Pathogenesis of interstitial nephritis

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

The development of postinfectious tubulointerstitial nephritis is associated with the effect of microorganism toxins and their antigens on the endothelium of interstitial capillaries and the basement membrane of the tubules. This leads to direct cell damage, increased capillary permeability, and the inclusion of nonspecific inflammatory factors. In addition to direct toxic effects, immunologically mediated damage to the endothelium and tubules develops.

Chemicals, heavy metal salts, and medications, when eliminated by the kidneys, can also have a direct damaging effect on the tubular epithelium. However, the development of immune reactions, in which medications act as allergens or haptens, will be of primary importance for the development and maintenance of inflammation, especially in drug-induced tubulointerstitial nephritis.

In primary and secondary dysmetabolic nephropathies, primarily in the case of purine and oxalic acid metabolism disorders, crystals accumulate in the cells of the tubules and interstitium, and are damaged by the direct mechanical action of salts, activation of phagocytosis, and release of inflammatory mediators by macrophages and neutrophils. Subsequently, cellular sensitization to antigens of the brush border of the tubular epithelium and interstitium, as well as to antigens of the glomerular basement membrane, develops.

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

Severe disturbances of blood and lymph circulation, developing both acutely (shock, collapse, DIC syndrome, etc.) and chronically (with various developmental anomalies), disturbances of urodynamics will contribute to the development of hypoxic dystrophy and atrophy of tubular cells and vascular endothelium, activation of macrophages and fibroblasts, which leads to the development of autoimmune processes.

Thus, despite the diversity of causes underlying tubulointerstitial nephritis, its pathogenesis undoubtedly involves immune mechanisms, circulatory disorders, and membranopathological processes.

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

1. Cytotoxic mechanism. Damage to the tubular basement membrane due to the impact of various factors (infectious agents, toxins, chemical compounds, etc.) leads to the release of autoantigens, their entry into the blood with subsequent production of autoantibodies (autoimmune mechanism). In addition, various drugs, toxins and other chemical compounds can act as haptens and, being fixed on the tubular basement membrane, impart new antigenic properties to it, causing the production and deposition of antibodies (immunologically mediated cytotoxicity). In addition, the formation of antibodies to cross-antigens of microorganisms and the tubular basement membrane is possible. The formed antibodies (IgG) are deposited linearly along the tubular basement membrane and in the interstitium, causing activation of the complement system and cell damage, with the development of cellular infiltration and interstitial edema.
2. Immune complex mechanism. Immune complexes can form both in the circulatory bed and in situ. In this case, circulating immune complexes often contain extrarenal antigens (e.g., microbial), and immune complexes in situ are often formed with the participation of tubular antigens. Accordingly, immune complexes can be deposited not only along the tubular basement membrane, but also perivascularly and in the interstitium. Immune complex deposition will lead to activation of the complement system, cellular destruction of tubules and vascular endothelium, lymphohistiocytic infiltration, changes in the tubular basement membrane, and the development of fibrosis.
3. Reaginic mechanism. The development of inflammation with this mechanism is caused by increased production of IgE due to atopy. In this case, the kidney acts as a "shock organ". As a rule, with this mechanism, other manifestations of atopy (rash, eosinophilia) occur. Interstitial infiltration 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 in the tubules, their infiltration of the interstitium, and the development of a delayed-type hypersensitivity reaction. Often, a violation of the T-helper/T-suppressor ratio is detected.

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

Semi-synthetic penicillins Sulfonamides Rifampicin Diuretics (especially thiazides, furosemide) Allopurinol

Azathioprine Antipyrine Anticonvulsants (especially phenytoin) Gold Phenylbutazone

Immune inflammation leads to increased vascular permeability, blood stasis, and the development of interstitial edema, which will lead to compression of the renal tubules and vessels. As a result, intratubular pressure increases, and hemodynamic disorders worsen. With severe hemodynamic disorders, the glomerular filtration rate decreases, and the level of creatinine and urea in the blood increases. Compression of the tubules and hemodynamic disorders will lead to epithelial dystrophy and dysfunction of the tubules, primarily to decreased water resorption with the development of polyuria and hyposthenuria, and later to electrolyte disorders, tubular acidosis, etc. With severe ischemia, papillary necrosis with massive hematuria may develop.

