NEPHROTIC SYNDROME

DR. AWUONDA B. O.
CONSULTANT PAEDIATRICIAN
OUTLINE 2

 DEFINITIONS
 AETIOLOGY/CLASSIFICATION
 PATHOGENESIS/pathophysiology
 Differential diagnosis
 INVESTIGATIONS
 MANAGEMENT
 General measures
 STEROIDS
 OTHER alternative DRUGS
 Counseling
 Prognosis
DEFINITION

 The nephrotic syndrome is caused by renal

diseases that increase the permeability across
the glomerular filtration barrier.
 classically characterized by four clinical
features:
1. Nephrotic range proteinuria of >40mg/m2/hr
or (> 50 mg/kg/d)
2. Hypoalbuminemia (<2.5-3 g/dl)
3. Edema
4. Hyperlipidemia
Other terminologies 4

 Remission- urinary protein excretion

<4mg/m2/hr or albustix nil x 3
consecutive days.
 Steroid responsive- remission with
steroid therapy alone
 Late responder- remission after 4/52
prednisone 60mg/m2/day alone
 Relapse- nephrotic range proteinuria
having been in remission.
 Frequent relapser- 2 or more relapses
within 6/12 of initial response or 4
relapses in 1 year.
Other terminologies….ctd 5

 Steroid dependence- 2 consecutive relapses

during steroid Rx or within 14 days of its
cessation.
 Steroid resistance- failure to achieve
response despite 4/52 prednisone @
60mg/m2/day
 Early non responder – steroid resistance in
the initial episode.
 Late non responder- steroid resistance in
patient who had previously been responsive
Etiology in children

 Idiopathic NS – 90%
 Minimal change disease (85%),
 mesangial proliferation (5%), &
 focal segmental glomeruloscrelosis (10%).
 MCD: -Age younger than six years
 Absence of hypertension
 Absence of hematuria
 Normal complement levels (C3 & C4)
 Normal renal function.
Etiology in children--- 2
 Secondary Nephrotic Syndrome – 10%
 Causes:
 membranous nephropathy,
 Mesangio-proliferative GN,
 hepatitis,
 HIV,
 Malaria,
 poststreptococcal,
 infective endocarditis,
 schistosomiasis,
 drugs,
 vasculitides,
 amyloidosis,
 SLE,
 sickle cell disease,
 Alport syndrome,
 HUS, etc
Congenital NS
 CNS of Finnish type
 Autosomal Recessive
 severe loss of protein starting in- utero. Serum
albumin usually < 10g/l.
 premature birth – mean 36 wk gestation
 Placenta larger than normal
 edema and abdominal distension at birth in 25%
pts, > 90% by one week.
 NPHS1 gene on chr 19q13.1 which encodes
nephrin, a trans-membrane protein involved in
glomerular filtration barrier
Etiology in adults 9

 Membranous nephropathy (24%)

 Minimal change disease (16%)
 Lupus nephritis (14%)
 Focal and segmental glomeruloscrelosis
(12%)
 membranoproliferative glomerulonephritis
(7%)
 Amyloidosis (6%)
 IgA nephropathy (6%).
Epidemiology of NS

 15 times more common in pediatrics than

adults
 Incidence: 2-3/100,000children/year.
 Majority have steroid sensitive MCD
 Peak age: 2-6 yrs
 MCD M:F 3:2; adults M:F almost equal
Pathophysiology/
Complications
 Proteinuria
 Hypoalbuminaemia
 Edema
 Hyperlipidemia
 Thromboembolism
 Malnutrition
 Anaemia
 Endocrine disturbances
1. Proteinuria

 The initiating event remains unknown.

Primary NS is believed to have an
immune pathogenesis, but the precise
nature of the process has yet to be
defined.
 Several hypothesis including:
1. Lymphocyte dysfunction
2. A highly cationic plasma protein that
may neutralize the anionic charge on
the glomerular capillary wall.
Proteinuria contd----

3. Cytokines – IL8, INF gamma, IGF

gamma, TNF alpha, vascular permeability
factor.
4. Alterations in molecules expressed in
the epithelial cell podocyte, including
nephrin, podocin and alpha actin
5. Change in negative charge usually
conferred by polyanions – reduced content
of sialic acid from the basement
membrane.
6. Genetic factors
2. Hypoalbuminaemia

