NEPHROTIC SYNDROME

BY
DR. CLIVE BOWMAN: Dip. Rad;
MBBS; M.Med (PAEDIATRICS)
 CHILDHOOD NEPHROTIC SYNDROME
• A clinical syndrome characterized by:
• oedema
• massive proteinuria
• Hypoproteinaemia
• Associated hyperlipidaemia and lipiduria (serum
cholesterol >200 mg/dl)
• Proteinuria:
– >40mg/m2 BSA/hr
– Or > .05gm/kg/24hr (> 50 mg/kg/24hr)
• hypoalbuminemia: < 25g/L (< 2.5 g/dL)
 NEPHROTIC SYNDROME

• Nephrotic range proteinuria:

– Early morning urine protein = 3+/4+
– Spot protein/creatinine ratio >2 mg/mg
– or urine albumin excretion >40 mg/m 2/hr (on a
timed-sample).
• Precise quantitative assessment of proteinuria,
including 24-h urine protein measurement is seldom
necessary.
 PATHOGENESIS
• Main pathogenic abnormality is increase glomerular
capillary wall permeability.
• Normal glomerular wall is remarkably selective for
retaining protein in the serum. Once this selectivity is
lost, the excretion of large amounts of protein will
follow.
• Hypotheses:
– Incompletely understood
– PNS is believed to have an immune
pathogenesis.
• Lymphocyte dysfunction:
–Alterations in either T-lymphocyte number
and/or function.
»Increased rate of apoptosis in circulating T-
lymphocytes has been found
 PATHOGENESIS
• Hypotheses:
– PNS is believed to have an immune
pathogenesis.
• Elevated levels of IgE and an association with
atopy in steroid-responsive NS
–Current data suggest a common immune
activation rather than a direct association.
• Suppresser cytokines or lymphokines
–changes in interleukin-8, interferon-g, IGF-1,
TGF-a, and vascular permeability factor
(VPF).
–role of the kinin system => excretion of kinins
is increased during exacerbations of the
disease
 PATHOGENESIS
• Hypotheses:
– Highly cationic plasma protein that may neutralize the
anionic charge on the glomerular capillary wall
– Alterations of molecules on the epithelial cell podocyte
(visceral epithelial cells):
• Nephrin: structural protein of slit diaphragm (some
researchers do not feel this is involved in MCNS)
• Podocin (protein component of slit diaphragm)
• A-actin
– Reduced antioxidant defence.
– Leptin
• In MCNS, serum levels are low at onset of the disease
and are associated with elevated serum levels of TGF-b1.
– Genetic factors
 PATHOPHYSIOLOGY: PROTEINURIA
• In PNS, selectively increased glomerular capillary permeability
to albumin
• Increase in filtered load overcomes ability of tubules to
reabsorb protein.
– In GN the proteinuria unselective.
• Part of this increase in albumin excretion may be because of it’s
smaller size, but since the excretion of some even smaller
weight plasma proteins is not proportionally increased, the
presence of other factors is obvious.
• Proposed hypotheses the increased permeability:
– Traditional hypothesis => changes in the anionic
composition of the GBM:
• Normal state: polyanions along the surface glomerular
endothelium => negatively charged glomerular
endothelium => negatively-charged albumin is repelled.
• Loss of negatively charged glycoproteins => increased
permeability.
• Predominant protein lost is albumin
• Iimmunoglobulins also excreted.
 PATHOPHYSIOLOGY : PROTEINURIA
• Some Studies show that: decrease in the normal
content of sialic acid (a polyanion) from the basement
membrane => selective alteration of GBM permeability
=> increased capillary transport of anionically charged
particles such as albumin:
– Not confirmed by all investigators
• Alteration of epithelial cell podocytes:
– Flattening, retraction, and effacement of the
podocyte foot processes is a constant feature of
heavy proteinuria.
• Traditional view is that these changes are
consequences of the proteinuria.
