Kidney transplantation, presence of transplanted kidney, failure and rejection of renal transplant: clinical guidelines

List of Abbreviations

HLA – human leukocyte antigen, human major histocompatibility complex

IgG – immunoglobulin G

IgM – immunoglobulin M

mTOR – mammalian target of rapamycin

ALT – alanine aminotransferase

anti-HLA – anti-HLA antibodies

ACE – angiotensin-converting enzyme

AST – aspartate aminotransferase

HIV – human immunodeficiency virus

GGT – gamma-glutamyl transferase

DNA – deoxyribonucleic acid

PAD – peripheral artery disease

RRT – renal replacement therapy

IL-2 – interleukin-2

CHD – coronary heart disease

BMI – body mass index

IMPDH – inosine monophosphate dehydrogenase

IF – interstitial fibrosis

TA – tubular atrophy

CT – computed tomography

NMU — nomenclature of medical services

DGF – delayed graft function

PCR – polymerase chain reaction

РКИ – randomized controlled trial

GFR – glomerular filtration rate

TIA – transient ischemic attack

KT – kidney transplantation (MRM: kidney transplant).

US – ultrasound examination

CKD – chronic kidney disease

CVP – central venous pressure

ECG – electrocardiography (MRM: electrocardiogram recording)

EchoCG – echocardiography

Terms and Definitions

Allograft – a donor organ obtained from a non-identical twin human and surgically placed into the recipient's body.

Hemodialysis– a method based on the principle of diffusive and filtration transfer of low-molecular-weight substances and fluid through a semipermeable membrane between extracorporally circulating blood and dialysate.

Living (related) donor– a competent individual aged 18 years or older who has given consent to provide and/or has provided their donor organ during their lifetime for related transplantation.

Renal replacement therapy– a set of specialized methods to replace excretory renal function. These include dialysis (hemo- and peritoneal) and kidney transplantation. The latter restores the full range of lost renal functions.

Acute kidney injury is a pathological condition developing as a result of a direct acute impact of renal and/or extrarenal damaging factors, lasting up to 7 days and characterized by the rapid (hours to days) development of signs of renal damage or dysfunction of varying severity. Since acute renal parenchymal injury can be caused not only by renal (kidney) factors, but also by prerenal and postrenal factors, the English term "acute kidney injury" corresponds to the translation "острое повреждение почек" (acute kidney injury). The term "острое почечное повреждение", which arose by analogy with the term "acute renal failure", is not recommended for use.

Renal allograft rejection– a pathological process in which the recipient's immune system recognizes the kidney graft as foreign, activating antibody-mediated (humoral) and/or cellular inflammatory responses, which can lead to severe graft dysfunction.

Peritoneal dialysis– a method of renal replacement therapy based on diffusive exchange, filtration, and convective transfer of low- and medium-molecular-weight substances, proteins, and fluid from the blood into the dialysate located in the peritoneal cavity through the peritoneal membrane.

Deceased (cadaveric) organ donor – an individual declared dead in the prescribed manner (biological death or brain death) who serves as a source of organs (transplantable objects).

Potential kidney recipient — a patient with stage 5 chronic kidney disease who has no contraindications to kidney transplantation and is included in the waiting list.

Kidney transplant recipient– a patient who has undergone kidney transplantation and is undergoing a set of therapeutic measures aimed at preventing graft dysfunction caused by such pathological processes as rejection, recurrence of primary disease, infectious lesions, nephrotoxic drug effects, and others.

End-stage renal disease (ESRD)– a pathological condition characterized by a GFR of less than 15 mL/min/1.73 m², corresponding to stage 5 CKD.

Kidney transplantation– a medical technology aimed at replacing irreversibly lost renal function, which inherently includes surgery to move a kidney obtained from another person (donor) into the recipient's body with restoration of blood supply and urine outflow (MRM: kidney transplant).

Kidney transplantation– a surgical operation and a method of renal replacement therapy consisting of transplanting a kidney obtained from another person.

Chronic kidney disease– kidney damage or decreased function lasting for 3 months or more due to various etiological factors, anatomically based on the replacement of normal structures with fibrosis leading to dysfunction. The disease is classified into 5 stages, which differ in management tactics and the risk of end-stage renal disease and cardiovascular complications.

1. Brief information on the disease or condition

These guidelines describe medical care technologies involving evaluations to select management tactics for patients with end-stage chronic kidney disease, determine indications for kidney transplantation, establish the procedure for placing patients on the waitlist, and stabilize clinical status and assess the potential for recovery/rehabilitation after kidney transplantation. The global goal of kidney transplantation is the longest possible satisfactory function of the renal allograft and maximum patient survival in a dialysis-free state.

The causes of renal graft failure are quite diverse. In the early post-transplant period, they are primarily associated with surgical complications such as severe ischemic and reperfusion injuries, graft vascular thrombosis and stenosis, wound infections, and urological complications. Another major cause of loss is the immunological reaction to foreign antigens, manifested as hyperacute (antibody-mediated), accelerated, acute cellular, and chronic antibody-mediated rejection. In the long-term period, a significant proportion of graft losses is attributed to calcineurin inhibitor nephrotoxicity, recurrent renal disease, and patient death with a functioning graft.

These guidelines are intended for transplant surgeons, nephrologists, and general practitioners.

1.1 Definition of the disease or condition

Kidney transplantation– a medical technology aimed at replacing irreversibly lost renal function, including as an essential stage a surgical intervention consisting of moving a kidney obtained from another human (donor) into the recipient's body with the restoration of blood supply and urine outflow.

Kidney recipient– a patient who has undergone a kidney transplantation procedure, who is undergoing a set of therapeutic measures aimed at preventing renal graft dysfunction caused by pathological processes such as rejection, recurrent pathology, infectious lesions, drug nephrotoxicity, and others.

Renal allograft rejection– a pathological process in which the recipient's immune system recognizes the kidney graft as foreign, activating an antibody-mediated (humoral) and/or cellular inflammatory response, which can lead to pronounced graft dysfunction.

Age category: adults, children;

Gender: any;

Stage: C5, end-stage (according to the CKD staging and stratification classification by GFR level);

Complications: necrosis and rejection of the kidney graft;

Type of medical care: high-tech medical care, compulsory medical insurance;

Care settings: outpatient, inpatient;

Form of medical care delivery: elective, urgent, emergency.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The indication for kidney transplantation is stage 5 chronic kidney disease (CKD) requiring renal replacement therapy. The very concept of CKD is supra-nosological [1,2], but CKD is not a formal combination of chronic kidney injuries of various origins. The etiology and pathogenesis of CKD are detailed in the clinical guidelines for CKD [3].

Despite the fact that attempts to provide a systematic assessment of the etiological causes of CKD can still be encountered (most often, the causes of end-stage CKD are glomerulonephritis/glomerulosclerosis (46.1%), diabetes mellitus (12%), polycystic kidney disease (10%), pyelonephritis (9.4%), as well as vascular kidney diseases (1.2%), nephropathies of unknown etiology (3%), and other kidney disease causes (13.3%) [4]), it is now clear that this condition is polyetiological, and primary importance should be given to assessing risk factors for the development and progression of the chronic pathological process in the renal tissue. Only by taking such factors into account, assessing their significance and modifiability, can primary and secondary prevention measures for chronic kidney diseases be effectively implemented (see Table 1) [5-16].

Table 1. Main risk factors for CKD development

The etiology of having a transplanted kidney is the surgical procedure performed to move it from the donor's body into the recipient's body, the purpose of which is to provide one of the options for renal replacement therapy. A patient who has undergone kidney transplantation surgery is called a kidney recipient.

In turn, renal graft rejection is a pathophysiological process involving innate and acquired immune responses in the recipient's body in response to the appearance of donor allogens. Cells of the immune system, as well as immunologically active molecules—immunoglobulins (antibodies) and cytokines—take part in the rejection reaction. The result of this interaction is the recognition of the antigenic foreignness of the graft and its destruction. Rejection is one of the significant factors determining the prognosis after kidney transplantation. Being a manifestation of the recipient's defense reaction against foreign cells, the rejection reaction includes mechanisms of innate, cellular, and antibody-mediated humoral immune responses. The rejection process is implemented through T-cell-mediated (type IV hypersensitivity reaction) or antibody-mediated cytotoxicity (type II hypersensitivity reaction).

Depending on the pathogenesis, renal graft rejection can be divided into the following categories [17,18]:

Hyperacute rejection: develops immediately—within an hour after the restoration of blood flow, and is caused by preformed antibodies against blood group antigens (AB0) and the major histocompatibility complex (HLA). The pathogenesis of hyperacute rejection includes the formation of antigen-antibody complexes on the endothelium of the graft vessels, which leads to endothelial cell damage, impaired vascular permeability, altered hemorheological parameters, and the appearance of disseminated microvascular thrombosis in the graft. Currently rare due to the availability of highly sensitive pre-transplant crossmatching tests.

Acute rejection: can occur at any time after transplantation, usually within days or weeks following transplantation.

1) Antibody-mediated rejection due to endothelial injury of the graft by circulating donor-specific alloantibodies. Activated T lymphocytes can stimulate B lymphocytes, promoting their activation, proliferation, and differentiation into antibody-producing plasma cells. Humoral (or antibody-mediated) rejection is primarily driven by recipient antibodies against the vascular endothelial antigens of the donor organ. It is diagnosed based on morphological signs of antibody-mediated renal injury, such as microvascular inflammation of the glomeruli (glomerulitis) or peritubular capillaries (peritubular capillaritis) combined with the deposition of the C4d complement component.

2) Acute T-cell-mediated rejection is a delayed-type hypersensitivity reaction (type IV reaction) driven by activated T lymphocytes, characterized by lymphocytic infiltration of the tubules, interstitium, and sometimes the arterial intima. Signs of rejection appear no earlier than 24–48 hours after transplantation, most commonly within the first 3–6 months after kidney transplantation.

Chronic rejection: usually develops more than 3 months after transplantation. Its mechanism is not fully understood; presumably, chronic rejection is a consequence of the activation of both specific cellular and humoral immunity in response to the presentation of donor alloantigens by antigen-presenting cells (APCs).

Mixed rejection: a combination of signs of acute rejection superimposed on chronic rejection.

Since in the vast majority of cases the kidney is obtained from a donor with a different genotype than the recipient, the rejection process begins from the moment of organ reperfusion and continues throughout the entire period of its presence in the recipient's body. Therefore, patients who have undergone kidney transplantation surgery receive continuous maintenance immunosuppressive therapy aimed at slowing down the processes of immunological damage to the donor organ.

1.3 Epidemiology of the Disease or Condition

According to World Health Organization statistics, in 2010 about 2.6 million people received renal replacement therapy [19], and by 2030 this number is estimated to increase to 5.4 million. In 2020, kidney transplantation was performed in 93 countries worldwide, with a total of 81,005 procedures (10.4 procedures per 1 million population) [20].

According to the report of the All-Russian Renal Replacement Therapy Registry of the Russian Dialysis Society [21], the prevalence of renal replacement therapy in Russia in 2020 was 414.2 patients/million, the total number of patients receiving dialysis therapy as of December 31, 2020, was 50,563 people (83.5% of the total number of RRT recipients), and 9,984 (68.3 patients/million) people were living with a functioning kidney graft. According to the 15th report of the Russian Transplant Society registry, in 2023, 1,817 kidney transplantations were performed in Russia (12.4 operations per 1 million population). Compared to 2022, the number of kidney transplants increased by 16.3% (+255). The number of deceased-donor kidney transplants in 2022 was 1,620. The number of living-related donor kidney transplants was 197. In 2022, 8 kidney transplant centers performed more than 50 operations per year: Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs of the Ministry of Health of Russia (359), N.V. Sklifosovsky Research Institute for Emergency Medicine of the Moscow Healthcare Department, Moscow (238), S.P. Botkin City Clinical Hospital of the Moscow Healthcare Department, Moscow (118), Republican Clinical Hospital, Kazan (116), N.A. Lopatkin Scientific Research Institute of Urology and Interventional Radiology – branch of the National Medical Research Center of Radiology of the Ministry of Health of Russia, Moscow (76), Kuzbass Regional Clinical Hospital named after S.V. Belyaev, Kemerovo (64), Moscow Regional Research Clinical Institute named after M.F. Vladimirsky, Moscow Region (63), Samara State Medical University of the Ministry of Health of Russia, Samara (51). From 30 to 49 operations per year were performed by 11 centers, and another 12 centers performed from 15 to 29. The remaining 19 (38%) performed fewer than 15 kidney transplants per year. In 2023, living-related kidney transplants were performed in 30 centers (60%), with a total of 197 transplantations. Only 4 kidney transplant centers performed 7 or more operations per year: Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs (96) and its branch (9), National Medical Research Center for Children's Health (11), Academician B.V. Petrovsky National Research Center of Surgery (8), V.I. Razumovsky Saratov State Medical University (7). At the same time, 53.3% of all living-related kidney transplants in the Russian Federation are performed by the Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs and its branch (105). The average rate of living kidney donation in 2023 was 10.8% of the total number of kidney transplants (in 2022 – 14.6%). Kidney transplantations in children (minors up to 17 years of age inclusive) in 2023 were performed in 6 centers, with a total of 133 transplantations (in 2022 – 118), including at the Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs (61), the Russian Children's Clinical Hospital (41), and the National Medical Research Center for Children's Health (20) [22].

1.4 Features of Coding the Disease or Condition

Since kidney transplantation is a type of renal replacement therapy used for end-stage renal diseases, coding the disease must also take into account the classification of chronic kidney disease specified in the clinical guidelines for CKD [323].

