Kidney Amyloidosis

What is Kidney Amyloidosis?

Amyloidosis is a complex violation of protein-carbohydrate metabolism, which leads to the formation in the internal organs and systems of a special substance – amyloid (R. Virchow, 1853). Thanks to the latest research methods, the physical, chemical, and antigenic properties of the amyloid substance have been studied in sufficient detail. However, despite the fact that more than 140 years have passed since the discovery of amyloid (S. Rokitansky, 1842), many questions concerning the problem of amyloidosis still remain unresolved.

With the help of intravital biopsy and histochemical studies of punctates taken from organs affected by amyloidosis, it was established that amyloid substance is a complex protein product – glycoprotein, in which proteins are strongly associated with polysaccharides and differ in amino acid composition from tissue and plasma proteins.

The spread of amyloidosis among the population of different countries has significant differences. Thus, according to autopsy data, in the United States and some European countries, renal amyloidosis is detected in 0.7%, whereas in Asian countries it is less common – up to 0.2%, which is explained by the nutritional characteristics of the population of these countries, in particular, its low content in food The diet of animal protein and cholesterol. The high prevalence among the population of Spain (1.92%) and Portugal (1.43%) is explained by the development of familial amyloidosis in these countries. According to V.V. Serov and I.A. Shamov (1977), on average amyloidosis occurred in 1.08% of the dead. It most often affects males aged 40-50 years, however, cases of kidney amyloidosis in children and even newborns are described.

Causes of Kidney Amyloidosis

The causes of this disease are very diverse. It is known that many diseases can be complicated by the development of amyloidosis, but it can also be an independent disease. With this in mind, primary amyloidosis is isolated, when the cause cannot be established, and secondary, the occurrence of which is due to a number of chronic diseases and pathological conditions.

In recent years, primary amyloidosis occurs more frequently. Secondary amyloidosis develops as a result of chronic suppurative processes or infectious-allergic diseases, usually several years after the onset of the underlying disease. In this case, the deposition of amyloid occurs primarily in the affected organ, and then it accumulates in other parenchymal organs. Depending on the intensity of amyloid deposition in a particular organ, nephropathic, hepatopathic, cardiopathic, or mixed types of amyloidosis are isolated.

The most common cause of secondary amyloidosis is pulmonary tuberculosis. Moreover, despite the progress achieved in the treatment of tuberculosis, the percentage of its complications with amyloidosis has increased significantly. Such an increase in amyloidosis can be explained by an increase in the life expectancy of patients with tuberculosis, as well as by autoimmune reactions, caused both by the disease itself and by the use of antimicrobial agents. It should be borne in mind that amyloidosis in some cases occurs in people with inactive or cured pulmonary tuberculosis, but with severe pneumosclerosis, emphysema.

Among other diseases in the development of amyloidosis, purulent processes (bronchiectasis, lung abscessing, osteomyelitis, etc.) are essential. Second place among the causes leading to the development of amyloidosis is rheumatoid arthritis, which in 20% of cases is complicated by amyloidosis. At about the same frequency of 26.5%, amyloidosis occurs in patients with recurrent disease, mainly affects the kidneys. It can be caused by lymphogranulomatosis, tumors, myeloma, and other diseases.

Senile amyloidosis, many authors consider as a universal sign of aging, which is found in 80% of people older than 80 years. More often, old people find amyloid deposition in the heart, brain, pancreas, and kidneys.

Pathogenesis during Amyloidosis of the Kidneys

A number of theories have been proposed to explain the mechanism of development of amyloidosis.

According to the theory of dysproteinosis, or organoproteinosis, an amyloid substance is the product of a perverted protein synthesis. The blood plasma accumulates globulin fractions of protein and abnormal proteins (paraproteins), which, penetrating from the bloodstream into the tissue, form an amyloid substance in the cells of the active mesenchyme. According to this theory, the development of amyloidosis is usually preceded by dysproteinemia, resulting from any chronic disease – tuberculosis, bronchiectasis, rheumatoid arthritis, malignant neoplasms, etc. At the same time, there is an increase in blood levels of globulin fractions, especially a2-globulins, and a decrease albumin level.