• Other investigators believe that primary
distortions of the slit diaphragm filaments are
present and that a redistribution of nephrin from
the podocyte slit pores into the cytoplasm occurs

A – Renal corpuscle
B – Proximal tubule
C – Distal convoluted tubule
D – Juxtaglomerular apparatus
RENAL
CORPUSCLE
1. Basement membrane (Basal
lamina)
2. Bowman's capsule – parietal
layer
3. Bowman's capsule – visceral
layer
3a. Pedicels (Foot processes
from podocytes)
3b. Podocyte
4. Bowman's space (urinary
space)
5. 5a. Mesangium –
Intraglomerular cell 5b.
Mesangium – Extraglomerular
cell
6. Granular cells
(Juxtaglomerular cells)
7. Macula densa
8. Myocytes (smooth muscle)
9. Afferent arteriole
10. Glomerulus Capillaries
11. Efferent arteriole
 FILTRATION BARRIER
Pedicles/foot processes of podocytes

Filtration barrier (blood-urine) in the kidney:

•A. The endothelial cells of the glomerulus:
– 1. pore (fenestra)
•B. Glomerular basement membrane (basal lamina):
– 1. lamina rara interna
– 2. lamina densa
– 3. lamina rara externa
•C. Podocytes (visceral epithelium of Bowman’s capsule):
– 1. enzymatic and structural protein
– 2. filtration slit
– 3. diaphragm
– Pedicles
 PATHOPHYSIOLOGY: OEDEMA
• Protein excretion:
– Drop in plasma albumin concentration
– Drop in plasma oncotic pressure
– Intravascular to interstitial fluid shift
– Oedema
– Liver has a very large capacity to synthesize protein
– The persistent hypoalbuminemia in NS likely not entirely due
to increased losses.
• Reduction of the intravascular volume:
– Activation of RAAS
– Sodium and water retention
– Contributes to the oedema.
• Other factors also likely involved in formation of oedema:
– Some patients with NS have normal or increased
intravascular volume.
 PATHOPHYSIOLOGY: HYPERTENSION
• Some small children:
– Low plasma volume (PV)
– Increased SNS activity
– Tachycardia & elevated BP:
• BP falls following an infusion of albumin.
• Most older patients:
– PV either normal or increased:
• In some, BP returns to normal with diuresis.
• Plasma renin:
– Levels normal or slightly increased:
• Non-response of the Htn to blockade of the renin-
angiotensin system does not support this as the primary
cause of the hypertension.
• Cytokines:
– Cytokines known to have pressor effects are increased:
• May be the primary cause of hypertension.
 PATHOPHYSIOLOGY: HYPERLIPIDEMIA
• Hyperlipidemia:
– Characterized by:
• Elevated triglycerides
• Elevated cholesterol
– Possibly secondary to:
• Hypoproteinemia:
–Stimulation of protein synthesis in the
liver:
»Overproduction of lipoproteins.
–Reduced lipoprotein lipase:
»Decreased lipid catabolism
 NEPHROTIC SYNDROME
• Annual incidence:
– 2-7/100,000 children
• Prevalence:
– Approx. 16/100,000 children
• Peak age for the onset:
– 2-3 years of age.
• Early childhood:
– M:F = 2:1 for new cases
• Adolescence and adults:
– M:F is more equal.
 PRIMARY NS
• Diseases limited to the kidney
• Has replaced the older designation of idiopathic
NS (INS)
• More common in children < six years of age
• > 90% of cases
• Sporadic inheritance
• A congenital form (Finnish type congenital
nephrosis) is autosomal recessive
– Mapped to a defect in the nephrin gene on
chromosome 19q13.1 that codes for nephrin
(protein in GBM).
 PRIMARY NS
• Minimal change disease:
– Most common in paediatrics
• Diffuse proliferative glomerulonephritis/Diffuse
mesangial proliferative glomerulonephritis
(DPGN/DMPGN))
• Focal segmental glomerulosclerosis (FSGS)
• Membranoproliferative GN (MPGN)
• Membranous GN (MGN):
– Adolescents and adults:
 PRIMARY NS
• Most common:
– MCD/MCNS/"NIL DISEASE“:
• 80-85%
• Less common:
– FSGS
– MGN
– MPGN
 MCD
• Glomeruli appear normal
– Or minimal increase in the mesangial cells/matrix
• Most common
• Mildest clinical course.
• Children usually present with oedema:
– Usually not Clinically apparent until serum albumin < 2 g/dL.
