2. Nephrotic Syndrome
1. Massive proteinuria - 40 mg/m2/hr
(50 mg / kg / d or 3.5 gm/day)
2. Hypoalbuminemia (<2.5 g/dL)
3. Hypercholesterolemia (>220 mg/dL)
With or without
4. Edema
ISKDC Definition :
•Nephrotic range of proteinuria =
Urine Protein 3+ or 4+
•Urine protein / creatinine ratio of > 2.0
3. Nephrotic Syndrome
• 2 to 7 cases per 100,000 childre
• 10-fold lower in adults
• Male-to-female ratio is reported to be 2:1
for children and 1:1 in adolescents and
adults
• MCNS peaks between 2-5 years of age
• 92% of these will experience remission of
their disease when treated
• Adolescents are more likely to have a
more aggressive cause of the nephrotic
syndrome
Incidence of Idiopathic form
4. Nephrotic Syndrome - Children
Etiology
• 90 % - primary
glomerular
abnormality
(Idiopathic)
• Rest – part of renal
involvement in
different diseases
15. MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS
(mesangiocapillary glomerulonephritis)
• MPGN types 1, 2, and 3 account for 44%, 20%, and 36%
of cases, respectively.
• All 3 types appear similar by light microscopy and have
increased mesangial cellularity and matrix expansion.
• By electron microscopy,
– type 1 shows normal-appearing GBM, with subendothelial electron-
dense deposits.
– MPGN type 2, also known as dense-deposit disease, appears to
be a distinct disease and has thickening and increased electron
density of the lamina densa of the GBM.
– In MPGN type 3, deposits are present on both the subepithelial and
the subendothelial sides of the GBM, as well as within the GBM. With
special stains the GBM appears fenestrated, and deposits are
covered by layers of new GBM
16. MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS
(mesangiocapillary glomerulonephritis)
• Etiology:
– Type-1 MPGN:
• Caused by immune complex formation and deposition
• Of the classical pathway of complement consumption
– MPGN type 2:
• (Dense Deposit Disease), Mesangiocapillary GN
• thought to be the result of the presence of circulating
autoantibodies called nephritic factors (NFs) that stabilize the C3
convertases activating the alternative (NFa) and respectively
– MPGN type 3:
• Activation of (NFt) pathways of complement activation
• Candidate gene on Chromosome 1
17. Idiopathic Nephrotic Syndrome - Children
Pathological Types
3 Focal Segmental Glomerular Sclerosis (10%)
idiopathic or secondary to a number of different causes (e.g., heroin abuse,
HIV infection, sickle cell disease, obesity, reflux of urine from the bladder to the
kidneys, and lesions associated with a single or remnant kidneys).
18. Disease processes associated with FSGS
lesions
• Diabetic nephropathy
• Sickle cell disease
• HIV nephropathy
• Glomerulonephritides
– IgA nephropath
– MPGN
– Lupus nephritis
• Frasier syndrome, consisting of male
pseudohermaphroditism (Mutations in WT1 gene)
• Diffuse mesangial sclerosis
– May be part of Denys-Drash syndrome
19. Idiopathic Nephrotic Syndrome
Pathological Types
4 Membranous nephropathy (1%)
most common pattern of idiopathic NS in white Americans
- Hepatitis B, Sjögren's syndrome, Systemic lupus erythematosus
(SLE), Diabetes mellitus, Sarcoidosis, Syphilis, Drugs, Malignancy
20. MCNS Nephrotic Syndrome
(Nil Disease or Lipoid Nephrosis)
– In 3 months to 16 years of age, 76%
have minimal change nephrotic
syndrome (MCNS)
– No glomerular abnormalities in light
microscope
– Effacement of foot processes in electron
microscopy
– Minimal deposition of mesangial matrix
– Serum complement (C3) normal
– Circulating immune complexes absent
21. Pathophysiology of NS
Increased permeability of glomerular capillary
wall, which leads to massive proteinuria and
hypoalbuminemia.
