Nephrotic syndrome in children: definition and principles of therapy

Nephrotic syndrome is a condition in which a child has massive swelling, including fluid accumulation in the abdominal cavity, excretion of large amounts of protein in the urine and a decrease in the concentration of blood proteins, as well as an increase in the level of blood fats.

The disease is rare, the cause of its occurrence in children has not been established, and is more common in boys.

Nephrotic syndrome can be primary or secondary. Primary can be congenital or idiopathic (from unknown causes), occurs in the first year of life and after a year.

Secondary complicates the course of other diseases, especially diabetes and infections.

The basis of the disease is an increase in the permeability of the glomerular membranes, through which an abnormal amount of protein is released into the urine. Due to a decrease in the concentration of plasma proteins, primarily albumin, the liquid part of the blood cannot be retained in the vascular bed and penetrates the tissues, saturating them.

Nephrotic syndrome in children: definition and principles of therapy

Nephrotic syndrome (NS) is a clinical and laboratory symptom complex, clinically characterized by peripheral or generalized edema up to ascites and anasarca, and laboratory - proteinuria more than 2.5 g / day or more than 50 mg / kg / day, hypoproteinemia, hypoalbuminemia (below 40 g /l), dysproteinemia, hyperlipidemia and lipiduria.

Hypoproteinemia in nephrotic syndrome develops due to the loss of proteins (primarily albumin) in the urine due to impaired permeability of the glomerular filter. Hypoproteinemia leads to a decrease in plasma oncotic pressure, due to which the fluid does not completely return to the vascular bed, but is retained in the tissues, which causes the development of nephrotic edema. In their occurrence, the condition of the lymphatic capillaries is of no small importance, since tissue hyperhydration causes, through a feedback mechanism, a compensatory increase in lymphatic drainage and the removal of tissue proteins with lymph, which reduces the oncotic pressure of the interstitial fluid. Such a compensatory mechanism can, to a certain extent, prevent the development of edema during hypoproteinemia.

Despite the proven role of hypoalbuminemia in the development of nephrotic edema, there is no clear mathematical relationship between the level of hypoproteinemia and the degree of edema. Moreover, edema may not develop at all, even with a marked decrease in the level of albumin in the blood. Thus, in patients with congenital hypoalbuminemia, associated with a congenital defect in the rate of albumin synthesis, edema may not occur even with the almost complete absence of albumin in the blood. This may be due to the inclusion of various compensatory mechanisms (increased lymphatic drainage, shunting of blood through arteriovenular anastomoses). In addition, in approximately 10% of cases with nephrotic syndrome, the development of edema occurs along an alternative pathway, in which primary renal sodium retention is the leading one.

Clinically, nephrotic edema is usually defined as generalized. They start from the eyes and ankles, then spread to the torso and reach the degree of anasarca and cavitary edema (ascites, hydrothorax). The swelling is soft, mobile (shifts with changes in the patient’s body position), often asymmetrical due to body position or thrombosis of the superficial veins. With severe edematous syndrome, skin tears, stretch marks, and liver enlargement may be observed.

Nephrotic syndrome in some cases may be a manifestation of primary glomerulonephritis (GN). There are also congenital nephrotic syndrome (Finnish type) and familial nephrotic syndrome. In addition, nephrotic syndrome can be secondary and accompany many diseases that involve kidney damage (systemic lupus erythematosus, hemorrhagic vasculitis, rheumatoid arthritis, microscopic polyangiitis, diabetes mellitus, renal amyloidosis, etc.).

In some cases, nephrotic syndrome is not accompanied by the development of edema and is called incomplete nephrotic syndrome. Classic nephrotic syndrome is not characterized by the presence of hematuria or hypertension - it is a “pure” nephrotic syndrome, which corresponds to the nephrotic form of acute or chronic glomerulonephritis according to the Vinnitsa classification (1980). Mixed nephrotic syndrome is defined when NS is combined with hematuria (more often) and/or hypertension, which corresponds to a mixed form of GN.