The theory of “cellular local genesis” explains the formation of amyloidosis by the perversion of the protein-synthetic function of the cells of the reticuloendothelial system. In this case, the synthesis of amyloid occurs in two phases. In the first – active, or pre-amyloid, as a result of proliferation of the elements of the reticuloendothelial system, so-called pyroninophilic cells appear and the level of γ-globulins in the blood serum increases. The second, actually amyloid, phase suppresses the cellular transformation of the reticuloendothelial system and “exhausts” pyroninophilic cells, decreases the u-globulin level and increases the content of a-and b-globulins in the blood serum.

The immunological theory of the pathogenesis of amyloidosis links the formation of amyloid substance with autoimmune reactions. According to this theory, in many primary diseases there is an accumulation of decay products of tissues, leukocytes, bacterial toxins, which can play the role of autoantigens with the subsequent formation of autoantibodies. The reaction of the interaction of an antigen with an antibody leads to the development of amyloidosis and its deposition in places of accumulation of antibodies, i.e. in the elements of the reticuloendothelial system.

The mutational theory of the formation of a clone of cells, amyloidoblasts, is considered universal in the explanation of amyloidosis (with the exception of idiopathic). In secondary amyloidosis, mutations of amyloidoblast clones appear due to prolonged antigenic stimulation; with genetic – we are talking about a gene mutation that can occur in different loci with the formation of a diverse composition of amyloid substance. According to this theory, senile amyloidosis should be regarded as a genetic phenocopy. The mutational theory of amyloidogenesis allows us to understand the closeness of amyloidosis and the tumor process.

Since the discovery of amyloid, ideas about the nature and structure of amyloid substances have changed several times. R. Virchow (1853) considered amyloid as a “blood product”. Currently, with the help of experimental studies, methods of puncture biopsy, electron microscopy, histochemistry and others, it has been established that the structure of the amyloid substance consists of several stages. At the first stage, in the pyroninophilic, or pre-amyloid, stage, cellular transformation of the reticuloendothelial system occurs with the appearance of amyloidoblasts. At the second stage of amyloidogenesis, the fibrillar protein is synthesized by amyloidoblasts. Then aggregation of fibrils takes place with the formation of the “framework” of the amyloid substance. A significant stage in the formation of amyloid substance is the combination of amyloid fibrils with proteins and plasma glucoproteins and acidic mucopolysaccharides of the tissue.

Compared with amyloidosis of other organs, renal amyloidosis is most important in clinical practice, since it often ends with the development of chronic renal failure with all the ensuing consequences. Macroscopically, the kidneys are enlarged, dense to the touch, their surface is smooth. On a section cortical and medulla are well distinguishable. At the same time, the cortical substance of the kidney is somewhat enlarged, in the early stage of the disease it is grayish-red, later (in the proteinuric and nephrotic stage) it acquires a matte shade, and the medulla becomes sebaceous (“big fat kidney”). In the azotemic stage, the kidneys are reduced in size; they have uneven contours with many cicatricial depressions.

Histologically, in the latent stage, the amyloid substance is detected slightly in the basement membrane of the glomerular capillaries of the kidney, and then along the direct vessels, the pyramids. In the proteinuric stage, the amyloid is deposited in the glomeruli: first in the mesangium, then in separate capillary loops and arterioles. The epithelium of the proximal tubules is in a state of hyaline droplet or vacuolar dystrophy. In the nephrotic stage, the amyloid substance is found in the capillary loops of many clumps, in the walls of their arterioles, along the basement membrane, in the tubules; amyloidosis becomes diffuse. In addition to fatty dystrophy of the epithelium of the tubules, often hyaline droplet or vacuolar dystrophy. In the azotemic stage, the amyloid substitution of most glomeruli is observed, which leads to the death and atrophy of nephrons, the proliferation of connective tissue.

Symptoms of Amyloidosis of the Kidneys

There is no generally accepted classification of amyloidosis. The classification of V.V. Serov and I.A. Shamov (1977) is considered to be the most convenient for the practical doctor. In her amyloidosis is grouped depending on the types, forms and species, as well as the causes leading to its development.

