Amyloidosis and Kidney Damage: Treatment

According to modern ideas, the treatment of amyloidosis is a reduction in the number of progenitor proteins (or, if possible, their removal) in order to slow or stop the progression of amyloidosis. An unfavorable prognosis for the natural course of amyloidosis justifies the use of some aggressive medicinal 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 is to stabilize or restore the function of vital organs, as well as to prevent further generalization of the process, which increases the life expectancy of patients. The morphological criterion for the effectiveness of treatment is the decrease in amyloid deposits in tissues, which can now be estimated using radioisotope scintigraphy with the serum beta-component. In addition to the main therapeutic regimens, the treatment of amyloidosis should include symptomatic methods aimed at reducing the severity of congestive circulatory insufficiency, arrhythmias, edematous syndrome, correction of arterial hypotension or hypertension.

[1], [2], [3], [4], [5], [6], [7], [8]

Treatment of amyloidosis AA-type

The goal of secondary amyloidosis treatment is the suppression of the production of the SAA precursor protein, which is achieved by the treatment of chronic inflammation, including surgical treatment (sequestrectomy for osteomyelitis, removal of the lung lobe with bronchiectasis), tumor, tuberculosis. Of particular importance are currently given to the treatment of rheumatoid arthritis, given its leading position among the causes of secondary amyloidosis. In the basic therapy of rheumatoid arthritis with cytostatic drugs: methotrexate, cyclophosphamide, chlorambucil, - prescribed for a long term (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 treatment with amyloidosis, a decrease in proteinuria, a reduction in nephrotic syndrome, and stabilization of kidney function are noted. Some patients manage to prevent the development of chronic renal failure or slow its progression, which significantly improves the prognosis. Control of the effectiveness of treatment with amyloidosis with cytostatics is the normalization of the concentration of C-reactive protein in the blood. A promising method of treatment that can supplant traditional cytotoxic drugs is the use of TNF-a inhibitors.

A means of choice for the treatment of amyloidosis AA with periodic disease is colchicine. With his constant reception, you can completely stop the recurrence of attacks in most patients and ensure the prevention of the development of amyloidosis. With the development of amyloidosis, prolonged (possibly lifelong) colchicine intake in a dose of 1.8-2 mg / day leads to remission, manifested in the elimination of nephrotic syndrome, the 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, an increase in the dose to a standard dose is possible. Colchicine also prevents the recurrence of amyloidosis in the transplanted kidney. Patients tolerate this drug well. With dyspepsia (the most common side effect of colchicine), there is no need to cancel the remedy: it usually disappears on its own or with the appointment of enzyme preparations. Lifetime reception colchicine is safe. The antiamyloid effect of colchicine is based on its ability to suppress the acute phase synthesis of the SAA protein precursor in the experiment, block the formation of an amyloid-accelerating factor, which inhibits the formation of amyloid fibrils. If the efficacy of colchicine in amyloidosis is not in doubt within the framework of the periodic disease, then there are only a few studies that indicate its successful use in patients with secondary amyloidosis. The assumption that the drug can be used effectively for the treatment of AA-type amyloidosis in general has not yet been proved. In addition to colchicine, with AA-amyloidosis, dimethyl sulfoxide is used, which causes 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 comes from patients when it is taken. A modern drug aimed at resorption of amyloid is fibrillex; its use is justified as a supplement to the main therapy of predisposing disease or treatment with colchicine.