The term “idiopathic nephrotic syndrome” is used to refer to the nephrotic syndrome that develops with primary glomerulonephritis. Morphologically, idiopathic NS in children is based on minimal changes (MI) - up to 85%, focal segmental glomerulosclerosis (FSGS) - up to 5-7%, mesangioproliferative glomerulonephritis (MzPGN), usually immunonegative - 4-6%) and membranous glomerulonephritis (MGN) - up to 1–2%. In subsequent age periods, this ratio changes (see table). In minimal change nephrotic syndrome (MCNS), the glomerular basement membrane is permeable predominantly to low molecular weight protein molecules (albumin, transferrin, etc.), so proteinuria is selective. More pronounced changes in the glomerular filter lead to the filtration of large proteins (globulins), which causes the non-selectivity of proteinuria. Due to the pronounced predominance of NSMI in childhood, especially before 8–10 years of age, a kidney biopsy is not indicated for children with new-onset “pure” NS with selective proteinuria. The presence of mixed NS (with arterial hypertension and/or hematuria) and resistance to corticosteroid therapy indicate other variants of GN that require morphological clarification.

Complications of nephrotic syndrome

Complications of nephrotic syndrome are associated primarily with the loss of proteins that perform various functions and hypovolemia. Loss of albumin, in addition to the above effects, increases the toxicity of albumin-related drugs. The loss of immunoglobulins and components of the complement system leads to decreased immunity and frequent infections. A low concentration of the iron transport protein, transferrin, results in the development of hypochromic microcytic iron deficiency anemia, resistant to iron therapy. Deficiency of high-density lipoproteins leads to impaired cholesterol transport, and loss of orosomucoid and decreased levels of lipoprotein lipase lead to triglyceridemia, which increases the risk of atherosclerosis. In addition, the development of rickets-like syndrome is possible due to the loss of vitamin D-binding protein, increased bleeding due to a deficiency of procoagulants (factors IX, X, XII), functional hypothyroidism due to the loss of thyroid-binding globulin and an increase in free thyroxine in the blood, a tendency to exogenous hypercortisolism due to transcortin deficiency and increased concentration of free cortisol, etc.

Immunosuppressive therapy for idiopathic NS

The basis of pathogenetic treatment of idiopathic NS is immunosuppressive therapy. Traditional, non-selective drugs (glucocorticoids, cytostatics and antimetabolites) and selective immunosuppressants (cyclosporine A, tacrolimus, mycophenolate mofetil) are used as immunosuppressive drugs.

Glucocorticoids (GC) - prednisolone (PZ) (medopred, prednisol, prednisolone) and methylprednisolone (MP) (metipred, solu-medrol) - are the first drugs of choice in the immunosuppressive treatment of GN. GCs influence the redistribution of immunocompetent and inflammatory cells, preventing their entry into the site of inflammation, suppressing their sensitivity to inflammatory mediators, and inhibiting the secretion of proinflammatory cytokines such as TNF-α, IL-1, IL-2, IL-6. GCs trigger the processes of gluconeogenesis, promoting the inclusion of antibodies in carbohydrate metabolism and thereby reducing their number, tonify the capillary wall and reduce hyperemia due to the activation and swelling of pericytes. The administration of large doses of GC in the form of MP “pulses” inhibits the formation of DNA antibodies, stops the formation of immune complexes, reduces their mass and promotes the release of the glomerular basement membrane from the subendothelial layers, increases glomerular filtration and renal blood flow.

Depending on the response to hormonal therapy, hormone (steroid) sensitive and hormone (steroid) resistant nephrotic syndrome are distinguished. In primary nephrotic syndrome, which is based on minimal changes in the glomeruli, the patient’s body in the vast majority of cases (up to 90%) responds well to prednisolone therapy (complete clinical and laboratory remission develops). Resistance to glucocorticoid therapy or partial remission (incomplete resistance or sensitivity) suggests other, not minimal, changes in the glomeruli in primary glomerulonephritis or a secondary nature of kidney damage.

GCs are prescribed to children in all cases of new-onset NS, with relapses of hormone-sensitive NS (as a rule, NSMI), with a progressive course of GN, in combination with other immunosuppressants, etc.

In practice, three modes of GC therapy are used.

Continuous oral administration of PZ at a dose of 1–2 mg/kg in 2–4 doses, taking into account the daily activity of the adrenal cortex (maximum doses of the drug in the morning with subsequent reduction, the last dose no later than 16.00) is prescribed at the beginning of treatment to achieve remission.

