Glomerulonephritis clinical guidelines. Clinical recommendations for general practitioners glomerulonephritis: diagnosis, treatment, prevention. History and physical examination

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1 1 Clinical guidelines for the diagnosis, treatment and prognosis of membranoproliferative glomerulonephritis Developed by: Research Institute of Nephrology, First St. Petersburg State Medical University. acad. I.P. Pavlova (2013) Authors: Smirnov A.V. Doctor of Medical Sciences, Professor, Nephrologist Dobronravov V.A. Doctor of Medical Sciences, Professor, Nephrologist Sipovsky V.G. senior researcher, pathologist Trofimenko I.I. Candidate of Medical Sciences, Associate Professor, Nephrologist Pirozhkov I.A. Junior Researcher, Pathomorphologist, Specialist in Immunomorphology Kayukov I.G. Doctor of Medical Sciences, Professor, Nephrologist, Clinical Physiologist Lebedev K.I. junior researcher, pathomorphologist, immunomorphologist

2 2 Methodology for assessing the strength of recommendations and the level of their predictiveness used in compiling these clinical recommendations * Based on the strength of recommendations, they are divided into three categories in descending order: level 1 (experts recommend); level 2 (experts suggest); “undifferentiated level” (Table 1). The predictive power of recommendations is divided into 4 levels (Table 2). Table 1. Assessment of the strength of recommendations Level Level Level 1 “Experts recommend” Level 2 “Experts believe” “Undifferentiated level” Not Graded - NG Evaluation of recommendations From the side of patients The vast majority of patients in a similar situation would prefer to follow the recommended path and only a small part of them would reject this path Most patients in a similar situation would be in favor of following the recommended path, but a significant proportion would reject this path On the part of the doctor For the vast majority of his patients, the doctor will recommend following this path For different patients it should select various recommendations that suit them. Each patient needs assistance in selecting and making decisions that are consistent with that patient's values ​​and preferences Future Directions The recommendation can be adopted as a standard of practice for health care personnel in most clinical situations Recommendations are likely to require discussion with all stakeholders before they are adopted as a clinical standard This level is applied in cases where the recommendation is based on the common sense of the investigator or when the topic under discussion does not allow adequate application of the evidence system used in clinical practice.

3 3 Table 2 Predictor levels of recommendations Level Characteristic Meaning/description of predictive level A High Experts are absolutely confident that if this recommendation is implemented, the observed effect will almost completely coincide with the expected one. B Moderate Experts expect that if this recommendation is implemented, the observed effect will most likely be close to the expected effect, but it is possible that it will differ significantly from it. C Low The predicted effect may differ significantly from the actual one. D Very low Prediction of the effect is extremely unreliable and will very often differ from the real one. Note: * compiled in accordance with KDIGO clinical guidelines. Section 1. Definition of membranoproliferative glomerulonephritis. Terminology. Recommendation 1.1. Membranoproliferative glomerulonephritis (MPPGN) is a generic term (“morphological syndrome”) that unites a group of glomerulopathies that have a similar morphological picture on light microscopy of biopsy specimens, but differ in etiology, pathogenesis, immunohistochemical and ultrastructural (electron microscopy) changes in the renal parenchyma (NG). Comment Currently, significant progress has been made in understanding the etiology and especially the pathogenesis of MBPGN, which allows us to consider this morphological form as a very heterogeneous group of diseases. Previous ideas about the clinical division of MBPGN into idiopathic (with unknown etiology) and secondary forms have been preserved, with the latter being predominant. In this regard, past data on the prevalence of MBPGN in the population should be taken with caution. According to large morphological registers in Western European countries, the prevalence of MBPCN varies from 4.6% to 11.3%, and in the USA it does not exceed 1.2%, amounting to approximately 1 6 people per 1 million population. On the contrary, in the countries of Eastern Europe, Africa and Asia, the prevalence of MBPGN, according to some data, reaches 30%, which is associated with a higher prevalence of infections, primarily viral hepatitis B and C. Active measures to prevent infections seem to explain the apparent increase in recent years. a downward trend in the prevalence of MBPGN in most regions

4 4 of the world, however, MBPGN remains the 3rd and 4th cause of end-stage renal failure (ESRD) among all other forms of primary glomerulonephritis. Synonyms for the term membranoproliferative glomerulonephritis are mesangiocapillary glomerulonephritis, and in the domestic literature membranous proliferative glomerulonephritis. The preferred term is membranoproliferative glomerulonephritis. Section 2. Clinical presentation of MBPGN Recommendation 2.1. The clinical presentation of MBPGN (renal syndromes) is identical in idiopathic (with unknown etiology) and secondary variants of the disease (1B). Recommendation 2.2. Based on the nature of the clinical picture, it is impossible to predict the morphological type of MBPGN (1B). Recommendation 2.3. Clinical differential diagnosis of MBPGN should initially be based on the complete and reliable exclusion of all possible secondary causes (Tables 3, 4) (NG). Comment: Despite the pathogenetic and morphological heterogeneity of MBPGN, the clinical presentation from the kidneys is identical. Half of the patients have a history of a recent (up to one week) upper respiratory tract infection. In some cases, the clinical phenomenon of sinpharyngitis macrohematuria is detected, which forces a differential diagnosis with IgA nephropathy. Among the clinical symptoms, the following prevail: arterial hypertension, which at its onset is observed in more than 30% of patients, but over time develops in almost all patients, sometimes acquiring a malignant course; macro- and microhematuria (almost 100%); high proteinuria (nephrotic); progressive decrease in glomerular filtration rate (GFR). The leading clinical syndrome at the onset of the disease in 20–30% of cases is acute or rapidly progressive nephrotic syndrome (APNS). In the first case, there is a need for differential diagnosis with acute post-streptococcal glomerulonephritis, especially since in 20-40% of cases of MBPGN there is a high titer of ASL-O; in the second case, differential diagnosis is carried out with anti-GBM nephritis, ANCA-associated vasculitis and thrombotic microangiopathies. In 40-70% of patients, nephrotic syndrome develops from the very beginning (if it does not exist, then in most patients it appears later, in 10-20% of cases

5 5 recurrent macrohematuria (usually synpharyngitis) is noted. However, in 20-30% of patients it is possible to register (usually by chance) only changes in the general urine analysis in the form of a combination of proteinuria with microhematuria and cylindruria (isolated urinary syndrome). In all patients with ONS, BPNS, and in 50% of cases with other types of clinical presentation, a decrease in GFR is observed (in BPNS it is progressive) and multiple disorders of tubular functions are detected (decreased concentrating ability of the kidneys, aminoaciduria, glucosuria, hyperkalemia, etc.). Based on the clinical picture of kidney damage, it is impossible to predict the type of MBPGN or speak definitely about its cause. More often (up to 80% of all cases) immunoglobulin-positive MBPGN type I is diagnosed, which affects people of any age and gender. The immunoglobulin-positive variant of type III MBPGN is detected less frequently (5–10%). Currently, there is a consensus among nephrologists regarding idiopathic, immunoglobulin-positive MBPGN type I (less commonly type III), the diagnosis of which can be established only after excluding secondary causes (Table 3). In the clinical picture of C 3 -negative glomerulopathy, as a rule, at the onset, clinical and laboratory symptoms of the underlying disease prevail (Table 4) in combination with acute kidney damage, most often in the form of BPNS. Only after the acute period, high proteinuria, microhematuria appear, or nephrotic syndrome is formed. Clinical diagnosis of dense deposit disease (DDD) is facilitated if, in addition to renal syndromes, associated conditions are identified in the form of acquired partial lipodystrophy and/or macular degeneration of the retina (see below). Section 3. Morphological and immunomorphological differential diagnosis of MBPGN Recommendation 3.1. To diagnose MBPGN in accordance with international standards, it is necessary to combine several methods of morphological examination of intravital renal tissue biopsies, namely: light microscopy, immunomorphology, ultrastructural analysis (transmission electron microscopy) (NG). Recommendation 3.2. To conduct a light-optical examination of nephrobiopsy specimens, it is necessary to carry out the following stains on paraffin sections: hematoxylin and eosin, Masson trichromatic staining, PAS reaction, Congo-ort, staining for elastic fibers and fibrin (AFOG) (1A).

6 6 Recommendation 3.3. For immunomorphological studies, it is necessary to use the following antibodies to identify diagnostically significant epitopes: IgA, M, G, light chains lambda, kappa and fibrinogen, complement fractions C3, C1g, C 2 and C 4 (2B). Recommendation 3.4. Based on the data of ultrastructural analysis (electron microscopy), one should distinguish: membranoproliferative glomerulonephritis type I, dense deposit disease and membranoproliferative glomerulonephritis type III (1A). Recommendation 3.5. Morphological differential diagnosis of MBPGN is carried out on the basis of immunomorphology and electron microscopy data (1A). Recommendation 3.6. The result of morphological differential diagnosis should be the establishment of the following pathogenetic variants of MBPGN: immunoglobulin-positive, C3-positive MBPGN types I or III, immunoglobulin-negative, C3-positive MBPGN types I or III and dense deposit disease, immunoglobulin- and C3-negative MBPGN ( 1A). Recommendation 3.7. When conducting an immunomorphological study, it is necessary to consider the intensity of deposition of the reaction product to immunoglobulins A, M, G in the structures of glomeruli 2+ as diagnostically significant, both with fluorescent and light-optical (transmitted light) microscopy (immunoglobulin-positive variant of MBPGN). The remaining variants of the intensity of deposition of the product of the reaction to immunoglobulins (less than 2+) should be considered negative (immunoglobulin-negative variant of MBPGN) (2B). Recommendation 3.8. When conducting an immunomorphological study, it is necessary to consider the intensity of deposition of the reaction product to the C3 fraction of complement in the structures of 2+ glomeruli as diagnostically significant, both with fluorescent and light-optical (transmitted light) microscopy (C3-positive variant of MBPGN). The remaining variants of the intensity of deposition of the product of the reaction to immunoglobulins (less than 2+) should be considered negative (C3-negative variant of MBPGN) (2B). Recommendation 3.9. In the absence of the possibility of ultrastructural analysis (electron microscopy), a morphological diagnosis should be formulated based on light microscopy and immunomorphology data (2B). Recommendation According to light microscopy and immunomorphology, three variants of MBPGN should be distinguished (2B): immunoglobulin- and C3-positive MBPGN; C3-glomerulopathy; immunoglobulin- and C3-negative MBPGN. Recommendation The term C3 glomerulopathy refers to immunoglobulin-negative and C3-positive MBPGN, including 2 forms of MBPGN, which with further ultrastructural analysis can be specified as: immunoglobulin-negative, C3-positive MBPGN type I or III or dense deposit disease (1A). A comment. The main morphological signs with light microscopy are represented by proliferation of cells and the main substance of the mesangium and thickening of the walls of capillaries (basal membranes), which often undergo pseudo-cleavage with the formation of double-circuited basement membranes

