Introduction and Causes
Nephrotic syndrome is a common kidney disease characterized by heavy
loss of protein in urine, low blood protein levels, high cholesterol levels
and swelling. This disease can occur at any age but is seen more frequently
in children compared to adults. Nephrotic syndrome is characterized
by its cycle of response to treatment, manifested by gradual tapering
and discontinuation of medication, treatment free period of remission
and frequent relapses causing swelling. As the cycle of recovery and
recurrence repeats for a long period (years), this disease is a matter of
worry for both the child and the family.
What is nephrotic syndrome?
The kidney works as a sieve (filter) in our body that removes waste
products and extra water from blood and passes them out via the urine.
The size of the holes of these filters is so small so that in normal
circumstances proteins that are large in size do not pass into the urine.
In nephrotic syndrome the holes of these filters become large, so protein
leaks into the urine. Because of the loss of protein in urine, the level of
protein in the blood falls. Reduction of protein level in blood causes
swelling (the medical term for the swelling seen in these patients is edema).
The severity of edema varies depending on the amount of protein lost in
the urine and reduction in protein level of blood. The kidney function
(i.e., the ability to filter waste products or the glomerular filtration rate),
per se, is normal in most patients with nephrotic syndrome.
Most important cause of recurrent swelling
in children is nephrotic syndrome.
What causes nephrotic syndrome?
In over 90% of children the cause of nephrotic syndrome (called primary
or idiopathic nephrotic syndrome) is not known. Primary Nephrotic
Syndrome is caused by four pathological types: minimal change disease
(MCD), focal segmental glomerulosclerosis (FSGS), membranous
nephropathy and membranoproliferative glomerulonephritis (MPGN).
Primary nephrotic syndrome is a “diagnosis of exclusion”, i.e. they are
diagnosed only after secondary causes have been excluded.
In less than 10 % of cases, nephrotic syndrome may be secondary to
different conditions such as infection, drug exposure, malignancy,
hereditary disorders or systemic diseases such as diabetes, systemic
lupus erythematosus and amyloidosis.
Minimal change disease
The most common cause of nephrotic syndrome in children is minimal
change disease (MCD). This disease occurs in 90 percent of cases of
idiopathic nephrotic syndrome in young children (under age six) and in
65% of cases in older children.
In a typical child with minimal change disease, blood pressure is normal,
red blood cells are absent in urine and the values of serum creatinine
and complement 3 (C3) are normal. Of all the causes of nephrotic
syndrome, minimal change disease is the least stubborn, as over 90%
of the patients respond well to steroid therapy.
Nephrotic syndrome commonly occurs in
children between the ages of 2 to 8 years.
Symptoms and Diagnosis
CHP. 22. Nephrotic Syndrome 163.
Symptoms of nephrotic syndrome
- Nephrotic syndrome can occur at any age but is most common
between the ages of 2 to 8 years. It affects boys more often than girls.
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What are the complications of nephrotic syndrome?
- The first sign of nephrotic syndrome in children is usually puffiness
or swelling around the eyes and swelling of the face. Because of
puffiness around the eyes, the patient is likely to consult an
ophthalmologist (eye doctor) first.
- In nephrotic syndrome swelling of the eyes and the face is most
noticeable in the morning and is less marked in the evening.
- With time, the swelling develops in the feet, hands, abdomen and all
over the body and is associated with increase in weight.
- Swelling may occur after a respiratory tract infection and fever in
- Excluding swelling, the patient is usually well, active and does not
- A decreased urine output compared to normal is common.
- Frothy urine and white stain on tiles due to albumin in urine may be
a revealing feature.
- Red urine, breathlessness and high blood pressure are less common
in nephrotic syndrome.
Possible complications of nephrotic syndrome include an increased risk
of developing infections, blood clots in the veins (deep vein thrombosis),
malnutrition, anemia, heart disease due to high cholesterol and
triglycerides, kidney failure and different treatment-related complications.