An alternative (alternative) regimen for taking PZ is used when switching to maintenance therapy. It consists of taking a daily dose of PZ every other day, which allows, while maintaining the clinical effect, to significantly reduce side effects: acute - insomnia, euphoria, psychosis, increased appetite; chronic - edema, obesity, myopathy, stretch marks, skin atrophy, hirsutism, acne, osteoporosis, cataracts, increased blood pressure, steroid diabetes; adrenal crisis - acute adrenal insufficiency with abrupt discontinuation of the drug. There is also the option of an alternating regimen with taking PZ daily for 3 days, then a 3-4 day break. In terms of effectiveness, both modes of alternating intake of PZ are approximately the same.

MP pulse therapy is used to achieve very high plasma concentrations of GC. It consists of intravenous drip administration of about 30 mg/kg MP (no more than 1 g per pulse) over 20–40 minutes once every 48 hours. The number of injections, as well as the single and total dose, are determined by the chosen treatment regimen for this pathology.

Side effects of glucocorticoids can be the following: insomnia, euphoria, psychosis, increased appetite, edema, obesity, myopathy, stretch marks, skin atrophy, hirsutism, acne, osteoporosis, cataracts, increased blood pressure, steroid diabetes, adrenal crisis (acute adrenal insufficiency with abrupt withdrawal drug).

Cytostatic (cytotoxic) drugs (CDs). Alkylating agents: cyclophosphamide (cyclophosphamide, cytoxan) and chlorambucil (chlorbutin, leukeran) - disrupt cell division by binding to nuclear DNA nucleic acids. They enter the body in an inactive state and are activated in the liver. They act non-selectively on all dividing cells (non-selective immunosuppressants).

Cyclophosphamide is prescribed orally or in the form of “pulses”. The drug is prescribed orally at a rate of 2.0–2.5 mg/kg/day for 8–12 weeks in the treatment of hormone-dependent or frequently recurrent NS against the background of a gradual reduction in the dose of the alternating PZ regimen, as well as in case of hormone resistance.

Pulse therapy with cyclophosphamide is carried out against the background of an alternating course of PZ for hormone-dependent and hormone-resistant NS at the rate of 12–17 mg/kg intravenously. The number of “pulses” and the time interval between them depend on the chosen therapy regimen. Another option is a “pulse” once a month for 6–12 months, at a cumulative dose not exceeding 250 mg/kg.

Chlorambucil is taken orally at a dose of 0.15–0.2 mg/kg/day for 8–10 weeks for the treatment of hormone-dependent and frequently recurrent NS, less often with hormone-resistant NS, against the background of an alternating course of PZ with a gradual decrease.

Antimetabolites—azathioprine and methotrexate—are currently rarely used in the treatment of GN. Side effects of cytostatics are possible: when using cyclophosphamide - nausea, vomiting, leukopenia, hemorrhagic cystitis, gonadal failure; chlorbutin - pulmonary fibrosis, dermatitis, convulsions, hepatopathy, leukopenia.

Selective immunosuppressants

Cyclosporin A (CiA) - sandimune, sandimune neoral, consupren, bioral, ecoral, etc. - suppresses the production of IL-2, IL-3, IL-4, g-IF activity of (CD4+) T-helper cells at the time of antigen presentation, proliferation cytotoxic T lymphocytes. It does not affect the developed antibody response.

It is used for hormone-dependent and often recurrent NS; in 95% of cases it is effective in patients with sensitivity to GC. The initial dose is 5–6 mg/kg. The further dose is determined by the tolerability of the drug and the concentration in the blood (not higher than 80–150 ng/ml). Before prescribing CyA, a kidney biopsy is necessary; after 1–1.5 years of CyA therapy, a repeat biopsy is performed (due to the nephrotoxic effect and sclerosing effect on the tubules and interstitium). Constant monitoring of blood creatinine levels and drug concentrations is necessary. In case of overdose, the following may develop: hypertrichosis, hypertrophic gingivitis, dyspepsia, lymphoproliferative diseases, hypertension, renal and liver dysfunction. GCs, calcium antagonists, ketoconazole, macrolides increase the concentration of CyA in the blood (when combined with GCs, the dose of CyA can be reduced). Barbiturates, alcohol, rifampicin, trimetaprim and other sulfonamides reduce the concentration of CyA in the blood.

