Nephrology for General Practitioners - O.I. Bakaliuk 2003

Pediatric Nephrology
Glomerulonephritis in Children

Among various pediatric Kidney diseases, Glomerulonephritis (GN) holds a special place. This is due to multiple factors, including their incidence, severity, uncertain prognosis, Treatment complexity, the rising frequency of latent and chronic forms, early decline in renal function, and The Development of Chronic Kidney Disease (CKD) (K.M. Sergeyeva, 1999). It should be emphasized that managing the active phase of GN in children is the prerogative of specialized pediatric departments; therefore, we will limit our Structure/133.html">Discussion to the underlying principles and Characteristics of Specific drug groups (glucocorticoids, immunosuppressants, antihypertensives, NSAIDs, and membrane stabilizers).

The clinical Classification of GN involves categorizing it by form (hematuric, nephrotic, mixed), course (acute, chronic, rapidly progressive), phase (active with periods of initial flare-up, remission, and inactive), and the degree of renal impairment (preserved, partial impairment, Acute Kidney Injury [AKI], or CKD).

Acute glomerulonephritis. This term refers to a form of renal pathology that develops acutely following an infection. It is characterized by well-defined clinical symptoms, a cyclical course, and the achievement of clinical and laboratory remission in 50–60% of cases. At the same time, most pediatric nephrologists recommend a very cautious approach regarding the likelihood of a child's complete recovery from acute GN.

The onset of acute GN is not exclusively linked to streptococcal infection; in the majority of cases (52%), it is preceded by acute respiratory viral infections, Influenza, or Pneumonia (N.A. Korovina et al., 1990). In some instances, acute GN may develop following hypothermia, vaccination, or the ingestion of food additives and Dyes.

It should be noted that the manifestation of a particular form of GN depends to some extent on the child's age.

Thus, the hematuric form of GN typically occurs in children over 5 years of age. It often presents with massive edema, oliguria, hyperthermia, and Hypertension. Urinalysis reveals macroscopic Hematuria, proteinuria (within 1–3 g/day), and mild leukocyturia (neutrophiluria). An elevated ERYTHROCYTE SEDIMENTATION RATE (ESR), hyper-alpha₂-globulinemia, and hypergammaglobulinemia are also observed.

The nephrotic form is more common in boys aged 1–7 years. The predominant features are edema syndrome (sometimes reaching anasarca) and endogenous Intoxication syndrome. Arterial hypertension (AH) is rare; proteinuria is selective, ranging from 5–20 g/day. Hematuria usually presents as microhematuria, while Blood tests reveal a significantly accelerated ESR (up to 60–70 mm/h), hypoalbuminemia, dysproteinemia, hyperlipidemia, and a tendency toward blood hypercoagulation.

In the mixed form of GN, which is more frequently seen in children aged 10–12 years, arterial hypertension syndrome is dominant. Edema syndrome and blood test abnormalities vary in severity. The disease progresses relentlessly, and renal filtration function declines rapidly.

Considering certain differences in Pathogenesis—and consequently in therapeutic strategies—acute poststreptococcal and acute non-streptococcal GN are distinguished.

Acute poststreptococcal GN most commonly develops following tonsillitis, other Upper Respiratory Tract infections, or certain Skin infections. Group A beta-hemolytic streptococci, specifically M-types (most frequently strains 3, 4, 6, 12, and 49 after respiratory infections, and strains 2, 55, 56, 57, and 60 after skin infections), are considered the etiologic factors. The disease is most prevalent in children aged 5–12 years, as well as in adolescents (6–20 cases per 100,000 population).

Acute poststreptococcal GN is considered a classic example of immune-complex pathology, in which circulating immune complexes formed in the bloodstream are secondarily trapped on the glomerular capillary basement membrane (BM). However, as early as 1986, C. Lange et al. isolated a positively charged antigen, named endostreptosin, from Cell/30.html">The Plasma Membrane of nephritogenic streptococcal strains. Therefore, it is now believed that the pathogenesis of this type of GN is also associated with the penetration of this soluble, positively charged streptococcal antigen through the negatively charged glomerular capillary BM, followed by The formation of immune complexes directly on the BM (in situ).

The process of immune complex formation within the BM can be potentiated by IMMUNOGLOBULINS G altered by streptococcal toxins, and by the direct activation of The Complement System via The alternative pathway by specific streptococcal factor D against the Background of genetic predisposition (HLA-Drw 4 antigen).

