Transplant rejection reaction: why it occurs and how to eliminate it. Transplant rejection Severe signs of foreign tissue rejection

The transplant rejection reaction (synonymous with the “host-versus-graft” reaction) is the immune response of the recipient’s body to transplantation, blood transfusion of genetically incompatible blood, bone marrow or organs, which leads to necrosis.

The transplant rejection reaction occurs when tissues or organs are transplanted from one individual to another, which is genetically different from the donor line, which leads to rejection of the biological material. On average, transplant rejection occurs after two weeks. The secondary transplant undergoes faster rejection; the reaction occurs on the fifth to seventh day. The most common is acute graft rejection, which can last from several days to several months. Moreover, the first signs of rejection can appear even after several months and progress rapidly from the moment they appear. Acute rejections are characterized by cell necrosis and dysfunction of various organs. Both humoral and cellular mechanisms are involved in acute rejection. To prevent acute transplant rejection, immunosuppressive drugs are used.

However, there is another type of common rejection called chronic rejection. Chronic rejection occurs in the largest number of transplanted tissues and causes progressive deterioration of organ function over months or years.

The rejection reaction has 2 components:

- specific, which is directly related to the activity of cytostatic T cells.

- nonspecific, which is inflammatory in nature.

The transplantation immune response develops according to the following scheme:

- foreign graft antigens are recognized,

— effectors of the transplantation rejection reaction mature and accumulate in the peripheral lymphoid tissue closest to the transplant

- the graft is destroyed.

During the formation of a reaction to the transplant, activation of macrophages occurs as a result of exposure to T-cell cytokines or as a result of passive sorption of immunoglobulins on the surface of macrophages by analogy with NK cells.

Clinical manifestations of transplant rejection include a feeling of fatigue, fever, hypotension, increased central venous pressure, pericardial friction rub, leukocytosis, supraventricular arrhythmias, and the presence of a gallop rhythm.

Factors limiting tissue transplantation are considered to be immunological reactions against transplanted cells and the presence of appropriate donor organs.

Autotransplantation, namely the transplantation of the host's own tissues from one place to another, does not cause graft rejection. A rejection reaction is not observed during tissue or organ transplantation in monozygotic twins.

Transplantation of avascular grafts also does not cause graft rejection and this is primarily explained by the lack of blood circulation in the graft, which reduces the contact of immune cells with antigens.

As mentioned above, the transplant rejection reaction is an immunological response, and the severity of the reaction increases as the genetic differences that occur between the recipient and the donor grow.

In modern medicine, all human organs are subject to transplantation.

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One of the main reasons for poor outcome after corneal transplantation.

Etiology

Symptoms

Blurred vision, slight discomfort, redness, photophobia, eye irritation, but may be asymptomatic.

Clinical signs

Pericorneal injection of the eyeball, signs of an inflammatory reaction in the anterior chamber.

Subepithelial infiltrates (Kramer spots), epithelial rejection line, precipitates, endothelial rejection line (Khodadoust line) in the donor cornea (Fig. 8-11, A-D).

Edema of the epithelium or stroma, superficial or stromal neovascularization in the donor cornea (Fig. 8-11, E).

Rice. 8-11. Transplant rejection reaction. A, This corneal graft shows multiple subepithelial infiltrates. Usually mistaken for post-viral infiltrates, in reality they are a manifestation of a mild transplant rejection reaction. Although these infiltrates do not cause significant graft damage or visual impairment, they are often a precursor to more severe forms of rejection, such as endothelial rejection, which can cause significant graft damage; B - raised, weakly stained, curved epithelial line on the periphery of the corneal graft along the meridians from 10 to 6 o’clock, representing the line of epithelial rejection, the “front line” between the donor and own epithelium. This type of rejection also usually does not threaten the graft or vision, but does indicate an active immune response with an increased risk of more severe rejection.

Rice. 8-11. Continuation. B — multiple pigmented precipitates on the endothelium of the corneal graft. Mild clouding indicates the presence of moderate corneal edema. The presence of fresh precipitates is a sign of endothelial rejection. Corneal edema indicates endothelial damage. Endothelial rejection should be treated aggressively to preserve as many healthy endothelial cells as possible; G - line of precipitates on the endothelium of the transplant, the so-called endothelial rejection line (Khodadoust line), located along the 2-7 o'clock meridians. These lines tend to move from the periphery to its center and can cross the entire cornea. Note the corneal edema towards the periphery of this line of endothelial rejection. If an endothelial rejection line is present, active therapy is required.

Rice. 8-11. Continuation. D - pronounced diffuse edema of the cornea with multiple precipitates on the endothelium (in the form of a line in the area of the lower edge of the pupil) indicates a developed reaction of endothelial rejection. Conjunctival injection and iritis are common. Treatment is with local and occasionally systemic corticosteroid therapy to conserve as many endothelial cells as possible.

Differential diagnosis

Primary graft rejection: Graft swelling is present from the first day after surgery. No infiltration. Usually associated with poor quality of the donor graft or intraoperative damage to the donor cornea.

Reactivation of herpetic keratitis: rashes in the form of a tree branch, stromal infiltrates, precipitates on the endothelium of the cornea not only of the donor, but also of the recipient. May progress with the use of only glucocorticoid therapy (topically).

Uveitis: Can be confused with early rejection reaction. When in doubt, treat in the same way as a rejection reaction.

Epithelial ingrowth: An advancing line with rounded, scalloped edges on the endothelium of the donor and recipient corneas, with minimal or no corneal edema. Epithelium can grow on the surface of the iris.

Progresses despite intensive corticosteroid therapy.

Treatment

Urgent therapy with local glucocorticoid drugs (prednisolone 1%, dexamethasone 0.1%) every hour for a week, except at night, and reducing the dose to 4 times a day for 3-4 weeks. It is possible to additionally use glucocorticoid ointment 4 times a day.

Additionally, it is possible to use instillations of cyclosporine 1-2% every 2-6 hours.

Initiation of systemic glucocorticoid therapy (prednisolone 1 mg/kg per day 4 times a day) for 2 weeks, then gradually reducing the dose over 1 week, should determine whether there is an insufficient response to local glucocorticoid therapy or recurrent graft rejection.

In the presence of severe iritis, use local cycloplegics (cyclopentolate 1% or scopolamine 0.25% twice a day).

Local antibiotic therapy (erythromycin, bacitracin, tetracycline ointment 2 to 4 times daily) to prevent infection.

Forecast

Very good in case of early diagnosis and treatment; unfavorable if treatment is started 1-2 weeks after the start.

A.A. Kasparov

(ROT) is an immunological process directed against tissues foreign to the body, transplanted during a transplantation operation. It is accompanied by a complex of local (swelling, inflammation) and general (intoxication phenomena, fever, weakness) manifestations, the severity and speed of development of which depend on the type of reaction. Diagnosis is made by studying the clinical picture, histological examination of transplanted tissues, and a number of laboratory and instrumental methods, depending on the type of transplant. Treatment boils down to immunosuppressive therapy, the use of cytotoxic agents, and some drugs are prescribed for life.

General information

Immunological reactions of transplant rejection occur when using allogeneic (transplanted from person to person) or xenogeneic (from animal to person) tissues and organs. Autografts, such as skin transplanted from the thigh to the face, have the same antigenic structure as other body tissues, so they do not cause reactions. Rejection extremely rarely occurs when transplanting avascular structures - the cornea, some cartilage - since in this case there is no contact of foreign tissues with immunocompetent cells. The condition was the most common complication in the early days of transplantation, but has become increasingly rare in recent years, despite an increase in the number of surgeries of this type. This is due to advances in determining the histocompatibility of donor and recipient tissues and the development of more effective methods of immunosuppressive therapy.

Causes of transplant rejection

Antigenic compatibility of tissues is determined by the combination of a number of antigens - first of all, the major histocompatibility complex (six major antigens and a number of minor or minor ones). In addition, other protein antigenic complexes (AB0, connective tissue proteins) can also have an effect. In many ways, rejection reactions are similar to the normal immune response when foreign antigens enter the body or (in some cases) hypersensitivity reactions of types 2 and 3. Humoral and cellular mechanisms of immunity take part in their development. The rate of occurrence of pathological changes in the graft depends on the type of reaction, the activity of the recipient’s immune system, and the magnitude of the antigenic differences between the tissues.

The cause of fulminant types of transplant rejection is sensitization of the recipient's body, as a result of which, during transplantation, processes similar to intolerance reactions occur with the formation of immune complexes and activation of the complement system. More common acute types of immunological reactions to transplanted tissues usually develop due to incompatibility with MHC antigens; a predominantly cellular immune response is involved in the pathogenesis. Chronic forms of ROT are caused by both cellular and humoral reactions; they are often caused by incorrect immunosuppressive therapy prescribed after surgery.

Pathogenesis

The pathogenesis of transplant rejection differs in different forms of this condition. Hyperacute or lightning-fast reactions are caused by the body’s sensitization to the antigens of the transplanted organ, and therefore occur as an intolerance or allergy. When allograft tissue comes into contact with the recipient's blood, the formation of immunocomplexes is stimulated, settling on the inner surface of the vessels. They provoke activation of the complement system, severely damaging the endometrium of the transplant vascular network, which causes the formation of multiple microthrombi and vascular embolization. This leads to ischemia of the transplanted tissues, their swelling, and, in the absence of therapeutic measures, to necrosis. The rate of development of pathological processes is only a few hours or days.

Acute and chronic types of ROT are based on the processes of the cellular immune response, so such reactions develop somewhat more slowly - over several weeks. In case of antigenic incompatibility of the graft and recipient tissues against the background of adequate or increased immune activity, recognition of foreign cells by macrophages and T-lymphocytes (helpers or inducers) occurs. The latter activate killer T cells, which secrete proteolytic enzymes that destroy the cell membranes of allograft structures. The result is the development of an inflammatory reaction in the transplanted organ, the severity of which depends on the level of activity of the immune system. With a long-term process, it is possible to involve humoral immune factors with the synthesis of specific antibodies directed against transplant antigens.

Classification

There are several forms of the rejection reaction, differing in the speed of development and a number of clinical manifestations. The reason for this difference is different types of ROT, which have different rates of occurrence, as well as predominant damage to certain graft structures. Knowing the approximate timing of the formation of a particular type of immune response, a specialist can determine its nature and prescribe the optimal treatment. In total, there are three main clinical forms of graft tissue intolerance reactions:

Lightning-fast or ultra-sharp. It occurs in the first minutes or hours after the transplanted organ is “connected” to the recipient’s systemic bloodstream and is caused by the latter’s sensitization to the transplant antigens. It is characterized by massive microcirculatory disorders with ischemic phenomena in the allograft and the development of necrosis, while inflammation is secondary.
Spicy. Registered during the first three weeks after transplantation, the pathogenesis is based on the cellular immune response when the donor and recipient are incompatible. The main manifestation is the development of inflammatory processes in the transplanted tissues, their severity depends on the activity of the immune system.
Chronic. It occurs several months after transplantation, can be recurrent, and is highly dependent on the immunosuppressive therapy regimen. It develops through both cellular and humoral mechanisms of the immune response.

Symptoms of transplant rejection

All manifestations of allograft rejection are divided into systemic, depending only on the pathogenesis of the process and the reactivity of the immune system, and local, associated directly with the transplanted organ or tissue. Among the general symptoms, there is always an increase in temperature, chills, and fever of greater or lesser severity. Manifestations of general intoxication are recorded - headache, nausea, vomiting, decreased blood pressure. Symptoms of intoxication of the body sharply intensify with the development of necrosis processes in the graft; in severe cases, against this background, toxigenic shock may occur.

Local manifestations of ROT are associated with the transplanted organ, and therefore may vary in different patients. When transplanting a whole organ, symptoms caused by dysfunction of its function come to the fore - for example, cardialgia, arrhythmias, heart failure during heart transplantation. Acute renal failure may be associated with a rejection reaction of a transplanted kidney, hepatic failure - with the liver. When allotransplantation of a skin flap occurs, it becomes swollen, red, even purple, and a secondary bacterial infection is possible. The timing of the appearance of local and general symptoms of rejection depends on its form - the fulminant type is characterized by a severe reaction within 2-3 hours after transplantation, while acute and chronic types can appear after several weeks or even months.

Complications

The earliest and most severe complication of the reaction of rejection of transplanted tissue is the development of shock associated with immunological processes or caused by intoxication of the body. Necrosis and tissue damage of a transplanted organ, the work of which is vital for the body (for example, the heart), often leads to death. Some experts also consider infectious diseases caused by enhanced immunosuppressive therapy to be complications of ROT. In the long term, against the background of an artificial decrease in the activity of cellular immunity, the development of cancer is possible.

Diagnostics

A feature of diagnosing a transplant rejection reaction is the need for it to be carried out as quickly as possible, which allows not only to improve the patient’s condition, but also to preserve the transplanted organ. Some researchers include in the diagnosis of ROT a number of immunological studies performed before surgery at the stage of donor selection - typing the spectrum of transplantation antigens, determining the biological compatibility of tissues. High-quality performance of these tests allows you to avoid the development of a hyperacute reaction and significantly reduce the likelihood of other forms of rejection. Among the diagnostic procedures performed after transplantation, the most informative are the following:

Laboratory research. During the rejection process, a general blood test will reveal signs of nonspecific inflammation - lymphocytosis, an increase in ESR. A study of the immune status makes it possible to detect immune complexes, an increase in the level of complement components (in fulminant forms), and immunoglobulins. Under the influence of immunosuppressive therapy, test results may be distorted, which must be taken into account when interpreting them.
Instrumental research. Instrumental diagnostic methods (radiography, ultrasound, ultrasound, CT, MRI) are used to assess the functional activity and structure of the transplant - kidney, liver, heart, lung. In general terms, ROT is manifested by swelling of the organ, disruption of its functioning, and the presence of circulatory disorders (ischemia, infarction, necrosis). In chronic and recurrent types of reaction, areas of sclerosis can be detected in the graft structure.
Histological studies. Biopsy of allograft tissue and their subsequent histological and histochemical study is the gold standard in determining ROT. With the fulminant type of reaction, the biopsy specimen reveals damaged capillaries, perivascular edema, signs of ischemia and tissue necrosis, biochemical studies determine immune complexes on the surface of the endometrium. In chronic or acute types of rejection, lymphocytic infiltration of the graft tissue and the presence of areas of ischemia and sclerosis are detected.

Approaches to diagnosing rejection reactions may vary depending on the specific transplanted organ. For example, during kidney transplantation, general and biochemical urine analysis, ultrasound examination and other ultrasound examinations of the organ are indicated, with caution - excretory urography. In case of heart transplantation, electrocardiography, echocardiography, and coronary angiography are necessary.

Treatment of transplant rejection

Treatment of ROT consists of reducing the activity of the immune response; the development of the most effective methods is still ongoing. An immunologist in collaboration with a transplantologist is involved in drawing up a treatment regimen. The development of immunological tolerance to allograft antigens is considered a promising technique, but its mechanisms are quite complex and have not yet been sufficiently studied. Therefore, practically the only method of treatment and prevention of rejection is nonspecific immunosuppressive therapy, carried out by several groups of drugs:

Steroid drugs. This group includes prednisolone and its derivatives, dexamethasone and other drugs. They reduce the rate of lymphocyte proliferation, are antagonists of many inflammatory factors, and effectively reduce the severity of the immune response. In some cases, a course of use of these drugs after transplantation is prescribed for life.
Analogues of nitrogenous bases. These drugs are able to integrate into the process of nucleic acid synthesis and inhibit it at a certain stage, reducing the rate of formation of immunocompetent cells and the severity of rejection processes. For preventive purposes, they are used soon after organ transplantation.
Alkylating agents. A group of drugs that can attach to the DNA of cells and block their division. Medicines are used for acute forms of this condition due to their rapid and reliable cytotoxic effect.
Folic acid antagonists. Vitamin B9 is involved in the synthesis of certain nitrogenous bases and the proliferation of lymphocytes; its antagonists slow down the development of the immune response during ROT. The drugs are used for chronic forms of reaction as part of complex therapy.
Antibiotics. Some drugs in this group (cyclosporine, chloramphenicol) block RNA synthesis, inhibiting both cellular and humoral immune responses. Sometimes used for life after transplantation to prevent rejection.

According to indications, other medications may be prescribed to improve the patient’s condition - detoxification drugs, diuretics, cardiac stimulants, anti-inflammatory and antipyretic drugs. In case of severe complications (shock, acute cardiac or renal failure), resuscitation measures and hemodialysis are necessary. When an infection occurs against the background of immunosuppression, timely administration of antibiotics, antifungal or antiviral (taking into account the nature of the pathogen) agents is required.