7 7 (the “tram line” phenomenon). The mechanism of formation of the second basement membrane is associated with the interposition (introduction) of mesangiocyte processes into the subendothelial space, where they, in cooperation with endothelial cells, produce a new basic substance of the second intracapillary membrane located inside. In addition to the proliferation of resident cells, there is infiltration of the glomeruli by neutrophils and macrophages (an exudative component of the inflammatory response). It is important to note that the severity of proliferative and exudative changes may vary from case to case. Thus, in some observations, these changes may be focal in nature (i.e., some of the glomeruli may remain intact). It is believed that in this case we can talk about the debut of the disease. In other observations, most often noted, morphological changes are diffuse in nature. Cases of regression of diffuse changes into focal ones have also been described, for example, when the secondary cause of glomerulopathy is eliminated. In 10% of all cases of MBPGN, crescents can be recorded in more than 50% of the glomeruli, as a reflection of the severity of the activity of the proliferative-exudative reaction. As a rule, in this case, rapidly progressive nephritic syndrome (RPNS) is clinically noted. Pronounced proliferative changes in the mesangium very often lead to the division of the glomerular capillary loops into separate bundles (lobules), giving the glomerulus a lobular structure. Previously, such changes were classified as a special form of lobular MBPGN. Nowadays, glomerular lobulation is considered one of the variants of the course of the pathological process, reflecting the severity of the proliferative reaction and, possibly, associated with the duration of the course of MBPGN. With further progression, zones of hypercellularity of the mesangium are replaced by the matrix and glomerular sclerosis develops. At this stage, pathomorphological changes can mimic nodular diabetic glomerulosclerosis. Changes in blood vessels reflect the duration and severity of arterial hypertension. Morphological changes in tubular cells and interstitium are usually significant and, as a rule, do not correlate with glomerular lesions, but are clinically associated with renal dysfunction. A more detailed characterization of morphological changes in MBPGN is possible only with ultrastructural analysis, which

8 8 allows us to distinguish three types of MBPGN. In type I MBPGN, electron microscopy reveals subendothelial and mesangial deposits. In type II MBPGN, intramembranous electron-dense deposits are noted, which can give the membrane a “sausage-ligament” appearance, and mesangial deposits are also present. In type III MBPGN, in addition to subendothelial ones, subepithelial (subpodocytic) deposits are recorded (Burkholder a subtype); in some cases, outgrowths are formed on the basement membrane near subepithelial deposits (the morphological picture resembles membranous nephropathy), combined with the presence of intramembranous deposits (as in type II MBPGN) The latter give the lamina densa an uneven appearance (subtype Strife a and Anders a). We emphasize that with light microscopy there are no typical morphological features that would make it possible to predict the diagnosis of one of the three types of MBPPGN with electron microscopy. Moreover, with BPD, only 25% of cases show typical signs of MBPGN (described above) by light microscopy; in 44% mesangial proliferative glomerulonephritis is diagnosed, in 17% glomerulonephritis with crescents, in 11% - acute exudative-proliferative glomerulonephritis, and in 3% of cases the morphological signs cannot be classified. Many researchers also point out that there are many transitional types in electron microscopy, meaning that even ultrastructural analysis does not guarantee a definitive diagnosis. That is why the modern classification of MBPGN was based on information about immunopathogenesis, which can be judged from immunomorphology (immunohistochemistry) of kidney biopsy sections. Based on the analysis of deposits in the kidney biopsy of immunoglobulins and complement fractions, immunoglobulin-positive and immunoglobulin-negative MBPGN are distinguished (Fig. 1). The presence of immunoglobulins and the C3 fraction of complement indicates an immunocomplex variant of MBPGN, which is characterized by activation of the complement system along the classical pathway. As a result, in addition to globulins and the C 3 fraction of complement in the renal biopsy, complement fractions C1 q, C 2, C 4, characteristic of the classical pathway of complement activation, are detected. With immunoglobulin-negative MBPGN, detection of a positive reaction to the C3 fraction of complement in the absence of fractions

9 9 C1 q, C 2, C 4 will indicate complement activation via the alternative pathway. Already on the basis of these data, it is possible to formulate a preliminary diagnosis of C3-positive glomerulopathy or C3-glomerulopathy, which can then be clarified using electron microscopy as C3-MBPGN type I or III or dense deposit disease (Fig. 1).

10 10 Considering the fact that in case of BPD the light-optical morphological picture may not include signs characteristic of MBPPH (see above), a diagnosis of C3 glomerulopathy is allowed, but we emphasize once again that in this case there should be no deposits of immunoglobulins, C1g and C4 complement fractions , and the intensity of deposition of the reaction product on the C 3 - fraction of complement should be at least 2+. The absence of immunoglobulins in an immunomorphological study and a negative reaction to the C 3 fraction of complement (less than 2+) will allow diagnosing C3-negative glomerulopathy. Section 4. Clinical, pathogenetic and laboratory diagnosis of MBPGN Recommendation 4.1. The term idiopathic MBPGN should mean immunoglobulin- and C3-complement-positive variant of MBPGN types I or III of unknown etiology (1A). Recommendation 4.2. Immunoglobulin-negative, C3-positive MBPGN type I or III and dense deposit disease are caused by hereditary or acquired disorders in the alternative pathway of complement activation (1A). Recommendation 4.3. Clinicopathological diagnosis of various variants of MBPGN should include determination of the total level of serum complement (CH 50), as well as its fractions in the blood serum: C3 and C4 (1A). Recommendation 4.4. A normal level of the complement C4 fraction indicates an alternative pathway of complement activation (immunoglobulin-negative, C3-positive MBPGN), and a decrease in its concentration indicates the classical pathway of complement activation (immunoglobulin-positive, C3-positive MBPGN). In both of these cases, the total level of serum complement (CH 50) and its C3 fraction (1A) is reduced. Recommendation 4.5. For a more complete assessment of the pathogenesis of immunoglobulin-negative, C3-positive MBPGN types I or III and dense deposit disease, it is necessary to determine the titer of C3-nephritic factor in the blood serum, to study the level of regulatory proteins of the alternative pathway of complement activation: factors H, I, B, properdin (1A). Recommendation 4.6. The immunoglobulin- and C3-negative variant of MBPGN should be considered as a reparative phase of the inflammatory process caused by primary damage to endothelial cells (Table 4) (2B). Recommendation 4.7. In case of immunoglobulin and C3-negative variant of MBPGN, the concentration of the total level of complement in the blood serum (CH 50) and its fractions (C3, C4) does not change (1A). Comment Immunoglobulin and complement positive variant of MBPCN types I and III (Fig. 1), as a rule, is secondary in nature and is associated with chronic antigenemia, circulation of autoimmune complexes in the blood, or deposition of monoclonal immunoglobulins in the glomerulus. In relatively rare cases, when it is not possible to establish the cause of chronic antigenemia, confirm

11 11 the presence of plasma cell dyscrasia or an autoimmune process, diagnosis of the idiopathic form of MBPGN type I or III is allowed. The cause of chronic antigenemia, as a rule, is torpid viral, bacterial, protozoal and other infections (Table 3). The pathogenesis of immunoglobulin-positive MBPGN types I and III has common features. Immune complexes formed in the blood circulation or in situ, due to chronic antigenemia (infection), or circulating immune complexes during autoimmune processes (SLE, Sjögren's syndrome, mixed cryoglobulinemia, etc.), or immune complexes formed during paraproteinemia (monoclonal gammopathies, lymphoproliferative diseases) are deposited in the glomeruli mesangially (for large sizes), subendothelially (for medium sizes) or subepithelially (for small sizes). Table 3. Secondary causes of immunoglobulin- and C3-positive MBPGN A. Infections viral hepatitis B, C human immunodeficiency virus bacterial infectious endocarditis abscess septicemia infected ventriculoatrial and ventriculoperitoneal shunts protozoal malaria schistosomatosis other mycoplasma mycobacterial B. Autoimmune diseases systemic red lupus scleroderma mixed Sjogren's syndrome cryoglobulinemia transplantation nephropathy B. Hematological malignant diseases lymphoma lymphocytic leukemia MGUS* myeloma Waldenström macroglobulinemia G. Other diseases cirrhosis of the liver carcinomas (lungs, kidneys, stomach, intestines) sarcoidosis Immune complexes activate complement along the classical pathway, which involves complement fractions C1q, C2, C4 c the formation of C3 convertase of the classical pathway (C4bC2a), which cleaves the C3 fraction into C3a and C3b subfractions, followed by the formation of C5 convertase of the classical pathway of complement activation (C4bC2aC3b). C5 convertase, acting on the C5 fraction of complement, leads to the formation of C5a and C5b subfractions, the latter

12 12 ultimately leads to the formation of the membrane attack complex (MAC) (C5b-9). Complement subfractions C3a and C5a, acting chemotactically, determine the influx of macrophages and neutrophils from the circulating blood to the location of immune complexes, which, due to proinflammatory cytokines and proteolytic enzymes, cause the formation of an exudative-inflammatory reaction in the glomerulus. Resident cells of the glomerulus (endotheliocytes, mesangiocytes), in response to damage by proinflammatory cytokines and the cytopathic effect of MAC (C5b-9), respond with proliferation, synthesis of the main substance (basal membranes, mesangial matrix) and production of growth factors (transforming growth factor β1, platelet factor growth). Ultimately, morphological signs are formed in the form of doubling of basement membranes, proliferation of mesangiocytes and mesangial matrix with lobulization of the glomerulus, and the formation of zones of sclerosis (glomeruli and tubulointerstitium). Note that secondary MBPGN in HCV infection (hepatitis C virus) can have a dual pathogenesis. In some cases, it may be associated with the formation of immune complexes to hepatitis C virus antigens deposited initially in the glomerulus (i.e. formed in situ), in other cases we are talking about circulating immune complexes of mixed cryoglobulins (type II cryoglobulinemia). Mixed cryoglobulins (type II) during HCV infection are immune complexes that precipitate in the cold, consisting of IgMκ-rheumatoid factor, polyclonal IgG and hepatitis C virus RNA. The primary reason for the formation of cryoglobulins is the formation of a clone of B cells in the body (liver, lymph nodes) under the influence of the hepatitis C virus, which synthesize monoclonal IgMκ (rheumatoid factor). The presence of mixed cryoglobulinemia associated with HCV infection is considered by some authors to be a subclinical form of lymphoma. Among immunoglobulin-positive variants of MBPGN, transplantation glomerulopathy occupies a special place. For a long time, pathomorphological changes in a transplanted kidney were considered from the point of view of the mechanisms of chronic transplant rejection (chronic transplantation nephropathy). Currently, scientific data have been accumulated that make it possible to distinguish transplantation glomerulopathy into an independent clinical and morphological nosological unit with immune pathogenesis. Transplant glomerulopathy is