A. Basic laboratory tests
In patients with swelling the first step is to establish a diagnosis of nephrotic syndrome. Laboratory tests should confirm (1) heavy loss of
protein in the urine, (2) low blood protein levels, and (3) high cholesterol
The first sign of nephrotic syndrome in children is
swelling around the eyes and swelling of the face.
CHP. 22. Nephrotic Syndrome 165.
1. Urine tests
- Urine examination is the first test used in the diagnosis of nephrotic
syndrome. Normally, routine examination of urine will show negative
or trace protein (albumin). The presence of 3+ or 4+ protein in a
random urine sample is suggestive of nephrotic syndrome. Remember
though that the presence of albumin in urine is not a specific diagnostic
confirmation of nephrotic syndrome. It only suggests urinary loss of
protein. Further investigations are necessary to determine the exact
cause of urine protein loss.
- After starting treatment, urine is tested regularly to assess its response
to treatment. The absence of protein in urine tests suggests a positive
response to treatment. For self monitoring, protein in urine can be
estimated by using a urine dipstick at home.
- In microscopic examination of urine, red blood cells and white blood
cells are usually absent.
- In nephrotic syndrome, the loss of protein in urine is more than 3.5
grams in a day. The amount of protein lost in 24 hours can be
estimated by a 24-hour urine collection or more conveniently by a
spot urine protein/creatinine ratio. These tests provide precise
measurements of the amount of protein lost and identify whether
protein loss is mild, moderate or heavy. In addition to its diagnostic
value, estimation of urine protein loss in 24 hours is useful for
monitoring response to treatment.
Urine test is very important for diagnosis as well as
monitoring of treatment of nephrotic syndrome.
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2. Blood tests
B. Additional tests
- The characteristic findings of nephrotic syndrome that accompany
the high urine protein levels are low blood albumin level (less than 3
g/dL) and elevated cholesterol (hypercholesterolemia) in blood tests.
- The value of serum creatinine is normal in nephrotic syndrome due
to minimal change disease, but may be increased in patients with
more severe kidney damage from other forms of nephrotic syndrome
like focal segmental glomerulosclerosis. Serum creatinine is measured
to assess overall kidney function.
- Complete blood count is a routine blood test performed in most of
Once the diagnosis of nephrotic syndrome has been established,
additional tests are performed selectively. These tests determine whether
the nephrotic syndrome is primary (idiopathic) or secondary to a systemic
disorder; and to detect the presence of associated problems or
1. Blood tests
2. Radiological tests
- Blood sugar, serum electrolytes, calcium and phosphorus.
- Testing for HIV, hepatitis B and C and VDRL test.
- Complement studies (C3, C4) and ASO titer.
- Antinuclear antibody (ANA), anti–double-stranded DNA antibody,
rheumatoid factor and cryoglobulins.
3. Kidney biopsy
- An ultrasound of the abdomen is performed to determine the size and shape of the kidney, and to detect mass, kidney stone, cyst or
other obstruction or abnormality.
- X-ray of the chest is done to rule out infections.
The kidney biopsy is the most important test used to determine the
exact underlying type or cause of nephrotic syndrome. In a kidney biopsy,
a small sample of kidney tissue is taken and examined in a laboratory.
(for further information read Chapter 4).
Important diagnostic clues are loss of protein in urine and low
protein, high cholesterol and normal creatinine in blood tests.
CHP. 22. Nephrotic Syndrome 167.
In nephrotic syndrome the goals of treatment are to relieve symptoms,
correct urinary loss of protein, prevent and treat complications and
protect the kidney. Treatment of this disease usually lasts for a long
1. Dietary advice
The dietary advice/restriction for a patient with swelling differs once the
swelling disappears with effective treatment.
- In a patient with swelling:Restriction of dietary salt and avoidance
of table salt as well as foods that are high in sodium content, so as to
prevent fluid accumulation and edema. Restriction of fluid is usually
Patients receiving high doses of daily steroids should restrict salt
intake even in the absence of swelling to decrease the risk of
For patients with swelling, adequate amounts of proteins should be
provided to replace the urine protein loss and prevent malnutrition.An adequate amount of calories and vitamins should also be provided
to these patients.