Prognosis and prevention

The prognosis for fulminant types of transplant rejection is unfavorable in almost 100% of cases - surgery to remove the transplanted organ, selection of a new donor and re-transplantation are required. At the same time, the risk of developing ROT during a secondary transplant increases several times. Timely initiation of immunosuppression in acute or chronic variants of the condition often allows preserving the allograft, but increases the risk of infectious complications and the likelihood of cancer in the future. An effective prevention of rejection is careful selection of a donor for transplantation, checking compatibility for all possible antigenic systems - especially for MHC; at least 4 of the 6 main alleles must be compatible. The presence of a direct blood relationship between the donor and recipient sharply reduces the likelihood of developing pathology.

RCHR (Republican Center for Health Development of the Ministry of Health of the Republic of Kazakhstan)
Version: Clinical protocols of the Ministry of Health of the Republic of Kazakhstan - 2014

Presence of a transplanted kidney (Z94.0), Death and rejection of a kidney transplant (T86.1), End-stage renal disease (N18.0)

Transplantology

general information

Short description

Expert Council of the Republican State Enterprise at the Republican Exhibition Center "Republican Center for Healthcare Development"

Ministry of Health and Social Development of the Republic of Kazakhstan

Kidney transplant rejection- a complex of immunological and clinical reactions that occur in the post-transplantation period in response to the interaction of the recipient’s body and the donor’s organ, characterized by graft dysfunction.

Graft dysfunction- a condition characterized by the appearance of a symptom complex that includes all pathological manifestations of renal failure.

I. INTRODUCTORY PART

Protocol name: Renal transplant rejection crisis

Protocol code:

ICD-10 code

N 18.0 Terminal chronic renal failure

Z 94.0 Presence of a transplanted kidney

T 86.1 Death and rejection of a kidney transplant

Abbreviations used in the protocol:

BP - blood pressure

ALT/AST - alanine transferase/aspartate transferase

APTT - activated partial thromboplastin time

VAR MS - congenital anomalies of the urinary system

EBV - Epstein-Barr virus

GGTP - gammaglutamyl transpeptidase

DIC - disseminated coagulation syndrome

DSA - donor-specific antibodies

IPTG - intact parathyroid hormone

ISP - immunosuppressive drugs

MK - mycophenolic acid

MMF - mycophenolate mofetil

INR - international normalized ratio

CBC - complete blood count

OAM - general urine analysis

PT - prothrombin time

PTH - parathyroid hormone

PCR - polymerase chain reaction

Radiography of the chest organs - radiography of the chest organs

GFR - glomerular filtration rate

ABPM - 24-hour blood pressure monitoring

CRP - C-reactive protein

ESRD - end-stage chronic renal failure

Doppler ultrasound

Ultrasound - ultrasound examination

CKD - chronic kidney disease

CVP - central venous pressure

ALP - alkaline phosphatase

ECG - electrocardiogram

EchoCG - echocardiography

Date of development of the protocol: year 2014.

Protocol users: nephrologists, transplantologists, anesthesiologists-resuscitators, surgeons, urologists, therapists, general practitioners, emergency physicians.

Classification

Clinical classification

By development time:

Hyperacute rejection - in the first hours after transplantation;

Accelerated rejection - 12-72 hours after transplantation;

Acute rejection - after 72 hours after transplantation;

Chronic rejection (see KP Chronic transplantation nephropathy).

Banff classification, 2007:

I Norm;

II Antibody-mediated changes;

III Boundary changes;

IV T-cell mediated rejection;

V Interstitial fibrosis and tubular atrophy;

VI Other changes.

A. Hyperacute rejection;

B. Acute transplant rejection;

1. Acute cellular rejection;

A. Tubulo-interstitial;

B. Endoarteritis;

C. Glomerular (acute graft glomerulopathy);

2. Acute humoral rejection;

A. Capillary (peritubular +/- glomerular);

B. Arterial (fibrinoid necrosis).

Diagnostics

II. METHODS, APPROACHES AND PROCEDURES FOR DIAGNOSIS AND TREATMENT

List of basic and additional diagnostic measures

Basic (mandatory) diagnostic examinations performed on an outpatient basis:

General blood test (determination of hemoglobin, erythrocytes, leukocytes, platelets, hematocrit, ESR);

Biochemical blood test (determination of total protein, creatinine, urea, potassium/sodium, glucose, bilirubin, ALT, AST);

Determination of bleeding duration, blood clotting;

Ultrasound of the graft;

Radiography of the chest organs (one projection).

Additional diagnostic measures carried out at the outpatient level:

Biochemical blood test (determination of phosphorus, iron, ferritin, amylase, cholesterol, lipoproteins, alkaline phosphatase, uric acid, albumin, protein fractions, C-reactive protein, serum iron, calcium, phosphorus, potassium, sodium, bilirubin);

Determination of cytomegalovirus, herpes types 1 and 2, Epstein-Barr virus, toxoplasma, candida in the blood by ELISA;

HIV ELISA;

ELISA for syphilis;

Bacteriological examination of biomaterials (urine, sputum, throat swab);

Determination of quantitative PCR for hepatitis B, C, D

Determination of tumor markers using ELISA;

Echocardiography;

Doppler ultrasound of graft vessels;

Cystoscopy (diagnostic);

Colonoscopy;

Computed tomography with contrast;

BP profile;

Ultrasound of the abdominal organs;

Anthropometry, BMI calculation.

Minimum list of examinations required when referring for planned hospitalization: not carried out

Basic (mandatory) diagnostic examinations carried out at the hospital level:

Complete blood count with platelet count;

Determination of blood group;

General urine test (if diuresis is present);

Biochemical blood test (determination of total protein, albumin, creatinine, urea, potassium, sodium, phosphorus, calcium, glucose, bilirubin, ALT, AST, C-reactive protein);

Coagulogram (APTT, PTT, INR, fibrinogen);

Determination of the basic concentration of the immunosuppressive drug -C0 (cyclosporine A, tacrolimus) in the blood;

Determination of cytomegalovirus, herpes type 1 and 2 in the blood by ELISA;

Ultrasound of the graft;

Doppler ultrasound of renal transplant vessels;

Radiography of the chest organs (one projection);

Determination of the concentration of tacrolimus/cyclosporine A in the blood.

Additional diagnostic examinations carried out at the hospital level:

Calculation of GFR;

BMI calculation;

Biochemical blood test (determination of alkaline phosphatase, GGTP, iron, protein fractions, test for glucose tolerance of amylase, cholesterol, uric acid);

Determination of parathyroid hormone, ferritin in the blood by ELISA;

Blood ELISA for Epstein-Barr virus, toxoplasma, candida IgG/IgM;

Blood ELISA for HIV;

Determination of markers of hepatitis B (HBsAg) and C (anti-HCV) by ELISA;

Determination of quantitative PCR for cytomegalovirus, herpes types 1 and 2, Epstein-Barr virus (with positive Ig M);

Determination of herpes simplex virus types 6, 8, polyomavirus, parvovirus, Pneumocystis IgG/IgM by ELISA;

Determination of procalcitonin by ELISA;

Immunogram (determination of immunoglobulins of classes A, M, G, the number of subpopulations of T- and B-lymphocytes) by ELISA;

Determination of the two-hour concentration of the immunosuppressive drug -C2 (cyclosporine A, tacrolimus) in the blood;

Determination of Decoi cells in urine;

Urinalysis according to Nechiporenko;

Ultrasound of the abdominal organs (kidneys, liver, gall bladder, spleen, pancreas) and pleural cavities, pelvic organs in women, prostate, bladder;

Vaccine cystography;

Survey urography;

Cystoscopy (therapeutic and diagnostic);

Echocardiography;

Radioisotope renography of the graft;

Osteodensitometry;

Bacteriological examination of biomaterials (urine, blood, sputum, throat swab, rinsing water, discharge from a wound, from a catheter);

Examination of biomaterials (urine, blood, sputum, throat swab, washing water) for fungi;

Thromboelastogram;

Determination of donor-specific antibodies by ELISA and PCR;

MRI/CT of the thoracic, abdominal segments, pelvis (according to indications);

Percutaneous biopsy with histological examination of the biopsy;

Fiberoptic bronchoscopy;

Pleural puncture with cytological examination of punctate;

Examination of sputum (punctate) for Mycobacterium tuberculosis.

Determination of daily proteinuria;

Determination of acid base and blood gases.

Diagnostic measures carried out at the stage of emergency care:

Collection of complaints and medical history;

Physical examination.

Diagnostic criteria

Complaints and anamnesis

Complaints:

General malaise, weakness;

Decreased performance;

Decreased appetite;

Headache;

Sleep disturbance;

Decreased amount of urine/absence of urine;

Skin itching;

Temperature increase;

Cough;

Dyspnea;

Nausea, vomiting;

Induration/bulging/pain in the graft area.

Anamnesis:

Previous surgery - kidney transplantation;

The presence of concomitant/background somatic pathology (long-term diabetes mellitus and/or arterial hypertension, primary and/or secondary kidney diseases (glomerular, tubulointerstitial, VARMS), systemic diseases, corrective operations on the urinary system).

Hypothermia factor;

The presence of viral hepatitis, viral, fungal and/or bacterial infection.

Physical examination:

Objectively: moderate or severe general condition, pallor of the skin and mucous membranes, skin rashes, herpes on the lips, papillomas on the skin, hemorrhages, petechiae, hyperthermia, swelling, sudden weight loss, shortness of breath, increased body temperature, dry or cough sputum, enlarged lymph nodes, the presence of enlarged tonsils, dullness of pulmonary sound, weakening of vesicular breathing, the presence of dry, crepitant and/or moist rales, cardiac arrhythmias, hypertension, hypotension, scratch marks on the skin, enlarged borders of the heart, accent of 2 tones over the aorta , pulmonary artery, systolic murmur at the apex of the heart, enlarged liver, spleen, increased graft size, compaction, pain on palpation, the presence of an arteriovenous fistula, subclavian catheter, postoperative suture, drainage tube.

Laboratory research:

General blood analysis:

Renal anemia (hypochromic)/decreased hemoglobin level:

Below 125 g/l in women;

Below 135 g/l in men;

Decrease in the level of leukocytes, platelets, red blood cells;

Leukocytosis with a shift to the left;

Impaired blood clotting ability;

Increasing ESR;

Acidosis (pH< 7,37);

Hyperkalemia (potassium > 7 mmol/l);

Hypokalemia - a decrease in potassium below 3.0 mmol/l;

Calculation of GFR: decrease in GFR below 90 ml/min.

Blood chemistry:

Uremia—increased creatinine levels above 97 µmol/l in women, 115 µmol/l in men, or an increase over time compared to the initial level;

Increase in blood urea by 3-5 mmol/l per day from the initial level;

Hyperkalemia - an increase in blood potassium above 7 mmol/l;

Hypokalemia - a decrease in blood potassium below 3.5 mmol/l;

Violation of phosphorus-calcium metabolism (hypocalcemia, hyperphosphatemia above 1.76, elevated parathyroid hormone levels above 300), hypophosphatemia);

Hypoproteinemia - a decrease in total blood protein below 60 g/l;

Hypoalbuminemia - less than 35 g/l;

Proteinuria - daily protein loss greater than 1 g/day;

Hyposthenuria - a decrease in the specific gravity of urine below 1018;

Bacteriuria, pathological urinary sediment (leukocyturia, hematuria, cylindruria).

Instrumental studies

Kidney ultrasound:

Reduction in kidney size (except for diabetic nephropathy, kidney transplant and polycystic kidney disease).

Ultrasound of the abdominal and pleural cavities:

Diffuse changes in the tissue of the liver and pancreas, hepatosplenomegaly, ascites, the presence of fluid in the cavities.

Doppler ultrasound of renal vessels:

Decrease/absence of linear blood flow velocities, increase in resistance indices of more than 0.7.

Ultrasound of the graft:

Increased graft volume, expansion of the collecting system, expansion of the ureter, the presence of effusion in the perinephric space, lymphocele, pathological formations, cavities, fistulas, stones, microliths, urinary tract fistulas, expansion of the collecting system, swelling (hypoechogenicity) of the renal tissue, symptom "prominent pyramids". Doppler ultrasound of renal transplant vessels - decrease/absence of linear blood flow velocities, increase in resistance indices of more than 0.7, presence of avascular

Zones larger than 0.3 cm, decreased or absent arterial blood flow in diastole, the appearance of reverse blood flow in diastole (a sign of severe rejection).

ECG:

Signs of hypertrophy of the atria and/or ventricles of the heart, hyperkalemia, conduction disorders, myocardial dystrophy.

Ophthalmoscopy:

Hypertensive, diabetic retinopathy, the presence of stasis, plethora, petechiae, hemorrhages.

EchoCG:

Signs of heart failure (HF)<60%), снижение сократимости, диастолическая дисфункция, легочная гипертензия, пороки и регургитации клапанов.

ABPM:

Increased blood pressure, changes in the circadian rhythm of blood pressure.

FGDS:

Uremic gastropathy: signs of esophagitis, gastritis, bulbitis, duodenitis (superficial, catarrhal, erosive, ulcerative).

Colonoscopy:

Uremic colitis, the presence of ulcers, hemorrhoids, polyps.

Cardiovascular research:

Arterial hypertension, arterial hypotension, arrhythmias. X-ray of the lungs:

Hydrothorax, congestive pneumonia, signs of pulmonary edema/pre-edema, lobar/hilar/subtotal/total pneumonia, bronchitis, presence of cavities, formations.

Densitometry:

Signs of osteodystrophy (decreased bone mineral density).

Vaccination urography: signs of vesicoureteral reflux.

Cystoscopy: signs of cystitis, bladder stones.

Survey urography: nephroptosis, presence of stones, formations.

FEGDS:

Uremic gastropathy, duodenitis, ulcers, erosions, gastroesophageal reflux disease, education.

Radioisotope renography of the graft: decreased/absent graft perfusion.

MRI/CT of the thoracic, abdominal segments, pelvis:

Enlarged lymph nodes, cavities, pathological formations, threads, fungal mycelium, effusion, lymphocele, fistulas.

Biopsy with histological examination of the biopsy sample: signs of cellular or humoral rejection, tubulointerstitial fibrosis, signs of intoxication with calciumneurin inhibitors, autoimmune complexes, immunofluorescence, viral inclusions, stasis, thrombosis, petechiae, tubular atrophy, tubulitis, arteritis, interstitial inflammation.

Fiberoptic bronchoscopy: signs of bronchitis, bronchiectasis.

Indications for consultation with specialists:

Cardiologist - for the correction of persistent hypertension, chronic heart failure, cardiac arrhythmias.

Ophthalmologist - for diagnosing angiopathy, cataracts.

Neurologist - for the treatment of uremic encephalopathy.

Psychologist - for diagnosis and correction of psychological disorders (depression, anorexia, etc.).

Anesthesiologist - if it is necessary to catheterize a central vein for hemodialysis/preparation for surgery.

Hepatologist - for the diagnosis and treatment of viral hepatitis.

Hematologist - in order to exclude hematological diseases with the development of leukemoid reaction, cytopenia, development of DIC syndrome.

Thoracic surgeon - to determine indications and perform pleural puncture.

Endocrinologist - for diagnosis and correction of treatment of diseases of the endocrine system (diabetes mellitus, primary and secondary hyperaldosteronism, hyperparathyroidism, etc.)

Otorhinolaryngologist - to diagnose and treat inflammation of the paranasal sinuses.

Psychiatrist - for the correction of acute mental disorders.

Differential diagnosis

Other causes of renal graft dysfunction (vascular, surgical, urological) must be excluded.

Treatment abroad

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Treatment

Treatment goals:

Restoring or improving graft function;

Transplantectomy according to indications.

Treatment tactics

Treatment tactics for a kidney transplant rejection crisis include:

Correction (decrease/increase) doses of immunosuppressive drugs;

Conversion (replacement) and/or use of additional immunosuppressive drugs (as indicated);

Conducting plasmapheresis;

Diagnostic graft biopsy;

Carrying out pulse therapy with corticosteroids/treatment with intravenous immunoglobulin/antilymphocyte antibodies (ATG/OCT3);

Antibacterial, antiviral, antifungal and symptomatic therapy;

Transplantectomy (if the measures taken are ineffective and there are indications).

Dose adjustment of immunosuppressive drugs is carried out under the control of the concentration of the level of immunosuppressants in the blood according to target concentrations (see KP Management of the recipient after kidney transplantation) taking into account the background and concomitant pathology. In the presence of an active, life-threatening infection, it is allowed to reduce the doses of calcineurin inhibitors (cyclosporine/tacrolimus) and short-term (for 2-3 days) withdrawal of MMF/MK.