Signs of renal involvement typically appear after a fairly long interval following a respiratory infection or tonsillitis (6–21 days) or a skin infection (18–21 days). If the interval between the streptococcal infection and the onset of GN is less than four days, the underlying cause is most frequently unrelated to this factor.

The onset of the disease is usually gradual, characterized by fatigue, loss of appetite, and headache. Subsequently, edema (most often facial), transient macrohematuria (60–90%), and arterial hypertension (20–45%) develop. In some cases, poststreptococcal GN begins abruptly with symptoms of acute kidney injury, hypertensive encephalopathy, or acute left ventricular failure. Urinalysis shows hematuria and cylindruria (granular and erythrocyte casts). Non-selective proteinuria rarely exceeds 2–3 g/day. Creatinine clearance, tubular reabsorption, and urine output are reduced, while relative urine density is increased. Blood tests reveal an accelerated ESR, anemia, leukocytosis, moderate hypercreatininemia, hyponatremia, elevated anti-streptococcal antibody titers, and a tendency toward hypercoagulation.

For acute poststreptococcal GN, supportive therapy in a hospital Setting is recommended, centered on an appropriate regimen, diet, and antibacterial therapy.

Criteria for discontinuing strict bed rest (usually 2–3 weeks) include the resolution of edema, normalization of blood pressure, and a reduction in proteinuria and hematuria by at least 10-fold.

In cases of arterial hypertension and edema, dietary sodium chloride is restricted; for oliguria, fluid intake is limited; and for hyperkalemia, fruit juices are restricted.

Antibiotics, typically Semisynthetic Penicillins, are prescribed for a 10–14-day course; the advisability of prolonged antibiotic administration (e.g., benzathine benzylpenicillin for 4–6 months) remains unresolved. Children with chronic tonsillitis should be advised to undergo tonsillectomy during a period of remission.

Diuretics (usually furosemide or ethacrynic acid) are recommended for massive edema accompanied by fluid restriction in the daily diet (down to 700–800 mL/m² of body surface area).

The presence of arterial hypertension serves as an indication for antihypertensive therapy (excluding ACE inhibitors and angiotensin II receptor type 1 blockers), while hypertensive encephalopathy calls for diazepam, and hyperkalemia requires a glucose-Insulin mixture and calcium gluconate.

Acute kidney injury, which in this context arises exclusively from local activation of the Blood Coagulation SYSTEM, requires the administration of anticoagulants and antiplatelet agents—heparin (intravenous drip at 100–200 IU/kg of body weight over 4 hours) every 12 hours, low-molecular-weight heparins, dipyridamole, pentoxifylline, or ticlopidine.

In acute non-streptococcal GN, the infection is identifiable in the body prior to the onset of the disease; thus, it is a bacterial rather than an immune-mediated condition with a more serious prognosis. These forms of GN are caused by various pathogens (Bacteria, Viruses, Protozoa, parasites, and Molds).

The most frequent causative agents are *Streptococcus viridans*, *Staphylococcus albus*, *Staphylococcus aureus*, *Bacillus subtilis*, *Listeria monocytogenes*, and viruses—particularly herpes simplex, hepatitis B and C, and enteroviruses (K.M. Sergeyeva et al., 2000). According to L.N. Gorchakova et al. (2000), Herpes simplex virus type 1 is detected in 86% of children with acute non-streptococcal GN, including isolated detection in 27% and in combination with cytomegalovirus in 59%, with these cases frequently developing a chronically relapsing disease course.

According to N.A. Korovina et al. (1996), there is currently an increasing incidence of acute GN associated with enteroviral and yersinial infections. Furthermore, a worsening of its clinical course is noted, characterized by an increasing number of children experiencing acute-period renal involvement and The addition of a tubulointerstitial component.

The clinical picture is characterized by endogenous intoxication syndrome, hyperthermia, lymphadenopathy, Splenomegaly, anemia, and frequently Nephrotic Syndrome.

Given similar clinical and laboratory symptoms, the Diagnosis of acute non-streptococcal GN primarily comes down to ruling out acute post-streptococcal GN. This is essential because, while non-streptococcal GN follows the same dietary, regimen, and symptomatic treatment requirements as acute streptococcal GN, its management relies on prolonged, aggressive antibiotic therapy using at least two different classes of antibiotics.

Prognostically unfavorable factors contributing to the chronicity of both subtypes of acute GN in children include a family history of kidney disease, the development of GN against the background of congenital or acquired renal pathology (cysts, Nephroptosis, renal agenesis) and functional urodynamic disorders (bladder atony, Urinary Tract dyskinesia), the presence of chronic infection foci, and prolonged arterial hypertension (AH) syndrome (M.S. Basalaeva, 2000).

