Amyloidosis and Kidney Damage: Symptoms

In clinical practice, the most important are AA- and AL-types of systemic amyloidosis that occur with the involvement of many organs in the pathological process, but more often manifest symptoms of mono-organ damage. AA and AL types of amyloidosis in men are 1.8 times more frequent than in women. The secondary amyloidosis is characterized by an earlier onset than with the primary (the average age of the diseased is about 40 and 65 years, respectively). Symptoms of amyloidosis of AL kidneys are more diverse: in addition to numerous clinical manifestations common with AA-type, there are characteristics characteristic only for AL-type (periorbital purpura, macroglossia and other muscle pseudohypertrophies). On the other hand, some clinical manifestations of primary amyloidosis are possible with ATTR (polyneuropathy, carpal tunnel syndrome) and Abeta ₂ M-amyloidosis (carpal tunnel syndrome).

Kidney damage is the main clinical sign of AA- and AL-amyloidosis. In the AA-type, the kidneys are involved in the pathological process in almost all patients, with the AL-type, the incidence of nephropathy is also high and approaches 80%. Kidney damage is also observed in the ATTR-type of amyloidosis, however, in many patients with familial amyloid neuropathy, there are no symptoms of amyloidosis of the kidneys in the presence of morphological signs of amyloid renal disease.

Macroscopically, the kidneys in amyloidosis are enlarged in size, whitish, have a smooth surface, the boundary between the cortical and marrow is not distinct. In approximately 10% of cases, wrinkled kidneys with an uneven surface are found due to focal atrophy of the cortex, presumably associated with ischemic changes due to arteriolosclerosis and / or amyloid deposition in the vessels.

Amyloid with AA and AL types of kidney amyloidosis is localized mainly in the glomeruli, however, in 10% of patients with primary amyloidosis and a significant proportion of patients with hereditary neuropathy, deposits are noted only outside the glomeruli. In the early stage of amyloid nephropathy, focal amyloid deposits are found in the mesangium in the region of the glomerulus pole, but as the disease progresses, they spread along the capillary bundle to the periphery. In this case, the proliferation of mesangial cells does not occur, the basal membrane of the glomeruli remains intact. Progressive accumulation of amyloid leads to uneven infiltration of the capillary wall, first along the endothelial surface of the basal membrane of the glomerulus, and in later stages - in the subepithelial space, gradually enveloping the entire capillary bundle. As amyloid accumulates in the glomeruli, changes in the basal membrane are noted, which seems sparse or completely absent in large amyloid deposits. In far-reaching cases, the normal structure of the glomerulus is disturbed by the disappearance of the boundary between the amyloid masses and the basal membrane of the glomeruli. In the final stage, complete replacement of the glomeruli with amyloid is possible.

It was found that when the podocytes come in contact with the subepithelial deposits of amyloid, the podial processes of the podocytes are spreading, and in some areas the detachment from the basal membrane is exposed. These changes correlate with the severity of proteinuria. Podocytes play a key role in the repair of glomeruli in amyloidosis of the kidneys. During the reparative phase lasting several years, the podocytes gradually recover and begin to synthesize the material of the basal membrane, which forms a new membrane layer, which is accompanied by a decrease in proteinuria and an improvement in kidney function.

The amyloid is also deposited in other renal structures: in the basal membrane of the tubules (mainly distal and the Henle loop), interstitium, vessel walls.

Symptoms of renal amyloidosis manifest, as a rule, isolated proteinuria and are characterized by a steadily progressing course in the majority of patients (80%) with AA-type with a successive change of stages: proteinuric, nephrotic, chronic renal failure. With the AL-type of amyloidosis, the staging of the flow of amyloid nephropathy is less pronounced.

The peculiarities of kidney amyloidosis include the rarity of hematuria and leukocyturia ("poor" urinary sediment), as well as arterial hypertension, which even in chronic renal failure is noted in only 20% of patients with AA type of amyloidosis and even less often with AL-type amyloidosis. Nephrotic syndrome and large size of the kidneys persist in the development and progression of chronic renal failure.

The magnitude of proteinuria does not correlate with the severity of amyloid deposits in the kidneys (with a predominantly vascular lesion of proteinuria may be minimal) and depends on the degree of destruction of the sub-cytoplasm. The maximum protein loss is found through the areas of the basal membrane that are impregnated with amyloid and are devoid of epithelial coating.

The kidney function in amyloidosis correlates with the severity of tubulo-interstitial damage leading to interstitial fibrosis. These data suggest the generality of some mechanisms of the progression of amyloid nephropathy and chronic renal failure through the development of tubulointerstitial fibrosis. A definite contribution to the progression of renal failure in patients with amyloidosis can also be made by arterial hypertension, due to ischemia aggravating glomerular damage.