Conversion and/or use of additional immunosuppressive drugs is performed in the presence of complications from taking ISP, as well as in the development of resistance to standard immunosuppressive therapy regimens, in order to enhance and/or prolong the immunosuppressive effect.

The presence of diarrhea that does not stop after reducing the dose of MMF is an indication for conversion from MMF (Cellcept) to MK (Mayfortic), and the dose of MK after conversion should be standard (1440 mg/day). If a rejection crisis is diagnosed while taking cyclosporine (Sandimmune-Neoral), the issue of conversion to tacrolimus (Prograf) or long-acting tacrolimus (Advagraf) is considered. In case of severe toxicity of calcineurin inhibitors and the risk of developing oncopathology, there are indications for conversion to everolimus (Certican).

The inclusion of methylprednisolone/oral prednisolone in the treatment regimen following prior drug withdrawal is considered as an additional IPI.

To obtain an adequate immunosuppressive effect, target levels of ISP concentrations while minimizing the risk of side effects and adverse events, it is preferable to use the original forms of ISP.

Plasmapheresis indicated in the presence of diagnosed antibody-mediated (humoral) rejection. Assigned 3-10 times. It is advisable to monitor the level of donor-specific antibodies.

Diagnostic graft biopsy is carried out before prescribing aggressive immunosuppressive therapy - pulse therapy with corticosteroids/treatment with intravenous immunoglobulin/antilymphocyte antibodies (ATG/OCT3).

Technique of graft biopsy.

The graft biopsy is performed by a trained specialist with the assistance of an experienced radiologist under ultrasound or CT guidance. The area where the biopsy needle is inserted is numbed with a local anesthetic. The use of tomography allows one to determine the exact location of the pathological formation and the safest route for needle insertion. Once the lesion is located, the needle insertion point is marked with a marker. Hair is carefully removed from the skin, it is disinfected, and a sterile surgical drape is applied. A minor puncture of the skin is made at the site where the biopsy needle is inserted. Using imaging guidance, the doctor inserts a needle through the skin, advances it to the suspicious area, and removes a tissue sample. A complete analysis may require several samples. After the procedure is completed, the needle is removed, bleeding is stopped, and a pressure bandage and ice are applied to the wound. Sometimes stitches are required. For several hours after the biopsy, the patient is under the supervision of medical personnel and remains in bed. To monitor possible complications, a visual assessment of urine for gross hematuria and a laboratory study of TAM are performed, and the next day a control ultrasound of the graft is performed to exclude hematoma.

Pulse therapy with corticosteroids/treatment with intravenous immunoglobulin/antilymphocyte antibodies (ATG/muromonab CD3)

Treatment of Acute Cellular Rejection Rejection

GCS pulse therapy regimens:

500-1000 mg, single dose of methylprednisolone intravenously for 30-60 minutes for 3 days in a row;

120-250 mg prednisolone orally for 3-5 days.

After pulse therapy, the maintenance dose of GCS can be maintained at the same level after completion of pulse therapy, or their dose can be increased followed by a rapid decrease. Co-trimoxazole prophylaxis should also be resumed for 3–6 months. During the period of pulse administration of GCS, it is necessary to temporarily discontinue oral GCS.

The effectiveness of GCS pulse therapy is assessed on the 2-3rd day of treatment based on the dynamics of creatinine level recovery. If on the 5th day after pulse therapy the creatinine level has not returned to the initial level from the beginning of the acute rejection episode, a repeat puncture biopsy is performed with a morphological assessment. It is necessary to monitor the concentration of calcineurin inhibitors within the therapeutic range with dose adjustment of ISP. After treatment, the dose of MMF should not be lower than 2 g/day, MK should not be lower than 1440 mg/day. If an episode of acute rejection develops in the presence of adequate cyclosporine concentrations, conversion to tacrolimus may be considered.

Antilymphocyte antibodies can stop more than 95% of the first episodes of rejection.

Intravenous immunoglobulin applied according to the scheme 0.5-1.5 g/kg/day for 3-14 days.

Treatment of recurrent and steroid-resistant rejection

The method of choice for the treatment of steroid-resistant severe cellular rejection is the administration of antithymocyte antibodies (Thymoglobulin). A recurrent episode of acute rejection is usually severe steroid-resistant acute cellular rejection requiring the use of polyclonal antibody drugs. Approximately 50% of cases show signs of acute humoral rejection. The development of repeated rejection is accompanied by a worsening long-term prognosis for graft survival.

Repeated pulse therapy with GCS can be effective in the treatment of acute rejection, but more than two courses of pulse therapy should not be prescribed before using antibodies. Many protocols suggest antibody treatment for all recurrent rejections except those that are ongoing.

Beneficial or develop at least several weeks after the first episode.

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 renal function rapidly deteriorates despite pulse therapy, treatment with antithymocyte immunoglobulin (Thymoglobulin) should be started immediately.

The doses at which antithymocyte globulin is used in the treatment of rejection may be higher compared to induction, and the duration of treatment should be at least 5-7 days. During the course of treatment, monitoring of hematological parameters and prophylactic use of ganciclovir for 2-3 weeks is necessary. Switching from cyclosporine to tacrolimus or adding mycophenolates in patients who have not previously received them may also be indicated after recurrent episodes of rejection.

Treatment of humoral (antibody-mediated rejection)

The term “refractory rejection” is used to define rejection that continues despite treatment with corticosteroids and antibodies. Most often it is of a humoral nature. Treatment of such patients is extremely difficult. Repeated courses of treatment with depleting antibodies allow maintaining graft function in 40-50%. When a decision is made to initiate a second course of antibody therapy, the severity and potential reversibility of rejection based on biopsy data, the risks of infectious complications and malignancy, which increase significantly as a result of massive anti-crisis therapy, should be assessed, especially if two courses are prescribed with a short interval.

A marker of activation of the complement system is the formation of the C4d fragment of complement, which does not have its own functional activity, but covalently binds to kidney tissue. It has been shown that C4d fluorescence in the wall of peritubular capillaries closely correlates with the appearance of anti-donor antibodies in the patient’s serum. Thus, acute humoral rejection can be diagnosed and considered reliable if four criteria are met:

Deterioration of renal function;

Fixation of C4d in the wall of peritubular capillaries;

Histological signs of damage to renal tissue;

Identification of donor-specific anti-HLA antibodies.

If only two of the listed criteria are present, the diagnosis is considered probable, but not reliable.

Antibacterial, antiviral, antifungal and symptomatic therapy- see KP Management of the recipient after kidney transplantation.

Transplantectomy

Indications for transplantectomy:

Ineffectiveness of ongoing activities;

Infectious complications;

Constant pain syndrome;

Threat to the life of the recipient.

Non-drug treatment:

Mode

Mode 2 - for moderate severity of the condition.

Mode 1 - in severe condition.

Strict adherence to the rules of asepsis and antisepsis is necessary.

Diet

The goal of diet therapy is to correct malnutrition.

Principles of diet therapy:

The calorie content of the daily diet for the period of treatment should be 3000-3500 kcal/day.

The diet should be as balanced as possible in terms of the amount of proteins, fats, carbohydrates, vitamins, macro- and microelements, and liquid.

The total amount of carbohydrates in the diet should be 45-50%, with a limit on rapidly absorbed refined sugars and an increase in dietary fiber. Preference should be given to products of plant origin (cereals, vegetables, fruits).

Preference should be given to proteins of animal and plant origin (lean meat, poultry, dairy products, legumes, etc.).

It is necessary to consume foods rich in vitamins and microelements: folic acid, vitamins B, C, L-carnitine, etc.

Patients should be taught to calculate daily energy requirements using tables.

If independent nutrition is insufficient and there is a pronounced BMI deficiency, take into account feeding through a nasogastric tube.

Drug treatment

Drug treatment provided on an outpatient basis: no.

Drug treatment provided at the inpatient level

. Corticosteroids and synthetic analogues:

Methylprednisolone, powder for the preparation of solution for injection complete with solvent 4 ml in a two-capacity bottle 250 mg;

Methylprednisolone, powder for the preparation of solution for injection in a bottle complete with a solvent 15.6 ml in a 1000 mg bottle;

Methylprednisolone, powder for the preparation of solution for injection in a bottle complete with a solvent 7.8 ml in a 500 mg bottle;

Methylprednisolone, tablets in a bottle 4 mg;

Methylprednisolone, tablets in a bottle 16 mg;

Methylprednisolone, tablet 4 mg, 16 mg;

Dexamethasone, solution for injection 0.4%;

Prednisolone, solution for injection 25 mg/ml, 30 mg/ml;

Prednisolone, tablet 0.005 g.

. Immunosuppressive drugs:

Cyclosporine A, capsules 100 mg;

Cyclosporine A, capsules 50 mg;

Cyclosporine A, capsules 25 mg;

Sandimmune-neoral, bottle solution 100 mg/1 ml;

Tacrolimus, capsules 0.5 mg;

Tacrolimus, capsules 1 mg;

Tacrolimus, ampoule 5 mg/1ml;

Tacrolimus extended release, capsules 0.5 mg;

Tacrolimus extended release, capsules 1 mg;

Mycophenolate mofetil, capsules 250 mg;

Mycophenolic acid, tablets 180 mg;

Mycophenolic acid, tablets 360 mg;

Rabbit anti-thymocyte immunoglobulin, lyophilisate for the preparation of solution for infusion 25 mg;

Rituximab, concentrate for the preparation of solution for intravenous infusion in a 100 mg/10 ml vial;

Rituximab, concentrate for the preparation of solution for intravenous infusion in a 500 mg/50 ml 50 ml bottle;

Everolimus, tablet 0.25 mg;

Everolimus, 0.75 mg tablet.

. Opioid analgesics:

Tramadol; solution for injection 100 mg/2ml.

. Medicines that affect phosphorus-calcium metabolism:
Alfacalcidol, capsules 0.25 mcg, 1 mcg;

Sevelamer, tablets 180 mg;

Cinacalcet, tablets 30 mg, 60 mg, 90 mg;

Calcium carbonate, tablets 25 mg, powder.

. Medicines affecting the blood

. Antianemic drugs:

Iron (III) preparations, solution for injection 100 mg/2 ml, 5 ml;

Iron (II) preparations for oral administration;

Epoetin beta; solution for injection 2000IU/0.3ml., spr/tube;

Epoetin alfa, solution for injection in ready-to-use syringes 1000 IU/0.5 ml;

Epoetin alfa, solution for injection in ready-to-use syringes 2000 IU/0.5 ml.

. Anticoagulants:

Heparin; injection solution 5000 IU/ml, gel 1000 IU/g;

Nadroparin; injection solution 3800 IU anti-Xa/0.4 ml;

Nadroparin; injection solution 15200 IU antiXa/0.8 ml;

Enoxaparin; injection solution 4000 anti-Xa IU/0.4 ml;

Enoxaparin; injection solution 8000 anti-Xa IU/0.8 ml;

Warfarin; tablets 5 mg.

. Antiplatelet agents

Clopidogrel; film-coated tablets, 75 mg;

Clopidogrel; film-coated tablets, 300 mg;

Pentoxifylline, solution for injection 2%-5ml.

. Antifibrinolytic drugs and hemostatic drugs

. Medicines used for occlusive arterial diseases:

Alprostadil, lyophilisate for the preparation of solution for infusion 20 mcg.

Other medicines

. Plasma replacement products:

. Parenteral nutrition products

Albumen; solution for infusion 10%, 20% -100ml, 200 ml;

Fat emulsion for parenteral nutrition; emulsion for infusion 10% -500 ml.

. Solutions used to correct disturbances in water, electrolyte and acid-base balance

Complex of amino acids for parenteral nutrition; solution for infusion 4%, 10% -250 ml, 500 ml;

Potassium, magnesium aspartate, solution for infusion 250 ml;

Potassium, magnesium aspartate, solution for infusion 500 ml;

Magnesium lactate dihydrate, tablets;

Sodium glycerophosphate, granules in bottles 100g.

. Antibacterial agents

B-lactam drugs:

Ampicillin, powder for solution for injection 1000 mg;

Benzylpenicillin, powder for solution for injection 1 million units;

Cefazolin, powder for solution for injection in a bottle 1000 mg;

Cefazolin, powder for solution for injection in a 500 mg bottle;

Ceftazidime - powder for the preparation of solution for injection in a 1000 mg bottle;

Ceftriaxone, powder for solution for injection 1000 mg;

Ceftriaxone, powder for solution for injection 500 mg;

Ceftriaxone, powder for solution for injection 250 mg;

Cefuroxime, granules for the preparation of a suspension for oral administration in a bottle 125 mg/5 ml - 50 ml;

Cefuroxime, powder for the preparation of a solution for intravenous and intramuscular injections in a 750 mg bottle;

Cefuroxime, powder for solution for injection in a bottle 1500 mg;

Cefotaxime, powder for solution for injection 1000 mg;

Cefepime, powder for solution for injection 500 mg;

Cefepime, powder for solution for injection 1000 mg;

Cefoperazone, powder for solution for injection 1000 mg.

Carbopenems:

Doripenem, powder for solution for infusion 500 mg;

Meropenem, powder, lyophilisate for solution for injection 1000 mg;

Meropenem, powder, lyophilisate for solution for injection 500 mg;

Ertapenem, lyophilisate for solution for injection 1000 mg;

Imipenem, powder for solution for infusion 500 mg.

Macrolides:

Azithromycin, film-coated tablets, 500 mg;

Azithromycin, lyophilized powder for the preparation of solution for infusion 500 mg;

Clarithromycin, film-coated tablets 500 mg;

Glycopeptides:

Vancomycin; powder, lyophilisate for the preparation of solution for infusion 1000 mg;

Vancomycin, powder for the preparation of injection solution in a 500 mg bottle.

Aminoglycosides:

Amikacin, solution for injection 500 mg/2 ml, powder 0.5 g;

Gentamicin, solution for injection 80 mg/2 ml.

Tetracyclines:

Doxycycline; tablets, dispersible tablets, capsules 100 mg.

Amphenicols:

Chloramphenicol; powder for solution for injection 1000 mg; liniment 10%.

Quinolones, fluoroquinolones:

Levofloxacin; solution for infusion 500 mg/100 ml;

Moxifloxacin; solution for infusion 450 mg/250 ml; film-coated tablets, 400 mg;

Ciprofloxacin, film-coated tablets 500 mg;

Nitroimidazoles:

Metronidazole, solution for infusion 500 mg/100 ml; Amphotericin B + glucose, lyophilisate 500,000 units for preparation of infusion solution + 5% glucose.

Sulfonamides and trimethoprim:

Co-trimoxazole (Sulfamethoxazole + Trimethoprim), solution for intravenous administration 480 mg/5 ml;

Co-trimoxazole (Sulfamethoxazole + Trimethoprim), tablets 480 mg;

Co-trimoxazole (Sulfamethoxazole + Trimethoprim), suspension in a bottle 120 mg/5 ml 100 ml;

Co-trimoxazole (Sulfamethoxazole + Trimethoprim), suspension in a bottle 240 mg/5 ml 100 ml.

Nitrofurans:

Furazolidone; tablets 0.05 g;

Combined antibacterial agents:

Amoxicillin + Clavulanic acid, soluble tablets 625 mg;

Amoxicillin + Clavulanic acid, powder for the preparation of solution for intravenous and intramuscular administration 1000 mg + 500 mg;

Amoxicillin + Sulbactam, powder for solution for injection 1000 mg + 500 mg;

Imipenem + Cilastatin; powder for the preparation of solution for injection, infusion 500 mg/500 mg;

Piperacillin + Tazabactam, powder for solution for injection 4 g + 500 mg;

Cefoperazone + Sulbactam; powder for solution for injection 1.5 g.

. Other antibacterial agents:

Isoniazid; tablet 300 mg;

Amikacin; powder for solution for injection 0.5 g;

Metronidazole, solution for infusion in a bottle 0.5% 100ml.

. Antifungal drugs:

Nystatin; tablets 500,000 units;

Fluconazole; film-coated tablets 150 mg; solution for infusion 200 mg/100 ml;

Caspofungin, lyophilisate for solution for infusion 50 mg;

Micafungin, lyophilisate for solution for injection 100 mg; Micafungin, lyophilisate for solution for injection 50 mg.

