Berger's disease. Differential diagnosis

Mesangioproliferative glomerulonephritis is characterized by proliferation of mesangial cells, expansion of the mesangium, deposition of immune complexes in the mesangium and under the endothelium.

Mesangioproliferative glomerulonephritis is a fairly common morphological type of glomerulonephritis that meets (unlike the previous options) all the criteria for glomerulonephritis as an immunoinflammatory disease. The main symptoms of mesangioproliferative glomerulonephritis are: proteinuria, hematuria, in some cases - nephrotic syndrome, arterial hypertension. The course of mesangioproliferative glomerulonephritis is relatively favorable. In our early observations, the 10-year survival rate (before the onset of end-stage renal disease) was 81%. Currently, there is a tendency to isolate various clinical and morphological variants depending on the class of immunoglobulins that prevail in glomerular deposits.

Causes and pathogenesis of IgA nephropathy

The causes and pathogenesis of IgA nephropathy are being intensively studied. One hypothesis suggests abnormal glycosylation of IgA, leading to its deposition in the glomerulus and causing leukocyte activation and an inflammatory cascade.

Viral (and other infectious), food and endogenous antigens are discussed as possible etiological factors. Among viruses, the possible role of respiratory viruses, cytomegalovirus and Epstein-Barr virus is being studied. UHF-irradiation of the tonsils (possibly stimulating ARVI) causes a deterioration in urine tests, especially in those patients who had a history of gross hematuria.

There are reports of the etiological role of mycotoxin. It is believed that mycotoxin, entering the intestine and disrupting the function of the immune system of the mucous membrane, can cause IgA-H in humans.

Among food antigens, the role of gluten has been proven in some patients. In the serum of patients with IgA-H increased titers of IgA-AT to gliadin and other food proteins. The role of endogenous antigens, including hit-shock proteins, is possible.

Genetic factors also play a role. Associations between lgA nephritis and HLA-BW35, as well as with the HLA-DR4 antigen, have been described. Familial cases are possible. There are indications of a relationship between IgA-H progression and ACE gene polymorphism.

Renal involvement is characterized by focal or diffuse mesangioproliferative glomerulonephritis or other types of proliferative glomerulonephritis. Currently, there is a tendency to classify other morphological types of glomerulonephritis with IgA deposition in the kidneys as IgA-H. Morphologically, IgA-H activity is assessed by the same criteria as the activity of other morphological types.

Symptoms of IgA nephropathy

Symptoms of IgA nephropathy develop at a young age, more often in men. 50% of patients experience recurrent macrohematuria, which occurs during febrile respiratory diseases in the first days or even hours of illness (“sinpharyngitis macrohematuria”), less often after other diseases, vaccination or heavy physical activity. Gross hematuria is often accompanied by mild dull pain in the lower back, transient hypertension, and sometimes fever. Episodes of gross hematuria may occur with transient oliguric acute renal failure, presumably caused by tubular obstruction by red blood cell casts.

In most cases, these episodes pass without a trace, but patients have been described in whom renal function was not completely restored after acute renal failure.

In other patients, IgA nephritis occurs latently, with microhematuria, often with slight proteinuria. In 15-50% of patients (usually older and/or with microhematuria), nephrotic syndrome may develop in the later stages (in our observations in 25% of patients), and in 30-35% - arterial hypertension. Among our patients with microhematuria, systemic symptoms were often noted: arthralgia, myalgia, Raynaud's syndrome, polyneuropathy, hyperuricemia.

IgA nephropathy

The main place among the variants of mesangioproliferative glomerulonephritis is occupied by glomerulonephritis with deposition of immunoglobulin A in the glomeruli - IgA nephritis, IgA nephropathy (IgA-H), Berger's disease. It was described by J. Berger et al. in 1967 as recurrent benign hematuria. In subsequent years, with long-term observation, it was found that in 20-50% of adult patients, kidney function deteriorates over time. It is now considered to be a persistent or slowly progressive disease.

Currently, the scope of IgA-H is expanding significantly. A number of researchers also include other types of nephritis in this group, in which IgA is detected in the glomeruli. At the same time, the terms “IgA nephritis” or more often “IgA nephropathy” are gradually beginning to be replaced by the term “Mesangioproliferative glomerulonephritis”, although it is mentioned that IgA-H belongs to a large group of mesangioproliferative nephritis, which includes glomerulonephritis with deposits of C3 and IgG, as well as glomerulonephritis with IgM deposits.

