Amyloidosis and kidney damage: causes and pathogenesis

The basis of tissue deposits of amyloid is amyloid fibrils - special protein structures with a diameter of 5-10 nm and a length of up to 800 nm, consisting of 2 or more parallel filaments. The protein subunits of amyloid fibrils are characterized by a peculiar spatial orientation of the molecule-a cross-P-fold conformation. It determines the inherent amyloid tinctorial and optical properties. The most specific of these is the property of double refraction of the beam with microscopy of stained Congo red preparations in polarized light, giving an apple-green glow. The identification of this property is the basis for the diagnosis of amyloidosis.

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

Pathogenesis of amyloidosis

Despite the difference in types of amyloid protein, the mechanisms of amyloidosis formation are similar. The main condition for the development of the disease is the presence of a certain, often increased amount of amyloidogenic precursor. The appearance or amplification of amyloidogenicity may be due to the molecular heterogeneity of progenitor proteins (variant transthyretins, light chains with amino acid substitutions, different isotypes of the SAA protein) and, as a consequence, circulation of protein variants with increased total hydrophobicity of the molecule and a disturbed ratio of surface molecular charges, instability of the protein molecule and contributes to its aggregation into amyloid fibril. These mechanisms are particularly clearly traced on the example of proteins, the function of which is the need for a physiological change in the conformation. Thus, virtually all apolipoproteins, the secondary structure of which is formed during the translocation of cholesterol through the vessel wall, are involved in the pathogenesis of various forms of amyloidosis.

At the last stage of amyloidogenesis, the amyloid protein interacts with blood plasma proteins and glycosaminoglycan tissues. Amyloid deposits include serum amyloid P-component, heparan sulfates and dermatan sulfates of the interstitial glycocalyx. In addition to structural features, the physico-chemical properties of the intercellular matrix, in which the amyloid fibril is assembled, also have significance (for example, a low pH of renal interstitium may promote the aggregation of negatively charged proteins). In the practice of experimental amyloidosis, the ability of a suspension of amyloid masses obtained from tissues of animals afflicted with amyloid is known to provoke it when administered to a healthy animal (amyloid-accelerating substance). The ability of amyloid for transmission is also known in clinical practice - in patients with ATTR-amyloidosis: despite the cessation of circulation of pathological transthyretin after transplantation of a healthy liver, the mass of amyloid deposits in the heart continues to grow due to the capture of normal, unchanged transthyretin. A peculiar form of infectious amyloidosis is brain damage in prion diseases. Many forms of amyloidosis combine the fact that they arise in the elderly and senile age (AL, ATTR, AIAPP, AApoAl, AFib, ALys, AANF, Abeta); this indicates the presence of mechanisms of the age-related evolution of the structure of a number of proteins towards increasing amyloidogenicity and allows treating amyloidosis as one of the models of aging of the organism.

Characteristics of the main types of amyloidosis

With the P-fold configuration of the fibril, the stability of amyloid is related to proteolytic enzymes of the intercellular matrix, which causes its significant accumulation with progressive destruction of the affected organ and loss of its function. Despite the heterogeneity of amyloid fibrils (glycoproteins), the conformational lability of amyloid precursor proteins, specific for each type of amyloidosis, whose content in the fibril reaches 80%, is the leading role among amyloidogenic factors.

Among other proteins of amyloid, the so-called amyloid P-component, a derivative of the acute phase protein synthesized by the liver, structurally similar to the C-reactive protein, is of particular importance. The ability to inhibit cellular adhesion explains the involvement of amyloid P protein in limiting the inflammatory response and blocking autoimmunity. In the amyloid composition, the P-component protects the fibrils from enzymatic destruction by amyloid-macrophage macrophages. Depending on the main protein, which is part of amyloid fibrils, several types of amyloidosis are distinguished.

[7], [8], [9], [10], [11], [12]

AA-amyloidosis

This group includes reactive (secondary) amyloidosis; The most frequent causes are rheumatoid arthritis (30-50%), chronic purulent-destructive diseases (osteomyelitis, bronchiectasis), inflammatory bowel diseases (ulcerative colitis, Crohn's disease), tuberculosis, tumors (often lymphogranulomatosis and kidney cancer). AA also includes amyloidosis in cryopyrinopathies (for example, with McLean Wells syndrome - familial periodic fever in combination with deafness and urticaria), a recurrent disease.