. Medicines used for herpes and other viral infections:

Acyclovir; film-coated tablets, 200 mg;

Acyclovir, powder for solution for infusion in a 250 mg bottle;

Valganciclovir; tablets 450 mg;

Valganciclovir, tablets 450 mg;

Valaciclovir, tablets 500 mg;

Ganciclovir, powder in vials containing 0.546 g (546 mg) of ganciclovir sodium, lyophilized (dehydrated by freezing in a vacuum);

Antiseptics:

Iodine, alcohol solution 5%;

Hydrogen peroxide, tablets 1.5 g;

Hydrogen peroxide, solution 3%;

Povidone - iodine, solution for external use;

Chlorhexidine, solution for external use 0.05%;

Ethanol, solution 70%;

Ethanol, 90% solution.

. Nitrates:

Isosorbide dinitrate; injection solution 0.1%; concentrate for cooking. solution for infusion 1 mg/ml; aerosol, spray;

Nitroglycerin, sublingual tablets 0.5 mg; concentrate for the preparation of solution for infusion 1 mg/ml; therapeutic transdermal system, aerosol.

. :

Nifedipine, solution for infusion 0.01% 50 ml;

Nifedipine, film-coated tablets, 10 mg;

Amlodipine, tablet 10 mg;

Diltiazem, retard film-coated tablets, 90 mg;

Lercanidipine, film-coated tablets 10 mg.

Antiarrhythmic drugs:

Lidocaine hydrochloride; injection solution 2%, 10%; aerosol 10%;

Amiodarone; solution for injection 150 mg/3 ml; tablets (divisible) 200 mg.

Beta blockers:

Bisoprolol, film-coated tablets, 10 mg;

Metoprolol, solution for intravenous administration 5 ml;

Bisoprolol, tablets, 10 mg;

Nebivolol, tablets 5 mg.

Clonidine; tablets 0.15 mg;

Alpha blockers:

Urapidil; solution for intravenous administration 5 mg/ml; extended-release capsules 30 mg;

Doxazosin; tablets 4 mg.

Diuretics:

Mannitol, solution for infusion in a bottle 15% 200ml;

Mannitol, solution for infusion in a bottle 15% 400ml;

Furosemide; solution for injection 1%-20 mg/2ml;

Hydrochlorothiazide; tablets 100 mg;

Indapamide; tablets 2.5 mg.

. Cardiotonic drugs:

. Antacids and other antiulcer drugs:

Famotidine, lyophilized powder for solution for injection 20 mg;

Omeprazole, enteric capsules 20 mg;

Omeprazole, lyophilized powder for the preparation of solution for injection 40 mg;

Pantoprazole, enteric-coated tablets, 40 mg; Pantoprazole, powder, lyophilisate for solution for injection 40 mg;

Esomeprazole, tablets 20 mg.

. :

. Laxatives:

Lactulose; syrup, oral solution;

Macrogol 4000; powder for the preparation of oral solution 10 g;

Bisacodyl; tablets, 5 mg; rectal suppositories 10 mg.

. Vitamins and minerals:

Ascorbic acid; dragee 50 mg; injection solution 5%;

A nicotinic acid; solution for injection 1%;

Pyridoxine; injection solution 5%; tablets 2 mg;

Thiamine; injection solution 5%;

Tocopherol; capsules 100 mg;

Cyanocobalamin; solution for injection 200 mcg/ml;

Cyanocobalamin; solution for injection 500 mcg/ml;

Omega-3 acids ethyl esters 90; capsule 1000 mg.

. :

Octagam, concentrate for the preparation of solution for intravenous infusion in a bottle of 500 mg/50 ml 50 ml;

Diphenhydramine, solution for injection in ampoule 1% 1ml;

Human daily action insulin (average), suspension 100 U/ml 10.0 ml;

Drug treatment provided at the emergency stage:

List of essential medicines:

. Antifibrinolytic drugs and hemostatic drugs:

Local hemostatic agents; native plasma from human donor blood or dry plasma; sponge, tampons in different shapes and sizes; hemostatic spray; hemostatic solution;

Aminocaproic acid; solution for infusion 5%-100ml;

Aprotinin; solution for infusion 10,000 KIU/ml, 20,000 KIU; lyophilized powder for the preparation of solution for injection 15 IU, 10,000 ATRE; injection solution 20,000 KIU;

Etamsylate; injection solution 12.5% -2 ml.

Blood products, plasma substitutes and parenteral nutrition products:

. Plasma replacement products:

Dextrose, solution for infusion 5%: 10%, 200 ml, 400 ml;

Dextrose, solution for injection 40% -10ml.

. Parenteral nutrition products:

Hydroxyethyl starch (pentastarch); solution for infusion 5%, 10% -250 ml, 500 ml;

. Solutions used to correct disturbances in water, electrolyte and acid-base balance:

Sodium chloride; solution for infusion 0.9%,3%,4.5%,10% -200ml, 400 ml;

Sodium acetate; solution for infusion 200 ml;

Calcium chloride; solution for infusion 1% -200 ml;

Calcium chloride; solution for infusion 10% -5 ml;

Calcium gluconate, solution for infusion 10% -5 ml;

Potassium chloride; solution for infusion 4% -10ml;

Potassium chloride; solution for infusion 7.5% -100ml;

Magnesium chloride; solution for infusion 25% -5 ml;

Sodium bicarbonate; solution for infusion 4% -200 ml;

. Antiseptics:

Iodine, alcohol solution 5%;

Ethanol, solution 70%;

Ethanol, 90% solution.

. Cardiovascular drugs

. Nitrates:

Isosorbide dinitrate; injection solution 0.1%; concentrate for the preparation of solution for infusion 1 mg/ml; aerosol, spray;

Isosorbide-5-mononitrate; tablets, 40 mg;

Nitroglycerin, sublingual tablets 0.5 mg; concentrate for the preparation of solution for infusion 1 mg/ml; therapeutic transdermal system,

Aerosol.

. Antihypertensive drugs:

Calcium channel antagonists:

Nifedipine, film-coated tablets, 10 mg.

Antiarrhythmic drugs:

Verapamil hydrochloride; solution for injection 0.25% -2 ml;

Lidocaine hydrochloride; injection solution 2%, 10%; aerosol 10%.

Central acting agents:

Clonidine, solution for injection 0.01% - 2ml;

Diuretics:

Furosemide; solution for injection 1%-20 mg/2ml.

. Cardiotonic drugs:

Dopamine; concentrate for the preparation of solution for infusion 0.5%, 4%.

. Antispasmodic drugs:

Drotaverine; tablets 40 mg, solution for injection 40 mg/2 ml;

Platyfillin; injection solution 0.2%;

Papaverine hydrochloride; injection solution 2%;

Buscopan, solution for injection, 20 mg/ml.

. Other medicines:

Short-acting human insulin, solution 100 U/ml, 3.0 ml;

Metoclopramide (cerulin), solution for injection in ampoule 0.5%/2ml.

Other treatments- therapeutic exercises, breathing exercises, physiotherapy.

Extracorporeal treatment methods (acute PD, intermittent daily bicarbonate HD, constant venovenous HD, therapeutic plasmapheresis and plasmasorption, albumin dialysis/modified hemodiafiltration with dialysate enriched with albumin for acute hepatorenal failure and hepatorenal syndrome, hemosorption (selective and non-selective) for sepsis). Indications for the use of these methods of renal replacement therapy - according to paragraphs. 37, 38, 41 of the Standard for organizing the provision of nephrological care to the population of the Republic of Kazakhstan, approved by order of the Minister of Health of the Republic of Kazakhstan No. 765 dated December 30, 2014.

Surgical intervention- transplantectomy.

Preventive actions

Primary prevention is aimed at preventing the development of infectious complications, including viral, bacterial, fungal, antiulcer drugs, uroseptics, antiplatelet agents, and includes taking medications, maintaining personal hygiene, avoiding contact with an infectious agent or allergen, timely sanitation of foci of infection, excluding self-medication and strict adherence to doctor's orders.

Prevention of fungal infections includes the appointment of nystatin 10,000 U/kg 3-4 times a day by mouth every day for 4 weeks or fluconazole 3-6 mg/kg/day on the first day, then 3 mg/kg/day every other day (maximum dose 100 mg/day). days) - 4 weeks. A decrease in GFR ≤50 ml/min requires a 2-fold reduction in the dose of fluconazole. When prescribing antibacterial therapy or increasing doses of immunosuppressants, repeated courses may be required.

Prevention of Pneumocystis pneumonia includes the administration of trimethoprim-sulfamethoxazole (400 mg/80 mg) 12 mg/kg/day trimethoprim once a day daily by mouth for 3-6 months after transplantation. A decrease in GFR ≤30 ml/min requires a 2-fold reduction in dose; GFR ≤15 ml/min is not recommended. During and after treatment of acute rejection, a repeat course of trimethoprim-sulfamethoxazole is necessary for at least 6 weeks.

Prevention of cytomegalovirus infection includes the prescription of valganciclovir (450 mg tablets) - 450-900 mg/day/valaciclovir 2000 mg/day. The duration of treatment is 100 days for a seropositive recipient, and 200 days for a seronegative recipient provided there is a seropositive donor. If Ig M is detected and/or in the presence of clinical signs of cytomegalovirus infection and/or a positive result for CMV using quantitative PCR after a course of treatment, additional prescription of valganciclovir until seronegativity is achieved.

Further management

After discharge from the hospital, the patient is observed for life on an outpatient basis according to the list of examinations of the recipient at the primary health care level, and the patient must keep a self-observation diary after discharge (Appendices 12 - 16 to the Standard for organizing the provision of nephrological care to the population of the Republic of Kazakhstan, approved by order of the Minister of Health of the Republic of Kazakhstan No. 765 dated December 30, 2014).

In the case of a transplantectomy, treatment with outpatient program hemodialysis or continuous outpatient peritoneal dialysis.

Indicators of treatment effectiveness:

Restoration or improvement of graft function (decrease or normalization of creatinine levels, increase in diuresis);

Normalization or improvement of indicators according to clinical, laboratory, instrumental research methods (disappearance of pain in the graft area, reduction in graft volume according to ultrasound, restoration of the RI index according to ultrasonography of graft vessels, normalization of BC, TAM, biochemical studies, negative results of blood ELISA tests IgM to cytomegalovirus);

Return to outpatient program hemodialysis or continuous ambulatory peritoneal dialysis after transplantectomy.

Drugs (active ingredients) used in treatment

Azithromycin
Alprostadil
Albumin human
Alfacaltsidol
Amikacin
Aminocaproic acid
Amiodarone
Amlodipine
Amoxicillin
Ampicillin
Aprotinin
Ascorbic acid
Acyclovir
Benzylpenicillin
Bisacodyl
Bisoprolol
Valganciclovir
Vancomycin
Warfarin
Verapamil
Hydrogen peroxide
Ganciclovir
Gentamicin
Heparin sodium
Hydroxyethyl starch
Hydrochlorothiazide
Hyoscine butylbromide
Dexamethasone
Dextrose
Diltiazem
Diphenhydramine
Doxazosin
Doxycycline
Dopamine
Doripenem
Drotaverine (Drotaverinum)
A fat emulsion for parenteral nutrition
Isoniazid
Isosorbide mononitrate
Isosorbide dinitrate
Imipenem
Immunoglobulin antithymocyte
Human normal immunoglobulin
Indapamide
Short-acting human insulin
Insulin human daily actions
Iodine
Potassium aspartate (Potassium aspartate)
Potassium chloride (Potassium chloride)
Calcium gluconate
Calcium carbonate
Calcium chloride
Caspofungin
Clavulanic acid
Clarithromycin
Clonidine
Clopidogrel
Complex of amino acids for parenteral nutrition
Lactulose
Levofloxacin
Lercanidipine
Lidocaine
Magnesium aspartate
Magnesium lactate
Magnesium chloride
Macrogol 4000 (Macrogol 4000)
Mannitol
Meropenem
Methylprednisolone
Metoclopramide
Metoprolol
Metronidazole
Micafungin
Mycophenolic acid (Mycophenolate mofetil)
Moxifloxacin
Nadroparin calcium
Sodium acetate
Sodium hydrocarbonate
Sodium chloride
Nebivolol
Nicotinic acid
Nystatin
Nitroglycerine
Nifedipine
Omega-3 acid ethyl esters 90
Omeprazole
Pantoprazole
Papaverine
Pentoxifylline
Piperacillin
Pyridoxine
Platifillin
Povidone - iodine
Prednisolone
Rituximab
Sevelamer
Sulbactam
Sulfamethoxazole
Tazobactam
Tacrolimus
Thiamin
Tocopherol
Tramadol
Trimethoprim
Urapidil
Famotidine
Fluconazole
Furazolidone
Furosemide
Chloramphenicol
Chlorhexidine
Cefazolin
Cefepime
Cefoperazone
Cefotaxime
Ceftazidime
Ceftriaxone
Cefuroxime
Cyanocobalamin
Cyclosporine
Cilastatin
Cinacalcet
Ciprofloxacin
Everolimus
Esomeprazole
Enoxaparin sodium
Epoetin alfa
Epoetin Beta
Ertapenem
Etamsylate
Ethanol

Groups of drugs according to ATC used in treatment

Hospitalization

Indications for planned hospitalization: is not carried out.

Indications for emergency hospitalization:

Graft dysfunction;

Absence or decrease in diuresis;

Swelling, pain/tension/bulging in the area of the kidney graft;

Increased blood pressure;

Weakness;

Dysuria;

Hyperthermia.

