Amyloidosis and kidney damage - Treatment

According to modern concepts, the treatment of amyloidosis is a reduction in the amount of precursor proteins (or, if possible, their removal) in order to slow down or stop the progression of amyloidosis. The unfavorable prognosis in the natural course of amyloidosis justifies the use of some aggressive drug regimens or other radical measures (high-dose chemotherapy followed by autologous stem cell transplantation in patients with AL amyloidosis). The clinical improvement that can be achieved with these types of treatment consists in stabilization or restoration of the function of vital organs, as well as in preventing further generalization of the process, which increases the life expectancy of patients. The morphological criterion for the effectiveness of treatment is considered to be a decrease in amyloid deposits in tissues, which can currently be assessed using radioisotope scintigraphy with a serum beta component. In addition to the main therapeutic regimens, treatment of amyloidosis should include symptomatic methods aimed at reducing the severity of congestive circulatory failure, arrhythmias, edema syndrome, and correction of arterial hypotension or hypertension.

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Treatment of AA amyloidosis

The goal of secondary amyloidosis treatment is to suppress the production of the SAA precursor protein, which is achieved by treating chronic inflammation, including surgery (sequestrectomy for osteomyelitis, removal of a lung lobe for bronchiectasis), tumors, and tuberculosis. Of particular importance at present is the treatment of rheumatoid arthritis, given its leading position among the causes of secondary amyloidosis. With basic therapy of rheumatoid arthritis with cytostatic drugs: methotrexate, cyclophosphamide, chlorambucil, prescribed for a long period (more than 12 months), amyloidosis develops less often. In patients with already developed amyloidosis, treatment with cytostatics allows in most cases to reduce the clinical manifestations of amyloid nephropathy. As a result of amyloidosis treatment, a decrease in proteinuria, relief of nephrotic syndrome, and stabilization of renal function are noted. In some patients, it is possible to prevent the development of chronic renal failure or slow its progression, which significantly improves the prognosis. Monitoring the effectiveness of amyloidosis treatment with cytostatics is the normalization of the concentration of C-reactive protein in the blood. A promising treatment method that can replace traditional cytostatics is the use of TNF-a inhibitors.

The drug of choice for the treatment of AA amyloidosis in periodic disease is colchicine. With its constant use, it is possible to completely stop the recurrence of attacks in most patients and ensure the prevention of amyloidosis development. In the case of developed amyloidosis, long-term (possibly lifelong) use of colchicine at a dose of 1.8-2 mg/day leads to remission, expressed in the elimination of nephrotic syndrome, a decrease or disappearance of proteinuria in patients with normal renal function. In the presence of chronic renal failure, the initial dose of colchicine is reduced depending on the value of glomerular filtration, although in the case of a decrease in the concentration of creatinine in the blood, it is possible to increase the dose to the standard. Colchicine also prevents recurrence of amyloidosis in the transplanted kidney. Patients tolerate this drug well. In case of dyspepsia (the most common side effect of colchicine), there is no need to cancel the drug: it usually disappears on its own or with the appointment of enzyme preparations. Lifelong administration of colchicine is safe. The anti-amyloid effect of colchicine is based on its ability to experimentally suppress acute-phase synthesis of the SAA precursor protein and block the formation of amyloid-accelerating factor, which inhibits the formation of amyloid fibrils. While the effectiveness of colchicine in amyloidosis in the context of periodic disease is beyond doubt, there are only a few studies indicating its successful use in patients with secondary amyloidosis. The assumption that the drug can be effectively used to treat AA-type amyloidosis in general has not yet been proven. In addition to colchicine, dimethyl sulfoxide is used for AA amyloidosis, causing resorption of amyloid deposits. However, its use in high doses (at least 10 g/day), necessary for successful treatment, is limited due to the extremely unpleasant odor that patients emit when taking it. A modern drug aimed at amyloid resorption is Fibrillex; its use is justified as an addition to the main therapy of the predisposing disease or treatment with colchicine.