Morphologically, acute tubulointerstitial nephritis is characterized by the most pronounced signs of exudative inflammation: interstitial edema, focal or diffuse lymphohistiocytic, plasmacytic or eosinophilic infiltration. The cellular infiltrate, initially located perivascularly, penetrates into the intertubular spaces and destroys nephrocytes. In addition to necrosis, signs of tubular dystrophy are noted: flattening of the epithelium up to complete atrophy, thickening, sometimes double-contour basement membrane, ruptures of the basement membrane. Glomeruli in acute tubulointerstitial nephritis are usually intact.

In chronic tubulointerstitial nephritis, the morphological picture is dominated by signs of connective tissue proliferation 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 hyalinization of the glomeruli. The cellular infiltrate is represented mainly by activated lymphocytes and macrophages.

Dynamics of morphological changes in interstitial nephritis

Days of illness	Morphological changes
Day 1	Interstitial edema, cellular infiltrates with plasma cells and eosinophils that phagocytose immune complexes containing IgE
Day 2	Infiltrates with large mononuclear cells and eosinophils are found around the tubules of the cortical zone. The epithelial cells of the tubules contain many vacuoles.
Day 5	Increased edema and spread of infiltrates into the interstitium. Significant dystrophic changes in the tubules, especially in the distal part
Day 10	Maximum morphological changes are detected by the 10th day. Cellular infiltrates are abundant not only in the interstitium, but also in the cortex. There are leukocytes in the glomeruli. The tubules are dilated, with protein inclusions and oxalate crystals. The basement membrane has unclear contours and is damaged.
Days 11-120	Reversal of morphological changes

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

The phenomena of instability of cell membranes and activation of lipid peroxidation processes of cytomembranes are expressed to varying degrees in tubulointerstitial nephritis of any genesis. However, they acquire the greatest significance in tubulointerstitial nephritis that has developed as a result of metabolic disorders. In most cases, it is the primary instability of the tubular epithelium membranes that is one of the causes of crystalluria. Due to genetic predisposition or toxic and hypoxic effects, lipid peroxidation processes are disrupted with the formation of free radicals, toxic forms of oxygen, 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 system enzymes is noted, including superoxide dismutase, the activity of which can decrease fourfold. The active course of free-radical reactions on cell membranes under conditions of reduced antioxidant protection leads to tubular membranopathy, cellular destruction, and secondary crystalluria.

The involvement of tubulointerstitial tissue in the pathological process in other nephropathies requires special consideration, primarily the tubulointerstitial component (TIC) in glomerulonephritis. Research by many authors shows that the prognosis of glomerulonephritis (functional disorders of the kidneys, resistance to pathogenetic therapy) depends to a greater extent on interstitial fibrosis than on the severity of morphological changes in the glomeruli.

The mechanisms of tubulointerstitial apparatus involvement in the pathological process in primary glomerulonephritis include: impaired blood supply to the tubules and stroma; migration of inflammatory cells, and the entry of inflammatory mediators. Damage to the tubular epithelium may be the result of an immunological process. The tubulointerstitial component is possible in all morphological types of glomerulonephritis. According to localization and prevalence, three types of such changes can be distinguished: changes in the tubular epithelium (tubular dystrophy), which occur in all patients; changes in the tubular epithelium in combination with focal changes in the interstitium; changes in the tubular epithelium in combination with diffuse changes in the stroma. Changes in the interstitium do not occur without changes in the tubular apparatus. The above changes are represented by two types:

1. cellular infiltration with stromal edema;
2. cellular infiltration with sclerosis.

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

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

In glomerulonephritis with tubulointerstitial nephritis, selective disturbances of tubular functions or a combined decrease in tubular functions and glomerular filtration are detected. As tubulointerstitial nephritis spreads, the osmotic concentration function decreases, enzymuria and secretion of fibronectin in the urine increase.

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

In the vast majority of patients, the number of suppressor-cytotoxic lymphocytes (CD8+) exceeds the number of helper-inducers (CD4+). The development of TIC in GN is determined mainly by cellular immune reactions, which is confirmed by the presence of T-lymphocytes in the renal interstitium.

Thus, TIC of varying severity accompanies all morphological types of glomerulonephritis and significantly affects the prognosis of glomerulonephritis.

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