According to this classification are distinguished:

  1. Idiopathic (primary) amyloidosis: generalized (classical), nephropathic, neuropathic, cardiopathic, localized.
  2. Hereditary (genetic) amyloidosis: intermittent illness (familial Mediterranean fever); familial amyloidosis with fever, urticaria and deafness; familial amyloidosis with allergic manifestations, fever and nephropathy; familial neuropathic amyloidosis; family cardiopathic amyloidosis.
  3. Acquired (secondary): amyloidosis as a complication of chronic infections, collagen diseases and malignant tumors; paraamyloidosis (amyloidosis with paraproteinemic hemoblastosis).
  4. Senile amyloidosis.
  5. Local tumor amyloidosis.

Clinical manifestations of kidney amyloidosis are very diverse: they depend on the localization of amyloid deposits in other organs, the duration of the disease, the severity of the structure and function of the affected organ, and the severity of the primary disease that caused the development of amyloidosis.

As already noted, in contrast to primary, hereditary and senile amyloidosis, secondary develops against the background of any chronic disease or after it. At the same time, according to available data, its appearance does not depend on the duration and severity of the underlying disease. Nevertheless, secondary amyloidosis often occurs several or many years after the underlying disease, although there are cases of amyloidosis after 3 months from the onset of the underlying disease. It is impossible to establish the exact dates of the end of the underlying disease and the onset of the development of amyloidosis, as it is usually recognized in the late stage of its development.

Of great practical importance is the timely detection of amyloidosis at an early stage, when it is possible to achieve the reverse development of this pathological process, whereas in the later stages it is practically irreversible or recovery occurs extremely rarely. From this point of view, differentiation of the course of kidney amyloidosis by stages seems practically important.

Four stages of renal amyloidosis are clinically distinguished: latent, proteinuric, nephrotic, and azotemic.

The latent stage of amyloidosis is almost asymptomatic. When diagnosing it, it is necessary to pay attention to the symptoms of the underlying disease, which can be potentially dangerous in relation to the development of amyloidosis. The possibility of this factor increases in cases where the underlying disease is accompanied by the periodic occurrence of a small proteinuria. It is necessary to take into account such symptoms as an increase in the size of the liver and spleen.

The main clinical and laboratory sign of the latent stage is proteinuria, usually transient, unstable and insignificant. Minor microhematuria can be detected rarely, and even less often – minimal leukocyturia. Characterized by persistent dysproteinemia, which persists even with a favorable course of the underlying disease and is manifested by an increase in globulin fractions, mainly a2-and y-globulins. The level of glycoproteins and mucopolysaccharides, as well as fibrinogen is increased to the upper limit of normal. Most patients have a significant and persistent increase in ESR in the absence of signs of exacerbation of the underlying disease. Kidney function in this stage does not suffer. In the biopsy of the renal tissue, taken with the help of an intravital puncture biopsy, an amyloid substance is found, which is located along the basement membranes of the direct vessels, tubules, collecting tubes, and in some cases also in the glomeruli.

The main clinical manifestation of the proteinuric stage of kidney amyloidosis is a constant proteuria, which is characterized by significant protein fluctuations (from 0.1 to 3.0 g/l) in urine with microhematuria, cylindruria, and occasionally leukocyturia. The most pronounced proteinuria is observed in secondary amyloidosis, although it is observed in primary and hereditary amyloidosis, but to a lesser extent. Permanent loss of protein in the urine through the gastrointestinal tract, an increase in its breakdown in the body leads to the development of hypoproteinemia with hypoalbuminemia.

Significant shifts in blood biochemical parameters are noted: severe dysproteinemia with hypoalbuminemia (up to 36.0%) and hyperglobulinemia as an increase in the a1- fractions (up to 9.0%), a2- (up to 15.0-16.0%) and y- globulins (up to 23.0-25.0%); hyperfibrinogenemia (up to 5.5 g/l), increase in the content of sialic acids (up to 0.300) with normal or even low cholesterol concentration. ESR increases significantly, moderate anemia appears. The electrolyte balance changes, the amount of sodium and potassium decreases.

The main clinical manifestation of the nephrotic stage of amyloidosis is nephrotic syndrome, characterized by massive proteinuria, pronounced hypo- (up to 5.0-3.0 g/l) and dysproteinemia in the form of significant hypoalbuminemia (up to 20-30% and below), hyperalpha 2-globulinemia (up to 20-30%) and hypergammaglobulinemia (up to 25%); hyperlipidemia, in particular hypercholesterolemia (up to 12.0 mmol/l and more), the presence in most patients (70-75%) of common pronounced edema, characterized by great persistence to diuretics. Characterized by hypotension, which is sometimes associated with lesions of the adrenal glands amyloidosis. Anemia and sharply accelerated ESR are noted. In addition to proteinuria, microhematuria, cylindruria and leukocyturia are often observed. Blood electrolyte balance is disturbed: sodium and potassium levels decrease; the content of b-lipoproteins and fibrinogen increases.