13 13 is the initial damage to endothelial cells by autoantibodies to class HLA-II antigens, which are present on the outer cell membrane of endothelial cells. In the acute phase, the so-called glomerulitis develops, characterized by damage to glomerular capillaries, mononuclear cells and neutrophils migrating from the circulating blood. An acute, exudative reaction in the glomerulus (glomerulitis) is replaced by a reparative phase, in which proliferation and expansion of the mesangial matrix occurs, duplication of basement membranes develops, and the morphological picture under light microscopy becomes similar to immunoglobulin-positive MBPGN. Immunofluorescence records the deposition along the capillary loops of the glomerulus of the complement fraction C4d - a product of complement activation along the classical pathway, however, even the absence of C4d deposits will not contradict the diagnosis of transplantation glomerulopathy. The etiology of immunoglobulin-negative, C3-positive glomerulonephritis, called C3 glomerulopathy, is explained by dysregulation of the alternative pathway of complement activation and disruption of the terminal stage of MAC formation (C5b-9). Disruption of the normal physiology of the alternative pathway of complement activation can be caused either by mutations in the genes of various factors of the complement system, or be acquired. In the latter case, autoantibodies to regulatory factors of complement activation are formed in the body along the alternative pathway. The chemical structure of deposits in C3 glomerulopathy has not been fully established, but it has been found that they consist of glycosaminoglycans with inclusions of the C3b fraction of complement, its degradation products (ic3b, C3dg, C3c), as well as MAC components (C5b-9). In contrast to the classical pathway of complement activation, when cascade-type reactions are triggered by immune complexes, the alternative pathway is normally characterized by constant, persistent low-level activity, consisting in the formation of small amounts of the C3b fraction due to spontaneous hydrolysis of the thioester bond of the C3 protein. The complement C3b fraction generated in small quantities further binds to the membranes of various cells, including the membranes of pathogenic microorganisms, which is the physiological meaning of this reaction. In order to prevent the transition of this spontaneous activity into an uncontrolled reaction (cascade), the body has a whole system of regulatory factors (proteins) operating at various levels

14 14 cascade reaction, especially during the formation of C3 and C5 convertases. Factor “H” (CFH) promotes the breakdown of the spontaneously formed C3 convertase of the alternative pathway (C3bBb), and together with factor “I” (CFI) (for which CFH is a cofactor) lead to inactivation of the C3b subfraction. A group of proteins (from 1 to 5) similar to factor “H” (CFHR 1-5 complement factor H related proteins) also takes part in the regulation of the complement activation system along the alternative pathway in the circulating blood (regulators of the “liquid phase”). Their function has not been fully studied. It is believed that CFHR1 inhibits the action of MAC, and the mechanism of action of CFHR5 is similar to the regulatory activity of factor “H”. The cause of the formation of C3-positive MBPGN, including BPD, may be mutations in the H factor gene. The monogenic CFHR5 mutation, inherited in an autosomal dominant manner, is the cause of endemic Cyprus nephropathy, which is C3-positive MBPGN type I or III. It should be noted that factors “H” and CFHR5, acting in blood plasma, also have tropism for extracellular membranes, where they retain their inactivating activity against the membrane-bound subfraction of complement C3b. This fact implies several important circumstances for understanding the pathogenesis of C3-positive glomerulopathy. It is known that the pathogenesis of atypical hemolytic-uremic syndrome (agus) can also be associated with genetic mutations of the regulatory factor “H”. However, in this disease, dysregulation of the alternative pathway of complement activation occurs mainly on the surface of the cell membranes of endothelial cells, without affecting the complement activation system in the circulating blood. Therefore, although in rare cases the initial formation of C3-positive glomerulopathy in a-hus is possible, the most typical scenario of the pathological process in it is the initial damage to endothelial cells with the formation of microthrombosis of the glomerular capillaries and only after some time, when reparative (proliferative) processes are activated, such as response of resident glomerular cells to endothelial damage, the morphological picture of MBPGN begins to form (C3-negative and without electron-dense deposits). CFHR5 has an affinity for glycosaminoglycans, and therefore, when the gene for this factor is mutated (Cyprus nephropathy), primary activation of the alternative complement pathway occurs on the glomerular basement membrane. As a result, C3-positive MBPGN is formed with subendothelial and/or

15 15 subepithelial electron-dense deposits (type I or III). The inhibitory effect of factors “H” and CFHR5 on C3b on the surface of the glomerular basement membrane forms the physiological “protection” of the kidneys from immune-complex glomerulonephritis and explains those rare cases of immunoglobulin-positive MBPGN (i.e., immune-complex), in which gene mutations are detected factor "N". Mutations in the genes of the main proteins of the complement system are also described in the literature. Thus, with a heterozygous mutation of the C3 protein, both the mutant C3 protein and the native one synthesized by the gene of the allele not involved in the mutation are present in the blood plasma. As a result of spontaneous hydrolysis of the mutant C3 protein, C3 convertase is formed, resistant to the action of factor “H”, which breaks down the C3 protein synthesized by the normal gene, resulting in the formation of excess degradation products of the C3 fraction of complement, which triggers a cascade reaction of complement activation by an alternative path. A similar mechanism may underlie the glomerular response in the form of the formation of BPD. Genetic polymorphism of complement system factors, leading to changes in protein structure and disruption of their function, may also play an important role in the pathogenesis of C3-positive glomerulopathy. It should be emphasized that the complement system has a multi-stage regulation system, and therefore not every genetic mutation or gene polymorphism is realized clinically. In most cases, a combined action of environmental factors is necessary to form a genetically programmed phenotype. These provoking factors include, first of all, infections, and possibly other causes (lifestyle, nutrition, chronic intoxication, concomitant diseases, etc.). This can be confirmed by well-known cases of synpharyngitis macrohematuria with MBPGN, which are well known to the clinician. The cause of acquired disorders in the system of regulation of the alternative pathway of complement activation is the formation in the body of autoantibodies to regulatory proteins (factors H, B, etc.) or to the main fractions of complement. The most well-known and studied is C3 nephritic factor (C3NeF), which is an autoantibody (IgG) to C3 convertase (C3bBb) of the alternative pathway of complement activation. The attachment of an autoantibody to C3 convertase makes it more resistant to action

16 16 regulatory proteins (CFH, factor I, CFHR 1-5), which prolongs its circulation in the blood. The result of the unregulated activity of C3 convertase is the activation of complement with a gradual depletion of the C3 fraction pool and a decrease in its concentration in the blood plasma. C3NeF is detected in 86% of patients with BPD and in 49% of patients with C3-positive glomerulonephritis, however, not in all patients this is combined with a decrease in the C3 fraction of complement, which indicates the existence of other regulatory mechanisms in the body that counteract C3NeF. Dysregulation of the alternative complement pathway in BPD is associated with two conditions often associated with this disease. The first is represented by acquired partial lipodystrophy, clinically characterized by a gradual (over many years), symmetrical loss of subcutaneous fat in the “cephalocaudal” direction, starting from the face, neck, arms, and chest. At the final stage, the subcutaneous fatty tissue of the lower extremities may be involved. It is believed that C3NeF causes activation of complement on the cell surface of adipocytes, which leads to their death through apoptosis. The second condition is characterized by the formation of whitish-yellow “drusen” (plaques) in the pigment membrane of the retina. The visual picture of the fundus and the clinical course are similar to age-related macular degeneration of the retina. It is believed that the leading pathogenetic mechanism of this process is a violation of the local regulatory activity of factor “H”. Electron microscopy of autopsy material (retina) reveals electron-dense deposits along the basement membranes of the retinal capillaries. Due to choroidal neovascularization, which develops over time, there is a gradual loss of vision. The reason for the fact that in one case of C3-positive glomerulopathy the morphological picture of type I or III MBPGN is formed, and in another case BPD is detected, remains unclear. Apparently, the heterogeneity of genetic mutations, the initial localization of the process, and the degree of activation of the complement system are important. Activation of the alternative complement pathway, as mentioned above, can also be involved in cases of a primary immune complex mechanism of damage, especially when the main pathological process is accompanied by genetic polymorphism of regulatory protein genes (CFH, CFI). With monoclonal gammopathies, with

17 17 which usually forms immunoglobulin-positive MBPGN (which is characterized by the classical pathway of complement activation), another pathogenesis pathway has recently been discovered. It turned out that monoclonal immunoglobulin can act as an antibody to factor H and other regulatory proteins, leading to dysregulation of the alternative complement pathway and the formation of C3-positive glomerulopathy. The etiology of immunoglobulin- and C3-negative MBPGN consists of primary damage to endothelial cells (thrombotic microangiopathy, malignant hypertension syndrome, etc.), followed by a reparative phase in the form of proliferative changes in the glomerulus, identified optically as MBPGN. Electron microscopy in these cases does not reveal electron-dense deposits, and therefore it is not possible to establish the type of MBPGN (Fig. 1, Table 4). Table 4 Causes of immunoglobulin and C 3 -complement negative MBPGN thrombotic thrombocytopenic purpura atypical HUS associated with disturbances in the complement regulation system antiphospholipid syndrome drug thrombotic microangiopathies nephropathy after bone marrow cell transplantation radiation nephritis malignant hypertension syndrome α-1-antitrypsin deficiency sickle cell anemia Morphopathogenesis of C3-negative glomerulopathy in most diseases listed in Table. 4, comes down to damage to endothelial cells in the acute phase, which is manifested by their swelling, mesangiolysis develops, and fibrin thrombi form in the capillaries of the glomeruli. The acute phase of damage is replaced by a reparative phase, characterized by a response from resident glomerular cells. There is an increase in the mesangial matrix and proliferation of mesangial cells, double-circuit basement membranes of capillaries appear, i.e. a morphological picture of MBPGN is formed.