Rapidly progressive GN (synonyms: extracapillary proliferative, subacute malignant, crescentic GN) occurs in 1–2% of cases. Its common morphological feature is extracapillary proliferation of cellular elements combined with pronounced local hypercoagulation. In 50% of children, the history (4–6 weeks before the onset of the disease) reveals previous acute respiratory infections, viral Infections caused by influenza A₂ virus or paramyxovirus, or contact with nephrotoxic substances or medications.

The clinical picture is characterized by marked skin pallor, nephrotic syndrome, oliguria, and less frequently, anuria; arterial hypertension is moderately pronounced. Proteinuria is of a non-selective nature; the urinary sediment shows micro- or macrohematuria and cylindruria (granular casts). The relative urine density is high, and the Glomerular Filtration rate progressively decreases from the very onset of the disease. Blood tests reveal hypercreatininemia, leukocytosis, anemia, thrombocytosis, elevated circulating immune complexes (CICs), cryoglobulinemia, and occasionally thrombocytopenia and hemolytic anemia.

An unfavorable prognosis for rapidly progressive GN is indicated by onset in adolescence, hypercreatininemia, oliguria, and proteinuria exceeding 3 g/day.

Goodpasture's syndrome is an independent form of rapidly progressive GN in childhood. Notably, boys are affected more often (9:1). From a etiopathogenic perspective, it involves the formation of Antibodies against the glomerular basement membrane (BM), which localize linearly along the BM of glomerular and pulmonary capillaries. A specific clinical feature of Goodpasture's syndrome in children is the rapid development of renal failure from the moment renal symptoms appear.

Treatment of rapidly progressive GN should be initiated as early as possible. It is primarily based on Pathogenetic Therapy using glucocorticoids and cytostatics. Glucocorticoids (most commonly prednisolone) are prescribed at a dose of 20–30 mg/kg of body weight/day intravenously, every other day, for 3–6 doses; cytostatics (cyclophosphamide, azathioprine) are given at 1 mg/kg of body weight/day. Combining them is considered appropriate as it allows for lower daily doses of these drugs while achieving a better clinical effect and reducing side effects. Maintenance doses of these agents must be prescribed for a prolonged period (months, years). Such treatment can be combined with anticoagulants (heparin at 200–500 mg/kg of body weight/day for 10–12 days, followed by a transition to low-molecular-weight heparins) and antiplatelet agents.

Anticoagulant therapy is not indicated for Goodpasture's syndrome.

Among apheresis techniques, plasmapheresis is used.

Chronic GN is a heterogeneous group of kidney diseases in terms of Etiology, pathogenesis, and Morphology, characterized by a slowly progressive course with prolonged (years-long) remissions, increasing destruction and sclerosis of nephrons and the interstitium, and the inevitable development of chronic renal failure (CRF). Notably, sclerotic changes are detected in nephron biopsies in 49.6% and 62.6% of children with chronic GN as early as 2 and 5 years after disease onset, respectively (B.G. Makarets et al., 2000).

The three most common forms of chronic GN include chronic non-specific GN, membranoproliferative GN, and membranous GN, which, apart from morphological features, also have specific clinical characteristics.

It is reasonable to acknowledge the well-substantiated view that the development of chronic non-specific GN is not a consequence of a prior acute post-streptococcal GN. Morphological changes are characterized by cellular proliferation, diffuse glomerular sclerosis, and tubulointerstitial sclerosis.

Chronic non-specific GN has no distinct clinical pathognomonic signs. The onset of the disease is often insidious, presenting with endogenous intoxication syndrome, anemia, arterial hypertension, mild dysuric disorders, and less frequently, nephritic or nephrotic syndromes. Remissions are prolonged; sometimes an exacerbation of symptoms occurs following an intercurrent infection, which may be misinterpreted as acute GN. The urinary syndrome is characterized by proteinuria combined with hematuria and varying degrees of cylindruria, often punctuated by prolonged periods of asymptomatic proteinuria and hematuria.

The diagnosis of chronic non-specific GN is based on a detailed analysis of clinical symptoms and dynamic monitoring data reflecting the glomerular filtration rate and the concentration function of the Kidneys—specifically, their steady decline as the disease progresses. Ultrasound examination (reduction in kidney size) and isotope Methods (parenchymal renogram type) can provide valuable diagnostic information.