Information

Sources and literature

Minutes of meetings of the Expert Council of the RCHR of the Ministry of Health of the Republic of Kazakhstan, 2014
1. 1. Immunosuppression during solid organ transplantation / Ed. S. Gauthier. – M. – Tver: Triada Publishing House LLC, 2011. – 382 p. 2. Moysyuk Ya.G., Stolyarevich E.S., Tomilina N.A. Kidney graft disease / Nephrology: national guide // ed. ON THE. Mukhina. – M.: GEOTAR-Media, 2009. – 588 p. (National Guidelines Series). 3. Kidney transplantation: principles and practice. 6th ed. /Ed. by Sir Peter J. Morris and Stuart J. Knechtle // Philadelphia: Elsevier Saunders, 2008. 4. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant, 2009. 9 Suppl 3: p. S1-155. 5. T. Kable, A. Alcaraz, K. Budde, U. Humke, G. Karam, M., Lucan, G. Nicita, C. Susal Kidney transplantation: Clinical guidelines of the European Association of Urology, 2010 / Translation from English, ed. . D.V. Perlina. – M.: ABV-Press, 2010.2010. – 100 s. 6. Danovich Gabriel M. Kidney transplantation / Trans. from English edited by Y. G. Moysyuk. – M: GEOTAR-Media, 2013. – 848 p. 7. Wolfe RA, Ashby VB, Milford EL et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med1999; 341:1725–1730. 8. Szczech LA, Berlin JA, Aradhye S et al. Effect of anti-lymphocyte induction therapy on renal allograft survival: A meta-analysis. J Am Soc Nephrol 1997; 8: 1771–1777. 9. Thibaudin D, Alamartine E, de Filippis JP et al. Advantage of antithymocyte globulin induction in sensitized kidney recipients: A randomized prospective study comparing induction with and without antithymocyte globulin. Nephrol Dial Transplant 1998;13:711–715. 10. Brennan DC, Daller JA, Lake KD et al. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl JMed 2006; 355: 1967–1977. 11. Ciancio G, Burke GW, Gaynor JJ et al. A randomized trial of three renal transplant induction antibodies: Early comparison of tacrolimus, mycophenolate mofetil, and steroid dosing, and newer immune-monitoring. Transplantation 2005; 80:457–465. 12. Gore JL, Pham PT, Danovitch GM et al. Obesity and outcome following renal transplantation. Am J Transplant 2006; 6:357–363. 13. Pallardo Mateu LM, Sancho Calabuig A, Capdevila Plaza L et al. Acute rejection and late renal transplant failure: Risk factors and prognosis. Nephrol Dial Transplant 2004 19(Suppl. 3): iii38–42. 14. Boom H, Mallat MJ, de Fijter JW et al. Delayed graft function influences renal function, but not survival. Kidney Int 2000; 58:859–866. 15. Webster AC, Woodroffe RC, Taylor RS et al. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: Meta-analysis and meta-regression of randomized trial data. BMJ 2005; 331: 810. 16. Ekberg H, Tedesco-Silva H, Demirbas A et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007; 357:2562–2575. 17. Rostaing L, Cantarovich D, Mourad G et al. Corticosteroid-free immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab induction in renal transplantation. Transplantation 2005; 79:807–814. 18. Ekberg H, Grinyo J, Nashan B et al. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: The CAESAR Study. Am J Transplant 2007;7:560–570 19. Knight SR, Russell NK, Barcena L et al. Mycophenolate mofetil decreases acute rejection and may improve graft survival in renal transplant recipients when compared with azathioprine: A systematic review. Transplantation 2009; 87:785–794. 20. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation 1996; 61:1029–1037. 21. Ojo AO, Meier-Kriesche HU, Hanson JA et al. Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection. Transplantation 2000; 69:2405–2409. 22. Opelz G, Dohler B. Influence of immunosuppressive regimens on graft survival and secondary outcomes after kidney transplantation. Transplantation 2009; 87:795–802. 23. Kasiske BL, Chakkera HA, Louis TA et al. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol 2000; 11: 1910–1917. 24. Pascual J, Quereda C, Zamora J et al. Steroid withdrawal in renal transplant patients on triple therapy with a calcineurin inhibitor and mycophenolatemofetil: A meta-analysis of randomized, controlled trials. Transplantation 2004; 78:1548–1556. 25. Kasiske BL, de Mattos A, Flechner S Met al. Mammalian target of rapamycin inhibitor dyslipidemia in kidney transplant recipients. Am J Transplant 2008; 8:1384–1392. 26. Langer RM, Kahan BD. Incidence, therapy, and consequences of lymphocele after sirolimus-cyclosporine-prednisone immunosuppression in renal transplant recipients. Transplantation 2002;74:804–808. 27. Troppmann C, Pierce JL, GandhiMMet al. Higher surgicalwound complication rates with sirolimus immunosuppression after kidney transplantation: A matched-pair pilot study. Transplantation 2003; 76:426–429. 28. Maes B, Hadaya K, de Moor B et al. Severe diarrhea in renal transplant patients: Results of the DIDACT study. Am J Transplant 2006; 6:1466–1472. 29. Kyllonen LE, Salmela KT. Early cyclosporine C0 and C2 monitoring in de novo kidney transplant patients: A prospective randomized single-center pilot study. Transplantation 2006; 81:1010–1015. 30. 85. Jorgensen K, Povlsen J, Madsen S et al. C2 (2-h) levels are not superior to trough levels as estimates of the area under the curve in tacrolimus-treated renal-transplant patients. Nephrol Dial Transplant 2002; 17: 1487–1490. 31. Knight SR, Morris PJ. Does the evidence support the use of mycophenolate mofetil therapeutic drug monitoring in clinical practice? A systematic review. Transplantation 2008; 85:1675–1685. 32. Nashan B. Review of the proliferation inhibitor everolimus. Expert Opin Investig Drugs 2002; 11: 1845–1857. 33. Solez K, Colvin RB, Racusen LC et al. Banff 07 classification of renal allograft pathology: Updates and future directions. Am JTransplant 2008; 8:753–760. 34. Rush D, Nickerson P, Gough J et al. Beneficial effects of treatment of early subclinical rejection: A randomized study. J AmSoc Nephrol 1998; 9:2129–2134. 35. Kurtkoti J, Sakhuja V, Sud K et al. The utility of 1- and 3-month protocol biopsies on renal allograft function: A randomized controlled study. Am J Transplant 2008; 8: 317 323. 36. Webster AC, Pankhurst T, Rinaldi F et al. Monoclonal and polyclonal antibody therapy for treating acute rejection in kidney transplant recipients: A systematic review of randomized trial data. Transplantation 2006; 81:953–965. 37. Zarkhin V, Li L, Kambham N et al. A randomized, prospective trial of rituximab for acute rejection in pediatric renal transplantation. Am J Transplant 2008; 8:2607–2617. 38. Solez K, Colvin RB, Racusen LC et al. Banff ‘05 Meeting Report: Differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN’). Am J Transplant 2007;7:518–526. 39. Briganti EM, Russ GR, McNeil JJ et al. Risk of renal allograft loss from recurrent glomerulonephritis. N Engl JMed 2002; 347:103–109. 40. Nankivell BJ, Borrows RJ, Fung CL et al. The natural history of chronic allograft nephropathy. N Engl J Med 2003; 349:2326–2333. 41. Nankivell BJ, Chapman JR. Chronic allograft nephropathy: Current concepts and future directions. Transplantation 2006; 81:643–654. 42. Roodnat JI, Mulder PG, Rischen-Vos J et al. Proteinuria after renal transplantation affects not only graft survival but also patient survival. Transplantation 2001; 72: 438– 444. 43. David-Neto E, Prado E, Beutel A et al. C4d-positive chronic rejection: A frequent entity with a poor outcome. Transplantation 2007; 84:1391–1398. 44. American Diabetes Association clinical practice recommendations 2001. Diabetes Care 2001; 24(Suppl 1): S1–133. 45. Hogg RJ, Furth S, Lemley KV et al. National Kidney Foundation’s K/DOQI clinical practice guidelines for chronic kidney disease in children and adolescents: Evaluation, classification, and stratification. Pediatrics 2003; 111:1416–1421. 46. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 2002; 39(2 Suppl 1):S1–266. 47. Gaspari F, Perico N, Remuzzi G. Measurement of glomerular filtration rate. Kidney Int 1997; (Suppl 63): S151–154. 48. Hollenbeck M. New diagnostic techniques in clinical nephrology. Color coded duplex sonography for evaluation of renal transplants–tool or toy for the nephrologist? Nephrol Dial Transplant 1994; 9: 1822–1828. 49. Nankivell BJ, Borrows RJ, Fung CL et al. Natural history, risk factors, and impact of subclinical rejection in kidney transplantation. Transplantation 2004; 78:242–249. 50. Fereira LC, Karras A, Martinez F et al. Complications of protocol renal biopsy. Transplantation 2004; 77:1475–1476.
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Chapter 10
TRANSPLANTOLOGY

The human body usually does not die suddenly, like an exploding balloon; organ after organ gradually loses its function. Clinical methods of organ transplantation are being developed to replace organs whose function has been irreversibly lost. Since there is an immunological barrier to the engraftment of genetically foreign tissue in the body, which manifests itself in the reaction of transplant rejection, immunologists and surgeons have been working together since World War II to find a solution to this problem.

Transplantation of whole organs or even cell suspensions to treat end-stage organ failure, genetic and metabolic diseases is one of the greatest achievements of immunobiology and surgery of this century. After the description of the technique of vascular anastomosis, transplantation of vascularized organs became technically possible. The rejection reaction that develops against all transplants, with the exception of transplants obtained from identical twins, leads to the understanding that each individual has innate individual antigenic differences in histocompatibility.

Allograft immunobiology

In general, the greater the genetic differences between the graft and recipient, the more severe the rejection reaction. The severity of this reaction during tissue or organ transplantation in individuals of the same biological species (allografts or homotransplants) is proportional to the degree of genetic difference between them. When transplanting grafts from individuals of another species (xenografts, or heterografts), the rejection reaction develops even faster. Grafts from identical twins (isografts, isogenic, or syngeneic grafts) or grafts transplanted within the same body survive without complications after their normal blood supply is restored.

TRANSPLANT ANTIGENS (HISTO COMPATIBILITY ANTIGENS)

The graft rejection reaction is caused by foreign histocompatibility antigens on the surface of the graft cells. Likewise, xenografts from other species are quickly rejected because the tissue incompatibility between most species is so profound that the corresponding antibodies may be circulating in the host serum even before transplantation. Alloantigenic incompatibility between individuals of the same species is variable, however, strong antigens can lead to graft rejection after 8 days, while weaker differences allow the graft to survive for more than 100 days.

Major histocompatibility complex (MHC) genes are divided into three classes: class I, class II, class III. Only class I and class C molecules play a significant role in transplantation. Although class I and class II determinants were once considered antigens, they are now known to play a key role in the activation of T and B lymphocytes in addition to mediating histocompatibility recognition. Class I human leukocyte antigen (HLA) molecules can be found on the surface of almost all nucleated cells. In contrast, HLA class II molecules are found only on the surface of cells of the immune system - macrophages, dendritic cells, B lymphocytes and activated T lymphocytes. The heavy chains of class I (37-45 kDa) are largely polymorphic and are non-covalently associated on the cell surface with the light chain of B2-microglobulin (B2M), which is surprisingly stable. Class I genes, also known as immune response genes, encode the genetic material for an immune response. They provide an immune response to many antigens. They also encode a number of antigens expressed by lymphocytes. Class II loci in humans include HLA DR, DQ, DP. Expression of class II antigens is normally present in cells derived from bone marrow stem cells.

SELECTION BY HISTOSCOMPATIBILITY

To demonstrate the antigenic similarity of donor and recipient tissues before transplantation, various methods have been developed so that relatively histocompatible donor and recipient pairs can be selected. The best modern method is called serological, or leukocyte, typing. HLA antigens expressed by circulating lymphocytes can be determined using sera obtained from patients who have undergone multiple blood transfusions or from women who have had multiple pregnancies. Using the patient's white blood cells and a range of standard sera, most strong antigens can be characterized in both the donor and recipient.

Several points regarding histocompatibility selection deserve special attention.

1. Recipients who receive transplants, even from HLA-matched donors, will develop graft rejection unless immunosuppressive drugs are used. Only an identical twin is an ideal donor. ; . "

2. Even with poor selection of histocompatibility donors from among the recipient’s relatives, the results are often good.

3. Even with a good histocompatibility selection, the transplant will not take root if the recipient’s body already has antibodies against the donor’s tissue, according to the cytotoxic test.

4. The presence of ABO-isohemagglutins will lead to rapid rejection of most transplanted organs carrying substances incompatible with the blood group.

5. Tissue typing of cadaveric tissues of persons who were not relatives of the recipient is not successful.

IMMUNE APPARATUS

At birth, the human body is already immunocompetent and undergoes a process of complex development. It is currently accepted that there is a single pluripotent hematopoietic stem cell found in the extraembryonic yolk sac. Daughter stem cells migrate to various organs for further differentiation.

Ontogenesis of the immune response. The first immature cell lines to be created are lymphoid and myeloid. Lymphoid progenitor cells migrate to the thymus (T cells) or the equivalent of the bursa of Fabricius (B cells) to differentiate into mature T and B lymphocytes. Two main types of lymphoid cells - B and T lymphocytes - play a major role in transplant rejection. B lymphocytes provide the humoral, or antibody response to antigen, while T lymphocytes are responsible for the cell-related functions of the immune system. There are two main types of T lymphocytes. CD8+ mature T lymphocytes contribute to the functions of effector cells, such as direct cytotoxic attack for graft rejection, while CD4+ T lymphocytes play the role of immunoregulators (helpers) through the secretion of cytokines, which have a paracrine effect aimed at activating or suppressing almost all immune response mechanisms.

T lymphocytes are a population of immunocompetent cells responsible for cellular rather than humoral immunity. T cell responses include delayed hypersensitivity reactions, antiviral activity, and many of the early responses involved in graft rejection.

B lymphocytes develop from bone marrow stem cells and become responsible for the production of circulating immunoglobulins and thereby humoral immunity.

Lymphocytes -these are cells that specifically respond to transplant rejection. T-lymphocyte precursor cells arise from a pluripotent bone marrow stem cell through the formation of a number of intermediate forms. These cells then migrate to the thymus gland and mature there, undergoing a series of genetically determined changes, which leads to their acquisition of specific membrane receptors.

CD antigens determine the function of T-lymphocytes: the CD8+ cytotoxic/suppressor group lyses target cells and destroys cells infected with the virus, and CD4+ T-lymphocytes function as immunoregulatory cells (helpers/inducers), the mediating role of which is to organize the interaction of T-lymphocytes , B lymphocytes, macrophages and other cells due to the release of cytokines.

A generalized idea of the reaction of rejection of a transplanted organ. After an organ transplant, a typical chain of events develops. The first detectable change is the appearance of perivascular circle-cell infiltrates. A complex of cells accumulates: cells resembling small lymphocytes are visible, as well as large transformed lymphocytes. Large histiocytes, or macrophages, also begin to arrive here in significant quantities.

Antibodies and complement accumulate in the capillary area and some of the lymphoid cells in the infiltrate produce antibodies by the 3rd day.

Sensitized lymphoid cells, when recognizing foreign tissue, release various mediators of inflammation and cellular damage. The released cytotoxic substances directly damage the membranes of nearby cells. Mitogenic products stimulate division of lymphoid cells, thereby likely increasing the population of immunocompetent cells. Activated phagocytic macrophages are concentrated in this zone due to the migration inhibitory factor, other chemotactic factors and cytokines secreted by the activated cells. In addition, substances are released that increase vascular permeability.

Meanwhile, complement is fixed here, resulting in the release of chemattractants, anaphylatoxins, and ultimately, when the final fractions of the complement cascade are activated, cell damage occurs. Due to anaphylatoxins, which represent fractions of the complement cascade, and probably due to kinins, capillary permeability increases. Interstitial edema becomes pronounced. At the same time, various additional factors influence the infiltrate. As part of the complement cascade, fractions are generated that have adhesive and hemattractant properties. Damaged cells produce additional substances that promote tissue infiltration by polymorphonuclear leukocytes (PMNL), as well as other cells. PMNs, in turn, release vasoactive amines (including histamine or serotonin, depending on the biological species) and additional factors that increase vascular permeability. PMNs penetrate through the widened interendothelial gaps of the capillaries and secrete proteolytic substances - cathepsins D and E, which cause damage to the basement membranes.

By the 7th day, fibrin and a-macroglobulins are deposited, the significance of which in the graft rejection reaction is not clear. At this time, lymphoid cells continue to accumulate and, together with plasma cells and PMNs, change the picture of the normal structure of the graft tissue. In this place, the infiltrate presumably contains many macrophages and other immunologically nonspecific cells. An increased number of mitoses in the infiltrate may indicate proliferation of immunocompetent cells in the graft.

Small vessels become clogged with fibrin and platelets, which impairs graft perfusion and function. In this relatively fast-paced chain of events, the transplanted organ has little chance of response, and the pathological process is dominated by the recipient's response.

Damage to endothelial cells also causes a process traditionally called accelerated atherosclerosis. Platelet aggregates in the upper layer are resorbed, and lysis of blood clots is accompanied by infiltration of the vessel wall with macrophages and foam cells. As a result, there is a thickening of the intimal layer with loss of the smooth endothelial lining and the presence of vacuolated cells.

Although damage to endothelial cells and marked proliferation of smooth muscle cells suggest that they are important target cells in the immune response, there is evidence that the basal and elastic membranes of blood vessels bear the brunt of the immune attack.

Platelets may play a greater role than PMN in causing damage. Immune complexes (which activate complement) lead to platelet adhesion and the release of vasoactive substances. Platelet aggregation is accompanied by the release of histamine, serotonin and other factors that increase capillary permeability, which have a greater effect on the basement membranes. The exposed collagen fibers of these membranes further enhance platelet aggregation.

Preventing graft rejection

DRUG IMMUNOSUPRESSION

The development of immunosuppressive drugs has revolutionized transplantation. In most cases, if these drugs are stopped, graft rejection will occur.

Theoretically, there are several ways to suppress the rejection reaction: 1) destroy immunocompetent cells before transplantation; 2) make reactive lymphocyte cells unable to recognize antigens or even develop a toxic reaction against them; 3) influence the reaction of recipient cells with antigens; 4) inhibit the transformation and proliferation of lymphocytes; 5) limit the differentiation of lymphocytes to T-killers or to plasma cells that synthesize antibodies; 6) activate a sufficient number of suppressor lymphocytes; 7) suppress the destruction of transplant cells by killer T cells; 8) influence the interaction of immunoglobulins with target antigens; 9) prevent tissue damage by nonspecific cells or immune complexes; 10) induce true specific immunological tolerance to transplant antigens.

ANTI-PROLIFERATIVE DRUGS

Most traditional immunosuppressive drugs act as substances that impair lymphocyte proliferation. Such drugs include antimetabolites, alkylating agents, toxic antibiotics and radioisotopes. They suppress the entire immune response by preventing the differentiation and division of immunocompetent cells after they encounter an antigen. They all, however, fall into one of two broad categories. Either they structurally resemble essential metabolites or they form combinations with certain cellular components, such as DNA, and thereby interfere with the functioning of the cell.

Purine analogues. The purine analogue azathioprine (imuran) is the drug most widely used in organ transplantation. Azathioprine is a b-mercaptopurine + side chain protecting a labile sulfhydryl group. In the liver, the side chain is cleaved off and the active substance is formed - 6-mercaptopurine. Its main toxic effect is inhibition of hematopoiesis, leading to leukopenia. A hepatotoxic effect is also characteristic, probably due to the high level of RNA synthesis by these cells.

