Immunosuppressive therapy complications. Immunosuppressants: classification and description

Performed on all patients before and after transplantation. The exception is when the donor and recipient are identical twins. Modern approaches to immunosuppressive therapy include the simultaneous use of several immunosuppressive drugs and their administration before and after transplantation to prevent and treat graft rejection. Currently, corticosteroids, azathioprine, cyclosporine, mono- and polyclonal antibodies are used as immunosuppressants. These drugs interfere with the activation of the immune response or block immune effector mechanisms.

A. Cyclosporine is one of the new, but already widely used immunosuppressants. It is prescribed before, during and after transplantation. The drug inhibits the synthesis of interleukin-2, thereby suppressing the proliferation of cytotoxic T-lymphocytes. In high doses, cyclosporine has a nephrotoxic effect, and with prolonged use it causes pneumosclerosis. Despite this, compared with the combination of prednisone and azathioprine, cyclosporine reduced the rejection of a transplanted kidney within 1 year by 10-15%. Transplant rejection within 1 year when using cyclosporine is 10-20%. Cyclosporine does not affect transplant rejection at a later date.

B. Tacrolimus has a mechanism of action similar to cyclosporine, but differs from it in chemical structure. Tacrolimus inhibits the activation and proliferation of cytotoxic T lymphocytes by suppressing the production of interleukin-2 and interferon gamma. The drug is effective in lower doses than cyclosporine, but also has a nephrotoxic effect, so it is not yet widely used. The drug is currently undergoing clinical trials for kidney, liver and heart transplantation. Preliminary results suggest that tacrolimus is highly effective in acute and chronic rejection after liver transplantation. Tacrolimus, to a greater extent than cyclosporine, delays transplant rejection and increases patient survival. In addition, the appointment of tacrolimus allows you to reduce the dose of corticosteroids, and sometimes completely eliminate them.

IN. Muromonab-CD3 is a murine monoclonal antibody against CD3, which is closely related to the human T-lymphocyte antigen recognition receptor. After binding to the antibody, CD3 temporarily disappears from the surface of T-lymphocytes, making their activation impossible. After some time, CD3 reappears on the surface of T lymphocytes, but remains blocked by muromonab-CD3. The drug is used for transplant rejection in cases where corticosteroids are ineffective. It has been shown to significantly reduce the number of CD3 lymphocytes in the blood and suppress transplant rejection. Muromonab-CD3 is used for both the prevention and treatment of transplant rejection. The drug has serious side effects: it can cause pulmonary edema and neurological disorders. In some patients, antibodies to muromonab-CD3 appear in the serum, inactivating it. To assess the effectiveness of treatment, the number of CD3 lymphocytes in the blood is measured. If the graft is rejected again, the use of muromonab-CD3 is resumed only in the absence of signs of immunization, to identify which special studies are required (see Chapter 17, paragraph IV.B).

G. Polyclonal antibodies To lymphocytes, such as antilymphocyte immunoglobulin and antithymocyte immunoglobulin are obtained from the serum of rabbits and other animals after immunization with human lymphocytes or thymus cells. The mechanism of action of polyclonal antibodies is to destroy lymphocytes and reduce their number in the blood. These drugs are used for both preventive and therapeutic purposes. Antilymphocyte and antithymocyte immunoglobulins increase the risk of infections. Other complications are also possible, such as thrombocytopenia, associated with the presence of antibodies of different specificities in the drugs. Treatment with these drugs may cause a false-positive lymphocytotoxicity test result. Since exogenous antibodies make it difficult to detect the recipient's own antibodies to donor antigens, this study is not performed during treatment with antilymphocyte immunoglobulin. The activity of antilymphocyte immunoglobulin, like other drugs of biological origin, is unstable.

IV. Immunological research after transplantation

A. Diagnostics rejection transplant is carried out regularly in all patients who have undergone transplantation. There are no reliable methods for immunological diagnosis of transplant rejection. Thus, the study of indicators of activation of the immune response, for example, the determination of cytokines, is not very informative, since they change in many diseases, in particular during infections. Changes in the ratio of CD4 and CD8 lymphocytes also do not reflect the activity of the immune response to the transplant. A number of studies have shown that during transplant rejection, receptors for interleukin-2 appear in the recipient's serum, but the relationship between their level and the rate of transplant rejection has not yet been established. The only reliable method for diagnosing transplant rejection today remains its biopsy.

B. Definition absolute numbers T-lymphocytes V blood-- the best way to evaluate the effectiveness of muromonab-CD3, antithymocyte and antilymphocyte immunoglobulins. The number of T-lymphocytes in the blood is determined by flow cytometry using labeled antibodies to CD3. Because different drugs of these antibodies are directed to different parts of the CD3 molecule, the results of studies using drugs from different companies may vary. Determining the number of T-lymphocytes in the blood allows you to select the dose and determine the duration of use of mono- and polyclonal antibodies.

