Nephrology for the Family Physician - O.I. Bakaliuk 2003

Dysmetabolic and Toxic Nephropathies
Renal Amyloidosis

There are A number of pathological processes whose precise identification is impossible without morphological confirmation. These include amyloidosis, a condition characterized by a highly polymorphic Clinical presentation, even when predominantly affecting a single organ—the Kidneys.

Amyloidosis is a systemic disorder driven by the extracellular deposition of a unique eosinophilic protein known as amyloid. Amyloid is a complex glycoprotein in which fibrillar and Globular Proteins (alpha₂-, beta-, and gamma-globulins, fibrinogen), neuraminic acid, and Amino Acids (Glycine, Alanine, leucine, valine, Tyrosine, Histidine) are closely bound to Polysaccharides (galactose, glucose, mannose, fructose, hyaluronic acid, glucosamines, galactosamines, chondroitin sulfate, heparin, and the P-component), immunoglobulin light chains, and certain THYROID Hormones. In fact, amyloidosis is not a single disease per se, but rather a term describing a group of conditions united by a common feature: the extracellular deposition of pathological insoluble Fibrillar Proteins.

The exact prevalence of amyloidosis in the general population remains undetermined, with estimates suggesting it affects between 0.1% and 6.6% of individuals (based on autopsy data; D.Z. Kagan, 1992). In the USA, the incidence rate is reported to be 5–13 cases per 100,000 population for primary amyloidosis and 50–143 cases per 100,000 for secondary amyloidosis (H. Rodney et al., 1997); such statistical data are lacking in Ukraine.

Depending on the serum precursor proteins, at least 8 distinct variants of amyloid protein are distinguished. The most common types include the following (WHO, 1993):

- AL. The precursor protein consists of immunoglobulin light chains or their fragments (associated with multiple myeloma, primary (idiopathic) amyloidosis, and B-Cell malignancies such as Waldenström's macroglobulinemia).

- ATTR. The precursor protein is transthyretin, with variants including Met³⁰ (familial amyloid polyneuropathy), Met¹¹¹ (familial amyloid cardiomyopathy), as well as transthyretin with a normal Amino Acid Sequence and specific subtypes that determine the predominant localization of amyloid deposition (aorta, Heart, Pancreas)—namely, systemic senile amyloidosis.

- Abeta2M. The precursor protein is beta-2-microglobulin, which is normally catabolized primarily by the kidneys (dialysis-related amyloidosis, Carpal tunnel syndrome).

- AE. The precursor protein remains unknown. This variant of amyloidosis develops in the context of certain endocrine disorders.

- AA. The precursor protein is SAA. This category encompasses secondary (reactive) amyloidosis associated with familial Mediterranean fever (AF-amyloidosis), Muckle-Wells syndrome (familial nephropathy with urticaria and deafness), and amyloidosis with primary cutaneous involvement (AD-amyloidosis). Renal amyloidosis is specifically linked to this type of protein.

It has been established that the AA protein is derived from a humoral precursor, the SAA protein, via proteolysis within transformed macrophages, leading to the generation of a clone of amyloidoblast Cells. The initiating event in the Pathogenesis of amyloidosis is recognized to be the activation of the mononuclear phagocyte system (potentially involving neutrophils) with the release of interleukin-1. The latter acts as an inducer of SAA synthesis by hepatocytes, neutrophils, and fibroblasts.

The SAA protein is classified as an acute-phase reactant of inflammation. It is produced in response to prolonged antigenic stimulation and is detected in the Blood during acute inflammation, malignancies, Pregnancy, rheumatic diseases, and chronic purulent processes. In healthy individuals, blood concentrations of SAA are negligible. SAA is tightly bound to high-density Lipoproteins; consequently, a reduction in the latter may be a contributing factor promoting the extra-vascular deposition of this protein. During the acute phase of any inflammatory response, SAA levels can surge 100- to 1000-fold within 12–24 hours following the initial stimulus. In terms of this sharp acute-phase elevation, SAA closely mirrors C-reactive protein.

The precise Functional Significance of elevated SAA levels during acute inflammation, much like C-reactive protein, is not yet fully elucidated. It is believed that they participate in immunoregulation; specifically, SAA is known to suppress both humoral and cellular immune responses.

