Pediatric idiopathic nephrotic syndrome

What is pediatric idiopathic nephrotic syndrome?

Nephrotic syndrome is a disease characterized by low levels of protein (especially albumin) in the blood (hypoproteinemia/hypoalbuminemia) due to large amount of proteinuria. Because protein (albumin) acts to keep water in the blood vessels, hypoproteinemia/hypoalbuminemia causes water to leak out of the blood vessels, resulting in a tendency to have edema (swelling).
Nephrotic syndrome without any obvious cause is called idiopathic (primary) nephrotic syndrome, while nephrotic syndrome caused by a systemic disease such as diabetes and collagen disease is called secondary nephrotic syndrome. Idiopathic nephrotic syndrome is typically observed more often in children (about 90%) than in adults (about 40%).

Symptoms of pediatric idiopathic nephrotic syndrome

Edema, fluid accumulation under the skin, frequently develops and is most severe on the face during the night or in the legs during the daytime due to the effects of gravity. Fluid may accumulate not only under the skin, but also in the chest (pleural effusion) and belly (ascites). In addition, swelling of the intestine may cause abdominal symptoms such as nausea/vomiting, stomachache, and diarrhea.Also, because water leaks out of the blood vessels, the amount of blood circulating in the vessels decreases, sometimes causing low blood pressure or renal dysfunction.

Treatment for pediatric idiopathic nephrotic syndrome

Because pediatric idiopathic nephrotic syndrome rarely improves spontaneously and typically responds well to steroids (about 90%), drug therapy using steroids is given first.
Proteinuria disappears in about 90% of patients treated with steroids, and this is called remission. However, pediatric idiopathic nephrotic syndrome often relapses, with about 70 to 80% of patients experiencing recurrence of proteinuria after remission, followed by repeated remissions and relapses.
About 30 to 40% of patients have the frequently relapsing type of the syndrome and have experience strong side effects of steroids, and so immunosuppressive agents are used in these patients to prevent relapse. Recently, in patients who have relapses even after treatment with immunosuppressive agents, biological drugs, which are antibodies against lymphocytes, are sometimes used.

Diuretics may be used for severe edema to help urinate, and albumin preparations, which are blood products made from human blood, may be used for severe abdominal symptoms or a low level of circulating blood.
In some patients (about 10%) who do not respond sufficiently to steroids (steroid-resistant), a variety of treatments combining steroids and immunosuppressive agents are tried.

Q&A

1. What is the approximate number of patients with this disease?

In Japan, idiopathic nephrotic syndrome newly occurs in 6.5 out of 100,000 children per year (about 1000 children per year). The number is estimated to be twice or three times larger than in Western countries.

2. In whom is this disease common?

Nephrotic syndrome can occur in people of any age from children to the elderly, but pediatric idiopathic nephrotic syndrome occurs more often in boys, with an incidence of 1.2 times to twice that reported for girls. The peak age of onset is around 2 to 5 years, and about a half of children develop the disease before the age of 5.

3. Is the cause of this disease known?

Approximately 90% of pediatric nephrotic syndrome is categorized as idiopathic nephrotic syndrome, the cause of which is unknown. It is becoming known that gene abnormalities are involved in some cases of steroid-resistant nephrotic syndrome, which responds poorly to various treatments.

4. Is this disease hereditary?

About 90% of pediatric nephrotic syndrome is categorized as idiopathic nephrotic syndrome with unknown causes and is not hereditary. However, inherited cases have been reported in the family of some patients with steroid-resistant nephrotic syndrome, for which the involvement of genes has been confirmed.

5. What is the clinical course of this disease?

The clinical course differs significantly depending on the type of nephrotic syndrome.

Nephrotic syndrome responding to steroids (steroid-sensitive), which is the most common type of pediatric idiopathic nephrotic syndrome, rarely causes reduced renal function but often relapses (in about 70 to 80% of patients), and about a half of these cases are categorized as a frequently relapsingtype, which requires treatment with immunosuppressive agents because of frequent relapses. Moreover, many patients have repeated relapses when the doses of immunosuppressive agents are reduced or discontinued. In the past, it was believed that few patients (about 10%) experience relapses in adulthood, but recently, it is estimated that about 20 to 50% of patients have repeated relapses even in adulthood, and therefore transition to adult treatment (internal medicine) is considered necessary.

In the past, patients with nephrotic syndrome responding poorly to steroids (steroid-resistant), whose proteinuria did not become reduced or disappear, often experienced progression to end-stage kidney disease and required dialysis or kidney transplantation, but the prognosis has recently been improved because of advancement in treatment. However, there are still some patients who do not respond sufficiently to any of the various treatments and develop end-stage kidney disease.
Long-term follow-up and treatment are required in either types of nephrotic syndrome, and many patients need to continue treatment with steroids and/or immunosuppressive agents for 2 or more years.