 Most of albumin loss is due to urinary

excretion
 Normally, hepatic albumin synthesis is
appropriately enhanced in response to
the albumin loss. This effect is mediated
by an increase in hepatic albumin gene
expression stimulated by the low oncotic
pressure.
 Hypoalbuminemia may also lead to the
release of an as yet unidentified
circulating factor that contributes to the
elevation in hepatic albumin synthesis
Hypoalbuminemia---- ctd

 In nephrotic syndrome, the liver is usually

unable to sufficiently increase albumin
synthesis to normalize the plasma albumin
concentration, the reason for this is not clear.
3. Edema

 Two main mechanisms:

 Arterial under filling as the low plasma oncotic
pressure leads to plasma volume depletion
 Sodium retention directly induced by the renal
disease
4. Hyperlipidaemia

 2 most common lipid abnormalities in NS are

hypercholesterolemia & hypertriglyceridemia.
 These occur possibly due to:
 Impaired metabolism
 Increased hepatic synthesis of lipoproteins
containing apoB and cholesterol
5. Thromboembolism

 Patients with the NS have an increased

incidence (10 % to 40 % ) of arterial and venous
thromboemboli, particularly deep veins (DVT)
and renal vein thrombosis ( RVT).
Thromboembolism---ctd
 Even asymptomatic NS patients have evidence of ongoing
coagulation. Why this occurs is not clearly understood.

 Postulated haemostatic abnormalities may include:

 decreased levels of antithrombin III (due to urinary losses)

 Altered levels and activity of protein C & S
 increased platelet activation
 presence of high molecular weight fibrinogen moieties
 possibility that immune-mediated injury in the glomerulus
results in increased procoagulant activity that is sufficient to
have a systemic effect
 haemoconcentration
6. Malnutrition

 Possible causes:

 Hypoalbuminemia
 Increased GI losses
 Reduced intake
7. Anaemia

 Possibly due to:

 Loss of transferrin
 causes an iron-resistant microcytic, hypochromic
anaemia
 Reduced erythropoietin synthesis
8. Endocrine
disturbances
 Reduced T4 due to loss of thyroxin binding
globulin, transthyretin and albumin.
 Loss of vit D binding protein hence:
 reduced levels of D3
 hypocalcaemia
 secondary hyperparathyroidism
9. Infections

 Commonly cellulitis and peritonitis

 Due to:
 loss of Immunoglobulins in urine,
 Loss of properdin factor B,
 defective CMI,
 immunosuppressive RX,
 malnutrition,
 ascites & edema acting as potential culture
medium.
 Strep pneumonia most common, Gram -ves also
common esp E. coli.
Differential diagnosis

 Primary renal disease: AGN, ARF, CKD

 Heart failure
 Protein losing enteropathy
 PEM (kwashiorkor)
 Cirrhosis/ portal hypertension
 Angioedema: Allergic/hereditary
 Sepsis
 INVESTIGATIONS
 Urinalysis (3+ to 4+; 300 to >1000 mg/dL).
 First morning void to measure prot:creat ratio (> 3mg prot/mg creat
or >300mg prot/mmol creat)
 Blood tests: U/E/Cr, BUN, albumin,
 Serum total cholesterol, triglycerides, and total lipids are elevated.
 Other blood tests: ANA for patients ≥ 10 years or with signs of SLE;
serology for hepatitis B, C, and HIV in high-risk ;
 LFTs
 Complement: C3& C4 normal in MCD; C3 low in MPGN & postinfectious;
C3 & C4 low in lupus nephritis
 CBC: hemoconcentration and thrombocytosis
 Renal biopsy for children ≥ 12 years of age
 T4 levels,
 serum calcium,
 transferrin
MANAGEMENT 2
6

 AIMS:
 induce and maintain complete remission with
resolution of proteinuria and edema and
minimal side effects of therapy.
 have clear strategies for relapse management
to maintain sustained remission and minimize
steroid toxicity.
General measures 2
7

 In persistent proteinuria, salt and fluid restriction,

and diuretics (alone or in combination with salt-
poor albumin) are used to control edema.
 Avoid thromboembolic complication by
mobilization, avoidance of hemoconcentration
from hypovolemia, and early treatment of sepsis
or volume depletion
 Elevate swollen scrotum with pillows
 Due to increased risk for both bacterial and viral
infections they need PCV and varicella vaccines
 Immunizations – avoid live vaccines till off steroids
for >6/52 and/or not on cycloph or cyclosporin.
General measures

 optimal treatment of hyperlipidemia in

persistent NS is unknown- statin therapy may
be tried (adult data)
 persistent hypertension- likely CKD with poor
outcome.
 ACE inhibitors or ARBs be used to treat their
hypertension
 Due to potential additive antiproteinuric benefit
and ability to slow progression of renal
impairment
Steroids…….. Protocol 1 2
9