- In symptom- free patients:The dietary advice during the symptom-
free period is a normal healthy diet. Unnecessary dietary restrictions
should be avoided. Avoid restriction of salt and fluid. Provide an
adequate amount of proteins. Avoid moderately high protein diets
to prevent kidney damage and restrict protein intake in the presence
of kidney failure. Increase intake of fruits and vegetables. Reduce
the intake of fat in diet to control blood cholesterol levels.
In patients with swelling, salt restriction is necessary but during
symptom-free period avoid unnecessary dietary restrictions.
2. Drug therapy
A. Specific drug treatment
B. Supportive drug treatment
- Steroid therapy: Prednisolone (steroid) is the standard treatment
for inducing remission in nephrotic syndrome. Most children respond
to this drug. Swelling and protein in the urine disappear within 1-4
weeks (urine free of protein is labeled as a remission).
- Alternate therapy:A small group of children who do not respond
to steroid treatment and continue to lose protein in their urine need
further investigation such as a kidney biopsy. Alternate drugs used in
such patients are levamisole, cyclophosphamide, cyclosporin,
tacrolimus and mycophenylate mofetil (MMF). These alternate drugs
are used along with steroid therapy and help to maintain remission
when the dose of steroid is tapered.
3. Treatment of underlying causes
- Diuretic drugs to increase urine output and reduce swelling. They
should be used only under supervision by a doctor as excessive use
may cause kidney failure.
- Antihypertensive drugs such as ACE inhibitors and angiotensin II
receptor blockers to control blood pressure and to reduce the urinary
loss of protein.
- Antibiotics to treat infections (e.g. bacterial sepsis, peritonitis,
- Statins (simvastatin, atorvastatin, rosuvastatin) to reduce cholesterol
and triglycerides and prevent the risk of heart and blood vessel
- Supplement calcium, vitamin D and zinc.
- Rabeprazole, pantoprazole, omeprazole or ranitidine for protection
against steroid induced stomach irritation.
- Albumin infusions are generally not used because their effects last
- Blood thinners such as warfarin (Coumadin) or heparin, may be
required to treat or prevent clot formation.
Meticulous treatment of underlying causes of secondary nephrotic
syndrome such as diabetic kidney disease, lupus kidney disease,
amyloidosis etc. is important. Proper treatment of these disorders is
necessary to control nephrotic syndrome.
Prednisolone (steroid) is the standard first
line treatment of nephrotic syndrome.
Treatment - General advice
CHP. 22. Nephrotic Syndrome 169.
4. General advice
- Nephrotic syndrome is a disease that lasts for several years. The
patient and his/her family should be educated about the nature of the
disease and its outcome; type of medication used and its side effects;
and benefits of prevention and early treatment of the infection. It is important to emphasize that extra care is necessary during relapse
when swelling is present, but during remission the patient should be
treated as a normal child.
- The infection should be treated adequately before initiating steroid
therapy in case of nephrotic syndrome.
- Children with nephrotic syndrome are prone to respiratory and other
infections. Prevention, early detection and treatment of infection are
essential in nephrotic syndrome because infection can lead to a relapse
of controlled disease (even when the patient is receiving treatment).
- To prevent infection, the family and child should be trained to drink
clean water, wash hands thoroughly and avoid crowded areas or
contact with infectious patients.
- Routine immunization is advised when steroid course is completed.
Infection is an important cause of recurrence of nephrotic
syndrome, so it is essential to protect children against infection.
5. Monitoring and follow up
- As nephrotic syndrome is likely to last for a long period (years), it is
important to have regular follow ups with a doctor as advised. During
the follow up the patient is evaluated by the doctor for loss of protein
in urine, weight, blood pressure, height, side effect of medication
and development of complications, if any.
- Patients should weigh themselves frequently and record it. Weight
chart helps to monitor fluid gain or loss.
- The family should be taught to test urine for protein at home regularly
and maintain a diary of all urine test results and dosage and the
details of all medications. It helps in early detection of relapse and its
prompt treatment subsequently.
As nephrotic syndrome lasts for years, regular urine
tests and follow up with the doctor are crucial.