Cyclosporines. Cyclosporines are a completely new class of immunosuppressive drugs. These are cyclic peptides produced by fungi (Fig. 10.1). Many of their suppressive effects are specific to T lymphocytes. The effect of cyclosporine on lymphocytes leads to inhibition of their synthesis of IL-2. However, if T lymphocytes are activated, cyclosporine is not able to suppress the immune response (Fig. 10.2).

Rice. 10.1. Molecular structure (up) and amino acid sequence (at the bottom) in cyclosporine. Unique structure at position 1; is MeBmt, a new unsaturated B-hydroxy-9-carboxylic amino acid: (4H-4-[(E)-2-butenyl)]-4, N-dimethyl-L-threonine. Designations: Abu- a-aminobutyric acid, Sar- sarcosine, MeLeu - N-Meran-L-leucine, Val- valine, Ala-L-alanine* D-Ala- alanine and MeVal- M-methyl-b-valine. (By- Starzl T. E., Shapiro R., Simmons R. L././ Atlas of organ transplantation. - N.Y.: Gower Med. Pub!., 1992. - P. 1. 24.)

Rice. 10.2. Pharmacodynamics of cyclosporine (CS). The drug is absorbed in the gastrointestinal tract and enters the vessels, where a significant part of it binds to cells, and the largest part binds to lipoproteins, while only a small fraction remains “free”. The entry of the drug into the tissue causes immunosuppression of lymphoid cells, on the one hand, and toxic damage to ectodermal and mesodermal structures, on the other. After the drug is taken up by hepatocytes, it is metabolized in them with the participation of cytochrome P-450, which is accompanied by the production of metabolites that are secreted mainly into bile and, to a lesser extent, excreted in the urine. Designations: CNS - central nervous system. (By: Starzi T. E., Shapiro R., Simmons R. L.//Atlas of organ transplantation. - N. Y.: Gower Med. Publ., 1992. - P. 1. 26.)

Side effects of cyclosporine are hirsutism, neurotoxicity, hyperkalemia, nephro- and hepatotoxicity. The most common toxic effects are kidney damage, hypertension and tremor. Clinical trials in kidney, liver, lung, heart and small bowel transplants have shown that cyclosporine provides potential immunosuppression without the hematopoietic suppression associated with antimetabolic drugs.

FK506. An antibiotic from the macrolide group, which, like cyclosporine, is of fungal origin. Like cyclosporine, FK506 inhibits cell activation, but does not prevent the functioning of previously activated T lymphocytes. Its mechanism of action is associated with inhibition of IL-2 production. Although it inhibits the production of interleukin-3 (IL-3) and interferon-γ (IFN-γ), it does not suppress hematopoiesis. ^Preliminary clinical trials have identified two main side effects: 1) anorexia and weight loss and 2) nephrotoxicity associated with vascular changes, including fibrinoid necrosis of small arteries and arterioles. The severity of these effects depends on the dose of the drug.

IMMUNOSUPRESSION DUE TO A DECREASE IN THE NUMBER OF LYMPHOCYTES

Corticosteroids. Steroids penetrate the cell membrane and bind to specific receptors in the cytoplasm of most cells. The steroid-receptor complex then enters the nucleus and interacts with DNA through a mechanism that is unknown. The synthesis of DNA, RNA and proteins is inhibited, as is the transport of glucose and amino acids. With significant doses of steroids, dystrophic and necrotic changes in lymphocytes occur. Cytolysis can be easily induced in vivo, with T lymphocytes appearing to be the most susceptible. The main antilymphocyte effect of steroids may be to deplete the pool of small lymphocytes before they are activated by antigen. Steroids also inhibit most of the ancillary functions of macrophages, including their ability to secrete IL-1. Although steroids have relatively no effect on B cell activity and antibody production, they damage many other cell types involved in transplant rejection. Chemotaxis and phagocytosis of both macrophages and neutrophils are inhibited. The accumulation of neutrophils, macrophages and lymphocytes in the area of immune and inflammatory activity is reduced. Steroids alone cannot prevent clinical manifestations of transplant rejection, but in combination with other drugs they can both prevent and suppress rejection reactions. Typical problems that arise with steroid therapy are hypertension, obesity, ulceration and bleeding from the gastrointestinal tract, euphoric personality changes, cataract formation, hyperglycemia up to steroid diabetes and osteoporosis with avascular necrosis of bones.

Antilymphocyte globulin. Heterologous antilymphocyte globulins (ALGs) are produced when lymphocytes from the thoracic duct, peripheral blood, lymph nodes, thymus or spleen are introduced into the blood of animals of other species. For clinical transplantology, rabbits and horses are usually used for this purpose. Antibodies produced in this crude manner are polyclonal and therefore react with a range of epitopes on the injected lymphocytes of different types.

The action of heterologous polyclonal ALG is manifested mainly against T lymphocytes. ALGs therefore interfere with most cell-mediated reactions - graft rejection, tuberculin reaction and graft-versus-host disease.

Although these drugs, administered in purified intravenous form, have been widely used with success in clinical transplantation to both prevent and control graft rejection, clinicians now have available monoclonal antibodies with more predictable reactivity.

Monoclonal antibodies are used in clinical practice to monitor rejection reactions and monitor changes in lymphocyte subsets during immunosuppressive therapy. Their prototype is OKTZ. OKTZ are monoclonal antibodies against the CD3 antigen that attach to the receptor complex (CD3) of T lymphocytes, which is present on the surface of all mature T lymphocytes. Since the CD3 receptor, to which OKTZs attach, is the signaling part of the T-lymphocyte receptor complex, the function of these lymphocytes is inhibited.

The toxicity of any heterologous antibodies produced against human tissue depends partly on their cross-reaction with other tissue antigens and partly on the ability of the body itself to produce antibodies against foreign proteins. Polyclonal ALG can cause anemia and thrombocytopenia, despite their pre-absorption by platelets and red blood cells. Monoclonal antibodies exhibit minor cross-reactions, but fever, chills, nausea, diarrhea, and aseptic meningitis are common during the first few doses of the serum. All heterologous globulins can be accompanied by allergic reactions to them. These reactions are usually mild and infrequent, but monoclonal antibodies are powerful antigens, so after one or two weeks, antibodies directed against them become less effective as a result of the formation of antibodies directed against them.

Irradiation. Total body irradiation has limited use in clinical transplantation because the toxic effect is too pronounced. The possibility of using fractional dose irradiation of lymphoid tissues (total lymphoid irradiation), similar to that used in the treatment of Hodgkin's disease (Hqdgkin), is being investigated.

COMPLICATIONS OF IMMUNOSUPRESSION

Infections, severe toxic damage to organs and the appearance of malignant tumors are the most common complications associated with the use of nonspecific immunosuppressants. Sometimes the rejection reaction cannot be controlled and can occur despite complex therapy.

Infectious complications. Immunosuppression, due to its nonspecific mechanism of action, increases the risk of infectious complications caused by viral, fungal and bacterial pathogens. Currently, the use of more effective antibiotics and immunosuppressants has shifted the spectrum of microbes towards opportunistic pathogens, which are normally weakly pathogenic or not pathogenic at all.

Viral infections. Viral infections are widespread among kidney transplant patients. The group of herpetic DNA viruses is among the most common etiological factors. Infection or the presence of antibodies to cytomegalovirus (CMV) is detected in 50-90% of kidney transplant patients. Epstein-Barr virus infection (Epstein-Barr), accompanied by post-transplant malignant tumors, is, however, rare.The prophylactic use of the antiviral drugs acyclovir and ganciclovir has led to a significant reduction in viral complications.

The presence of hepatitis B virus antigens after organ transplantation can be detected in many patients, and non-A, non-B hepatitis is likely to cause liver failure in some long-term survivors.

CMV is the most important infectious complication of immunosuppression in the post-transplant period. CMV infection can cause a spectrum of characteristic symptoms such as fever, neutropenia, arthralgias, weakness, myocarditis, pancreatitis, or gastrointestinal ulcers. The highest risk group consists of recipients who do not have antibodies against CMV and who received organ transplants from donors who had such antibodies.

Malignant tumors. Such tumors surprisingly often accompany organ transplants. The incidence of malignant tumors is not so high, but is a known contraindication for organ transplantation. There are two main types of tumors that occur in transplant patients: lymphomas and skin cancers. Inadvertent transplantation of a malignant tumor from a cadaveric donor to an unsuspected donor is a rare cause.

The most common malignancies are primary tumors in recipients receiving immunosuppressive therapy. 75% of malignant tumors are of either epithelial or lymphoid origin. In situ cervical cancer, lip cancer and squamous cell and basal cell skin cancer make up about half of this group, while the other half are B-cell lymphomas. It is estimated that transplant patients have a 4-fold, 40-fold, and 350-fold increased risk of developing cervical cancer, skin cancer, or lymphoma, respectively. Lymphomas appear to be unusual not only in their frequency, but also in their biological behavior.

The results of recent studies convince us that not all lymphomas are true tumors. Immunological analysis showed that these tumors secrete different types of immunoglobulins, i.e. they are not monoclonal, as should be the case with malignant lymphomas. Most evidence suggests that some of these may represent uncontrolled B cell proliferation in response to Epstein-Barr virus in seronegative patients. At this stage, antiviral therapy with acyclovir appears promising.

Itsenko-Cushing syndrome. Most patients receiving steroid therapy after organ transplantation develop Cushing's syndrome.

Gastrointestinal bleeding. Such bleeding as a result of exacerbation of a pre-existing chronic ulcer or diffuse acute ulcers of the stomach and intestines can be fatal.

Other intestinal complications. A number of intestinal complications are associated with immunosuppressive therapy, including diverticulitis, intestinal bleeding, or ulceration. The syndrome of acute cecal ulcers with bleeding is a manifestation of CMV infection. The latter also underlies the occurrence of acute ulcers in other parts of the intestine.

Cataract. Often occurs in patients receiving steroid therapy. Cataracts, which develop slowly, do not appear to be affected by prednisone dosage.

Hypertension. Many of the patients who need a kidney transplant already have high blood pressure. Hypertension is apparently associated not only with prednisone, but also with insufficient regulation of water-sodium metabolism in the early post-transplant period and with the secretion of renin by the kidneys. Hypertension is also a well-known side effect of cyclosporine.

Disorders of calcium metabolism. Renal osteodystrophy is often observed in patients requiring kidney transplantation. Sometimes parathyroidectomy is required to stop the progression of bone damage, but hypercalcemia after transplantation alone is not an indication for this operation.

Complications from the musculoskeletal system. A serious complication of chronic use of nonspecific immunosuppressants is avascular necrosis of the femoral head and other bones. Its frequency is highly correlated with the doses of steroid drugs.

"Pancreatitis. In organ transplant patients, the onset of the disease may be sudden and unexpected, and recurrence may be fatal. The occurrence of pancreatitis is associated with corticosteroid therapy, the action of azathioprine, CMV infection or infection with hepatitis viruses.

Height. After successful transplantation, growth rates in children vary greatly and may be affected by age, previous growth rates, renal function, and immunosuppressant regimen. Many children regain normal growth rates; Unfortunately, the lack of growth during the disease is not compensated for.

Pregnancy. Many children of women with kidney transplants are born normal, despite the mothers taking immunosuppressive drugs. Pregnancy in women with kidney transplants, however, is often complicated by toxicosis, bacterial and viral infections, especially urinary tract infections.

Bone marrow transplantation

Autologous bone marrow transplantation and transplantation from identical twins are very successful. These methods are used to treat radiation sickness, aplastic anemia and leukemia. Because the donor's bone marrow cells are identical to those of the recipient, the transplanted bone marrow is well accepted by the recipient's body and graft-versus-host disease (see below) does not occur. Autologous bone marrow transplantation makes it possible to treat malignant tumors in much higher doses without causing bone marrow damage, which is usually observed as a side effect of anticancer drugs associated with the rapid division of bone marrow cells.

Allogeneic transplantation has been successfully used for a number of diseases. To accept donor bone marrow, the recipient's body must be prepared by using pharmacological drugs or radiation to destroy stem cells in his bone marrow. This is usually done for leukemias, in which the desired outcome is complete replacement of the recipient's bone marrow (and therefore the tumor cell pool) with that of the donor. Unlike other types of transplantation, if the donor bone marrow has engrafted in the recipient, no permanent immunosuppression is required in the future. Such a transplantation leads to a chimeric state when tissues (recipient and donor) from genetically different organisms coexist in the body. Indeed, a transplantation bone marrow provides a unique opportunity to give the body tolerance in the form of permanent receptivity to transplants, for subsequent tissue and organ transplants. The recipient's body becomes tolerant to donor tissues and perceives them as its own. However, if mature T- lymphocytes, they can attack the recipient's body, which is antigenically foreign to them, which leads to the development of graft-versus-host disease (GVHD). The target cells for donor T-lymphocytes are the recipient's epithelial cells, including the epithelium of the skin and liver and gastrointestinal tract, which is accompanied by the appearance of a generalized rash, liver failure, diarrhea and exhaustion. The greater the genetic differences between the recipient and the donor, the more pronounced the GVHD reaction.

Although it was previously thought that the GVHD reaction could not occur in the absence of donor bone marrow, it is now clear that this is not the case. Three factors are essential for the development of a GVHD reaction: 1) recognizable antigenic differences between the donor and the recipient, 2) the immunocompetence of the donor T lymphocytes, and 3) the relative immune deficiency of the recipient.

The use of bone marrow transplantation to create tolerance to subsequently transplanted organs, such as the liver, heart and kidneys, is considered as a potential technique that allows the patient to ensure long-term freedom from rejection of the transplanted organ without permanent nonspecific immunosuppression. Significant experience in this direction exists in the experiment with different animal species, and currently some progress has been made towards the clinical implementation of the method.

Organ transplant

PANCREAS

It has now been revealed that type I diabetes mellitus is a true autoimmune disease, in which immunological tolerance to one’s own tissues is lost, which is accompanied by an immune attack on these tissues. In patients with diabetes mellitus, kidney damage is 17 times more common, gangrene of the extremities is 5 times more common, and heart disease is approximately 2 times more common. Diabetes has become the number one cause of kidney failure requiring hemodialysis or kidney transplantation in the United States today.

Various observations support the hypothesis that angiopathy is partly associated with diabetes mellitus and metabolic disorders.

1. Nephropathy and retinopathy are observed in patients in whom diabetes mellitus has developed as a result of other disease states.

2. Numerous longitudinal clinical studies have demonstrated an association between disease duration, plasma glucose control, and lesion development.

3. Animals with experimental diabetes mellitus develop nephropathy and retinopathy.

4. Animal studies have shown that reduction of hyperglycemia through insulin therapy, whole pancreas transplantation, or islet of Langerhans alone prevents or minimizes diabetic damage to the eyes, kidneys, and nerves.

5. When kidneys are transplanted from normal rats into rats with experimental diabetes mellitus, histological changes characteristic of diabetes develop in these kidneys, while transplantation of kidneys from animals suffering from diabetes into healthy rats is accompanied by the disappearance or inhibition of the progress of the disease.

The modern technique for isolating the islets of Langerhans from the pancreas consists of its mechanical destruction, enzymatic treatment and separation along a density gradient. Portal vein infusion of isolated adult islets results in long-term control of blood glucose levels in diabetic rats. This technique has also been successfully used for islet autotransplantation in people who have undergone total pancreatectomy for chronic pancreatitis.

More than 100 crossings of the islets of Langerhans have been carried out. It has now been proven that transplantation of insulin-producing islets is sufficient to ensure normal glucose metabolism. The clinical application of islet allotransplantation is limited by the obvious increase in sensitivity to islet antigens with the development of graft rejection. Long-term graft survival is difficult to achieve, even with the use of immunosuppression to ensure long-term functioning of skin, kidney or cardiac grafts.

By October 1990, more than 3,800 clinical pancreas transplants had been performed. Cadaveric organs are usually used, and most recipients already have end-stage renal failure. The kidneys and pancreas are transplanted simultaneously. Increasingly, however, as success develops, pancreas transplantation is performed before severe kidney damage occurs. Indeed, 25% of all patients who underwent pancreas transplantation in 1986-1990 did not undergo a simultaneous kidney transplant.

Successful transplantation of the entire pancreas or its segments is accompanied by normalization of insulin and glucose levels in the blood.

Transplant rejection is as difficult to treat as it is to diagnose. By the time glucose levels become abnormal, rejection is usually advanced and irreversible. Serum enzyme activity does not increase and therefore cannot be used to diagnose incipient rejection. However, when an anastomosis is created between the pancreatic duct and the bladder, urine amylase levels can be monitored. When the transplant is rejected, it decreases early. Thus, the most successful technical solution also improves the immune system< логический контроль за реакцией отторжения.