To code the etiological factor (the disease that led to CKD), appropriate ICD-10 codes must be used in addition to the primary code. To code CKD complications and associated conditions, appropriate ICD-10 codes must be used in addition to the CKD code in accordance with the clinical guidelines for CKD [323].

To indicate the presence of a transplanted kidney in the absence of any signs of its dysfunction—clinical, laboratory, instrumental, or morphological—it is recommended to use the code Z94.0 – Presence of kidney transplant.

In case of detecting signs of dysfunction or structural changes in the renal graft (see section 1.5.1), it is necessary to use the code T86.1 – Kidney transplant failure and rejection.

1.5 Classification of the disease or condition

Due to the large number of different aspects in kidney transplantation, there are several classifications in use. Regarding the kidney transplantation procedure itself, the following classification can be applied (Table 2):

Table 2. Classifications of kidney transplantation

1.5.1 Classification of renal graft rejection

The Banff classification, which is an attempt to standardize pathological findings in renal graft biopsies, was created at a conference held in Banff, Canada, August 2–4, 1991, and was first published in 1993. Currently, its 2022 modification is used [24].

Banff lesion criteria evaluate the presence and severity of histopathological changes in various compartments of the renal graft biopsy, focusing primarily, but not exclusively, on diagnostic features observed during rejection. These lesion scores alone are not always sufficient; additional diagnostic parameters may be required to establish a diagnosis. The Banff classification of renal allograft rejection (2022) is presented in Appendix A3.

1.6 Clinical presentation of the disease or condition

1.6.1 Clinical presentation

Kidney transplantation is a medical technology aimed at replacing irreversibly lost renal function. As an essential stage, it includes a surgical intervention involving the transfer of a kidney obtained from another person (donor) into the recipient's body, with the restoration of blood supply and urine outflow. Consequently, it cannot be described in terms of the clinical presentation of a disease. The clinical picture of end-stage renal disease is described in the relevant section of the clinical guidelines for "Chronic Kidney Disease" [3].

The presence of a transplanted kidney is identified during history taking by establishing the fact that the patient has undergone kidney allotransplantation, through physical examination revealing a postoperative scar (typically in the left or right iliac region—in most cases, the renal graft is also palpable in these areas), and by using instrumental imaging methods (ultrasound, computed tomography, magnetic resonance imaging, and radioisotope scintigraphy) that visualize the renal graft. The diagnostic value of imaging methods is higher because the patient may have undergone a third or fourth kidney transplantation, in which the postoperative scar and renal graft may be located in an atypical site. It should be noted that the condition described by code Z94.0 (presence of a transplanted kidney) implies a well-functioning renal graft without surgical complications, functional defects, or signs of rejection. If the aforementioned disorders are present, the ICD code T86.1 is used to describe the condition. The causes of renal graft dysfunction are broad and diverse: hemo- and urodynamic, infectious, recurrent pathology, calcineurin inhibitor-induced nephrotoxicity, and the immune system's reaction to foreign allogeneic antigens. Nevertheless, the primary focus of these clinical guidelines regarding the etiological causes of renal graft dysfunction is renal graft failure and rejection (T86.1).

Clinically, renal graft dysfunction can manifest with various symptoms and syndromes. It may present either as acute kidney injury or as the progression of chronic kidney disease manifested by a decrease in the glomerular filtration rate. At the same time, renal graft dysfunction immediately after the transplantation surgery may be a variant of the natural course of the post-transplantation period, during which gradual recovery of renal function occurs. This condition can be considered analogous to the recovery of renal function in acute kidney injury. The complexity of managing a patient with delayed graft function lies in the fact that a rejection reaction may develop against the background of graft dysfunction caused by ischemic and tubular epithelial injuries.

Acute cell-mediated rejection.

Acute cellular rejection most commonly develops no earlier than the fourth day and can occur throughout the entire lifespan of the renal graft; it is primarily driven by activated T lymphocytes. During the first year after kidney transplantation, acute cellular rejection develops in 5–20% of recipients. In the majority of patients, early acute graft rejection presents with typical clinical signs: decreased urine output, elevated blood pressure, graft enlargement and increased firmness detected upon palpation, altered renal blood flow patterns detected by ultrasound, and elevated serum creatinine and urea levels. At the same time, in some patients, graft rejection may lack overt clinical manifestations and present with nonspecific symptoms—general malaise, fatigue, weakness, nausea, vomiting, and fever. This necessitates regular scheduled follow-up examinations by a nephrologist, as well as laboratory and instrumental studies aimed at assessing the condition of the renal graft and determining indications for biopsies to enable early detection of rejection signs and timely initiation of treatment.

Antibody-mediated rejection and microvascular inflammation/injury (humoral rejection).

Humoral (antibody-mediated) renal graft rejection is one of the main causes of renal graft failure. Antibody-mediated rejection can manifest as rapid graft dysfunction in the early post-transplantation period, but it may also have an insidious or subclinical onset, appearing later after transplantation. At the same time, signs of humoral rejection can be detected on histological examination of tissue samples in the absence of any clinical symptoms. HLA antibodies may also be present prior to transplantation (preformed donor-specific antibodies) or form de novo after transplantation under conditions of insufficient immunosuppression. In some cases, morphological signs of rejection are present without the detection of HLA antibodies. Based on the time of onset of clinical manifestations, antibody-mediated rejection can be divided into early (<30 days post-transplantation) and late (>30 days post-transplantation) in patients with preformed and de novo donor-specific antibodies, which may influence the choice of treatment tactics for the kidney recipient with rejection [25].

Early antibody-mediated rejection is typically observed in high-risk sensitized patients (with preformed donor-specific antibodies). This form of active rejection is usually accompanied by a sharp increase in donor-specific antibodies and allotransplant dysfunction (elevated creatinine, oliguria with or without proteinuria). If left untreated, cortical necrosis and graft loss may develop within several days. As a rule, C4d deposition and signs of active antibody-mediated rejection are noted upon morphological examination of the graft [26]. Interstitial hemorrhages, fibrin thrombi, and glomerular capillary necrosis may be detected. With the timely initiation of treatment, recovery of allotransplant function is possible [26,27].

In other cases, signs of active antibody-mediated rejection persist, leading to chronic active antibody-mediated rejection and allotransplant dysfunction progressing to complete loss of function.

In most patients, signs of antibody-mediated rejection are observed more than 30 days post-transplantation. The clinical picture is characterized by a gradual but steady decline in the GFR and/or proteinuria, ultimately leading to graft failure over the course of several years [28,29]. Morphological examination of the graft in such patients reveals predominantly signs of microvascular inflammation (in glomeruli and peritubular capillaries) and C4d deposition [30,31]. The form of antibody-mediated rejection associated with de novo DSA production (>3 months post-transplantation) also manifests as graft dysfunction combined with prior or concomitant cellular rejection. One study showed that the rejection form associated with de novo DSAs has a more aggressive course and is accompanied by poorer renal graft survival; however, it cannot be excluded that such outcomes in the study were related to later diagnosis of rejection [32].

2. Diagnostics, medical indications and contraindications for diagnostic methods

2.1 Complaints and Anamnesis

Comment: kidney transplantation may not be indicated for patients with mental disorders if it is impossible to ensure an adequate immunosuppressive therapy regimen. Transplantation can be performed if the patient is capable of adequately understanding and following the necessary procedures and therapy.

• All candidates for kidney transplantation are recommended to abstain from tobacco use at least 1 month prior to being placed on the waiting list or undergoing living-related donor transplantation [36–39].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comment: the periods of recommended disease-free survival of malignant neoplasms prior to kidney transplantation in patients with CKD are presented in Appendix A3.

Comment: obesity is a major risk factor for the development of diabetes mellitus, arterial hypertension, and cardiovascular disease. Nevertheless, kidney transplantation helps to increase the life expectancy and quality of life of overweight dialysis patients.

Obesity is widespread in developed countries and is increasingly common in developing countries. In the US, nearly 70% of the adult population is overweight or obese, and 6.7% have stage III obesity (BMI ≥ 40). Obesity as part of the metabolic syndrome is a strong risk factor for stage 5 CKD. However, no clear association between obesity and end-stage CKD in the absence of metabolic syndrome has been identified.

Obesity was associated with an increased incidence of surgical complications, such as wound infection (P < 0.001), anastomotic leak (P = 0.023), and lymphocele (P = 0.010). A BMI ≥ 25 is an independent risk factor for delayed graft function and primary non-function. In addition, the length of hospital stay was significantly longer in the obese patient groups compared to normal-weight and overweight patients. Mean survival is significantly lower in obese patients. For patients with grade II or III obesity (BMI ≥ 35 kg/m²), a consultation (examination, counseling) with a clinical nutritionist or bariatric surgery is advisable. There are no strict BMI restrictions when placing patients on the waiting list.

Some studies have shown that robotic transplantation has better outcomes in obese patients [46]. Kidney transplantation in patients with a BMI ≥ 40 kg/m² should be approached with caution. In such cases, it is important to warn patients about the extremely high risk of post-transplant complications.

In the UK, between 2015 and 2021, only 0.2% of transplants were performed in recipients with a BMI ≥ 40 kg/m². Most transplant centers do not perform kidney transplantation in severely obese patients. Successful transplantation is possible in patients with a BMI ≥ 40 kg/m², but carries additional risk. Obesity should not be the only factor considered when deciding on the feasibility of kidney transplantation. To optimize outcomes, restriction of transplantation to a small number of high-volume centers should be considered.

Comments: patients with a history of coagulopathy require additional evaluation and special attention, since hypercoagulability can lead to graft vessel thrombosis and graft loss, while hypocoagulability can lead to bleeding and recipient death. A history of vascular access thrombosis or prolonged bleeding suggests coagulopathy [48-51].

2.2 Physical Examination

Comments: the psychosocial evaluation of potential kidney transplant candidates is usually performed in an interdisciplinary context. This provides an opportunity to assess the patient's psychological and behavioral health, as well as the family and social environment, which can facilitate or hinder adaptation to the complexities and challenges of chronic illness, transplantation, and lifestyle modification [52-56].

Comments: all kidney transplantation procedures are associated with the risk of wound complications, including infection and hernia formation, which is partly due to the effects of immunosuppressants on wound healing. Comorbidities that increase this risk include diabetes, polycystic kidney disease, previous surgical procedures (including a history of transplantation or hernioplasty), and tobacco smoking. The incidence of postoperative hernia is approximately 7% at 10 years and doubles in patients who lead an active lifestyle or are smokers. Wound healing is also affected by the development of superficial and deep tissue infections. Risk factors for post-transplant wound infections include obesity, diabetes, peripheral vascular disease, rheumatologic diseases (including lupus), and prior substance use [57-59].

Overweight patients have a higher incidence of surgical and non-surgical complications, as well as an increased risk of delayed graft function [20].

Comments: dental examination is important to identify oral infections and sanitize sources of infection prior to transplantation and the initiation of immunosuppressive therapy. Diabetics have an increased risk of periodontal disease [61-63].

Comments: it is suggested to refrain from placing patients on the waiting list earlier than 6 months after a stroke or 3 months after a TIA. Patients should undergo carotid artery screening [69-72].

Comments: diabetic nephropathy is the most common cause of CKD. Due to the higher prevalence of comorbidities among patients with diabetes mellitus, the likelihood of kidney transplantation is somewhat lower than in patients with CKD caused by conditions such as glomerulonephritis and polycystic kidney disease; therefore, these patients require more thorough preoperative preparation. Lower patient and renal survival rates in diabetic patients have been observed for many years, which is explained by a higher incidence of vascular, surgical, and infectious complications [73-75]. De novo post-transplantation diabetes mellitus is a common complication occurring in 10–40% of recipients [76].

• If simultaneous pancreas-kidney transplantation is not feasible, it is recommended to consider a patient with type 1 diabetes mellitus and stage 5 chronic kidney disease as a candidate for islet cell transplantation to improve glycemic control, increase hypoglycemia awareness, reduce the rate of progression of renal graft dysfunction, and improve patient survival [312,313,314,315,345-346].

AG RLE 2Level of Recommendations Assurance A (Level of Evidence – 2) - adults.

AG RLE 4Level of Recommendations Assurance C (Level of Evidence – 4) - children.

Islet cell transplantation in patients with type 1 diabetes mellitus can be performed either simultaneously with kidney transplantation or after kidney transplantation, and is not accompanied by an increased risk associated with immunosuppression, since kidney transplant recipients receive this therapy for life. Furthermore, islet cell replacement therapy leads to a slower rate of progression of renal failure and higher graft and patient survival rates [314,315,316].

Donor pancreas utilization rates are higher with islet cell transplantation (40% donor pancreas utilization) [317] than with pancreas transplantation (17.6% donor pancreas utilization) [318]. A multicenter prospective phase III study demonstrated a reduction in the number of severe hypoglycemia episodes and an improvement in overall glycemic control. Approximately half of the patients discontinued insulin therapy within 1 year [319, 320]. Confirmation of these results was obtained in another multicenter study using the same endpoints: HbA1c < 7% and elimination of severe hypoglycemia episodes in 82% of recipients, discontinuation of insulin therapy in 53% at a median of 26 months, and 35% remaining insulin-independent at the end of follow-up [321,344-346].

Comment: immunosuppressive therapy after kidney transplantation may cause exacerbation of certain diseases and pathological conditions, which in turn can lead to life-threatening complications. Typical examples include diverticulosis (with or without prior episodes of diverticulitis), cholelithiasis, and hyperparathyroidism. Pre-transplant management in such cases should be determined by a multidisciplinary team (involving various specialists) and take into account the specifics of the particular clinical case. Kidney diseases characterized by a high recurrence rate leading to early graft loss are a contraindication to kidney transplantation. Such nosological groups include Waldenström's disease, primary oxalosis, and others.