18 18 In rare cases of genetic anomaly of α-1-antitrypsin deficiency, a mutant protein Z is synthesized in the liver, which, entering the glomeruli with circulating blood, is polymyrized and deposited subendothelially. Z-protein deposits are the cause of the response of resident glomerular cells, which at the final stage leads to the formation of a morphological picture of MBPGN under light microscopy. The diagnosis can be clarified by immunofluorescence using specific antisera to the Z-protein. Section 5. Treatment of idiopathic MBPGN Recommendation 5.1. When deciding on the nature of pathogenetic therapy for idiopathic MBPGN, it is necessary to take into account the leading clinical syndrome and data from a morphological study of kidney biopsies (NG). Recommendation 5.2. Immunosuppressive therapy for idiopathic MBPGN is indicated only in cases with nephrotic syndrome, with a slowly progressive but steady decline in renal function despite nephroprotective therapy, or with rapidly progressive nephritic syndrome (2D). Recommendation 5.3. The most optimal regimen for immunosuppressive therapy for idipathic MBPGN with nephrotic syndrome or with a slowly progressive decline in renal function is the use of cyclophosphamide (2-2.5 mg/kg/day) or mycophenolate mofetil (1.5-2 g/day) in combination with prednisolone ( 40 mg/day) according to an alternating regimen. The duration of therapy should be at least 6 months (2D). Recommendation 5.4. In case of idiopathic MBPGN with rapidly progressive nephritic syndrome, plasmapheresis is indicated (3 liters of plasma per session 3 times a week), pulse therapy with methylprednisolone (0.5-1.0 g/day for 3 days) and further maintenance immunosuppressive therapy according to the regimen (see. rec 5.3) (2D). Commentary There is currently no consensus regarding the treatment tactics for immunoglobulin-positive idiopathic MBPGN. When deciding on the nature of pathogenetic therapy for idiopathic MBPGN, it is necessary to take into account the clinical variant of the disease (leading clinical syndrome) and data from a morphological study of kidney biopsies. If the clinical picture is dominated by isolated urinary syndrome (IUS) or the syndrome of recurrent gross hematuria, then they limit themselves to renoprotective therapy (ACE inhibitors, AT 1 antagonists, statins, diet) and strive for complete normalization of blood pressure (not higher than 130/80 mm Hg). If the patient has subnephrotic proteinuria (less than 3.5 g/day) and a decrease in renal function to the level of CKD 3-4 tbsp. , and during morphological examination

19 19 If severe tubulointerstitial sclerosis is detected, then aspirin (975 mg/day) and dipyridamole (325 mg/day) can be additionally prescribed (there is no evidence base for the effectiveness of such therapy). In cases of nephrotic syndrome and progressive deterioration of renal function, a combination of cyclophosphamide (2-2.5 mg/kg per day) or mycophenolate mofetil (1.5-2 g/day) in combination with low doses of prednisolone (40 mg/day) is used. better with an alternating regimen for 6 months (KDIGO recommendations). For BPNS with the presence of crescents in more than 50% of the glomeruli, plasmapheresis, pulse therapy with methylprednisolone followed by oral administration of cyclophosphamide in combination with prednisolone are recommended (see above for the regimen). We emphasize that in all clinical variants of the course of MBPCN, renoprotection measures are always carried out. Section 6. Treatment of secondary MBPGN Recommendation 6.1. In secondary forms of MBPGN, the main direction of treatment is therapy of the underlying disease (Tables 3, 4) (1A). Recommendation 6.2. The use of immunosuppression in secondary forms of MBPGN is allowed only in cases with rapidly progressive nephritic syndrome (2B). A comment. In case of immunoglobulin-positive MBPGN, first of all, it is necessary to establish or exclude the secondary cause of the disease (Tables 3, 4). In secondary forms of MBPGN, the main condition remains treatment of the underlying disease. This is especially true for infections. With HCV associated MBPGN with CKD stages 1 and 2. Regardless of the pathogenesis (non-cryoglobulinemic or cryoglobulinemic variants), the first line of therapy is the use of pegylated interferon alpha and ribavirin in normal doses, taking into account the genotype of the virus. For CKD stages 3, 4 and 5. (regardless of dialysis therapy) recommended: pegylated interferon alfa 2a: 135 mcg subcutaneously once a week or interferon alfa 2b: 1 mcg/kg subcutaneously once a week. According to the latest KDIGO guidelines, ribavirin should be used with caution in GFR.< 50 мл/мин/1,73 м 2 (табл. 5). При криоглобулинемическом варианте МБПГН, который резистентен к применению антивирусных препаратов или протекает с выраженными признаками криоглобулинемического васкулита (кожа, легкие, гломерулонефрит с полулуниями) препаратом выбора является ритуксимаб (анти-cd-20 моноклональное антитело), применение которого приводит к истощению пула В-

20 20 lymphocytes producing cryoglobulins (375 mg/m 2 once a week for 4 weeks). Table 5. Treatment of hepatitis C viral infection according to CKD stages (KDIGO) CKD stage Interferon a Ribavirin b 1 and 2 Pegylated IFNα -2a: 180 μg SC weekly Pegylated IFNα -2b: 1.5 μg/kg SC weekly mg/day divided into two doses 3 and 4 PEGylated IFNα -2a: 135 μg SC weekly PEGylated IFNα -2b: 1 μg/kg SC weekly * 5 PEGylated IFNα -2a: 135 μg SC weekly PEGylated IFNα -2b: 1 mcg/kg s.c. weekly * rskf estimated glomerular filtration rate, IFN - interferon; s/c subcutaneously. a Patients with genotypes 1 and 4 should receive IFN therapy for 48 weeks if early viral/virological response is achieved within 12 weeks (>2 log reduction in viral titer). Genotypes 2 and 3 should receive therapy for 24 weeks b Patients with genotypes 2 and 3 should receive 800 mg/day in stages 1 and 2 CKD. Infected patients with genotypes 1 and 4 should receive mg/day in stages 1 and 2 CKD * Since the publication of the KDIGO guideline on hepatitis C in patients with CKD, the drug label has changed to allow concomitant use of ribavirin in patients with CKD 3 -5 stages if side effects are minimal and can be corrected. With clearance (creatinine)<50 мл/мин рекомендуется осторожность, что может потребовать существенного снижения дозы. Информация о модификации дозы изложена в инструкции по применению препарата. Менее эффективной альтернативой в этих случаях является плазмаферез (3 л плазмы 3 раза в неделю, 2-3 недели) в сочетании с пульс-терапией метилпреднизолоном (0,5 1 г/сут 3 дня), преднизолоном (1-1,5 мг/кг в день) и циклофосфамидом (2 мг/кг в день) в течение 2 4 мес. Дозы препаратов следует соотносить со значениями СКФ. При некриоглобулинемическом HCVассоциированном МБПГН от иммуносупрессии следует воздержаться, за исключением случаев с БПНС и наличием полулуний в клубочках. При бактериальных инфекциях (например, при инфекционном эндокардите) иммуносупрессия не рекомендуется (рекомендации KDIGO). При остальных заболеваниях, перечисленных в табл. 3 и являющихся причиной вторичного МБПГН, проводят лечение основной болезни. При иммуноглобулин-негативных вариантах МБПГН лечение назначается также с учетом данных о патогенезе заболевания. При С3-позитивной гломерулопатии, обусловленной мутациями генов регуляторных факторов системы комплемента (H, I) показаны инфузии свежезамороженной донорской плазмы крови (донатор

21 21 native factors). If the cause of C3-positive glomerulopathy is autoantibodies to C3 convertase (C3NeF), regulatory factors H, I, etc., then it is advisable to start treatment with plasmapheresis (in plasma exchange mode and using a replacement solution in the form of donor plasma and albumin). Next, as a rule, glucocorticoids or rituximab are indicated (they block the production of autoantibodies). Recently, studies have appeared on the high effectiveness of eculizumab, which is a monoclonal antibody to the C5 fraction of complement (blocks the formation of MAC), for genetic variants of C3-positive glomerulopathy. As is known, eculizumab was initially proposed for the treatment of paroxysmal nocturnal hemoglobinuria and atypical HUS. For other pathogenetic variants of C3-negative glomerulopathy, treatment tactics depend and are determined by the underlying disease. Section 7. Prognosis of MBPGN Recommendation 7.1. When determining the prognosis of MBPGN, it is necessary to take into account clinical, laboratory and morphological factors (Table 6) (2C). Commentary It is difficult to determine the exact prognosis for the development of MBPGN, since in recent years ideas about the pathogenesis of the disease have changed, which makes the use of “historical control” impossible. The 10-year renal survival rate for immunoglobulin-positive MBPGN appears to be 50-60% and depends on many factors (Table 6), the main one being the formation of crescents in more than 50% of the glomeruli. With C3 glomerulopathy, the 10-year renal survival rate is 30-50% (lower with genetic variants). The frequency of recurrent glomerulonephritis in the graft with immunoglobulin-positive MBPGN ranges from 18-50% (HLA haplotype B8DR3 is an unfavorable predictor). Graft survival may be improved by adding cyclophosphamide to immunosuppressive therapy. With BPD, the incidence of recurrent glomerulonephritis ranges from 67 to 100%. If the cause of BPD is a mutation of the factor H gene, plasmapheresis and infusions of fresh frozen plasma are indicated before and after kidney transplantation.

22 22 Table. 6. Predictors of unfavorable prognosis for renal survival in immunoglobulin-positive MBPGN Clinical male gender nephrotic syndrome arterial hypertension gross hematuria absence of spontaneous or drug-induced clinical remission during the disease Laboratory low Hb level increased creatinine and/or decreased GFR at the onset of the disease Morphological diffuse doubling of basal values membranes compared to the focal segmental crescent in more than 20% of the glomeruli, pronounced mesangial proliferation (lobular variant), mesangial deposits and sclerosis, pronounced tubulo-interstitial changes References 1. Dobronravov V.A., Dunaeva N.V. Kidney damage and chronic viral hepatitis C // Nephrology; v. 12, 4, with Laura S., Fremu-Bachi V. Atypical hemolytic-uremic syndrome // Nephrology; t. 16, 2, with Ferry S. Mixed cryoglobulinemia // Nephrology; v.14, 1, with Appel G.B. Membranoproliferative glomerulonephritis - mechanisms and treatment // Contrib Nephrol. 2013; 181: D Agati V.D., Bomback A.S. C3 glomerulopathy: what's in a name? // Kidney Int. 2012; 82: Bomback A.S., Appel G.B. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN // Nat. Rev. Nephrol. 2012; 8: Bomback A.S., Smith R.J., Barile G.R. et al. Eculisumab for dense deposit disease and C3 glomerulonephritis // Clin. J. Am. Soc. Nephrol. 2012; 7:

23 23 8. KDIGO Clinical practice guideline for glomerulonephritis // Kidney Int. Suppl. 2012; 2(2): Fervensa F.C., Sethi S., Glassock R.J. Idiopathic membraneproliferative glomerulonephritis: does it exist? // Nephrol Dial Transpant. 2012; 27(12): Fregonese L., Stolk J. Hereditary alpha-1-antitrypsin deficiency and its clinical consensus // Orphanet J. Rare Diseases. 2008; 3: Hou J., Markowitz G.S., Bomback A.S. et al. Toward a working definition of C3 glomerulopathy by immunofluorescence // Kidney Int 2013; Sept 25 12. Morales J.M., Kamar N., Rostaing L. Hepatitis C and renal disease: epidemiology, diagnosis, pathogenesis and therapy // Contrib Nephrol. Bazel Karger 2012; 176: Pickering M.C., Cook H.H. Complement and glomerular disease: new insights // Curr Opin. Nephrol Hypertens. 2011; 20: Pickering M.C., D Agati V.D., Nester C.M. et al. C3 glomerulopathy: consensus report // Kidney Int 2013, Oct 30 15. Sethi S., Fervenza F.C. Memranoproliferative glomerulonephritis a new look at an old entity // N. Engl. J. Med. 2012; 366: Servias A., Noel L-H., Roumenina L.T. et al. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies// Kidney Int 2012; 82: Smith R.J.H., Harris C.Z., Pickering M.C. Dense Deposit Disease // Mol. Immunol. 2011; 48: Sun Q., Huang X., Jiang S. et al. Picking transplant glomerulopathy out of the CAN: evidence from a clinico-pathological evaluation // BMC Nephrology 2012; 13:128

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Glomerulonephritis is a disease that occurs due to an allergic or infectious nature.