Experience with pancreas transplantation in humans has shown that a vascularized allograft corrects metabolic disorders in diabetes mellitus. Graft survival has been steadily improving; in patients who underwent transplantation in the period 1988-1990, slightly more than 60% of the grafts functioned for 36 months, while in those who underwent surgery in 1978-1982. - only 18%.

GASTROINTESTINAL TRACT

WITH With increasing success, transplantation of several abdominal organs is performed, including liver - duodenum - pancreas, liver - stomach - duodenum - pancreas, or liver and intestines in one block. “Cluster” transplants are performed after removal of the recipient’s liver, pancreas, stomach, spleen, duodenum and proximal jejunum. Most of these operations are performed for extensive but localized intra-abdominal tumor lesions involving the liver or pancreas. :

The clinic now performs small intestine allotransplantation. There are a number of reports of successful operations. Although success is hampered by a GVHD reaction due to the large amount of lymphoid tissue in the intestine, this does not significantly limit the feasibility of surgery. Most often, recipients are children whose intestine was resected due to volvulus or necrotizing enterocolitis.

LIVER

Liver transplantation has served as a successful solution to the problem associated with a number of congenital or acquired liver lesions in thousands of patients. The transplanted liver is usually placed in its normal anatomical location (orthotopic transplant) after the recipient has undergone a total hepatectomy.

Rice. 10.3. Performing orthotopic liver transplantation in an adult (A) and the child (B). The two most preferred methods for reconstruction of the biliary tract are shown. (By: Ascher N./., Najarian J. S. et. at. Manual of vascular access, organ donation, and transplantation / Eds R. L. Simmons et al. - N.Y.: Springer Verlag, 1984)

Indications. Theoretically, liver transplantation is indicated for any disease leading to liver failure. In children, the most common indication for transplantation is atresia of the extrahepatic biliary tract. Transplantation is contraindicated in the following patients: 1) with difficult-to-treat infectious diseases, 2) with extensive tumor lesions, 3) with a competing pathology (for example, heart failure, old age), which significantly worsens survival, 4) with a high risk of disease relapse in transplanted organ; Since active hepatitis usually recurs, the presence of HB s and HB e antigens in the blood may be a relative contraindication. In children, organ size is the main obstacle to liver transplantation and limits the number of possible donor organs. Transplantation of liver grafts of reduced size provides a solution to this problem.

Methodology. Liver transplantation is a relatively simple procedure, although excessive bleeding associated with extensive dilation of venous collaterals as a result of portal hypertension makes removal of the recipient's own liver the most difficult part of the operation. If technical difficulties prevent completion of the liver transplant, the patient usually dies.

In children, the donor liver may be 20% less, JHO may be only minimally more than required.

Allograft anastomoses are shown in Fig. 10.3. The most difficult thing to perform is the suprahepatic caval anastomosis. The second anastomosis is usually a portal vein anastomosis to minimize venous congestion in the intestine. After suturing the portal vein, the clamps should be removed from the subhepatic part of the vena cava for a short time, leaving it clamped in the suprahepatic zone. The clamp is removed from the portal vein to ensure perfusion of the organ with warm blood. This sequence is used to remove cold perfusate from the liver and prevent systemic hypothermia and heparinization. Once the perfusate is washed out of the liver and it becomes thick and pink, a clamp is applied to the subhepatic part of the vena cava, and the clamp is removed from the suprahepatic part. After this, anastomoses are performed between the remaining vessels (hepatic artery, inferior vena cava).

After creating anastomoses between the vessels, the outflow of bile must be ensured. In adults, direct suturing of sections of the bile ducts is preferable. In children, preference is given to common bile duct nostomy.

Postoperative treatment. Treatment of patients in the early post-transplant period is so complex that special protocols are required to ensure that key details are not missed. If renal function is satisfactory, immunosuppression is preferably carried out with cyclosporine and prednisone. If renal function is poor, then cyclosporine is not used, but antilymphoblastic serum is used until the patient's condition is stabilized in the early postoperative period. Mandatory monitoring of the functioning of the liver graft is carried out by biochemical determination of coagulation parameters (especially prothrombin time, factor V level, serum bilirubin, transaminase and alkaline phosphatase activity). Changes in these indicators may signal graft rejection, ischemia, viral infection, cholangitis, or mechanical obstruction.

During the rejection reaction, lymphocytes infiltrate the portal tracts and central veins with varying degrees of damage to the bile duct epithelium; therefore, percutaneous biopsy and microbiological examination seem to be the only way to distinguish between rejection, ischemia, viral infection and cholangitis. For graft rejection, steroids, OKTZ, or antilymphoblastic globulins are initially administered intravenously. The presence of PMN in the portal tracts indicates cholangitis. Patients are prescribed antibiotics and evaluated for mechanical obstruction as a possible cause of cholangitis. CMV hepatitis is treated with ganciclovir.

Recent protocols using this drug prophylactically have shown lower rates of life-threatening infectious complications.

Postoperative complications. The most serious complication is primary organ failure, in which the function of the transplanted liver is insufficient to support the body. This may be due to ischemia, technical factors, or accelerated rejection. 8 Primary organ failure should be suspected first when factor V levels are low. blood levels decrease irreversibly.

Intraoperative bleeding occurs for many reasons; pronounced portocaval shunting almost always occurs, and coagulation disorders almost always occur. Even when adequate hemostasis is achieved during surgery, there is always a particular risk of bleeding in the immediate postoperative period. When suturing the abdominal cavity, coagulation parameters, including platelet counts and calcium levels, should be measured so that appropriate adjustments can be made if necessary.

Thrombosis of the hepatic artery or portal vein causes sudden loss of liver function. Bilirubin levels and transaminase activity increase sharply, signs of bleeding disorders, hyperkalemia and hypoglycemia appear, and a scan reveals that the liver does not absorb the isotope.

Prophylactic oral administration of bactrim, as in the case of kidney transplantation, reduces the incidence of postoperative infections caused by Pneumocystis carinii And Nocardia.

Viral infections are a major problem. The most serious is CMV infection, for which treatment is prescribed with acyclovir or ganciclovir.

Subclinically reversible episodes of rejection are usually detected by liver biopsy if performed weekly. Graft rejection can occur at any time after surgery, including within the first 24 hours, but in most cases it occurs at least several weeks after transplantation.

Transplant results. Although the first liver transplants were performed as early as 1963, operations were not successful until 1967. From this time until 1978, the results of the operation were poor, with a 25-30% one-year survival rate. Adding cyclosporine to prednisone or using prednisone with azathioprine resulted in significant improvements in outcomes, with 1-year survival rates rising to 80%. Liver transplantation is currently considered as the method of choice in the treatment of the final stage of liver failure of any origin.

HEART TRANSPLANT

Story. After the first human heart transplant was performed by Christiaan Barnard in 1967, numerous attempts at similar operations began around the world. Disappointing initial results led to waning interest in the operation.

Indications. Most cases requiring a heart transplant fall under the category of congestive cardiomyopathy, which is a group of diseases of various origins. i “Idiopathic” cardiomyopathies are a heterogeneous group of diseases that make up a significant proportion among the causes of the final stage of pathology, characterized by dilation of the heart chambers, degenerative changes in the myocardium and cardiosclerosis. Viral infections are considered the etiological factor of most “idiopathic” cardiomyopathies.

Ischemic cardiomyopathy is the final manifestation of coronary atherosclerosis. Compared with patients with idiopathic cardiomyopathy, patients with ischemic cardiomyopathy are generally older and have a higher incidence of comorbid problems such as diabetes mellitus and peripheral vascular disease. 90% of patients undergoing heart transplantation suffer from either idiopathic (49%) or ischemic (41%) cardiomyopathy. 10% have end-stage ventricular failure associated with valve damage or a congenital heart defect that cannot be reconstructed. In children, these proportions are different: 93% of all diseases in general are idiopathic cardiomyopathy (49%) and congenital heart defects (44%).

Selection of recipients. Recipients are selected from patients with end-stage New York Heart Association class III-IV ventricular failure who are unlikely to survive more than a year without surgery and for whom there are no alternative treatments.

Contraindications include systemic diseases that may adversely affect survival, such as malignancies, severe peripheral vascular disease or autoimmune vasculitis and renal or hepatic dysfunction, and which are unlikely to resolve after improvement in cardiac output.

Donor assessment. Ischemia time (the time between arrest of coronary circulation and its restoration in an already transplanted heart) should ideally be less than 4 hours. Sizing is carried out to avoid serious discrepancies when creating atrial and vascular anastomoses and hemodynamic disturbances. An extremely important research method is echocardiography, which allows assessing cardiac contractility and identifying focal disorders of contractile function.

Operation on the recipient. To minimize ischemia time, close contact is maintained with the surgical team providing the donor heart to ensure that implantation begins as soon as possible after delivery of the donor heart to the operating room. The recipient's aorta is clamped transversely immediately before the brachiocephalic trunk leaves it, the heart is removed by crossing the great vessels at their commissures and separating the atria from the ventricles along the atrioventricular groove. Both atrial appendages are excised. The posterior sections of both atria are left intact and connected by the interatrial septum. The donor heart is removed from the transport container and trim it accordingly. Implantation is carried out by sequentially suturing the graft to the left atrium, to the right atrium, to the pulmonary trunk and to the aorta. The transverse clamp is removed and spontaneous rhythm is restored. The sinus node of the donor heart becomes the leading pacemaker The recipient's own rhythm often persists, causing regular non-conducted contractions of the tissue of the own atria and an independent wave R on the electrocardiogram after transplantation.

Immunosuppression. The most commonly used combination of drugs is daily oral cyclosporine, azathioprine, and prednisone. The dosage of cyclosporine is adjusted to maintain its appropriate serum level. The side effects of cyclosporine are significant and include nephrotoxicity, hypertension, hirsutism and gingival hypertrophy. The possibility of using FK506, RS61443 and rapamycin as substitutes for cyclosporine is being studied.

Transplant rejection. Monitoring of the graft rejection reaction is carried out by endomyocardial biopsies of the right ventricle, performed at least once a week for 1 month, and then at least as often as indicated in the control table. During each biopsy, right heart catheterization is performed. Most episodes of rejection are characterized by normal hemodynamics, but decreased cardiac output, decreased venous oxygenation, and increased right atrial pressure or wedge pressure suggest incipient rejection. The biopsy is performed during the same venipuncture using flexible biopsy forceps inserted into the right ventricle. Histological signs of cardiomyocyte necrosis (grade 2 or more) are considered a diagnostic sign of severe rejection. Inflammatory infiltration of the 1st degree is considered a pathology, but in the absence of cardiomyocyte necrosis, treatment for graft rejection is not carried out. All episodes suspicious for rejection are considered in their clinical context, especially if the histological findings are equivocal.

\ Approximately 95% of rejection cases are initially treated with steroids, either as a three-day supplement of oral prednisone followed by a dose reduction on days 7 to 10, or with intravenous methylprednisone 1 g per day for three days. Oral or intravenous steroid treatment is effective in 95% of all rejection reactions, with half of the remaining cases requiring emergency treatment. Patients who initially develop hemodynamic instability are at high risk and should receive intensive initial treatment with intravenous steroids and cytolytics.

Results. The one-year survival rate for heart transplants performed in the last 5 years is 80%, compared to 73% in the previous 5 years. In other words, the five-year survival rate today is essentially the same as at the beginning of the past decade. The results of an examination of the functional state of patients 2 years after heart transplantation showed that 85% of them had class I heart failure, and 13% had class II heart failure according to the New York Heart Association classification.

One-year survival rate currently exceeds 80% in patients under 18 years of age, and has increased to 70% in patients under 1 year of age.

Mortality in the first 30 days is consistently 9-10%. It is associated with graft rejection or infectious complications in 40% of patients, as well as with cardiac and other early causes of death, such as poor donor selection, poor preservation of the donor heart, and pulmonary hypertension in the recipient that prevents success. A small number of patients with early donor heart dysfunction can be supported using left ventricular assist devices. Cyclosporine and cytolytic drugs significantly reduce the incidence of early deaths associated with transplant rejection, but do not significantly affect other causes of death.

LUNG TRANSPLANT AND HEART-LUNG COMPLEX

Story. The first lung transplant was a single lung transplant performed in 1963 by Hardy, which was fatal in the immediate postoperative period. Following this attempt, over the next 20 years, 46 single lung transplants were performed, with a mortality rate in the first 18 days of more than 80%, an average postoperative survival rate of 10 days, and a one-year survival rate of 20%. Almost all deaths were associated with failure of bronchial anastomoses.

Selection of recipients. Recipients, who need a lung transplant are patients with the final stage of lung damage, which significantly limits normal life activities, and with a poor prognosis for the next 1-2 years. Obstructive/fibrotic pulmonary diseases such as chronic emphysema, cystic fibrosis and idiopathic pulmonary fibrosis are the most common examples of such pulmonary lesions. In contrast, pulmonary vascular diseases such as primary pulmonary hypertension or Eisenmenger syndrome are characterized by right ventricular heart failure with nearly normal bronchoalveolar function.

Patients with heart defects that cannot be corrected and the final stage of Eisenmenger syndrome should undergo a heart-lung transplant.

Double-lung transplant recipients also undergo a complex operation, but it is not performed on an old patient (under 60 years of age). Current experience suggests that patients with chronic emphysema do well after single lung transplantation. There is a belief among various transplant centers that patients with primary or secondary pulmonary hypertension should receive a double lung transplant to avoid acute or chronic problems associated with shunting in the vessels of the transplanted lung.

A single lung transplant is technically simpler than a double lung or heart-lung transplant, and when selecting candidates for such an operation, older patients (up to 65 years) may be included in the number of recipients.

Postoperative treatment. Lung transplantation poses a special problem (compared to other organ transplantation) in the form of more frequent and more serious complications, which should always be considered when changes in the radiographic picture or in the composition of blood gases indicate a graft rejection reaction. According to the International Society of Heart and Lung Transplantation Registry, infectious complications were the direct cause of death in 34% of heart-lung transplants and in 55% of single-lung transplants. The most important difficulty is the differential diagnosis of transplant rejection and viral pneumonia. Often, the correct diagnosis of CMV lung disease is based entirely on the detection of intracellular bodies in lung tissue obtained by transbronchial biopsy.

Most centers use triple-drug immunosuppression. The prevailing opinion among specialists is that lung transplant rejection occurs more frequently, is more severe, and is more difficult to reverse than heart transplant rejection, and immunosuppression during lung transplantation should be correspondingly more aggressive. . ,..;...

Single lung transplants present the unique challenge of having a second lung of their own.

In recipients with chronic emphysema, the greater compliance of the native lung is accompanied by its overextension during positive pressure ventilation, which can cause a significant displacement of the mediastinal organs, which can negatively affect the return of venous blood and gas exchange.

Patients with a transplanted heart-lung complex in the early postoperative period require inotropic and chronotropic support of the denervated heart and, in addition to the risk of lung graft rejection, are also at risk of rejection of the transplanted heart. Rejection of the heart and lungs can develop independently of each other. For a reason that is not entirely clear, heart graft rejection during heart-lung transplantation occurs much less frequently (p<0,01), чем при пересадке одного только сердца. Эндомиокардиальные биопсии у таких пациентов проводятся по программе с уменьшающейся частотой и через 1 год становятся ненужными.

Results. By the end of 1991, 1212 heart-lung transplants had been performed over 10 years. The one-year survival rate after such an operation is disappointing and, according to the Registry, is 64%. The one-year survival rate for all types of lung transplantation is 68%; for one or two lung transplants, the statistics are almost identical - 69 and 68%, respectively, with a worse result in the case of a two-lung transplant in one block - 57%.

Further prospects. When performing a lung transplant, the problem of diagnosing a potential donor is not solved satisfactorily. The limited number of donors is a strong argument for the priority use of single lung transplants when indicated; three patients could have their lives prolonged if the organs in the heart-lung complex were transplanted individually. There is no doubt that patients with chronic emphysema feel well after a single lung transplant. Double-lung transplantation clearly produces greater improvement in function, with mortality in the first 30 days after transplantation comparable to that of single-lung transplantation, and also avoids the ventilation-perfusion disturbances encountered with single-lung transplantation. Heart-lung transplantation continues to be considered as a reserve in patients with heart pathology that cannot be corrected.

KIDNEYS

The technical concepts necessary to perform a kidney transplant developed at the beginning of the century, when the vascular suture technique was developed. Kidney transplantation is now the treatment of choice for many patients with renal failure, although hemodialysis and peritoneal dialysis serves as an adequate replacement for this; surgery for most patients.