In MCNS :
T Cell dysfunction leads to alteration of cytokines which
causes a loss of negatively charged glycoproteins within
capillary wall
In FSGS:
A plasma factor produced by lymphocytes responsible
Mutations in podocyte proteins (podocin, a – actinin 4)
In Steroid resistant NS:
Mutations in NPHS 1(nephrin) & 2(podocin) and WT1 or
ACTN4 (a-actinin) genes
22. Clinical Features
• Age of onset : 85 - 90% < 6 yrs yrs
• 30% adolescents may have MCNS
• Onset : insidious
• Initial episode & subsequent
relapses may follow minor
infections or insect bites, bee
stings, poison ivy, etc.
23.
24. Clinical Features
COMMON:
• Anorexia, irritability, abdominal pain, diarrhoea
and genital edema
• Frothy urine (high concentrations of protein)
• Edema may cause dyspnea (pleural effusion or
laryngeal edema),
• Chest discomfort (pericardial effusion), arthralgia
(hydrarthrosis), or abdominal pain (ascites or, in
children, mesenteric edema).
• Edema may obscure signs of muscle wasting and
cause parallel white lines in fingernail beds
(Muehrcke's lines).
UNCOMMON:
• Hypertension, Gross hematuria
26. Massive Proteinuria - Mechanism
• Loss of negatively charged
sialoproteins and glycoproteins
• Increased size of pores
• Loss of foot processes
• Increased excretion or decreased
absorption
• Release of platelet factor in
glomeruli
• Increased thromboxane production
27. Protein Loss
– Albumin
– Thyroxine-binding protein
– Cholecalciferol-binding protein
– Transferrin
– Metal binding proteins
– Anti Thrombin III, Proteins C & S
29. Oedema - Mechanism
Massive proteinuria – hypoalbuminemia - i
plasma oncotic pressure -> transudation of fluid
from intravascular compartment to interstitial
space.
Under Fill Theory :
Reduced renal perfusion leading to h production of renin-
angiotensin aldosterone system
Reduction of intravascular volume stimulates ADH
Over Fill Theory :
Defective excretion of sodium and water from kidney due
to dysfunction
h absorption of sodium and water from renal tubules
Circulation of unknown antigen causing h
capillary permeability
i production of atrial natriuretic peptide
Increased activity of aldosetrone & vasopressin
Activities of various cytokins and physical factors
within the vasa recti
30. Hyperlipidemia - Mechanism
i conversion of VLDL in to LDL by i of
lipoprotein lipase
Loss of apolipoprotein (apo CII) in urine
i levels of HDL
h synthesis of lipoproteins
Abnormalities in regulatory enzymes like licithin-
cholesterol acyltranferase and cholesterol ester
transfer protein, lipoprotien lipase
• VLDL content is more increased
• Triglyceride levels are decreased when albumin level is < 1 g
31. Hypercoagulable State
Occur when serum albumin < 2g/dL
Causes :
– Urinary loss of antithrombin III, Factor
IX, X, XI - > thrombin activity increase
– Protein C, S activity or level decrease
– Hyperfibrinogenemia
– Platelet activation increase
– Hyperlipidemia
• Combined with hypovolemia, immobility, increased incidence of infection
40. Blood
• S.Cholesterol ( > 250 mg/dL)
• S.Albumin (<2.5 gm/dL)
• S. A/G ratio - reversal
• S.Creatinine
• Bl. Urea
• S . C3 and C4 levels
• CBC : Increased Hb, Platelets, Hct
Normal
41. Imaging
• U/S : Nonspecific.
– Enlarged kidneys – due to tissue edema
– Increased echogenicity/Small Kidneys : Chronic kidney
disease other than MCNS
• CXR:
– Pleural effusion
– Pulm edema - rare
42. Kidney Biopsy
Indications:
• Patients younger than 1 year and older than 8 yrs
• Symptoms of systemic disease ( fever, rash, joint
pain)
• Labs suggestive of sec nephrotic syndrome
(Positive Ana, Positive anti-double stranded DNA
antibody, Low complement)
• Elevated creatinine levels unresponsive to
correction of volume depletion
• Family history of kidney disease
• Patients initially or subsequently unresponsive to
steroid treatment.
