A syndrome is a group of signs and/or symptoms that typically occur together. It can be the principal feature of a disease or may occur as a trait in other disorders. The classic signs and symptoms of childhood nephrotic syndrome (NS) include edema, massive loss of proteins (mainly albumin) in the urine, low levels of albumin in the blood, and elevated blood lipid levels. Nephrotic syndrome is associated with numerous kidney diseases in infants, children, and adults. It is a disorder with potentially serious health consequences.
The characteristics of NS include massive loss of albumin into the urine, consequent low serum albumin levels, edema, and elevated unfavorable lipid profiles.
A subset of these disorders occurring mostly in children has NS as its primary or only feature.
Between 80% and 95% of children with NS have minimal change disease (MCD) that is highly likely to be controlled with steroid medications. However, subsequent relapses are common and require retreatment.
Relapsing MCD resolves after an average of eight years.
At least half of those primary NS children who do not respond to steroid treatment will have focal segmental glomerulosclerosis (FSGS) with a high risk of progression to kidney failure. Several other drugs that suppress immune function show promise in treating FSGS.
NS may also occur as part of other kidney diseases, certain drugs, and hereditary factors.
Complications of NS include increased risks of serious infections, severe side effects of medications, and thrombosis (clot formation) that can substantially injure major organs such as the brain, lungs, and kidneys.
The two principal kidney diseases with primary nephrotic syndrome may have similar characteristics at the onset but have distinct medical courses and outcomes. The most frequent forms of NS in children and teens are commonly referred to as:
Minimal change disease (MCD): often also called idiopathic nephrotic syndrome or steroid-sensitive nephrotic syndrome).
Focal segmental glomerulosclerosis (FSGS):, also referred to as a steroid-resistant nephrotic syndrome.
The first part of this article provides background information about the nephrotic syndrome disease process and its consequences. Following this is information about the similarities and differences between the principal types of childhood NS.
What causes nephrotic syndrome?
Kidney function includes filtration of the blood and excretion of waste products and other substances into the urine. To accomplish this, normal adult kidneys filter around 152 quarts (144 Liters) of blood per day! In children, this number is smaller but proportionate to their body size. Albumin (ALB) is an abundant protein in the blood, making up around half of the total circulating proteins. ALB has numerous properties. Of particular relevance to the NS, ALB prevents water in the bloodstream from “leaking” into surrounding tissue.NS occurs when the specialized kidney filters lose the ability to prevent ALB and other large proteins from passing into the urine to be excreted. Given the very high rate of blood filtration and the abundance of ALB in the blood, the body is unable to synthesize sufficient ALB to replace the losses in the urine. As a result, blood levels of albumin drop considerably.
Characteristics and complications of the NS
Severe albumin loss in the urine is suspected when urine appears “foamy” in the toilet. Screening for high concentrations of albumin in the urine can be easily done using a urine dipstick. Notably, kidney function is otherwise generally preserved in most cases. Essentially, the clinical findings of childhood NS are directly or indirectly related to the very low serum albumin levels.
Albumin plays an important role in keeping water within the bloodstream. A great deal of fluid can “leak” into surrounding tissues when the serum albumin is <2.5 grams /100ml (normal = 3.5-5.5). The excess water that accumulates in body tissues is called edema. This may initially be seen surrounding the eyes upon awakening (Figure 1) and in the upper and lower extremities during the day (Figure 2).
Large amounts of fluid also may accumulate in the abdomen, causing discomfort and a distended belly. Importantly, edema can also result from other serious diseases, including heart failure, liver dysfunction, gastrointestinal malabsorption, vein diseases, and lung disease.
Elevated blood lipids, including total and LDL (“bad”) cholesterol, occur in NS. These and related lipid disturbances are most likely due to liver overproduction as a response to low serum albumin. Studies show that nephrotic children develop cholesterol deposits in arterial walls similar to that seen in atherosclerosis. Some patients can require treatment with lipid-lowering medications.
There are increased risks of serious bacterial and viral infections in NS. ALB is not the only protein lost in large amounts in the urine. Others include proteins that play central roles in immune defense. To make matters worse, most drugs used to treat NS suppress immune function. Common serious and potentially life-threatening infections include peritonitis (inflammation in the abdominal cavity), pneumonia, meningitis, cellulitis (deep skin infections), and sepsis (systemic bacterial infections).
Childhood NS is associated with an increased risk of serious blood clots (thrombosis), especially in large veins. Regulation of normal blood clotting requires a balance between coagulants and anticoagulants that promote or impair the formation of blood clots. In NS, there is an abnormal balance of those factors that increase the risks of spontaneous blood clots. These clots may cause significant injury to the kidneys, lungs, brain, and numerous other structures.
Children with NS who have poor to no response to medication treatment often have progressive deterioration of kidney function and kidney failure.
Principal types of childhood NS
The terminology used to classify the types of childhood NS can be confusing. MCD and FSGS describe how kidney filters appear under the microscope. Steroid-responsive, steroid-dependent, and steroid-resistant NS are classifications according to the initial clinical response to steroid therapy (usually prednisone or prednisolone). However, there is some overlap between the two conditions (Table).
|Average age of onset||Age 2-4 years||Age 8-10 years|
|Microscopic appearance*||Normal||Scars in kidney filters|
|Albumin lost into the urine||Yes||Yes|
|Low serum albumin levels||Yes||Yes|
|Elevated lipid levels||Yes||Yes|
|Response to steroid therapy||Yes||No|
|Response to other immunosuppressive drugs||Yes||Approximately half|
|Hypertension||Around 20%**||50% and greater|
|Recurrence after transplant||Rare||Frequent|
* Refers to the appearance of the kidney filters using the common light microscope.
** When off steroids and other immunosuppressive medications.
Minimal change disease (MCD, aka steroid-responsive nephrotic syndrome, idiopathic nephrotic syndrome)
Pediatric MCD generally begins at younger ages compared to FSGS. MCD is, by definition, responsive to initial high-dose corticosteroid therapy (prednisone or prednisolone). Remission from corticosteroid treatment is the single best clinical predictor of a favorable long-term outcome.
Approximately 50% of MCD patients achieve complete remission within eight days, and the remainder by around four weeks. However, half of these responders will have subsequent relapses requiring retreatment. Infections of the upper respiratory tract and allergic reactions are among the common triggers for relapses. When managing recurrent MCD, it can be challenging to find an optimal balance between controlling the disease and minimizing steroid side effects. Some patients who have frequent relapses and unacceptable side effects can be successfully treated with other immunosuppressive drugs.
Focal segmental glomerulosclerosis
Like MCD, FSGS is a microscopic descriptive term: sclerosis refers to scars within parts of the kidney filtering units (glomeruli) and segmental means that not all filtering units are affected initially. Approximately half of the children with NS who do not respond to steroids will have FSGS (5%-10%). This condition was long considered to have no treatment alternative and a high likelihood of progressing to chronic kidney failure. Symptomatic management includes diet and medications to reduce protein losses and reduce elevated lipid levels are routinely used, although they do not modify the course of the disease. More recently, several powerful immunosuppressive drugs have achieved complete or partial remission in some of these individuals. These include cyclosporine, tacrolimus, mycophenolate mofetil, and possibly rituximab. There are numerous new drugs currently under clinical investigation for the treatment of FSGS, but none have, as yet, shown definite benefits.
Other types of primary NS
There are many diseases in childhood that present with nephrotic syndrome. The majority can be linked to genetic causes, resulting from immune-mediated kidney diseases, or be associated with certain drugs, including heroin. Although rare in children, lymphoma can be associated with NS.