Mycophenolate mofetil (Celsept) is a new selective immunosuppressant that inhibits inosine monophosphate dehydrogenase and depletes the reserves of guanosine nucleotides in cells. Selectively inhibits the proliferation of T and B lymphocytes, the formation of cytotoxic T lymphocytes and the production of antibodies. Currently, it has just begun to be used in pediatric nephrology for the treatment of hormone-dependent and hormone-resistant variants of NS, but the first results are assessed as positive.

Tacrolimus (FK-506) is a new selective immunosuppressant, like Selcept, which has proven itself in transplantology. Similar in mechanism of action to CyA. Suppresses T-helper cells, production (or release) of TNF-α and IL-1. It has not yet received widespread use in the treatment of GN in children.

New directions in immunosuppressive therapy for GN

Currently, two areas of therapy for GN are being actively developed:

• inhibition of the action of cytokines using monoclonal cytokine-neutralizing antibodies, aimed mainly at the inactivation of pro-inflammatory and proliferative cytokines - TNF-α, IL-1, IL-2, IL-6, TGF-β and adhesion molecules;
• changing the activity of macrophages by stimulation with anti-inflammatory interleukins - IL-10, IL-4, IL-13.

The effectiveness of these methods has been proven experimentally. Their introduction into clinical practice can significantly improve the prognosis of patients with GN. These methods allow, by determining the individual cytokine profile of the patient, with the help of monoclonal antibodies and macrophages stimulated by proinflammatory cytokines, to precisely correct disturbances in intercellular communication, selectively suppressing or activating certain factors, to eliminate imbalances in the course of the immunoinflammatory reaction in a particular patient. In the same way, it is possible to prevent the development of prosclerotic activity during GN.

Treatment of new-onset idiopathic NS begins with PZ at a dose of 2 mg/kg or 60 mg/m2, but not more than 80 mg/day. The response to therapy with PZ in MI is 90-95%, in FSGS - 20-22%, in MzPGN - about 7%.

With the development of remission of NS (usually within 1–4 weeks with MI), treatment at the maximum dose is continued for up to 6 weeks, then the intake of PZ is transferred to an alternating course at the rate of 1.5 mg/kg for 48 hours for 6 weeks, followed by a gradual (slow!) dose reduction over several months.

It must be remembered that the further course of idiopathic NS depends 90% on the correct treatment of the first episode. The following should be taken into account.

• Early initiation of treatment for PZ - no later than one month from the first signs of the disease - significantly reduces the risk of further development of exacerbation.
• Prescribing an adequate dose (2 mc/kg or 60 mg/m2) significantly reduces the risk of further development of exacerbation.
• The longer the treatment for the first episode, the lower the risk of further exacerbation.

Difficulties in treating patients with idiopathic NS may be associated with the following factors.

• Frequent relapses (more than two exacerbations in 6 months or more than four exacerbations per year). NSMI has a high probability of recurrence (up to 50%).
• Steroid dependence (exacerbation of nervous system when the dose of prednisolone is reduced or within 2 weeks after discontinuation of the drug).
• Steroid resistance.

Criteria for identifying steroid resistance: absence of remission of NS after treatment with PZ at a full dose of 2 mg/kg or 60 mg/m2 for 8 weeks or absence of remission of NS after treatment with PZ at a full dose for 6 weeks and three “pulses” of MP.

Steroid resistance suggests that the basis of idiopathic NS is not MI, but FSGS, MzPGN, or rarer variants of nephritis.

Identified steroid resistance serves as an indication for nephrobiopsy. Further treatment of NS is based on the morphological picture of GN.

Treatment of the first relapse of NSMI: PZ at a dose of 60 mg/m2 (2 mg/kg) until proteinuria disappears (absence of protein in three consecutive tests) + 3 days; then an alternating course - 1.5 mg/kg over 48 hours for 6 weeks; then slowly reduce the dose on an alternating course. In case of frequent relapses or the development of hormone dependence, therapy with cytostatics against the background of an alternating course of PZ or the appointment of CyA is advisable.

Principles of treatment for primary FSGS

Treatment for FSGS is initiated as therapy for idiopathic NS. Achieving remission with adequate therapy for PZ is a very good prognostic sign: the 10-year survival rate of such patients is about 95%.

When remission of NS is achieved, further treatment is similar to NSMI therapy.

