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18
Раздел III
СОВРЕМЕННЫЕ АСПЕКТЫ МЕДИЦИНСКОГО ОБРАЗОВАНИЯ
UCD 616-092.19
Ye.A.Yenin', A.V.Khilko2*
'National Scientific Center of Surgery named after A.N.Syzganov :Almaty department SEC «Center of forensic medicine MJ RK»
DIAGNOSTICS OF RENAL ALLOGRAFT DYSFUNCTION: OUR EXPERIENCE IN APPLICATION OF BANFF-07
CLASSIFICATION
SUMMARY
Aim of research is practical application of the given classification of a pathology closely related kidneys allotransplantate and revealing the value of a complex of morphological researches in dynamics. Materials and Methods: was performed retrospective descriptive study, the depth of 5 years from January 2012 till February 2016. Sample - solid. Exclusion criteria - cadaver kidney transplantation. The work was conducted in the archive of pathomorphologic laboratory of National Scientific Surgery Center named after A.N.Syzganov. Results and discussion: it was about 48 cas es of kidney transplantation. 64,58% (n-31) cases is related transplantations. According to Banff-07 classification they have been divided into groups by investigated signs. Diagnostic categories of Banff-07 classification renal allograft biopsias was following: the norm - 51,61 % (n-16), antibody associated rejection - 3,22% (n-1), boundary changes - 9,67% (n-3), acute rejection - 9,67% (n-3), chronic nephropathy of transplantate - 25,80 % (n-8), with inherent morphological signs.
Conclusion: future advances in analysis of renal allograft biopsies can already be predicted, and the classification and grading of acute/active rejection will continue to evolve. The significance of specific morphologic findings-including glomerulitis, arteriolitis, and infiltrates with unusual cellular features-for acute and chronic allograft dysfunction and outcome will continue to be investigated. Emphasis in biopsy assessment will shift from diagnosis to prediction of later allograft function and outcome, potentially enabling early intervention. Results of research have shown that lifetime morphological research of kidney transplant biopsies allows to give full representation about dynamics of a current, a stage of pathological process, a qualitative and quantitative estimation.
Key words: renal allograft biopsy, related transplantations, renal allograft rejection,lifetime morphological research.
According to the statement of Arthur Cohen, which is one of famous morphologist in the field of nephrology: the kidneys is mysterious and frightening organ for many medical students and young doctors, it is impossible so to probe or see kidneys simply, The anatomy and physiology, seems so difficult and difficult, clinical features of nephritic frustration are indirect and are not easily distinguished, and there are a secret language is necessary, used by nephritic pathologists.The anatomy of kidneys is a difficult and have structures with special type of blood supply by arteries and arterioles by the type
of an ended vessels, If occurs occlusion, the kidney tissue, blood supplied them is exposed to an ischemia, and result of which is necrosis. Almost all grafts have these displays in various degree [1].
One of prominent aspects is clinical diagnostics and timeliness of carrying out punction biopsy for recognition and probably, prevention of development of certain symptomatics. At the elementary level, pathologists should see in kidneys bioptates, at least one of these infringements connected with nephritic insufficiency, proteinuria and hematuria. Biopsy of kidney allograft should become ordinary
as only it works properly, in an equivalent to nephritic insufficiency [1].
Kidney transplant is the most common type of organ transplant and one of the most effective treatments for patients with end-stage renal disease. Management of patients with kidney transplant is a difficult clinical challenge and is often associated with a number of problems. Renal biopsy remains the gold standard by which essential diagnostic and prognostic information is obtained after kidney transplantation [1]. Biopsy methodologies have been devised to assess the acceptability of an organ before transplantation and to assess and predict renal allograft performance after implantation [2, 3].
Optimal method of treatment of patients with a chronic renal failure is heterotopic allotransplantation of a donor kidney and the result from such treatment directly depends on quality of receiving and the quality of the received donor kidney [1,2]. Living and cadaveric donors can be a source of donor kidneys for transplantation to recipients. In case of an organ donorship from the living donor quality of the received donor kidneys and respectively result of transplantation are more optimal in comparison with transplantation when receiving a donor kidney from the cadaver, such difference of results is explained by various duration and intensity of influence of the damaging factors which are followed throughout time as at their receiving, preservation, and at their transplantation. Intensity of ischemic damage of a parenchyma of donor kidneys can have various expression, and its expression depends on aggression of a vasoconstriction of the dosage of cardiotonic support depending on level, which is directly dictated by an initial condition of a hemodynamics of a donor's organism [3].