6. What precautions are required in everyday life?

6-1．What precautions are required when taking medicines?

First of all, please make sure to take prescribed medicines, including steroids and immunosuppressive agents, as instructed. There are some patients who do not take their medicines as instructed due to fear of possible side effects of steroids such as weight gain, and as a result, experience repeated relapses or, in some cases, even fall into a life-threatening condition.

In addition, if you are taking ciclosporin (trade name: Neoral) or tacrolimus (trade name: Prograf), both are immunosuppressive agents, you should avoid eating grapefruits (as well as sweetie, pomelo, bitter orange, hassaku orange, etc.) because they increase the blood concentration of these medicines. As citrus juice may also contain these fruits even if this is not very visible on the label, caution is advised.

6-2. Is it advised to do a urine test at home?

In nephrotic syndrome, proteinuria often reappears (relapses) later after resolution (remission). If the relapse is detected early, treatment with steroids can be initiated before swelling (edema) or various complications of nephrotic syndrome occur, resulting in a reduced burden on the patient’s body. Therefore, it is important not only to make sure to regularly consult with your doctor, but also to regularly do a urine test at home.

6-3．Are there any cautions to be taken about diet?

During relapse (when proteinuria is present), you should decrease salt intake because a salt-rich diet worsens swelling (edema). Fluid intake should not be restricted because fluid restriction has a risk of reducing the level of circulating blood, leading to the worsening of general condition. The appropriate amount of protein and energy (calories) based on age should also be taken without restriction.

During remission (when proteinuria is absent), there are no special dietary restrictions. However, due to the side effects of steroids, you may easily gain weight and have increased appetite, and so you should be very careful not to consume too much energy (calories). It is advised to measure your weight regularly.

While you are taking specific immunosuppressive agents, you should avoid eating grapefruits (as well as sweetie, pomelo, bitter orange, hassaku orange, etc.) (see Section 6-1).

6-4．Can I do exercises?

Basically, there are no exercise restrictions. Participation in an excursion or athletic meeting, etc. is also not restricted. However, when you have severe swelling (edema) during relapse, exercises may be restricted. In addition, long-term use of steroids may cause fragile bones. If your bone density test shows severe abnormalities, contact sports (e.g., judo, rugby), which involve a strong impact on the spine, may be restricted.

6-5．Please explain about infection prevention and vaccine

Infection prevention is important because infection often triggers relapses, and there is also a risk that infection becomes severe due to the side effects of steroids or immunosuppressive agents. Wash hands and gargle well right after getting up, when coming home, before meals, etc.

Even while taking steroids or immunosuppressive agents, inactivated vaccines for influenza, Streptococcus pneumoniae, etc. are allowed and recommended. However, please consult with your doctor because the amount and type of medicine matters. Live vaccines are, in principle, not allowed while undergoing treatment with steroids or immunosuppressive agents, but again please consult with your doctor because vaccination is still necessary in some cases. There is a system that allows individuals who missed regular vaccination due to illness to take the missed vaccination as regular vaccination up to 2 years after the date when the condition that prohibits vaccination disappeared (Chouki Ryouyou Tokurei). For details, please ask your doctor or the relevant department of your municipality of residence.

Diagnosis and treatment guidelines
(For healthcare providers)