– Initially noted around the eyes and in the lower extremities
– Over the course of a day, distributes to more dependent
areas.
– After time, becomes more pronounced, generalizes and
there can be weight gain
• Scrotal or labial oedema often occurs.
• Pleural effusions, ascites and decreased urine output
may develop.
 MCD
• May have a history of preceding upper
respiratory symptoms.
• May have anorexia, abdominal pain and
diarrhoea:
– Possibly secondary to ascites.
• BP & RF usually normal.
• Hallmark is severe proteinuria:
– Most reliably diagnosed using a 24-hour urine
collection.
• Spot urinalysis is also informative:
– +3 to +4 proteinuria (300 to 1000 mg/dL)
– SG usually > 1.020.
– Gross haematuria not common.
 MCD
• Blood chemistry:
• Albumin usually < 2.0 mg/dL
• Elevated triglyceride
• Elevated cholesterol
• Hypocalcemia:
– Because of the hypoalbuminemia
– < 9.0 mg/dL.
– ionized calcium normal.
• Hyponatremia
• Hyperkalemia:
– in patients who are oliguric.
• Serum C3:
– Normal
 FSGS
• 7-15% of patients
• Second most common primary renal lesion.
• More severe clinical course:
– Persistent proteinuria
– Progressive decline in GFR
– Hypertension that can be unresponsive to therapy.
• Renal failure occurs
– Dialysis or transplant necessary.
• Recurrence rate as high as 40% after renal
transplant.
 MPGN
• 7% of primary NS
• > 8 yrs
• Haematuria
• Hypertension
• Mild azotemia.
• Persistently depressed C3 levels.
• Variable clinical course:
– Small percentage go into remission.
 MGN
• Rare in the paediatric age group
• More common into adolescence and adulthood.
• Often associated with infections:
– Hepatitis B most common.
• Variable clinical course:
– Overall prognosis good:
– Spontaneous remission 50-60%
 SECONDARY NS
• Systemic disease with kidney involvement.
• Predominates for patients > 6 years of age
• multisystemic diseases:
– SLE
– HSP
• malignancies such as:
– HD
– Leukaemia
• Drug/toxin:
– Mercury
– Gold
– Penicillamine
– Bee sting
 SECONDARY NS
• There are many different causes of secondary nephrotic syndrome in
children. These include:
– infectious aetiologies such as:
• HBV
• PSGN
• Congenital and secondary syphilis
• HIV
• Epstein-Barr virus
• Cytomegalovirus
• tuberculosis.
– Others:
• Haemolytic uraemic syndrome
• Congestive heart failure
• Constrictive pericarditis
• Bacterial endocarditis
• Alport’s syndrome
• Renal vein thrombosis
 DIFFERENTIALS
• APSGN
• Angioedema
• CHF
• Nephritis
• NS
• Obesity
• Protein-Losing Enteropathy:
– Infants with CF , particularly)
• SLE
• Allergic reactions
• Congenital defects in albumin synthesis
 INVESTIGATIONS
• Urine analysis
– 2+ protein
– high specific gravity
• Urine microscopy
– Hyaline casts
– Granular casts
• Spot urine protein:creatinine ratio
– >1
 INVESTIGATIONS
• Serum protein < 25g/l (2.5g/dL)
• Serum lipids 
• Serum triglycerides
– variable
• Blood Urea
• SE
• SCr
• CBC
• Serology:
– VDRL
– ASOT
– C3
– C4
– ANA
• HBsAg
• HIV
 RENAL BIOPSY
• Not necessary for newly diagnosed Pts.:
– Initial treatment will be the same, regardless of the cause.
• Response to corticosteroids may help dictate the need for biopsy:
– With good response and a normal RF, the diagnosis of MCD may be
presumed.
– If relapses respond to corticosteroids and there is no proteinuria during
disease free periods, this diagnosis is strengthened.
• Indications:
– Poor or no response to corticosteroids
– < 1 year old:
• Likelihood of congenital nephrotic syndrome
– > 10 years old:
• MGN
– Secondary nephrotic syndrome is suspected
– Corticosteroid toxicity
– Use of a cytotoxic agent being considered.
– Low serum complement
– Hypertension on presentation
• The latter two are not characteristic of MCD
 HISTOLOGY
• MCD:
– Glomerular morphology on LM practically normal.