With sustained overproduction of SAA (resulting from chronic antigenic stimulation or Gene mutation), its blood levels rise—a stage referred to as pre-amyloidosis. This state triggers enhanced intracellular degradation of SAA, and macrophages begin to assemble amyloid fibrils from its fragments. Subsequently, globular blood proteins, polysaccharides, and the P-component join these fibrils, resulting in The formation of the amyloid protein.

However, a prolonged elevation in blood SAA levels alone is insufficient to drive AA-amyloidogenesis. For amyloid formation to occur, the blood must also contain an aggregation-competent AA protein. This is made possible by the incomplete proteolytic Cleavage of the SAA protein by activated macrophages (neutrophils). Another essential prerequisite for the initiation of amyloidogenesis is the active Synthesis of the amyloid-accelerating factor by the reticuloendothelial Cells of the Spleen and Liver—acting as a universal catalyst for all types of generalized amyloidosis (O.M. Vinogradova et al., 1990).

An essential structural component of any amyloid protein is the P-component. This glycoprotein has been isolated from various types of amyloid deposits and exists in both tissue and serum forms. The P-component is not unique to amyloidosis; it is also a normal constituent of basement membranes (BM). The tissue P-component accounts for 15–20% of the mass of isolated amyloid fibrils and is identical to a plasma glycoprotein known as serum P-component (SAP).

SAP is produced by hepatocytes, and its normal blood level ranges from 50 to 70 µg/mL. In terms of ultrastructure, SAP is identical to C-reactive protein. It circulates in the blood, reaching adult levels within several weeks after birth and remaining stable thereafter. The tissue P-component is predominantly fixed within Connective Tissue, and it takes several years for its concentration to reach a steady-state level.

The formation of amyloid substance—namely, the binding of amyloid fibrils to Plasma Proteins, Glycoproteins, and the P-component—occurs extracellularly in close association with connective tissue fibers, specifically reticular or Collagen fibers. These observations formed the basis for classifying amyloidosis into two types: perireticular and pericollagenous.

At The final stage of amyloidogenesis, an increase in vascular-tissue permeability is of paramount importance, as it greatly facilitates the assembly and integration of all Components of the amyloid protein (both tissue- and serum-derived).

Recently, so-called R-proteins and impaired cellular receptor function have been assigned a major role in the pathogenesis of amyloidosis. Let us examine this in greater detail.

Receptor-mediated signaling is a vital component of membrane-level regulation of leukocyte Functions, including phagocytosis, chemotaxis, immune adhesion, participation in inflammatory processes, and the resorption of tissue structures. Cellular receptors, which include R-proteins, belong to the Class of Membrane Proteins. Studies on cellular receptor METABOLISM have demonstrated that any alterations in cellular physiology primarily manifest as an accelerated turnover of receptor proteins overall, and particularly an upregulation of their Catabolic pathways (A.Ya. Kulberg, 1991).

The accumulation of R-proteins at the site of a pathological process, regardless of its Etiology, and their subsequent diffusion into surrounding Tissues lead to tissue disorganization and thereby expand the lesion zone. Along their entire path of dissemination from the focus of injury, their concentration escalates in an avalanche-like manner because R-proteins generated in each new region disrupt the normal functioning of adjacent cells, thereby stimulating The production of even more such proteins (forming a sort of chain reaction). Spreading via the bloodstream and Lymphatic vessels, R-proteins induce a shift in biological equilibrium at the level of the entire Organism.

L.V. Kozlovskaya et al. (1992), investigating R-protein levels in amyloidosis and Glomerulonephritis (GN), revealed elevated serum concentrations (more pronounced in amyloidosis) that inversely correlated with leukocyte chemotactic properties, ultimately resulting in impaired cellular responsiveness to various antigenic stimuli.

Amyloid deposition in the kidneys is not merely a passive accumulation within glomeruli, tubules, or the interstitium. It should be emphasized that the actual alterations in the tubular epithelium along with progressive sclerosis of the interstitium and vascular walls dictate the clinical prognosis for an individual patient (B.I. Shulutko et al., 1987).