Amyloidosis of the kidneys in most patients is diagnosed only in the stage of nephrotic syndrome, in 33% - even later, in the stage of chronic kidney failure. In rare cases, amyloid nephropathy can be manifested by acute nephritic syndrome and macrogematuria, which makes diagnosis even more difficult. Fanconi syndrome and thrombosis of renal veins are also described.

Heart failure is noted in the vast majority of patients with AL-type amyloidosis and in some patients with ATTR-type amyloidosis; for AA-type amyloidosis, heart damage is not typical. As a result of the replacement of the myocardium with amyloid masses, restrictive myocardiopathy develops.

Clinically defined cardiomegaly, deafness of cardiac tones, early heart failure develops (in 22% of patients already in the onset of the disease), which rapidly progresses and almost 50% of patients, along with arrhythmias, cause death. The peculiarity of heart failure in primary AL-amyloidosis is its refractoriness to therapy.

Violations of rhythm and conductivity in the AL-type of amyloidosis are diverse: atrial fibrillation, supraventricular tachycardia, premature ventricular arousal syndrome, various blockades, and sinus node weakness syndrome. Due to the deposition of amyloid in the coronary arteries, it is possible to develop a myocardial infarction found on autopsy in 6% of patients. Amyloid deposits in valve structures simulate a picture of valvular defect.

The main symptom of heart amyloidosis on the ECG is the decrease in the voltage of the QRS complex. An infarct-like type of ECG is described.

The most appropriate method for diagnosing amyloid cardiomyopathy is Echocardiography, which can diagnose symmetrical thickening of ventricular walls, atrial dilatation, thickening of valves with regurgitation of blood, effusion in the pericardial cavity, signs of diastolic myocardial dysfunction. For the diagnosis of amyloidosis of the heart, it is also possible to perform myocardial scintigraphy with a technetium isotope labeled with pyrophosphate, but it has no advantages over echocardiography.

Serious prognostically significant symptom in AL-type amyloidosis is orthostatic arterial hypotension, which is observed in 11% of patients already at the time of diagnosis. Usually this symptom is associated with the defeat of the autonomic nervous system and in severe cases is accompanied by syncopal conditions. Arterial hypotension also occurs in patients with AA-type amyloidosis, but in this case it is associated more often with adrenal insufficiency due to the deposition of amyloid in the adrenal glands.

The defeat of the respiratory system occurs in primary amyloidosis in approximately 50% of patients, and in the secondary - in 10-14%. In most cases, it is asymptomatic or with poor clinical symptoms. In the AL type of amyloidosis, one of the earliest signs of the disease may be hoarseness or a change in the tone of the voice due to the deposition of amyloid in the vocal cords, which outstrips its appearance in the distal parts of the respiratory tract. In the lungs, amyloid is deposited mainly in the alveolar septa (which leads to the appearance of dyspnea and cough) and the walls of the vessels. Atelectasis and infiltrates in the lungs are also described. The radiological picture is non-specific, death from progressive respiratory failure rarely occurs.

The defeat of the digestive organs is observed in amyloidosis in 70% of cases. In 25% of patients with primary AL-amyloidosis, amyloid esophageal lesions are noted , manifested primarily by dysphagia, which may be one of the earliest symptoms of the disease.

The defeat of the stomach and intestine is the ulceration and perforation of their walls with possible bleeding, as well as the pre-piloric obstruction of the stomach or mechanical intestinal obstruction due to the deposition of amyloid masses. Patients with a predominant lesion of the colon may experience clinical symptoms that mimic ulcerative colitis.

A frequent gastrointestinal manifestation of AL-amyloidosis, noted in almost 25% of patients, is severe motor diarrhea with a secondary impairment of absorption. The cause of severe diarrhea along with infiltration of the intestinal wall, including villi, amyloid in patients with AL-type amyloidosis is autonomic (vegetative) dysfunction, the true syndrome of impaired absorption develops in about 4-5% of patients. With AA-type amyloidosis, severe diarrhea is also possible; sometimes it can be the only clinical manifestation of amyloidosis.

Lesion of the liver with AA and AL types of amyloidosis is observed in almost 100% of cases, with a marked increase in the liver and a 3-4-fold increase in y-glutamyltranspeptidase and alkaline phosphatase. Heavy liver damage with severe hepatomegaly and unfolded signs of severe cholestasis is noted much less often (in 15-25% of patients); it is more typical for AL-amyloidosis. In this case, despite pronounced hepatomegaly, liver function usually remains intact. A rare sign of amyloidosis of the liver is intrahepatic portal hypertension, which is combined with severe jaundice, cholestasis, and liver failure and indicates a far-gone defeat with a risk of esophageal bleeding, a hepatic coma. In some variants of familial ALys-amyloidosis, severe spontaneous intrahepatic bleeding is described.

