Pathogenesis of interstitial nephritis

The variety of etiological factors makes the pathogenesis of tubulointerstitial nephritis ambiguous.

The development of postinfection tubulointerstitial nephritis is associated with the effect of toxins of microorganisms and their antigens on the endothelium of the capillary interstitium and the basal membrane of the tubules. This leads to direct cell damage, increased capillary permeability, the inclusion of nonspecific inflammation factors. In addition to direct toxic effects, immunologically mediated damage to the endothelium and tubules develops.

Chemicals, heavy metal salts, drugs, kidney-edged can also have a direct damaging effect on the tubular epithelium. However, the main importance for the development and maintenance of inflammation, especially with medicinal tubulointerstitial nephritis, will be the development of immune reactions in which drugs play the role of allergens or haptens.

In primary and secondary dysmetabolic nephropathies, primarily in the violation of the exchange of purines and oxalic acid, there is an accumulation of crystals in the tubules and interstitium cells, their damage due to direct mechanical action of the salts, activation of phagocytosis and the release of inflammatory mediators by macrophages and neutrophils. Later, cell sensitization to the brush border antigens develops the tubular epithelium and interstitium, as well as to the glomerular basement membrane antigens.

The development of tubulointerstitial nephritis in the dysembryogenesis of the renal tissue is associated with immaturity and disruption of the tubular structure, hemodynamic disorders, possible disrupted specificity of the structural proteins of the tubular cells and their basal membrane on the one hand, and partial immune disorders, on the other.

Expressed disorders of blood and lymph circulation, developing as acute (shock, collapse, DIC syndrome, etc.), and chronically (with various developmental abnormalities), urodynamic disorders will contribute to the development of hypoxic dystrophy and atrophy of tubule cells and vascular endothelium, activation of macrophages and fibroblasts, which leads to the development of autoimmune processes.

Thus, for all the variety of reasons underlying tubulointerstitial nephritis, the involvement of immune mechanisms, circulatory disorders, and membranopathological processes is undoubtedly in its pathogenesis.

In the development of immune reactions with tubulointerstitial nephritis four mechanisms can be distinguished:

1. Cytotoxic mechanism. Damage to the basal membrane of the tubules due to the action of various factors (infectious agents, toxins, chemical compounds, etc.) leads to the release of autoantigens, their entry into the blood with further production of autoantibodies (autoimmune mechanism). In addition, various drugs, toxins and other chemical compounds can act as haptens and, fixing on the basal membrane of the tubules, give it new antigenic properties, causing the production and deposition of antibodies (immunologically mediated cytotoxicity). In addition, the formation of antibodies to cross antigens of microorganisms and the basal membrane of the tubules is possible. The formed antibodies (IgG) are deposited linearly along the basal membrane of the tubules and in the interstitium, triggering the activation of the complement system and cell damage, with the development of cellular infiltration and edema of interstitium.
2. Immunocomplex mechanism. The formation of immune complexes can occur both in the circulatory bed and in situ. In this case, circulating immune complexes often contain extrarenal antigens (for example, microbial), and immune complexes in situ are often formed with tubular antigens. Accordingly, the deposition of immune complexes can occur not only along the basal membrane of the tubule, but also perivascularly and in the interstitium. The deposition of immune complexes will lead to the activation of the complement system, cell destruction of the tubules and the vascular endothelium, lymphohistiocytic infiltration, changes in the basal membrane of the tubules, and the development of fibrosis.
3. Reaginovy mechanism. The development of inflammation in this mechanism is due to increased production of IgE due to atopy. In this case, the kidney acts as a "shock organ". As a rule, with this mechanism, there are other manifestations of atopy (rash, eosinophilia). Infiltration interstitium develops mainly due to eosinophils.
4. Cellular mechanism. This mechanism is based on the accumulation of a pool of T-lymphocyte killers sensitized to antigens, the infiltration of interstitium and the development of a delayed-type hypersensitivity reaction. Often a violation of the T-helper / T-suppressor ratio is detected.

Substances that cause the development of allergic (IgE-mediated) tubulointerstitial nephritis

Semisynthetic penicillins Sulfonamides Rifampicin Diuretics (especially thiazides, furosemide) Allopurinol

Azathioprine Antipyrine Anticonvulsants (especially phenitonin) Gold Phenylbutazone

Immune inflammation leads to increased vascular permeability, a stasis of blood, the development of interstitial edema, which will lead to compression of the tubules of the kidneys and blood vessels. As a result, intrachannel pressure rises, hemodynamic disturbances are aggravated. With pronounced violations of hemodynamics, the glomerular filtration rate decreases, the level of creatinine and urea increases in the blood. The collapse of the tubules and the violation of hemodynamics will lead to dystrophy of the epithelium and disruption of the function of the tubules, primarily to a decrease in the resorption of water with the development of polyuria and hypostenuria, and further to electrolyte disturbances, tubular acidosis, etc. With severe ischemia, the development of papillary necrosis with massive hematuria.

Morphologically, with acute tubulointerstitial nephritis, the most prominent signs of exudative inflammation: edema interstitium, focal or diffuse lymphohistiocytic, plasmacytic or eosinophilic infiltration. Cellular infiltrate, initially located perivascular, penetrates into the interchannel spaces and destroys nephrocytes. In addition to necrosis, there are signs of dystrophy of the tubules: flattening of the epithelium up to complete atrophy, thickening, sometimes the double-contour of the basal membrane, rupture of the basal membrane. The glomeruli in acute tubulointerstitial nephritis, as a rule, are intact.