Treatment - Steroid Therapy
CHP. 22. Nephrotic Syndrome 171.
Why and how is prednisolone given in nephrotic syndrome?
What are the side effects of prednisolone (corticosteroids)?
- The first drug used in the treatment of nephrotic syndrome is
prednisolone (a steroid) that effectively corrects the disease and
stops loss of protein in urine.
- The doctor decides on the dosage, duration and method of
administration of prednisolone. The patient is advised to take this
drug with food to avoid irritation of the stomach.
- In the first attack the drug is usually given for about 4 months, divided
into three phases. The drug is given daily for 4 to 6 weeks initially, as
a single dose on alternate mornings subsequently and finally the dose
of prednisolone is gradually decreased and then discontinued. The
treatment for relapse of nephrotic syndrome is different from the
treatment given for the first attack.
- Within 1 to 4 weeks of the treatment the patient is symptom free
and the leakage of protein in the urine stops. It is very important to
complete the course as advised by the doctor to prevent frequent
relapses. One must not make the mistake of discontinuing the
treatment out of the fear of side effects of prednisolone.
Prednisolone is the most commonly used drug for the treatment of
nephrotic syndrome. Because of the possibility of several side effects
this drug should be taken strictly under medical supervision.
Common short-term side effects are increase in appetite, weight gain,
swelling of the face, stomach irritation causing abdominal pain, increased susceptibility to infection, increased risk of diabetes and high blood pressure, irritability, acne and excessive growth of facial hair.
Optimum steroid therapy is essential to control the disease,
prevent frequent relapses and reduce side effects of steroid.
Common long-term side effects are weight gain, stunted growth in
children, thin skin, stretch marks on thighs, arms, and abdominal area,
slow wound healing, development of cataracts, hyperlipidemia, bone
problems (osteoporosis, avascular necrosis of the hip) and muscle
Why are corticosteroids used in the treatment of nephrotic
syndrome in spite of multiple side effects?
Serious side effects of corticosteroids are known but at the same time
untreated nephrotic syndrome has its potential dangers.
Nephrotic syndrome can cause severe swelling and low protein in the
body. Untreated disease may cause numerous complications, such as
increased risk of infections, hypovolemia, thromboembolism (blood clots
may obstruct blood vessels and cause strokes, heart attacks, and lung
disease), lipid abnormalities, malnutrition and anemia. Children with
untreated nephrotic syndrome quite often die from infections.
With the use of corticosteroids in childhood nephrotic syndrome the
mortality rate has been reduced to around 3%. The optimal dose and
duration of corticosteroid therapy under proper medical supervision
are most beneficial and least harmful. Majority of steroid effects disappear
with time after the discontinuation of therapy.
In order to obtain potential benefits of the therapy and avoid life-
threatening complications of the disease, the developement of some
side effects of corticosteroid is unavoidable.
Steroids should be taken strictly under medical
supervision to reduce the possibility of side effects.
CHP. 22. Nephrotic Syndrome 173.
In the nephrotic child, with initial steroid therapy swelling
subsides and urine becomes protein free, but swelling of face
is seen again during the third or fourth week of steroid
Two independent effects of steroids are increased appetite leading to
weight gain and redistribution of fat. These lead to a round or swollen
face. Steroid induced moon-shaped face is seen during the third or
fourth week of steroid therapy, which mimics swelling of the face due
to nephrotic syndrome.
How does one differentiate swelling of the face due to
nephrotic syndrome from steroid-induced moon-shaped
Swelling of nephrotic syndrome starts with puffiness or swelling around
the eyes and the face. Later swelling develops in feet, hands and all
over the body. Swelling of the face due to nephrotic syndrome is most
noticeable in the morning, immediately after waking and is less noticeable
in the evening.
Swelling due to steroids predominantly affects the face and abdomen
(because of redistribution of fat), but arms and legs remain normal or
thin. Steroid-induced swelling remains the same all throughout the day.
Different characteristics of distribution and time of its maximum
appearance help in the differentiation of these two similar conditions. In
certain patients, blood tests are needed to resolve the diagnostic dilemma.