Treatment of AL-type amyloidosis

In AL-type amyloidosis, as in myeloma, the goal of treatment is to suppress proliferation or completely eradicate the plasma cell clone to reduce the production of immunoglobulin light chains. This is achieved by prescribing melphalan in combination with prednisolone. Treatment is continued for 12-24 months in 4-7-day courses with an interval of 4-6 weeks. The dose of melphalan is 0.15-0.25 mg/kg of body weight per day, prednisolone - 0.8 mg/kg of body weight per day. In patients with chronic renal failure (SCF less than 40 ml/min), the dose of melphalan is reduced by 50%. If there are signs of amyloidosis progression after 3 months of treatment, therapy should be discontinued. An undoubted indicator of the effectiveness of therapy after 12-24 months is considered to be a 50% decrease in proteinuria without impairment of renal function, normalization of the elevated concentration of creatinine in the blood before the start of treatment, disappearance of symptoms of circulatory failure, as well as a 50% decrease in the content of monoclonal immunoglobulin in the blood and urine. However, long-term (at least 12 months) treatment cannot be carried out in all patients, since the progression of the disease can outpace the positive effect of melphalan: it has myelotoxic properties, which can lead to the development of leukemia or myelodysplasia. Treatment of amyloidosis with melphalan and prednisolone according to the specified scheme allows to avoid the myelotoxicity of melphalan: a positive effect is achieved in 18% of patients, and the best results are noted in NS without impairment of renal function and circulatory failure. The life expectancy of patients who have developed a positive response to treatment is on average 89 months.

Recently, more aggressive polychemotherapy regimens with the inclusion of vincristine, doxorubicin, cyclophosphamide, melphalan, and dexamethasone in various combinations have been increasingly used for AL amyloidosis (not only in the context of myeloma disease, but also in primary amyloidosis). Recent studies indicate greater effectiveness of high-dose chemotherapy. Thus, RL Comenzo et al. in 1996 published preliminary results of treating 5 patients with AL amyloidosis with intravenous infusions of melphalan at a dose of 200 mg/m2 ^of body surface area, followed by the introduction of autologous stem cells (CD34 ⁺ ) in the blood. Autologous stem cells are obtained by leukapheresis of the patient's blood after their preliminary mobilization from the bone marrow under the influence of granulocyte colony-stimulating factor introduced from outside. However, severe agranulocytosis and other complications of this therapy significantly limit the use of ultra-high-dose melphalan therapy, particularly in patients with circulatory failure. Low survival rates in patients with AL amyloidosis do not allow a definitive assessment of the effectiveness of these regimens. The use of colchicine for the treatment of AL amyloidosis has proven ineffective.

Treatment of dialysis amyloidosis

The goal of treatment is to reduce the amount of precursor protein by increasing the clearance of beta ₂ -microglobulin using modern blood purification methods: high-flow hemodialysis on synthetic membranes, which improves the absorption of beta,-microglobulin, hemofiltration, and immunosorption. These methods can reduce the concentration of precursor protein by about 33%, which can delay or slow down the development of dialysis amyloidosis. However, the only truly effective treatment is kidney transplantation. After transplantation, the beta ₂ -microglobulin content decreases to normal values, which is accompanied by a rapid disappearance of the clinical signs of amyloidosis, although amyloid deposits in the bones persist for many years. The reduction in disease symptoms is apparently associated with the anti-inflammatory effect of immunosuppressive therapy after transplantation and, to a lesser extent, with the cessation of hemodialysis procedures.

Treatment of hereditary amyloid neuropathy

The treatment of choice for ATTR-type amyloidosis is liver transplantation, which removes the source of amyloidogenic precursor synthesis. After this operation, if there are no signs of advanced neuropathy, the patient can be considered practically cured.

Renal replacement therapy

Since chronic renal failure is one of the main causes of death in patients with systemic amyloidosis, hemodialysis or continuous ambulatory peritoneal dialysis improves the prognosis of these patients. Survival of patients with amyloidosis during hemodialysis, regardless of its type, is comparable to the survival of patients with other systemic diseases and diabetes mellitus. At the same time, good and satisfactory rehabilitation is noted in 60% of patients with AA and AL types of the disease. Heart and vascular damage is the main cause of death in patients with amyloidosis during hemodialysis. Continuous ambulatory PD has some advantages over hemodialysis, since there is no need for permanent vascular access, arterial hypotension does not occur during the dialysis procedure, and in patients with AL type amyloidosis, removal of immunoglobulin light chains is possible during the procedure. Kidney transplantation is equally effective in both types of systemic amyloidosis. Five-year survival rates of patients and transplants are 65 and 62%, respectively, and are comparable with the corresponding indicators in other groups of patients with chronic renal failure.

Kidney transplantation is indicated for patients with slow progression of amyloidosis without heart or gastrointestinal involvement. According to various data, amyloidosis in the transplanted kidney occurs in approximately 30% of patients, but it causes transplant loss in only 2-3% of patients.