Disease history

Diagnosis of the disease

At the first visit, the patient is examined for the first signs glomerulonephritis.

Visible signs of glomerulonephritis include high blood pressure and confirmation by the patient of the fact that he has recently suffered an infectious disease or inflammation in the kidney area, and may be subject to severe hypothermia.

Since complaints and visible symptoms may be similar to signs of pyelonephritis, the specialist will prescribe a series of tests for a more accurate picture of the disease.

During the appointment, the doctor tries to understand whether the complaints indicate on the inflammatory process in the kidneys or is it a manifestation of another disease.

Diagnostic tests to detect acute glomerulonephritis always require thorough examination of general blood and urine tests patient. To do this, the patient must undergo the following types of tests:

1. Clinical urine analysis.
2. Urine analysis using the method.
3. Urinalysis using the Kakovsky-Addis method.

Based on the results of the analysis, the doctor will determine glomerulonephritis according to the following indicators:

• oliguria, that is, a decrease in the volume of urine excreted from the body;
• proteinuria, which means the protein content in urine;
• hematuria, that is, the presence of blood particles in the urine.

First of all, for the presence of glomerulonephritis indicates proteinuria, which is a consequence of improper filtration by the kidneys. Hematuria also indicates damage to the glomerular apparatus, as a result of which blood particles enter the urine.

Sometimes it takes taking kidney tissue biopsy and tests that reveal an immunological predisposition to this disease.

In order to accurately determine whether the inflammation is glomerulonephritis, the doctor will give a referral for an ultrasound scan, which can find the main signs of this disease.

Such signs include increase in kidney volume with smooth contours, thickening of tissue structures and, of course, changes in diffuse character in the tubules, glomerular apparatus and connective tissue.

Kidney biopsy to identify the disease

The kidney tissue biopsy method is used to study in detail a small fragment taken from the kidney tissue. During the study, a morphological analysis will be carried out to identify the factor that initiated the inflammatory process and other indicators.

This is a method of intravital examination of an organ for the presence of a pathological process.

This type of research allows you to study the immune complex to accurately determine the shape and size, as well as severity and form of the disease in organism.

In cases where the definition of glomerulonephritis has become difficult or the doctor cannot differentiate this disease from another, this method becomes indispensable in terms of its informativeness.

There are several methods for conducting such research. These include:

1. Open.

This type of material collection is carried out during surgery when there is a need to remove operable tumors or when there is only one kidney. This procedure is performed under general anesthesia. In most cases, taking a small piece of tissue ends without complications.

2. Biopsy in tandem with urethroscopy.

This method is used for people suffering from urolithiasis, as well as pregnant women and children. Sometimes it is performed on those patients who have an artificial kidney.

3. Transjugular.

This type of research is carried out through catheterization of the renal vein. The doctor prescribes this type of material collection when the patient is clearly obese or has poor blood clotting.

4. Transdermal.

This method is carried out under control using X-rays, as well as ultrasound or magnetic resonance imaging.

Is it possible to cure glomerulonephritis forever?

Glomerulonephritis can occur in two forms: acute and chronic. The acute form is curable with timely diagnosis and correct treatment methods.


If time for drug treatment was missed, and the disease smoothly turned into a chronic form, then you cannot completely get rid of this disease, but you can maintain your body in a state where the disease cannot develop further and affect more and more kidney elements.

In this case, the doctor will prescribe a specific diet and tell you on compliance with a special regime, which can protect the patient from developing a new relapse of the disease.

If a complete cure cannot be achieved, the doctor recommends following all established rules and preventive measures so that the symptoms become less noticeable. Sometimes, with successful therapeutic treatment, it is possible to achieve temporary disappearance of symptoms.

It is necessary to support the body for as long as possible before a new relapse occurs.

Treatment

When the acute stage of glomerulonephritis appears, the patient should be hospitalized.

At the same time, he will be required to be placed on bed rest. This is important in order for the kidneys to be at a certain temperature, that is, the regime for maintaining a particular temperature must be balanced. This method, with timely hospitalization, can optimize kidney function.

The average length of hospitalization is from two weeks to one month, that is, until symptoms are completely eliminated and the patient’s condition improves.

If the doctor considers that there is an additional need to extend the hospital stay, then the patient's stay in the ward may be increased.

Medication

If, based on the results of studies conducted, it has been proven that the disease is caused by infectiously, then the patient is prescribed antibiotics to take.

In most cases, several weeks before the onset of the acute phase of the disease, the patient suffered an infectious sore throat or other disease. Almost always, the causative agent of the disease is β-hemolytic streptococcus.

In order to get rid of the causative agent of the disease, the patient is prescribed the following drugs:

• Ampicillin;
• Penicillin;
• Oxacillin;
• Ampiox with intramuscular administration;
• Sometimes doctors prescribe Interferon for rapidly progressing glomerulonephritis.

A common occurrence in such a disease is the damaging effect against the glomerular apparatus by one’s own antibodies in the body. That's why use of immunosuppressants is an integral part of complex treatment against glomerulonephritis. These drugs are able to establish a suppressive reaction of the immune response.

If the disease develops rapidly, the patient is prescribed large doses of IV drips for several days. After several days of administration of this drug, the dose is gradually reduced to the usual level. For such purposes it is often prescribed cytostatics, such as Prednisolone.

Treatment with Prednisolone in the first stages is prescribed by a doctor in the prescribed dosage, which is also prescribed by a specialist. The course of treatment is continued for one and a half or two months. In the future, when relief occurs, the dose is reduced up to twenty milligrams per day, and if the symptoms begin to disappear, then the drug can be discontinued.

In addition to this drug, medical experts often advise taking Cyclophosphamide or Chlorambucil in the dosage prescribed by the doctor. Experienced medical specialists, in addition to immunosuppressants, prescribe anticoagulants such as Curantil or Heparin.

The combination of these remedies must be justified by the form of the disease and the degree of its neglect.

After the main symptoms have subsided and a period of remission has begun in the body, then maintenance and treatment of glomerulonephritis is allowed traditional medicine.

Exercise therapy

Physical therapy for the treatment and prevention of glomerulonephritis should be prescribed by the treating specialist, taking into account all the tests and indicators of the person.

In this matter, the doctor also focuses to activity mode patient, which can be bed, general or ward. Typically, a set of exercises is prescribed for stable conditions during the acute course of the disease or for chronic glomerulonephritis during remission.

These types of physical exercises are carried out for the purpose of:

1. Improves blood flow to the kidneys and other organs.
2. Reducing blood pressure and improving metabolism in the body.
3. Increasing the body's strength to fight the disease.
4. Increased performance.
5. Elimination of stagnation formed in the human body.
6. Creating a general positive attitude to fight the disease.

Before starting the exercises, it is recommended to measure your blood pressure level and only then begin the set of exercises.

The classic exercise therapy complex for eliminating glomerulonephritis includes exercises performed in a lying position or on a chair. The practitioner's attention should be completely concentrated on the time of inhalation and exhalation.

All types of movements must be performed at a slow pace with smooth amplitude. Types of loads alternate for different muscle groups in order not to overload any of them excessively.

Duration of such classes should not be more than half an hour, otherwise it may have a negative impact on the patient and cause various complications.

ethnoscience

When visiting your doctor, they may be prescribed various infusions and decoctions of herbs, which have a beneficial effect on the functioning of the renal system.

• 100 grams of walnuts;
• 100 grams of figs;
• a few spoons of honey;
• three lemons.

All ingredients are crushed and mixed. The mixture is taken within three times a day one tablespoon, usually before meals. These components must be consumed until tests show improved results.

There are special decoctions designed to eliminate swelling and bring blood pressure back to normal. The following recipe applies to such decoctions:

• Flaxseed in the amount of four tablespoons is mixed with three tablespoons of dry birch leaves.
• To this mixture you need to add three tablespoons of field steelroot.
• It is recommended to pour the resulting mixture with 0.5 liters of boiling water and leave for two hours.

The infusion is consumed three times a day, one third of a glass. The effect will be visible in one week.

All herbs that have an antimicrobial and anti-inflammatory effect will be suitable for preparing medicinal infusions. These herbs include:

• rose hip;
• calendula;
• St. John's wort;
• sea ​​buckthorn;
• sage;
• yarrow;
• birch leaves, as well as its buds;
• burdock root.

Herbs can be brewed separately or combined with each other, of course according to certain recipes.

In addition to decoctions and infusions, experts in the field of traditional medicine recommend drinking as much as possible natural juices mainly from cucumber and carrots, and also eat a lot of fruits and vegetables that can fill a weakened body with vitamins.

In addition, the doctor will prescribe a special diet, called, which will strengthen the body while fighting the disease. The main rule of the diet is to exclude salted, smoked and fried foods from the diet. Eating protein foods should be somewhat limited.

Drinking alcohol during treatment is prohibited, as is coffee.

Disease prevention

In order to avoid further development of the disease and its transition to a chronic form, it is necessary to adhere to dietary nutrition and completely give up alcoholic drinks.

If a person works at a chemical plant or is engaged in other activities where he may be exposed to heavy metals, he needs to protect his body from harmful effects or change his profession.

If glomerulonephritis has advanced to the stage, then every effort must be made to avoid recurrence of exacerbation diseases. It is necessary to be vaccinated according to the schedule established by a specialist, and also to remain calm psychologically and physically.

Regular examination in the office of a specialist will protect the body from new manifestations of the disease. The main rule is to prevent bacteria from entering the human body. It is necessary to avoid working in damp areas or activities involving heavy lifting.

The patient must follow a therapeutic diet and fill the body with vitamins. It is advisable to carry out at least once a year sanatorium treatment.

A urologist will tell you more about the causes of the disease in a video clip:

Medical science does not stand still, constantly expanding with new methods for diagnosing various diseases and methods of treating them. Based on the latest scientific and practical developments in each country, including ours, recommendations for practicing doctors regarding many diseases are updated annually. Based on the diagnostically and therapeutically complex renal disease glomerulonephritis, let us consider the clinical recommendations that were published in 2016.

Introduction

These recommendations, which summarize diagnostic and therapeutic approaches to some forms of glomerulonephritis, are collected on the basis of progressive world practice. They were compiled taking into account domestic and international standards for the treatment of this type of nephropathy, based on clinical observations and scientific research.

These recommendations are not considered as a certain standard for the provision of medical care, taking into account the different diagnostic capabilities of clinics, the availability of certain medications and the individual characteristics of each patient. Responsibility regarding the appropriateness of the recommendations below rests with the attending physician on an individual basis.