The increase in spleen caused by amyloid damage occurs in most patients and usually accompanies liver enlargement. Splenomegaly may be accompanied by functional hypersplenism, which leads to thrombocytosis. A rare manifestation of the amyloidosis of the spleen is its spontaneous rupture.

The defeat of the nervous system, represented by the symptoms of peripheral neuropathy and autonomic dysfunction, is noted in 17% of patients with AL-type of amyloidosis and in patients with family amyloid neuropathy of different types (ATTR, AApoAl, etc.). The clinical picture of neuropathy with all types of amyloidosis is almost the same, because it is due to similar processes, primarily the degeneration of the myelin sheath of nerves, as well as the compression of nerve trunks with amyloid deposits and ischemia as a result of amyloid deposits in the vessel walls.

In most cases, there is a symmetrical distal neuropathy with a steady progression. In the onset of nervous system damage, mainly sensory disturbances are observed, primarily pain and temperature, later of vibration and positional sensitivity, then motor disruptions are attached. The earliest symptoms of neuropathy are paresthesia or painful dysesthesia (numbness). Lower extremities are involved in the pathological process more often than the upper ones.

Autonomic dysfunctions are often manifested with orthostatic arterial hypotension (see above), sometimes with syncope, diarrhea, impaired bladder function, impotence.

In 20% of patients with AL-type amyloidosis, in most patients with dialyzed amyloidosis, a syndrome of the carpal tunnel due to compression of the median nerve with amyloid deposited in the wrist ligament is detected in some patients with ATTR. Clinically, this syndrome is manifested by intense pain and paresthesia in the I-III fingers of the hand with a gradual atrophy of the tenar muscles. The features of carpal tunnel syndrome in dialysis amyloidosis include its predominant development on the arm where the fistula is formed, as well as pain during the hemodialysis procedure, possibly as a result of the development of the fecal-induced stealing phenomenon, which leads to ischemia of the median nerve.

Skin lesions are observed in almost 40% of patients with primary amyloidosis and, more rarely, in patients with AA-type. Characteristic variety of manifestations, the most frequent of which are paraorbital hemorrhages (pathognomonic for AL-amyloidosis), arising at the slightest stress. Also described are papules, plaques, nodules, and bubble rashes. Often observed skin induration, similar to scleroderma. A rare variant of skin lesion with AL-type amyloidosis is a violation of pigmentation (from pronounced enhancement to total albinism), alopecia, trophic disorders.

The defeat of the musculoskeletal system is characteristic for patients with dialyzed amyloidosis and rarely (in 5-10% of cases) occurs in patients with AL-type (excluding bone changes in myeloma). In this case, the nature of the tissue deposition of amyloid is similar: the amyloid is deposited in the bones, articular cartilage, synovia, ligaments and muscles.

In case of dialyzed amyloidosis, the triad of signs is most often noted: humeropathy periarthritis, carpal tunnel syndrome, and affection of tendon sheath of flexor flexors, leading to the development of flexural contractures of the fingers. In addition, they are characterized by the development of cystic bone damage due to the deposition of amyloid. Typical are amyloid cysts in the bones of the wrist and the heads of tubular bones. Over time, these deposits increase in size, causing pathological fractures.

A frequent sign of dialysis amyloidosis is also destructive spondyloarthropathy as a result of amyloid involvement of intervertebral discs, mainly in the cervical spine.

Amyloid deposits in muscles are more often observed in primary amyloidosis. They are manifested by pseudohypertrophy or atrophy of muscles, which impede movement, muscle pain.

Macroglossia, a pathognomonic symptom of AL-type amyloidosis, noted in about 20% of patients, is often combined with pseudohypertrophy of other groups of striated musculature and is caused by pronounced muscle infiltration with amyloid. In severe cases, macroglossia complicates not only food intake and speech, but also leads to airway obstruction. With AA-amyloidosis it does not develop.

Among other organ disorders in amyloidosis, thyroid involvement is known with the development of a clinical picture of hypothyroidism (AL-type amyloidosis), adrenal glands with the appearance of symptoms of their insufficiency (more often with AA-type amyloidosis), exocrine glands leading to dry syndrome, lymphadenopathy. Rarely (described with AL- and ATTR-types of amyloidosis) is affected by eye damage.

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