In patients with swelling, low serum protein/ albumin and high cholesterol
indicate relapse whilenormal values of both tests suggest steroid effect.
Why is it important to differentiate between swelling of the
face due to nephrotic syndrome and steroid side effects?
To determine precise treatment strategy in a patient, it is important to
differentiate between swelling due to nephrotic syndrome and steroid
Swelling due to nephrotic syndrome needs an increase in steroid dose,
modification in the method of its administration, and at times, addition
of other specific drugs and temporary supplementation of water pills
Facial swelling due to steroids, on the other hand, is the proof of long
term steroid intake, and one should neither worry that the disease is out
of control nor reduce the dose of the steroid rapidly out of fear of the
drug toxicity. For long term control of nephrotic syndrome, continuation
of steroid therapy as per recommendation of the doctor is essential.
Diuretics should not be used to treat steroid induced swollen face because
it is ineffective and can be harmful.
Steroid therapy can increase appetite, weight
and cause swelling of the face and abdomen.
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What are the chances of recurrence of nephrotic syndrome
in children? How frequently does relapse occur?
Chances of recurrence or relapse of nephrotic syndrome is as high as
50-75% in a nephrotic child. The frequency of relapse varies from patient
Which drugs are used when steroid is ineffective in the
treatment of nephrotic syndrome?
When steroid is ineffective in the treatment of nephrotic syndrome, other
specific drugs used are levamisole, cyclophosphamide, cyclosporine,
tacrolimus and mycophenolate mofetil (MMF).
To plan optimum therapy, it is essential to differentiate
between swelling due to disease and steroids.
CHP. 22. Nephrotic Syndrome 175
What are the indications suggesting the need for kidney
biopsy in children with nephrotic syndrome?
There is no need to do a kidney biopsy before starting steroid treatmen
in children with nephrotic syndrome. But kidney biopsy is indicated in
the presence of:
What is the prognosis of nephrotic syndrome and what is the
expected time factor for its cure ?
- Absence or inadequate response to adequate doses of steroid
treatment (steroid resistance).
- Frequently relapsing or steroid dependent nephrotic syndrome. In
the latter case, withdrawal of steroids results in relapse (reappearance
of protein in the urine) necessitating reinstitution and eventual
maintenance of steroid therapy.
- Atypical features of childhood nephrotic syndrome such as onset in
the first year of life, elevated blood pressure, persistent presence of
red cells in urine, impaired kidney function and low blood C3 level
Nephrotic syndrome of unknown origin in adults requires a kidney biopsy
for diagnosis before initiating steroid therapy.
The prognosis depends on the cause of nephrotic syndrome. The mos
common cause of nephrotic syndrome in children is minimal change
disease which carries good prognosis. Majority of children with minima
change disease respond very well to steroids and there is no risk of
developing chronic kidney failure.
A small proportion of children with nephrotic syndrome may not respond
to steroid therapy and may require further evaluation (additional blood
tests and kidney biopsy). These children with steroid resistant nephrotic syndrome need treatment with alternative drugs (levamisole,
cyclophosphamide, cyclosporin, tacrolimus etc) and have a high risk of
developing chronic kidney failure.
There is no risk of kidney failure in
children with minimal change disease.
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With proper treatment of nephrotic syndrome protein leak stops and
the child becomes almost normal. In majority of children, relapse occurs
for many years (throughout childhood). As the child grows, frequency
of relapse decreases. Complete cure of nephrotic syndrome usually
occurs between the age of 11 to 14 years. These children have an
excellent prognosis and lead a normal life as adults.
When should a person with nephrotic syndrome consult a
The family of a child with nephrotic syndrome should immediately consult
a doctor if he or she develops:
- Pain in the abdomen, fever, vomiting or diarrhea.
- Swelling, rapid unexplained weight gain, marked reduction in urine
- Signs of illness, e.g. if he or she stops playing and is inactive.
- Persistent severe cough with fever or severe headache.
- Chicken pox or measles.
Nephrotic syndrome which lasts for
years slowly disappears with age.