2.3 Laboratory Diagnostics

Comments: for deceased-donor kidney transplantation, the potential kidney donor and recipient must be ABO blood group compatible [33,35,81-83].

Comments: in deceased-donor kidney transplantation, preference should be given to recipients with the highest level of match for major histocompatibility complex antigens (genes). At the time of transplantation, the recipient must have a negative complement-dependent lymphocytotoxic crossmatch result [33,35,85-89].

Comments: human immunodeficiency virus (HIV-1 and HIV-2), hepatitis B virus (HBV), and hepatitis C virus (HCV) must be ruled out in potential donors. Cytomegalovirus (CMV) infection and Epstein-Barr virus are not contraindications for organ donation and are the most common clinically significant viral infections following kidney transplantation. However, they increase the risk of chronic graft dysfunction, as well as post-transplant lymphoproliferative disorders and opportunistic infections, and therefore require laboratory monitoring via molecular biological blood testing in the post-transplant period [35,92-99].

2.4 Instrumental Diagnostics

Comment: potential kidney recipients without obvious clinical manifestations of peripheral artery disease (PAD), but at risk for it, should undergo non-invasive vascular testing. Potential kidney recipients with symptomatic PAD should undergo imaging and treatment for PAD after consultation with a cardiovascular surgeon (phlebologist) prior to kidney transplantation. Potential kidney recipients with symptomatic PAD must undergo computed tomography of the abdominopelvic cavity to assess arterial calcification and clarify the clinical picture for surgical planning [104,105]. Our expert opinion is that duplex scanning of the pelvic and lower extremity vessels (arteries and veins) prior to kidney transplantation should also be performed in children to evaluate potential vascular developmental anomalies.

Comment: potential kidney recipients who have been on dialysis for at least two years or have risk factors for pulmonary hypertension (e.g., portal hypertension, connective tissue disease, congenital heart disease, chronic obstructive pulmonary disease) must undergo echocardiography. There is evidence that abnormal echocardiography results and positive non-invasive stress test results are significant prognostic factors for coronary artery disease, cardiac events, and patient death. There is currently no conclusive evidence that coronary angiography is required in asymptomatic patients with a negative non-invasive stress test.

2.5 Other Procedures

Comment: to monitor graft function, blood creatinine and eGFR should be assessed daily for 7 days postoperatively, 2-3 times a week for 4 weeks, once a week during months 2 and 3, every 2 weeks during months 4-6, monthly during months 7-12, and subsequently every 3 months (Appendix A3).

Calcineurin inhibitor blood concentrations should be measured every other day until the target level is reached postoperatively, twice a week for the first month, once a week for the second month, every 2 weeks for the third month, monthly for a year (4-12 months), and subsequently every 3-4 months.

Comment: post-transplant diabetes mellitus (NODAT) is reported to occur in 4–25% of kidney transplant recipients. Risk factors for NODAT include older age, family history of type 2 diabetes, obesity, systemic corticosteroids, and calcineurin inhibitors (tacrolimus** carries a higher risk than ciclosporin**) [126,127].

Kidney transplant recipients who develop NODAT have a 2-3 times higher risk of fatal and non-fatal cardiovascular events compared to non-diabetic patients. NODAT has also been shown to adversely impact patient survival and increase the risk of rejection, graft loss, and infectious complications, while early diagnosis and treatment initiation reduce this risk [128,129,130].

Glycemic screening in patients without pre-transplant diabetes is performed once a week for 1 month, every 3 months for a year, and annually thereafter; lipid levels are checked every 2-3 months post-transplantation.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

Comments: in the absence of contraindications, patients must be provided with complete information on the kidney transplantation procedure, its advantages over other RRT modalities, and potential complications of kidney transplantation [33,115].

Kidney transplantation is of questionable appropriateness in patients with:

• Multiple myeloma;

• Amyloidosis with significant extrarenal involvement;

• Decompensated cirrhosis (simultaneous liver transplantation should be considered);

• Malignant organ tumors;

• Irreversible stage obstructive pulmonary disease, decompensated respiratory failure;

• Severe, medically refractory cardiovascular disease (cardiology consultation required);

• Progressive degenerative CNS disease.

If a living related kidney donor is available, kidney transplantation may be performed prior to the initiation of dialysis, or the patient may be placed on the deceased donor waitlist (in the presence of symptoms or an estimated GFR < 10 mL/min/1.73 m² (< 15 mL/min/1.73 m² in pediatric practice, for end-stage renal disease secondary to diabetic nephropathy)) [33-35,115,131,132].

Comments: routine use of hemodialysis immediately prior to kidney transplantation is not indicated [134]. Hyperkalemia is the most common indication for preoperative hemodialysis. The risks of hemodialysis compared with medical therapy must be weighed against the risks of intraoperative fluid overload, electrolyte and acid-base disturbances, especially in cases where a deceased-donor kidney is transplanted with a significant risk of delayed graft function (DGF). Preoperative hemodialysis may induce a pro-inflammatory state, delay surgery, prolong cold ischemia time, and increase the risk of DGF.

Comments: many patients on the active waiting list have vascular disease and/or prothrombotic conditions that must be assessed prior to transplantation. Dual antiplatelet therapy is generally prescribed to patients with coronary artery stents for six to twelve months; perioperative management plans for these patients should be discussed with a cardiologist to completely rule out the risk of discontinuing antithrombotic agents. The feasibility of discontinuing anticoagulant and postoperative anticoagulant therapy should be discussed before placing patients on the waiting list.

Some waiting list patients continue to take antithrombotic agents. The indications for antithrombotic agents must be clearly documented for each individual. The potential increased risk of perioperative bleeding must be balanced against the risk of arterial or venous thrombosis. A study in a small number of patients showed that continuing antiplatelet therapy with clopidogrel** (antiplatelet agents other than heparin) or acetylsalicylic acid** does not confer a significantly higher risk of peri-/postoperative complications. The effect of antithrombotic agents can be mitigated by the intraoperative administration of platelet concentrate.

Comments: perioperative administration of antithrombotic agents (heparin group) reduces the postoperative risk of venous thrombosis (including in the iliofemoral and renal veins); however, due to the concomitant increased blood loss, administration requires knowledge of the patient's individual risk factors. None of the existing major guidelines on thrombosis prophylaxis directly address thromboprophylaxis in the perioperative period of kidney transplantation. A small randomized clinical trial (RCT) showed no differences in early postoperative graft loss or thromboembolic complications with or without prophylactic anticoagulant therapy [99]. Those who received prophylactic anticoagulant therapy had significantly lower hemoglobin levels, whereas those who received prophylactic heparin sodium** had prolonged lymphorrhea. Based on this study, routine pharmacological prophylaxis may not be used in low-risk recipients who received a living-related donor organ. Mechanical measures to reduce iliofemoral deep vein thrombosis may be used in the absence of contraindications due to peripheral vascular disease, particularly where there are concerns about bleeding risk with pharmacological prophylaxis.

Data from a systematic review of all available case studies on anticoagulant and/or antiplatelet prophylaxis for thrombosis in kidney transplantation, the results of which were pooled in a proportional meta-analysis, indicate that anticoagulants and antiplatelet agents (B01A antithrombotic agents), both alone and in combination, reduce the incidence of acute allograft thrombosis following kidney transplantation. Nevertheless, a higher incidence of hemorrhagic complications was noted in the group of patients who received anticoagulants [138].

Another meta-analysis of randomized controlled trials found that studies in the field of transplant thrombosis prophylaxis are scarce. Due to the lack of high-quality evidence, it remains unclear whether any therapy can reduce the incidence of early graft thrombosis in any type of solid organ transplantation. In turn, unfractionated heparin (heparin sodium**) may increase the bleeding risk in kidney transplant recipients, although this conclusion is based on low-quality evidence [139].

Comments: there is a limited number of well-designed randomized trials regarding the efficacy of perioperative antibiotic prophylaxis in kidney transplantation. Traditionally, perioperative antibiotic prophylaxis is used in kidney transplant surgery. A retrospective comparison of perioperative intravenous prophylaxis with cefazolin** versus no antibacterial therapy revealed no differences in infectious complications (surgical site, urinary tract, bacteremia, or central venous catheter-related infection) within the first month after kidney transplantation [141]. A meta-analysis of randomized controlled trials identified only 8 trials suitable for analysis, leading the authors to conclude that due to methodological limitations and significant heterogeneity of the conducted studies, current evidence for the prophylactic perioperative use of systemic antibacterials in transplantation is based on very low-quality studies [142].

Comments: optimal renal graft function requires careful management of peri- and postoperative fluid balance. When using normal (0.9%) sodium chloride** solution in the perioperative period, monitoring for metabolic acidosis is necessary [102]. A prospective double-blind RCT compared the use of normal (0.9%) sodium chloride** solution with compound sodium chloride solution [Potassium chloride + Calcium chloride + Sodium chloride]** as intraoperative intravenous fluid therapy. Serum creatinine levels on the third postoperative day did not differ between the two groups. However, compound sodium chloride solution [Potassium chloride + Calcium chloride + Sodium chloride]** caused less hyperkalemia and metabolic acidosis than normal (0.9%) sodium chloride** solution. Balanced solutions may be an optimal and safer option for intraoperative intravenous fluid therapy [143].

A small prospective non-blinded RCT compared two regimens of normal (0.9%) sodium chloride** solution administration: continuous infusion (10-12 ml/kg-1/h-1 from the start of surgery to reperfusion) and central venous pressure-guided infusion (target CVP corresponding to the surgical stage) [144]. CVP-guided infusion provided a more stable hemodynamic profile, better diuresis, and earlier graft function. Guided hydration can reduce DGF, and CVP measurement can help optimize early graft function.

Comments: due to the shortage of donor organs, a living donor can be a relative who is blood-group compatible or incompatible with the recipient. Most protocols use therapeutic plasma exchange, double filtration plasmapheresis, or specific immunoadsorption combined with immunosuppressive therapy. In addition, high-dose intravenous human normal #immunoglobulin** and antithymocyte globulin** are used [331-332].

The most common protocol in European countries is the so-called "Stockholm protocol," which includes a single dose of #Rituximab** at 375 mg/m² given 14–30 days prior to transplantation, sessions of selective immunoadsorption (4 mandatory sessions before surgery and 3 after, regardless of antibody titer), and a single intravenous infusion of human normal #immunoglobulin** at a dose of 0.5 mg/kg of body weight. In children, #Rituximab** has been used at a dose of 375 mg/m² from the age of 10 [152]. The regimen is supplemented by prescribing a three-drug immunosuppressive therapy in the preoperative period [152]. The number of therapeutic apheresis procedures included in the preparation course for ABO-incompatible kidney transplantation depends on the anti-blood group antibody titer. Once the target level is reached, kidney transplantation is performed. After transplantation, if anti-blood group antibody titers rise, additional sessions of therapeutic apheresis are performed [151].

Comments: HLA antibodies are formed as a result of the recipient's contact with foreign major histocompatibility complex antigens, for example, during blood transfusions, previous transplantations, or in women during pregnancy. The presence of antibodies is a barrier to transplantation due to the high risk of antibody-mediated rejection in the early post-transplant period.

Desensitization protocols are based on therapeutic plasma exchange, double filtration plasmapheresis, or immunoadsorption. Currently, patient desensitization involves a combination of 3–5 sessions of plasma exchange followed by an intravenous infusion of human normal #immunoglobulin** (500 mg/kg) and, on day 8, a single dose of #Rituximab** 375 mg/m² (for children aged 10 and older) [152,331-332].

The exact number of therapeutic apheresis procedures included in the desensitization course has not been strictly defined. The target indicators during the procedure are a negative crossmatch lymphocytotoxic test, as well as a decrease in mean fluorescence intensity (MFI) when determining antibodies on the Luminex platform [151].

3.2 Surgical Treatment

Comment: in the presence of polycystic kidney disease, as well as under certain conditions (insufficient space for the graft, presence of complications, chronic infections, suspected malignancies), there are indications for pre-transplant or simultaneous nephrectomy with kidney transplantation.

Comments: back-table preparation of the graft is an important step in the transplantation process. To assess organ quality and rule out exophytic tumors, the kidney should be prepared while immersed in sterile ice slush, removing the perirenal fat whenever possible. A kidney biopsy can be performed on the back table. Suspicious parenchymal lesions also require biopsy.

It is necessary to identify the quantity, quality, and integrity of the renal vessels and ureter(s). Lymphatic vessels at the renal hilum must be ligated. The quality of the donor renal artery intima should be assessed. Branches of the renal artery not supplying the kidney or ureter(s) must be ligated.

During deceased-donor kidney transplantation, the quality of the aortic patch must be determined. If severe atheromatosis of the patch, ostium, or distal renal artery is visible, the aortic patch and/or the distal part of the renal artery may be trimmed to ensure better quality of the donor renal artery for implantation.

The length of the renal vein should be assessed. Tributary branches of the renal veins must be securely ligated. For a right deceased-donor kidney, if necessary, the renal vein can be lengthened on the back table using the donor inferior vena cava. Methods for lengthening a short right living-donor renal vein using the gonadal vein or the recipient's greater saphenous vein require preoperative planning.

The length, quality, and quantity of the ureter(s) should be determined. Peripyeloureteral and periureteral adipose tissue must be preserved.