The Mechanism of amyloid resorption is linked to its phagocytosis by free and fixed macrophages in the spleen, Kupffer cells and monocytes in the liver, and mesangial cells in the kidneys.

At least three major theories exist that explain various aspects of amyloid formation and deposition from different Perspectives.

According to the first theory (dysproteinosis theory), amyloid is a product of disturbed Protein metabolism resulting from the leakage of coarsely dispersed protein fractions and abnormal proteins from the bloodstream, which are capable of depositing beneath the endothelium and the argyrophilic vascular sheath in various regions.

The immunological theory explains amyloidogenesis through an antigen-antibody immune reaction with precipitation of the protein complex at the sites of antibody production (the reticuloendothelial system) under conditions of antigen excess. Amyloid, as an abnormal protein, is considered an antigen, and autoimmunization is viewed as a crucial link in the progression of amyloidosis.

According to the secretory theory, amyloid is a secretion produced by mesenchymal (reticuloendothelial) cells As a result of impaired protein-synthetic function, and amyloidosis is regarded as a "disease of the mesenchyme".

Although Heart Failure has quite frequently been recorded as a cause of death in amyloidosis in recent years, uraemia resulting from renal amyloidosis—not only secondary, but also its primary and genetic variants—unquestionably remains the most frequent cause of death. No specific Clinical Features or patterns of disease progression dependent on The Nature of the underlying condition have been identified (B. Sarkar et al., 1996).

Overall, patients with renal amyloidosis account for 5-8% of all patients in specialized nephrology departments.

Until recently, Renal Involvement in primary amyloidosis was not considered a leading syndrome (O.M. Vinogradova, 1980), although predominantly laboratory-based symptoms of Kidney damage (urinary syndrome) occur frequently (80-85%).

Initial symptoms are quite diverse in this regard, whereas signs such as weakness and weight loss appear rather late. Paresthesias, periorbital and subconjunctival hemorrhages, firm edema of the hands, Muscle induration and tenderness, and muscle atrophy are observed in 25% of patients.

A distinctive feature of renal involvement in primary amyloidosis is its combination with pathology in other systems and Organs.

Cardiac pathology (100%) is characterized by general and nonspecific clinical and instrumental signs (dyspnea, palpitations, changes in cardiac dullness borders, symptoms of heart valve disease, myocardial infarction, pericarditis, arrhythmia, and therapy-resistant heart failure).

Lung involvement (50%) manifests as dyspnea, hemoptysis, hemorrhagic infarcts, recurrent Pneumonia, and The Development of fibrosing alveolitis and respiratory failure.

Gastrointestinal changes (50%) are characterized by abdominal pain, vomiting, constipation, atony of The Stomach and intestines, malabsorption, the development of amyloid ulcers with potential perforation and Peritonitis, intestinal lumen stenosing, and macroglossia with fissures and dysarthria.

Involvement of the reticuloendothelial system (30-40%) manifests as hepatosplenomegaly without portal Hypertension, and lymphadenopathy.

Involvement of the Adrenal Glands, accompanied by persistent hypotension and adynamia, is quite characteristic (30-40%).

Of note is the Guttmann-Freudenthal Skin syndrome characteristic of amyloidosis (D. Guttmann, A. Freudenthal) — the appearance of firm papules on the extensor surfaces of the lower legs, which cause intense itching and spontaneously disappear or diminish within several weeks or months.

Renal alterations in primary amyloidosis occur in 10-15% of cases and can occasionally be its initial manifestation.

In secondary amyloidosis, the kidneys are affected in 90-100% of cases, and depending on the intensity of amyloid deposition in other organs, V.V. Serov (1995) distinguishes nephropathic, epinephropathic, hepatopathic, and mixed variants.

In recent years, The Role of rheumatoid Arthritis, Bechterew's disease, psoriatic arthritis, thyroid Cancer, hematological malignancies (lymphomas, lymphogranulomatosis), Ulcerative Colitis, and Crohn's disease among the causes of secondary AA amyloidosis has been increasing (10-43%). Regarding the role of chronic purulent-destructive processes of the Respiratory system and tuberculosis as causes of secondary renal amyloidosis, literature data are contradictory—some consider it the primary cause (A.N. Shishkin et al., 1998; B. Sarkar et al., 1996), while others view it as secondary (Mayo Clinic Materials (USA) published in 1991 (L.V. Kozlovskaya, 1998)).

