Nephrotic Syndrome

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.

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.

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.
• 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 many patients.
• Excluding swelling, the patient is usually well, active and does not seem sick.
• 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.

What are the complications of 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.

Diagnosis:

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 levels.

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.

Blood 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 the patients.

Additional tests

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 complications.

Blood 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.

Radiological tests

• 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.

Kidney biopsy

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.

Treatment

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 period (years).

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 not required. Patients receiving high doses of daily steroids should restrict salt intake even in the absence of swelling to decrease the risk of developing hypertension.

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.

Drug therapy

• Specific 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.

Supportive drug treatment

• 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, pneumonia).
• Statins (simvastatin, atorvastatin, rosuvastatin) to reduce cholesterol and triglycerides and prevent the risk of heart and blood vessel problems.
• 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 only transiently.
• Blood thinners such as warfarin (Coumadin) or heparin, may be required to treat or prevent clot formation.

Treatment of underlying causes

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.

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.

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.

Why and how is prednisolone given in nephrotic syndrome?

• 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.

What are the side effects of prednisolone (corticosteroids)?

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.

Short-term effects

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.

Long-term effects

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 weakness.

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.

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 therapy. Why?

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 face?

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 side effects.

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 (diuretics).

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.

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 to 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).

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:

• 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.

What is the prognosis of nephrotic syndrome and what is the expected time factor for its cure ?

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.

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 doctor?

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 volume.
• 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.

Source: Kidney Education Foundation