Comments: technical approaches for a short renal vein can be considered in both the donor and the recipient. Ligation of the internal iliac veins may be required to elevate the iliac vein and prevent tension on the renal vein anastomosis. Transposition of the iliac artery and vein can also improve the position of the venous anastomosis [159]. The right renal vein can be lengthened. In deceased-donor kidneys, this is usually done using the donor inferior vena cava [160]. In living donors, renal vein lengthening can be achieved using the donor gonadal vein harvested during donor nephrectomy or using the recipient's greater saphenous vein [161], although both require special consent and the aforementioned methods are generally preferred.

Comments: a small RCT (n = 38) comparing end-to-end anastomosis with the internal iliac artery versus end-to-side anastomosis with the external iliac artery showed that both methods have similar outcomes in the early postoperative period and during three years of follow-up. Vascular anastomosis sites should be carefully chosen depending on the length of the renal artery and vein to avoid vessel kinking when placing the kidney in its final position, usually in the iliac fossa. Atheromatous plaques in the iliac artery should be avoided at the arterial anastomosis site to reduce the risk of iliac artery dissection. The intima of both donor and recipient arteries must be inspected before starting the arterial anastomosis to ensure there is no tearing or dissection; if present, it must be repaired before or during the arterial anastomosis.

Comments: multiple renal arteries supplying a kidney from a deceased donor can be preserved on an aortic patch (Carrel patch of appropriate length) and implanted as a single anastomosis. In living-donor kidney transplantation, multiple renal arteries require different techniques to achieve optimal reperfusion. Two arteries may be implanted separately or as a single combined anastomosis; a very small second artery (especially if it supplies the upper pole) may be ligated; two arteries may be joined together ("trouser" plasty); or the smaller artery may be anastomosed to the side of the main artery ("end-to-side" anastomosis). The lower pole artery can be revascularized via an anastomosis to the inferior epigastric artery.

Comments: the results of a meta-analysis of two RCTs and 24 observational studies favor the extravesical Lich-Gregoir technique for reducing overall complications (specifically urinary leakage, stricture, and postoperative hematuria). According to one RCT, the extravesical approach showed a lower rate of urinary tract infections compared to the intravesical method. The donor ureter should be kept as short as possible while preserving the periureteral fat to ensure adequate blood supply to the ureter.

Comments: pyeloureterostomy or ureteroureterostomy to the ipsilateral native ureter is described as a primary method in recipients with non-refluxing native ureters. In cases of donor ureter injury during extraction, native pyeloureterostomy or pyeloneocystostomy can be performed. Monofilament absorbable sutures should be used for urinary anastomosis to prevent suture-induced stone formation.

Comments: the transplant ureteral anastomosis can be performed with or without a ureteral stent. A Cochrane review demonstrated that stents are used to reduce major urological complications, particularly urinary leaks. The optimal timing for stent removal has not yet been established; however, if the stent remains in place for more than 30 days, a high rate of urinary tract infections is observed.

• In cases of duplex ureters, it is recommended to apply the same surgical principles as for single ureters, anastomosing them either separately or together [178,179].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Specific features of surgical treatment in children

Comment: if it is impossible to place the graft in the retroperitoneal space, it is placed intraperitoneally.

Comment: urological anomalies are the cause of end-stage renal disease in children in more than one-third of cases. Urological complications and genetic developmental anomalies are frequently associated with pathology of other organs [181].

3.2.1 Surgical complications

Comments: graft artery thrombosis is a rare complication with an incidence of 0.5–3.5%. It is typically the result of a technical error during anastomosis creation. However, other causes are possible, related to either the donor or recipient artery (atherosclerosis), intimal tear during explantation, an episode of acute rejection, external compression by a hematoma, thrombophilia, severe hypotension, or toxicity of immunosuppressive therapy components (cyclosporine** [capsules, oral solution, taking into account age restrictions per instructions]). Clinical manifestations include anuria, rising serum creatinine and urea levels, which frequently lead to graft loss.

Comments: one of the causes of graft loss within the first month after surgery is renal allograft vein thrombosis (incidence 0.5–4%). The causes include intraoperative surgical complications as well as occult thrombophilia in the recipient. Duplex scanning of the renal allograft veins will reveal the absence of venous blood flow and atypical arterial flow (most commonly reverse diastolic flow resembling a plateau). Additionally, due to venous thrombosis, an increase in graft size may be observed. Although venous thrombosis leads to graft loss in the majority of cases, surgical revision is indicated. If venous thrombosis has not resulted in graft loss, thrombectomy with preliminary clamping of the iliac vein may be performed during revision.

Comments: The incidence of transplant artery stenosis ranges from 1% to 25%. Risk factors include small diameter and atherosclerosis of the transplant artery, arterial trauma during explantation or kidney graft processing, absence of an arterial patch, surgical technique (interrupted or continuous sutures), and iliac artery injury during transplantation. Stenosis most frequently occurs in the anastomotic region. Diagnosis is performed using color Doppler ultrasound (renal duplex ultrasound), which shows a peak systolic velocity in the transplant artery of greater than 200 cm/s. In doubtful cases, magnetic resonance angiography (contrast-enhanced magnetic resonance angiography (single region)) or CT angiography (computed tomography angiography of a single anatomical region or computed tomography angiography of the abdominal aorta and iliac vessels) may be performed. It is important to determine whether the stenosis is hemodynamically significant. Typically, the presence of stenosis greater than 50% is considered a high risk for graft injury. In cases of mild stenosis (< 50%) and absence of symptoms of graft injury, conservative management is performed; however, due to the potential risk of graft dysfunction, close monitoring of the clinical and ultrasound picture is carried out. In cases of clinically significant stenosis and/or > 50% on color Doppler ultrasound, (renal vessel angiography) is performed for confirmation. If the diagnosis is confirmed, endovascular intervention is initiated, whereas in patients with recently performed transplantation, multiple, lengthy, and critical stenoses, or after a failed angioplasty attempt, surgical intervention may be more effective.

Comments: laparoscopic fenestration of lymphoceles, in cases of clinically significant lymphoceles, has the lowest rate of recurrence (8%) and complications (14%) compared to open surgery and aspiration therapy.

Comments: Urinary leakage occurs in 0–9.3% of cases [154]. Urinary leakage in the anastomotic area can originate from either the ureter or the urinary bladder. The most frequent causes are ureteral necrosis and/or anastomotic leakage. Urinary leakage may be suspected in the event of pain in the surgical wound area, heavy soaking of the surgical wound, decreased urine output, or increased drainage output via the safety drain (if present). To reduce the risk of ureteral necrosis, it is important to preserve the vascularization of its distal part. In addition, routine ureteral stenting during kidney transplantation is indicated. The management of urinary leakage depends on the location (transplant renal pelvis, proximal or distal ureter, urinary bladder), time of onset, and volume of leakage. Conservative management (including Foley catheter placement, ultrasound-guided percutaneous puncture nephrostomy, renal transplant ureteral stenting) may be used for early, low-volume leaks. If conservative management fails, surgical correction is required: creation of a neoureterocystostomy.

Comments: Ureteral stenosis is a frequent complication in kidney recipients, with an incidence of 0.6–10.5%. The causes of early stenosis (within three months of surgery) are surgical error or compromised ureteral blood supply. Causes of stenosis in the long-term postoperative period (more than six months from surgery) include infection, fibrosis, progressive vascular insufficiency, and/or rejection. A clinically significant ureteral stricture manifests as persistent hydronephrosis on ultrasound with deterioration of graft function. First and foremost, ultrasound-guided percutaneous puncture nephrostomy with antegrade pyeloureterography is performed to treat the stricture. Subsequent therapeutic measures depend mainly on the timing, degree of recovery of graft function, location of the stricture, patient condition, comorbidities, and the surgeon's preference. Correction of strictures less than 3 cm in length is performed endoscopically either by percutaneous balloon dilation or antegrade ureteroscopy with laser incision of fibrous tissues. In this case, the probability of a successful outcome is about 50%. In case of recurrence after an attempt at endoscopic stricture correction and/or if the stricture is greater than 3 cm in length, surgical reconstruction should be performed in the form of reimplantation, pyelovesical reimplantation (with psoas hitch and/or Boari flap creation), or ureteroureterostomy, if the native ureter is preserved.

3.3 Other Treatment

3.3.1. Induction immunosuppressive therapy after kidney transplantation

• Basiliximab** is recommended as induction therapy in kidney recipients with standard immunological risks to reduce the incidence of acute rejection [214-219].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comments: Basiliximab** is a monoclonal antibody with high affinity for interleukin-2 (IL-2) receptors. The drug is approved for the prevention of post-transplant rejection [214-219]. Basiliximab** is administered intraoperatively and on the fourth day after transplantation. Randomized clinical trials have demonstrated that IL-2 receptor antibodies are safe and reduce the incidence of acute cellular rejection by approximately 40% [214-219]. Meta-analysis data confirm its efficacy [214-216,219]. The positive clinical effect of basiliximab**, as well as improved graft survival, has been demonstrated by prospective studies [217,218].

Interleukin-2 receptor antibodies may enable the withdrawal of prednisolone** or methylprednisolone** [219], despite the high rejection rates described in the literature. The use of IL-2 receptor antibodies allows for a significant reduction in the dosage of calcineurin inhibitors while maintaining efficacy and renal function [214-219]. For this reason, this regimen is proposed as a first-line option in patients with medium or low immunological risk [218].

• Antithymocyte globulin** may be recommended as induction immunosuppressive therapy in patients with high immunological risk [214,220,221,217-219].

Level of Recommendations C (Level of Evidence – 1).

Comments: "Induction" therapy using antithymocyte globulin** can be used as prevention of acute rejection in high immunological risk kidney recipients [214,220,221,217,218,219]. In addition, the drug is used for the treatment of episodes of severe steroid-resistant rejection [220].

The use of antithymocyte globulin** in patients with low immunological risk does not improve long-term postoperative outcomes, as it increases the risk of developing severe opportunistic infections and malignancies, especially post-transplant lymphoproliferative disorders [214,220,221,217,218,219]. Some transplant centers use these drugs in kidney recipients with ischemic graft injury for rejection prophylaxis until the therapeutic concentration of calcineurin inhibitors is achieved, but studies confirming the efficacy of this technique are insufficient [220].

Comments: #Mycophenolate mofetil** and #mycophenolic acid** are used off-label in children. The doses of immunosuppressants used in childhood are presented in Table 1 (Appendix A3) [336].

3.3.2. Maintenance immunosuppressive therapy

Immunosuppressive therapy is particularly important in the early postoperative period, as the risk of rejection is high during this time. The underlying principle of successful immunosuppressive therapy is maintaining a balance of drug dosages to preserve the graft without posing a health risk to the patient. Expanding knowledge about immunological rejection has led to the development of modern immunosuppressants [217,218] that reduce the activity of sensitized lymphocytes against the graft.

In the long-term postoperative period, so-called "graft adaptation" occurs, manifested by a lower incidence of rejection against the background of maintenance immunosuppressive therapy. Consequently, rejection prophylaxis is attenuated by the gradual withdrawal of methylprednisolone** and a reduction in the dosage of calcineurin inhibitors (cyclosporine**, tacrolimus** (capsules), tacrolimus** (prolonged-release capsules)) [217,218,225].

Side effects of immunosuppressants include a high risk of malignancies and infectious diseases, particularly opportunistic infections [217,218,225]. At the same time, all immunosuppressants have dose-dependent specific side effects. The goal of modern immunosuppressive therapy protocols is to reduce specific side effects by utilizing drug synergy to preserve efficacy while minimizing adverse reactions.

Modern baseline immunosuppressive therapy regimens provide excellent efficacy with good tolerability [217,218,219,225]. The list of main medications that patients currently receive:

  calcineurin inhibitors (primarily tacrolimus** (capsules), tacrolimus** (prolonged-release capsules), less commonly cyclosporine** (subject to age restrictions per instructions));

  mycophenolate mofetil** or mycophenolic acid**;

  prednisolone** (tablets) or methylprednisolone** (tablets);

  induction therapy (in patients with low risk, basiliximab** is predominantly used, while in high-risk patients, antithymocyte globulin** is used).

The doses of drugs used in childhood are presented in Table 1 (Appendix 3) [336]. #Mycophenolate mofetil** and #mycophenolic acid** are used off-label in children.

Multi-drug immunosuppressive therapy is the standard treatment method for the majority of recipients worldwide and can be adjusted depending on the specific conditions of side effects, efficacy, and immunological risk [217,218,225].

3.3.2.1. Calcineurin inhibitors

Comments: both cyclosporine** and tacrolimus** have significant side effects that are potentially hazardous to both the graft and the patient [219,225-227]. The drugs exhibit nephrotoxicity, and their long-term use is a major cause of chronic graft dysfunction, which can lead to the loss of the kidney transplant. Calcineurin inhibitors belong to drugs with a "narrow therapeutic window" (deviation from which can lead to severe intoxication or lack of sufficient effect) and a high probability of drug-drug interactions, therefore monitoring their blood levels is necessary.

A meta-analysis of the efficacy of tacrolimus** and cyclosporine** revealed similar results regarding patient and graft survival [217,218,219,224-234]. According to censored studies, tacrolimus** provides better rejection prophylaxis and superior graft survival. Renal function in patients taking tacrolimus** is satisfactory. Due to higher efficacy in acute rejection, current international guidelines suggest using tacrolimus** as the first-line calcineurin inhibitor [218].

Calcineurin inhibitors have several pharmacological analogs. When converting from one analog to another, precautions must be observed (including monitoring laboratory parameters and determining the plasma concentration of calcineurin inhibitors) [229-233]. When specific side effects of calcineurin inhibitors occur (such as hirsutism, alopecia, gingival hyperplasia, polyomavirus nephropathy), conversion to another calcineurin inhibitor can reduce adverse manifestations [214-217,220-224,235-237]. Since there are significant differences in efficacy and safety among various calcineurin inhibitors, the prescription of a specific drug should be based on individual risks and benefits for each patient.