Features of the disease

Acute glomerulonephritis, which occurs after a streptococcal infection, manifests itself morphologically as diffuse inflammation of the renal medulla with a predominance of proliferation of intervascular tissue of the renal parenchyma. Mostly this form of the disease occurs in childhood between 4 and 15 years (about 70% of registered cases). The pathology is also typical for adults under 30 years of age, but with a lower incidence for a certain number of the population in this age group.

Causes and mechanism of pathological changes

The main cause of inflammatory processes in the renal medulla is considered to be an autoimmune attack by immune complexes based on immunoglobulins (antibodies) produced in response to streptococcal infection localized in the upper respiratory tract (pharyngitis, tonsillitis). Once in the renal intervascular tissue, immune complexes damage connective tissue cells, simultaneously provoking the production of bioactive substances that stimulate proliferative processes. As a result, some cells become necrotic, others grow. In this case, there is a violation of capillary circulation, dysfunction of the glomeruli and proximal tubules of the renal medulla.

Morphology

Histological examination of tissue from the medullary layer of the kidneys taken for biopsy reveals proliferative inflammation with deposition of immune complexes, accumulation of neutrophilic leukocytes in intercapillary cells and in the endothelium of glomerular vessels. They are deposited as merging granules that form conglomerates. Damaged cells are filled with fibrin and other connective tissue substances. The cell membranes of glomerular and endothelial cells are thinned.

Clinical manifestations

The severity of symptoms is very variable - from microhematuria to the full-blown form of nephrotic syndrome. Symptoms appear after a certain period after a streptococcal infection (2-4 weeks). Among the manifestations of a detailed clinical picture, the following symptoms are noted, including laboratory ones:

• Decreased amount of urine excreted associated with impaired glomerular filtration, retention of fluid and sodium ions in the body.
• Swelling localized on the face and in the ankle area of ​​the lower extremities, which also becomes a consequence of insufficient removal of fluid from the body by the kidneys. The renal parenchyma often swells, which is determined by instrumental diagnostic methods.
• Increased blood pressure numbers observed in approximately half of the patients, which is associated with an increase in blood volume, an increase in peripheral vascular resistance, and an increase in cardiac (left ventricle) output. Various degrees of hypertension are observed, from slight increases in blood pressure to high numbers, at which complications are possible in the form of hypertensive encephalopathy and congestive heart failure. These conditions require urgent medical intervention.
• Hematuria of varying degrees severity accompanies almost all cases of the disease. Approximately 40% of patients have macrohematuria, in other cases microhematuria determined by laboratory tests. Approximately 70% of red blood cells are determined to have a violation of their shape, which is typical when they are filtered through the glomerular epithelium. Cylinders of red blood cells, characteristic of the pathology in question, are also detected.
• Leukocyturia is present in approximately 50% of patients. The sediment is dominated by neutrophilic leukocytes and a small number of lymphocytes.
• Proteinuria with this type of glomerulonephritis is rarely detected, mainly in adult patients. The content of protein in urine, characteristic in quantity for nephrotic syndrome in children, is practically not found.
• Impaired renal function(increased serum creatinine titer) is detected in a quarter of patients. Cases of rapid development of severe renal failure with the need for hemodialysis are extremely rarely recorded.

Important! Due to the wide variety of clinical manifestations, including in children, the disease requires careful diagnosis, where modern laboratory and instrumental techniques come first in terms of information content.

When making a diagnosis, an important role is played by anamnestic data on an acute infection of the upper respiratory organs suffered several weeks ago with confirmation of hemolytic streptococcus as the causative agent. Next, the necessary laboratory tests of urine are carried out to detect changes characteristic of the disease. Blood is also examined, and an increase in the titer of antibodies to streptococcus is of diagnostic significance.

In cases with rapid development of clinical manifestations, a puncture biopsy of renal medulla tissue is allowed for cytological studies to confirm the diagnosis. If the clinical picture is not aggravated and corresponds to the main manifestations of acute glomerulonephritis of streptococcal origin, a biopsy is not indicated as an additional diagnostic method. Tissue collection for research is mandatory in the following situations:

• severe long-lasting (more than 2 months) urinary syndrome;
• severe manifestations of nephrotic syndrome;
• rapid progress of renal failure (a sharp decrease in glomerular filtration along with an increase in creatinine titer in the blood serum).

With a confirmed history of streptococcal infection shortly before the onset of acute glomerulonephritis, typical clinical and laboratory symptoms, the correctness of the diagnosis is beyond doubt. But with long-term hypertension, hematuria, absence of positive treatment dynamics or undocumented streptococcal infection, it is necessary to differentiate the pathology from other forms of damage to the renal medulla, such as:

• IgA nephropathy;
• membranoproliferative glomerulonephritis;
• secondary glomerulonephritis against the background of systemic autoimmune connective tissue diseases (hamorrhagic vasculitis, SLE).

Treatment

Therapy for this form of glomerulonephritis includes etiotropic effects (sanitation of the focus of streptococcal infection), pathogenetic (inhibition of immune reactions and proliferation of renal cells) and symptomatic treatment.

To influence streptococcal microflora, antibiotics are prescribed to which these microorganisms are most sensitive. These are the latest generations of macrolides and penicillin drugs.

To relieve autoimmune inflammation and prevent the proliferation of renal tissue, hormonal drugs (glucocorticosteroids) and cytostatics (antitumor pharmacological agents) are used. In the presence of an inactive inflammatory process with minimal symptoms and no signs of renal failure, such drugs are used with caution or are not used at all.

To relieve symptoms, antihypertensive drugs (ACE inhibitors) and diuretics are prescribed for significant edema. Diuretics are prescribed only according to indications, including the following conditions:

• severe form of arterial hypertension (pressure is not relieved by antihypertensive drugs);
• respiratory failure (swelling of lung tissue);
• severe swelling in the cavities, threatening the vital functions of organs (hydropericardium, ascites, hydrothorax).

The prognosis for this form of glomerulonephritis is favorable. Long-term cases of total renal failure do not exceed 1%. Unfavorable factors that determine long-term negative prognosis are the following conditions:

• uncontrolled arterial hypertension;
• elderly age of the patient;
• rapid development of renal failure;
• long-lasting (more than 3 months) proteinuria.

© E.M.Shilov, N.L.Kozlovskaya, Yu.V.Korotchaeva, 2015 UDC616.611-036.11-08

Developer: Scientific Society of Nephrologists of Russia, Association of Nephrologists of Russia

Working group:

Shilov E.M. Vice-President of NONR, Chief Nephrologist of the Russian Federation, Head. Department of Nephrology and

hemodialysis IPO GBOU VPO First Moscow State Medical University named after. THEM. Sechenov, Ministry of Health of the Russian Federation, Dr. med. Sciences, Professor Kozlovskaya N.L. Professor of the Department of Nephrology and Hemodialysis IPO, senior researcher Department of Nephrology Research Center

First Moscow State Medical University named after I.M. Sechenov, Dr. med. Sciences, Professor Korotchaeva Yu.V. senior researcher Department of Nephrology Research Center, Associate Professor of the Department of Nephrology and Hemodialysis IPO GBOU VPO First Moscow State Medical University named after. I.M., Ph.D. honey. sciences

CLINICAL GUIDELINES FOR DIAGNOSIS AND TREATMENT OF RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (EXTRACAPILLARY GLOMERULONEPHRITIS WITH CRESCENT FORMATION)

Developer: Scientific Society of Nephrologists of Russia, Association of Nephrologists of Russia

Shilov E.M. Vice President of SSNR, chief nephrologist of the Russian Federation, head of Department

of Nephrology and hemodialysis FPPTP of the First Moscow state medical university. I. M. Sechenov, MD, PhD, DSci, professor Kozlovskaya N.L. professor of Department of Nephrology and hemodialysis FPPTP, leading researcher of the Department of Nephrology of Scientific Research Center of the First Moscow state medical university. I. M. Sechenov, MD, PhD, DSci, professor Korotchaeva Ju.V. senior researcher of the Department of Nephrology of Scientific Research Center of the First Moscow state medical university. I. M. Sechenov, MD, PhD

Abbreviations:

BP - blood pressure AZA - azathioprine

ANCA - antibodies to the cytoplasm of neutrophils ANCA-SV - ANCA-associated systemic vasculitis

ANCA-GN - ANCA-associated glomerulo-

AT - antibodies

RPGN - rapidly progressive glomerulonephritis ARB - angiotensin receptor blockers UDP - upper respiratory tract IVIG - intravenous immunoglobulin HD - hemodialysis

GPA - granulomatosis with polyangiitis (Wegener's)

GK - glucocorticoids

GN - glomerulonephritis

RRT - renal replacement therapy

ACEi - angiotensin-converting inhibitors

enzyme

IHD - coronary heart disease

LS - drugs MMF - mycophenolate mofetil MPA - microscopic polyangiitis MPO - myeloperoxidase MPA - mycophenolic acid NS - nephrotic syndrome PR-3 - proteinase-3 PF - plasmapheresis

eGFR - estimated glomerular filtration rate

SLE - systemic lupus erythematosus Ultrasound - ultrasound examination UP - periarteritis nodosa CKD - ​​chronic kidney disease ESRD - chronic renal failure CNS - central nervous system CF - cyclophosphamide ECG - electrocardiogram EGPA - eosinophilic granulomatosis with polyangiitis (synonym - Churg-Strauss syndrome)

From the patient's side From the doctor's side Further direction of use

Level 1 “Experts Recommend” The vast majority of patients in a similar situation would prefer to follow the recommended path and only a small proportion of them would reject this path The doctor will recommend to the vast majority of his patients to follow this path The recommendation can be accepted as the standard of medical action personnel in most clinical situations

Level 2 “Experts believe” Most patients in a similar situation would be in favor of following the recommended path, but a significant proportion would reject this path. For different patients, different recommendations should be selected to suit them. Each patient needs assistance in choosing and making decisions that are consistent with that patient's values ​​and preferences Guidelines will likely require discussion among all stakeholders before they are accepted as a clinical standard

“No gradation” (NG) This level is used in cases where the recommendation is based on the common sense of the expert researcher or when the topic under discussion does not allow for adequate application of the system of evidence used in clinical practice

table 2

Assessment of the quality of the evidence base (compiled in accordance with the clinical guidelines of the KEYO)

Quality of evidence Meaning

A - high Experts are confident that the expected effect is close to the calculated one

B - average Experts believe that the expected effect is close to the calculated effect, but may differ significantly

C - low The expected effect may differ significantly from the calculated effect

O - very low The expected effect is very uncertain and may be very far from the calculated one

2. Definition, epidemiology, etiology (Table 3)

Table 3

Definition

Rapidly progressive glomerulonephritis (RPGN) is an urgent nephrological situation that requires urgent diagnostic and therapeutic measures. RPGN is clinically characterized by acute nephritic syndrome with rapidly progressing renal failure (doubling of creatinine within 3 months), morphologically by the presence of extracapillary cellular or fibrocellular crescents in more than 50% of glomeruli.