In the nephrotic stage, the symptoms of the underlying disease are mild, the clinic of nephrotic syndrome comes to the fore. Half of the patients have hepatomegaly and hepatolienal syndrome.

The azotemic stage of amyloidosis corresponds to the clinic of chronic renal failure, which is not significantly different from that in other primary and secondary kidney diseases. The final CID is considered to be azotemic uremia, which is the main cause of deaths in this disease.

In renal amyloidosis, there may be no parallelism between the severity of chronic renal failure and the morphological picture of the amyloid wrinkled kidney. Often in patients who died of uraemia, there are no signs of amyloid-shriveled kidney. Renal failure can develop and cause death in the proteinuric, nephrotic, and even latent stage of amyloidosis. The most common causes of rapid progression of renal failure in amyloidosis may be exacerbation of the underlying disease, the addition of an intercurrent infection or complications such as renal vein thrombosis, a sharp drop in blood pressure, and hence glomerular filtration, for example, in adrenal amyloidosis, etc.

Amyloidosis of the kidneys can occur in different ways. It depends on the location and degree of amyloid deposition, the involvement of other organs and systems in the process, the nature and severity of the underlying disease. However, kidney amyloidosis almost always has a chronic progressive course, which ultimately leads to impaired renal function, the development of chronic renal failure and its final phase — azotemic uremia with a fatal outcome.

The life expectancy of patients with renal amyloidosis varies from 1 year to 3 years from the time of diagnosis. Cases when patients lived till 10 years and more are described. The lethal outcome largely depends on the course of the underlying disease, in some cases death occurs from the underlying disease, which caused the development of amyloidosis. The outcome of amyloidosis depends on various complications: hemorrhage, thrombosis, intercurrent infections, etc. Recovery from amyloidosis may be extremely rare when a diagnosis is made in the early (early) stages of the disease, promptly initiated active treatment and complete cure of the underlying disease that caused the development of amyloidosis.

Diagnosis of Kidney Amyloidosis

It is rather difficult to diagnose the diagnosis of amyloidosis of the kidneys in the early period of the disease, despite the fact that recently the diagnostic capabilities have increased significantly. In recognition of secondary amyloidosis, the nature, clinical presentation, course and duration of the underlying amyloidosis of the underlying disease play an undoubted role. It should be borne in mind that in some cases, the primary disease may occur latently or be cured. Of paramount importance is the correct interpretation of urinary syndrome. In this case, the most important initial diagnostic sign of amyloidosis is proteinuria, which is steadily increasing as amyloidosis progresses.

Leukocyturia in amyloidosis is found quite often without a clinical picture of pyelonephritis, which is considered a valuable diagnostic sign, especially in the latent stage.

Microhematuria in amyloidosis, according to the data of EM Tareev (1983), occurs in 11.5% of cases.

The frequency and severity of cylinduria depend on the presence and severity of proteinuria. Hyaline cylinders are found more often granular. In the far advanced stage of secondary amyloidosis, birefringent lipids are detected in the urine.

Dysproteinemia in secondary amyloidosis is a characteristic sign and depends both on the underlying disease and on the amyloidosis itself. Amyloidosis is characterized by an increase in a2 globulin content.

In secondary amyloidosis, a regular increase in fibrinogen is observed as the disease progresses. There is even a definite relationship between the level of fibrinogen and the stage of amyloidosis: the higher the level of fibrinogen, the more reason to think about the late stage of amyloidosis. Hyperfibrinogenemia is a characteristic symptom for some forms of hereditary amyloidosis, especially for amyloidosis in intermittent illness, when high levels of fibrinogen are found regardless of the phase of the disease (V.V. Serov, I.A. Shamov, 1977).

Hyperlipidemia is detected in primary, secondary and hereditary amyloidosis. Severe hypercholesterolemia in the nephrotic and azotemic stages of secondary amyloidosis is considered one of the criteria for the diagnosis of late stages of amyloidosis.