IN. Antibodies that inactivate it may appear in the serum of recipients receiving muromonab-CD3. If, with the introduction of high doses of muromonab-CD3, the number of CD3 lymphocytes does not decrease, the level of antibodies to the drug is determined. The level of antibodies to muromonab-CD3 is measured using flow cytometry using the following procedure: 1) microspheres coated with muromonab-CD3 are treated with recipient serum; 2) add antibodies to human immunoglobulins labeled with a fluorescent label. To exclude previous immunization with mouse antibodies, the level of antibodies in the recipient's serum is determined before treatment. If necessary, the level of antibodies to muromonab-CD3 is determined during the first course of treatment and always before re-prescribing the drug. Commercial kits are available to determine the level of muromonab-CD3 and antibodies to it.

V. Control behind engraftment transplant bone brain

A. Engraftment of a bone marrow transplant is monitored by identifying cells with donor HLA antigens in the recipient's blood. Such a study is possible only if the donor and recipient differ in HLA, which is rare, since usually during bone marrow transplantation a donor is selected that is completely identical to the recipient in HLA antigens. Differences in HLA antigens are observed in cases where the recipient is a child and the bone marrow donor is one of the parents. In this case, the recipient and donor each carry the same HLA haplotype. Such bone marrow transplantation is only possible in cases of severe combined immunodeficiency, since in this disease the immune reactivity is reduced or absent. Donor lymphocytes in the recipient's blood are detected using a lymphocytotoxic test. This is possible if they make up at least 20% of the total number of lymphocytes in the recipient’s blood. If the donor differs from the recipient in HLA class II antigens, molecular genetic methods are used to identify them (see Chapter 17, paragraph II.A.2). They are more sensitive than the lymphocytotoxicity test. Thus, analysis of restriction fragment length polymorphism identifies donor lymphocytes if their content in the recipient’s blood is 5%, and determination of specific oligonucleotide sequences - if their content is no more than 0.1%.

B. In a fully HLA-matched bone marrow transplant, donor cells can be distinguished from recipient cells by non-HLA genes. Oligonucleotide probes have been synthesized for non-HLA genes, as well as for certain tandem nucleotide sequences. Genetic typing of the donor and recipient for these genes and tandem sequences is carried out before transplantation. Based on the identified genetic differences, donor cells in the recipient's blood are subsequently determined.

IN. If the recipient and donor are of different sexes, graft engraftment can be monitored by identifying sex chromosomes. Male and female cells can be distinguished from each other by introducing fluorescently labeled oligonucleotide probes complementary to specific DNA sequences of the X and Y chromosomes into isolated cell nuclei. This method allows you to identify donor cells in the recipient's blood, but not to determine their number. Flow cytometry is used to count cells containing X and Y chromosomes, as well as other human chromosomes.

Considering the pathogenesis of most autoimmune diseases, basic therapy is used for their treatment, which in most cases consists of the use of immunosuppressive drugs in the following sequence: GCS – cytostatics – various methods of extracorporeal detoxification.

Immunosuppression- this is an effect on the immune system aimed at suppressing or removing antibodies and/or lymphocytes that specifically respond to allo- or autoantigens.

1. GKS– their anti-inflammatory and immunomodulatory effect is based on the classical “genomic” mechanism, based on the interaction of GCS with transcription factors that regulate the genes of cytokines, adhesion molecules, matrix proteinases, etc.; at the cellular level, GCS suppress predominantly the T-helper immune response.

In particular, GCS suppress: a) the production of proinflammatory cytokines; b) inducible phospholipase A2; c) inducible cyclooxygenase and NO synthetase; e) adhesion molecules, enhances: a) production of IL-10; b) expression of IL-1 receptor antagonist, etc.

Depending on the dose The effects of GCS can be realized at different levels(in low concentrations, a genomic mechanism is realized; when high and ultra-high doses are prescribed, both genomic and non-genomic: changes in the physicochemical properties of biomembranes, suppression of receptor expression, regulation of lymphocyte activation, inhibition of TNF synthesis, and other mechanisms).

2. Cytostatics– have an immunosuppressive effect through the following mechanisms:

a) suppression of calcium metabolism, leading to disruption of the production of IL-2 by T-helper cells (cyclosporine, FK-506 / tacrolimus).

B) suppression of nucleotide synthesis, reduction of mitosis and clonal expansion (mycophenolate mofetil - acts selectively in lymphocytes, azathioprine - acts non-selectively on all proliferating cells)

B) suppression of T-cell recognition receptor function (monoclonal anti-CD3 antibodies)

D) disruption of signal transmission from IL-2 to the cell nucleus due to suppression of its binding to IL-2 receptors (rapamycin)

D) multiple mechanism of action (GCS, polyclonal antilymphocyte globulins)

e) suppression of glycolysis of adhesive molecules – integrins and selectins (mycophenolate mofetil)

g) suppression of tyrosine kinases associated with T-cell recognition receptors or cytokines (leflunamide)

Any immunosuppressive agent has three types of effects:

1) immunosuppressive effect, i.e. the therapeutic effect that we are trying to obtain by prescribing this or that drug to the patient

2) non-immune toxicity of the drug, due to its chemical structure (nephrotoxicity of cyclosporine or FK-506, etc.) - must be taken into account when prescribing maintenance immunosuppressive therapy for a long time, both after transplantation and in autoimmune pathology.