○　Overview

Overview
Nephrotic syndrome is a group of kidney diseases where damage to the glomerular capillary wall causes a large amount of glomerulus proteinuria, leading to hypoalbuminemia or edema. Pediatric nephrotic syndrome is diagnosed when (1) hyperproteinuria (≥ 40 mg/hr/m² on overnight urine collection) or morning urine protein/creatinine ratio of ≥ 2.0 g/gCr continues and (2) hypoalbuminemia (serum albumin ≤ 2.5 g/dL) is present. Nephrotic syndrome associated with a causative disease is diagnosed as secondary nephrotic syndrome, and nephrotic syndrome without any obvious causative disease is diagnosed as primary (idiopathic) nephrotic syndrome.
(*Adult nephrotic syndrome is diagnosed when urine protein of ≥ 3.5 g/day (or spot urine protein/creatinine ratio of ≥ 3.5 g/gCr) continues, and serum albumin decreases to ≤ 3.0 g/dL).
Causes
The causes of nephrotic syndrome are considered to vary depending on disease type. The possible causes of minimal change nephrotic syndrome, which accounts for the majority cases of pediatric idiopathic nephrotic syndrome, are (1) T-cell functional abnormality, (2) circulating factor, and (3) genetic abnormalities (podocyte components such as mainly slit membrane). Firstly, in 1974, Shalhoub proposed T-cell-related “lymphocyte function abnormality theory.” Subsequently, many attempts have been made to identify circulating factors of steroid-resistant nephrotic syndrome, and hemopexin, vascular permeability factor (VPF), vascular endothelial growth factor (VEGF), active oxygen, soluble urokinase receptor (suPAR), interleukin-13 and -18, tumor necrosis factor alpha (TNFα), cardiotrophin-like cytokine factor 1 (CLC-1), etc. were identified. However, reproducible results have not been obtained yet for any of these factors. In addition, the possible involvement of HLA as a disease-susceptibility gene in idiopathic nephrotic syndrome (especially, steroid-sensitive type) has long been suggested, based on the involvement of immunopathy in the pathology and racial differences in the frequency, while association with HLA-DR/DQ in Japanese patients is suggested by the Genome Wide Association Study (GWAS) in recent years.
Symptoms
Systemic edema caused by a large amount of proteinuria, hypoalbuminemia/ hypoproteinemia appears, and weight gain by ≥ 5% often occurs. In severe cases, various symptoms, including pleural effusion and ascites, decreased kidney function (acute kidney injury, chronic kidney injury), dyslipidemia, coagulation-fibrinolytic system abnormalities and associated thrombosis, immune disorder and associated infection, are observed.
Complications due to medications are also important. Treatment with steroids may cause hypertension, ocular hypertension, cataract, stomach ulcer, osteoporosis, growth impairment, etc. In addition, concomitant use of immunosuppressive agents may increase the risk of infection.
Treatment
The most common variety of pediatric idiopathic nephrotic syndrome is the minimal change type. Therefore, steroid (prednisolone) is recommended as first-line drug for both at the first onset and relapse. In Japan, ciclosporin, cyclophosphamide, or mizoribine (off-label use) is often used for frequently relapsing and steroid-dependent nephrotic syndrome. Rituximab may be used for the treatment of refractory frequently relapsing and steroid-dependent types of nephrotic syndrome, which are difficult to manage with existing immunosuppressive agents. Furthermore, oral steroids combined with ciclosporin and/or steroid pulse therapy are used for steroid-resistant nephrotic syndrome.
In general, mild edema does not require any treatment, and unnecessary use of diuretics or albumin preparations is not recommended. For the treatment of refractory and symptomatic edema, salt restriction, diuretics, or albumin preparations are chosen based on the evaluation of body fluid distribution.
Prognosis
Complete remission is achieved with steroids in 80 to 90% of cases of pediatric idiopathic nephrotic syndrome, which are categorized as steroid-sensitive nephrotic syndrome. However, 70 to 80% of them relapse, with half of them frequently relapsing (frequently relapsing and steroid-dependent). Patients with frequently relapsing and steroid-dependent nephrotic syndrome are vulnerable to steroid-related adverse drug reactions such as obesity, growth impairment, hypertension, diabetes, osteoporosis, and adrenal insufficiency.
Steroid-resistant nephrotic syndrome, which does not respond to steroid therapy, accounts for 10 to 15%. Of patients with steroid-resistant nephrotic syndrome in whom remission cannot be induced by concurrent immunosuppressive agents, etc., 30 to 40% experience progression to kidney failure in 10 years.

Hyperproteinuria (≥ 40 mg/hr/m²on overnight urine collection) or morning urine protein/creatinine ratio of ≥ 2.0 g/gCr
Hypoalbuminemia (serum albumin ≤ 2.5 g/dL)

Diagnostic category

If both criteria 1 and 2 are met, and there is no obvious causative disease, a diagnosis of pediatric idiopathic (primary) nephrotic syndrome is made.

Differential diagnosis

All of the following differential conditions are excluded.
(Causative diseases of secondary nephrotic syndrome)
・Autoimmune diseases: lupus nephritis, IgA vasculitis, vasculitis
・Metabolic diseases: diabetic nephropathy
・Paraproteinemia: amyloidosis, cryoglobulin, heavy chain deposition disease, light chain deposition disease
・Infections: hemolytic streptococcal infection, staphylococcal infection, hepatitis B/C, human immunodeficiency virus (HIV), parvovirus B19, syphilis, parasite (malaria, schistosoma )
・Allergic hypersensitivity diseases: pollinosis, bee venom, black fly bite, snake venom, vaccination
・Tumors: solid cancer, multiple myeloma, malignant lymphoma, leukemia
・Drugs: bucillamine, D-penicillamine, gold preparations, nonsteroidal anti-inflammatory drugs
・Hereditary diseases: Alport’s syndrome, Fabry’s disease, nail-patella syndrome
・Other: pregnancy-induced hypertension, radiation nephropathy, rejection of transplanted kidney

＜Severity grading criteria＞

Any of the following criteria 1 to 3 is met.
1. At least 3 relapses in 6 months or at least 4 relapses in 1 year*
2. Use of immunosuppressive agents or biological drugs for treatment
3. Kidney transplantation
*Relapse
Morning urine protein ≥ 3+ on a urine dipstick for 3 consecutive days