Acute post-streptococcal glomerulonephritis in children

Acute poststreptococcal glomerulonephritis (acute glomerulonephritis, acute nephritis, postinfectious glomerulonephritis) is an immune complex disease with diffuse damage to the kidneys, primarily the glomeruli, which occurs 10-14 days after a streptococcal infection (tonsillitis, impetigo, scarlet fever, pyoderma, etc.) and is characterized by nephritic syndrome.

ICD-10 codes

• N00. Acute nephritic syndrome.
• N00.0. Acute nephritic syndrome with minor glomerular abnormalities.
• N04. Nephrotic syndrome.

Epidemiology of acute glomerulonephritis in children

The incidence of post-streptococcal glomerulonephritis averages 32.4 cases per 100,000 children. Most cases are sporadic; epidemic outbreaks are rare. In winter and spring, post-streptococcal glomerulonephritis is associated with acute respiratory viral infections, and in summer and autumn - with pyoderma. In recent decades, developed countries have seen a decrease in the incidence of glomerulonephritis to 10-15% of all glomerulonephritis, which is associated with improved socio-economic conditions. In developing countries, post-streptococcal glomerulonephritis is the cause of 40-70% of all glomerulonephritis. The peak incidence occurs in preschool and primary school age (5-9 years), less than 5% of children suffer from glomerulonephritis before the age of 2. Post-streptococcal glomerulonephritis is 2 times more common in boys. In recent years, the incidence of acute post-streptococcal glomerulonephritis has increased in Russia, which is associated with an increase in the frequency of streptococcal infections in children due to the emergence of strains resistant to the main antibacterial drugs used in clinical practice.

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Causes of acute glomerulonephritis in children

The etiological factor can be established in 80-90% of cases of acute glomerulonephritis and only in 5-10% of chronic cases.

The main etiological factors of acute glomerulonephritis

• Infectious.
  • Bacteria: group A beta-hemolytic streptococcus, enterococci, pneumococci, staphylococci, corynebacteria, klebsiella, salmonella, mycoplasma, yersenia, meningococci.
  • Viruses: hepatitis B, measles, Epstein-Barr, Coxsackie, rubella, chickenpox, cytomegalovirus, less often - herpes simplex virus.
  • Parasites: malaria plasmodia, toxoplasma, schistosomes.
  • Fungi: Candida.
• Non-infectious.
• Foreign proteins.
• Serums.

The most common cause of acute glomerulonephritis in children is a previous streptococcal infection, which is why all guidelines distinguish acute poststreptococcal GN. Most often, 1-3 weeks before acute glomerulonephritis, children suffer from tonsillitis, pharyngitis, skin infections, and less often, scarlet fever. These diseases are caused by beta-hemolytic streptococcus group A, most often M-type strains 1, 3, 4, 6, 12, 25, 49 after upper respiratory tract infections, as well as M-type strains 2, 49, 55 after skin infections. These types are called nephritogenic, of which strains 12 and 49 are the most common.

Other bacterial antigens cause disease less frequently.

Viral antigens cause the development of acute glomerulonephritis in children in a small percentage of cases. Puncture biopsy reveals viral antigens in deposits with immunofluorescence. Diseases caused by protozoa and fungi play an even smaller role in the etiology of AGN.

The resolving factors may be: cooling, excessive insolation, physical trauma.

The peak incidence of acute glomerulonephritis in children occurs in the autumn-winter period, at low temperatures and high humidity.

What causes acute glomerulonephritis?

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Pathogenesis of acute glomerulonephritis

In the pathogenesis of acute glomerulonephritis in children, two mechanisms can be distinguished: immune complex and non-immune complex.