3) inadequate suppression of the immune response, contributing to the development of secondary immunodeficiency with the subsequent occurrence of infectious complications or tumors.

3. Extracorporeal detoxification– plasmapheresis – improves the function of the reticuloendothelial system, allows the removal of AT, CEC and inflammatory mediators from the bloodstream, and has an immunomodulatory effect.

Immunocorrection is divided into:

A) immunostimulation– method of immune activation (specific – activation of a specific clone

Immunocompetent cells and nonspecific - general strengthening of immune defense); indicated for primary and secondary immunodeficiencies, accompanied by recurrent bacterial and viral infections affecting the respiratory tract, food canal, urogenital tract, skin, etc., in the complex treatment of patients with cancer pathology.

B) immunomodulation– a system of measures to return the immune status to its original, balanced state; indicated for healthy individuals who have suffered psycho-emotional stress or maximum physical exertion, and for individuals with increased fatigue syndrome.

Main groups of immunocorrectors:

I. Products of physiological origin:

1. Preparations obtained from the thymus: timoptin, vilosen, tactivin 0.01% - 1 ml subcutaneously, 1 ml at night for 5-14 days, thymalin, thymostimulin - enhance lymphopoiesis, induce T-cell differentiation, increase their response to mitogens, production of various cytokines

2. Preparations of bone marrow origin: myelopid subcutaneously, 1-2 ampules (powder dissolved in 1 ml of saline solution) every other day, a total of 3-5 injections - helps accelerate the maturation of B-lymphocytes in the bone marrow, increases the number of cells producing AT, increases overall resistance of the body, has an anti-stress effect.

3. Spleen preparations: splenin 2 ml IM 1 time/day for 20 days, leukomax - normalize the immune system, increase the content of T-lymphocytes, enhance their ability to respond to mitogens and corticosteroids, reduce the content of CEC

4. Immunoglobulin preparations for intravenous administration (IVIG): sandoglobulin, pentaglobin N, cytotec, antistaphylococcal human immunoglobulin, complex immunoglobulin preparation, etc. - for replacement treatment and immunomodulation

II. Products of microbial origin:

1. Live bacteria: BCG

2. Extracts: biostim, picibanil, urovaxom

3. Lysates: bronchomunal 3.5 mg in the morning for 10-30 days in the acute phase, 10 days a month for prevention, IRS-19, 2 aerosol injections into each nasal passage daily until the symptoms of infection disappear, Imudon, bronchovaxom, Rinovac, etc.

4. Lipopolysaccharides: pyrogenal, prodigiosan – enhance AT synthesis and phagocytic activity of a number of cells

5. Yeast polysaccharides: zymosan, sodium nucleinate – stimulants of leukopoiesis

6. Fungal polysaccharides: kestin, bestatin, lentinan, glucan – increase the phagocytic activity of a number of cells, enhance the synthesis of AT

7. Ribosomes + proteoglycan: ribomunil 3 tablets on an empty stomach in the first 4 days during 3 weeks of the 1st month of treatment, and then in the first 4 days of each of the next 5 months; contains ribosomes of bacteria that most often cause respiratory tract infections (vaccine with immunomodulatory activity)

8. Probiotics: blasten, biosporin, linex – normalize, preserve and maintain the physiological balance of intestinal microflora (local immunity)

III.Synthetic drugs: thymogen, lycopid, diucifon, levamisole (decaris), kemantan, leakadine, polyoxidonium, groprinosin, isoprinosine, neovir, cycloferon.

IV. Vitamins and antioxidant complexes: Tri-Vi, Tri-Vi plus, vitamins A, C, E, etc.

V. Herbal preparations: immunoflam, difur, blastophage, manax, immunal, echinin

VI.Complex enzyme preparations: wobenzym, phlogenzyme according to schemes depending on the disease (for RA - 10 tablets 3 times a day for up to a year or more) - stimulate phagocytosis, destroy the CEC and immune complexes deposited in tissues, reduce damage induced by complement for

By reducing the activity of the latter, they normalize the production of pro-inflammatory cytokines, regulate the expression of adhesion molecules, etc.

A. S. Nikonenko, corresponding member of the National Academy of Sciences of Ukraine,
Doctor of Medicine, Professor, National Institute of Surgery and Transplantology
them. A. A. Shalimova NAMS of Ukraine", Kyiv

Organ transplantation has become the leading treatment for many chronic diseases around the world. Every year, tens of thousands of transplants of various organs are performed around the world. The maximum life expectancy after transplantation is more than 25 years. After organ transplantation, the patient was completely rehabilitated, which is confirmed not only by the restoration of his professional activities, but also by the participation of people with transplanted organs in the Olympic Games. Every year, tens of thousands of patients who have received donor organs participate in these sporting events.