Despite side effects, calcineurin inhibitors have been the backbone of modern immunosuppressive therapy protocols for over 20 years, as they have demonstrated a significant improvement in renal graft survival. The goal of developing immunosuppressive therapy protocols is to reduce the dosage or completely discontinue calcineurin inhibitors [225,228,234,238]. However, until new protocols demonstrate higher efficacy, calcineurin inhibitors will remain in standard treatment regimens [217,218,239]. In cases of severe side effects from calcineurin inhibitors, dose reduction, conversion, or complete withdrawal of calcineurin inhibitors is possible if necessary [217,225,228,234,238]. Cyclosporine** is prescribed taking into account age restrictions according to the instructions. The doses of drugs used in childhood are presented in Table 1 (Appendix A3) [336].

3.2.2 Mycophenolate mofetil** (mycophenolic acid**)

Comments: #Mycophenolate mofetil** and #mycophenolic acid** are used off-label in children. The doses of immunosuppressants used in childhood are presented in Table 1 (Appendix A3) [336].

Mycophenolate mofetil** (mycophenolic acid**) inhibits inosine monophosphate dehydrogenase (IMPDH) [239-244]. This leads to the suppression of the de novo purine metabolic pathway by decreasing the rate of guanosine monophosphate synthesis. Since lymphocyte function and proliferation depend more on de novo purine nucleotide synthesis compared to other cells, IMPDH inhibitors can provide more selective immunosuppressive therapy targeted at lymphocytes.

The combined administration of mycophenolate mofetil** (mycophenolic acid**), prednisolone**, and calcineurin inhibitors provides a sustained reduction in biopsy-proven rejection rates [217,219,240-244]. Mycophenolic acid** is not nephrotoxic, but it suppresses bone marrow function and can cause CMV infection as well as gastrointestinal disorders, particularly diarrhea [217,219,240-244]. The use of mycophenolate mofetil** (mycophenolic acid**) increases the risk of developing polyomavirus nephropathy, especially in combination with tacrolimus** [245].

Mycophenolate mofetil** (mycophenolic acid**) are effective and have virtually equal safety profiles [238-242]; however, according to some prospective studies, patients suffering from gastrointestinal complications report improvement when taking mycophenolic acid**, although the validity of prospective randomized studies is questionable [240-244].

Standard adult dosages in combination with cyclosporine** are 1 g twice daily for mycophenolate mofetil** or 720 mg twice daily for mycophenolic acid**, although higher starting doses have been suggested [217,219,240-244]. Despite the frequent use of mycophenolate mofetil** (mycophenolic acid**) with tacrolimus**, the dosage for this combination lacks scientific validation [217,240,242]. Tacrolimus** does not affect the blood levels of mycophenolic acid**, but the systemic exposure (bioavailability) of mycophenolic acid** is 30% higher compared to cyclosporine**. Due to the high incidence of adverse effects, some centers practice routine dose reduction of mycophenolate mofetil** (mycophenolic acid**) in patients receiving tacrolimus** [219,245]. Patients receiving mycophenolate mofetil** (mycophenolic acid**) in combination with tacrolimus** should be regularly monitored for polyomavirus viral load [217,245]. The clinical utility of therapeutic drug monitoring for mycophenolate mofetil** (mycophenolic acid**) blood levels is questionable and currently not routinely indicated [240,242,243,246].

In the majority of kidney transplant recipients receiving mycophenolate mofetil** (mycophenolic acid**), successful withdrawal of methylprednisolone** is feasible [219], or a substantial reduction in calcineurin inhibitor dosage can be achieved, which helps reduce nephrotoxicity and improve graft function [217,218,219,225,228,229]. Despite publications demonstrating calcineurin inhibitor-free protocols utilizing only mycophenolate mofetil** (mycophenolic acid**) and methylprednisolone**, prospective randomized studies indicate that calcineurin inhibitor withdrawal within the first three years is associated with a significantly increased risk of rejection and poorer outcomes [217,225,238]. At the same time, limited data suggest that calcineurin inhibitor withdrawal may be feasible in recipients receiving mycophenolate mofetil** (mycophenolic acid**) and methylprednisolone** at 5 years post-transplantation, ultimately resulting in improved renal function [238,247].

Due to the high incidence of CMV infection in patients receiving mycophenolate mofetil** (mycophenolic acid**) [244], CMV prophylaxis or a preemptive strategy with regular monitoring of CMV viremia is performed [97,99,180,217].

3.3.2.3 Prednisolone** or methylprednisolone**

Comments: prednisone** or methylprednisolone** have numerous side effects [217,218,219,225,248], especially with long-term use. Prednisone** or methylprednisolone** are still considered a cornerstone of immunosuppressive therapy, even accounting for subsequent successful withdrawal reported in many prospective randomized trials [217,218,219,225,248]. These studies suggest that the risks associated with prednisone** or methylprednisolone** withdrawal depend on concomitant immunosuppressants, immunological risk, recipient race, and the time elapsed post-transplantation. Although the risk of rejection decreases over time, the potential benefit of withdrawal after a prolonged period of prednisone** or methylprednisolone** therapy may be less significant [217,218,219,225,248].

3.3.2.4 Azathioprine**

• Azathioprine** may be recommended for use in low immunological risk patients as an immunosuppressant, particularly in patients with intolerance to mycophenolate mofetil** (mycophenolic acid**) [217,218,219,240-244].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comments: instead of azathioprine**, mycophenolate mofetil** (mycophenolic acid**) is used as standard immunosuppressive therapy in most transplant centers worldwide. According to prospective randomized trials, mycophenolate mofetil** (mycophenolic acid**) significantly reduces the incidence of rejection compared to azathioprine** [217,218,219,240-244]. Although a large prospective study indicates that azathioprine** can yield acceptable results in low immunological risk patients, it is more commonly used in patients with intolerance to mycophenolate mofetil** (mycophenolic acid**) [217,218,240-242]. According to meta-analysis data, there are no significant improvements in major clinical endpoints when azathioprine** is added to dual therapy with cyclosporine** and prednisone** or methylprednisolone** [249].

3.3.2.5 Everolimus** (sirolimus)

• Everolimus** (sirolimus) may be recommended for use to prevent rejection in kidney transplant recipients who do not tolerate standard immunosuppressive therapy [219,225,228,234,250-253].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comment: in adults, sirolimus is prescribed at a single loading dose of 6 mg, followed by a reduction to 2-4 mg daily (target concentration 4-12 ng/mL) [340,341]. Everolimus** (tablets) in adults is used at a dose of 1.5-3 mg daily with a target concentration of 3-8 ng/mL achieved [342,343].

#Everolimus** and #sirolimus are used off-label in pediatric practice. The doses of drugs used in childhood are presented in Table 1 (Appendix A3) [336].

Comments: the immunosuppressants sirolimus and everolimus** inhibit the mammalian target of rapamycin (mTOR), thereby suppressing lymphocyte proliferation and differentiation [217,234,250-252]. They inhibit multiple intracellular pathways and block cytokines that signal T-lymphocyte proliferation. A similar effect can be observed with B lymphocytes, endothelial cells, fibroblasts, and tumor cells. For the prevention of rejection, everolimus** has the same efficacy as mycophenolic acid** in combination with calcineurin inhibitors [217,219,234,250-252]. However, everolimus** (sirolimus) exhibit dose-dependent myelotoxicity [217,219,234,250-253]. Other side effects include hyperlipidemia, edema, lymphocele formation, delayed wound healing, pneumonitis, proteinuria, and reproductive impairment.

To date, there are no studies comparing the efficacy of sirolimus and everolimus**. Both drugs have almost identical side effects and differ mainly in pharmacokinetic properties [217,234,250-253]. Everolimus** has a half-life of about 24 hours, is taken twice daily, and is indicated for the prevention of rejection in kidney, liver, and heart transplant recipients. Everolimus** is approved for use with cyclosporine**, and therefore it can be taken simultaneously with cyclosporine**, whereas sirolimus is taken 4 hours after cyclosporine** administration. Sirolimus is approved for use in combination with prednisolone** or methylprednisolone** for the withdrawal of cyclosporine** in standard triple therapy. Due to its narrow therapeutic window and high risk of undesirable drug interactions, monitoring of the trough blood concentration of the drug should be performed [217,234,250-253].

When used in combination with calcineurin inhibitors, for the prevention of Pneumocystis jirovecii pneumonia, antibiotic prophylaxis, including low-dose co-trimoxazole [sulfamethoxazole + trimethoprim]**, is administered during the first year after transplantation [217,250-252]. Although everolimus** (sirolimus) are not nephrotoxic, in combination with calcineurin inhibitors they significantly enhance the nephrotoxicity of calcineurin inhibitors [217]. According to some studies, this combination does not yield satisfactory results in the long-term postoperative period, especially if standard dosages of calcineurin inhibitors are maintained [217,219,228]. Due to synergy, combination with everolimus** (sirolimus) allows for a reduction in the calcineurin inhibitor dosage without loss of efficacy [234,250-254].

Some studies suggest that everolimus** (sirolimus) cannot replace calcineurin inhibitors in the early post-transplantation period due to low efficacy and adverse side effects, particularly delayed wound formation and lymphocele development [217,218,232,249,250,252]. According to other studies, in later stages (>3 months post-transplantation), converting calcineurin inhibitors to everolimus** (sirolimus) is possible and improves graft function [217,219,225,228,234,250-252,254]. However, despite the benefit of avoiding nephrotoxicity, there is a concurrent increase in the risk of rejection and anti-HLA antibody formation [217,225,234,255]. Currently, there is extremely limited data regarding patients receiving everolimus** (sirolimus) in the long-term postoperative period.

Proteinuria and deterioration of graft function during conversion are signs of an unfavorable outcome [217,225,234,250,251,252]. Conversion is not advisable in patients with proteinuria exceeding 800 mg/day, and should be considered on an individual basis in patients with a GFR below 30 mL/min.

In patients at high risk for malignancies or those diagnosed with malignancies post-transplantation, converting from calcineurin inhibitors to everolimus** (sirolimus) may be beneficial due to the low rate of malignancy and the antiproliferative effect of everolimus** (sirolimus) [217,225,234,250-252,254,256,257]. Several clinical studies and published case reports have noted a positive clinical effect of conversion from calcineurin inhibitors to everolimus** (sirolimus) in patients with Kaposi sarcoma [257].

Overall, everolimus** (sirolimus) are considered immunosuppressants in the early postoperative period due to side effects and a high discontinuation rate [218]. Despite this, everolimus** (sirolimus) have been sufficiently studied to serve as second-line immunosuppressants.

#Everolimus** and #sirolimus are used off-label in pediatric practice. Drug doses used in children are presented in Table 1 (Appendix A3) [336].

Treatment of Acute Cellular Kidney Transplant Rejection

Comment: in one randomized trial, intravenous high-dose prednisolone** was comparable in efficacy to high-dose oral prednisolone**, but glucocorticoid toxicity was lower with the intravenous route [259]. In a prospective study, administration of 250–500 mg of intravenous methylprednisolone** was not associated with the development of steroid-resistant cellular rejection compared with higher doses [260,261,262].

Comment: approximately 25–30% of patients do not experience rejection reversal with corticosteroid therapy alone. These recipients require more intensive immunosuppressive therapy. When serum creatinine does not return to baseline (pre-rejection) values following glucocorticoid pulse therapy within 14 days of initiation, the episode is considered steroid-resistant [264]. Up to day 5, patients with steroid-sensitive and steroid-resistant acute rejection exhibited similar serum creatinine trajectories. However, after day 5, serum creatinine significantly decreased in responding patients while remaining elevated in non-responders [265].

A meta-analysis of 11 randomized trials (76 reports, 1680 participants) demonstrated that antibody therapy is superior to steroid therapy (RR = 0.50; 95% CI: 0.30–0.82) in reversing the first episode of acute rejection and preventing subsequent rejections (RR = 0.70; 95% CI: 0.50–0.99), and leads to improved graft survival (death-censored RR = 0.80; 95% CI: 0.57–1.12) [263].

Treatment of Active Antibody-Mediated Kidney Transplant Rejection

Comment: three randomized trials with longer follow-up periods (2–5 years) demonstrated the benefit of antibody removal—plasmapheresis and immunoadsorption [266,267,268]—compared with no intervention. The long-term effect of DSA removal, which consisted of increased graft survival, was confirmed in a meta-analysis of these studies (n = 92; HR 0.46; 95% CI 0.26–0.82; P = 0.009) [269]. In a well-designed randomized trial comparing an immunoadsorption group with a control group receiving only normal human #immunoglobulin**, 80% of patients in the control group experienced graft loss, leading to premature termination of the trial [270].

Comment: two retrospective cohort studies investigating plasmapheresis with intravenous normal human #immunoglobulin** have also been conducted, which included patients with acute and chronic antibody-mediated kidney transplant rejection, with some patients exhibiting both components. The first study, with a median follow-up of 7 years, noted improved graft survival in the intervention group compared with the comparison group (HR 0.26; 95% CI not reported; P < 0.001) [271].

The second study found no statistically significant difference in the development of graft dysfunction between the groups, although the majority (63% of patients) already had signs of chronic injury at the time of diagnosis [272].

