NEPHROTIC

SYNDROME
By A.M.A

OUTLINE
Introduction
Diagnostic marker of N.S
Physiology
Pathogenesis
Incidence
Aetiology- 10and 20
Clinical presentation- Hx and
Examination
Investigations

Introduction
Definition- A persistent,
nonsuppurative, progressive,
inflammatory disease of the
glomerulus which may be immune
or non-immune mediated.
The commonest disorder of the
kidney all over the world.
The underlying pathogenetic
abnormality is proteinuria.

Diagnostic marker of N.S

1.

2.

3.

4.

Massive Generalized Oedema

Usually on/off in early stages
Permanent and generalized in late stages
Starts from face and spreads to other parts
(pitting)
Worse in the morning and better in the day

Hypoalbuminemia
Usually plasma albumin is < 25g/L

Massive Proteinuria
Protein in urine >/= 40mg/m2/hr (24hr urine
sample)
2g/m2/day, 3.5g/1.73m2/day
Urine protein/creatinine ratio (UPCR) >/=
200mg/mmol
Proteinuria by Dipstick of 3+ or 4+

Hypercholesterolemia
Not diagnostic, may be there if the disease is

The Glomerular Apparatus

Urine formation begins with filtration of
large amounts of fluid through the
glomerular capillaries into Bowman's
capsule.
Like most capillaries, the glomerular
capillaries are relatively impermeable to
proteins.
Normal urine is protein free
The glomerular membrane
The capillary endothelium
Basement membrane

Reasons why proteins dont pass

through easily
Filterability of solutes is inversely related to their
size.

Negatively charged large molecules are

filtered less easily than positively charged
molecules of equal molecular size.

Postulated theories on
how protein passes
Loss of vely charged glycoproteins
through
Immunological injury at glomerular
membrane due to antibody
reacting to deposited antigens
Production of plasma factor that
increases vascular permeability
Ig-E mediation of the disease

Pathogenesis
Hypoproteinuria
The dominant cause is the
immunologic damage to the
filtration pit which causes
excessive loss of protein.
Remarkable changes occur in
serum albumin & plasma proteins
of similar molecular characteristic
e.g.
Transfferin

Examples of serum protein that are

increased in their serum levels are:
2- globulin
B-globulin
Pre-B lipoprotein
Fibrinogen etc

There is increased catabolism of

tubular albumin

Oedema
Excessive protein loss

Hypoalbuminemia Low Oncotic pressure

Reduced intravascular volume

Loss of fluid into the interstitial space

Compensations

Increased ADH secretion leads to increased water reabsorption and

thus worsen the oedema
Activation of the Renin- Angiotensin -Aldosterone system leads to
increased reabsorption of sodium & water, and loss of potassium
Stimulation of the sympathetic nervous system
Suppression of atrial natriuretic factor leading to Na & water
retention.

Hyperlipidaemia
In response to the
hypoalbuminaemia, there is
compensatory secretion of
albumin and concomitant
production of lipoproteins.

Incidence
Age
Temperate- Preschool age children
</= 4yrs
Tropics- School age children 5-8
yrs

Sex
Temperate- m:f =2:1
Tropics no sex predilection

Types of N.S
Congenital- Occurring before the
age of 3months
Infantile- Btw 3months to 1 year
Childhood- Above 1 year of age

Congenital N.S
Primary Congenital Nephrotic
Syndrome
Is a heterogeneous
collection of primary or secondary
disease that may share only the
fact that the onset occurs in the 3
months of life.
A notable example is Finish
type of Primary congenital

Secondary Congenital
Nephrotic Syndrome
Causes
Syphilis
Toxoplasmosis
Cytomegalovirus
Renal vein thrombosis etc

Aetiology Of Childhood
N.S
It is divided into

Primary or Idiopathic the

cause is unknown
Secondary is associated
with some diseases

Primary Nephrotic
Syndrome (Histologic
1. Minimally Change Nephrotic
Types)
Syndrome (NIM)

Is the commonest type in Europe &

America (90% in caucasians, 18% in
Africans)

Non MCD types are the commonest in

Africa (90% in tropics)

2. Membranoproliferative
Glomerulonephritis (MPGN)
Most of the cases in UCH are of this histologic

3. Membranous Nephropathy
Some cases e.g. Plasmodium malariae
nephropathy & SLE have this type of histology.

4.