• May be minimal mesangial alterations
• IGs usually absent.
– EM:
• No deposits observed
• Only significant change seen is flattening and
fusion of the podocytes.
• Focal global glomerulosclerosis (FGGS):
– Globally sclerotic glomerulus occurring in focal
areas
– Remaining glomeruli normal
– Normal glomerular attrition occurs by global
sclerosis:
• Therefore, if <5% of the glomeruli are globally
sclerotic, it is usually considered normal
 HISTOLOGY
• FSGS:
– Some glomeruli are involved with segmental sclerosis:
• One lobule
• Or one section within a glomerulus
– Remaining glomeruli are normal.
– May be overlooked on renal biopsy examination:
• Lesion is focal
• Lesion often confined to the juxtamedullary nephrons.
– Immunofluorescent microscopy yields a variable picture:
• In some patients, all classes of immunoglobulins and
complement appear to be trapped in the sclerotic area
• In others, distinct immune-complex-type, particularly IgM,
deposits are found.
 HISTOLOGY
• Mesangial proliferative glomerulonephritis:
– LM:
• Minimal to moderate proliferation of the
mesangial cells, with some mesangial
expansion
– Immunofluorescent microscopy:
• Most striking change is observed
• IgM, IgG, and C3 are often seen.
 HISTOLOGY
• Membranoproliferative glomerulonephritis
(MPGN):
– Also called mesangiocapillary
glomerulonephritis
– All glomeruli are involved
– Proliferation of cells and extensive immune
deposits demonstrated by immunofluorescent
and electron microscopy.
• MGN:
– Wiith Well-developed lesions, findings on LM
are typical
– Detection of early lesions requires
immunofluorescent and electron microscopy.
 DIAGNOSIS OF MCD
• Peak age group(2-3)
• Range 2-6 years
• No hypertension
• No gross haematuria
• Normal renal function
• Normal serology
• Steroid responsive
• No clinical stigmata of other disease
 TREATMENT
• General measures:
– Vital signs
– Daily weight
– Urine analysis and microscopy
– Dietary sodium restriction
– Protein
• normal to increase
– Intake output chart
 TREATMENT
• Specific measures:
• Prednisolone
• Fluids
– Do not restrict
• Indications for salt poor albumin and diuretics
• Antibiotics
• Talk to family
 TREATMENT
• Corticosteroid therapy and supportive care.
• Many patients may be treated on an outpatient:
– Newly diagnosed patient is sometimes admitted for diagnostic and
educational purposes.
• Oedema:
– Sodium restriction:
• "no added salt diet"
– Diuretics:
• Hydrochlorothiazide 2 mg/kg/d ( max. 100 mg)
• + spironolactone, 3 mg/kg/d (max. 200 mg)
• In 2/3 doses.
• If hypokalemia develops:
– oral potassium supplement
– or spironolactone
• Aggressive use of loop diuretics may be harmful:
– Most patients hypovolemic on initially presention.
• Close monitoring of patients.
• Close weight monitoring
• adequate protein consumption.
 TREATMENT
Immediate attention and hospitalization:
– Severe scrotal oedema
– Dehydration (> 10% dehydrated)
– Respiratory compromise:
• Pulmonary oedema
• Pleural effusions
– Peritonitis
– Suspected bacterial infection.
• Therapy is aimed at the restoration of intravascular volume and preventing
volume overload.
– Intravenous fluids:
– Used, sometimes with the infusion of albumin to increase the serum
oncotic pressure.
– Albumin:
• 1g/kg given slowly, over 8-12 hours ( 2h), to prevent fluid overload
from rapid intravascular volume expansion.
• Some debate over its the use, since the effect seems to be transient
and it is presumably excreted rapidly.
– Electrolyte levels and renal function must be closely monitored.
 TREATMENT
• Once the intravascular volume is restored,
diuretic therapy is used to mobilize the fluid and
prevent volume overload.
• Paracentesis:
– Performed if there is respiratory compromise
• Antibiotic:
– Broad spectrum
– if there is evidence of bacterial infection
 DIURETIC
ALTERNATIVE VIEW ABOUT DIURETIC THERAPY:
• May be beneficial, particularly in children with symptomatic
oedema
• Furosemide given orally (1-2 mg/kg/d) is safe and moderately
effective
• Avoid overly aggressive therapy.