Modern transplantology can be considered simultaneously as an indicator of the level of health care in a particular country and as an indicator of the civilization of society. Taking into account the fact that transplantation is not only one of the most high-tech, but also one of the most expensive fields, which also carries complex ethical, social and other objective problems, for its successful development it is necessary to comply with a number of conditions. First of all, an effective legislative framework, adequate government funding and a full understanding of society are needed. This situation is observed today in many developed countries, in which transplantation has become a standard clinical treatment for many diseases. Many facts about transplantation indicate high efficiency and complete rehabilitation of recipients (Fig. 1).

In developed countries, organ transplantation is the standard treatment for many diseases of the kidneys, heart, liver, lungs, and intestines.

There have been significant changes in the use of immunosuppressive agents over the past 10 years. In particular, along with the use of cyclosporine, tacrolimus began to be used more widely, and azathioprine began to be gradually replaced from practice by mycophenolate mofetil (MMF). Increasingly, immunosuppression protocols include induction therapy with daclizumab or basiliximab, an antithymocyte globulin. The main direction in the development of modern immunosuppression protocols is to increase long-term graft survival.

Immunosuppressive therapy is a mandatory section of clinical transplantology, with which the progress of this branch of medicine is associated. Organ transplantation within a species stimulates an immune response that is initiated by antigen recognition by T lymphocytes, the end result of which is organ rejection. Long-term functioning of the graft is only possible under conditions of lifelong immunosuppressive therapy.

Kidney transplantation is the most popular and economically justified. Before the introduction of replacement therapy methods (dialysis and transplantation) into clinical practice, renal failure led to the death of patients in 100% of cases. Since the first successful kidney transplantation in 1954, considerable experience has been accumulated regarding improvements in surgical techniques, organ preservation, improvement and optimization of immunosuppression protocols, and postoperative patient management. Kidney transplantation is the method of choice in the treatment of end-stage chronic renal failure (CKD). The risk of death for patients with a kidney transplant is 2 times less than the risk of death for patients on dialysis.

However, even after successful organ transplantation, the risk of graft rejection at various times after surgery cannot be ruled out. For this purpose, immunosuppressive therapy protocols have been developed. When carrying out immunosuppression, the main attention should be paid to the timely diagnosis of the rejection reaction, prevention and correction of side effects. It should be remembered that an overdose of immunosuppressive drugs can lead to infectious complications and increases the risk of developing malignant tumors, and cyclosporine has severe nephrotoxicity.

To date, there is no ideal, much less standard, immunosuppression regimen after kidney transplantation. This is confirmed by the use of many combinations of already known and new immunosuppressants in various transplant centers. However, one should strive to adhere to a protocol based on the results of large clinical trials and existing recommendations. At the same time, there is always the opportunity to deviate from the protocol and choose a non-standard approach to treatment to minimize unwanted side effects in a particular patient. The use of an individual approach in certain categories of recipients should be based on generally accepted international recommendations and the transplant center’s own experience.

All recipients vary in their risk of developing rejection or graft loss, and dosages of immunosuppressive medications should be individualized. Children and adolescents who are recipients of simultaneous kidney and pancreas transplants or who have high levels of pre-existing antibodies (as well as those who have undergone unsuccessful transplants in the past) require more intense immunosuppression, and recipients of transplants from well-matched cadaveric donors or from living related donors require significantly less aggressive immunosuppression.

The main goal of immunosuppression is to prevent acute rejection. The latter naturally occurs during the first year, and an episode of rejection is considered to have taken place when it is morphologically confirmed. The severity of acute rejection is assessed using the modified Banff criteria. Subclinical rejection detected by protocol biopsies reaches 9% by 6 months. after transplantation.

One of the objective indicators of the adequacy of immunosuppression is the concentration of calcineurin inhibitors (CNIs) in the blood. A low concentration is accompanied by an increase in the frequency of acute rejection, a high concentration inevitably leads to the development of nephrotoxicity, is a common cause of late renal transplant dysfunction, and has clear morphological signs (Fig. 5).

Due to the fact that the immunological response is maximally expressed during the immediate post-transplantation period and then usually weakens, the entire period after transplantation of any organ can be divided into stages of immunosuppression, each stage corresponding to a special set of immunosuppressants (Table 1). Examples of immunosuppression regimens are presented in Table 2.

Induction therapy (before and during transplantation) is designed to reduce or modulate the T cell response during antigen presentation. For induction therapy use:

Biological agents - antibodies to interleukin-2 (IL-2) receptors - daclizumab or basiliximab, which bind CD25 antigen on the surface of activated T lymphocytes and thereby inhibit lymphocyte activation, which is a decisive phase of the cellular immune response of transplant rejection.
Depleting antibody induction (antithymocyte globulin) is absolutely indicated in patients at high immunological risk or in patients likely to have delayed graft function (extended criteria donors, suboptimal donors), but it should be taken into account that, compared with daclizumab or basiliximab, there is a risk of infections with antithymocyte globulin. and malignant neoplasms are higher.

High immunological risk factors include:

HLA-DR incompatibility;
young age of the recipient;
presence of donor-specific antibodies;
delayed graft function;
cold ischemia time >24 hours.

Initial basic therapy covers the first 3 months. after transplantation, which are characterized by unstable graft function and a high probability of rejection crises. The goal of immunosuppression at this stage is to prevent and treat acute rejection. At the same time, the tactics of immunosuppressive therapy should include reducing the risk of side complications, primarily infectious.