Synonyms of the term: subacute GN, malignant GN; The generally accepted morphological term used to refer to RPGN is extracapillary glomerulonephritis with crescents.

Epidemiology

The frequency of RPGN is 2-10% of all forms of glomerulonephritis registered in specialized nephrology hospitals.

Etiology

RPGN can be idiopathic or develop as part of systemic diseases (ANCA-associated vasculitis, Goodpasture syndrome, SLE).

3. Pathogenesis (Table 4)

Table 4

Crescents are a consequence of severe damage to the glomeruli with rupture of the capillary walls and penetration of plasma proteins and inflammatory cells into the space of the Shumlyansky-Bowman capsule. The main cause of this severe damage is exposure to ANCA, anti-BMK antibodies and immune complexes. The cellular composition of the crescents is represented mainly by proliferating parietal epithelial cells and macrophages. The evolution of crescents - reverse development or fibrosis - depends on the degree of accumulation of macrophages in the space of the Shumlyansky-Bowman capsule and its structural integrity. The predominance of macrophages in the cellular crescents is accompanied by rupture of the capsule, the subsequent entry of fibroblasts and myofibroblasts from the interstitium, and the synthesis by these cells of matrix proteins - collagen types I and III, fibronectin, which leads to irreversible fibrosis of the crescents. An important role in regulating the processes of attraction and accumulation of macrophages in the crescents belongs to chemokines - monocyte chemoattractant protein-I (MCP-I) and macrophage inflammatory protein-1 (MIP-1). High expression of these chemokines in the areas of crescent formation with a high content of macrophages is found in RPGN with the most severe course and poor prognosis. An important factor leading to fibrosis of the crescents is fibrin, into which fibrinogen is transformed, entering the capsule cavity due to necrosis of the capillary loops of the glomerulus.

4. Classification

Depending on the predominant mechanism of damage, clinical picture and laboratory parameters, five immunopathogenetic types of RPGN are currently identified (Glassock, 1997). The main immunopathological criteria that define each type of RPGN are the type of luminescence of immunoreactants in the renal biopsy and the presence of a damaging factor (antibodies to BMK, immune complexes, ANCA) in the patient’s serum (Table 5).

Table 5

Characteristics of immunopathogenetic types of ECGN

Pathogenetic type ECGN Serum

IF microscopy of renal tissue (luminescence type) Anti-BMK Complement (decreased level) ANCA

I linear + - -

II granular - + -

IV linear + - +

Type I (“antibody”, “anti-BMK-nephritis”). Caused by the damaging effect of antibodies to BMK. It is characterized by a “linear” glow of antibodies in a renal biopsy and the presence of circulating antibodies to BMK in the blood serum. It exists either as an isolated (idiopathic) kidney disease, or as a disease with concomitant damage to the lungs and kidneys (Goodpasture syndrome).

Type II (“immune complex”). Caused by deposits of immune complexes in various parts of the renal glomeruli (in the mesangium and capillary wall). In a renal biopsy, a mainly “granular” type of luminescence is revealed; anti-BMK antibodies and ANCA are absent in the serum; in many patients, complement levels may be reduced. It is most typical for RPGN associated with infections (post-streptococcal RPGN), cryoglobulinemia, and systemic lupus erythematosus (SLE).

Type III (“low-immune”). The damage is caused by cellular immune responses, including neutrophils and monocytes activated by antineutrophil cytoplasmic antibodies (ANCA). The fluorescence of immunoglobulins and complement in the biopsy specimen is absent or insignificant (paradise, “low-immune” GN); ANCA directed against proteinase-3 or myeloperoxidase are detected in the serum. This type of ECGN is a manifestation of ANCA-associated vasculitis (MPA, GPA, Wegener's).

Type IV is a combination of two pathogenetic types - antibody (type I) and ANCA-associated, or low-immune (type III). At the same time, both antibodies to BMK and ANCA are detected in the blood serum, and a linear glow of antibodies to BMK is detected in the renal biopsy, as in classic anti-BMK nephritis. In this case, proliferation of mesangial cells is also possible, which is absent in the classic antibody type of ECGN.

Type V (true “idiopathic”). In this extremely rare type, immune factors of damage cannot be detected either in the circulation (there are no anti-BMK antibodies and ANCA, the complement level is normal) or in a renal biopsy (the fluorescence of immunoglobulins is completely absent). It is assumed that it is based on a cellular mechanism of damage to renal tissue.

Among all types of RPGN, more than half (55%) are ANCA-associated RPGN (type III), the other two types of RPGN (I and II) are distributed approximately equally (20 and 25%). Characteristics of the main types of RPGN are presented in Table. 6.

Based on the presence of certain serological markers (and their combinations), one can assume the type of luminescence in the renal biopsy and, accordingly, the mechanism of damage - the pathogenetic type of RPGN, which is important to consider when choosing a treatment program.

Table 6

Classification of types of RPGN

RPGN type Characteristics Clinical variants Frequency, %

I Mediated by antibodies to BMK: linear IgG deposits on immunohistological examination of kidney tissue Goodpasture's syndrome Isolated kidney damage associated with antibodies to BMK 5

II Immunocomplex: granular deposits of immunoglobulin in the glomeruli of the kidney Post-infectious Post-streptococcal For visceral abscesses Lupus nephritis Hemorrhagic vasculitis 1dA nephropathy Mixed cryoglobulinemia Membranoproliferative GN 30-40

III ANCA-associated: Low-immune with the absence of immune deposits in the immunological study of GPA MPA EGPA 50

IV Combination of types I and III - -

V ANCA-negative renal vasculitis: with absence of immune deposits Idiopathic 5-10

Recommendation 1: In all cases of RPGN, a kidney biopsy should be performed as soon as possible. Morphological examination of kidney tissue should be carried out with the mandatory use of fluorescent microscopy.

Comment: ANCA-SV is the most common cause of RPGN. Renal involvement in these diseases is a factor of poor prognosis for both renal and overall survival. In this regard, kidney biopsy is extremely important not only from a diagnostic but also from a prognostic point of view.

5. Clinical manifestations of RPGN (Table 7)

Table 7

The clinical syndrome of RPGN includes two components:

1. acute nephritis syndrome (acute nephritis syndrome);

2. rapidly progressive renal failure, which, in terms of the rate of loss of renal function, occupies an intermediate position between acute renal failure and chronic renal failure, i.e. implies the development of uremia within a year from the moment of the first signs of the disease.

This rate of progression corresponds to a doubling of the serum creatinine level for every 3 months of illness. However, often fatal loss of function occurs in just a few (1-2) weeks, meeting the criteria for AKI

6. Principles of diagnosing RPGN

RPGN is diagnosed based on assessing the rate of deterioration of renal function and identifying the leading nephrological syndrome (acute nephritic and/or nephrotic).

6.1. Laboratory diagnosis of RPGN (Table 8)

Table 8

Complete blood count: normochromic anemia, possible neutrophilic leukocytosis or leukopenia, thrombocytosis or thrombocytopenia, increased ESR

General urine analysis: proteinuria (from minimal to massive), erythrocyturia, usually severe, the presence of erythrocyte casts, leukocyturia

Biochemical blood test: increased concentrations of creatinine, uric acid, potassium, hypoprotein and hypoalbuminemia, dyslipidemia in cases of nephrotic syndrome

Decrease in GFR (determined by creatinine clearance - Rehberg test and/or calculation methods SKR-EP1, MRY; the use of the Cockcroft-Gault formula is undesirable due to the “overestimation" of GFR by 20-30 ml

Immunological studies: definition

Immunoglobulins A, M and B

Complement

ANCA in blood serum by indirect immunofluorescence or by enzyme-linked immunosorbent assay with determination of specificity for PR-3 and MPO

Anti-BMK antibodies

6.2. Histological examination of kidney biopsy

Comment: All patients with RPGN undergo a kidney biopsy. It is necessary to carry it out primarily in order to assess the prognosis and select the optimal treatment method: a timely applied aggressive regimen of immunosuppressive therapy sometimes allows for the restoration of renal filtration function even in a situation where the degree of its deterioration has reached end-stage renal failure (ESRD). In this regard, in case of RPGN, a kidney biopsy must also be performed in cases of severe renal failure requiring hemodialysis (HD).

For morphological characteristics of different types of RPGN, see recommendations for anti-BMK GN, ANCA-GN and lupus nephritis.

6.3. Differential diagnosis

When identifying RPGN syndrome, it is necessary to exclude conditions that superficially resemble (imitate) RPGN, but are of a different nature and therefore require a different therapeutic approach. By their nature, these are three groups of diseases:

(1) nephritis - acute post-infectious and acute interstitial, usually with a favorable prognosis, in which immunosuppressants are used only in some cases;

(2) acute tubular necrosis with its own patterns of course and treatment;

(3) a group of vascular diseases of the kidneys, combining damage to vessels of different sizes and different natures (thrombosis and embolism of large vessels of the kidneys, scleroderma nephropathy, thrombotic microangiopathies of various origins). In most cases, these conditions can be excluded clinically (see Table 9).

On the other hand, the presence and characteristics of extrarenal symptoms may indicate a disease in which RPGN often develops (SLE, systemic vasculitis, drug reaction).

7. Treatment of RPGN

7.1. General principles of treatment of RPGN (extracapillary GN)

RPGN occurs more often as a manifestation of a systemic disease (SLE, systemic vasculitis, essential mixed cryoglobulinemia, etc.), less often as an idiopathic disease, but the principles of treatment are general.

It is necessary - if possible - to urgently test serum for the presence of anti-BMK antibodies and ANCA; A kidney biopsy is necessary for timely diagnosis (detection of ECG and the type of antibody glow - linear, granular, “low-immune”), assessment of prognosis and choice of treatment tactics.

Recommendation 1. To prevent irreversible catastrophic loss of renal function, it is necessary to begin urgently and immediately after establishing a clinical diagnosis of RPGN (acute nephritic syndrome combined with rapidly progressive renal failure with normal kidney sizes and exclusion of other causes of AKI). (1B)

Comments: Delaying treatment for several days may impair the effectiveness of treatment, since treatment is almost always unsuccessful once anuria develops. This is the only form of GN in which the risk of developing side effects of immunosuppressive therapy is not comparable with the possibility of an unfavorable prognosis in the natural course of the disease and untimely initiation of treatment.

