
unchanged or is low.

14. INCREASED SUSCEPTIBILITY TO
INFECTIONS-
 Susceptible to infections such as cellulitis,
spontaneous bacterial peritonitis, and bacteremia.
 As result of many factors, particularly
hypoglobulinemia as a result of the urinary losses
of immunoglobulin G(Ig)
 In addition, defects in the complement cascade
from urinary loss of complement factors
(predominantly C3 and C5), as well as alternative
pathway factors B and D, lead to impaired
opsonization of microorganisms

15. HYPERCOAGULABILITY-
 Nephrotic syndrome is a hypercoagulable state resulting from
multiple factors like vascular stasis, increased platelet number
and aggregability, and changes in coagulation factor levels.
 increase in hepatic production of fibrinogen along with urinary
losses of antithromboticfactors such as antithrombin III and
protein S.
 Deep venous thrombosis may occur in any venous bed,
including the cerebral venous sinus,renal vein, and pulmonary
veins.
 clinical risk is low in children (2-5%), but has the potential for
serious consequences.

16. IDIOPATHIC NEPHROTIC SYNDROME
 90% of children with nephrotic syndrome have
idiopathic nephrotic syndrome.
 Idiopathic nephrotic syndrome includes multiple
histologic types: minimal change disease,
mesangial proliferation,focal segmental
glomerulosclerosis, membranous nephropathy,
and membranoproliferative glomerulonephritis

17.  PATHOGENESIS
In minimal change nephrotic
syndrome (MCNS) (approximately 85% of
total cases), the glomeruli appear normal or show a
minimal increase in mesangial cells and matrix.
 Findings on immunofluorescence microscopy are
typically negative, and electron microscopy simply
reveals effacement of the epithelial cell foot
processes.
 More than 95% of children with minimal change and
disease respond to corticosteroid therapy

19. Mesangial proliferation is
characterized by a diffuse increase in mesangial
cells and matrix on light microscopy.
 Immunofluorescence microscopy might reveal trace
to 1+ mesangial IgM and/or IgA staining.
 Electron microscopy reveals increased numbers of
mesangial cells and matrix as well as effacement of
the epithelial cell foot processes.
 Approximately 50% of patients with this histologic
lesion respond to corticosteroid therapy

20.  In focal segmental
glomerulosclerosis (FSGS), glomeruli
show lesions that are both focal and segmental .
 The lesions consist of mesangial cell proliferation and
segmental scarring on light microscopy .
 Immunofluorescence microscopy is positive for IgM and C3
staining in the areas of segmental sclerosis.
Electron microscopy demonstrates segmental scarring of the
glomerular tuft with obliteration of the glomerular capillary
lumen.
 Only 20% of patients with FSGS respond to prednisone. The
disease is often progressive, ultimately involving all glomeruli,
and ultimately leads to end-stage renal disease in most
patients.

21.  MINIMAL CHANGE NEPHROTIC SYNDROME-
Clinical Manifestations-
 The idiopathic nephrotic syndrome is more common
in boys than ingirls and most commonly appears
between the ages of 2 and 6 yr
 MCNS is present in 85-90% of patients <6 yr of
age.
 Only 20-30% of adolescents who present for the
first time with nephrotic syndrome have MCNS.

22.  Children usually present with mild edema, which is
initially noted around the eyes and in the lower
extremities.
 Nephrotic syndrome can initially be misdiagnosed as an
allergic disorder because of the periorbital swelling that
decreases throughout the day.
 With time, the edema becomes generalized, with the
development of ascites, pleural effusions,and genital
edema.
 Anorexia, irritability, abdominal pain, and diarrhea are
common.
 Important features of minimal change idiopathic
nephrotic syndrome are the absence of
hypertension and gross hematuria

23. DEFINITIONS TO CLARIFY THE COURSE
 Remission-
urine albumin nil or trace for 3 consecutive
early morning specimens
 Relapse-
urine albumin 3+ or 4+ trace for 3 consecutive
early morning specimens, has been in remission
previously.
 Frequent relapse-
two or more relapses in initial 6 months or more
than 3 relapse in any 1 month

24.  Steriod dependence-
relapse when on the alternate day steroids or
within 14 days of discontinuation
 Steroid resistance-
absence of remission despite therapy with
daily steroids for 4 weeks.