• If the oedema is significant that intravenous diuretic therapy
seems indicated:
– Salt-poor albumin should be infused simultaneously:
• 1 gram/kg IV over 2-4 hours.
• Diuretics other than loop diuretics (eg, thiazides,
spironolactone, metolazone):
– Generally not potent enough alone to effect diuresis
– May give an added effect when combined with furosemide.
• For resistant oedema.
 ANTIHYPERTENSIVE
• Antihypertensive therapy should be given when
hypertension is present and particularly if it persists:
– Caution should be exercised.
• In some patients the hypertension responds to
diuretics alone.
• Preferred therapy:
– Angiotensin-converting enzyme inhibitors (ACEI)
– Or angiotensin II receptor antagonist (A2RA)
• Calcium channel blocking agents have been used
effectively in short term therapy.
• In those patients in whom significant proteinuria
persists, therapy with ACEI or A2RA are preferred for
their antiproteinuric effects
 STEROID
• Prednisone:
– initiated with a dose of 60 mg/sq-meter/day or 2 mg/kg/day
– Divided in 2-3 doses
– Maximum 80 mg/24h
• Continue daily dose until proteinuria resolves and remains normal for 10-
14d:
– Usually requires 2-3 weeks.
• Some sources suggest continuing the daily dose for 4-6 weeks.
• Majority of children with MCD will respond between the 10th and 14th days:
– A full course of at least 4 weeks of daily therapy is still recommended.
• Steroid is then tapered over the course of 3-6 months.
• 98% of MCD eventually have satisfactory therapeutic responses.
• MCD is one of frequent relapse:
– Two thirds of patients having a single relapse
– One third experiencing repeated relapses over many years.
• Most patients with steroid-responsive nephrotic syndrome will continue to
have relapses until they are in their late teens.
• Relapses:
– Treated the same as the initial presentation
– followed by alternate day regime given in the am.
 STEROID
• Maintenance glucocorticoid therapy:
– Duration still controversial
– Following the 4-8 weeks of daily therapy, the standard
recommendation has been for the dose to be reduced to 1.5
mg/kg/day (40 mg/m2/d) given as a single dose every other
morning for a 4-week period.
• Some investigators feel that such a brief period of
maintenance therapy is associated with a higher rate of
early recurrence than in those patients in whom the
maintenance therapy is continued for between 3-6
months.
– Some investigators have accentuated the steroid
effectiveness without increasing the side effects by giving
intravenous pulse doses of methylprednisolone
 STEROID
• Daily prednisone for 4 weeks followed by alternate day
therapy for 6 months would be expected to reduce the
number of children experiencing a relapse by about
33%
– 4 weeks: intensive (daily) treatment-as above
(2mg/kg)
– 8 weeks: 1.5 mg/kg/d (one dose every other
morning)
– 8 weeks: 1.0 mg/kg/d (one dose every other
morning)
– 8 weeks: 0.5 mg/kg/d (one dose every other
morning)
– Therapy stopped
 DIET & ACTIVITY
• Diet:
– Alterations in protein intake are not indicated.
• Activity:
– A normal activity plan is recommended.
– Since viral respiratory illnesses are usually
responsible for initiating exacerbations of NS, it may
be beneficial, if possible, to keep the child away
from those who have obvious respiratory tract
infections.
– Do not restrict activity unless the child is severely
oedematous.
 COMPLICATIONS
• Infections:
– Common
– Especially "primary peritonitis" (a type of
pneumococcal sepsis)
• Increased risk thought to be due to:
–IgG excretion
–Decreased complement function
–Diminished splanchnic blood flow.
• Organisms causing peritonitis are most
commonly Streptococcus pneumoniae and
Escherichia coli.
• Consider peritonitis in a patient who has
nephrotic syndrome and abdominal pain or fever.
• Vancomycin + a third generation
cephalosporin/an aminoglycoside would provide
good empiric coverage.
 COMPLICATIONS
– Other infections such as sepsis, cellulitis,
pneumonia and UTI are also seen.