Focal Segmental

Glomerulosclerosis (NIM)
Seen in Diabetes mellitus and HIV
Nephropathy in blacks

5.

Proliferative Glomerulonephritis

Secondary Nephrotic
5% in Caucasians, 40% in Africans
Syndrome
Post-infectious
Multisystemic & Connective Tissue
Diseases
Allergic disorders
Drugs & Heavy metals
Neoplastic
Heredofamilial disorders
Metabolic disorders

Post Infectious
Protozoal
Plasmodium malariae (Quartan Malarial
Nephropathy)
Is very important in this environment.
In 1960s, it is responsible for 80% of cases in Ibadan
and 25% in Zaria.
There is no typical histological picture that is currently
accepted but more show membranoproliferative
glomerulonephritis.
QMN is an immulogically mediated disorder
initiated by Quartan malarial infection which once
established pursues a progressive course.
It is graded into I, II & III depending on the severity of
glomerular affectation.
I - < 30% of tubules are affected
II - 30-70%
III - > 70%

 Parasitic- S. mansoni, S.
haematobium, Filariasis.

Viral- Hepatitis B & C, Cytomegalovirus, Varicella, HIV.

Bacterial - Post-strep. AGN, rarely Syphilis

Infective endocarditis, Shunt Nephritis.

Multisystemic &
Connective
Tissue
Systemic lupus
erythematosus
Diseases
Henoch-Schonlein Purpura
Sarcoidosis
Amyloidosis

Allergic disorders
Bee sting
Serum sickness
Pollens
Poison oak
Poison ivy

Drugs & Heavy metals

Mercury : in bleaching creams
Lead
Gold in the treatment of
rheumatoid arthritis
Penicillamine Wilsons disease
Trimethadone in the treatment of
Petit mal epilepsy

Neoplastic

Heredofamilial disorders
Sickle cell disease
Alports syndrome
Nail-Patella syndrome

Metabolic disorders
Diabetes mellitus
Hypothyroidism

Clinical Presentation

Oedema Usually starts from the face (periorbital swelling), then involves the abdomen,
genitalia. The oedema subsides with
ambulation.
It may also be responsible for weight
increase despite poor appetite
Patient presents about 1 2 months after
the onset of symptoms
reduced urinary output depending on
the oedema
Abdominal swelling due to ascites
pleural effusion features
Features of infection
Blood pressure is usually normal in the
early stage, but in some types e.g.

History
Symptoms

Periorbital swellingDuration when did it start?

Which time of the day is it worse ?
Progression Is it worsening ?
Relieving factor

Associated symptoms
Fever, if yes clerk
Abdominal swelling
Leg swelling
Urine
Quantity - oliguria
Colour dark coloured
Frequency
Pain during micturition
Blood in urine terminal or during the urination

Evidence of pulmonary oedema

Cough
Breathlessness

Vomiting
Diarrhea

Aetiology
Fever
Degree : Low or high
Pattern : continous or intermittent
Periodicity : Is it every 2 -3hours (QMN)

Insect bite (Bee sting)

Bathing soap Does it contain mercury?
Drugs ingestion or Is the child being treated for
any illnesses like rheumatoid arthritis (Gold),
Epilepsy (Trimethadone), Wilson disease

Genotype of the patient

Do you have stream or river in your vicinity where
the child goes to?
Family history of similar illness
Recent history of skin infection
Recent history of sore throat
Passage of dark coloured urine

Chronic liver disease

Abdominal pain
Yellowness of eyes
Pale stool
Body itching

Nutritional
Does he feed well
What kind of food does he eat?