Edema occurs in the nephrotic stage of kidney amyloidosis. However, in some cases they may occur at an earlier stage. Thus, their detection in the proteinuric stage is associated with the development of pulmonary heart disease caused by the underlying disease (with lung lesions). In contrast to edemas of the nephrotic type in glomerulonephritis, which develop rapidly at the onset of the disease, edema increases slowly with amyloidosis of the kidneys. The onset of edema syndrome at an early stage of kidney amyloidosis can also be triggered by the addition of intercurrent infection, drug intolerance, and other causes.

In all forms of amyloidosis of the kidneys, and especially often in the secondary, hepato-and splenomegaly are found. Liver enlargement is detected in 60%, spleen – in 24% of patients. Hepatomegaly in amyloidosis is caused by a number of factors, including the deposition of amyloid substance and stagnation. In the early stage of amyloid hepatomegaly, the deposition of amyloid substance in the liver occurs only in minimal quantities, therefore, there is no violation of its functional ability. In advanced stages, the amyloid substance is deposited in significant quantities and violates the structural and functional ability of the liver with the subsequent development of liver failure. The liver at the same time becomes dense, painful, sometimes develop jaundice, ascites. An enlarged spleen is found only in the far advanced stage of amyloidosis.

For the diagnosis of amyloidosis, the complement binding reaction (RAC) with the serum of patients is used, while amyloid protein is used as the antigen. ASC with an amyloid antigen is considered a highly sensitive diagnostic test.

Special colorful tests (with Congo red, with methylene blue, with Evans’ paint) have a certain value in the diagnosis of amyloidosis.

The most informative and reliable method for the diagnosis of amyloidosis is an intravital organ and tissue biopsy. Detection of amyloid in the organs makes it possible not only to confirm the diagnosis, but also to determine the stage of amyloidosis. This method allows setting kidney amyloidosis in 87-100% of cases. Particularly valuable is a kidney biopsy for identifying the nature of the nephrotic syndrome: is it caused by kidney amyloidosis, glomerulonephritis or other diseases, which is very important to know when choosing a treatment method and determining the prognosis of the disease.

A high diagnostic value in systemic amyloidosis has an intravital liver biopsy. Biopsy of the spleen is not widespread due to the possibility of bleeding. Biopsy of the colon mucosa confirms the diagnosis of primary and secondary amyloidosis in about 70% of cases.

Biopsy of the gum mucosa is the most accessible method for the diagnosis of amyloidosis, in addition, it does not give complications. However, its diagnostic value is not recognized by all; positive results in the presence of amyloidosis are obtained only in 40% of cases.

Treatment of Kidney Amyloidosis

With kidney amyloidosis, treatment still remains ineffective, especially with its late diagnosis. Scientifically, theoretically and experimentally substantiated treatment is directed mainly to the individual links of the pathogenesis of amyloidosis, i.e., to eliminate those factors that contribute to the formation of amyloid, to the use of agents that inhibit the production and stimulate resorption of amyloid.

In secondary amyloidosis, methods and means aimed at eliminating the main symptoms or completely curing the disease, the consequence of which it is, are of paramount importance. For this purpose, both conservative and radical (surgical) treatment methods are used.

In the complex therapy of amyloidosis of the kidneys, a significant place is occupied by the diet. In the initial stage of amyloidosis, a low-protein diet is recommended (at the rate of 0.7 g of protein per 1 kg of body weight) with a high content of carbohydrates, rich in vitamins. The inclusion in the diet of fruits, berries, especially containing a lot of vitamin C (black currant, broth, strawberries), as well as products rich in potassium salts (unpeeled potatoes, rice, cabbage, apricots, apricots, raisins, oranges, bananas, figs and etc.). The daily need for proteins of animal origin, it is advisable to carry out by including in the diet raw liver. Zucchini, carrots, watermelons, melons, cucumbers are recommended. In order to increase the food intake, marmalade, marshmallow, butter and sunflower are allowed. Limit the use of such products as meat, eggs, beans, peas, beans, cocoa, halva, cheese. In the nephrotic stage, in connection with a significant loss of protein in the urine, a diet with a protein content of up to 1.5 g per 1 kg of body weight is recommended. In the presence of edema, table salt is limited, with massive edema up to 2-3 g per day and liquids up to 800-1000 ml, taking into account liquid dishes. Fats are allowed in normal amounts.