 Prednisolone 60mg/m2/day od x 28 days

 Pred 40mg/m2 alt days x 28 days
 Pred 30mg/m2 alt days x 28/7
 Pred 20mg/m2 alt days x 28 days
 Pred 10mg/m2 alt days x 28 days
 Pred 5mg/m2 alt days x28 days
 Stop
Children's Nephrotic Syndrome
Consensus (USA 2009)..protocol 2

 Initial therapy — Initial prednisone therapy of

2 mg/kg/d for six weeks, followed by alternate
day prednisone of 1.5 mg/kg for an additional
six weeks.
 First relapse/Infrequent relapse —
Prednisone therapy of 2 mg/kg/d until the urine
protein tests are negative or trace for three
consecutive days, followed by alternate day
prednisone of 1.5 mg/kg for four weeks.
Children's Nephrotic Syndrome
Consensus (USA 2009)
 Frequent relapses — Prednisone therapy of 2
mg/kg/d until the urine protein tests are
negative or trace for three consecutive days,
followed by alternate day prednisone of 1.5
mg/kg for four weeks, which is then tapered
over two months by 0.5 mg/kg every other day.
 Steroid-sparing agents may be used to sustain
remission and thereby reduce cumulative
steroid doses and toxicity.
 These include oral cyclophosphamide,
cyclosporine, and mycophenolate mofetil.
Children's Nephrotic Syndrome
Consensus (USA 2009)

 Steroid-dependent disease — Prednisone

remains the preferred therapy in the absence of
significant steroid toxicity.
 Steroid-sparing agents, such as cyclosporine,
tacrolimus, and mycophenolate, may be helpful
in reducing steroid dosing.
Children's Nephrotic Syndrome
Consensus (USA 2009)

 Steroid-resistant disease — Therapy is

based upon the histologic findings found on
renal biopsy.
 Additional treatment includes:
 angiotensin antagonism (ACEIs)
 supportive care focused on managing the
complications of NS (edema, hypertension,
infection, dyslipidemia, thromboembolism).
Indications for alternative 3
4
therapy
1. Relapse on pred >0.5mg/kg alt days
plus one of:
a) Unacceptable side effects of steroid Rx
b) High risk of toxicity – boys
approaching puberty or diabetes
c) Severe relapses: hypovolemia,
thrombosis, severe sepsis or ARF.
d) Inadequate facilities for follow-up or
concern about compliance.
2. Relapse on prednisone >1mg/kg alt
days.
OTHER ALTERNATIVE 3
5
DRUGS
 Mycophenolate- reduces relapse rate and has a
steroid sparing effect. Need RCT
 Chlorambucil- toxic thus limited use.
 Vincristine- no controlled studies
 ACEI- nonspecific reduction of proteinuria. All
pts should receive. Need RCT.
 azathioprine, mizoribine,immunoglobulins,
sodium cromoglycate- RCT no benefit.
RENAL BIOPSY- 3
6
indications
 Onset < 6mo of age
 Initial macroscopic hematuria
 Persistent microscopic h’turia with HTN
 ARF not attributable to hypovolemia
 Low plasma C-3 level
 Onset >12 years
 Steroid resistance
 FRNS
Renal biopsy--
contraindications
 Percutaneous renal biopsy is generally
contraindicated in the following settings:
 Uncorrectable bleeding diathesis
 Small kidneys which are generally indicative of
chronic irreversible disease
 Severe hypertension, which cannot be controlled
with antihypertensive medications
 Multiple, bilateral cysts or a renal tumor
 Hydronephrosis
 Active renal or perirenal infection
 An uncooperative patient
Counseling caretaker 3
8

 Chronic nature of disease

 Relapses common thus monitor proteinuria and
refer to renal unit if 2+ or more.
 Compliance to medications
 Vaccines if in remission or on low dose steroid
 Side effects of drugs
Prognosis

 Relapses common in steroid responsive NS but

reduce as child grows old
 Rapid responders or those without relapse
within 6/12 follow infrequent relapsing course
 Steroid responsive NS unlikely to develop CKD
and remain fertile and normal in remission
 Steroid resistant NS poorer outcome with
possible ESRD needing dialysis