Investigations
1 Urinalysis
Proteinuria : +++ or ++++ (+=30mg%, ++
100mg%, +++
300mg%, ++++ = 1g%)
Frothy urine
Haematuria
Hyaline cast
Glucosuria due to transient tubular dysfunction or
DM

2. Urine microscopy
For rbc, wbc casts

3. Stool microscopy - for S. mansoni ova

4. Serum electrolyte & urea

Sodium Low or normal
Urea - Usually normal, unless in malnourished px
Chloride, Bicarbonate, Creatinine - normal


5. Serum calcium the ionized calcium is
normal, but total calcium is low because of
low albumin in blood
6.

7.

8.

9.

Blood film for malarial parasite

24-hour Urinary Protein
Creatinine clearance
Renal biopsy Indications include

Occurring less than 1yr or greater than 8yrs

Steroid-dependent
Steroid-nonresponsive
Frequent relapses
Hypertension
Renal failure, Haematuria

10 G6PD Assay Because of the drug used to

11. Protein Selectivity Index

- Is done to detect the severity of damage
- The glomerulus is seen as a sieve. The lesion is
classified as
a. Highly Selective Proteinuria
- Renal lesions
showing only minimally change, albumin is lost
mainly.
b. Poorly Selective Proteinuria - There is lesion with
marked histologic changes, and loss of larger
molecules in addition to albumin.

Protein Selectivity Index = Clearance of Albumin X

100
Clearance of IgG

1. Highly Selective1 15

Others include
12 Haemolytic component 50
13 Antinuclear antibody
14 AntiDNA antibody
15 Lupus erythematosus cells
16 Direct Coombs test
17 P-ANCA, C-ANCA
18 Renal USS
19 GFR
20 VDRL test
21 Clotting time, bleeding time, PTTK

Treatment
Objective of treatment of
Idiopathic type
To abort inflammation
To abort proteinuria
To prevent disease progression
The drug of choice is STEROID i.e.
Prednisolone or Prednisone

Dosage
60mg/m2/day for 4-8 weeks avg 4
weeks
Then reduce to
40mg/m2/48hrs for 4weeks
Then
10-20mg/m2/48hrs for at least 4weeks
Total of a minimum of 12 weeks
Generally, steroids are helpful in
I. Minimal change nephritic syndrome (90%)
II. Focal segmental glomerulosclerosis
III. Mesangial NS
IV. Proliferative GN
Non minimal change N.S responds poorly to
therapy (49.6% respond in OAUTHC).

Supportive treatment
1. Daily weighing
2. Monitoring of blood pressure
3. Urinalysis
4. Monitoring of Input/output of fluid
5. Diuretics using mild and not fast-acting
e.g. thiazides is preferred. For secondary
hyperaldosteronism, use spironolactone.
1. Diet
2. Protein of high biologic value (when
broken down, gives essential amino acids).
Normal intake should be maintained if the
renal function is normal
3. Cholesterol & saturated fatty acids should

7. Salt poor albumin (expensive) + IV

lasix or
Fresh frozen plasma
10ml/kg + wait for 30 minutes, then
give lasix (unlike in adults & other
conditions).
Mechanism of action : the salt-poor
albumin or
FFP draws water into the vessels first
while the lasix aids the excretion.
Metolazone + Frusemide require close
monitoring

8. Modest exercise should be encouraged to

prevent thromboembolic phenomenon
because
Nephrotic patients are prone to
hypercoagulable state.

Complete remission:
This refers to a urine protein ratio that is less than
4mg/m2/hr on 3 consecutive occasions
Or UPCR <20mg/mmol on 3 consecutive occasions
Or A dipstick proteinuria that is 0 or trace on 3
consecutive
occasions
Following daily Prednisolone therapy for at least 4
weeks

Partial remission

Urine protein of >4-39mg/m2/hr

or UPCR >20-199mg/mmol
or dipstick proteinuria of + or ++ on 3 consecutive
occasions
Following daily Prednisolone therapy for at least 4
weeks

