Amyloidosis and kidney damage - Symptoms

In clinical practice, the most significant are the AA and AL types of systemic amyloidosis, which involve many organs in the pathological process, but often manifest with symptoms of single-organ damage. AA and AL types of amyloidosis are observed in men 1.8 times more often than in women. Secondary amyloidosis is characterized by an earlier onset than primary amyloidosis (the average age of patients is about 40 and 65 years, respectively). Symptoms of renal amyloidosis AL are more diverse: in addition to numerous clinical manifestations common to the AA type, there are signs characteristic only of the AL type (periorbital purpura, macroglossia and other muscular pseudohypertrophies). On the other hand, individual clinical manifestations of primary amyloidosis are also 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. With the AA type, the kidneys are involved in the pathological process in almost all patients, with the AL type, the frequency of nephropathy is also high and approaches 80%. Kidney damage is also observed with the ATTR type of amyloidosis, however, many patients with familial amyloid neuropathy with morphological signs of amyloid kidney damage do not have symptoms of renal amyloidosis.

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

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

It was found that when podocytes come into contact with subepithelial amyloid deposits, the pedunculated processes of podocytes spread out, and in some areas, they detach from the basement membrane with its exposure. These changes correlate with the severity of proteinuria. Podocytes are also assigned a key role in the processes of glomerular reparation in renal amyloidosis. During the reparative phase, which lasts for several years, podocytes gradually recover and begin to synthesize the substance of the basement membrane, which forms a new membrane layer, which is accompanied by a decrease in proteinuria and an improvement in kidney function.

Amyloid is also deposited in other renal structures: in the basement membrane of the tubules (mainly distal and the loop of Henle), the interstitium, and the walls of blood vessels.

Symptoms of renal amyloidosis usually manifest as isolated proteinuria and are characterized by a steadily progressive course in most patients (80%) with the AA type with a sequential change of stages: proteinuric, nephrotic, chronic renal failure. With the AL type of amyloidosis, the staging of the course of amyloid nephropathy is less clearly manifested.

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

The amount of proteinuria does not correlate with the severity of amyloid deposits in the kidneys (with predominantly vascular damage, proteinuria may be minimal) and depends on the degree of podocyte destruction. Maximum protein loss is detected through areas of the basement membrane that are impregnated with amyloid and lack an epithelial coating.

Renal function in amyloidosis correlates with the severity of tubulointerstitial damage leading to interstitial fibrosis. These data suggest the commonality of some mechanisms of progression of amyloid nephropathy and chronic renal failure through the development of tubulointerstitial fibrosis. Arterial hypertension, which aggravates glomerular damage due to ischemia, may also contribute to the progression of renal failure in patients with amyloidosis.

In most patients, renal amyloidosis is diagnosed only at the stage of nephrotic syndrome, in 33% - even later, at the stage of chronic renal failure. In rare cases, amyloid nephropathy can manifest itself as acute nephritic syndrome and macrohematuria, which further complicates diagnosis. Fanconi syndrome and renal vein thrombosis have also been described.

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

Clinically, cardiomegaly, muffled heart sounds are detected, heart failure develops early (in 22% of patients already at the onset of the disease), which progresses rapidly and in almost 50% of patients, along with arrhythmias, is the cause of death. A feature of heart failure in primary AL amyloidosis is its refractoriness to therapy.

Rhythm and conduction disturbances in AL-type amyloidosis are varied: atrial fibrillation, supraventricular tachycardia, premature ventricular excitation syndrome, various blockades and sick sinus syndrome. Due to amyloid deposition in the coronary arteries, myocardial infarction may develop, which is detected at autopsy in 6% of patients. Amyloid deposits in valve structures simulate the picture of valve defect.

The main symptom of cardiac amyloidosis on ECG is a decrease in the voltage of the QRS complex teeth. An infarction-like ECG type has been described.

The most adequate method for diagnosing amyloid cardiomyopathy is considered to be echocardiography, which can diagnose symmetrical thickening of the ventricular walls, dilation of the atria, thickening of the valves with blood regurgitation, effusion in the pericardial cavity, signs of diastolic dysfunction of the myocardium. For the diagnosis of cardiac amyloidosis, it is also possible to perform myocardial scintigraphy with the isotope technetium labeled with pyrophosphate, but it has no advantages over echocardiography.

A 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 damage to the autonomic nervous system and in severe cases is accompanied by syncopal states. Arterial hypotension also occurs in patients with AA-type amyloidosis, but in this case it is more often associated with adrenal insufficiency due to amyloid deposition in the adrenal glands.

Respiratory system involvement occurs in approximately 50% of patients with primary amyloidosis and in 10-14% with secondary amyloidosis. In most cases, it is asymptomatic or has few clinical symptoms. In AL amyloidosis, one of the early signs of the disease may be hoarseness or a change in the timbre of the voice due to amyloid deposition in the vocal cords, which precedes its appearance in the distal respiratory tract. In the lungs, amyloid is deposited primarily in the alveolar septa (which leads to dyspnea and cough) and vascular walls. Atelectasis and pulmonary infiltrates have also been described. The radiographic picture is nonspecific; death from progressive respiratory failure is rare.

