Amyloidosis and kidney damage - Causes and pathogenesis

The basis of tissue deposits of amyloid are 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. Protein subunits of amyloid fibrils are characterized by a specific spatial orientation of the molecule - cross-P-folded conformation. It is this that determines the tinctorial and optical properties inherent in amyloid. The most specific of them is the property of double refraction of the beam during microscopy of preparations stained with Congo red in polarized light, giving an apple-green glow. The detection of this property is the basis for the diagnosis of amyloidosis.

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Pathogenesis of amyloidosis

Despite the difference in the 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 increase in amyloidogenicity can be due to the molecular heterogeneity of precursor proteins (variant transthyretins, light chains with amino acid substitutions, various isotypes of the SAA protein) and, as a consequence, the circulation of protein variants with increased overall hydrophobicity of the molecule and a disturbed ratio of surface molecular charges, which leads to instability of the protein molecule and promotes its aggregation into an amyloid fibril. These mechanisms are especially clearly seen in proteins whose function includes the need for a physiological change in conformation. Thus, almost all apolipoproteins, the secondary structure of which is formed during the translocation of cholesterol through the vessel wall, participate in the pathogenesis of various forms of amyloidosis.

At the last stage of amyloidogenesis, the amyloid protein interacts with blood plasma proteins and tissue glycosaminoglycans. In this case, the amyloid deposits include the serum amyloid P-component, heparan sulfates and dermatan sulfates of the interstitial glycocalyx. In addition to structural features, the physicochemical properties of the intercellular matrix in which the amyloid fibril is assembled are also important (for example, the low pH of the renal interstitium can promote the aggregation of negatively charged proteins). In the practice of experimental amyloidosis, the ability of a suspension of amyloid masses obtained from the tissues of animals affected by amyloid to provoke it when administered to healthy animals (amyloid-accelerating substance) is well known. The ability of amyloid to transmit 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 increase due to the capture of normal, unchanged transthyretin. A peculiar form of infectious amyloidosis is brain damage in prion diseases. Many forms of amyloidosis are united by the fact that they occur in old and senile age (AL, ATTR, AIAPP, AApoAl, AFib, ALys, AANF, Abeta); this indicates the presence of mechanisms of age-related evolution of the structure of a number of proteins towards increased amyloidogenicity and allows us to consider amyloidosis as one of the models of aging of the body.

Characteristics of the main types of amyloidosis

The β-folded configuration of the fibril is associated with the resistance of amyloid 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), among amyloidogenic factors, the leading role is given to the conformational lability of amyloid precursor proteins, specific for each type of amyloidosis, the content of which in the fibril reaches 80%.

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

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AA amyloidosis

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

Periodic disease (familial Mediterranean fever) is a disease with an autosomal recessive type of inheritance that occurs in residents of the Mediterranean: Jews, Armenians, less often Arabs, Turks, as well as residents of Greece, Italy, and the coast of North Africa. It is 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 about the hereditary nature of periodic disease was based on the ethnic character of the lesion, familial nature of the disease and the onset of the disease in childhood. The genetic concept of the disease was confirmed in 1997, when the MEFV (Mediterranean Fever) gene was identified on the short arm of chromosome 16. The MEFV gene, expressed mainly by neutrophils, codes for the synthesis of the protein pyrin (marenostrin). According to modern concepts, pyrin is the main regulator of the inflammatory response of neutrophils. More than 20 mutations of the pyrin gene are known, associated with the development of periodic disease. These mutations lead to the synthesis of a defective protein and, ultimately, to a violation of the control of inflammation by neutrophils, maintaining their constant proinflammatory potential.

The connection between a hereditary chronic inflammatory disease and AA amyloidosis complicating it led to the hypothesis of a genetic predisposition to amyloidosis in periodic disease. The concept of the hereditary nature of amyloidosis in this disease existed for a long time, despite the fact that it was contradicted by the same type of amyloid ultrastructure (AA protein) as secondary amyloidosis, which allowed classifying amyloidosis in periodic disease as reactive, developing as a result of recurrent aseptic inflammation. Only the discovery of the SAA gene on chromosome 11 and the identification of its mutations made it possible to refute the hypothesis of a single genetic nature of periodic disease and amyloidosis and to recognize the secondary nature of the latter.

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

However, a high concentration of SAA alone is not enough to develop amyloidosis - the precursor protein must also be amyloidogenic. The human genotype encodes 4 SAA proteins, of which only SAA1 and SAA2 are acute phase proteins. The development of amyloidosis in humans is associated with the deposition of SAA1; 5 isotypes of SAA1 are known, of which the highest amyloidogenicity is attributed to 1a/a- and 18-isotypes. The final stage of amyloidogenesis - the formation of amyloid fibrils from the precursor protein occurs with incomplete cleavage by proteases associated with the surface membrane of monocytes-macrophages. Subsequent aggregation of AA protein into amyloid fibrils also occurs on the surface of macrophages under the activating influence of membrane enzymes. The stabilization of the amyloid fibril and the sharp decrease in the solubility of this macromolecular complex are largely due to the addition of the P-component and interaction with interstitial polysaccharides.