The foundation of treatment for chronic non-specific GN is symptomatic therapy, similar to that for acute post-streptococcal GN (bed rest during the acute phase, appropriate diet, antihypertensive drugs, diuretics, antiplatelet agents, and antioxidants). The prescription of glucocorticoids and cytostatics for this pathology must be preceded by a renal biopsy and a careful risk-benefit analysis compared to the overall prognosis of the disease.

In membranoproliferative (mesangiocapillary, lobular) GN, alterations in the glomerular capillary basement membrane and mesangial structures predominate. Its pathogenesis involves the formation of circulating or local immune complexes, alternative pathway complement activation, enhanced platelet aggregation with Excessive production of thromboxane, and platelet-derived growth factor. The deposition of immune complexes in the mesangium triggers mesangial cell proliferation followed by sclerosis of glomerular structures. Glomerular sclerosis progresses at a rate of 3.5% per year, meaning that 10 years after disease onset, only 40–50% of children remain alive.

Membranoproliferative GN frequently begins with acute nephritic (40%) or acute nephrotic (50%) syndromes.

Acute Nephritic Syndrome is characterized by facial and lower extremity edema combined with macrohematuria, arterial hypertension, proteinuria, and cylindruria. Unlike acute post-streptococcal GN, these symptoms are significantly more pronounced and persist longer, serving as an important differential diagnostic criterion between these two pathological forms.

In acute nephrotic syndrome in children, massive edema progressing to anasarca is observed, along with heavy, non-selective, hormone-resistant proteinuria and prolonged, persistent arterial hypertension. In one-third of children, renal function declines in the early stages, and clinical signs of nephrotic syndrome persist even at the stage of chronic renal failure.

Treatment of membranoproliferative GN involves pathogenetic agents (Hormones, cytostatics, antiplatelet agents) alongside symptomatic measures (appropriate diet, diuretics, antihypertensives, and antioxidants).

According to G.-D. West (1986), hormones (prednisolone) are administered every other day at a dose of 1.5–2 mg/kg of body weight/day (maximum 80 mg/day) for one year, followed by a taper to 0.5 mg/kg of body weight/day, every other day, for 4–5 years.

Cytostatic drugs (1 mg/kg of body weight/day) are also used for prolonged periods (years), adhering to the maintenance-dose principle.

Antiplatelet agents (dipyridamole at 75–225 mg/day, aspirin at 0.1–0.3 g/day) are prescribed for 6–18 months.

Glucocorticoid resistance can be mitigated by performing several plasmapheresis sessions.

The development of end-stage renal failure is an indication for kidney transplantation.

Membranous GN is characterized by focal alterations in the glomerular capillary basement membrane, specifically its diffuse thickening due to the accumulation of subepithelial deposits. This also represents a classic example of immune-complex GN featuring local immune complex formation, yet without a prominent reaction of the renal mesangial structures.

A distinction is made between primary (idiopathic) membranous GN—where the causative antigen of the immune complexes remains unknown—and secondary membranous GN, which develops in association with various underlying systemic conditions. Notably, secondary membranous GN can be triggered by infectious diseases (hepatitis B and C, latent HBsAg antigenemia, infective endocarditis), immune-mediated disorders (collagenoses, sarcoidosis, vasculitis, thyroiditis, Guillain-Barré syndrome, Weber-Christian disease, Berger's disease), metabolic abnormalities (Diabetes Mellitus, primary biliary cholangitis), hematological malignancies (leukemias, Hodgkin's lymphoma, non-Hodgkin's lymphomas), as well as tubular dysfunctions (Fanconi Syndrome, tubulointerstitial nephritis).

Membranous GN develops insidiously; for a long time, the disease remains asymptomatic and is usually discovered incidentally during the investigation of significant proteinuria. In a subset of cases (10-30%), membranous GN manifests as acute nephrotic syndrome. Non-selective, persistent proteinuria with a progressive tendency is frequently accompanied by microhematuria, whereas arterial hypertension is uncommon. Overall, the condition follows a slowly progressive course, with chronic renal failure documented in 50% of children within 10-15 years of disease onset.

The management of primary membranous GN remains somewhat controversial, although the necessity of pathogenetic therapy coupled with an appropriate diet providing 1 g of protein/kg of body weight per day is well established.

Prednisolone is recommended at a dosage of 40 mg/m²/day administered as a single morning dose, or alternatively, 100-200 mg/day on an alternate-day schedule. In cases resistant to this regimen, methylprednisolone therapy at 10-20 mg/kg of body weight/day is employed. Treatment outcomes improve when combined with cytostatic agents (1-3 mg/kg of body weight/day), achieving remission in 56% of cases. In secondary membranous GN, the prognosis depends primarily on the efficacy of treating the underlying disorder.