Most true glomerulonephritides are immune complex, with soluble immune complexes "antigen-antibody" being deposited in the glomeruli. Immune complexes can form in the blood circulation - circulating immune complexes (CIC) - or in situ in the renal tissue. The formation of CIC is based on a protective mechanism aimed at removing the antigen. In conditions of excess antigen, antibody production increases, the size of the complexes increases, they activate the complement and are removed from the circulation by the mononuclear phagocytic system. Some of the immune complexes that have not been phagocytized are carried by the bloodstream to the kidneys and deposited in the glomerular capillaries, causing glomerulonephritis. There are other factors leading to the deposition of CIC:

• large endothelial surface of the glomerular capillaries;
• large volume of blood passing through the glomeruli;
• positive electric charge of the antigen, since complexes with a positively charged antigen are deposited on the negatively charged wall of the glomerular capillaries. Immune complex glomerulonephritides differ depending on the localization of immune complexes (IC), the class of immunoglobulins and the presence of complement components in the renal tissue.

Immune complexes can be formed and deposited in the kidney in different ways and in different structures of the glomeruli:

• from the circulation (CIC), while they are located subendothelially and/or in the mesangium;
• IK can be formed "in situ" by antibodies to glomerular antigens or to antigens not related to the glomerular basement membrane. In this case, IK are located subepithelially;
• These may be altered immunoglobulins rather than immune complexes. For example, the deposition of polymeric forms of immunoglobulin A in the mesangium.

Immune complexes attract inflammatory cells (neutrophils, monocytes, platelets) to the site of their deposition, which produce proinflammatory cytokines (IL-1, TNF, TGF-a). Cytokines activate the accumulation of vasoactive substances, which leads to damage, cracks, and increased permeability of the basement membranes. The kidney responds to the damage by proliferation of mesangial and endothelial cells. An inflammatory infiltrate develops. Damage to the capillary endothelium leads to local activation of the coagulation system and parietal thrombus formation, narrowing of the vascular lumen. As a result of inflammation, hematuria, proteinuria, and renal dysfunction occur. A picture of acute proliferative GN develops, often with a clinical picture of ANS.

In non-immunocomplex glomerulonephritis, cell-mediated immune reactions develop. In this case, the leading role is given to the emergence of a pathological clone of T-lymphocytes, which stimulates hyperproduction of lymphokines that damage the glomerulus.

A pathological clone of T lymphocytes may exist as a primary defect or arise under the influence of immune complexes that are not localized in the glomerulus but have the ability to activate a pathological clone of T lymphocytes. Dysfunction of T cells promotes hyperproduction of vasoactive interleukin. The object of action of cytokines are the epithelial cells of the glomerulus, responsible for the synthesis of negatively charged proteoglycans and sialoproteins, which are part of the glomerular basement membranes. This leads to the loss of the negative charge on the basement membrane (BM) and podocytes. Direct effect of neuraminidase, a virotoxin, on the BM is also possible. Loss of the negative charge on the BM and podocytes leads to selective loss of large volumes of finely dispersed proteins (mainly albumins). Expressed proteinuria causes the development of a clinical and laboratory syndrome called nephrotic syndrome (NS).

Pathomorphology of acute glomerulonephritis

Acute poststreptococcal glomerulonephritis in children is characterized by a diffuse endocapillary proliferative process. The glomerulus shows proliferation of mesangial and endothelial cells. The capillary loops in the glomeruli appear swollen, with thickened walls. The lumen of the capillaries is narrowed. In the first 4 weeks of the disease, inflammatory cells are present in the glomerulus: neutrophils, eosinophils, lymphocytes, macrophages. Proliferation of epithelial cells is minimal. The subcapsular space also narrows. The BM are thickened or thinned, and ruptures are found in them.

Electron microscopy shows large deposits in the form of humps (IR+C+), located on the inner or outer side of the BM and, less often, inside it in the form of lumpy deposits.

During immunohistological examination, complement components, various immunoglobulins (B, M, A, E), streptococcal antigens or other antigens are determined in the deposits.