Digestive system damage is observed in 70% of cases of amyloidosis. In 25% of patients with primary AL amyloidosis, amyloid damage to the esophagus is noted, manifested mainly by dysphagia, which can be one of the early symptoms of the disease.

Damage to the stomach and intestines consists of ulceration and perforation of their walls with possible bleeding, as well as prepyloric obstruction of the stomach or mechanical intestinal obstruction due to deposition of amyloid masses. In patients with predominant damage to the colon, clinical symptoms may appear that mimic ulcerative colitis.

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

Liver damage in AA and AL types of amyloidosis is observed in almost 100% of cases, with liver enlargement and a 3- to 4-fold increase in y-glutamyl transpeptidase and alkaline phosphatase usually noted. Severe liver damage with pronounced hepatomegaly and extensive signs of severe cholestasis is noted much less frequently (in 15-25% of patients); it is more typical of AL amyloidosis. At the same time, despite pronounced hepatomegaly, liver function usually remains intact. A rare sign of liver amyloidosis is intrahepatic portal hypertension, which is combined with pronounced jaundice, cholestasis, liver failure and indicates advanced damage with the risk of esophageal bleeding, hepatic coma. Severe spontaneous intrahepatic bleeding has been described in some variants of familial ALys amyloidosis.

Splenic enlargement due to amyloid lesions occurs in most patients and is usually accompanied by liver enlargement. Splenomegaly may be accompanied by functional hyposplenism, which leads to thrombocytosis. A rare manifestation of splenic amyloidosis is its spontaneous rupture.

Nervous system damage, represented by symptoms of peripheral neuropathy and autonomic dysfunction, is observed in 17% of patients with AL-type amyloidosis and in patients with familial amyloid neuropathy of different types (ATTR, AApoAl, etc.). The clinical picture of neuropathy in all types of amyloidosis is almost the same, since it is caused by similar processes, primarily degeneration of the myelin sheath of the nerves, as well as compression of nerve trunks by amyloid deposits and ischemia as a result of amyloid deposits in the walls of blood vessels.

In most cases, symmetrical distal neuropathy develops with steady progression. At the onset of damage to the nervous system, sensory disturbances are mainly observed, primarily pain and temperature sensitivity, later vibration and positional sensitivity, then motor disturbances join. Early symptoms of neuropathy are paresthesia or painful dysesthesia (numbness). The lower extremities are involved in the pathological process more often than the upper ones.

Autonomic dysfunctions often manifest as orthostatic arterial hypotension (see above), sometimes fainting, diarrhea, bladder dysfunction, and impotence.

In 20% of patients with AL-type amyloidosis, in most patients with dialysis amyloidosis, in some patients with ATTR, carpal tunnel syndrome is detected, caused by compression of the median nerve by amyloid deposited in the wrist ligaments. Clinically, this syndrome is manifested by intense pain and paresthesia in the I-III fingers of the hand with gradual atrophy of the thenar muscles. The features of carpal tunnel syndrome in dialysis amyloidosis include its predominant development on the hand where the fistula is formed, as well as increased pain during the hemodialysis procedure, possibly as a result of the development of the steal phenomenon induced by the fistula, 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 the AA type. A variety of manifestations is characteristic, the most common of which are paraorbital hemorrhages (pathognomonic for AL amyloidosis), which occur with the slightest tension. Papules, plaques, nodules, and vesicular rashes have also been described. Skin induration, similar to scleroderma, is often observed. A rare variant of skin lesions in AL amyloidosis is pigmentation disorders (from pronounced enhancement to total albinism), alopecia, and trophic disorders.

Musculoskeletal system damage is typical for patients with dialysis amyloidosis and rarely (in 5-10% of cases) occurs in patients with the AL type (excluding bone changes in myeloma). In this case, the nature of tissue deposition of amyloid is similar: amyloid is deposited in bones, articular cartilage, synovium, ligaments and muscles.

In dialysis amyloidosis, the most common triad of symptoms is: scapulohumeral periarthritis, carpal tunnel syndrome, and damage to the tendon sheaths of the flexors of the hand, leading to the development of flexion contractures of the fingers. In addition, the development of cystic bone lesions due to amyloid deposition is characteristic. Amyloid cysts in the bones of the wrist and the heads of tubular bones are typical. Over time, these deposits increase in size, causing pathological fractures.

A common symptom of dialysis amyloidosis is also destructive spondyloarthropathy as a result of amyloid lesions of the intervertebral discs, primarily in the cervical spine.

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

Macroglossia is a pathognomonic symptom of AL-type amyloidosis, observed in approximately 20% of patients, often combined with pseudohypertrophy of other groups of striated muscles and caused by pronounced infiltration of muscles with amyloid. In severe cases, macroglossia complicates not only eating and speaking, but also leads to airway obstruction. It does not develop in AA amyloidosis.

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

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