IgA nephropathy

Along with idiopathic forms, IgA nephropathies are common in the framework of diseases of the gastrointestinal tract (primarily celiac disease, as well as inflammatory bowel diseases, liver diseases), systemic diseases (systemic lupus erythematosus (SLE), rheumatoid arthritis, ankylosing spondylitis), psoriasis, sarcoidosis, etc. As possible etiological factors, infectious (hepatitis B viruses, herpes viruses, E. coli, fungi, Koch's bacillus, etc.), food (gluten, alpha-lactalbumin, beta-lactalbumin, casein, etc.) are discussed and endogenous antigens (with tumors of lymphoid tissue - lymphogranulomatosis, lymphoma). There is also evidence of a genetic predisposition to developing Berger disease. The association of IgA nephropathy with autosomal dominant mutations of the 6q22-23 chromosome is shown, the relationship between IgA nephritis and HLA BW35 and HLA-DR-4 antigen is described. The relationship between the progression of IgA nephropathy and the polymorphism of the angiotensin converting enzyme gene (ACE) was revealed.

It is known that with IgA nephropathy there is an increase in the concentration of immune complexes containing IgA, both as a result of increased production of antibodies and as a result of a violation of their clearance. The main hypothesis of pathogenesis, currently widespread, suggests abnormal glycosylation and polymerization of IgA with the deposition of immune complexes containing abnormal IgA in the glomeruli, with the activation of leukocytes and the cascade of inflammation. Normally, predominantly monomeric IgA circulates in human serum, while polymer forms secreted by mucous membranes practically do not enter the circulation. This hypothesis is supported by a number of studies. In 2003, Haddad E. et al. showed a decrease in the synthesis of monomeric IgA in the mucous membranes and an increase in the production of polymeric IgA in the bone marrow with IgA nephropathy. Based on research by Kar Neng Lai et al. it was suggested that serum IgA defective in galactose and sialic acids is probably produced by mucosal lymphoid cells, but its mechanism of transfer into the blood remains unknown.

As a result of changes in the structure of the IgA molecule, there is a violation of its clearance by the liver cells - an asialoglycoprotein receptor, ASGPR, is recognized on the liver cells, which recognizes the final galactose residues and catabolizes IgA. In addition, the formation of the antigen – antibody complex suffers, including through interaction with the Fc receptor. Deglycosylated IgA polymerizes and acquires an affinity for extracellular proteins - fibronectin, laminin, type IV collagen. As a result of a change in the C3 binding site on the IgAl molecule, the activation process of the complement system is disrupted. Insufficiently glycosylated IgA begins to act as an antigen - the production of IgA and IgG against insufficiently glycosylated IgA increases. In addition, it was shown that insufficiently galactosylated IgA from patients with IgA nephropathy significantly increases apoptosis and N0 synthesis by mesangial cells compared to healthy IgA. The binding of immune complexes by renal glomerular mesangial cells with the formation of IgA deposits leads to the activation of the complement system, starts the synthesis of various cytokines and growth factors by kidney cells and circulating cells, which leads to characteristic histopathological signs.

In mesangia, diffuse, sometimes incorrectly distributed IgA deposits are detected. Perhaps the presence of IgM or IgG. Often met focal and segmental glomerulonephritis with proliferation of mesangium. Sometimes swelling of mesangium may be the only find.

The diagnosis is made on the basis of clinical manifestations and laboratory diagnosis results (first of all, the presence of macro- or microhematuria). In a significant part of patients, the content of IgA in the blood serum is increased with the predominance of its polymeric forms. According to most researchers, the degree of its increase does not reflect the degree of activity of nephropathy and does not affect the prognosis. However, in the absence of biopsy data for the latent course of the disease, the diagnostic criterion for IgA nephropathy is considered to be an increase in serum IgA levels above 3.15 g / l. High titers of IgA containing immune complexes are also observed. The level of complement is usually normal.

The main diagnostic method is a kidney biopsy with a morphological study of the biopsy. With light microscopy of the drug, an increase in the number of cells in the mesangium and an increase in the number of mesangial extracellular matrix are detected. An immunohistochemical study reveals an accumulation of IgA in the mesangium in the form of individual granules fusing together, often in combination with C3 and IgG.

The differential diagnosis is carried out primarily with urological pathology, accompanied by hematuria: urolithiasis, tumors of the kidneys and urinary tract, tuberculosis of the urinary system, etc. Cystoscopy for this category of patients remains the “gold standard” of diagnosis, although its diagnostic value in young patients (up to 40 years old) is low, since the risk of bladder cancer in this age group is negligible. Modern methods of radiation diagnostics - ultrasound scanning, X-ray or magnetic resonance computed tomography can clearly visualize not only the upper urinary tract, but also the bladder and have obvious advantages over cystoscopy in terms of tolerability and risk of damage to the lower urinary tract. However, they do not completely exclude a bladder tumor and in patients with a high risk of its development should be supplemented with cystoscopy.

