Causes and pathogenesis of renal damage in Wegener's granulomatosis

The exact cause of Wegener's granulomatosis has not been established. It is assumed that there is a connection between the development of Wegener's granulomatosis and infection, 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 entry of an antigen (possibly of viral or bacterial origin) through the respiratory tract. A higher frequency of exacerbations of the disease is also known in carriers of Staphylococcus aureus.

In recent years, a key role in the pathogenesis of Wegener's granulomatosis has been attributed to anti-neutrophil cytoplasmic antibodies (ANCA). In 1985, F. J. Van der Woude et al. first demonstrated that ANCA are 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 small vessel vasculitis (microscopic polyangiitis and Churg-Strauss syndrome), which is why this group of diseases began to be called ANCA-associated vasculitis. In addition to the listed diseases, this group also includes extracapillary glomerulonephritis with crescents, which occurs without extrarenal manifestations, which is today considered a local vasculitis of the renal vessels. Their distinctive feature is the absence or scarcity of immune deposits in the vascular wall, which led to the emergence of the term "low-immune vasculitis".

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

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

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

Research result	Wegener's granulomatosis, %	Microscopic polyangiitis, %
C-ANCA (ANCA to proteinase-3) positive	65-70	35-45
Positive p-ANCA (ANCA to myeloperoxidase)	15-25	45-55
Negative ANCA	10-20	10-20

To date, data have accumulated indicating that ANCA not only serves as a serological marker of Wegener's granulomatosis and microscopic polyangiitis, but also plays an important pathogenetic role.

• It has been established that ANCA activate neutrophils, inducing their adhesion to the vascular endothelium, degranulation with the release of proteolytic enzymes, and the generation of highly active oxygen metabolites, which leads to damage to the vessel wall.
• The ability of ANCA to accelerate neutrophil apoptosis has been shown, which, in combination with defective clearance of these cells by phagocytes, can lead to the progression of necrotic changes in the vascular wall.
• It is suggested that ANCA may interact with its targets (proteinase-3 and myeloperoxidase) on the endothelial surface, which also contributes to its damage. This interaction is possible as a result of either translocation of ANCA antigens after release from cytokine-activated neutrophils to the endothelial cell membrane, or synthesis of proteinase-3 by endothelial cells after stimulation with proinflammatory cytokines. The last two mechanisms practically lead to the formation of immune complexes consisting of ANCA and their antigens in situ in the vascular wall, which, at first glance, contradicts the idea of the "low-immune" nature of the process. It is likely that the level of these immune complexes is so low that they cannot be detected by standard immunohistochemical methods, but is sufficient to damage the vascular wall. Evidence has now been obtained confirming this assumption.

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Pathomorphology of Wegener's granulomatosis

Wegener's granulomatosis is characterized by widespread necrotizing panvasculitis of the microcirculatory bed and muscular arteries. In the acute phase of the process, segmental fibrinoid necrosis of the vascular wall and its infiltration by neutrophils are detected. The phenomenon of karyorrhexis is often noted. As the acute inflammation subsides, neutrophils are replaced by mononuclear cells, and necrosis is replaced by 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 granulomas is polymorphic: neutrophils, lymphocytes, epithelioid histiocytes, giant cells resembling Pirogov-Langhans cells predominate in fresh granulomas, and fibroblasts in maturing ones. Fresh granulomas in the lungs tend to merge and then disintegrate.

Kidney damage is the third main symptom of Wegener's granulomatosis, observed in 80-90% of patients. At the same time, at the onset of the disease, 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 kidneys are normal in size or slightly enlarged, their surface often has small hemorrhages; the parenchyma is pale and edematous. At autopsy, papillary necrosis is noted in approximately 20% of cases, which was not clinically diagnosed.

• The acute stage of Wegener's granulomatosis is characterized by a picture of focal segmental necrotizing glomerulonephritis with crescents. In the most severe cases, almost all glomeruli are affected, in which, as a rule, segmental necrosis is detected, covering individual capillary loops, although total necrosis of glomerular capillaries is also possible. The number of glomeruli with crescents varies depending on the severity of the process from 10 to 100%. By the nature of their location in the glomerulus, the crescents can be segmental, occupying less than 50% of the capsule circumference, or circular. In 15-50% of patients with Wegener's granulomatosis with kidney damage, according to various authors, granulomatous crescents containing numerous epithelioid and giant cells are found in biopsy specimens. In some patients, granulomatous crescents are combined with normal cellular ones. In the chronic stage of the pathological process, segmental or diffuse glomerulosclerosis and fibrous crescents are observed. Due to the rapid evolution of morphological changes, glomerulosclerosis phenomena can coexist with active glomerulitis.
• Tubulointerstitial changes in Wegener's granulomatosis in a small number of patients may be represented by typical interstitial granulomas. Autopsy studies reveal vasculitis of the ascending vasa recta with the development of papillary necrosis in approximately 20% of cases, which is almost impossible to detect using percutaneous puncture nephrobiopsy and which apparently develops more often than is diagnosed. The chronic stage of the process is characterized by tubular atrophy and interstitial fibrosis. Immunohistochemical studies do not reveal immunoglobulin deposits in the vessels and glomeruli of the kidneys, which is a characteristic feature of pauciimmune vasculitis and glomerulonephritis associated with the presence of ANCA (type III according to the classification of R. Glassock, 1997).