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%).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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
Morning urine protein ≥ 3+ on a urine dipstick for 3 consecutive days