The choice of the initial immunosuppressive therapy protocol is based on an assessment of the immunological status of the recipient and the characteristics of the renal transplant. Therapeutic strategies for initial immunosuppression include a combination of immunosuppressive drugs from several groups: CNIs, antiproliferative agents, corticosteroids.

A CNI (tacrolimus or cyclosporine A) should be started before or during transplantation. In the initial period, it is desirable to quickly achieve the required concentration of immunosuppressive drugs in the recipient’s blood. The sooner it is possible to achieve therapeutic levels of CNI in the blood, the more effective it will be in preventing acute rejection. It is preferable to use tacrolimus as a first-line CNI. Compared with cyclosporine, tacrolimus reduces the risk of acute rejection to a greater extent and increases the duration of graft function.

Corticosteroids have traditionally been considered the mainstay of maintenance immunosuppressive therapy. However, the side effects of corticosteroids have prompted a search for maintenance immunosuppressive therapy options that eliminate or minimize their use.

Minimizing the dose of corticosteroids or their complete withdrawal is recommended only under the following conditions: full induction with antithymocyte globulin, low immunological risk, good graft function, use of tacrolimus as a basic immunosuppressant and the absence of early episodes of rejection during the first 3 months. after transplantation.

One of the important steps in immunosuppressive therapy is the introduction into the practice of clinical transplantology of MMF, the morpholino-ethyl ester of mycophenolic acid (MPA), which is an enzymatic product of the Penicillium fungus. The multifunctional complex was opened in the 1960s. and was initially studied as an antibacterial, antineoplastic and antipsoriatic drug; later it began to be used in transplantology as an immunosuppressant.

MMF selectively and reversibly inhibits inosine monophosphate dehydrogenase (IMPDG), the main enzyme in the synthesis of nucleotides containing the purine base guanine, thereby blocking the proliferation of T and B lymphocytes, the production of antibodies and the generation of cytotoxic T cells. Thus, MMF affects cellular and humoral immunity. Other types of cells, for example, neutrophils, can synthesize purines in an alternative way, so their proliferation is disrupted by MMF to a lesser extent, which determines the high selectivity of action and lower cytotoxicity of MMF.

After oral administration, MMF is completely absorbed from the gastrointestinal tract and is further metabolized during the first passage through the liver to form its active metabolite MPA. The results of many studies have shown the high effectiveness of MMF in combination with cyclosporine or tacrolimus and corticosteroids for the prevention of acute rejection.

Maintenance immunosuppression

Maintenance immunosuppression should ensure maximum life expectancy for the recipient with a functioning transplant, which is determined by the adequacy of suppression of the immune response on the one hand and minimizing the risk of side effects of immunosuppressants on the other.

Maintenance immunosuppression can be divided into two periods. The first (up to 1 year) is a period of early maintenance therapy, when the doses of immunosuppressants are gradually reduced as planned. The second, which continues throughout the life of the transplanted kidney, is the period of maintenance immunosuppression, when the level of immunosuppression is relatively stable and sufficient to prevent rejection while minimizing the risk of complications.

Almost all modern immunosuppressive therapy protocols use mycophenolates. Compared with azathioprine, mycophenolates reduce the risk of acute rejection and increase long-term graft survival. There are two forms of the original MPA formulations: mycophenolate mofetil and enteric-coated mycophenolate sodium, both of which provide adequate levels of immunosuppression and have similar rates of side effects.

Thus, in a study by G. Ciancio et al. There were no differences in the incidence of the first episode of acute graft rejection, as well as in the level of patient survival and graft survival in the first 4 years after transplantation, depending on the form of MFC. In addition, no difference was found in the incidence of gastrointestinal side effects at 4 years after transplantation.

Gastrointestinal side effects with the use of MMF and enteric-coated mycophenolate sodium are associated with both systemic and local effects of MPA and its metabolites. Histological changes in MFC colitis are similar for both drugs. In the clinical guidelines of many countries, as well as in the combined international and European guidelines for kidney transplantation, there is no indication of the preference for the use of any of the MPA drugs. Risk factors for the development of diarrhea in kidney transplant recipients include female gender, diabetes, long-term renal replacement therapy with hemodialysis, genetic predisposition, and latent celiac disease.

Individual selection of immunosuppressive drugs based on the risk profile of the individual patient (risk of acute rejection, side effects) is considered standard practice. Discontinuing or switching individual medications is the standard solution if the benefits (reduction of symptoms) may outweigh the harms (acute rejection). Cases of post-transplant diabetes may be caused or aggravated by corticosteroids, tacrolimus and, to a lesser extent, cyclosporine. In patients with impaired glucose tolerance or in cases of post-transplant diabetes, dose reduction or discontinuation of steroids is advisable. If this is not sufficient, a switch from tacrolimus to cyclosporine A microemulsion should be considered.