The problem is complicated by the ambiguity of the relationship between IgA-H and hemorrhagic vasculitis (Schoenlein-Genoch purpura), in which the serum IgA content is also increased, and IgA deposits are found in the kidneys, and therefore it is assumed that IgA-H is a monoorganic form of hemorrhagic vasculitis.

The frequency of IgA nephritis among other types of glomerulonephritis is approximately 30% in Asia and 10-12% in Europe and Australia. In some countries (Japan), IgA nephritis began to predominate (25-50%) among all cases of chronic glomerulonephritis. According to our clinic, it was detected in 12.7% of 1218 morphologically confirmed cases of glomerulonephritis (8.5% of all biopsies).

Diagnosis of IgA nephropathy

In the blood serum of 35-60% of patients, the content of IgA is increased, its polymeric forms predominate. The degree of IgA increase does not reflect the clinical course of the disease and does not affect the prognosis. Serum also reveals high titers of IgA-containing immune complexes, which in some cases contain antibodies against bacterial, viral and food antigens. Serum complement is usually normal.

Differential diagnosis of IgA nephropathy is carried out with urolithiasis, kidney tumors, with IgA nephritis in hemorrhagic vasculitis and chronic alcoholism, with Alport's syndrome, thin basement membrane disease.

Thin basement membrane disease (benign familial hematuria) is a disease with a good prognosis that occurs with microhematuria; usually inherited in an autosomal dominant manner; there are no IgA deposits in the kidneys; for the final confirmation of the diagnosis, it is necessary to measure the thickness of the GBM by electron microscopy, which is 191 nm for thin membrane disease, and 326 nm for IgA-H.

The course of IgA-H is relatively favorable, especially in patients with gross hematuria. Renal failure develops after 10-15 years in 15-30% of patients, progresses slowly.

Factors that worsen the prognosis for IgA nephropathy:

• severe microhematuria;
• severe proteinuria;
• arterial hypertension ;
• renal failure;
• the severity of morphological changes (glomerular sclerosis, interstitium);
• deposition of IgA in the walls of peripheral vessels;
• male gender;
• older age at onset.

L. Frimat et al. (1997) in a prospective study identified 3 main clinical factors for poor prognosis: male gender, daily proteinuria level above 1 g and serum creatinine level more than 150 mmol/l.

IgA-H often recurs in the graft, in 50% of recipients within 2 years. However, with cadaveric kidney transplantation, graft survival is better than with other kidney diseases. Transplantation from HLA-matching siblings is not recommended.

Treatment of mesangioproliferative glomerulonephritis and lgA nephropathy

Currently, treatment for mesangioproliferative glomerulonephritis and IgA nephropathy has not been developed. This can partly be explained by the large variability of disease outcomes (end-stage renal failure develops only in some patients, and at different rates) and the difficulty of predicting the prognosis for each individual patient, even taking into account already established clinical and morphological prognostic factors. Most of the studies to date that have concluded that proteinuria is reduced or function is stabilized by therapy are based either on anecdotal evidence or on retrospective analysis of data.

Elimination of foci of infection, tonsillectomy

The effectiveness of other measures aimed at preventing exacerbations of infection, namely removal of the source of infection (tonsillectomy) and long-term antibiotic therapy, is still debated. Tonsillectomy does reduce the number of episodes of gross hematuria and sometimes also proteinuria and serum IgA levels. There is evidence of a possible inhibitory effect of tonsillectomy on the progression of the renal process. In this regard, tonsillectomy can be recommended for patients with frequent exacerbations of tonsillitis.

Glucocorticosteroids and cytostatics

There is no evidence of a significant effect of immunosuppressants (glucocorticoids or their combinations with cytostatics) on the course of slowly progressive forms of the disease.

A large multicenter Italian study that assessed the effectiveness of glucocorticoids (alternating regimen) in patients with a high risk of progression - proteinuria levels of 1-3.5 g/day, confirmed a decrease in proteinuria and stabilization of renal function.

In our observations, cytostatic therapy was effective in 59% of patients with mesangioproliferative glomerulonephritis. In a randomized prospective study, the effectiveness of pulse cyclophosphamide therapy was similar to oral cyclophosphamide, but there were significantly fewer side effects.

Cyclophosphamide, dipyridamole, warfarin (phenylin)

This three-component method (cyclophosphamide for 6 months, the remaining 2 drugs for 3 years) in a controlled study from Singapore reduced proteinuria and stabilized renal function. However, re-evaluation of patients in the Singapore study after 5 years did not reveal a difference in the rate of progression of renal failure in treated and untreated patients.