The presence of PU (more than 0.3 g / l), along with the appearance of erythrocyte cylinders in the sediment, testifies in favor of glomerular, tubular or non-renal diseases. To distinguish IgA nephropathy from other nephropathies (thin basement membrane disease, Alport syndrome, etc.), occurring with similar manifestations, is sometimes only possible morphologically. So, with a disease of thin basement membranes, inherited in an autosomal dominant type, in the absence of IgA deposits in the renal tissue, a significant thinning of the glomerular basement membrane, as measured by electron microscopy, is noted. In favor of hereditary Alport syndrome linked to the X chromosome, sensorineural hearing loss, lens deformation, and leiomyomatosis may indicate.

About 30 diseases associated with the deposition of IgA in the kidneys are known: Schonlein – Genoch purpura; celiac disease, including subclinical forms; nonspecific ulcerative colitis; Crohn's disease; herpetiform dermatitis; psoriasis; cystic fibrosis; sarcoidosis; lung cancer; intestinal tumors; monoclonal IgA gammopathy;

non-Hodgkin lymphomas; pancreas cancer; HIV infection; Mycoplasma infections toxoplasmosis; cirrhosis of the liver; chronic hepatitis;

hepatitis B; hemosiderosis of the lungs; cryoglobulinemia; polycythemia; Hard currency; Sjogren's syndrome;

rheumatoid arthritis; scleroderma; multiple myeloma; Behcet's disease;

ankylosing spondylitis (ankylosing spondylitis).

The clinical manifestations of Berger's disease in approximately 50% of patients are in sypharyngitis macrohematuria, i.e. macrohematuria (often visible to the naked eye) that occurs 1-3 days after acute respiratory or intestinal infection, hypothermia. It is known that UV radiation enhances hematuria, it may also appear after vaccinations, severe physical exertion. Some patients note dull pain and discomfort in the lumbar region. A persistent or transient increase in blood pressure (BP) is possible. Transient acute renal failure (ARF) is rare and is likely to be caused by tubular obstruction by red blood cells. Most often, over time, kidney function is fully restored.

In the latent course of IgA nephropathy, which is much more common, microhematuria is observed (i.e., erythrocyturia of more than 3-4 red blood cells in the field of view), often accompanied by small (less than 0.5 grams per day) proteinuria (PU). Some patients have arthralgia, myalgia, Raynaud's syndrome, polyneuropathy, hyperuricemia.

With the development of nephrotic syndrome (PU above 3 g / day, hypoalbuminuria, hyperlipidemia), increasing hypooncotic edema is noted, sometimes up to the development of ascites and anasarca, hypovolemia. In such situations, the prevention of complications - nephrotic (kinin) crisis with abdominal pain and erysipelas like skin erythema, hypovolemic shock, thrombosis, severe infections, circulatory failure, comes to the fore.

Treatment depends on the cause of the disease. Over the years, only symptomatic therapy has been recommended. The variability of the clinical and pathophysiological manifestations of the disease still does not allow us to find a generally accepted approach to treatment. Since acute respiratory or gastrointestinal infections provoke the occurrence or worsening of hematuria, it is considered advisable to conduct a course of antibacterial therapy, preferably taking into account the sensitivity of a likely pathogenic microorganism.

The need for full control of arterial hypertension, preferably with the use of ACE inhibitors (ACE inhibitors) or angiotensin II receptor antagonists (ARBs), is today beyond doubt. It is necessary to maintain blood pressure below 130/80 mm RT. Art. In addition to controlling hypertension, ACE inhibitors and angiotensin II receptor blockers (ARBs) also have antiproteinuric and antifibrotic effects. To enhance the hypotensive and antiproteinuric effect, combined therapy of ACE inhibitors and ARB is possible.

In case of isolated or sypharyngitis hematuria in combination with small PU and stable renal function, immunosuppressive therapy is not indicated. For nephroprotective purposes, ACE inhibitors, ARBs, and dipyridamole can be used. Dipyridamole has been proposed for the treatment of nephrological patients, taking into account its antiplatelet, antiplatelet effect. Subsequently, the ability of dipyridamole to moderately reduce PU and hematuria, as well as inhibit the deterioration of renal function, was shown. In recent years, the object of study has been the new nephroprotective properties of dipyridamole, including its antioxidant effect.

With more pronounced progression, PU more than 1 g / day, hypertension, normal or moderately reduced renal function, glucocorticosteroids (GCS) can be prescribed along with this: prednisolone according to an alternating scheme for 3 months with a subsequent assessment of activity and a gradual decrease in dose with effectiveness. However, the effect of immunosuppressants on the course of slowly progressive forms of the disease has not been proven. Ideally, corticosteroids should be prescribed with a proven combination of clinical and histological signs of active inflammation (for example, severe hematuria combined with proliferative and necrotic changes in the glomeruli of the kidneys).