Periodic illness (familial Mediterranean fever) is a disease with an autosomal recessive type of inheritance that occurs among the inhabitants of the Mediterranean: Jews, Armenians, less often Arabs, Turks, as well as residents of Greece, Italy, the coast of North Africa. Characterized by recurrent attacks of aseptic serositis (peritonitis, pleurisy, synovitis), manifested by pain in the abdomen, chest, joints in combination with fever and in 20-40% of cases leads to the development of amyloidosis. The assumption of the hereditary nature of the periodic illness was based on the ethnic character of the lesion, the family illness and the onset of the disease from childhood. The genetic concept of the disease was confirmed in 1997, when the MEFV gene (Mediterranian Fever) was identified on the short arm of chromosome 16. The MEFV gene, expressed mainly by neutrophils, encodes the synthesis of the pyrin protein (marenostrino). According to modern ideas, the pirin is the main regulator of the inflammatory response of neutrophils. There are more than 20 mutations of the pyrin gene associated with the development of the periodic disease. These mutations lead to the synthesis of a defective protein and, ultimately, to a violation of the control of inflammation by neutrophils, the preservation of their constant pro-inflammatory potential.

The connection of the hereditary chronic inflammatory disease and its complicating AA-amyloidosis led to the hypothesis of a genetic predisposition to amyloidosis in a periodic illness. The concept of the hereditary nature of amyloidosis in this disease has existed for a long time, despite the fact that it contradicted the amyloid ultrastructure (AA-protein), which is the same type with secondary amyloidosis, allowing amyloidosis to be classified as a periodic disease to a reactive one that develops as a result of recurrent aseptic inflammation. Only the discovery on the chromosome of the 11th SAA gene and the identification of its mutations allowed to refute the hypothesis of the unified genetic nature of the periodic disease and amyloidosis and to recognize the secondary nature of the latter.

AA-amyloid is formed from the serum protein precursor SAA - acute phase protein, normally synthesized by hepatocytes, neutrophils and fibroblasts in trace amounts. Its concentration significantly increases under the influence of interleukins-1 and -6, TNF-a in response to inflammation, tumor growth. An increase in the content of SAA in the blood plays a major role in the pathogenesis of AA-amyloidosis.

However, only a high concentration of SAA is not enough for the development of amyloidosis - it is also necessary that the precursor protein has amyloidogenicity. The human genotype encodes 4 SAA proteins, of which only SAA1 and SAA2 belong to the acute phase proteins. The development of amyloidosis in humans is associated with the deposition of SAA1; There are 5 isotypes of SAA1, of which 1a / a and 18 isotypes are attributed to the highest amyloidogenicity. The final stage of amyloidogenesis - the formation of amyloid fibrils from the precursor protein is carried out with incomplete cleavage by proteases bound to the surface membrane of monocytes-macrophages. Subsequent aggregation of the AA protein into amyloid fibrils also occurs on the surface of macrophages with the activating effect of membrane enzymes. Stabilization of amyloid fibril and a sharp decrease in the solubility of this macromolecular complex are largely due to the addition of the P component and interaction with polysaccharide interstitium.

With AA-amyloidosis, amyloid is found in various organs: kidneys, liver, spleen, adrenal glands, gastrointestinal tract. However, the clinical picture and prognosis are determined by renal damage.

[13], [14], [15], [16],

AL-amyloidosis

AL-amyloidosis includes primary (idiopathic) amyloidosis and amyloidosis, associated with myeloma, in which it develops in 7-10% of patients. According to modern ideas, primary AL-amyloidosis and myeloma (both associated with amyloidosis and not associated with it) are considered in the framework of a single B-lymphocytic dyscrasia - the proliferation of an abnormal clone of plasma cells or B cells in the bone marrow with excessive production of a monoclonal immunoglobulin , which has amyloidogenicity. Belkom-precursor in AL-amyloidosis is considered to be monoclonal light chains of immunoglobulins, from whose name abbreviation L occurs, and in primary amyloidosis, light A.-type chains occur 3 times more often than k-type, unlike myeloma disease, which is characterized by predominance of light chains of k-type. In the formation of AL-amyloid, the violation of light chain proteolysis is of great importance, with the formation of polypeptide fragments capable of aggregation.

AL-amyloidosis is a generalized process with a primary lesion of the heart, kidneys, gastrointestinal tract, nervous system and skin.

[17], [18], [19], [20], [21],

ATTR-amyloidosis

To ATTR-amyloidosis belong family amyloid polyneuropathy, inherited in autosomal dominant type, and systemic senile amyloidosis. The protein precursor in this form of amyloidosis is a transthyretin - a component of the prealbumin molecule, synthesized by the liver and carrying out the functions of the transport protein of the thyroxine.

It has been established that hereditary ATTR-amyloidosis is the result of a mutation in the gene encoding transthyretin, which leads to the replacement of amino acids in the TTR molecule. There are several types of hereditary amyloid neuropathy: Portuguese, Swedish, Japanese and several others. In the most common family variant (Portuguese) in the 30th position from the N-terminus of the molecule, transthyretin methionine is replaced by valine, which increases the amyloidogenicity of the precursor protein and facilitates its polymerization into amyloid fibrils. Several variants of transthyretin are known, which explains the variety of clinical forms of hereditary neuropathy.

Clinically, this disease is characterized by progressive peripheral and vegetative neuropathy, which is combined with damage to the heart, kidneys and other organs of varying degrees.