43. Management - Principles
• Admission
– For establishment of diagnosis
– For exclusion of infection
– To wait for spontaneous remission
• Treat infections
• Supportive therapy
• Steroid therapy
44. Supportive Care
• Diet : Balanced
– adequate protein (1.5 – 2 gm/kg)
– Not > 30% calories from fats
– Avoid saturated fats
– Reduction in salt intake (1-2 g/d) for
those with persistent edema
– Ensure physical activity
– Calcium and Vitamin D supplementation
45. Treatment of Initial Episode
• Prednisalone
– 2mg / kg / d in 2-3 divided doses for
4-6 weeks [60 mg / m2/d]
• Antacid dose steroid to prevent gastric
irritation ??
• After 6 wks, reduce dose
– 1.5 mg/kg/d [40 mg / m2/d ] as a
single dose every other day morning
slowly tapering in 2-3 months
• Then discontinue
Shorter duration of initial therapy in not recommended.
Steroid Therapy
46. Treatment of Initial Episode
• Acting through the nuclear
factor kappaB (NF-kB)
transcription pathway –
inhibiting cytokine production
and inhibiting T-Cell prouction
and proliferation.
Steroids – Mechanism of action
47. Diuretic Therapy
Indications
• To prevent secondary infections after breakdown
of skin
• To prevent GI and Resp. embarrassment
• To prevent urethral obstruction due to massive
edema of scrotum
Drugs
• Furosemide : 1-3 mg / kg / dose IV q12h
• Chlorthiazide : 10 mg / kg / d
• Spiranolactone : 3-4 mg /kg/ d in 3-4 div. doses
• 25% salt free albumin 0.5g / kg over 60 min
Patients with persistent edema and weight gain above 7 - 10% are
treated with oral frusemide
48. ISKDC Terminology
• Remission
– Urine albumin : Nil or Traces or <4 mg/m2/hr
for 3 consecutive early morning specimen
• Response
– Urine free of protein in 8 wks. (Steroid
sensitive)
• Late Response
– A response beyond 8 weeks
49. ISKDC Terminology
• Relapse
– Proteinuria 3+ plus edema or
40 mg/m2/ hr for 3 consecutive early
morning specimen
– (having been in remission previously)
• Frequent Relapse
– SSNS with 2 or more relapses in 6 mo. or
> 4 relapses in 1 year
50. ISKDC Terminology
• Steroid Dependent NS
SSNS with 2 or more consecutive relapses
during tapering or within 14 days of stopping
steroids.
• Steroid Resistant:
Either do not respond to the initial treatment
with prednisalone within 8 weeks of therapy
60mg/m2/d, or do so transiently and later
cease to respond [2-5%]
(FSGS= 80%, MPG = 20%, MCNS– rarely)
51. Treatment of Relapse
Relapse often precipitated by URI
• Prednisalone
– 2 mg/kg/d until the urine is protein free
for 3 consecutive days
– Thereafter – 1.5 mg/kg/d on alternate
days for 4 wks and stop.
(Total duration of therapy = 5 to 6 wks.)
52. Management of pt. with steroid sensitive NS
Prednisalone 2 mg/kg daily forr6 wks., followed by 1.5 mg/kg on alt
day for 6 wks.
Infrequent relapses Frequent relapses Steroid resistant
Therapy for relapse
Prednisalone 2 mg/kg daily
until remission, then 1.5
mg/kg on alt. days for 4
weeks
Alternate day prednisalone
to maintain remission
Therapy based on
renal histology
Threshold <0.5 mg/kg
on alt. days
Threshold >0.5 mg/kg on
alt. days / Steroid toxicity
Alt. day prednisalone
for 9-18 mo.
•Levamisole
•Cyclophosphamide
•Mycophenolate
•Tacrolimus
•Cyclosporine
53. Management of pt. with steroid sensitive NS
Infrequent relapses
• Examine for infections, which
should be treated before initiating steroid therapy.
• Prednisolone is administered at a dose of
2 mg/kg/day (single or divided doses) until urine protein is
trace or nil for 3 consecutive days.
• Subsequently, prednisolone is given in a single
morning dose of 1.5 mg/kg on alternate days for
4 weeks, and then discontinued.
• The usual duration of treatment for a relapse is 5-6 weeks.