Cyclosporine at a dose of 5 mg/kg/day) in a randomized trial reduced proteinuria, serum IgA concentration and expression of interleukin-2 receptors on T cells. V. Chabova et al. (1997) treated 6 patients with IgA nephropathy with cyclosporine A with proteinuria more than 3.5 g/day (average 4.66 g/day) and creatinine level less than 200 μmol/l; proteinuria decreased after 1 month to 1.48 and after 12 months to 0.59 g/day. Complications: hypertension (4 patients), hypertrichosis (2 patients), vomiting (1 patient). In our studies, cyclosporine A caused remission in 4 of 6 patients with steroid-resistant or steroid-dependent MPGN with nephrotic syndrome.

IgA nephropathy (Berger's disease). It is characterized by torpid microhematuria and persistent macrohematuria against the background of ARVI. Differential diagnosis can only be made by renal biopsy with light microscopy and immunofluorescence. IgA nephropathy is characterized by granular fixation of IgA deposits in the mesangium against the background of proliferation of mesangiocytes.

Membranoproliferative GN (MPGN) (mesangiocapillary). It occurs with nephritic syndrome, but is accompanied by more pronounced edema, hypertension and proteinuria, as well as a significant increase in the concentration of creatinine in the blood. With MPGN, there is a long-term (›6 weeks) decrease in the concentration of the C3 component of complement in the blood, in contrast to a transient decrease in the C3 component of complement in acute post-streptococcal GN. To diagnose MPGN, nephrobiopsy is necessary.

Disease of thin basement membranes. It is characterized by torpid microhematuria of a familial nature against the background of preserved renal function. A biopsy reveals typical changes in renal tissue in the form of diffuse uniform thinning of the glomerular basement membrane (‹200–250 nm in more than 50% of glomerular capillaries).

Hereditary nephritis. It may first appear after acute respiratory viral infection or streptococcal infection, including in the form of gross hematuria. However, with hereditary nephritis, the development of nephritic syndrome is not typical, and hematuria is persistent. In addition, families of patients usually have the same type of kidney disease, cases of chronic renal failure, and sensorineural hearing loss. The X-linked dominant type of inheritance of hereditary nephritis is the most common; autosomal recessive and autosomal dominant variants are less common. A presumptive diagnosis is made on the basis of a pedigree analysis.

Diagnosis of hereditary nephritis requires the presence of 3 of 5 signs:

1. hematuria in several family members;

2. patients with chronic renal failure in the family;

3. thinning and/or disruption of the structure (splitting) of the glomerular basement membrane (GBM) during electron microscopy of nephrobiopsy material;

4. bilateral sensorineural hearing loss, determined by audiometry;

5. congenital vision pathology in the form of anterior lenticonus (rare in Russia).

In hereditary nephritis, especially in boys, proteinuria progresses during the course of the disease, hypertension appears and GFR decreases. This is not typical for acute post-streptococcal GN, which occurs with the consistent disappearance of urinary syndrome and restoration of kidney function.

Detection of mutations in the type 4 collagen gene (COL4A3 and COL4A4) confirms the diagnosis of hereditary nephritis with the corresponding symptom complex of the disease.

Rapidly progressive glomerulonephritis. When renal failure develops against the background of acute post-streptococcal GN, it is necessary to exclude rapidly progressive GN (RPGN), which is manifested by a progressive increase in the concentration of creatinine in the blood over a short period of time and NS. In acute post-streptococcal GN, acute renal failure is short-term and renal function is quickly restored. RPGN associated with microscopic polyangiitis is characterized by signs of systemic pathology and ANCA in the blood.

In a broad sense, it includes all quantitative and qualitative changes in urine, and in a narrower sense, changes in urine sediment: proteinuria, hematuria, leukocyturia. More often, certain combinations of these urine components are observed (proteinuria with leukocyturia, proteinuria with hematuria, etc.), less often “isolated” proteinuria or hematuria occurs, when other signs are either absent or they are only slightly expressed.

Urinary syndrome is considered one of the most important signs of possible disorders in the urinary system, the essence of which is a laboratory-proven (statically reliable) and obvious deviation from the norm in the composition of urine.

Difficulties in the differential diagnosis of urinary syndrome arise mainly when it is the only manifestation of the pathological process. If this syndrome becomes the only manifestation of kidney disease, then in such cases a diagnosis is made - isolated urinary syndrome. Isolated urinary syndrome can occur with primary and, as well as with other kidney diseases.

Hematuria

Isolated glomerular hematuria can occur with primary and secondary glomerulonephritis, lesions of the renal vessels, tubulointerstitial disease and necrosis of the renal papillae. There is tubular and extrarenal hematuria, which develops with malignant tumors of the kidneys and urinary tract, kidney cysts, prostate adenoma, etc. Hematuria occurs in IgA nephropathy, thin membrane disease, and less commonly in Alport syndrome.