Comment: the efficacy of #rituximab** combined with plasmapheresis and intravenous normal human #immunoglobulin** has been demonstrated in several retrospective studies in patients with vascular antibody-mediated rejection [273,274,275]. Furthermore, in one non-randomized single-center study, the inclusion of #rituximab** in the combination regimen prevented DSA production and served as a desensitization approach in highly sensitized patients [276].

Treatment of Chronic Antibody-Mediated Kidney Transplant Rejection

Comment: in cases of chronic active antibody-mediated rejection or chronic transplant vasculopathy, treatment goals should include stabilizing or slowing the rate of GFR decline and reducing proteinuria while minimizing drug toxicity. The use of normal human #immunoglobulin**, plasmapheresis with or without #rituximab** has not demonstrated improved graft survival in patients with chronic active antibody-mediated rejection (unlike acute active antibody-mediated rejection). In this scenario, it is necessary to optimize immunosuppression and supportive therapy, maintain target CNI trough concentrations, and control arterial hypertension and metabolic disorders.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Medical rehabilitation is a set of medical and psychological measures aimed at the complete or partial restoration of impaired and/or compensation of lost functions of the affected organ or body system, maintaining body functions during the completion of an acutely developed pathological process or an exacerbation of a chronic pathological process in the body, as well as at the prevention, early diagnosis and correction of possible functional disorders of damaged organs or body systems, prevention and reduction of the degree of potential disability, improvement of the quality of life, preservation of the patient's working capacity and their social integration into society.

Sanatorium-resort treatment includes medical care provided by medical organizations (sanatorium-resort organizations) for prophylactic, therapeutic, and rehabilitative purposes based on the use of natural therapeutic resources, including staying in health-improving localities and resorts. Sanatorium-resort treatment is aimed at:

1) activation of the body's protective and adaptive reactions for the purposes of disease prevention and health improvement;

2) restoration and/or compensation of body functions impaired as a result of injuries, surgeries, and chronic diseases, reduction of the number of exacerbations, prolongation of the remission period, slowing down the development of diseases, and prevention of disability as one of the stages of medical rehabilitation [277].

While on renal replacement therapy, patients are often subject to dietary restrictions associated with progressive CKD. Post-transplantation, the nutritional factor is one of those contributing to weight gain, metabolic syndrome, diabetes, and its consequences. Transplant recipients must be provided with easily understandable dietary recommendations and, if necessary, weight loss guidance. In particular, grapefruit juice should be avoided due to the potential interference with the metabolism of immunosuppressants, which leads to elevated levels of calcineurin inhibitors.

It is important to maintain an active lifestyle. Following a kidney transplant, patients should avoid sports that involve potential direct impacts or other injuries to the transplanted kidney (e.g., kickboxing) [278-280].

Alcohol abuse or non-medical (inappropriate) recurrent use of chemical substances affecting a person's mood or behavior may increase the risk of adverse events [281,282].

4.1 Transplantation in pregnancy

4.1.1 Pregnancy planning

Comment: chronic renal failure is frequently accompanied by sexual and reproductive dysfunction. Following a kidney transplant, sexual life and reproductive function are restored [283]. Men and women with end-stage renal disease should be well-informed regarding pregnancy issues. Pregnancy should occur against the background of good general health and graft status, usually no earlier than 1–2 years post-transplantation [284]. If pregnancy occurs several years after transplantation, there is a risk of developing chronic rejection and/or deterioration of renal function.

With a stable functional state of the graft and ongoing immunosuppressive therapy, as well as in the absence of signs of graft rejection, arterial hypertension, proteinuria, hydronephrosis, or chronic infection, there is no significant difference in outcomes between early, optimal, or late pregnancy [285]. In hydronephrosis, there is a higher risk of miscarriage due to an increased likelihood of infection or urolithiasis, which may complicate the course of the third trimester of pregnancy. Pregnancy must be diagnosed as early as possible to initiate dynamic monitoring and adjustment of immunosuppressive therapy at the earliest opportunity. Pregnancy in organ transplant recipients is often unproblematic, but these patients must be categorized as high risk in all cases; pregnancy must proceed under the dynamic supervision of an obstetrician-gynecologist, nephrologist, and urologist.

4.1.2 Pregnancy management tactics

Comment: (general clinical urinalysis) should be performed once a month (early diagnosis of urogenital infections), and bacteriuria should be treated regardless of clinical manifestations. To avoid fetal and nephrotoxicity, beta-lactam antibacterial drugs (penicillins) should be prescribed. Prevention and suppression of any viral infections are necessary to avoid intrauterine defects (e.g., intellectual disability in the child following congenital CMV infection). If intrauterine infections are suspected, cytomegalovirus (Cytomegalovirus) DNA in the amniotic fluid should be detected using PCR.

4.1.3 Immunosuppressive therapy during pregnancy

Comment: tacrolimus** (capsules), tacrolimus** (extended-release capsules) used for immunosuppressive therapy after kidney transplantation is characterized by a fairly high safety profile. Only isolated studies indicate that mycophenolate mofetil** and sirolimus are teratogenic, which is why their use is contraindicated during pregnancy.

Comment: the rates of spontaneous (14%) or medically indicated (20%) abortions in organ transplant recipients are similar to those in the general population. Despite the fact that the presence of a transplanted organ in the pelvis does not mechanically impede the natural mechanism of labor, premature delivery and cesarean section are more frequently observed (50%) in the group of pregnant organ transplant recipients. This pattern is explained by the presence of multiple risk factors (uncontrolled arterial hypertension, fetal hypoxia, premature rupture of membranes against the background of corticosteroid therapy).

5. Prevention and Dispensary Observation

Comments: regular long-term follow-up by experienced surgeons (transplantologists) and nephrologists is essential for the early detection of complications or graft dysfunction and for monitoring strict adherence to the prescribed immunosuppressive regimen.

It is necessary to regularly monitor (approximately every 4–8 weeks in the first 6 months post-transplantation) serum creatinine levels, estimated glomerular filtration rate, blood pressure, urinary protein excretion, immunosuppression therapy, and post-kidney transplant complications. Changes in these parameters over time should prompt further diagnostic evaluations, including a kidney biopsy, screening for infectious causes, and anti-HLA monitoring.

The risk of malignancies and cardiovascular diseases is several times higher in transplant recipients than in the general population. Other important long-term issues include non-adherence to the prescribed therapy regimen, development of anti-HLA antibodies, recurrence of the primary disease, and calcineurin inhibitor-related nephrotoxicity [115,217,218,225,297,298].

Many patients lose their grafts due to chronic allograft dysfunction [120,121,217,218,295]. In cases of renal transplant dysfunction, an urgent work-up is indicated. A biopsy of the transplanted kidney typically reveals chronic interstitial fibrosis and tubular atrophy (IF/TA) [299]. Some patients exhibit chronic antibody-mediated rejection [300]. IF and TA develop over months or years, manifesting as proteinuria and hypertension with a concurrent or delayed rise in serum creatinine over the course of a month [218,299]. It is highly likely that IF/TA is more frequent in patients who have experienced early crises of acute rejection or infections. Chronic nephrotoxicity occurs in patients taking calcineurin inhibitors who received a graft from expanded criteria donors with pre-existing renal injury [295,299,301].

In patients with chronic nephrotoxicity diagnosed by early kidney transplant biopsy—especially in the presence of evidence of calcineurin inhibitor toxicity—disease progression may be slowed by switching to a calcineurin inhibitor-free regimen [228]. Conversion to everolimus** is an option for patients without significant proteinuria (< 800 mg/day) but with moderately satisfactory renal function. Alternatively, a successful conversion regimen based on mycophenolate mofetil** (mycophenolic acid**) has been described, particularly in patients beyond the first three years post-transplantation [217,218,225]. In addition, conversion to an azathioprine**-based regimen may be successful if there is intolerance to everolimus** or mycophenolate mofetil** (mycophenolic acid**), although this requires closer monitoring due to the higher risk of rejection [303,304].

A calcineurin inhibitor-free immunosuppressive regimen is associated with an extremely high risk of rejection and renal graft loss; therefore, it can be used only in exceptional cases with proven nephrotoxicity and lack of response to calcineurin inhibitor minimization regimens.

In patients with proteinuria, the use of ACE inhibitors or angiotensin II receptor blockers [218,295], along with strict blood pressure control, can slow the progression of renal failure. Other supportive measures include the management of hypertension, hyperlipidemia, diabetes, anemia, acidosis, and bone disease. However, the patient may ultimately require re-transplantation or dialysis therapy. With the advent of sodium-glucose cotransporter 2 (SGLT2) inhibitors, they have begun to be used for the treatment of patients with chronic kidney disease. Nevertheless, the number of studies and data regarding their efficacy and safety in post-renal transplant patients remain limited to date [305].

Comments: maintenance therapy should ensure the maximum lifespan of the recipient with a functioning graft, which is determined by the adequacy of alloimmune response suppression on the one hand, and the minimization of the risk of immunosuppressant side effects on the other. Following successful kidney transplantation, maintenance immunosuppressive therapy in the vast majority of cases includes three components, with the backbone drug typically being a calcineurin inhibitor (cyclosporine** or tacrolimus** (capsules, prolonged-release capsules)) in combination with mycophenolate mofetil** (mycophenolic acid**), less commonly azathioprine**, and a minimal dose of prednisone** or methylprednisolone**. In recent years, selective immunosuppressants (everolimus** (sirolimus)) have also been used for maintenance immunosuppressive therapy. At 3 months post-kidney transplantation, the tacrolimus** trough concentration is usually maintained at 8–10 ng/mL, and after six months, at 5–8 ng/mL. At more than 12 months post-transplantation, in patients with low graft functional reserve, a small mass of functioning nephrons, or specific sensitivity to the nephrotoxic effect of tacrolimus**, the concentration may be reduced to 3–5 ng/mL. It is also important to remember the risk of rejection and, if necessary, increase the dose of concomitant medications.

#Mycophenolate mofetil**, #mycophenolic acid**, #everolimus, and #sirolimus are used off-label in pediatric patients. The doses of immunosuppressants used in childhood are presented in Table 1 (Appendix A3) [336].

6. Organization of Medical Care

6.1 Indications for planned hospitalization

1. Preparation for ABO-incompatible transplantation.

2. Preparation for kidney transplantation (sanation of infection foci, nephrectomy).

3. Hospitalization for related kidney transplantation.

4. Renal transplant dysfunction.

5. Instability of calcineurin inhibitor concentrations.

6. Performance of transplant needle biopsy.

6.2 Indications for emergency hospitalization

1. Availability of a compatible donor kidney from a deceased donor.

2. Kidney graft dysfunction during life-threatening conditions.

3. Surgical/urological complications following kidney transplantation.

4. Acute conditions or exacerbations of chronic diseases in the early post-transplantation period.

6.3 Indications for hospital discharge

1. Satisfactory graft function.

2. Absence of indications for inpatient stay.

7. Additional Information

Morphological signs of renal graft dysfunction

An episode of acute rejection results from the recipient's immune response aimed at destroying the graft. It has a cellular (lymphocytes) and/or humoral (circulating antibodies) origin. Acute rejection is clinically suspected in patients with an elevated serum creatinine level after ruling out other causes of graft dysfunction (typically confirmed by biopsy). From the first days after transplantation until the initiation of effective immunosuppressive therapy, the lack of treatment for a rejection crisis inevitably leads to graft loss.

Acute rejection is characterized by a decrease in graft function combined with well-established morphological criteria detected on biopsy. Subclinical acute rejection is defined by the presence of histological changes characteristic of acute rejection on screening or protocol biopsies in the absence of clinical symptoms or signs [218].

I. Morphological types of transplanted kidney rejection

1. Hyperacute renal allograft rejection

The etiology is associated with the presence of preformed cytotoxic antibodies in the recipient's blood. Predicting this type of rejection is based on performing a cross-match between the donor's lymphocytes and the prospective recipient's serum (cross-match test). Rejection develops from the very first minute after the kidney is reperfused. The kidney becomes flabby and cyanotic, and vascular pulsation is absent. If the graft is removed, histological examination reveals widespread microcirculatory thrombosis, with no necrotic changes in any structures, showing only degenerative changes in the convoluted tubules. In biopsy specimens taken 1 to 3 days postoperatively, diffuse infiltration of the interstitium by neutrophil leukocytes joins. Less commonly, with a low level of preformed antibodies, delayed development of hyperacute rejection is possible (12–24 hours after surgery), requiring differential diagnosis between ischemic injury and hyperacute rejection based on puncture biopsy examination. Both types show renal parenchyma necrosis, but hyperacute renal allograft rejection features widespread microcirculatory thrombosis [116,118-122].

2. Accelerated renal allograft rejection

Accelerated renal allograft rejection develops within the first few days after the kidney is reperfused in the recipient (12 to 72 hours). The pathogenesis of this type of rejection involves not only humoral factors but also cellular immunity. Histology reveals congestion and blood stasis in the microvessels of the cortex, lymphocyte infiltration, and parenchymal organ damage [116,118-122].