Dyslipidemia can be caused by corticosteroids and cyclosporine. In this regard, control of dyslipidemia is mandatory, as is taking statins. Arterial hypertension can be caused by corticosteroids, cyclosporine and, to a lesser extent, tacrolimus. For patients with hypertension despite adequate antihypertensive therapy, reduction or discontinuation of steroids or CNIs is advisable. Myelosuppression may occur with MMF, azathioprine, and dose reduction of MMF or azathioprine is the first step suggested if anemia or leukopenia occurs. None of the immunosuppressive regimens used excludes the development of rejection, the likelihood of which is highest in the first 3 months. after transplantation.

The main cause of allograft loss in the long term after transplantation is progressive chronic graft dysfunction (CPGD). Chronic allograft nephropathy/Interstitial fibrosis and tubular atrophy - CAN/IF) is clinically manifested by increasing proteinuria, decreased graft function, resulting in end-stage chronic renal failure. For timely diagnosis and verification of the causes of renal graft dysfunction, morphological monitoring is necessary, since only special morphological techniques provide complete information about the condition of the allograft (Fig. 2–5). Graft damage assessment is based on the 2005 Banff classification.

Kidney transplant biopsies are performed for specific clinical indications or as part of a surveillance program (protocol biopsies scheduled at predetermined intervals after transplantation, regardless of renal function). A number of studies have shown that protocol biopsy can detect clinically unobvious (subclinical) acute rejection, CNI toxicity, and chronic graft damage (Fig. 2–5).

Treatment of acute transplant rejection

Acute rejection is the result of the recipient's immune response to donor antigens. This condition should be suspected when there is a sharp increase in creatinine levels (20–25% from the initial level) in combination with decreased urination, hardening and tenderness of the graft, as well as fever.

The presented clinical symptoms have low sensitivity and specificity and were characteristic of previously used immunosuppressive regimens. For this reason, at the first stage, other causes of renal transplant dysfunction (vascular, urological) must be excluded, and a biopsy is required to confirm acute rejection. It should be noted that ideally, biopsy should always precede treatment to avoid overdiagnosis of acute rejection.

Treatment of the first episode of rejection

The first episode of acute rejection in most cases is of the nature of acute cellular rejection, sensitive to glucocorticoids. Most protocols suggest glucocorticoid pulse therapy as first-line treatment for acute rejection.

Pulse therapy with intravenous glucocorticoids allows in most cases to stop the rejection crisis. For this, methylprednisolone is used at a dose of 500–1000 mg as an intravenous infusion over 30–60 minutes. (3 days). The maintenance dose of glucocorticoids can be maintained at the same level after completion of pulse therapy. The effectiveness of pulse therapy is assessed on days 2–3 of treatment based on the dynamics of creatinine level recovery. It is believed that on the 5th day after the start of treatment, the creatinine level should return to the original level or even become lower than that recorded at the start of the acute rejection episode. Simultaneously with the therapy, it is necessary to ensure that the concentration of CNI is within the therapeutic range. The dose of mycophenolates should not be lower than recommended. If an episode of acute rejection develops in the presence of adequate cyclosporine concentrations, conversion to tacrolimus may be considered.

Treatment of recurrent and steroid-resistant rejection

Repeated pulse therapy with glucocorticoids may be effective in the treatment of acute rejection, but more than two courses of pulse therapy should not be given before applying antibodies. A recurrent episode of acute rejection is usually severe steroid-resistant acute cellular rejection requiring the use of polyclonal antibody drugs.

It is recommended to start antibody treatment immediately if there is no immediate response to pulse therapy; other protocols suggest waiting for several days. If graft function rapidly deteriorates despite pulse therapy, treatment with antithymocyte immunoglobulin should be started immediately.

The doses at which antithymocyte globulin is used in the treatment of rejection may be higher than induction, and the duration of treatment should be at least 5–7 days. During the course, monitoring of hematological parameters and prophylactic use of ganciclovir for 2–3 weeks is necessary.

Treatment of humoral (antibody-mediated) rejection

The term “refractory rejection” is used to define rejection that continues despite treatment with glucocorticoids and antibodies. Most often it is of a humoral nature.

Repeated courses of treatment with depleting antibodies preserve graft function in 40–50% of recipients. When a decision is made to initiate a second course of antibody therapy, the severity and potential reversibility of rejection based on biopsy data should be carefully assessed, since the risks of developing infectious complications increase significantly as a result of massive anti-crisis therapy, especially if two courses are prescribed with a short interval.

The following alternatives (with or without corticosteroids) are also used to treat antibody-mediated acute rejection:

plasmapheresis;
intravenous administration of immunoglobulins;
antibodies against CD20 - B lymphocytes (rituximab);
lymphocyte-destroying antibodies.

For patients who have episodes of rejection, mycophenolate should be added if the patient is not receiving it.

Treatment of chronic graft damage

Kidney transplant recipients with progressively declining function associated with interstitial fibrosis and tubular atrophy are classified as having chronic rejection or chronic allograft nephropathy. However, HDT can occur as a result of antigen-independent causes, such as diabetes mellitus, hyperlipidemia, arterial hypertension, infections, CNI toxicity, etc.

