What causes glomerulonephritis?

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

Pathogenesis of glomerulonephritis

Infectious and other stimuli induce glomerulonephritis by causing an immune response with the formation and deposition of antibodies and immune complexes in the glomeruli of the kidneys and/or by enhancing the cell-mediated immune reaction. After the initial injury, complement activation, recruitment of circulating leukocytes, synthesis of various chemokines, cytokines and growth factors, secretion of proteolytic enzymes, activation of the coagulation cascade, and formation of lipid mediator substances occur. Activation of resident cells in the kidneys leads to further intensification of destructive changes and the development of extracellular matrix components (fibrosis). Such changes (remodeling) of the glomerular and interstitial matrix are facilitated by hemodynamic factors: systemic and adaptive intraglomerular hypertension and hyperfiltration, nephrotoxic effect of proteinuria, impaired apoptosis. With persistence of inflammatory processes, there is an increase in glomerulosclerosis and interstitial fibrosis - the pathophysiological basis for the progression of renal failure.

With immunofluorescence microscopy, the following is observed in the glomeruli of the kidneys:

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

Antibody (anti-GBM) glomerulonephritis. The antibodies are directed to the antigen of the non-collagen part of the glomerular basement membrane (glycoprotein), some of them also react with antigens of the basement membrane of the renal tubules and pulmonary alveoli. The most severe structural damage to the glomerular basement membrane is observed with the development of crescents, massive proteinuria and early renal failure. The main mediator of damage is monocytes, which infiltrate the glomeruli and also form crescents in the cavity of the Bowman's capsule (glomerular capsule), penetrating there following fibrin through anatomical defects in the glomerular basement membrane.

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

Immune complex nephritis

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

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

Deposits of immune complexes can also be formed in the glomeruli in another way - locally (in situ) with the deposition of first the antigen in the glomeruli, and then the antibody, which combines with the antigen locally, forming deposits of immune complexes in the mesangium and subendothelially. With increased permeability of the capillary wall, molecules of antigens and antibodies can cross the basal membrane of the glomeruli and combine with each other in the subepithelial space.

The negative charge of the glomerular basement membrane promotes the “implantation” of positively charged antigen molecules (bacterial, viral, tumor antigens, medicinal haptens, etc.) into the capillary wall, followed by the formation of immune complexes in situ.

In immunofluorescence studies of renal tissue, immune complexes produce a characteristic granular fluorescence of immunoglobulins in the mesangium or along the glomerular basement membrane.

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

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

Cytokines interact with other mediators of renal injury. 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 inhibited by the administration of ACE inhibitors or angiotensin II receptor antagonists.

Typical manifestations of the glomerular inflammatory response to immune damage are proliferation (hypercellularity) and expansion of the mesangial matrix. Hypercellularity is a common feature of many forms of glomerular inflammation, a consequence of glomerular infiltration by circulating mononuclear and neutrophilic leukocytes, which are the cause of damage, and increased proliferation of the glomerulus's own mesangial, epithelial, and endothelial cells. Many growth factors have been found to stimulate individual populations of glomerular and tubular cells to synthesize components of the extracellular matrix, which leads to its accumulation.

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

The pathological immune response that causes damage to renal tissue: glomeruli, interstitium and tubules, in many cases ceases over time, and the damage it causes ends in reparation (healing) with various outcomes - from complete restoration of the glomerular structure to global glomerulosclerosis - the basis of progressive renal failure.

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

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

The idea of the leading role of fibrogenesis regulation disorders in the progression of renal diseases largely explains the hypothesis of the importance of hemodynamic factors and glomerular hypertrophy. Although AN is better known as a factor influencing vascular tone, it has now been found to be an important factor in the proliferation of vascular smooth muscle cells and related mesangial cells of the renal glomeruli, induction of their 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 partly explain the observation that the use of ACE inhibitors protected against disease progression in the absence of any changes in glomerular hemodynamics or increases in glomerular capillary pressure, i.e. mechanisms of adaptation to renal mass loss may stimulate production and act in concert with factors that promote fibrosis.

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

Activation of tubular cells in response to protein overload leads to stimulation of genes encoding inflammatory and vasoactive substances - proinflammatory cytokines, MCP-1 and endothelins. These substances, synthesized in large quantities, are secreted through the basolateral parts of 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 synthesis and suppresses matrix degradation, being a strong chemoattractant for monocytes and fibroblasts. The main source of TGF-beta production in interstitial inflammation is apparently interstitial and tubular cells. Platelet-derived 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 TGF-beta production in renal tubular cells and induces TGF-beta expression in fibroblasts. Finally, another fibrogenic mediator is endothelial-1, which, in addition to other resident cells, is expressed by proximal and distal tubular cells. It is able to stimulate the proliferation of renal fibroblasts and enhance collagen synthesis in them.