Initial amyloid deposits are observed in the zone of the renal pyramids. Five stages of amyloid deposition in the glomeruli are distinguished: amyloid deposition in the mesangium or subendothelially in the area of individual loops; detection of amyloid in 50% of the loops across all glomeruli; diffuse amyloid deposition in 70% of the loops; diffuse global amyloid deposition; and transformation of the glomeruli into hyaline-like spheres. However, the debate regarding the correlation between the extent of renal amyloid deposits and the severity of clinical renal manifestations continues today (A.N. Shishkin et al., 1998).

Somewhat conventionally, the development of this pathology is divided into the following stages: asymptomatic, proteinuric, nephrotic, and terminal. B.I. Shulutko et al. (1987) identify several clinical courses of renal amyloidosis: glomerulonephritic, macrohematuric, interstitial, and pyelonephritic.

In the asymptomatic stage of renal amyloidosis, symptoms of the underlying disease dominate, laboratory findings are largely nonspecific, and urinalysis reveals inconstant proteinuria and microhematuria. Persistent dysproteinemia—which persists even with a favorable course of the underlying disease—along with an elevated ESR and moderate hepatosplenomegaly are characteristic.

Proteinuria is the most prominent symptom of all forms of amyloid renal involvement in the proteinuric stage, though it is most pronounced in secondary amyloidosis. Proteinuria is detected at various intervals following the onset of the underlying disease (from 1 to 37 years). Initially selective and subsequently non-selective, it rather quickly assumes a persistent and progressive character (3-40 g/day). Blood tests reveal hypoalbuminemia and dysproteinemia (hypergammaglobulinemia), hyperfibrinogenemia, elevated ESR, moderate anemia, and hypocholesterolemia. We emphasize once again that the level of proteinuria is determined not by the intensity of amyloid deposition in the glomeruli, but by the degree of tubular atrophy and the severity of interstitial fibrosis (B.I. Shulutko et al., 1997; H. Gise et al., 1997).

In addition to proteinuria, all urinary sediment components are present—hyaline casts, leukocytes, and erythrocytes. However, their numbers in amyloidosis are somewhat lower than in Other forms of nephropathy. Microhematuria is detected in 11.5% of cases, and macrohematuria is occasionally observed; Lipids are a constant component of the urinary sediment. In some instances, Bence-Jones protein is identified in the urine.

In the nephrotic stage of renal amyloidosis, the development of classical Nephrotic Syndrome is observed, accompanied by edema, hypoproteinemia, hypoalbuminemia, dysproteinemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia. A distinctive feature of nephrotic syndrome in this context is its stability and tendency to progress even upon the development of end-stage renal failure. Edema is typically pronounced, persistent, and resistant to Diuretics. In some cases, nephrotic syndrome may develop without preceding urinary abnormalities. Symptoms of renal pathology can be masked by signs of damage to other organs and systems (cardiovascular, respiratory, and digestive).

Thus, the clinical manifestations of secondary renal amyloidosis are quite diverse, which complicates timely Diagnosis. However, the onset and progression of proteinuria—and even more so nephrotic syndrome or renal failure—in the presence of diseases whose course can be complicated by amyloidosis, as well as the combination of proteinuria or nephrotic syndrome with diarrhea, malabsorption syndrome, hepatosplenomegaly, arterial hypertension, arrhythmia, and refractory heart failure, are of critical importance for diagnosing this condition.

The final (terminal) stage of renal amyloidosis exhibits all the hallmarks of impaired incretory, concentrating, and nitrogen-excreting renal functions, culminating in progressive renal failure. Tubular involvement manifests as hypo- and isosthenuria alongside the development of Renal Tubular Acidosis.

The described sequence of stages in the progression of renal amyloidosis is sometimes disrupted; There is a so-called primary azotemic (hypertensive) form of renal amyloidosis, the leading symptom of which is high hypertension with the rapid development of a hypertensive heart. HYPERTENSION AS A symptom of renal amyloidosis is more frequently observed in rheumatoid arthritis, chronic purulent pulmonary processes, skeletal tuberculosis, and inactive Pulmonary Tuberculosis.