The morphological variant of acute glomerulonephritis with nephrotic syndrome most often manifests itself in children with minimal changes. They are called the disease of "small legs of podocytes". Light microscopy does not allow detecting pathology. Only the introduction of electron microscopy made it possible to study changes in podocytes. Electron microscopy reveals severe changes in podocytes in the form of deformation, fusion and loss of small legs along the entire length of the capillary wall. Merging with each other, small legs form a layer of uneven thickness that covers the BM.

The BM remains unchanged, retains its structure and thickness. Protein and fatty degeneration is expressed in the cells of the tubular epithelium. This is due to the overload of the tubular epithelium with massive proteinuria and lipiduria. Glucocorticoid therapy leads to normalization of the podocyte structure.

Acute glomerulonephritis with nephritic syndrome

Acute nephritic syndrome (ANS) is a classic manifestation of acute glomerulonephritis. Most often, children of school age from 7 to 14 years old fall ill. ANS develops 1-6 weeks after an infection (usually streptococcal). In the latent period, the condition of children remains satisfactory. Often they begin to attend school, but then deterioration occurs again: lethargy, malaise, loss of appetite.

The main criteria for the diagnosis of acute glomerulonephritis with nephrotic syndrome:

• moderate edema with normal protein and albumin levels against the background of increased BCC;
• arterial hypertension;
• urinary syndrome in the form of macro- or microhematuria, proteinuria less than 2 g/day, non-selective in nature.

The onset of the disease can be rapid, acute, with a classic triad of symptoms: edema, arterial hypertension, macrohematuria. Children complain of malaise, headache, nausea, vomiting, change in urine color, and a decrease in its amount. The severity of these symptoms varies.

Less often, the disease develops gradually with scant clinical and laboratory changes.

During examination, swelling of the eyelids, shins, and paleness of the skin due to vascular spasm are always detected. Vascular spasm is also expressed in the retina of the fundus. Patients may complain of headache and lower back pain, which is explained by stretching of the renal capsule due to their swelling.

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Pathogenesis of the main symptoms in acute nephritic syndrome

Edema

Edema is one of the main manifestations of ANS and occurs in 60-80% of patients. The severity can vary widely: from swelling of the eyelids in the morning to severe swelling of the face, shins, and anterior abdominal wall. Very rarely, cystic edema can develop: hydrothorax, hydropericardium, ascites. During the period of increasing edema, patients can gain 2-5 kg in weight. Edema appears gradually. They are dense and slightly mobile.

The mechanism of edema formation:

• an increase in the volume of circulating blood as a result of a decrease in glomerular filtration - hypervolemia;
• sodium and water retention (hyperaldosteronism, increased secretion of ADH);
• increased vascular permeability as a result of the hyaluronidase activity of streptococcus, the release of histamine and the activation of the kallikrein-kinin system.

The formation of peripheral edema can be considered as a compensatory mechanism, since some of the fluid from the vascular bed moves into the tissues, reducing hypervolemia, and this prevents the development of complications. Enlargement of the liver and spleen can also be associated with fluid deposition. Edema is usually easily relieved by prescribing a salt-free diet and diuretics. The duration of edema is 5-14 days.

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Arterial hypertension

Arterial hypertension is one of the formidable symptoms of acute glomerulonephritis (AGN) - it occurs in 60-70% of patients. Patients complain of headache, nausea, vomiting. Arterial hypertension develops quickly. It is most often associated with complications: eclampsia and acute heart failure. Arterial hypertension is systolic-diastolic in nature, but with a large increase in systolic pressure. The mechanism of arterial hypertension in AGN:

• hypervolemia, i.e. an increase in the volume of circulating blood (VCB), occurs due to a decrease in glomerular filtration, water and sodium retention;
• Activation of the renin-angiotensin-aldosterone system plays a much smaller role.

Since the main mechanism of arterial hypertension development is hypervolemia, it is easily treated (salt-free diet, diuretics), and antihypertensive drugs are less often required. Drugs that increase the BCC should not be administered. The duration of the hypertensive syndrome is 7-14 days.