3. Acute renal allograft rejection

Acute rejection of a kidney allograft remains one of the major complications causing a decline and even cessation of graft function. When examining needle biopsy specimens of a kidney allograft, the presence or absence of acute cellular rejection is evaluated using the following semiquantitative parameters: a) assessment of the degree of glomerular inflammation (glomerulitis - g): g0 - no glomerulitis; g1 - glomerulitis in < 25% of glomeruli; g2 - glomerulitis in 25%-75% of glomeruli; g3 - glomerulitis in all or almost all glomeruli. b) assessment of tubular inflammation (tubulitis - t): t0 - absence of lymphocytes in the tubular basement membrane/walls; t1 - 1-4 lymphocytes in the cross-section of a tubule; t2 - 5-10 lymphocytes in the tubular cross-section; t3 - more than 10 lymphocytes in the cross-section of a tubule. c) assessment of the degree of arterial wall inflammation (vasculitis - v): v0 - no arteritis; v1 - endarteritis with inflammation involving < 25% of the intima circumferentially in at least one artery; v2 - endarteritis with inflammation involving > 25% of the intima circumferentially in at least one artery; v3 - severe panarteritis with smooth muscle cell necrosis and/or fibrinoid necrosis. d) assessment of the degree of interstitial inflammation (i): i0 - absence or interstitial infiltration by lymphocytes < 10% of the cortical layer; i2 - 26-50% of the cortical layer infiltrated by lymphocytes; i3 - lymphocyte infiltration > 50% of the cortical layer. Currently, the Banff 97 classification is used to grade acute cellular rejection of a kidney allograft. Depending on the semiquantitative parameters, the following types of rejection are diagnosed:

- borderline changes – not classified as acute rejection, but are predictors thereof: g0, t1, v0, i1;

- acute interstitial rejection (types 1a, 1b)

Type 1a: g0-1, t2, v0, i2-3;

Type 2b: g0-2, t3, v0, i2-3;

- acute vascular rejection (types 2a, 2b)

Type 2a: g0-1, t0-1, v1, i2-3;

Type 2b: g0-2, t0-2, v2, i2-3;

- severe acute rejection

Type 3: g2-3, t2-3, v3, i2-3.

The differentiation of acute cellular rejection types is of great clinical significance, as the treatment of the crisis and the adjustment of baseline immunosuppressive therapy depend on the rejection type.

Humoral factors play a significant role in acute rejection. Acute antibody-mediated (humoral) rejection is characterized by acute steroid-resistant graft dysfunction, the presence of donor-specific antibodies in the recipient's serum, and the presence of the C4d complement component in peritubular capillaries [116-122].

The most accurate differential diagnosis of kidney allograft pathology can only be achieved through vital pathomorphological examination of biopsy (surgical) kidney material using immunohistochemical methods. Morphological verification (morphological diagnosis) of pathology in the kidney allograft is carried out by examining percutaneous needle biopsy material. A clinical diagnosis of kidney rejection cannot be considered valid without confirmation by the results of histological examination of the transplanted kidney biopsy specimen [85]. To standardize approaches to grading allograft rejection under the auspices of the International Society of Nephrology (ISN), a classification was developed and adopted in August 1991 in Canada, named after the city where the commission worked – Banff. Subsequently, this classification has been repeatedly revised and supplemented [116-122].

4. Chronic rejection of the kidney allograft

Recently, great progress has been made in immunosuppressive therapy, which has led to a reduction in the rate of acute rejection and an increase in transplanted organ survival. However, chronic allograft dysfunction remains a major clinical problem. One of the causes is chronic nephropathy [87,88].

Chronic rejection represents an antibody-mediated process. The production of antibodies against vascular endothelial cell antigens of the graft, followed by the formation of antigen-antibody complexes on endothelial cells with the participation of complement, leads to endothelial damage, increased vascular permeability, plasma imbibition, proliferation of subendothelial connective tissue, and intimal infiltration by mononuclear cells. As a result, the lumens of small arteries become narrowed or may be completely obliterated. Blood flow insufficiency leads to parenchymal damage. The initial morphological signs of chronic rejection can appear as early as 4-6 months after surgery. Deposition of immunoglobulins of various classes, predominantly IgM, is detected in the arterial walls, alongside C4d complement component fixation in the intima [89-91]. According to the Banff 97 classification, chronic rejection reveals tubular atrophy, interstitial fibrosis, and productive endarteritis. In the interstitium, both within fibrotic areas and outside these zones (perivascularly), varying degrees of focal mononuclear cell infiltration are observed, including a large number of plasmablasts and plasma cells. In arterial branches, connective tissue proliferation in the intima is noted with a reduction in their lumen cross-section. Varying degrees of sclerotic glomerular damage are detected. Circulatory disturbances in chronic rejection lead to the development of diffuse nephrosclerosis [116,118-122].

II. Calcineurin Inhibitor Nephrotoxicity

Cyclosporine** and tacrolimus** reduce the risk of rejection and increase allograft and recipient survival. A low blood level of calcineurin inhibitors increases the risk of acute rejection, while a high level typically leads to cyclosporine nephrotoxicity. Both acute and chronic effects of the drugs are distinguished.

The histological sign of acute calcineurin inhibitor toxicity is the appearance of isometric vacuolization in the cytoplasm of proximal convoluted tubules, detected by hematoxylin and eosin staining.

Chronic nephrotoxicity develops no earlier than four months after kidney transplantation. Histologically, striped interstitial fibrosis, tubular atrophy, and nodular hyalinosis of arterioles and small arteries are revealed [116,118-122].

III. Infectious Complications After Kidney Transplantation

The etiology of infectious complications after kidney transplantation is associated with viral, bacterial, fungal flora, and protozoa. The incidence of bacterial infections in post-transplant patients has significantly decreased since the introduction of calcineurin inhibitors. Sources of bacterial infection in the kidney allograft can include the surgical wound in cases of nosocomial infection, hematomas and lymphoceles in the graft bed, and impaired urine outflow due to ureteral obstruction or fistulas. Histological examination of needle biopsy material reveals the nature of nonspecific or specific (e.g., tuberculous) inflammation, and bacterial or fungal flora can sometimes be identified. Bacterial infections in histological biopsy samples cause acute interstitial nephritis, manifested by edema of the renal tissue interstitium, leukocyte and eosinophil infiltration. Viral infections remain an urgent problem, among which cytomegalovirus (CMV) infection and polyomavirus infection (BK polyomavirus, Human polyomavirus I of the genus Betapolyomavirus) are of major importance. During vital pathomorphological examination of biopsy material (histological examination), specific inclusions are found in the nuclei of vascular endothelial epithelial cells [116,118-122].

IV. Ischemia-Reperfusion Injury

During the first two months after surgery, one of the causes of allograft dysfunction is ischemia-reperfusion injury. Examination of needle biopsies from transplanted kidneys obtained in the first weeks post-surgery consistently reveals signs of parenchymal ischemic injury. Its histological manifestation is acute tubular necrosis, the severity of which determines the degree of allograft ischemic damage.

1. Mild ischemic injury – dystrophic changes in epithelial cells of entire groups of convoluted tubules, necrosis of isolated epithelial cells.

2. Moderate ischemic injury – characterized by changes similar to those of mild injury, but with an increased number of necrotic cells.

3. Severe ischemic injury – diffuse necrosis of convoluted tubule epithelial cells, accompanied by tubulorrhexis and microcirculatory disturbances in intertubular vessels [116,118-122].

Criteria for Evaluating the Quality of Medical Care

Criteria for assessing the quality of medical care for patients placed on the waiting list for kidney transplantation, during the kidney transplantation surgery, and in cases of kidney transplant failure and rejection are presented in Tables 3-5.

Table 3. Criteria for assessing the quality of medical care for patients placed on the waiting list for kidney transplantation

Table 4. Criteria for evaluating the quality of medical care for patients undergoing kidney transplantation surgery

Table 5. Criteria for evaluating the quality of medical care for patients with kidney allograft failure and rejection

References

Appendix A1. Working Group Composition

Conflict of interest.

The working group declares no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Federal Law No. 323-FZ of November 21, 2011 (as amended on May 29, 2019) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation". Article 47. Donation of human organs and tissues and their transplantation.

Target audience for these clinical guidelines:

1. surgeons;

2. anesthesiologists-intensivists;

3. general practitioners (family doctors);

4. nephrologists;

5. urologists;

6. general practitioners (internal medicine);

7. pathologists.

Table 1. Scale for grading levels of evidence (LoE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing the levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines.

The clinical guidelines update mechanism provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Table 1.  Immunosuppressant dosage in pediatric practice [336]

Table 2. Initial immunosuppressive therapy protocol with tacrolimus** and basiliximab** induction [311].

Dosages of tacrolimus** and prolonged-release tacrolimus**, #mycophenolate mofetil** (#mycophenolic acid**) in children are presented in Table 1 (Appendix A3) [336].

Table 3. Target concentrations of immunosuppressants depending on the immunosuppressive therapy regimen and time post-kidney transplantation [311].

Summary of threshold values for all BANFF injury grades

* _{IFTA – interstitial fibrosis and tubular atrophy}

Diagnostic criteria of the Banff classification.

CATEGORY 1: Normal biopsy or nonspecific changes.

Exclusion of any condition from diagnostic categories 2, 3, 4, and 6 of the BANFF classification is required.

CATEGORY 2: Antibody-mediated rejection and microvascular inflammation/injury (AMR/MVI)

Active antibody-mediated rejection (three criteria must be met):

1. Acute tissue injury* is documented, with at least one of the following features:

   • Microvascular inflammation (g > 0 and/or ptc > 0), in the absence of recurrent or de novo glomerulonephritis (in the presence of acute cell-mediated rejection, borderline changes, or infection, ptc ≥ 1 is insufficient; g ≥ 1 is required)

   • Intimal or transmural arteritis (v > 0)

   • Acute thrombotic microangiopathy, in the absence of another apparent cause.

2. Evidence of current or recent antibody interaction with vascular endothelium, with at least one of the following features:

   • Linear C4d staining in peritubular capillaries or direct medullary vessels (C4d2 or C4d3 by immunofluorescence on frozen sections, or C4d > 0 by immunohistochemistry on paraffin sections)

   • Moderate microvascular inflammation ([g + ptc] ≥ 2) in the absence of recurrent or de novo glomerulonephritis; in the presence of acute cell-mediated rejection, borderline changes, or infection, ptc ≥ 2 alone is insufficient, g ≥ 1 is required

   • Increased expression of antibody-mediated rejection-associated genes in the biopsy tissue.

3. Serological evidence of donor-specific antibodies (DSA to HLA or other antigens). C4d staining or gene expression may replace DSA. However, testing for DSA is recommended when criteria 1 and 2 are met.

Chronic active antibody-mediated rejection (three criteria must be met):

1. Morphological evidence of chronic tissue injury, with at least one of the following features:

   • Transplant glomerulopathy (cg > 0 and/or severe peritubular capillaritis), in the absence of evidence of chronic TMA, chronic recurrent or de novo glomerulonephritis (changes apparent only by electron microscopy).

   • Severe degree of peritubular capillary basement membrane multilayering (electron microscopy required).

   • De novo arterial intimal fibrosis, excluding other causes. The presence of leukocytes in the sclerosed intima favors chronic antibody-mediated rejection, in the absence of a prior history of cell-mediated rejection.

2. Identical to criterion 2 for active antibody-mediated rejection specified above.

3. Identical to criterion 3 for active antibody-mediated rejection specified above.

Chronic antibody-mediated rejection (all three criteria must be met):

1. cg > 0 and/or severe ptcm (multilayering of peritubular capillary basement membranes) and/or de novo arterial intimal fibrosis, excluding other causes. The presence of leukocytes in the sclerosed intima favors chronic antibody-mediated rejection, in the absence of a prior history of T cell-mediated rejection.

2. Absence of criterion 2 defined above for active and chronic active antibody-mediated rejection.

3. Prior documented diagnosis of active or chronic active antibody-mediated rejection and/or documented previous (post-transplant) and/or current evidence of DSA (DSA as defined above in criterion 3 for active antibody-mediated rejection).

C4d staining without evidence of rejection (all 4 criteria must be met):

1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by immunofluorescence on frozen sections or C4d > 0 by immunohistochemistry on paraffin sections)

2. Criterion 1 for active or chronic active antibody-mediated rejection is not met.

3. Absence of molecular evidence of antibody-mediated rejection by criterion 2 for active and chronic active antibody-mediated rejection.

4. Absence of acute or chronic active T cell-mediated rejection or borderline changes.

Microvascular inflammation/injury, DSA-negative and C4d-negative (all 3 criteria must be met):

1. At least moderate microvascular inflammation (g + ptc ≥ 2), in the absence of recurrent or de novo glomerulonephritis (in the presence of acute T cell-mediated rejection, borderline changes, or infection, ptc ≥ 2 is insufficient, g must be ≥ 1)

2. Absence of linear C4d staining in peritubular capillaries (C4d0 or C4d1 by immunofluorescence on frozen sections or C4d = 0 by immunohistochemistry on paraffin sections)

3. Absence of serological evidence of circulating donor-specific antibodies (HLA-DSA or to other antigens, as defined in criterion 3 above for active antibody-mediated rejection).

Suspicious (borderline) antibody-mediated rejection (all 4 criteria must be met):

1. Identical to criterion 1 for active antibody-mediated rejection specified above.

2. Criterion 1 for chronic active and chronic antibody-mediated rejection is not met.

3. Absence of criterion 2 defined for active and chronic active antibody-mediated rejection specified above.

4. Identical to criterion 3 for active antibody-mediated rejection specified above (but C4d must be negative).

C4d staining in acute tubular injury (ATI) (all 3 criteria must be met):

1. Acute tubular injury (ATI) is present

2. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by immunofluorescence on frozen sections or C4d > 0 by immunohistochemistry on paraffin sections)

3. Criterion 1 for active and chronic active antibody-mediated rejection is not met.

CATEGORY 3: Suspicious (borderline) for acute T cell-mediated rejection

Banff lesions with t > 0 and Banff lesion score i = 1 OR Banff lesions with t1 and Banff lesion score i ≥ 2.