Table 9

Differential diagnosis of RPGN

Conditions reproducing RPGN Distinctive features

Antiphospholipin syndrome (APS nephropathy) The presence of serum antibodies to cardiolipin classes 1gM and!dv and/or antibodies to B2-glycoprotein 1, lupus anticoagulant. Increased plasma concentration of d-dimer, fibrin degradation products. Absence or minor changes in urine analysis (usually “trace” proteinuria, scanty urinary sediment) with a pronounced decrease in GFR. Clinical manifestations of arterial (acute coronary syndrome/acute myocardial infarction, acute cerebrovascular accident) and venous (deep vein thrombosis of the legs, pulmonary embolism, renal vein thrombosis) vessels, livedo reticularis

Hemolytic-uremic syndrome Association with infectious diarrhea (in typical hemolytic-uremic syndrome). Identification of triggers of complement activation (viral and bacterial infections, trauma, pregnancy, medications). Severe anemia with signs of microangiopathic hemolysis (increased LDH levels, decreased haptoglobin, schizocytosis), thrombocytopenia

Scleroderma nephropathy Skin and organ signs of systemic scleroderma. Pronounced and intractable rise in blood pressure. No changes in urine tests

Acute tubular necrosis Association with drug intake (especially NSAIDs, non-narcotic analgesics, antibiotics). Gross hematuria (possible passage of blood clots). Rapid development of oliguria

Acute tubulointerstitial nephritis Typically has a clear cause (drug use, sarcoidosis). Decreased relative density of urine in the absence of severe proteinuria

Cholesterol embolism of intrarenal arteries and arterioles* Association with endovascular procedure, thrombolysis, blunt abdominal trauma. Marked rise in blood pressure. Signs of an acute phase response (fever, loss of appetite, body weight, arthralgia, increased ESR, serum concentration of C-reactive protein). Hypereosinophilia, eosinophiluria. Livedo reticularis with trophic ulcers (usually on the skin of the lower extremities). Systemic signs of cholesterol embolism (sudden unilateral blindness, acute pancreatitis, intestinal gangrene)

* In rare cases, leads to the development of RPGN, including ANCA-associated.

Recommendation 1. 1. Treatment of RPGN should begin even before receiving the results of diagnostic studies (serological, morphological) with pulse therapy with methylprednisolone at a dose of up to 1000 mg for 1-3 days. (1A)

Comments:

This tactic is fully justified even if it is impossible to perform a kidney biopsy in patients whose severity of condition prevents this procedure. Immediately after verification of the diagnosis of RPGN, alkylating agents [cyclophosphamide (CP) in ultra-high doses] should be added to glucocorticoids, especially in patients with vasculitis (local renal or systemic) and circulating ANCA and lupus nephritis. It is advisable to combine intensive plasmapheresis (IP) with immunosuppressants in the following cases:

a) anti-BMK nephritis, provided that treatment is started before the need for hemodialysis arises;

b) in patients with non-anti-BMK ECGN who have signs of renal failure requiring treatment with hemodialysis at the time of diagnosis (SCr more than 500 µmol/l) in the absence of signs of irreversible kidney damage according to nephrobiopsy (more than 50% cellular or fibrocellular crescents ).

Initial therapy for RPGN depends on its immunopathogenetic type and the need for dialysis from the time of diagnosis (Table 10).

Table 10

Initial therapy for RPGN (ECGN) depending on the pathogenetic type

Type Serology Therapy/need for HD

I Anti-BMK disease (a-BMK +) (ANCA -) GC (0.5 -1 mg/kg orally ± pulse therapy at a dose of up to 1000 mg for 1-3 days) PF (intensive) Conservative management

II IR disease (a-BMK -), (ANCA -) GC (orally or “pulses”) ± cytostatics (CP) - orally (2 mg/kg/day) or intravenously (15 mg/kg, but not > 1 G)

III “Low-immune” (a-BMK -) (ANCA +) GC (inside or “pulses”) CF GS (inside or “pulses”) CF. Intensive plasma exchange - daily for 14 days with a replacement volume of 50 ml/kg/day

IV Combined (a-BMK +) (ANCA +) As with type I As with type I

V “Idiopathic” (a-BMK -) (ANCA -) As with type III As with type III

7.2.1. Anti-BMK nephritis (type I according to Glassock, 1997), including Goodpasture's syndrome.

diagnosis, having 100% crescents according to adequate nephrobiopsy and without pulmonary hemorrhages) immunosuppression with cyclophosphamide, corticosteroids and plasmapheresis should be started. (1B)

A comment:

When the blood creatinine level is less than 600 µmol/l, prednisolone is prescribed orally at a dose of 1 mg/kg/day and cyclophosphamide at a dose of 2-3 mg/kg/day. Once a stable clinical effect is achieved, the dose of prednisolone is gradually reduced over the next 12 weeks, and cyclophosphamide is completely discontinued after 10 weeks of treatment. Therapy with immunosuppressive drugs is combined with intensive plasmapheresis, which is performed daily. If there is a risk of developing pulmonary hemorrhage, part of the volume of removed plasma is replaced with fresh frozen plasma. A stable effect is achieved after 10-14 sessions of plasmapheresis. This treatment regimen allows for improvement of renal function in almost 80% of patients, and a decrease in azotemia begins within a few days after the start of plasmapheresis.

When the blood creatinine level is more than 600 μmol/L, aggressive therapy is ineffective, and improvement of renal function is possible only in a small number of patients with a recent history of the disease, rapid progression (within 1-2 weeks) and the presence of potentially reversible changes in the kidney biopsy. In these situations, the main therapy is carried out in combination with hemodialysis sessions.

7.2.2. Immune complex RPGN (type II according to Glassock, 1997).

Recommendation 6. For rapidly progressive lupus GN (type IV), it is recommended to prescribe cyclophosphamide (CP) (1B) intravenously at a dose of 500 mg every 2 weeks for 3 months (total dose 3 g) or mycophenolic acid (MPA) preparations (mycophenolate mofetil [MMF ] (1B) at a target dose of 3 g/day for 6 months, or mycophenolate sodium at an equivalent dose) in combination with GCS in the form of intravenous “pulses” of methylprednisolone at a dose of 500-750 mg for 3 consecutive

days, and then prednisolone orally 1.0-0.5 mg/kg/day for 4 weeks with a gradual decrease to<10 мг/сут к 4-6 мес (1А).

Clinical recommendations for glomerulonephritis refer to certain provisions that are designed to help the doctor and patient follow rational tactics in the treatment of a particular pathology. They are developed on the basis of scientific achievements not only in our country, but also foreign practices. The recommendations are reviewed and supplemented annually.

Based on the results of implementation of clinical recommendations, the attending physician monitors the patient’s management tactics. Previously, they were advisory in nature, but since 2017 they were introduced for mandatory implementation by the attending physician. At the same time, the characteristics of each patient are taken into account. The doctor must take a very deliberate approach to the treatment of each patient, following certain standards.

Glomerulonephritis refers to a group of kidney diseases when the renal parenchyma directly suffers due to one reason or another. These are inflammatory changes in the renal medulla with proliferation of connective tissue.

Variants of the course of glomerulonephritis

According to the development options, acute and chronic are distinguished. Glomerulonephritis is quite common in general practice. Primary glomerulonephritis is mainly registered in children under 15 years of age and adults under 30 years of age. The chronic form is typical for the older age group.

Glomerulonephritis may develop during pregnancy with a frequency of up to 0.2%. The glomeruli are predominantly affected. The tubules and interstitial tissue are also affected. Glomerulonephritis during pregnancy is a very serious condition. requiring immediate treatment. The disease threatens the life of the child and mother. Along the way, this may be a latent state. There are clinical recommendations for the management of pregnant women with glomerulonephritis.

Causes of the disease

The main pathogen that causes glomerulonephritis is group A hemolytic streptococcus. Glomerulonephritis can develop after erysipelas, scarlet fever, tonsillitis, and pyoderma. Viruses and bacteria can be causative agents. The main reason for the development of the disease is the launch of immunological mechanisms that have tropism for the kidney parenchyma. This causes chronic kidney disease.

Provoking agents are hypothermia, viral infections.

Symptoms of glomerulonephritis during pregnancy

Symptoms of the disease during pregnancy may be hidden. With the development of glomerulonephritis in pregnant women in the initial stage, there may only be changes in the urine. This is the appearance of red blood cells and protein. The difficulty of diagnosis in pregnant women is that changes can occur during pregnancy. Kidney disorders are caused by stress on the body, compression of the kidneys.

Impaired kidney function leads to edema, increased blood pressure, even eclampsia. Family doctors may mistake it for gestosis.

Clinical manifestations

Chronic glomerulonephritis, clinic. In this case, there may be minimal manifestations in the form of microhematuria - traces of blood in the urine.

In the nephrotic form, the clinical picture of the disease manifests itself:

• A decrease in the amount of urine excreted, swelling in the legs and face, and an increase in blood pressure.
• Protein, macro- and microhematuria, cylindruria, and leukocyturia are detected in the urine.
• Urea and creatinine levels increase in the blood.

Diagnostic methods

To confirm the diagnosis of glomerulonephritis, a thorough examination of the patient is necessary. Diagnosing the disease is not as simple as it seems. To confirm the diagnosis, a morphological examination of the renal parenchyma is performed. To do this, a kidney biopsy and examination of the biopsy material are performed. A biopsy is required:

• Long-term urinary syndrome
• Severe manifestations of nephrotic syndrome
• Rapid development of symptoms leading to renal failure
• Blood and urine examination, in particular increasing the titer of ASLO and CRP.
• Differential diagnosis with nephropathies, membranoproliferative glomerulonephritis and secondary glomerulonephritis against the background of systemic diseases.

Treatment

Treatment of glomerulonephritis is a rather lengthy and complex process. The treatment is complex. Great importance is given to nutrition with the exception of spicy foods, limiting salt and extractive substances. A vegetable-dairy diet is used.

Etiotropic therapy. This is the sanitation of the focus of streptococcal infection. For this purpose, antibacterial therapy is used, taking into account the sensitivity of the flora. These are macrolides and penicillin antibiotics of the latest generation.

Pathogenetic treatment. When the immune response is pronounced and the proliferation of connective tissue is prevented, hormones and antitumor drugs - cytostatics - are used. These are the drugs of choice, which are prescribed only when the process is severe. In mild forms, use is unacceptable due to serious side effects.

Symptomatic therapy. For severe hypertension, antihypertensive drugs are prescribed. The development of edematous syndrome requires the use of diuretics. In chronic renal failure, diuretics are used to relieve edema and respiratory failure.

By form:

• Diffuse nephritic syndrome - antiplatelet agents, antihypertensive drugs, diuretics;
• Diffuse nephrotic syndrome requires complex treatment with the use of hormones and cytostatics.

The criterion for the effectiveness of treatment is the absence of edema, a decrease in blood pressure, and normalization of urine and blood parameters.

Possible complications

Possible complications of glomerulonephritis are:

• Development of chronic renal failure;
• Respiratory and cardiovascular failure;
• A poor prognostic sign is persistent arterial hypertension;
• Elderly age;
• Rapid progression of symptoms - increased edema, severe proteinuria, hematuria.