From the means of pathogenetic therapy of amyloidosis, desensitizing agents are used (dimedrol, pipolfen, suprastin, etc.), ascorbic acid, liver preparations and crude liver. For the same purpose, drugs of the 4-aminoquinoline series (delagil, hingamin, resoquine, chloroquine, plaquenil) are prescribed, which inhibit the formation of mucopolysaccharides and nucleic acids, inhibit the enzyme systems of reticuloendothelial cells, change the content of sulfhydryl groups, i.e., affect some pathogenesis units amyloidosis by reducing the synthesis of amyloid. These drugs are prescribed at 0.25-0.5 g per day after meals for many months. However, it should be remembered that long-term admission may develop side effects such as dyspepsia, allergic skin reactions, leukopenia, corneal clouding, increased hematuria. At the same time prescribe vitamins of group B, ascorbic acid, antihistamines.

Uniethiol is used as a therapeutic agent – a 5% solution of 5 ml intramuscularly, 1 time per day. The course of treatment is 30-40 injections. It is believed that it causes inhibition of aggregation of protein substances of amyloid in fibrillar structures and has a competitive effect on SH-groups. Such a presentation is based on experimental data (V.S. Rukosueva, 1975), according to which there is a special factor in the body that stimulates the production by the cells of the reticuloendothelial system of a particular soluble protein, the amyloid precursor. Further transformation of this protein into amyloid fibrils occurs with the participation of disulfide bonds, on which unithiol acts.

In the treatment of recurrent nephropathic disease, complicated by amyloidosis, colchicine (colchamin), 0.5-0.2 mg per day for 4-6 months, is recommended. This drug prevents attacks of recurrent disease and reduces proteinuria.

Currently, glucocorticosteroid hormones are not recommended for the treatment of amyloidosis.

Anabolic steroids (nerobol, methandrostenolone, dianabol, etc.) have a therapeutic effect mainly by their positive effect on nitrogen metabolism. Their clinical effect is manifested by increased appetite, weight gain, improvement in the general condition of patients.

Levamisole has an immunostimulating effect, in particular, it stimulates humoral and cellular immunity; experimentally delayed the progression of amyloidosis. Recommend to take levamisole 150 mg 3 times a week. However, it is prescribed in combination with other drugs that enhance amyloid resorption, since it alone cannot change the course of the disease.

It has been established that Liver preparations and raw liver prevent the development of amyloidosis in the experiment and give a good clinical effect. Therefore, in case of amyloidosis, it is recommended to take a raw liver for a long time (for years), and in case of poor tolerance – after cooking. The liver contains a powerful antioxidant system, so a positive effect may be associated with the introduction into the body of a complete set of antioxidants close to endogenous (2 ml syrepar corresponds to 40 g of raw liver). The treatment is carried out according to the following scheme: administration of a raw liver for 1-2 months (100-150 g per day), for 2-3 months intramuscular injections of syrepar 5 ml 2 times a week, for 2-3 months liver intake after cooking, a month of hepatic ” cocktail “and again repeating the cycle.

There are reports in the literature about the successful use of chronic hemodialysis and kidney transplantation in the terminal stage of kidney amyloidosis. Cases have been described when, with the help of hemodialysis, it was possible to prolong the life of patients up to 4 years or more.

Symptomatic agents such as transfusion of native and dry plasma, plasma albumin are used to combat nephrotic syndrome, diuretics are prescribed. In the absence of the effect of conventional diuretics, osmouretics are used — a 20% solution of mannitol, 200-400 ml each, and polyglucine, 500 ml daily. With the appearance of heart failure, cardiac glycosides are prescribed.

Prevention of Kidney Amyloidosis

Patients with renal amyloidosis should be constantly monitored. With a favorable course with preserved renal function, a follow-up examination is carried out 1-2 times a year with the same amount of research as in chronic glomerulonephritis. In the presence of nephrotic syndrome – once a quarter.

Spa treatment is recommended only in the latent and proteinuric stages in the absence of contraindications from other organs and systems.

Leave a Reply

Your email address will not be published. Required fields are marked *