25. INVESTIGATION
 1-Urine analysis:-
A-Proteinuria : 3-4 + SELECTIVE.
b-24 urine collection for protein
>40mg/m2/hr for children
c- volume: oliguria (during stage of edema formation)
d-Microscopically:-
microscopic hematuria 20%, large number of hyaline cast

26.  2-Blood:
 A-serum protein: decrease >5.5gm/dL , Albumin
levels are low (＜2.5gm/dL).
 B-Serum cholesterol and triglycerides:
Cholesterol ＞5.7mmol/L (220mg/dl).
 C-- ESR↑＞100mm/hr during activity phase
 4.Renal function
 5. mountox test

27. Additional Tests
 C3 and antistreptolysin O
 Chest X ray and tuberculin test
 Hepatitis B surface antigen

28. TREATMENT
 Children with their first episode of nephrotic
syndrome and mild to moderate edema may be
managed as outpatients.
 Salt restriction-
140 mg less of sodium per serving
 Tuberculosis must be ruled out prior to starting
immunosuppressive therapy with corticosteroids.

29.  Fluid restriction-
total fluid intake should be restricted to the
urine output plus insensible water loss
insensible water loss is calculated as 30 ml/kg in
young children and 20 ml /kg in older children.
 Diet-
high protein intake is not recommended due to
glomerulosclerosis and renal failure.

30. DRUG THERAPY FOR PROTEINURIA
Steriods-
 should be started immediately after infection is
diagnosed.
 Prednisolone 2 mg/kg for 4 weeks. Tapper depending
upon the response
 After four weeks if proteinuria present continue same
dose of prednisolone for next 4 days.
 If proteinuria decrease start tappering the dose
 For relapse ,treat with daily same dose of
prednisolone till the remission occour and changed to
alternate-day dossing for 1 to 2 months
Deflazacort found as alternative with less side
effects in treating steriod sensitive nephrotic
syndrome.

31. APN REGIMEN
 Initial episode-
prednisolone 60 mg/m2/day should be
given daily for 6 weeks in two or three divided
doses followed by 40 mg/m2/day on alternate day
for 6 weeks.
 Relapse-
prednisolone 60 mg/m2/day should be
given till remission, followed by 40 mg/m2/day for 3
days in a week for 6 weeks

32.  MODIFIED APN REGIMEN-
Tablet prednisolone 2 mg/kg/day for 6
weeks, followed by 2 mg/kg/day on alternative day
for 6 weeks.

33. ISKDC REGIMEN(International study group on kidney
disease in children regimen)
 Initial episode-
prednisolone 60mg/m2/day should be administered in 2-
3 divided dose for 4 weeks,followed by 40 mg/m2/day daily for
3 consecutive days in a week for 4 consecutive weeks.
then stop steriod treatment without tappering
response occurs in 2 weeks with disappearance of
proteinuria
 Relapse-
same as initial attack, except the prednisolone is given
at a dose of 60 mg/m2/day till the urine has been free of
protein for 3 consecutive days

34.  MODIFIED ISKDC REGIMEN
after 4 weeks of treatment, prednisolone 40
mg/m2 is given as a single morning dose on
alternative days, rather than on 3 consecutive days

35.  Children with onset of uncomplicated nephrotic
syndrome between 1 and 8 yr of age are likely to
have steroid-responsive MCNS, and steroid therapy
may be initiated without a diagnostic renal biopsy.
 Children with features that make MCNS less likely
should be considered for renal biopsy before
treatment.

36.  Use of Corticosteroids to Treat Minimal Change
Nephrotic Syndrome Corticosteroids are the
mainstay of therapy for MCNS.
 Treatment of Initial Episode of Nephrotic Syndrome
prednisone or prednisolone should be administered
as a single daily dose of 60 mg/m2/day or 2
mg/kg/day to a maximum of 60 mg daily for 4-6 wk
followed by alternate-day prednisone for a period
ranging from 8 wk to 5 month, with tapering of the
dose.

37.  Approximately 80-90% of children respond to
steroid therapy.
 Response is defined as the attainment of remission
within the initial 4 wk of corticosteroid therapy.
 Remission consists of a urine protein : creatinine
ratio of <0.2 or <1+ protein on urine dipstick for 3
consecutive days.

38. MANAGING THE CLINICAL SEQUELAE
OF NEPHROTIC SYNDROME
Edema-
 Children with severe symptomatic edema, including
large pleural effusions, ascites, or severe genital edema,
should be hospitalized.
 Sodium restriction (<1500 mg daily), water/fluid
restriction may be necessary if the child is
hyponatremic.
 A swollen scrotum may be elevated with pillows to
enhance fluid removal by gravity.
 Administration of diuretics (furosemide), orally or
intravenously, although extreme caution should be
exercised.
 Aggressive diuresis can lead to intravascular volume
depletion and an increased risk for acute renal failure
and intravascular thrombosis.

39.  When a patient has severe generalized edema with
evidence of intravascular volume depletion IV
administration of 25% albumin (0.5-1.0 g
albumin/kg) as a slow infusion followed by
furosemide is sometimes necessary.
 Close monitoring -volume status, blood pressure,
serum electrolyte balance, and renal function.