In all patients with decreased renal function of unknown etiology, it is advisable to undergo a renal allograft biopsy to identify potentially reversible causes. In case of development of CDT and histological signs of CNI toxicity, it is necessary to reduce, discontinue or replace these drugs. A safe treatment option is to replace CNIs with MPA drugs, especially when treating patients during the first 3 years after transplantation. In the presence of proteinuria, administration of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker may help slow the progression of renal failure. Other necessary (supportive) measures include correction of blood pressure, lipidemia, glycemia, anemia, acidosis and treatment of diseases of the skeletal system.

Thus, good long-term results after kidney transplantation can be obtained only with the rational use of modern immunosuppressive therapy, complex drug therapy, timely diagnosis of the causes of allograft dysfunction and pathogenetically based treatment. Kidney transplantation is the treatment of choice for the treatment of end-stage chronic renal failure, as it is associated with lower economic costs, better treatment results and a higher quality of life for patients compared to dialysis.

The list of references is in the editorial office
“Health of Ukraine”, thematic issue “Urology”, June 2015.

Immunosuppressants (IDs) are drugs that inhibit the body as a result of inhibition of the functions of cells of the lymphoid system.

Such drugs include a number of static agents; they have a pronounced antiproliferative effect on cells, i.e., prevents their reproduction. Immunosuppressants are classified into several types:

those that completely suppress the immune response;
have a specific effect;
eliminate reactions that are accompanied by immune processes;
with anti-inflammatory effects.

There are special immunosuppressants aimed at reducing the body's defenses; they can cause inhibition of hematopoiesis, activation of secondary infections and other undesirable effects.

Photo 1. Immunosuppressants are always prescribed during organ transplantation or prosthesis installation. Source: Flickr (Andrew Cunningham)

When are immunosuppressants prescribed?

Immunosuppressants are used to suppress transplant rejection reactions, in the treatment of autoimmune and allergic diseases, and also as antitumor agents.

Medications will help cope with:

rheumatoid arthritis;
lupus erythematosus;
scleroderma;
vasculitis.

Immunosuppressants are prescribed for autoimmune hepatitis, cellular damage to liver or thyroid tissue, thyroid gland, multiple sclerosis, and diabetes mellitus.

The drugs have a selective effect and are used exclusively after transplantation.

This is interesting! In almost all cases, before the introduction of immunosuppressants into practice, patients were not able to transplant the organs of another person, and only with the use of these drugs did transplantation become possible.

Only a doctor should select medications from this group, since the drugs have different compositions and principles of action. Also, many of them can cause side effects.

List of immunosuppressants

There are many IDs, they differ in their composition and the nature of their effect on the body.

Azathioprine

The medication is prescribed to eliminate:

rheumatoid arthritis;
dermatomyositis, periarteritis nodosa;
hemolytic anemia;
gangrenous pyoderma;
psoriasis;
Reiter's syndrome;
Crohn's disease.

The active substance of the immunodeficiency drug is Azathioprine. The medicine is available in tablet form. The effect of the drug occurs when its active substances enter into metabolic reactions and disrupt the synthesis of nucleic acids.

Note! The manifestation of the therapeutic effect of Azathioprine may not be observed for several days or even 2-3 weeks after starting to use the substance. But if within 90 days the patient’s condition does not change for the better, then it is necessary to reconsider the feasibility of using the product.

There are contraindications. It should not be used by people hypersensitive to the active component, and the use of the drug in case of liver failure, pregnancy, breastfeeding, or leukopenia is prohibited. Children are not allowed.

The dosage of the medicine should be determined by the doctor depending on the individual indications of the patient.

Cyclosporine

Cyclosporine ( Cyclosporin) belongs to the polypeptide group, consists of amino acid substances (11 components). Available in the form of an injection solution. The drug has a powerful immunosuppressive effect, inhibits the body's protective functions, and increases the survival time of various types of transplants.

Cyclosporin is used as a prophylactic agent for graft rejection in organ transplantation.

Note! Cyclosporine has high hepatotoxicity, which adversely affects the functioning of the kidneys and liver.

Diclizuma

The drug is used for administration into a central or peripheral vein. 0.001 g per day is usually used per day, the drug is mixed with a solution of sodium chloride. Diclizuma effectively helps with organ transplantation, since it performs the rejection of foreign tissue.

Photo 2. All immunosuppressants should be taken under the strict supervision of a physician. Source: Flickr (Ken Hedlund)

Rules for taking immunosuppressants

Immunosuppressants are used depending on the type and form of the drug. Azathioprine used in organ transplantation. Therapy starts with internal administration of the drug at 0.005 g per day. If the patient has chronic active hepatitis or rheumatoid arthritis, the dose is reduced to 0.0012 g per day. For autoimmune diseases, the amount of the drug is 0.0015 g. The course of therapy is selected individually and lasts as directed by the doctor.

Cyclosporine most often prescribed for intravenous administration. But sometimes it can also be taken orally. For organ transplantation, therapy begins 5 days before surgery. When performing bone marrow transplantation, the drug is administered on the eve of the operation.