When hormone resistance is established, nephrobiopsy is indicated. The actual treatment of FSGS in pediatric practice begins only at this stage, since before this, therapy for idiopathic NS is carried out (without morphological specification). The goal of FSGS therapy is to achieve remission (improved prognosis); if this fails, reducing proteinuria is the only chance to slow down the development of chronic renal failure. With proteinuria values ​​below 2 g/day, the 10-year survival rate of patients is about 90%; with nephrotic proteinuria (2.5–5.0) 10-year survival rate is about 45%; with proteinuria equal to or more than 14 g/day, the maximum lifespan of patients is approximately 6 years (without replacement therapy).

In adults, high doses of PZ (1 mg/kg/day) are used for at least 4 months, after which, in the absence of remission, the patient can be considered hormone-resistant. In pediatric practice, since the treatment of PZ was carried out before the biopsy and hormone resistance was proven, alkylating agents (cyclophosphamide) are added to the therapy against the background of an alternating regimen of taking PZ; “pulses” of MP or cyclophosphamide are possible. The combination of CS and GC in the treatment of FSGS gives the most pronounced effect: 10-year renal survival is about 80%, in contrast to monotherapy with GC (about 40%) or CS (about 20%). In adult patients, the dependence of the frequency of remissions in FSGS on the cumulative dose of GC is shown: with an 8-9 month course of GC, the remission rate is close to 100%.

Principles of treatment for MzPGN

Initially, treatment for MzPGN manifesting as NS is carried out in the same way as therapy for idiopathic NS.

There is no single approach to the treatment of morphologically established MzPGN (IgA nephropathy). Given the frequent hormone resistance of MzPGN, prednisolone and cytostatics (usually cyclophosphamide) are usually prescribed according to the same regimens as for FSGS.

General recommendations for the management of patients with IgA nephropathy.

• A kidney biopsy is a necessary condition for proper treatment.
• In cases of development of nephrotic syndrome, rapidly progressing renal failure, nephritis with crescents and vasculitis - treatment with corticosteroids in combination with or without cytostatics.
• Hypertension must be strictly controlled to prevent the patient from developing renal failure for as long as possible. Renoprotective treatment with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers (in combination with diuretics) is recommended.
• For successful treatment of MzPGN, it is necessary to sanitize foci of chronic infection (the elimination of which in itself reduces the frequency of relapses of the disease) and eliminate, if possible, the etiological factor (for example, the agliadine diet contributes to the reverse development of symptoms of IgA nephropathy in celiac disease).

Principles of therapy for MGUS

Immunosuppressive therapy for MGN is not indicated for patients without NS and with normal renal function. However, such patients should be under constant supervision. Correction of arterial hypertension (if it develops) and proteinuria (more than 1 g/day) is carried out by prescribing angiotensin-converting enzyme inhibitors, correction of hyperlipidemia - with the help of diet.

In the case of manifestation of MGN in the form of NS (or its later development), treatment is carried out as for idiopathic NS. With frequent recurrence of NS, hormone dependence or resistance to therapy, MP, chlorambucil or CyA are added (regimens of C. Ponticelli, de Santo, etc.). The combined use of GC and CA reduces the frequency of relapses in the future, although in order to achieve remission, the administration of GC with CS differs little in effectiveness from GC monotherapy.

When choosing therapeutic tactics for MGN, it is important to remember that, according to C. Ponticelli, MGN is a potentially curable disease.

Thus, immunosuppressive therapy serves as the basis for the pathogenetic treatment of idiopathic nephrotic syndrome. In addition to immunosuppressive therapy, dietary and regimen measures, sanitation of foci of chronic infection, treatment of intercurrent diseases, elimination of allergens, etc. are no less important. And yet, timely administration, adequate dose and duration of glucocorticoid therapy, which can be considered the main conditions for achieving remission, are favorable influence the prognosis of the disease.

Literature

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S. V. Belmer , Doctor of Medical Sciences, Professor A. V. Malkoch , Candidate of Medical Sciences, Russian State Medical University, Moscow

Symptoms

The main manifestation is massive swelling that begins with the eyelids and gradually covers the entire body. A rapid increase in edema is characteristic, when it occurs within a few days and sometimes hours.

The child becomes lethargic, weak, constantly thirsty, and has dry mouth. Nausea and vomiting occur, appetite decreases, and the amount of urine excreted sharply decreases. If fluid fills the abdominal cavity, then abdominal pain and palpitations begin.

If swelling does not go away for a long time, the skin becomes dry, peels, and cracks appear on it.

In severe cases, respiratory failure may develop.