In the chronic course of tubulointerstitial nephritis in the morphological picture, the signs of proliferation of connective tissue against the background of tubular atrophy with the development of peritubular fibrosis and thickening of the basal membranes of the tubules, perivascular sclerosis, sclerosis of the renal papillae, and glomerularization are the foreground. Cellular infiltration is represented mainly by activated lymphocytes and macrophages.

Dynamics of morphological changes in interstitial nephritis

Days of illness	Morphological changes
1st day	Edema of interstitium, cellular infiltrates with plasma cells and eosinophils that phagocytize immune complexes containing IgE
2 nd day	Around the tubules of the cortical zone, infiltrates with large mononuclear cells, and zosinophils are revealed. Epithelial cells of the tubules contain many vacuoles
5th day	Increased edema and the spread of infiltrates in the interstitium. Significant dystrophic changes in the tubules, especially in the distal
10th day	The maximum morphological changes are detected by the 10th day. Cellular infiltrates in large quantities not only in the interstitium, but also in the cortical substance. In the glomeruli - leukocytes. The tubules are enlarged, with protein inclusions and oxalate crystals. Basal membrane with fuzzy contours, damaged
11th-120th days	The reverse development of morphological changes

Immunofluorescence study reveals on the basal membrane of the tubules linear (antibody) or granular (immunocomplex) deposits of immunoglobulins (IgG, IgE, in acute tubulointerstitial nephritis - IgM) and C3-components of complement.

Phenomena of instability of cell membranes and activation of processes of lipid peroxidation of cytomembranes are expressed to varying degrees with tubulointerstitial nephritis of any genesis. However, they acquire the greatest importance with tubulointerstitial nephritis, which developed as a result of metabolic disorders. In most cases, it is the primary instability of the membrane of the tubular epithelium that is one of the causes of crystalluria. Due to genetic predisposition or toxic and hypoxic effects, processes of lipid peroxidation with formation of free radicals, toxic forms of oxygen are violated, which leads to the accumulation of secondary toxic products of lipid peroxidation, in particular malonic dialdehyde. In parallel with the activation of lipid peroxidation processes in tubulointerstitial nephritis, a decrease in the activity of antioxidant defense enzymes, including superoxide dismutase, whose activity can be reduced by a factor of four, is noted. The active course of free radical reactions on cell membranes in conditions of decreasing antioxidant protection leads to tubular membranopathy, cell destruction, secondary crystalluria.

A special consideration is the involvement of tubulointerstitial tissue in the pathological process in other nephropathies, in the first place, the tubulo-interstitial component (TEC) with glomerulonephritis. A study by many authors shows that the prognosis of glomerulonephritis (functional kidney disorders, resistance to pathogenetic therapy) depends more on fibrosis of interstitium than on the severity of the morphological changes in the glomeruli.

Among the mechanisms of involvement of the tubulointerstitial apparatus in the pathological process in primary glomerulonephritis are considered: violations of the blood supply of tubules and stroma; migration of inflammatory cells, admission of inflammatory mediators. Damage to the tubular epithelium can be the result of an immunological process. The tubulointerstitial component is possible for all morphological types of glomerulonephritis. By localization and prevalence, three types of these changes can be distinguished: changes in the tubular epithelium (tubular dystrophy) that occur in all patients; change in tubular epithelium in combination with focal changes interstitium; changes in the tubular epithelium in combination with diffuse changes in the stroma. Interstitial changes do not occur without a change in the tubular apparatus. The above changes are represented by two types:

1. cellular infiltration with edema of the stroma;
2. cellular infiltration with sclerosis.

Most often, inflammatory infiltration and multiple sclerosis are combined. Thus, the character of tubulointerstitial changes in the development of various morphological forms of glomerulonephritis is represented by tubular dystrophy; focal and diffuse changes tubulointerstitia.

At the first stages of development of tubulointerstitial nephritis with various types of glomerulonephritis, such changes are not particularly evident, but as the severity of glomerulopathy increases, tubulointerstitial lesions increase. Tubulointerstitial nephritis in the form of diffuse changes is most pronounced in patients with membranous glomerulonephritis, mesangioproliferative glomerulonephritis (MZPGN), mesangiocapillary glomerulonephritis (MCGN), focal segmental glomerulosclerosis (FSGS), and in fibroplastic glomerulonephritis.

With glomerulonephritis with tubulointerstitial nephritis, selective disorders of tubular functions or a combined decrease in tubular functions and glomerular filtration are revealed. As the tubulointerstitial nephritis spreads, the function of osmotic concentration decreases, the enzymes and secretion with urine of fibronectin increase.

Sclerosis of the renal tissue is determined by the accumulation of fibronectin, collagen type 1 and type 3 in the interstitium of the kidney. Along with tissue it is not excluded the participation of plasma fibronectin in sclerosing the kidney tissue. In addition, the mesangial cells of the glomeruli produce interstitial collagen of the third type with progressive forms of glomerulonephritis. In a healthy kidney, collagen type 1 and type 3 is found only in the interstitium, whereas in some patients with MZPGN and MCGN with TEC it is also detected in the mesangium. Diffuse deposition of interstitial collagen type 1 and type 3 in interstitial space around the glomerulus, glomerulus capsule and mesangium leads to progression of sclerosis.

In the overwhelming majority of patients, the number of suppressor-cytotoxic lymphocytes (CD8 +) exceeds the number of helper-inducers (CD4 +). Development of TECs in cases of GN is mainly determined by cellular immune responses, which is confirmed by the presence of T-lymphocytes in the interstitium of the kidney.

Thus, TECs of different degrees of intensity accompany all morphological types of glomerulonephritis and significantly affect the prognosis of glomerulonephritis.

[1], [2], [3], [4], [5], [6], [7], [8]