The average dose of Cyclosporin is 0.004 g per day. When taken internally, the amount of the drug increases to 0.015 g per day. A prerequisite for using Cyclosporine without causing adverse reactions is that the drug administration procedure must be performed only by qualified doctors.

Adverse reactions and contraindications

Immunosuppressants are medications that are used only when indicated for a specified period of time and under the supervision of a qualified physician.

Serious contraindications are pregnancy, breastfeeding, renal failure, allergies to the components of the drug.

Reactions to medications may manifest as suppression of bone marrow hematopoiesis. Immunosuppressants can also cause:

hemolytic anemia;
nausea;
lack of appetite;
vomit;
stool disorder;
unpleasant feeling in the abdomen;
cholestasis;
malfunctions of the liver.

After use immunosuppressants for organ transplantation Pancreatitis, gastric ulcers, intestinal bleeding, perforation and intestinal necrosis may occur, and with prolonged use – toxic form of hepatitis.

There may be other consequences such as skin rashes, myalgia, and drug fever.

If you take immunosuppressants correctly and follow all recommendations, you will be able to avoid adverse reactions.

To treat rheumatic diseases, cytostatic drugs are sometimes used, in particular azathioprine, methotrexate, cyclophosphamide. These drugs have a relatively rapid and nonspecific cytostatic effect, especially pronounced in relation to rapidly proliferating cells, including lymphoid ones.

The following have been accepted basic rules for immunosuppressive therapy:

reliability of diagnosis;
presence of evidence;
no contraindications;
appropriate qualifications of the doctor;
patient consent;
systematic monitoring of the patient during treatment.

Immunosuppressants are considered “reserve drugs” and are traditionally used last among pathogenetic therapy agents. The reasons for their use are generally the same as for glucocorticosteroids in patients with rheumatoid arthritis, diffuse connective tissue diseases and systemic vasculitis.

Specific indications for immunosuppressive therapy of these diseases are their severe, life-threatening or disabling course, especially with damage to the kidneys and central nervous system, as well as with resistance to long-term steroid therapy, steroid dependence with the need to constantly take too high maintenance doses of glucocorticosteroids, contraindications to their use or poor tolerability of drugs.

Immunosuppressive therapy allows reduce the daily dose of glucocorticosteroids to 10-15 mg of prednisolone or even stop using them. Doses of immunosuppressants should be small or moderate, and treatment should be continuous and long-term. When remission of the disease is achieved, the patient continues to take the drug at a minimum maintenance dose for a long time (up to 2 years).

Contraindications to the use of immunosuppressants include: concomitant infection, including latent and chronic focal infection, pregnancy, lactation, hematopoietic disorders (hemocytopenia).

Among the adverse side effects, common to all immunosuppressants, relate suppression of bone marrow function, development of infections, teratogenicity, carcinogenicity. Based on the severity of side effects, the following sequence of use of immunosuppressants is recommended: azathioprine, methotrexate, cyclophosphamide.

Azathioprine is a purine analogue and belongs to antimetabolites. The drug is prescribed orally at a dose of 2 mg per 1 kg of body weight per day. The therapeutic effect appears 3-4 weeks after the start of therapy. Once a clear improvement is achieved, the dose of the drug is reduced to a maintenance dose of 25-75 mg/day. Among the adverse reactions specific to azathioprine, the most common are hepatitis, stomatitis, dyspepsia, and dermatitis.

Methotrexate- a folic acid antagonist, included, like azathioprine, in the group of antimetabolites. The drug is prescribed orally or parenterally at a dose of 5-15 mg per week (divided into three doses). A positive effect is observed 3-6 weeks after the start of treatment. To avoid kidney damage, it is not advisable to combine methotrexate with non-steroidal anti-inflammatory drugs. Clinical improvement can be achieved by using small doses of methotrexate, which almost do not cause serious complications, which is considered the basis for its administration to patients not only with rheumatoid arthritis, but also with psoriatic arthritis in severe, progressive forms of the disease, resistant to therapy with non-steroidal anti-inflammatory and disease-modifying drugs. Side effects characteristic of methotrexate include ulcerative stomatitis, skin depigmentation, baldness, liver fibrosis, and alveolitis.

Cyclophosphamide refers to alkylating agents and is a highly effective, but most dangerous drug among immunosuppressants. This drug is indicated mainly for the treatment of severe forms of systemic vasculitis, especially Wegener's granulomatosis and polyarteritis nodosa in cases of ineffectiveness of glucocorticosteroids and other drugs. Typically, cyclophosphamide is prescribed orally at 2 mg per 1 kg of body weight per day, but during the first few days it can be administered intravenously at 3-4 mg per 1 kg of body weight. Signs of the therapeutic effect are observed after 3-4 weeks. After stabilization of the clinical picture, the daily dose is gradually reduced to a maintenance dose of 25-50 mg/day. Side effects characteristic of cyclophosphamide include reversible baldness, menstrual irregularities, azoospermia, hemorrhagic cystitis, and bladder cancer. To prevent damage to the bladder, it is recommended, in the absence of indications, to take up to 3-4 liters of liquid prophylactically every day. In case of renal failure, the daily dose of cyclophosphamide is reduced.