What causes glomerulonephritis?

The causes of glomerulonephritis are still unknown. In the development of some of them, the role of infection - bacterial, especially nephritogenic strains of beta-hemolytic streptococcus group A (epidemics of acute post-streptococcal glomerulonephritis and present reality today), viral, in particular hepatitis B and C viruses, HIV infection; medicinal preparations (gold, D-penicillamine); tumors and other factors of exogenous and endogenous origin.

Pathogenesis of glomerulonephritis

Infectious and other stimuli induce glomerulonephritis, eliciting an immune response with the formation and deposition of antibodies and immune complexes in the glomeruli of the kidney and / or by enhancing the cell-mediated immune response. After initial damage, complement activation occurs, the involvement of circulating leukocytes, the synthesis of various chemokines, cytokines and growth factors, exclusion of proteolytic enzymes, activation of the coagulation cascade, and the formation of lipid mediator substances. Activation of resident cells in the kidneys leads to further strengthening of destructive changes and development of extracellular matrix components (fibrosis). Such a change (remodeling) of the glomerular and interstitial matrix is facilitated by hemodynamic factors: systemic and adaptive intraglomerular hypertension and hyperfiltration, nephrotoxic action of proteinuria, and disturbed apoptosis. When the inflammation processes persist, glomerulosclerosis and interstitial fibrosis, the pathophysiological basis of the progression of renal failure, increase.

When immunofluorescence microscopy in the glomeruli of the kidneys observed:

• 75-80% of patients - granular deposition of immune complexes containing IgG, on the glomerular basement membranes and in mesangium;
• in 5% of patients - continuous linear deposition of IgG along the walls of capillaries;
• in 10-15% of patients, immune deposits are not detected.

Antibody (anti-BMC) glomerulonephritis. Antibodies are directed to the antigen of the non-collagenous part of the basal membrane of the glomerulus (glycoprotein), some of them also react with antigens of the basal membrane of the renal tubules and lung alveoli. The most severe structural lesions of the glomerular basement membrane are observed with the development of semilunium, massive proteinuria and early renal insufficiency. The main mediator of damage is monocytes that infiltrate the glomeruli, and also form a half moon in the cavity of the Bowman capsule (capsule of the glomerulus), penetrating there after the fibrin through anatomical defects in the basal membrane of the glomeruli.

Immunofluorescence of antibodies to the basal membrane of the glomeruli gives a characteristic linear luminescence of immunoglobulins along the basal membrane of the glomeruli. The diagnosis of anti-BMC glomerulonephritis is based on the immunofluorescence detection of a characteristic deposition of IgG antibodies (but sometimes IgA or IgM-AT) along the basal membrane of the glomeruli. In 2/3 of patients, the deposits of immunoglobulins are accompanied by C3 deposits and components of the classical pathway of complement activation. Circulating antibodies to the basal membrane of the glomeruli are detected by indirect immunofluorescence or by a more sensitive radioimmunoassay.

Immunocomplex nephritis

Immune complexes (IR) are macromolecular compounds that arise during the interaction of an antigen with antibodies, which can occur both in the bloodstream (circulating immune complexes) and in tissues. From the bloodstream, circulating immune complexes are removed mainly by fixed mononuclear phagocytes of the liver.

In renal glomeruli under physiological conditions, circulating immune complexes are deposited in mesangium, where they are phagocytosed by resident mesangial phagocytes or from monocyte-macrophages coming from circulation. If the number of deposited circulating immune complexes exceeds the purifying capacity of mesangium, the circulating immune complexes persist for a long time in mesangium, undergo aggregation with the formation of large insoluble immune complexes, which creates conditions for the damaging activation of the entire complement cascade.

Deposits of immune complexes can form in the glomeruli and in another way - locally (in situ) with the first antigen deposited in the glomeruli, and then antibodies that bind to the antigen locally, forming the deposits of immune complexes in mesangium and subendothelial. With an increase in the permeability of the capillary wall, the molecules of antigens and antibodies can cross the basal membrane of the glomeruli and connect to each other in the subepithelial space.

Negative charge of the basal glomerular membrane facilitates the "implantation" of positively charged antigenic molecules (bacterial, viral, tumor antigens, medicinal haptenes, etc.) into the capillary wall, followed by the formation of immune complexes in situ.

In immunofluorescence studies of renal tissue, immune complexes give characteristic granular luminescence of immunoglobulins in mesangium or along the basal membrane of the glomeruli.

The role of complement in glomerular damage is associated with its local activation in the glomeruli of immune complexes or antibodies to the basal membrane of the glomeruli. As a result of activation, factors that have chemotactic activity for neutrophils and monocytes, causing degranulation of basophils and mast cells, and a "membrane attack factor" directly damaging the membrane structures are formed. The formation of a "membrane attack factor" is a mechanism of damage to the glomerular basement membrane in membranous nephropathy associated with local activation of complement with subepithelial deposits of immune complexes.