– The signs of infection may be masked if the
patient is currently on corticosteroid therapy.
– Because of their predilection for S.
pneumoniae infection, polyvalent
pneumococcal vaccine should be
administered to children over two years of
age
 COMPLICATION
• Thromboembolism:
– Common
– Secondary to:
• Increased platelet aggregation
• Increased fibrinogen concentration
• Decreased antithrombin III concentrations
• Increased blood viscosity
• Decreased blood flow.
– Venous thrombosis is most common, especially in:
• Renal vein
• Pulmonary artery
• Deep vessels of the extremities:
–Avoid femoral punctures.
– In patients with refractory NS, low dose
anticoagulants are sometimes used.
 COMPLICATION
• Prerenal azotemia
• Enhanced platelet aggregability
• Enhance drug toxicity cause by higher free circulating drug
• PEM
– Chronic and remitting cases
• Osteomalacia
– Loss of vitamin D binding globulin 25-OH Vit. D
• Complications secondary to medications:
– Gastric irritation and insulin resistance:
• Corticosteroids
– Hemorrhagic cystitis, sterility and leukopenia:
• Cyclophosphamide.
 OUTCOME
• Remission after 2-3 week s of starting steroids
• 60-80% relapse
• Long term outcome excellent
• More than 80% go into sustained remission by
adolescence
 OUTCOME
• Mortality is approximately 2% with the majority of
deaths being secondary to complications such as
peritonitis or thromboembolic disease.
• Complete unresponsiveness to steroids (with
persistence of proteinuria and edema) or partial
unresponsiveness (persistence of proteinuria following
diuresis and resolution of edema) occurs in
approximately 8% of children with MCD.
• Some of these children may also have unrecognized
FSGS.
• Seriously consider FSGS in children who remain
nephrotic after a standard course of prednisone
therapy
• In such patients, consider therapy with an alkylating
agent, such as cyclophosphamide, chlorambucil, or
nitrogen mustard
 RELAPSES
• With repeated relapses or severe steroid toxicity
(growth retardation, elevated blood pressure),
cytotoxic agents such as cyclophosphamide are
added to a lower corticosteroid dose.
• Chlorambucil and less commonly cyclosporine have
also been used for remission induction.
• Another regimen for patients refractory to
corticosteroids is indomethacin and an angiotensin-
converting enzyme (ACE) inhibitor
• Nitrogen mustard has also been suggested
• START STEROID => ALTERNATE DAY
• ADD OTHER AGENT
• WEAN STEROID
 STEROID DEPENDENCE
• Relapse during alternate day treatment or
within several weeks after it is discontinued.
• Restart daily Rx x 4/52 followed by alternate
day Rx.
• When in remission for 1-2m, lower to the lowest
necessary alternate day dose.
• To reduce Steroid toxicity an ankylating agent
can be added.
– Cyclophosphamide
– Chlorambucil is prefered by some
 STEROID DEPENDENCE
• Cyclophosphamide & chlorambucil:
– Cyclophosphamide (2 mg/kg/day)
– or chlorambucil (0.1-0.2 mg/kg/day), may be administered
along with alternate day prednisolone (1-1.5 mg/kg)
– 12 weeks.
– Only a single course of either of the medications is
recommended. In view of larger experience and safer
toxicity profile, cyclophosphamide is usually preferred.
– The total leukocyte count should be monitored every 2-3
weeks. Treatment is discontinued if the leukocyte count falls
below 4000/mm3.
– Increasing the fluid intake and frequent voiding can prevent
hemorrhagic cystitis. Treatment with cyclophosphamide may
rarely cause alopecia, nausea and vomiting.
 STEROID DEPENDENCE
• Levamisole:
– May be administered in a dose of 2 -2.5 mg/kg on
alternate days for 12- 24 months. Treatment with
prednisolone, 1.5 mg/kg on alternate days, is
continued.
– The dose of prednisolone is gradually reduced by
0.15-0.25 mg/kg every 4 weeks to a maintenance
dose of 0.25 mg/kg, which may be continued for
six months.
– The chief side effect of treatment with levamisole is
leukopenia; flu-like symptoms and skin rash may
occur rarely. The total leukocyte count should be
monitored every 4-8 weeks.