CATEGORY 4: T cell-mediated rejection

Acute T cell-mediated rejection IA: Banff lesion score i ≥ 2 and Banff lesion score t2

Acute T cell-mediated rejection IB: Banff lesion score i ≥ 2 and Banff lesion score t3

Acute T cell-mediated rejection IIA: Banff lesion score v1 regardless of Banff lesion score i or t

Acute T cell-mediated rejection IIB: Banff lesion score v2 regardless of Banff lesion score i or t

Acute T cell-mediated rejection III: Banff lesion score v3 regardless of Banff lesion score i or t

Chronic active T cell-mediated rejection Grade IA: Banff lesion score ti ≥ 2 and Banff lesion score i-IFTA ≥ 2, other known causes of i-IFTA (e.g., pyelonephritis, BK virus nephropathy, etc.) excluded, and Banff lesion score t2

Chronic active T cell-mediated rejection Grade IB: Banff lesion score ti ≥ 2 AND Banff lesion score i-IFTA ≥ 2, other known causes of i-IFTA excluded, AND Banff lesion score t3

Chronic active T cell-mediated rejection Grade II: Arterial intimal fibrosis with mononuclear cell inflammation in fibrosis and neointima formation

CATEGORY 5: IFTA

Grade I (mild): Banff lesion score ci1 OR Banff lesion score ct1

Grade II (moderate): Banff lesion score ci2 OR Banff lesion score ct2

Grade III (severe): Banff lesion score ci3 OR Banff lesion score ct3

CATEGORY 6: Other changes not considered to be caused by acute or chronic rejection

Polyomavirus nephropathy, post-transplant lymphoproliferative disorder, calcineurin inhibitor toxicity, acute tubular injury, disease recurrence in the graft, de novo glomerulopathy (other than transplant glomerulopathy), pyelonephritis, drug-induced interstitial nephritis.

Appendix B. Physician Action Algorithms

B.1. Preliminary evaluation plan for a potential kidney recipient

1. Key points in the medical and family history of a potential kidney recipient to be evaluated:

□ Presence or absence of hematuria, proteinuria, urinary tract infection.

□ Presence of peripheral edema.

□ Presence or absence of conditions such as gout, nephrolithiasis, hypertension, diabetes mellitus (including family history), coronary artery disease, peripheral arterial disease, other atherosclerosis.

□ Presence or absence of cardiovascular risk factors.

□ Presence or absence of a history of pulmonary embolism.

□ Presence or absence of sickle cell disease and other hemoglobinopathies.

□ Presence or absence of bowel disorders.

□ Past or current malignancy.

□ Presence or absence of systemic disease that may affect the kidneys.

□ Presence or absence of chronic infection, such as tuberculosis.

□ Family history of kidney disease.

□ Smoking.

□ Presence or absence of alcohol or substance dependence.

□ Mental health history.

□ Obstetric history.

□ Periods of residence abroad, if applicable.

□ Presence or absence of complications related to prior anesthesia.

□ History of back or neck trauma. Presence or absence of back or neck pain.

2. Key history points regarding transfusion-transmitted infections:

Past illnesses:

□ Jaundice or hepatitis.

□ Malaria.

□ History of blood transfusion.

□ Tuberculosis / Family history of tuberculosis.

Increased risk of acquiring HIV, hepatitis B and C:

□ Hemophilia.

□ Promiscuity.

□ History of infectious hepatitis or syphilis.

□ History of intravenous drug use.

□ Skin tattoo or piercing within the last 6 months.

□ Sexual partner with positive serology.

□ Sexual partner who is a drug user.

3. Required specialist consultations:

□ Surgeon (past surgeries, current pathology);

□ Dentist (oral cavity sanation);

□ Gynecologist (pelvic ultrasound) for women; women over 40 also require a consultation with an oncologist (mammologist);

□ Urologist (prostate ultrasound + blood PSA for men over 45);

□ Proctologist;

□ General practitioner / internist (with a detailed medical history, physical status, and medications taken);

□ Endocrinologist with thyroid hormone screening (thyroid-stimulating hormone (TSH) level in blood, total triiodothyronine (T3) level in blood, free thyroxine (FT4) serum level), thyroid ultrasound, and glycated hemoglobin blood level (if indicated).

4. Standard laboratory tests for a potential donor:

□ Blood group, Rh factor;

□ Hepatitis B and C (HBsAg, HCV);

□ HIV (determination of classes M, G antibodies (IgM, IgG) to human immunodeficiency virus HIV-1 / HIV-2 in blood);

□ Syphilis (Wassermann reaction, determination of antibodies to Treponema pallidum in blood);

□ Cytomegalovirus (determination of CMV DNA by PCR);

□ Epstein-Barr virus (determination of EBV DNA by PCR);

□ Complete blood count (CBC) with differential;

□ General clinical blood chemistry panel (creatinine, urea, alkaline phosphatase, ALT, AST, total cholesterol, GGT, total bilirubin, total protein, glucose, uric acid, calcium, phosphorus, magnesium, potassium, sodium);

□ Lipid profile;

□ Glomerular filtration rate + 24-hour proteinuria;

□ Coagulogram;

□ General urinalysis (if diuresis is present);

□ Nechyporenko urine test (if diuresis is present);

□ Urine culture (if diuresis is present).

5. Instrumental diagnostic reports:

□ ECG;

□ Echocardiography;

□ 24-hour ambulatory blood pressure monitoring (ABPM),

□ Holter ECG monitoring;

□ Treadmill test (if indicated);

□ Targeted chest X-ray;

□ Esophagogastroduodenoscopy;

□ Ultrasound examination of the kidneys and adrenal glands, pancreas, liver, gallbladder, and bile ducts;

□ Duplex scanning (DS) of renal vessels, lower extremity vessels, iliac arteries and veins, and neck vessels.

The diagnostic data must be presented in the form of an epicrisis.

Table 1. Recommended recurrence-free intervals for malignant neoplasms (MNs) in patients with CKD prior to kidney transplantation [311].

B.2. Regimens used in clinical guidelines

IS – immunosuppressive therapy; PE – plasmapheresis; IA – immunoadsorption;

KT – kidney transplantation, Rtm – #rituximab**, IVIG – human normal #immunoglobulin**, Tx – transplantation, mycophenolates – mycophenolate mofetil** (mycophenolic acid**).

#Mycophenolate mofetil** and #mycophenolic acid** are used off-label in children. The doses of immunosuppressants used in pediatric practice are presented in Table 1 (Appendix A3) [336].

Figure 2. Management algorithm for a patient with end-stage renal disease

#Mycophenolate mofetil**, #mycophenolic acid**, #everolimus**, and #sirolimus are used off-label in children. The doses of immunosuppressants used in pediatric practice are presented in Table 1 (Appendix A3) [336].

#Mycophenolate mofetil** and #mycophenolic acid** are used off-label in children. The doses of immunosuppressants used in pediatric practice are presented in Table 1 (Appendix A3) [336].

#Mycophenolate mofetil** and #mycophenolic acid** are used off-label in children. The doses of immunosuppressants used in pediatric practice are presented in Table 1 (Appendix A3) [336].

Appendix C. Patient Information

If you and your attending physician decide that a kidney transplantation surgery is necessary, you will need to undergo a typing procedure, during which your blood will be drawn for a corresponding test to detect the presence of specific antigens genetically characteristic of your body.

Antigens are defined types of proteins. These may include, for example, antigens specific to your blood group, Rhesus factor, etc. The typing procedure is necessary to select a donor organ that is genetically as close as possible to your body based on the samples of antigens present in it. The so-called human leukocyte antigens (HLA) play a crucial role in this process. As a result, it becomes possible to create the most favorable conditions for graft survival. A match of a large number of antigens can only be observed in very close relatives, so the donor kidney will be selected based only on a specific number of them, and the success of engraftment in the postoperative period and potential complications will largely depend on the accuracy of donor kidney selection according to the typing results.

Scientists have established that the following cells participate in the immune response: T-lymphocytes, macrophages (phagocytes), and B-lymphocytes. The goal of immunosuppressive therapy is to regulate the activity of these cells.

The immune reactions of your body to the presence of antigens in the donor organ that are not intrinsic to your body will be compensated for by the ongoing immunosuppressive therapy.

During the preoperative preparation period, you should avoid contact with foreign proteins of the future patient's immune system. Contact with foreign proteins leads to an increase in the blood levels of so-called preformed antibodies and their accumulation in the body, which hinders the transplantation surgery as it may lead to early graft rejection.

Based on the HLA typing results, you will be placed on the donor organ waiting list. The waiting period itself takes a rather long time, as the donor kidney must be healthy, match you according to the typing results, and have dimensions, mass, and age that correspond to your body as closely as possible. Note that the age difference between the donor and the recipient should not exceed 15 years.

The wait for a kidney can last up to two years, as this is associated with a severe shortage of donor organs. During this time, hemo- or peritoneal dialysis therapy will be continued. Always keep in mind that the surgery can be scheduled at any time. If by the time a suitable kidney is found you are unwell or for other reasons are not ready for a kidney transplant, the surgery may be postponed for a long period.

Try to prepare well for this moment. Visit a dentist. Caries, periodontal disease, and other oral cavity diseases are a source of infection that can manifest itself at a very inopportune time in the postoperative period.

Do not forget to leave all telephone numbers at the Transplant Center and the Dialysis Center where your attending physician can reach you at any time of the day or night in case a suitable donor organ is matched. At the Transplant Center, also leave the telephone number of the Dialysis Center where you are registered. If you need to leave, warn your attending physician and provide contact numbers. Always have everything necessary ready, including hygiene items, everyday items, and clothing that you might need during your stay at the Transplant Center.

Keep in mind that you may be called in for surgery at any moment, and from that moment on, time will be of the essence.

However, it should be noted that, unfortunately, not everyone in need can be helped, as there are a number of contraindications to kidney transplantation surgery.

Absolute contraindications include malignant neoplasms, metabolic disorders (oxalosis), active AIDS or hepatitis, active tuberculosis, terminal stage of another disease, severe vascular pathology, drug addiction, and a predicted life expectancy of the patient of less than five years.

Relative contraindications include primary kidney disease with a high probability of recurrence in the graft, chronic urinary tract infection that is difficult to treat, decompensated diabetes mellitus, and the patient's emotional instability.

Kidney transplantation surgeries

If doctors inform you that a suitable donor kidney is available, you must immediately gather your belongings, notify your attending physician at the dialysis center, and travel to the transplant center.

From the moment you are informed of the upcoming surgery, refrain from eating and drinking.

Ask your relatives or friends to accompany you to the transplant center by car or taxi.

If you are not ready for the upcoming surgery, immediately notify your attending physician at the transplant center, as the donor kidney will then be allocated to another patient in need of a transplant.

Upon arrival at the transplant center, you will undergo a pre-operative evaluation, which includes blood tests to detect severe electrolyte imbalances (K, Na), monitoring of hemoglobin and hematocrit levels, and measurement of your blood pressure, temperature, and weight. If blood parameters need correction, you will undergo a hemodialysis session. In addition, an anesthesiologist will consult with you to determine the gentlest form of anesthesia in order to minimize associated risks.

You must bring a hospital discharge summary detailing your recent laboratory tests and examinations.

You will also need to provide written consent for the surgery.

Following necessary hygiene and sanitation procedures, right before the transplantation, you will be taken to the operating table. A catheter will be inserted into your cubital or subclavian vein to administer fluids and medications during the surgery.

The surgery takes approximately three to four hours. The donor kidney is transplanted into the right or left iliac fossa in the retroperitoneal space, depending on which kidney is available to the surgeon. Your own kidneys will remain untouched. The blood vessels of the donor kidney are connected to your blood vessels, and its ureter to your urinary bladder. In addition, a drainage catheter may be placed to remove fluid accumulating around the transplanted kidney in the first days post-surgery.

Initially, you will be under continuous monitoring in the intensive care unit, and then, depending on your general condition, you will be transferred to a ward.

You may temporarily require one or more hemodialysis sessions. This is because the function of the donor kidney may be delayed due to the time the donor graft spent in preservation solution before surgery.

You are allowed to get out of bed the next day, provided you wear an abdominal binder. In the event of an uneventful postoperative recovery, early restoration of graft function, and normalization of blood parameters, you will be discharged home within 2-3 weeks after the kidney transplantation.

Throughout your hospital stay, the functional state of the transplanted kidney and your overall health will be continuously monitored, including regular measurements of temperature and weight, as well as blood and urine tests.

Postoperative monitoring of the transplanted kidney is carried out using ultrasound and radioisotope methods, as well as duplex Doppler ultrasonography of the arterial and venous blood flow in the transplanted organ.

Additionally, a biopsy procedure is sometimes required to monitor graft function. A kidney biopsy involves taking a sample of renal tissue for analysis to confirm the correctness of the chosen treatment regimen or to diagnose various dysfunctions of the kidney, allowing the most effective treatment method to be selected. For this purpose, under local anesthesia, the physician inserts a special needle into the area of the transplanted kidney and then examines the obtained renal tissue sample under a microscope.

High doses of medications prescribed immediately after surgery are intended to suppress the immune system so that your body does not reject the donor kidney. Immunosuppression, in turn, increases susceptibility to various infections.

Remember that contact with potential infections is especially dangerous at first, so inform your attending physician about any past or potential contacts with infectious patients.

Special attention must be paid to monitoring blood pressure and blood levels of the primary immunosuppressive drug. The physician will also prescribe and adjust the regimen and dosage of other medications.

Moving forward, you must remain under the regular supervision of your attending physician. This will allow for effective health monitoring and the prevention of potential complications.

_{"You've received a kidney transplant..." A guide for patients awaiting and recovering from kidney transplantation. Edited by Academician of the Russian Academy of Sciences V.I. Shumakov.}

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

No.