Treatment of AL-type amyloidosis

With AL-type amyloidosis, as in myeloma, the goal of treatment is to suppress proliferation or complete eradication of a clone of plasma cells to reduce the production of light chains of immunoglobulins. This is achieved with the appointment of melphalan in combination with prednisolone. Treatment continues for 12-24 months with 4-7-day courses at 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 (GFR less than 40 ml / min), the dose of melphalan is reduced by 50%. If there is evidence of progression of amyloidosis after 3 months of treatment, therapy should be discontinued. An indisputable index of the effectiveness of therapy after 12-24 months is a decrease in proteinuria by 50% without disturbing the kidney function, normalization of the increased creatinine level in the blood before starting treatment, the disappearance of symptoms of circulatory insufficiency, and a 50% decrease in monoclonal immunoglobulin content in blood and urine. However, long-term treatment (not less than 12 months) can not be performed in all patients, as the progression of the disease may outstrip 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 this scheme avoids the myelotoxicity of melphalan: a positive effect is achieved in 18% of patients, and the best results are noted with HC without renal impairment and circulatory failure. The life expectancy of patients who developed a positive response to treatment is an average of 89 months.

Recently, with AL-amyloidosis (not only in the framework of myeloma, but also in primary amyloidosis), more and more aggressive polychemotherapy regimens have been used, including vincristine, doxorubicin, cyclophosphamide, melphalan, dexamethasone in various combinations. Recent studies indicate a greater effectiveness of high-dose chemotherapy. Thus, RL Comenzo et al. In 1996, published preliminary results of treatment of 5 patients with AL-amyloidosis intravenous infusions of melphalan at a dose of 200 mg / m ^{2 of} the body surface followed by the introduction of autologous stem cells (CD34 ⁺ ) of blood. Autologous stem cells are obtained by the method of leukapheresis of the patient's blood after their preliminary mobilization from the bone marrow under the influence of the granulocyte colony-stimulating factor introduced from the outside. However, severe agranulocytosis and other complications of this therapy significantly limit the use of therapy with ultra-high doses of melphalan, in particular, in patients with circulatory failure. The low survival rates of patients with AL-amyloidosis do not allow for a definite evaluation of the efficacy of these regimens. The use of colchicine for the treatment of AL-type amyloidosis proved ineffective.

Treatment of amyloidosis dialysis

The goal of the treatment is to reduce the amount of the precursor protein by increasing the clearance of beta _2- microglobulin in modern blood purification methods: high-flow hemodialysis on synthetic membranes, which improves the absorption of p1, microglobulin, hemofiltration, and immunosorption. With these methods, it is possible to reduce the concentration of the precursor protein by about 33%, which allows delaying or inhibiting the development of dialyzed amyloidosis. However, the only truly effective method of treatment remains kidney transplantation. After it, the content of beta _2- microglobulin is reduced to normal values, which is accompanied by the rapid disappearance of clinical signs of amyloidosis, although the deposition of amyloid in the bones persists for many years. Reduction of the symptoms of the disease appears to be related to the anti-inflammatory effect of immunosuppressive therapy after transplantation and, to a lesser extent, termination of hemodialysis procedures.

Treatment of hereditary amyloid neuropathy

The choice of treatment for ATTR-type amyloidosis is liver transplantation, in which it is possible to remove the source of synthesis of the amyloidogenic precursor. After this operation, if there are no signs of far-gone neuropathy, the patient can be considered almost cured.

Renal Replacement Therapy

Since chronic renal failure is one of the main causes of death of patients with systemic amyloidosis, carrying out hemodialysis or permanent ambulatory peritoneal dialysis allows improving 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, 60% of patients with AA- and AL-types of the disease report a good and satisfactory rehabilitation. The defeat of the heart and blood vessels is the main cause of death of patients with amyloidosis during hemodialysis. Permanent ambulatory PD has some advantages over hemodialysis, since there is no need for constant vascular access, there is no arterial hypotension during the dialysis procedure, and in patients with AL-type of amyloidosis during the procedure it is possible to remove light chains of immunoglobulins. Kidney transplantation is equally effective in both types of systemic amyloidosis. The five-year survival rate of patients and graft is 65 and 62%, respectively, and is comparable with that in other groups of patients with chronic renal failure.

Kidney transplantation was shown to patients with slow progression of amyloidosis without cardiac and gastrointestinal lesions. Amyloidosis in the transplanted kidney occurs, according to various data, in about 30% of patients, but it becomes the cause of graft loss in only 2-3% of patients.