Thus, the treatment of all forms of GN in children should be supported by appropriate lifestyle modifications, dietary measures, vitamin therapy, antibiotic administration, and antihistamines.

Bed rest is recommended until extrarenal signs completely resolve and a clear positive trend in the urinary syndrome is achieved.

During the first few days of the illness, in the presence of edema and hypertension, Dietary intake of meat and common salt is restricted. It is recommended to provide the child with rice or buckwheat porridge, jam, sugar, vegetable puree, vegetable soup, croutons, lemon with sugar, and butter. As the child's condition improves, boiled meat, fruit salads, and sodium chloride (1-3 g/day) are gradually reintroduced into the menu. Smoked products, rich meat and fish broths, coffee, canned goods, and spices are excluded from the diet. The required fluid intake is calculated based on the previous day's diuresis plus 0.25 L/m² of the child's body surface area.

As previously mentioned, augmenting this therapeutic regimen with glucocorticoids, cytostatics, or membrane stabilizers depends on the specific clinical form of glomerulonephritis (Table 8; N.A. Korovina et al., 1990, 1996).

Class="center">Use of specific drug groups depending on the clinical form of GN

Among immunosuppressants, cyclosporine A (Sandimmune) has found widespread application in Pediatric Nephrology, particularly in children with renal transplants and steroid-dependent nephrotic syndrome (P.F. Hoyer et al., 1999). It is generally accepted that post-renal transplantation, the trough blood concentrations of Sandimmune should range between 150 ng/mL and 250 ng/mL. In triple-drug regimens comprising Sandimmune, azathioprine, and prednisolone, the dosage of Sandimmune may be reduced to 100-120 ng/mL, which significantly mitigates its nephrotoxicity.

Currently, Sandimmune is not recommended as a first-line treatment for all variants of nephrotic syndrome; however, it can be used as a substitute for prednisolone in cases of steroid-dependent or poorly responsive minimal-change nephrotic syndrome. The initial dose of Sandimmune should be 150 mg/m²/day (divided into two doses), and discontinuation is typically considered after 6 months to evaluate whether ongoing administration remains necessary.

For long-term therapy (spanning years), a gradual tapering of the daily dose to the individual patient's threshold level is advised; should a relapse occur, the Sandimmune dose should be promptly increased to the previous maintenance level.

According to F.I. Rusnak et al. (1997), the therapeutic regimen for children with chronic GN should also incorporate oxydetrit—a drug that undergoes hepatic METABOLISM independently of the kidneys, converting into the active form of vitamin D₃. According to these authors, its use resulted in the normalization of immunogenesis, potentiation of cytostatic efficacy, and a more rapid onset of remission.

Pronounced edema and oliguria serve as clinical indications for diuretic therapy. Furosemide, hydrochlorothiazide, clopamide, and spironolactone are the most frequently utilized agents, while triamterene, ethacrynic acid, and acetazolamide are employed less commonly. Furosemide is prescribed at a dosage of 1-5 mg/kg of body weight/day orally or intravenously, whereas spironolactone is given at 50-200 mg/day orally.

Diuretics can be combined with intravenous administration of aminophylline (2.4% solution, 0.12-0.18 mL/kg of body weight per administration), small volumes of albumin, fresh frozen plasma, and rheopolyglucin.

The dosage of antihypertensive medications must always be tailored individually. While all Major Classes of antihypertensive agents may be utilized, ACE inhibitors and angiotensin II receptor blockers should generally be avoided.

The most rational combinations of these agents in the event of an inadequate response to monotherapy include: beta-blocker + diuretic, beta-blocker + prazosin, prazosin + diuretic, clonidine + diuretic, methyldopa + diuretic, hydralazine + methyldopa, nifedipine + methyldopa, captopril + diuretic, or isobarin + diuretic.

The indications for prescribing NSAIDs include GN with isolated urinary syndrome, the hematuric form of acute GN, and 'incomplete' nephrotic syndrome, whereas acute and chronic renal failure represent absolute contraindications.

Below are the daily doses of commonly prescribed NSAIDs: aspirin, micristin — 25-50 mg; paracetamol — 15-20 mg; indomethacin — 2-3 mg; brufen — 10-12 mg; naproxen — 8-10 mg; diclofenac — 2-3 mg per kg of body weight.