Systemic senile amyloidosis develops after 70 years as a result of age conformational changes in normal transthyretin, apparently, enhancing its amyloidogenicity. Target organs of senile amyloidosis are the heart, vessels of the brain and aorta.

[22], [23], [24]

Other forms of amyloidosis

To the family forms of amyloidosis also include the more rare AGel, AFib, ALys, in which the mutant forms of gelsoline, fibrinogen, lysozyme are respectively amyloidogenic.

In these forms of amyloidosis, the primary lesion of the kidneys is noted, however, for nephropathy with nephropathy with mesh dystrophy of the cornea and peripheral neuropathy (mainly cranial nerves) is characteristic.

Currently, more than 20 amyloidogenic progenitor proteins and, accordingly, clinical forms of amyloidosis are known. Thus, AP-amyloid is the morphological basis of Alzheimer's disease, AIAPP-amyloid-type 2 diabetes, but for these forms of amyloidosis, renal damage usually does not have a significant clinical significance.

AP ₂ M-amyloidosis (associated with chronic hemodialysis) is of great importance in nephrological practice. Protein precursor with this form of amyloidosis, beta _2- microglobulin, is normally present in the blood, urine, cerebrospinal fluid and synovial fluids. With normal kidney function, its concentration in the blood is 1-2 mg / l. This protein is filtered in the glomerulus of the kidneys and is metabolized after reabsorption in the proximal tubules. In patients with chronic renal insufficiency, the concentration of beta _2- microglobulin in the blood increases, correlating with the content of creatinine, but it reaches its maximum values (20-70 times higher than normal) after several years of regular hemodialysis. Since beta _2- microglobulin is not removed during the procedure, there are prerequisites for the development of amyloidosis after 7 years of treatment or more. In patients older than 60 years dialyzed amyloidosis develops faster. In addition to the high concentration of the precursor protein in the pathogenesis of dialyzed amyloidosis, other factors play a significant role. Amyloidogenicity of beta _2- microglobulin increases with incomplete proteolysis associated with the action of cytokines (interleukins-1 and -6, TNF-a), whose production by monocytes stimulate the components of dialysate and dialysis membrane. It was found that beta _2- microglobulin has a high collagen-binding activity, increasing as its concentration in the blood increases. In addition, the affinity of beta- _2- microglobulin for cartilage glycosaminoglycans is shown , which explains the preferential deposition of amyloid fibrils in articular tissues. In this type of amyloidosis, damage to bones and periarticular tissues is noted, rarely to vessels.

Classification of amyloidosis

Until recently, the generally accepted classification of amyloidosis was based on the presence of the disease that caused it. After it was proved that the heterogeneity of amyloid is due to the diversity of serum protein proteins and there is a connection between the clinical forms of the disease and the type of these proteins, a classification of amyloidosis based on the biochemical type of the precursor protein was created.

Amyloid protein	Protein precursor	Clinical form of amyloidosis
AA	SAA-protein	Secondary amyloidosis in chronic inflammatory diseases, including periodic illness and McLean Wells syndrome
AL	Lambda, to-light chains of immunoglobulins	Amyloidosis in plasma cell dyscrasia is idiopathic, with myeloma disease and Waldenstrom macroglobulinemia
ATTR	Transthyretin	Family forms of polyneuropathic, cardiopathic and other amyloidosis, systemic senile amyloidosis
Abeta2M	Beta 2- Microglobulin	Dialysis amyloidosis
AGel	Gelsolin	Finnish family amyloid polyneuropathy
AApoAI	Apolipoprotein AI	Amyloid polyneuropathy (type III, according to van Allen, 1956)
Afib	Fibrinogen	Amyloid Nephropathy
Abeta	Beta-Protein	Alzheimer's disease, Down's syndrome, hereditary hemorrhages in the brain with amyloidosis (Holland)
APrpscr	Prion protein	Disease of Creutzfeldt-Jakob disease of Gertsmann-Straussler-Scheinker
AANF	Atrial natriuretic factor	Isolated amyloidosis of the atria
AIAPP	Amilin	Isolated amyloidosis in the islets of Langerhans with type 2 diabetes, insulin-number
ACal	Procalcitonin	With medullary thyroid cancer
ACys	Cystatin C	Hereditary hemorrhages in the brain with amyloidosis (Iceland)

According to the modern classification, all types of amyloidosis are designated by an abbreviation, in which the first letter A stands for "amyloidosis", and the subsequent ones abbreviate the name of the main fibrillar proteins of amyloid: A - amyloid protein A, L - light chains of immunoglobulins, TTR - trastiuretin, P2M - beta2- microglobulin, etc. From the clinical point of view, it is expedient to isolate systemic, or generalized, and local forms of amyloidosis. Among the system forms, the main ones are AA, AL, ATTR and Abeta ₂ M-amyloidosis.

[25], [26], [27], [28]