Prolongation of therapy is not necessary for patients with
infrequent relapses
54. Management of pt. with steroid sensitive NS
Frequent relapsers & Steroid Dependent
• Following treatment of a relapse, prednisolone is gradually
tapered to maintain the patient in remission on alternate
day dose of 0.5-0.7 mg/kg, which is administered for 9 -
18 months.
(a)Levamisole at a dose of 2-2.5 mg/kg on alternate days for 12-
24 months.
Co-treatment with prednisolone at a dose of 1.5 mg/kg on
alternate days is given for 2-4 weeks; its dose is 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.
The chief side effect of levamisole is leukopenia; flu-like symptoms, liver
toxicity, convulsions and skin rash. The leukocyte count should be monitored
every 12-16 weeks.
55. Management of pt. with steroid sensitive NS
Frequent relapsers & Steroid Dependent
(b) Cyclophosphamide at a dose of 2-2.5 mg/kg/day for 12
weeks.
Prednisolone is co-administered at a dose of 1.5 mg/kg on
alternate days for 4 weeks, followed by 1 mg/kg for the next 8
weeks;steroid therapy is tapered and stopped over the next 2-
3 months.
Therapy with cyclophosphamide should be instituted preferably
following remission of proteinuria. Total leukocyte counts are monitored
every 2 weeks; treatment is temporarily discontinued if the count falls below
4000/mm3. An increased oral fluid intake and frequent voiding prevents the
complication of hemorrhagic cystitis; other side effects are alopecia, nausea
and vomiting.
The risk of gonadal toxicity is limited with a single (12 weeks) course of
cyclophosphamide. The use of more than one course of this agent should
preferably be avoided.
56. Management of pt. with steroid sensitive NS
Frequent relapsers & Steroid Dependent
(c) Calcineurin inhibitors: Cyclosporin (CsA) is given at a
dose of 4-5 mg/kg daily for 12-24months.
Prednisolone is co-administered at a dose of 1.5 mg/kg on alternate days
for 2-4 weeks; its dose is 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 six
or more months. Occasionally, treatment with corticosteroids may be
discontinued.
Side effects of CsA therapy include hypertension, cosmetic
symptoms (gum hypertrophy, hirsutism) and nephrotoxicity;
hypercholesterolemia and elevated transaminases.
Estimation of blood levels of creatinine is required every 2-3 months and a
lipid profile annually. A repeat kidney biopsy, to examine for histological
evidence of nephrotoxicity, should be done if therapy with calcineurin
inhibitors is extended beyond 2 years
57. Management of pt. with steroid sensitive NS
Frequent relapsers & Steroid Dependent
Tacrolimus is an alternative agent, administered
at a dose of 0.1-0.2 mg/kg daily for 12-24 months.
Side effects include hyperglycemia, diarrhea and rarely
neurotoxicity (headache, seizures). The use of tacrolimus
is preferred especially in adolescents, because of lack of
cosmetic side effects(13). Blood levels of creatinine and
glucose should be estimated every 2-3 months.
58. Management of pt. with steroid sensitive NS
Frequent relapsers & Steroid Dependent
(d) Mycophenolate mofetil (MMF) at a dose of 800-1200
mg/m2 along with tapering doses of prednisolone for 12-24
months.
The principal side effects include gastrointestinal discomfort,
diarrhea and leukopenia.
Leukocyte counts should be monitored every 1-2 months;
treatment is withheld if count falls below 4000/mm3.
59. Management of pt. with steroid sensitive NS
Frequent relapsers & Steroid Dependent
Choice of agent
1. Levamisole has a modest steroid sparing effect and is a
satisfactory initial choice for patients with frequent
relapses or steroid dependence.
2. Treatment with cyclophosphamide is preferred in patients
showing:
(i) significant steroid toxicity,
(ii) severe relapses with episodes of hypovolemia or
thrombosis, and
(iii) poor compliance or difficult follow up, where 12 weeks
therapy possible to ensure than long-term compliance.
60. Management of pt. with steroid sensitive NS
Frequent relapsers & Steroid Dependent
Choice of agent
3. Treatment with CsA or tacrolimus is recommended for
patients who continue to show steroid dependence or
frequent relapses despite treatment with the above
medications
4. The lack of renal, hemodynamic and metabolic toxicity
with Mycophenolate maleate makes it an attractive
alternative to calcineurin inhibitors.