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

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AL amyloidosis

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

AL amyloidosis is a generalized process with predominant damage to the heart, kidneys, gastrointestinal tract, nervous system and skin.

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ATTR amyloidosis

ATTR amyloidosis includes familial amyloid polyneuropathy, inherited in an autosomal dominant manner, and systemic senile amyloidosis. The precursor protein in this form of amyloidosis is transthyretin, a component of the prealbumin molecule synthesized by the liver and acting as a thyroxine transport protein.

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

Clinically, this disease is characterized by progressive peripheral and autonomic 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-related conformational changes in normal transthyretin, apparently enhancing its amyloidogenicity. The target organs of senile amyloidosis are the heart, cerebral vessels, and aorta.

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Other forms of amyloidosis

Familial forms of amyloidosis also include the rarer AGel, AFib, ALys, in which mutant forms of gelsolin, fibrinogen, and lysozyme, respectively, have amyloidogenicity.

In these forms of amyloidosis, predominant damage to the kidneys is observed, however, gelsolin amyloidosis is characterized by a combination of nephropathy with reticular corneal dystrophy and peripheral neuropathy (the cranial nerves are predominantly affected).

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

AR ₂ M-amyloidosis (associated with chronic hemodialysis) is of great importance in nephrological practice. The precursor protein in this form of amyloidosis, beta ₂ -microglobulin, is normally present in the blood, urine, cerebrospinal and synovial fluids. With normal renal function, its concentration in the blood is 1-2 mg / l. This protein is filtered in the glomeruli of the kidneys and metabolized after reabsorption in the proximal tubules. In patients with chronic renal failure, the concentration of beta ₂ -microglobulin in the blood increases, correlating with the creatinine content, 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 over 60 years of age, dialysis amyloidosis develops more rapidly. In addition to the high concentration of the precursor protein, other factors also play a significant role in the pathogenesis of dialysis amyloidosis. The amyloidogenicity of beta ₂ -microglobulin increases with incomplete proteolysis associated with the action of cytokines (interleukins-1 and -6, TNF-a), the production of which by monocytes is stimulated by components of the dialysate and dialysis membrane. It was found that beta ₂ -microglobulin has high collagen-binding activity, which increases with increasing its concentration in the blood. In addition, the affinity of beta ₂ -microglobulin for cartilage glycosaminoglycans has been shown, which can explain the predominant deposition of amyloid fibrils in articular tissues. With this type of amyloidosis, damage to bones and periarticular tissues is noted, less often - 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 proven that the heterogeneity of amyloid is due to the diversity of serum precursor proteins and there is a connection between the clinical forms of the disease and the type of these proteins, a classification of amyloidosis was created based on the biochemical type of the precursor protein.

Amyloid protein	Precursor protein	Clinical form of amyloidosis
AA	SAA protein	Secondary amyloidosis in chronic inflammatory diseases, including periodic disease and Muckle-Wells syndrome
AL	Lambda, k-light chains of immunoglobulins	Amyloidosis in plasma cell dyscrasias - idiopathic, in myeloma disease and Waldenstrom's macroglobulinemia
ATTR	Transthyretin	Familial forms of polyneuropathic, cardiopathic and other amyloidosis, systemic senile amyloidosis
Abeta2M	Beta 2 -Microglobulin	Dialysis amyloidosis
AGel	Gelsolin	Finnish familial 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 syndrome, hereditary cerebral hemorrhage with amyloidosis (Holland)
APrpscr	Prion protein	Creutzfeldt-Jakob disease, Gertsmann-Straussler-Scheinker disease
AAN	Atrial natriuretic factor	Isolated atrial amyloidosis
AIAPP	Amilin	Isolated amyloidosis in the islets of Langerhans in type 2 diabetes, insulinoma
ACal	Procalcitonin	For medullary thyroid cancer
ACys	Cystatin C	Hereditary cerebral hemorrhage with amyloidosis (Iceland)

According to the modern classification, all types of amyloidosis are designated by an abbreviation, in which the first letter A means "amyloidosis", and the following letters are the abbreviated names of the main fibrillar proteins of amyloid: A - amyloid protein A, L - light chains of immunoglobulins, TTR - transthyretin, P2M - beta2-microglobulin, etc. From a clinical point of view, it is advisable to distinguish between systemic, or generalized, and local forms of amyloidosis. Among the systemic forms, the main ones are considered to be AA, AL, ATTR and Abeta ₂ M-amyloidosis.

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