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Urinary syndrome

Oliguria is a decrease in normal diuresis by 20-50% of the norm. Oliguria occurs due to a decrease in glomerular filtration and increased reabsorption of water and sodium, the development of "antidiuresis" and increased secretion of ADH. The relative density of urine is high. Oliguria occurs in the first days of the disease and lasts 3-7 days.

Hematuria is one of the main manifestations of urinary syndrome and occurs in 100% of patients. Macrohematuria is detected at the onset of the disease in 60-80% of patients, its severity gradually decreases by the 3rd-4th week. In the majority of patients, hematuria completely stops by the 8th-10th week, but in some, microhematuria remains for 6-12 months.

Hematuria is associated with increased permeability of the BM, its ruptures. Dysmorphic erythrocytes (changed, irregularly shaped) appear in the urine, which is due to their glomerular origin. Erythrocyte casts may also be encountered.

Proteinuria is one of the leading signs of kidney damage, in all cases it is necessary to establish the daily loss of protein. Normally, it is 100-200 mg/day. In ANS, daily proteinuria fluctuates between 1 and 2.5 g/day. The protein lost in the urine is of plasma origin and contains small and large proteins, i.e. proteinuria is non-selective. The leading mechanism of proteinuria is structural changes in the basement membrane (increased pore size, cracks) and functional changes (loss of negative charge). Proteinuria gradually decreases by the 2nd-3rd week of the disease. Long-term proteinuria up to 1.5-2 g/day is a poor prognostic sign.

Leukocyturia in ANS may occur in the first week of the disease and is of abacterial nature. It is explained by active immune inflammation with the involvement of neutrophils, lymphocytes, and monocytes in the inflammation focus in the 1st-2nd week.

Cylindruria may be present (30-60%) in the initial period. Structurally, the cylinders are tubular protein (Tamm-Horsfall uroprotein) with inclusion of formed elements, epithelial cells, and detritus. With AGN, erythrocyte, granular cylinders may appear.

Pathogenesis of acute glomerulonephritis

Symptoms of acute glomerulonephritis in children

The course of ANS is usually cyclical, with a gradual decrease in clinical and laboratory parameters.

First of all, clinical symptoms disappear, in the first week of the disease diuresis and blood pressure are normalized, edemas disappear, the concentration of urea and creatinine decreases. Normalization of the amount of complement occurs by the 6th-8th week, the disappearance of changes in urine sediment occurs more slowly. Macrohematuria disappears in 2-3 weeks, proteinuria - within 3-6 months, the disappearance of microhematuria occurs within a year.

Symptoms of acute glomerulonephritis

Classification

Clinical classification of acute glomerulonephritis

Clinical manifestations of acute poststreptococcal glomerulonephritis	Activity of the pathological process	Status of kidney function
Nephritic syndrome (NS) Isolated urinary syndrome Nephritic syndrome with hematuria and arterial hypertension	The period of initial manifestations. Period of reverse development. Transition to chronic glomerulonephritis	Without renal impairment. With impaired renal function. Acute renal failure

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Diagnosis of acute glomerulonephritis in children

In addition to the clinical picture, laboratory diagnostics are of great importance for making a diagnosis.

In the general blood test in the first days of the disease, anemia associated with hypervolemia, i.e. relative anemia, may be diagnosed. Slight leukocytosis and increased ESR may be detected.

The etiologic role of streptococcus is confirmed by an increase in the concentration of ASL-O, as well as the isolation of hemolytic streptococcus from the pharynx and nose.

An increase in the content of CRH and seromucoid indicates inflammation, and an increase in the amount of CIC, immunoglobulins (G, M), a decrease in the concentration of the complement component C3 indicate its immune nature. The content of total protein and albumin may be slightly reduced, and cholesterol - increased.