Only at a high risk of progression (PU above 1–3.5 g / day), the appointment of GCS in an alternating mode caused a decrease in PU and stabilization of renal function. The effectiveness of cytostatic therapy for the treatment of these types of Berger disease has been proven. Pulse therapy with ultrahigh-dose cyclophosphamide showed significantly lower toxicity than oral administration with the same efficacy of both regimens for disease activity.

With PU more than 3.5 g / day or an advanced nephrotic syndrome, active therapy with prednisone in combination with cytostatics is required, including in ultra-high doses - pulse therapy is carried out once every 3 weeks in combination with prednisolone with dynamic control over the effectiveness of treatment .

Cyclosporine can be used if the previous one is ineffective. Its use in most cases allows to reduce PU, serum IgA concentration and is effective in achieving remission in case of glomerulonephritis resistant to corticosteroids or dependent on them, with nephrotic syndrome.

Mycophenolate mofetil has not yet found wide application in the treatment of patients with Berger's disease, therefore, to date, there is still not enough data to judge its effectiveness in induction and monotherapy, as well as in the treatment of patients with a significant decrease in renal function. However, if treatment with GCS and / or CFA cannot be continued, this drug, when used for 1–2 years at a starting dose, showed good tolerance with a pronounced antiproteinuric effect and stabilization of the functional state of the kidneys.

The effectiveness of fish oil has not yet been proven, although many eminent clinics (Mayo Clinic et al.) Include high doses of polyunsaturated fatty acids in their patients' treatment courses for a long period. It has been proven that omega-3 fatty acids cannot reduce PU, but it has not yet been determined whether they can slow the progression of Berger's disease.

To reduce the increased risk of cardiovascular risk in patients with chronic kidney diseases, as well as for nephroprotective purposes, statins are widely used. Their effect on the progression of the renal process is carried out not only due to a lipid-lowering effect with a decrease in infiltration of the kidney interstitium by modified lipids and inhibition of sclerotic processes, but also due to multiple pleiotropic effects (antiaggregant, anti-inflammatory, cytostatic, antiproteinuric, etc.).

Dietary recommendations are developed individually, taking into account the peculiarities of the course of nephropathy in a particular person. Universal recommendations are strict limits on salt intake (up to 3-5 g / day) and extractive substances. With a decrease in filtration function (glomerular filtration rate (GFR) less than 60 ml / min / 1.73 m²) a moderate protein restriction is shown - up to 0.8–0.6 g / kg c. t / day, with nephrotic syndrome, protein intake should be 1 g / kg c. t./day Patients with obesity, decreased carbohydrate tolerance, and hyperlipidemia need to limit readily available carbohydrates and animal fats. Smoking cessation is not discussed. Physical activity involves the restriction of traumatic sports, and otherwise, in the absence of uncontrolled hypertension, nephrotic syndrome or a rapidly progressive decrease in filtration function, it is not limited.

The effectiveness of the therapy is indicated by: stabilization and normalization of the nitrogen-excreting function of the kidneys; normalization of blood pressure; decrease in PU and hematuria up to the normalization of urine tests; with high PU - a decrease in its level of less than 0.5–1 g / day; with nephrotic syndrome - the achievement of remission.

Even after achieving a remission of the disease, patients should be under the supervision of a nephrologist and therapist with control of the main indicators at least 2–4 times a year and when intercurrent diseases occur.

The prognosis of idiopathic IgA nephropathy is relatively favorable. Renal failure, which develops in 15-30% of patients over 15 years, progresses slowly. 20-year survival is about 50%.

Factors that worsen the prognosis are: male gender; severe PU (more than 1 g / day); renal failure (serum creatinine above 150 μmol / l); severity of hematuria (more than 50–100 in s / sp); arterial hypertension; the severity of morphological changes in the biopsy (glomerulosclerosis, the presence of half moon, synechia, immune deposits in the capillary loops, the severity of proliferation, changes in tubulointerstitia: atrophy of the tubules, interstitial fibrosis, etc.); metabolic disorders (hyperuricemia, hyperlipidemia); age; heredity (carriage of DD polymorphic marker I / D of the ACE gene). The older age at the time of the onset of the disease is associated with more pronounced sclerotic and tubulointerstitial changes. Worsening prognosis factors are also described for familial cases of Berger disease (autosomal dominant mutations 6q22-23, polymorphism of beta2-glycoprotein 1 genes, ICAM-1, development of nephropathy in one generation). In 20-50% of cases, it can recur after kidney transplantation. At the same time, better transplant survival is noted than with other nephropathies. In Berger's disease, transplantation from close relatives is not recommended.

There is no single approach to prevention. It is not even in relation to the feasibility of eliminating foci of infection (tonsillectomy, appendectomy). It is traditionally believed that tonsillectomy reduces the number of episodes of macrohematuria, and sometimes even the level of PU and the level of IgA in serum. However, many reputable researchers question the results of old works that confirm the effectiveness of tonsillectomy, since they have serious methodological errors and do not comply with modern principles of evidence-based medicine. Most authors agree that the data on the possible positive effect of tonsillectomy on the progression of Berger's disease require a comprehensive study and verification at the current level.

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