IgA nephropathy

IgA nephropathy can develop with Crohn's disease, adenocarcinoma of the stomach and colon, bronchitis obliterans, dermatitis herpetiformis, fungal mycosis, ankylosing spondylitis and Sjögren's syndrome, in which there is no inflammation in the glomeruli. A pathognomonic sign is IgA deposits in the mesangium, which can be combined with C3 deposits.

Clinical manifestations of IgA nephropathy are minimal. Macrohematuria, which occurs 24-48 hours after a sore throat, gastrointestinal infection and heavy physical activity, is the main manifestation of nephropathy. In some patients, microhematuria is detected during a routine examination. Arterial hypertension occurs in 20-30% of patients and in 10%.

IgA nephropathy flows for years. Terminal renal failure develops within 20 years in 30-50% of patients. The prognosis is worse in older men, with high proteinuria, renal failure at the onset of the disease, glomerulosclerosis and arteriolar hyalinosis. Microscopic examination reveals deposits of IgA and C3 in the kidney, expansion of the mesangium due to accumulation of the matrix and an increase in the number of glomerular cells, in severe cases - crescent, inflammatory infiltration of the interstitium and foci of glomerulosclerosis.

There is no treatment. In severe cases (rapidly progressive course, nephrotic and) recommend high doses of immunosuppressants with the obligatory consideration of the underlying disease that led to the development of IgA nephropathy.

Thin Membrane Disease

Thin membrane disease, an autosomal dominant hereditary disease, usually begins in childhood and presents with persistent or intermittent hematuria after acute respiratory infections. A morphological sign - a thin basement membrane (less than 275 nm in children and less than 300 nm in adults) - is detected by electron microscopy. The prognosis is good.

Alport syndrome

Alport syndrome is a hereditary nephropathy. The type of inheritance is dominant, linked to the X chromosome. It develops more often in men and is characterized by hematuria, proteinuria and progressive renal failure. In addition to kidney damage, 60% of patients have sensorineural deafness and 15-30% have eye damage - bilateral anterior lenticonus. In heterozygous women, the disease occurs in a mild form without renal failure. Microscopy reveals mesangial proliferation, focal segmental nephrosclerosis, tubular atrophy, and foam cells. Electron microscopy reveals a deformed and thickened basement membrane. The progression of the syndrome in men leads to the development, in which dialysis and are indicated.

Isolated proteinuria

Isolated proteinuria without any renal disease is found in 1-10% of the population. It can be benign or permanent.

Benign isolated proteinuria

Benign isolated proteinuria can have the following variants:

• Transient idiopathic proteinuria is detected in young people during a single urine test during routine examinations (in repeated examinations, protein is usually no longer present).
• Functional proteinuria - occurs with fever, hypothermia, emotional stress, heart failure (presumably due to increased intraglomerular pressure and glomerular filter permeability).
• Orthostatic proteinuria - caused by prolonged standing (usually does not exceed 2 g/day).

In all types of benign isolated proteinuria, a biopsy either does not reveal any changes or reveals minor changes in the mesangium and podocytes. The prognosis is favorable.

Persistent isolated proteinuria

Persistent isolated proteinuria is characterized by the constant presence of protein in the urine, regardless of external conditions and the condition of the patient. A biopsy reveals the morphological picture of any glomerulonephritis. Mesangioproliferative glomerulonephritis and focal segmental glomerulosclerosis are most often found. The prognosis for this syndrome is less favorable than for benign isolated proteinuria. Chronic renal failure develops in 20-30% of patients within 20 years, but it usually does not reach the terminal stage.

Isolated glomerular hematuria(with red blood cell casts) can be either a sporadic or familial disease. A biopsy with it often reveals a very thin basement membrane of the glomerulus. This condition is called thin basement membrane disease, or benign hematuria.

If disease affects several family members and they do not have it, then they speak of benign familial hematuria. Thinning of the glomerular basement membrane occurs in various diseases that differ in their molecular basis. Like Alport syndrome, benign familial hematuria is a hereditary lesion of the glomerular basement membrane. It also manifests itself as chronic hematuria, but has important differences:
1) extrarenal manifestations of the disease are rare;
2) proteinuria, arterial hypertension and the development of end-stage renal failure are not typical;
3) gender does not affect the course of the disease;
4) the disease is inherited in an autosomal dominant manner. This disease is difficult to distinguish histologically from the early stage of Alport syndrome: in both cases there is a uniform thinning of the glomerular basement membrane.