In the initial period of oliguria, an increase in the concentration of urea and creatinine is possible with a high specific gravity of urine, which is regarded as acute renal failure.

Ultrasound diagnostics reveal an increase in the size of the kidneys and a violation of the differentiation of structures.

Diagnosis of acute glomerulonephritis

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Indications for consultation with other specialists

In case of persistent arterial hypertension, an ophthalmologist consultation is necessary to examine the fundus of the eye in order to exclude retinal vascular angiopathy. An otolaryngologist consultation is necessary if chronic tonsillitis or adenoiditis is suspected to select a treatment method (conservative, surgical). If the child has carious teeth, a dentist consultation is necessary to sanitize the oral cavity.

Treatment of acute glomerulonephritis in children

General principles of treatment of acute post-streptococcal glomerulonephritis include adherence to a regimen and diet, etiotropic and pathogenetic therapy depending on the characteristics of the clinical course and complications of the disease.

Indications for hospitalization

In case of persistent arterial hypertension, severe proteinuria, decreased functional state of the kidneys, prolonged macrohematuria, it is necessary to hospitalize the child for differential diagnosis with other types of glomerulonephritis, optimal treatment, and determination of the functional state of the kidneys over time.

Non-drug treatment of acute glomerulonephritis

In acute post-streptococcal glomerulonephritis with nephritic syndrome and arterial hypertension, it is necessary to observe bed rest until blood pressure is normalized (>1 week). As the patient feels better and blood pressure decreases, the regimen is gradually expanded.

It is necessary to limit the intake of fluids, table salt and protein. Fluids are prescribed based on the diuresis of the previous day, taking into account extrarenal losses (approximately 500 ml for school-age children). When normal blood pressure is achieved and edema syndrome disappears, salt intake is gradually increased starting from 1 g/day. Limiting the consumption of animal proteins (up to 0.5 g/kg per day) is necessary for no more than 2-4 weeks until the concentration of creatinine and urea in the blood is normalized.

In isolated urinary syndrome without extrarenal manifestations of acute poststreptococcal glomerulonephritis, there is usually no need to limit the regimen and diet. Table No. 5 according to Pevzner is prescribed.

Drug treatment of acute glomerulonephritis

For arterial hypertension in children with acute poststreptococcal glomerulonephritis, thiazide diuretics and calcium channel blockers are used as antihypertensive agents.

Of the thiazide diuretics, furosemide is used orally (IM or IV as indicated) at 1-2 mg/kg of body weight 1-2 times a day, if necessary, the dose is increased to 3-5 mg/kg. Of the calcium channel blockers, nifedipine is used sublingually at a dose of 0.25-0.5 mg/kg per day, dividing the total dose into 2-3 doses, or amlodipine orally at 2.5-5 mg 1 time per day, until blood pressure is normalized. If kidney function is preserved and there is no hyperkalemia, as well as in case of insufficient effectiveness of calcium channel blockers, ACE inhibitors are prescribed: captopril orally at 0.5-1.0 mg/kg per day in 3 doses or enalapril orally at 5-10 mg/kg per day in 1-2 doses.

As antihypertensive agents in adolescents with acute streptococcal glomerulonephritis, it is possible to use angiotensin II receptor blockers (losartan orally 25-50 mg once a day, valsartan orally 40-80 mg once a day). Beta-blockers are used much less frequently in children.

Regardless of the clinical course of the disease, it is necessary to carry out antibacterial therapy taking into account the sensitivity of the streptococcal flora. Most often, penicillin antibiotics are used: amoxicillin orally at a dose of 30 mg / kg per day in 2-3 doses for 2 weeks or amoxicillin + clavulanic acid orally at 20-40 mg / kg per day in 3 doses for 2 weeks (amoxiclav, augmentin, flemoklav solutab). The second course is optimally used macrolides of the II or III generation:

• josamycin orally 30-50 mg/kg per day in 3 doses for 2 weeks;
• midecamycin orally 2 times a day before meals: children under 12 years old 30-50 mg/kg per day, children over 12 years old 400 mg 3 times a day for 7-10 days;
• roxithromycin orally 5-8 mg/kg per day 2 times a day for no more than 10 days.