Cytokines and growth factors are produced both by infiltrating inflammatory cells (lymphocytes, monocytes, neutrophils), and by their own glomerular cells and interstitium. Cytokines act paracrine (on neighboring cells) or autocratically (on the cell that synthesizes them). Growth factors that have an extrarenal origin can also cause inflammatory reactions in the glomeruli. Natural inhibitors of cytokines and growth factors, which include soluble forms and receptor antagonists, have been identified. Cytokines with pro-inflammatory (interleukin-1, TNF-alpha), proliferative (platelet-derived growth factor) and fibrosing (TGF-b) effects have been isolated, although this division is somewhat artificial due to a significant overlap in the spectra of their action.

Cytokines interact with other mediators of kidney damage. Angiotensin II (All) in vivo induces the expression of platelet-derived growth factor and TGF-b in smooth muscle and mesangial cells, leading to cell proliferation and matrix production. This effect is significantly suppressed by the administration of ACE inhibitors or angiotensin II receptor antagonists.

Typical manifestations of the inflammatory reaction of the glomeruli to immune damage are proliferation (hypercellularity) and expansion of the mesangial matrix. Hyper-cellularity is a common feature of many forms of glomerular inflammation, the consequence of infiltration of the glomeruli by circulating mononuclear and neutrophilic leukocytes, which are the cause of injury, and increased proliferation of intrinsic mesangial, epithelial and endothelial cells of the glomerulus. It was found that many of the growth factors stimulate individual populations of glomerular and tubular cells to synthesize components of the extracellular matrix, which leads to its accumulation.

Accumulation of the glomerular matrix is a manifestation of a long-term inflammation, often accompanied by sclerosis and obliteration of the glomeruli and interstitial fibrosis. This, in turn, is the brightest sign of the steady progression of the disease and the development of chronic renal failure.

The pathological immune response that causes damage to the renal tissue: glomeruli, interstitium and tubules - in many cases eventually stops, and the damage caused by it ends with repair (healing) with different outcomes - from the complete restoration of the glomerular structure to global glomerulosclerosis - the basis of progressive renal failure.

Modern ideas about the regulation of fibrogenesis allow us to consider that the differences between healing with the restoration of normal structure and function and the development of tissue fibrosis are a consequence of the disruption of the local balance between endocrine, paracrine and autocrine factors that regulate proliferation and the synthetic function of fibroblasts. A special role in this process is played by such growth factors as TGF-beta, platelet-derived growth factor, the main fibroblast growth factor, as well as angiotensin II, better known for its hemodynamic effects.

Resorption and utilization of the deposited mesangial and interstitial matrix occur under the action of the proteolytic enzymes released. In normal glomeruli there are matrix-degrading enzymes such as serine proteases (plasminogen activators, elastase) and matrix metalloproteinases (interstitial collagenase, gelatinase, stromolysin). Each of these enzymes has natural inhibitors, among which an important inhibitor of the activator of plasminogen type 1 plays an important regulatory role in the kidney. An increase in the secretion of the fibrinolytic enzyme or a decrease in inhibitor activity can promote the resorption of previously deposited extracellular matrix proteins. Thus, the accumulation of the extracellular matrix is due to both the enhancement of the synthesis of a number of its components and the reduction of their cleavage.

The idea of the leading role of disturbances in the regulation of fibrogenesis in the progression of renal diseases largely explains the hypothesis of the importance of hemodynamic factors and glomerular hypertrophy. Although AH is better known as a factor affecting vascular tone, it has now been found that it is an important factor in the proliferation of vascular smooth muscle cells and close mesangial cells of the renal glomeruli, induction of the synthesis of TGF-beta, platelet-derived growth factor, and activation of TGF -beta from its latent form.

The role of angiotensin II as a potentially damaging growth factor may partially explain the observations when the use of ACE inhibitors protected against disease progression in the absence of any changes in glomerular hemodynamics or a rise in pressure in the glomerular capillaries, i.e. Mechanisms of adaptation to the loss of renal mass can stimulate production and act together with factors contributing to the development of fibrosis.

A permanent feature of proteinuric forms of nephritis is the presence simultaneously with the glomerular and tubulointerstitial inflammation. In recent years, it has been established that pronounced and prolonged proteinuria acts on interstitium as an internal toxin, since the reabsorption of filtered proteins activates the epithelium of the proximal tubules.

Activation of tubular cells in response to protein overload leads to stimulation of inflammatory and vasoactive substances genes - pro-inflammatory cytokines, MCP-1 and endothelin. These substances, synthesized in large amounts, are secreted through the basolateral sections of the tubular cells and, by attracting other inflammatory cells, contribute to the inflammatory interstitial reaction, which in most forms of glomerulonephritis often precedes the development of nephrosclerosis.

TGF-beta is the most important fibrogenic cytokine, as it enhances the synthesis and inhibits the destruction of the matrix, being a strong chemoattractant for monocytes and fibroblasts. The main source of production of TGF-beta in interstitial inflammation, apparently, are interstitial and tubular cells. Thrombocyte growth factor also has a fibrogenic effect and, like TGF-beta, can transform interstitial fibroblasts into myofibroblasts. AN is also produced by tubular cells; it stimulates the production of TGF-beta in renal tubular cells and induces the expression of TGF-beta in fibroblasts. Finally, another fibrogenic mediator is endothelium-1, which, in addition to other resident cells, is expressed by the cells of the proximal and distal tubules. It is able to stimulate the proliferation of renal fibroblasts and enhance the synthesis of collagen in them.