Causes and pathogenesis of kidney damage with Wegener's granulomatosis

The exact cause of Wegener's granulomatosis is not established. We assume a connection between the development of Wegener's granulomatosis and infection, which is indirectly confirmed by the facts of frequent onset and exacerbation of the disease in the winter-spring period, mainly after respiratory infections, which is associated with the ingestion of an antigen (possibly of viral or bacterial origin) through the respiratory tract. There is also a higher frequency of exacerbations of the disease in carriers of Staphylococcus aureus.

In the pathogenesis of Wegener's granulomatosis, antineutrophilous cytoplasmic antibodies (ANCA-Anti-Neu-trophil Cytoplasmatic Antibodies) have played a key role in recent years. In 1985, FJ Van der Woude et al. First showed that ANCA were detected with high frequency in patients with Wegener's granulomatosis, and suggested their diagnostic significance in this form of systemic vasculitis. Later, ANCA were detected in other forms of vasculitis of small vessels (microscopic polyangiitis and Cherdja Strauss syndrome), and this group of diseases was called ANCA-associated vasculitis. In addition to the listed diseases, this group also includes extracapillary glomerulonephritis with semilunium, which proceeds without extra-renal manifestations, which is now regarded as a local vasculitis of renal vessels. Their distinctive feature is the absence or scarcity of immune deposits in the vascular wall, which led to the appearance of the term "low-immune vasculitis".

ANCA is a heterogeneous population of antibodies reacting with the contents of primary neutrophil granules and monocyte lysosomes: proteinase-3, myeloperoxidase and, less commonly, other enzymes (lactoferrin, cathepsin, elastase). There are two types of ANCA, differentiated based on the type of luminescence with indirect immunofluorescence of ethanol-fixed neutrophils: cytoplasmic (c-ANCA) and perinuclear (p-ANCA).

Cytoplasmic ANCA is directed primarily against proteinase-3 and is more often present in patients with Wegener's granulomatosis, although they are not considered specific for this disease. Perinuclear ANCAs are directed against myeloperoxidase in 90% of cases, they are detected mainly in microscopic polyangiitis, although they can be determined with Wegener's granulomatosis.

Frequency of detection of different types of ANCA in renal damage in patients with Wegener's granulomatosis and microscopic polyangiitis.

Result of research	Wegener's granulomatosis,%	Microscopic polyangiitis,%
Positive c-ANCA (ANCA to Proteinase-3)	65-70	35-45
Positive p-ANCA (ANCA to myeloperoxidase)	15-25	45-55
Negative ANCA	10-20	10-20

To date, evidence has been gathered that the ANCA not only serves as a serologic marker for Wegener's granulomatosis and microscopic polyangiitis, but also plays an important pathogenetic role.

• It has been established that ANCA activates neutrophils, inducing their adhesion to the vascular endothelium, degranulation with the release of proteolytic enzymes, the generation of highly active metabolites of oxygen, which leads to damage to the vessel wall.
• The ability of the ANCA to induce acceleration of neutrophil apoptosis has been demonstrated, which, in combination with the defective clearance of these cells by phagocytes, can lead to the progression of necrotic changes in the vascular wall.
• It is suggested that ANCA interacts with its targets (proteinase-3 and myeloperoxidase) on the surface of the endothelium, which also contributes to its damage. This interaction is possible either as a result of the translocation of ANCA antigens after release from the cytokine-activated neutrophils on the endothelial cell membrane, or the synthesis of proteinase-3 by endothelial cells after stimulation with pro-inflammatory cytokines. The latter two mechanisms practically lead to the formation in the vascular wall of immune complexes consisting of ANCA and their antigens, which, at first glance, contradicts the notion of a "low-immune" character of the process. It is likely that the level of these immune complexes is so small that they can not be determined by standard immunohistochemical methods, but it is sufficient to damage the vascular wall. At present, the evidence supporting this assumption has been obtained.

[1], [2], [3], [4], [5], [6], [7], [8], [9]

Pathomorphology of Wegener's granulomatosis

For Wegener's granulomatosis, a widespread necrotizing panvasculitis of the vessels of the microcirculatory bed and arteries of the muscular type is characteristic. In the acute phase of the process, segmental fibrinoid necrosis of the vascular wall and its infiltration by neutrophils are revealed. Often there is a phenomenon of karyorexis. With the reduction of acute inflammation, neutrophils are replaced by mononuclear cells, necrosis - fibrosis. A characteristic feature of Wegener's granulomatosis is the formation of necrotizing granulomas mainly in organs communicating with the external environment - in the upper respiratory tract and lungs. The cellular composition of the granule is polymorphic: in fresh granulomas, neutrophils, lymphocytes, epithelioid histiocytes, giant cells resembling Pirogov-Langhans cells prevail, in maturing fibroblasts. Fresh granulomas in the lungs tend to merge and subside.

Kidney damage is the third major sign of Wegener's granulomatosis, noted in 80-90% of patients. In the debut of the disease, the symptoms of renal pathology are present in less than 20% of patients. The nature of the renal process in ANCA-associated vasculitis is determined by their pathomorphological features: necrotizing inflammation of small vessels in the kidney is manifested by the development of necrotizing glomerulonephritis.

In the acute phase of the disease, the size of the kidneys is normal or slightly enlarged, their surface often has small hemorrhages; parenchyma pale, edematous. At autopsy in about 20% of cases, papillary necrosis is noted, which was not clinically diagnosed.

• The acute stage of Wegener's granulomatosis is characterized by a pattern of focal segmental necrotizing glomerulonephritis with semilunar nerves. In the most severe cases, lesions of almost all glomeruli are noted, in which, as a rule, segmental necrosis is detected, encompassing individual capillary loops, although total necrosis of the glomerular capillaries is possible. The number of glomeruli with semilunar varies depending on the severity of the process from 10 to 100%. By the nature of the arrangement in the glomerulus, the semilunium can be segmental, occupying less than 50% of the circumference of the capsule, or circular. In 15-50% of patients with Wegener's granulomatosis with renal damage, according to different authors, granulomatous semilunums containing numerous epithelioid and giant cells are found in biopsy specimens. In some patients, granulomatous semilunas are combined with ordinary cellular cells. In the chronic stage of the pathological process, segmental or diffuse glomerulosclerosis is noted, fibrous semilunium. In connection with the rapid evolution of morphological changes, the phenomena of glomerulosclerosis can coexist with active glomerulitis.
• Tubulo-interstitial changes in Wegener's granulomatosis in a small number of patients can be represented by typical interstitial granulomas. In an autopsy study, vasculitis of the ascending vasa recta is detected in approximately 20% of cases with the development of papillary necrosis, which is virtually impossible to detect with percutaneous puncture nephrobiopsy and which appears to develop more often than it is diagnosed. The chronic stage of the process is characterized by canal atrophy and interstitial fibrosis. Immunohistochemical studies show no deposits of immunoglobulins in the vessels and glomeruli of the kidneys, which is a characteristic feature of low-immunity vasculitis and glomerulonephritis associated with the presence of ANCA (type III according to the classification of R. Glassock, 1997).