The duration of antibacterial therapy is 4-6 weeks. Some specialists prescribe bicillin-5 intramuscularly for 4-5 months:

• for children of preschool age, 600,000 IU once every 3 weeks;
• children over 8 years old - 1,200,000 IU once every 4 weeks.

In case of severe hypercoagulation with an increase in the concentration of fibrinogen in the blood of more than 4 g/l, the following is used:

• antiplatelet agents - dipyridamole orally at 5-7 mg/kg per day in 3-4 doses on Snake;
• anticoagulants:
• sodium heparin 200-250 U/kg per day 4 times a day subcutaneously;
• low molecular weight heparins - calcium nadroparin (subcutaneously once a day at a dose of 171 IU/kg or 0.01 ml/kg for a course of 3-4 weeks), sodium dalteparin (subcutaneously once a day at a dose of 150-200 IU/kg, a single dose should not exceed 18,000 IU, a course of 3-4 weeks).

Patients with nephrotic syndrome that persists for more than 2 weeks, a stable increase in the concentration of creatinine in the blood (without a tendency to increase or normalize) in the absence of the possibility of performing a kidney biopsy should be prescribed prednisolone orally at a dose of 1 mg/kg per day (for children under 3 years old <2 mg/kg per day) for 2-3 weeks until kidney function is restored.

How is acute glomerulonephritis treated in children?

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Surgical treatment of acute glomerulonephritis

Tonsillectomy is necessary:

• for chronic tonsillitis;
• established connection between glomerulonephritis and exacerbation of chronic tonsillitis or angina;
• increased activity of ASLO in the blood and a positive result of a throat swab for hemolytic group A streptococcus.

Tonsillectomy is performed no earlier than 8-12 weeks from the onset of acute poststreptococcal glomerulonephritis.

How to prevent acute glomerulonephritis in a child?

Timely diagnosis and treatment of streptococcal diseases. Treatment of angina for at least 10 days with antibiotics. Sanitation of chronic foci of infection. Urine analysis after acute angina and exacerbation of chronic tonsillitis in the second-third weeks after streptococcal infections for the purpose of early diagnosis of possible acute glomerulonephritis.

Prognosis for acute glomerulonephritis in children

In 90-95% of children with acute poststreptococcal glomerulonephritis with nephritic syndrome, the manifestations of the disease gradually decrease and the edema syndrome disappears within 5-10 days, blood pressure normalizes within 2-4 weeks from the onset of the disease, hematuria disappears and kidney function is restored. In less than 1% of patients, the symptoms of the disease progress to the development of chronic renal failure.

One of the main factors of progression is tubulointerstitial changes:

• decrease in the optical density of urine;
• leukocyturia;
• decrease in the osmotic concentration function;
• increased urinary excretion of fibronectin - 0.040 g/day for focal lesions, 0.250 g/day for diffuse lesions;
• Ultrasound-documented presence of hypertrophied renal pyramids;
• resistance to pathogenetic therapy.

Outpatient observation

After discharge from the hospital, the patient is sent to a local sanatorium for patients with kidney diseases. After discharge from the sanatorium, the child is monitored by a pediatrician and a nephrologist - once a month in the first year, once a quarter in the second year. An examination by an ENT doctor and a dentist is required once every 6 months. During any intercurrent illness, urine testing and blood pressure measurement are mandatory.

Outpatient observation is carried out for 5 years. By the end of this period, a comprehensive examination with functional renal tests in a hospital or diagnostic center is necessary. If there are no deviations from the norm according to the results of the study, the child can be considered recovered and removed from the outpatient register.

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