Maintenance of remission
10-20mg/m2/48hrs tab Prednisolone for 1-2 years

Recalcitrant Nephrotic
Syndrome
Steroid resistance

Steroid dependence
Frequent relapses

Steroid Resistance- can be 10 or 20

10 steroid resistance N.S.
Failure to achieve complete remission following daily
steroid
therapy for 4 weeks
20 steroid resistance N.S.
Failure to respond to subsequent steroid therapy after
an
initial complete remission

Tx Of Steroid Resistance
Give Dexamethazone 3-5mg/kg/dose.
IV pulses on alternate days for 6 doses or daily for 3
doses.
Other centers
Methyl Prednisolone 500-750mg/m2 IV pulses
alternate days for
6 doses +
Cyclophosphomide 500mg/m2 as an infusion given
slowly
biweekly for 6 doses

Steroid dependence
Occurs when there is a relapse while tapering or
reducing the
dose of steroid or within 2 weeks of
cessation of steroid
therapy.

Mgt of steroid dependence

Still treat with steroid then use a steroid sparing drug
e.g.
ACE inhibitors like Lisinopril 2.5-5mg/day
ARB e.g. Valsartan 20-80mg/day
Spironolactone 3.5mg/day
Aldosterone is pro-inflammatory, they reduce the
level of
Aldosterone to abort proteinuria

Relapse
Reappearance of protein in
the urine after an initial complete
remission
Protein >40mg/m2/hr or
UPCR>20mg/mmol
Or dipstick of >/= ++ on 3 consecutive
day
Frequent relapsing There is an initial
complete relapse followed by 2 or more
relapses within 6 months or 4 or more
within a year
Infrequently relapsing An initial
complete remission followed by 1
relapse in 6 months or 2 relapses in a

Other Drugs used

Levamisole
Cytotoxics e.g.

Chlorambucil,
Cyclophosphamide, Methotrexate, vincristine
Cyclosporine A
Cod liver oil
Monoclonal antibodies e.g. Rituximab,
Dacliximab
Microfenolate mofetil

Complications of N.S
Acute Kidney Injury
Shock- due to massive oedema
Transient or sustained
Hypertension

Increased susceptibility to infections

Reduced immunoglobulin
Oedema fluid acting as culture medium
Protein deficiency
Reduced bactericidal activity of leucocytes
Immunosuppressive therapy
Reduced perfusion of the spleen due to
hypovolaemia
Loss in urine of factor B (alternative
pathway of the complement system is
particularly significant in the opsonization of
encapsulated organism)

End stage renal disease

Badly managed cases or failure to respond

MalnutritionOccurs as a direct consequent of

urinary protein loss and aggravated by
anorexia & vomiting.
Hyperlipidaemia Predisposing to increased risk of
ischemic vascular disease.
10 Peritonitis
Which is usually due to Streptococcus
pneumonia infection. Gram-ve
organism can also cause it.

Loss of transport protein-

Complications as a result
of treatment
Sepsis

Herpes infection
Alopecia of Cyclophosphamide
Pancytopenia of Cyclophosphamide
Anemia of ACEI
Leucopenia of Levamisole

Differential Diagnosis
Acute glomerulonephritis
Kwashiorkor
Congestive cardiac failure
Chronic Liver disease
Beriberi (Wet)
Malabsorption syndrome
Severe helminthiasis

Prognosis
Is variable
It is poor in Quartan Malarial
Nephropathy, which develops
hypertension and end-stage renal disease
within 5 to 7years
In Minimal Change disease, the outcome
is better. Patients may have relapses till
the 2nd decade.
For the secondary N.S prognosis depends
on the cause but are much better than
the 10 N.S

Conclusion
Renal disease is a silent killer especially in
our environment where facilities for renal
dialysis and transplantation are expensive
and lacking.
It is unfortunate that the 20 type of
Nephrotic syndrome which is steroid
resistant and whose burden of
management is enormous is the
predominant type here in Africa.
Improved diagnostic technology and better
health care facilities will go a long way in
helping us manage Nephrotic syndrome
better.