61. Frequent relapsers FRNS &
Steroid Dependent SDNS
• Prednisalone 2 mg/kg/d (60 mg/m2/d) as single morning
dose until patient has been free of protinuria for at least 3
consecutive days. Following remission, Prednisalone
reducetd to 1.5 mg/kg/d (40mg/m2) given as single dose on
alt days and tapered over 3 months.
• A steroid sparing agent conisered once protinuria is in
remission
• Alkylating agent : Cyclophosphamide, Chlorambucil
• Calcinurin inhibitors: Cyclosporin A, Tacrolimus
62. Management of NS
• ACE Inhibitors : to prevent proteinuria
– Act by alteration of capillary permeability
and reduction in glomerular hydrostatic
pressure
• HMG coenzyme-A reductase inhibitors
to reduce s. cholesterol
• Albumin Infusion : controversial
– Abdominal pain
– Hypotension
– Severe Oliguria
– Renal insufficiency
63. Management of NS
Immunization
• Patients on prednisalone therapy
are considered immunosuppressed
– avoid live attenuated vaccines
• All patients should receive
pneumococcal vaccine
64. Management of NS
Investigational Treatments
• Rituximab : A chimeric anti-CD20 antibody
that results in depletion of B Cells
• Plasmapheresis – esp with FSGS patients
who have received kidney transplans
• Galactose : high affinity for circulating
permeability factor (FSGS) after kidney
transplant
• Zinc
65. Initial Steroid Resistance
• Mesangial proliferative GN
• Focal segmental
glomerulosclerosis (FSGS)
• Membrano-proliferaive GN (MPGN)
– Type 1 : with intact BM
– Type 2: (30%) with dense deposits,
persistent low serum C3, abundant
immunonglobulin & C3 deposits
• Membranous nephropathy
66.
67.
68.
69. Initial Steroid Resistance
• Trial of pulse methylprednisalone
(30 mg/kg) or dexamethasone
– First 6 doses given every other day
followed by tapering for periods upto
18 months
• Cyclosporin A
• IVIG
• Mycophenolate mofetil
70. Steroid Adverse Effetcts
• Infection
• Obesity
• Growth delay
• Osteopenia
• Avascular necrosis of the hip
• Cataracts
• Hypertension
• Hyperglycemia
• Nephrolithiasis
• Hyperlipedemia
72. A. Complications Due to Disease
• PEM due to protein loss
• Infections:
– S.pneumonia, H. influenza - VPDs
• Thrombotic complications
• Iron, copper, zinc, and vitamin D
deficiencies
• Laryngeal edema - rarely
73. Infections
• Factors responsible :
– Urinary loss of Factor B and
immunoglobulins, properdin B
– Defective CMI
– Defective opsonization
– Ascitic fluid – good culture medium
– Immunosuppressive drugs
– Malnutrition
• Peritonitis
• Pneumonia
• Osteomyelitis
• Cellulitis
• Arthritis
74. B. Complications Due to Treatment
• Steroids
– Cushingoid syndrome
– Hypertension due to salt retention
– Osteoporosis
– Susceptibility to infections
– Growth failure
– Cateracts
– Glaucoma
– Gastritis
– Peptic ulcer
– Hypokalemia
– Behavioural changes
• Cyclophosphamide
– Alopecia
– Leucopenia
– Infertility
– Hemorrhagic cystitis
75.
76. Outcome of MCNS
• Most stop getting relapses by 11 to
15 yrs
• Full recovery
• Very small proportion – develop
late steroid resistance
• Mortality : 1-4 % sec. to infections
& hypovolemia
77. NS Variants
Congenital:
• Develop within first 3 mo.
• Cong. Syphilis, Intrauterine infections
Finnish Type :
• Autosomal recessive
• Mutations in the NPHS1 gene encoding nephrin or
NPHS2 gene encoding podocin
• Leads to renal failure
• Elevated alpha fetoprotein in amniotic fluid &
maternal serum
Dany-Drash Syndrome :
• Wilms tumor, NS, Genital anomalies
• Diffuse mesangial sclerosis