Among laboratory changes, we should also note hyperthrombocytopenia, impaired platelet adhesion, hyperfibrinogenemia, significantly prolonged Fibrinolysis time, and leukocytosis (B.M. Charyev et al., 1990). Procoagulant risk is also indicated by a stable decrease in plasma antithrombin III activity and hypo-alpha₁-antitrypsinemia.

Renal amyloidosis is frequently combined with adrenal amyloidosis. In such cases, all symptoms of adrenal insufficiency are observed (hypotension, adynamia, weakness, nausea, vomiting, diarrhea, weight loss, skin pigmentation). Such amyloidosis has a severe course and rapidly leads to the patient's death—there is always a risk of acute adrenal insufficiency arising in the event of trauma, surgery, or concurrent intercurrent infection.

The diagnosis of renal amyloidosis is based on the analysis of Anamnesis and clinical data, although it should be noted that the presence or absence of any disease associated with amyloidosis is of only relative significance for clarifying the Nature of the nephropathy, and that non-Invasive Methods for the absolutely precise diagnosis of renal amyloidosis do not exist.

In the absence of a family history, the next step in diagnosing primary amyloidosis should be screening the patient for plasma cell dyscrasia using immunofixation Electrophoresis of serum and urine, along with a Bone Marrow biopsy with immunohistochemical staining of plasma cells for the presence of kappa and lambda light chains. If the results of these tests are negative, a search for mutant (transthyretin) protein in blood serum and the mutant transthyretin gene in genomic DNA is carried out (K. Altland et al., 1986).

Quantitative scintigraphy with ¹²³I-labeled serum amyloid P component may also aid in the diagnosis of amyloidosis: this technique is effective for evaluating AL, ATTR, and AA amyloidosis (P.N. Hawkins et al., 1990). Certain diagnostic significance is also attributed to determining the blood and urine levels of beta-2-microglobulin (elevated levels).

When the probability of internal organ amyloidosis is high and a biopsy has not yet been performed, examination of an abdominal subcutaneous adipose tissue aspirate is recommended (M.A. Gertz et al., 1985)—its Congo red staining indicates AL amyloidosis with an 85% probability.

Biopsy of the rectal mucosa, Gums, and needle renal biopsy are considered reliable diagnostic methods, with the diagnostic value of rectal mucosa biopsy being twice as informative as gingival mucosa biopsy. This is related to the type of collagen deposition in the tissues: the perireticular type is found in the rectal mucosa, while the pericollagenous type is found in gingival tissues. Therefore, it is believed that gingival biopsy should be performed when primary amyloidosis is suspected, and rectal mucosa biopsy when secondary amyloidosis is suspected. Gingival biopsy more frequently yields positive results in the nephrotic and terminal stages, whereas rectal mucosa biopsy is informative even during the proteinuria stage of renal amyloidosis.

To clarify the type of amyloidosis, a technique involving the Treatment of biopsy material with potassium permanganate prior to Congo red staining is also used. Retention of the characteristic Congo red staining points to primary renal amyloidosis, while its disappearance points to secondary renal amyloidosis (I.E. Tareeva et al., 1995).

Treatment of renal amyloidosis. In secondary AA amyloidosis, 5- and 10-year survival rates are 77% and 44%, respectively, and the average life expectancy after the onset of renal involvement symptoms is 13.3 years, which significantly exceeds the corresponding figures for its hereditary form (48% and 24%, and 6.7 years, respectively; B.D. Tsykin et al., 1985), although A.N. Shishkin et al. (2000) cite somewhat different data—the 5- and 10-year survival rates for patients with secondary renal amyloidosis are 42% and 0%, respectively.

In the event of Chronic Kidney Disease (CKD), the average life expectancy in secondary amyloidosis is 2.5 years. Prognostically unfavorable factors include the presence of hypertension (L.N. Kochubei et al., 1993), as well as a blood deficiency of the highly specific protease inhibitor alpha-1-proteinase inhibitor (a-1-Pi).