40. INFECTIONS
 Families of children with nephrotic syndrome should
be counseled regarding the signs and symptoms of
infections such as cellulitis, peritonitis, and
bacteremia.
 In the case of spontaneous bacterial peritonitis,
peritoneal fluid should be collected if there is
sufficient fluid to perform a paracentesis and sent
for cell count, Gram stain, and culture.
 The antibioticprovided must be of broad enough
coverage to include Pneumococcus and Gram-
negative bacteria. A 3rd-generation cephalosporin
is a common choice of IV antibiotic.

41. OBESITY AND GROWTH
 Glucocorticoids may increase the body mass index
in children who are overweight when steroid
therapy isinitiated, and these children are more
likely to remain overweight.
 Anticipatory dietary counseling is recommended.
 Steroid-sparing strategies may improve linear
growth in children who require prolonged courses of
steroids

42. RELAPSE OF NEPHROTIC SYNDROME
 Relapse of nephrotic syndrome is defined as a
urine protein : creatinine ratio of >2 or ≥3+ protein
or urine dipstick testing for 3 consecutive days.
 Relapses are common, especially in younger
children, and are often triggered by upper
respiratory or gastrointestinal infections.
 Daily high-dose prednisone is given until the child
has achieved remission, and the regimen is then
switched to alternate-day therapy.
 The duration of alternate day therapy varies
depending on the frequency of relapses of the
individual child.

43. STEROID RESISTANCE
 Steroid resistance is defined as the failure to
achieve remission after 8 wk of corticosteroid
therapy.
 Children with steroid-resistant nephrotic syndrome
require further evaluation, including a diagnostic
kidney biopsy, evaluation of kidney function, and
quantitation of urine protein excretion
 Steroid-resistant nephrotic syndrome is usually
caused by FSGS (80%), MCNS, or
membranoproliferative glomerulonephritis.

44.  Choice of therapy in steriod resistant nephrotic
syndrome
I. Calcineurin inhibitors with alternate day
prednisolone
II. IV cyclophosphamide with alternate day
prednisolone
III. IV methylprednisolone followed by
cyclophosphamide
 Persistent nephrotic syndrome is associated with
poorquality of life, hypertension, serious infections,
and thromboembolic events.

45. ALTERNATIVE THERAPIES TO
CORTICOSTEROIDS
 Cyclophosphamide prolongs the duration of
remission and reduces the number of relapses in
children with frequently relapsing and steroid-
dependent nephrotic syndrome.
 Cyclophosphamide (2 mg/kg) is given as a single
oral dose for a total duration of 8-12 wk.
 Alternate-day prednisone therapy is often
continued.

46. INDICATIONS FOR RENAL BIOPSY
• Age below 12 months
• Gross or persistent microscopic hematuria
• Low blood C3
• Hypertension
• Impaired renal Function
• Failure of steroid therapy

47. SECONDARY NEPHROTIC SYNDROME
 Nephrotic syndrome can occur as a secondary
feature of many forms of glomerular disease like
Membranous nephropathy, membranoproliferative
glomerulonephritis, postinfectious
glomerulonephritis, lupus nephritis
 Secondary nephrotic syndrome should be
suspected in patients >8 yr and those with
hypertension, hematuria, renal dysfunction,
extrarenal symptoms (rash, arthralgias, fever), or
depressed serum complement levels.
 Other infectious agents associated with nephrotic
syndrome include hepatitis B virus, hepatitis C
virus, filaria,leprosy, and HIV.

48. CONGENITAL NEPHROTIC SYNDROME
 has a poorer prognosis when it occurs in the 1st yr
of life, when compared to nephrotic syndrome
manifesting in childhood.
 Congenital nephrotic syndrome is defined as
nephrotic syndrome manifesting at birth or within
the 1st 3 month of life.
 Congenital nephrotic syndrome may be classified
as primary or as secondary to a number of
etiologies

49. Denys-Drash syndrome is caused by
mutations in the WT1 gene, which results in
abnormal podocyte function.
 Patients present with early-onset nephrotic
syndrome, progressive renal
insufficiency,ambiguous genitalia, and Wilms
tumors.
 Mutations in the LAMB2 gene, seen in Pierson
syndrome, lead to abnormalities of β2-laminin,
a critical component of glomerular and ocular
basement membranes.

50. PROGNOSIS
 Long term outcome in MCNS is excellent, most
children are completely cured by 10 to 15 years.
 Impossible to predict the course or the age at which
cure might take place.
 Steroid resistant nephrotic syndrome has poor
prognosis.

51. REFERENCE
 Pediatric nephrology Arvind Bagga
 Nelson Textbook of paediatrics
 Aruchamy clinical paediatrics