Indications and contraindications. In principle, irreversible renal failure is the only indication for kidney transplantation in patients who do not have urinary outflow disorders, active infection, severe disturbances in trophic status, or metastatic tumor lesions. Diabetes mellitus is now the most common cause of kidney failure in the United States, with approximately 30% of all kidney transplants performed for kidney failure associated with diabetic nephropathy in type I diabetes.

Kidney transplantation, if successful, is accompanied by a significantly greater rehabilitation effect in patients with uremia than hemodialysis or peritoneal dialysis. Diabetics appear to have fewer problems after a kidney transplant than with dialysis. Most patients who have undergone a kidney transplant, even if it is unsuccessful, prefer life with a transplanted kidney to life on chronic dialysis.

Several diseases can recur in a kidney transplant, but these diseases are only a relative contraindication. Among them are focal glomerulosclerosis, hemolytic-uremic syndrome, membranous-proliferative glomerulonephritis with electron-dense deposits and diabetic nephropathy. A number of diseases with metabolic disorders (gout, oxalosis, cystinosis, hyperoxaluria, nephrocalcinosis and amyloidosis) play a minor role, with the exception of the accumulation of pathological deposits in the kidneys associated with renal failure. Kidney transplantation can be successful for most of these diseases, although the transplanted kidney may develop oxalosis.

Preparing for transplantation. The urinary tract should be examined to ensure there are no obstructions to the outflow of urine and the absence of ureterovesical reflux. Usually it is enough to perform cystoureterography during urination.

Tissue typing and donor selection. Due to the limited supply of donor kidneys, many centers do not routinely use HLA matching of cadaveric kidney donors. In addition to HLA matching, it is important to determine whether the potential recipient has antibodies to the donor tissue. Patients who were once sensitized by blood transfusion, pregnancy, or previous transplantation can be identified by testing their serum against a set of normal leukocytes with known HLA properties.

Since many patients have antibodies against the tissues of a potential donor kidney in their blood even before the transplant, immediately before the transplant a test is performed to determine the presence of antibodies against donor leukocytes in the patient’s serum. If such pre-existing antibodies are later found to be present, immediate (hyperacute) or accelerated graft rejection often occurs. P

Selection and examination of living donors. From the recipient's point of view, it is generally preferable for the donor to be a blood relative. Even without antigen matching, kidneys from donors who are siblings or parents of the recipient survive and function better and longer after transplantation than carefully selected cadaveric kidneys. Because genetically determined histocompatibility antigen diversity is determined at a single (complex) locus, there will always be one major allelic difference between parent and child. While one quarter of Bush siblings are identical, half will differ on one haplotype, and one quarter will differ on both haplotypes. Tissue typing| The test is usually able to identify siblings (if they exist) who share all serologically detectable major histocompatibility complex antigens. Such grafts from siblings have a greater than 95% chance of long-term function.

The main antigens that determine whether a person belongs to a certain blood group (A, B, 0) are strong transplantation antigens. Although a number of successful allotransplantations have been performed despite donor-recipient antigenic group differences, it is generally unwise to transplant a recipient with a kidney from a donor with a different blood type. In clinical transplantology, the same rule applies as for blood transfusion, i.e. persons with blood group A, B are universal recipients, and those with group 0 are universal donors. If such group barriers are encountered, the most severe type of hyperacute transplant rejection may develop.

Ethical issues. There is a practice of mandatory informing the recipient about the risks and benefits of receiving a kidney from a relative. The risk to life of an otherwise healthy recipient is 0.05%. The long-term risk is statistically equal to that which a person is exposed to when driving 29 km as a car driver every working day. On the other hand, it has been established that living with one kidney is not accompanied by any long-term adverse consequences.

Selection of cadaveric donor kidneys. Ideally, a person from whose corpse will be removed for a kidney transplant should be: 1) young enough, 2) have a normal body temperature during the immediate period before death, 3) not suffer from a contagious infectious disease or malignant tumor, and 4) before death in In the hospital, he must be examined for several hours, during which his blood type will be determined, tissue antigen typing and a study of urinary function will be performed. Given these ideal conditions, kidneys for transplantation can be removed in minutes to minimize warm ischemia time. Often, however, it would be necessary to compromise on these ideal principles. The age of the donor does not play a decisive role, although kidneys received from young children survive worse in the recipient's body. Donor kidneys, while still in the donor's body, can endure prolonged shock and anuria, which can occur before the donor's death, but the time of warm ischemia - that is, between death and kidney collection - should not exceed one hour.

It is possible to collect kidneys at the time of death and store them in an ice solution for more than 48 hours until recipients are prepared. Currently, kidneys can be preserved by hypothermic perfusion for more than 48 hours. The use of special devices for these purposes has increased the availability of cadaveric kidneys for transplantation, since they can be transported over long distances.

Criteria for brain death. The first problem is establishing the fact of death. Since a conclusion about death is made on the basis of clinical signs by a doctor in the interests of the patient (potential donor), it should be based primarily on clinical signs of irreversible changes in the brain stem: fixed dilated pupils, lack of reflexes and responses to external stimuli, inability to independently maintain vital functions such as breathing, heart rate and blood pressure, without artificially maintaining these functions. A determination of brain death must be made by doctors who have no connection with the potential recipient.

Preparing the operation. Most patients do not need to have their own kidneys removed before transplantation: During preparation for transplantation, the presence of sepsis from any source should be excluded through a thorough examination of the recipient. Common sources of sepsis include: 1) hemodialysis catheters, if present, 2) the bladder in patients with a pre-existing urinary tract infection, 3) skin in uremic dermatitis, and 4) carious teeth. The bladder of anuric patients is often infected and should therefore be flushed with an appropriate amount of antimicrobial agents.

Immediately before transplantation, dialysis must be performed frequently and intensively. Recipients who will receive cadaveric kidney transplants have little time to prepare for the transplant.

Transplantation. Surgical techniques for kidney transplantation have become standard. To approach the iliac vessels, a retroperitoneal approach is used and an anastomosis is created between the renal and iliac vessels. After anastomosis there should be no shortage of circulating blood volume. Hypovolemia adversely affects the rapid resumption of renal graft function. Urine usually appears after completion of vascular anastomoses; maschtol and furosemide may be helpful in accelerating urine production, which is a good indication that there are no serious technical deficiencies.

Post-transplant treatment. Treatment of patients with kidney transplants in the early post-transplantation period does not differ significantly from the treatment of other patients in the postoperative period. The urinary catheter is left in the bladder, which is not flushed; until there is a suspicion that it is clogged with blood clots. Di cut is measured every hour. The volume of urine must be replenished with: three times the amount of liquid. A typical replacement solution consists of half normal saline with 5% dextrose and half water with 10 mmol/L sodium bicarbonate. Patients with diabetes mellitus should receive a constant intravenous infusion of insulin to maintain blood glucose levels at the level of mild hyperglycemia (1.5 * 2 g/l). ;

Diuresis in the early postoperative period may be increased partly due to dysfunction of the tubular epithelium, but primarily due to the state of hyperhydration of the body, even after good dialysis.

Determination of blood urea nitrogen, serum creatinine, and its clearance is extremely important for assessing daily renal function. It is periodically necessary to examine the number of leukocytes and platelets in the blood to assess the state of hematopoiesis during immunosuppression. Hyperglycemia and hypercalcemia occur occasionally as complications, so blood glucose and calcium levels should be assessed from time to time. Patients with diabetes need more frequent monitoring of glucose levels and adjustment of insulin doses.

Preventive immunosuppression. Standard immunosuppression today consists of cyclosporine, azathioprine and prednisone. Because of the nephrotoxic properties of cyclosporine, antilymphocyte globulin (ALG) or azathioprine, or both, are used until kidney function approaches normal. When this function is stabilized, ALG is discontinued and cyclosporine is prescribed. In most centers, a combination of these four drugs is currently used individually for each patient. Complex therapy with drugs with multidirectional effects allows one to achieve maximum immunosuppression with minimal side effects accompanying the use of each drug separately in high concentrations. For episodes of rejection, higher doses of prednisone or methylprednisone are used. Most centers use monoclonal anti-lymphocyte antibodies; used to combat rejection in cases of steroid resistance.

Complications. Kidney failure. Renal failure is best assessed in relation to the time elapsed

after her transplant. The kidney may: 1) not begin to function at all, 2) begin to function late, 3) stop functioning after a short or long period of time, 4) gradually lose its function over months or years. In each case, in the diagnostic plan one should think about: 1) ischemic kidney damage,

2) rejection of the kidney due to a reaction directed against its histocompatibility antigens, 3) technical complications and 4) development of painful kidney damage - a new disease or relapse of a previously existing one.

Early anuria and oliguria. Early anuria and oliguria represent the main diagnostic problem. Their possible causes may be: 1) hypovolemia, 2) thrombosis of the renal artery or vein
3) hyperacute rejection reaction, 4) ischemic kidney damage,
5) compression of the kidney (by hematoma, edematous fluid or lymph),
6) obstruction of the urinary tract.

If oliguria is not associated with catheter blockage, bleeding and hypovolemia in combination with compression and displacement of the kidney by a hematoma should be excluded. If anuria or severe oliguria develops, restoration of circulating blood volume rarely restores renal function, even if furosemide or other diuretics are used. Many patients require reoperation to stop bleeding.

Technical complications. Thrombosis of the renal artery anastomosis is rare. Much more often, partial obstruction occurs as a result of torsion or displacement of blood vessels, which requires immediate elimination. Intrapelvic bleeding is a serious complication that can lead to infection. It requires urgent reoperation.

Hyperacute rejection reaction. Hyperacute renal transplant rejection almost always involves antibodies. The classic hyperacute reaction is now rarely observed because laboratory techniques can detect antibodies directed against donor histocompatibility antigens. Occasionally, a hyperactive reaction occurs in the absence of cytotoxic antibodies. Indeed, cytotoxic antibodies in patients awaiting transplantation are periodically detected or not detected. In a classic hyperacute reaction, the kidney does not restore its normal turgor and healthy pink color after vascular anastomosis. Histological examination of nephrobiopsy material at this time can detect leukocytes in the capillaries of the glomeruli and then vascular thrombosis.

Acute necrosis of the tubular epithelium. If all other causes of renal failure in the early post-transplant period are excluded, one should think about acute tubular epithelial necrosis (ATNE). The term “acute tubular epithelial necrosis” is used in clinical practice to refer to changes in the kidneys whose function is impaired due to ischemia or a number of other reasons. If in this case a nephrobiopsy is performed, most often only hydropic degeneration of the epithelium is detected.

ONEC occurs in a transplanted cadaveric kidney when the kidney has been stressed or hypotensive for a long period of time. Another cause of ONEC may be prolonged warm ischemia preceding transplantation. Kidneys with a warm ischemia time interval of more than 1 hour should not be used for transplantation, since their function is rarely restored to normal. Cold ischemia is much better tolerated and storing the graft for up to 48 hours gives good results.

Treatment of patients with ONEC is simple. Urination is restored in almost all cases after 2 or 3 weeks, but there are cases of anuria lasting up to 6 weeks, ending with complete restoration of function.

Transplant rejection. Most patients experience at least one episode of acute rejection during the first 3-4 months after kidney transplantation. Clinically, rejection is rarely an all-or-nothing reaction, and the first episode rarely progresses to complete graft failure. The functional changes associated with rejection are largely reversible. Therefore, recognizing and treating the onset of rejection before the development of severe kidney damage is extremely important. Rejection is usually suppressed by increasing the dose of prednisone and local radiation.

The clinical presentation of a rejection reaction may be extremely similar to a number of others: ureteral leak or obstruction, bleeding followed by UREC, infection, stenosis or torsion of the renal artery or vein. The classic kidney rejection reaction is characterized by oliguria, graft enlargement and tenderness, weakness, fever, leukocytosis, hypertension, weight gain and peripheral edema. Urine tests reveal lymphocyturia, red blood cell casts, protein, fragments of immunoglobulin and fibrin. There is a decrease in sodium excretion, renal tubular acidosis and an increase in lactate dehydrogenase activity in the urine. The level of urea nitrogen in the blood, as well as serum creatinine, increases. Creatinine clearance is usually reduced; Renograms show a slower absorption of hippuran by the kidney and a slower urine excretion. Sonography may reveal swelling of the renal papillae.

Most institutions have developed a standard scheme for the management of patients after kidney transplantation. This pattern can be repeated up to three times during 2 months in patients in whom, after the development of a rejection reaction, it is not possible to achieve remission.

Results. Outcomes after kidney transplantation are excellent (Fig. 10.4).

Rice. 10.4. A - survival rate (%) of transplanted cadaveric kidneys at UNOS in 1987-1990. compared to the second and third transplants. B - survival rate of kidney transplants received from living donors, a - HLA identical siblings (466), o - children (15.1), V - brothers (sisters) with a similar haplotype (385), G - parents (1230), d - spouses (43). IN - the effect of ignoring the selection of HLA A, B, C DR on the survival of a transplanted primary cadaveric kidney during its first transplantation. Numbers mean the number of cases of ignoring, P - number of patients. (By: Terasaki P.I. Clinical transplants, 1990. - Los Angeles, UCLA Tissue Typing Laboratory, 1991. - P. 2, 8, 590.)

Transplantation in children. The small caliber of blood vessels and the active social behavior of children make their treatment with hemodialysis extremely difficult. It is generally accepted that long-term immunosuppression also interferes with the rate of child development. Chronic hemodialysis rarely gives satisfactory results, and parents are almost always ready to donate their kidney as a donor. Most children with a kidney transplant grow a little slower than normal; as a result, their growth turns out to be significantly higher than with chronic hemodialysis.

Repeated transplants. A number of studies have shown that second and third kidney transplants are less successful than the first. This is especially true if the graft is rejected soon after transplantation. Rejection of one transplant may sensitize the patient to a number of weaker histocompatibility antigens that cannot be easily identified during antigen selection.

Methods of preserving organs for transplantation

When an organ is removed, it is deprived of normal oxygenation. ! The two main approaches to organ preservation can be referred to as the metabolic suppression method and the metabolic maintenance method.

At metabolic depression an attempt is made to prevent severe tissue damage by inhibiting normal catabolic processes. Currently, this is best achieved through hypothermia, which protects the organ by slowing metabolic processes and reducing oxygen demand. Currently, two cooling techniques are used: 1) simple cooling of the kidney by immersion or irrigation with a cold solution and 2) perfusion cooling, which provides a longer storage period.

At metabolic support, In the second approach to organ preservation, they try to maintain metabolic activity at a level as close as possible to physiological. This is usually achieved by perfusion of the organ in vitro with a carefully selected fluid, although oxygenation may also be attempted. In practice, metabolic support is always combined with perfusion cooling. The best systems currently use a pulsating pump and a special container filled with homologous plasma passed through a membrane oxygenator. Not all organs can be perfused well enough with this approach. A few warnings are in order. The period of time between the cessation of blood flow through the organ and its placement in a new environment (warm ischemia time) is critical for the preservation of the kidney. Temperature is also important. The latest perfusion systems include a hypothermia device to reduce the organ's need for oxygen and nutrients. Oxygenation also plays an important role. Oxygen dissolves better in an aqueous solution at lower temperatures; a membrane oxygenator is built into the system.

Another factor is pulsation. Perfusion is accompanied by less damage to the organ when fluid is pumped into its vessels in a pulsating manner, usually at normal temperature. The need for pulsatile perfusate delivery during hypothermia has not been precisely documented. The composition of the perfusate is of undoubted importance. Whole plasma is probably the most physiological perfusate and contains the greatest amount of nutrients, including fatty acids, that may be needed to support organ metabolism. The use of the UW (University of Wisconsin) composition recently developed for perfusion is accompanied by improved results of transplantation of cadaveric organs, including liver and kidneys, and a longer time of permissible organ ischemia.

There is evidence that organ transplantability and survival after transplantation are largely dependent on adequate perfusion during storage prior to transplantation.

Another important factor causing disturbances in blood flow in the transplanted organ is microvascular blockade. Many causes of this blockade have been described, including bubble formation in the perfusion system, fibrin precipitation, red blood cell agglutination, platelet and leukocyte adhesion to endothelial cells, cell damage due to technically poor perfusion, crystal formation, and even bacterial agglutination. Lipoproteins have been described as aggregate-forming materials. Fortunately, these substances can be easily removed from plasma by freezing, which causes the lipoproteins to flocculate, which can then be removed by filtration and/or ultracentrifugation.

Transplant rejection reaction: why it occurs and how to eliminate it. Transplant rejection Severe signs of foreign tissue rejection

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