The principles of treating renal amyloidosis can be formulated as follows:

- elimination of factors that promote amyloid formation;

- suppression of amyloid production;

- stimulation of the resorption processes of already formed amyloid.

Of great importance in this regard is the active treatment of diseases whose course is accompanied by prolonged antigenic stimulation.

In primary amyloidosis, various regimens are used—most frequently melphalan (0.15 mg/kg body weight/day) + prednisolone (0.8 mg/kg body weight/day) in 7-day cycles with a 4–6 week break, although the efficacy of such therapy is low (O.M. Vinogradova et al., 1996); vincristine, cyclophosphamide, liver transplantation, or stem cell transplantation (P.R. Bergethon et al., 1996).

Pathogenetic treatments for secondary renal amyloidosis include unithiol and colchicine (I.E. Tareeva et al., 1995). Unithiol is believed to inhibit the aggregation of amyloid fibrils. It is administered as a 5% solution intramuscularly in 30-day courses every 2–3 months. Treatment begins with the daily administration of 1–2 ml of unithiol, gradually increasing the dose (by 1 ml/day) until a dose of 5–10 ml/day is reached. Unithiol is capable of stabilizing The process of renal amyloid degeneration at all stages except the terminal stage. Dyspeptic disorders and allergic reactions may develop during this treatment.

The MECHANISM OF ACTION of colchicine in amyloidosis is not fully understood. It is believed to inhibit the Synthesis and Secretion of the amyloid precursor protein SAA by hepatocytes, as well as to suppress the synthesis of the amyloid-accelerating factor and the process of fibrillogenesis (O.M. Vinogradova et al., 1990).

Colchicine therapy is advisable to begin with a 10–15 day trial course to determine individual tolerance. The optimal daily intake is considered to be 1.8–2 mg of the drug. Colchicine should be used with caution in patients with marked renal failure; in such cases, treatment is initiated at a dose of 1 mg/day.

Colchicine therapy must be prolonged, potentially lifelong, at a minimum therapeutic dose of 1.75 mg/day. With the Introduction into practice of the amyloid visualization method using ¹²³I-labeled amyloid P component (SAP scintigraphy), it was established that the regression of amyloid deposits begins 3 years after the initiation of treatment (V.V. Rameev et al., 1999). Adverse effects include diarrhea, leukopenia, Hair loss, and allergic reactions.

According to sparse literature data, a positive clinical effect (reduction in proteinuria and improvement in renal functional parameters) has been achieved with the oral administration of dimethyl sulfoxide (dimethyl sulfoxide, 10–20% solution in distilled Water or juices). Unfortunately, the efficacy of dimethyl sulfoxide manifests at doses exceeding 10 g/day and with a treatment duration of at least 6 months, which is not always feasible given the high incidence of allergic reactions associated with it (L.V. Kozlovskaya, 1998).

Conventionally Pathogenetic Therapy for renal amyloidosis includes the consumption of raw liver (80–120 g/day) for 6–12 months.

Symptomatic treatment of this pathology differs little from the therapy of other nephropathies: an adequate nutritional regimen while nitrogen-excretory renal function is preserved; a low-protein diet; The Use of sorbents; correction of impaired electrolyte balance, blood pressure levels, and acid-base status in CKD; restriction of table salt in the presence of edema; red blood cell transfusions for anemia, etc.

Since the 1970s, attempts have been made to use chronic hemodialysis to treat terminal renal failure in renal amyloidosis. It is emphasized that, given the systemic nature of the process, careful patient Selection for hemodialysis is necessary—excluding those with marked functional insufficiency of other organs, primarily The Heart (J. Ben Ari et al., 1976; L.Yu. Mukharlyamova, 1985). Hemodialysis does not protect the patient from the progression of amyloidosis; such patients frequently experience vascular access thrombosis and hypotensive crises.

Peritoneal dialysis offers certain advantages over hemodialysis; however, this treatment modality is associated with a high incidence of infectious complications.

Kidney transplantation is a more promising therapeutic approach for AA amyloidosis. The overall survival and graft survival rates are 65% and 62%, respectively, while recurrent amyloidosis in the transplant develops on average after 3 years.