However, with Alport syndrome, the basement membrane remains thinned over time, while with Alport syndrome it becomes stratified and thickened over time.

If a patient is diagnosed benign familial hematuria proteinuria and arterial hypertension occur, then a variant of Alport syndrome should be suspected, in which thinning of the glomerular basement membrane predominates over its delamination and thickening.

One sick Dutch family, suffering from benign familial hematuria, turned out to be heterozygous carriers of a missense mutation in the COL4A4 gene. However, in other families suffering from this disease, mutations in the COb4A3 and COb4A4 genes were not identified, which indicates the genetic heterogeneity of this disease. To date, immunohistochemical studies of type IV collagen in the glomerular basement membrane of benign familial hematuria and sporadic thin basement membrane disease have not revealed any abnormalities in the distribution of any of its six chains.

If there is a family history hematuria without chronic renal failure, inherited in an autosomal dominant manner, and radiation diagnostics does not reveal changes in the kidneys and urinary tract, then a diagnosis of benign familial hematuria can be assumed without a kidney biopsy. If the family history is unclear or not known at all, or if there is an associated pathology, such as proteinuria or deafness, then a kidney biopsy is very helpful in diagnosis.

When thinning is detected glomerular basement membrane (< 250 нм у взрослых или, в зависимости от возраста, 200-250 нм и меньше у детей) исследуют распределение а-цепей коллагена IV типа. Нормальное распределение говорит в пользу доброкачественной семейной гематурии, но не доказывает этот диагноз.

Benign familial hematuria and sporadic form of thin basement membrane disease do not progress and do not require treatment.

Thin basement membrane disease is a hereditary pathology of the glomerular apparatus of the kidneys. The occurrence of the disease is associated with a mutation in type IV collagen genes. The main manifestation is microhematuria - a small amount of blood in the child’s urine. The disease does not affect kidney function and is not prone to progression, so it is often called “familial benign hematuria.” It is one of the most common causes of persistent (permanent) hematuria in children.

Symptoms

Thin basement membrane disease in children is asymptomatic, the main clinical sign is the constant presence of microscopic amounts of blood in the child's urine. In this case, the kidneys function normally, without any manifestations of their damage. In rare cases, there may be a short-term increase in the content of blood in the urine due to previous diseases of the upper respiratory tract.

Diagnostic tests

If microhematuria is detected in a child, the examination can be done on an outpatient basis or in a specialized hospital. Diagnosis of thin basement membrane disease in a child is carried out by a pediatric urologist or pediatric nephrologist. In this case, a high-quality collection and assessment of family history is extremely important. If there is pathology in family members, the child undergoes a kidney biopsy with histological examination of the biopsy to assess the condition of the basement membranes of the renal glomeruli and confirm the diagnosis. To differentiate the diagnosis, the doctor clarifies the presence in the family history of cases of hearing loss, renal failure and vision pathologies. This allows us to exclude Alport syndrome and IgA nephropathy.

Diagnosis confirmation

Urologist's report

Ultrasound results of the kidneys and adrenal glands

Results of transabdominal ultrasound of the pelvic organs

Nephrobiopsy results

Treatment methods

Thin basement membrane disease in children is not prone to progression, however, the child is recommended to undergo dynamic monitoring throughout his life with regular follow-up studies on an outpatient basis. If a case of gross hematuria (high blood content in the urine) and symptoms of renal dysfunction (swelling, worsening results of blood and urine tests, etc.) are detected, the child is hospitalized in the nephrology department of the children's hospital for a thorough diagnosis and, if necessary, a course of treatment. The average hospitalization period is about two weeks. The course of necessary therapy is developed individually based on research results. The treatment program usually includes:

• an individual diet designed taking into account the balance of essential nutrients;
• relief of identified infection;
• membrane stabilizing and antioxidant therapy with medications aimed at preventing the destruction of cell membranes;
• a course of sessions in a hyperbolic chamber (hyperbolic oxygenation), which helps enrich the patient’s body with oxygen. This procedure accelerates metabolism and promotes rapid tissue regeneration;
• renoprotective, antiproteinuric, antisclerotic therapy with ACE inhibitors - a set of measures aimed at preserving kidney function.

To reduce the risk of deterioration of the child’s condition, it is recommended to limit his contact with people suffering from infectious diseases.

The article was prepared on the basis of clinical recommendations and standards of medical care approved by the Ministry of Health of the Russian Federation and is for informational purposes only. Only a doctor can make a diagnosis and prescribe treatment during a face-to-face consultation.