Standardization of renal allograft biopsy interpretation and reporting is necessary to guide therapy in transplant patients and to establish an objective end point for clinical trials of new antirejection agents [4]. The Banff-07 Classification of Renal Allograft Pathology is an international scheme recently developed to fill this needs. The classification, which originated in a meeting held in Banff, Canada on August 2 to 4, 1991, was published in 1993, has been clinically validated in numerous studies, and is now widely used by center pathologists and in large international trials of immunosuppressive agents. Subsequent meetings have been held in Banff every two years to refine the classification. For National Institutes of Health clinical trials, a modification of the Banff grading system, the
Collaborative Clinical Trials in Transplantation classification was developed; this classification and a clinical validation study were published in late 2013 [5, 6].
There are two theories of the rejection development: -cellular theory (author is Peter Medawar): the process of graft rejection is immunologically dependent. The cells (easy to see on histological slides) were recognized and identified as a cause of tissue damage; humoral theory (author is Paul Te-rasaki): evidence that also in later periods after transplantation antibodies must participate in graft damage. Renal transplant biopsies uses for diagnosis of acute changes in renal function (acute rejection, drug toxic effects, infections), diagnosis of transplant-related changes in pancreas transplant, diagnosis of declining renal function over prolonged time (chronic rejection, recurrent diseases) and etc.
Approaches to renal transplant biopsy interpretation includes next positions: evaluation of all tissue components (glomeruli, interstitium, tubules, arteries and arterioles) and determination if changes are acute and/or chrome. There are standards for adequate renal biopsy: the cortex mandatory must present, at least 7 glomeruli, at least 2 arterial cross sections, not exclusively subcapsular, two cores are better than one for greater sensitivity. Tissue processing of renal transplant biopsies: light microscopy, immunofluorescence, immunoperoxidase C4d (may be limited) and electron microscopy if it is indicated.
The Banff classification characterizes five categories of renal allograft pathology: antibody-mediated rejection; suspicious of acute rejection; acute rejection; chronic sclerosing allograft nephropathy; and other - changes not considered due to rejection [7].
Aim of research is practical application of the given classification of a pathology closely related kidneys allotransplant and revealing the value of a complex of morphological researches in dynamics.
Materials and Methods: was performed retrospective descriptive study, the depth of 5 years from January 2012 till February 2016. Sample-solid. Exclusion criteria - cadaver kidney transplantation. The work was conducted in the archive of pathomorphologic laboratory of National Scientific Surgery Center named after AN Syzganov.The age of the donor ranged from 17 till 57 years.
Antiischemic actions provided by pharmacological protection of an organ which will be extract-
1 КАЗАХСКИЙ МЕДИЦИНСКИЙ IУНИВЕРСИТЕТ НЕПРЕРЫВНОГО ОБРАЗОВАНИЯ
cd according to the general demands of the maintaining the potential donor. At conditioning (he hemodynamics at the potential organ donor was corrected by the cardiotonic medicine «Dofaminum» and monitoring the blood pressure level demanded various dosage of cardiotonic. It is known that Dofaminum in a dose to 10 mkg/kg/min stimulates postsynaptic bctal-adrenorcceptors that causcs positive inotropic effect and augmentation of minute volume of a blood, and also provides intensifying of a circulation in kidneys, the glomerular filtration and is stimulates removing of sodium ions and a diuresis. In high doses - more than 10 mkg/kg/min. or more prevail stimulation of alfal-adrenoreceptors, there is a narrowing of renal vessels that in turn reduces earlier enlarged renal blood flow and a diuresis. For definition of a target dosage of Dofaminum counted intensity of its introduction to an organism of the donor, thus calculation was made on substance of the corresponding 1 kg of body weight of the donor and on rate of his introduction.
Extraction of donor kidneys at potential donors was made according to the standard scheme J.R.Ackermann. However the sequence of composition of solutions for primary perfusion of a kidney after their extraction was various. Options of sequences of solutions were such: either Custodiol solution, or a normal saline solution the incorporating Heparin divorced in the ratio 1:100 that is 1,0 ml of Solution of the Heparin on 100,0 ml ofNaCl of 0,9%, temperature of solution 14-16 C and after that further washing of kidneys with Custodiol.
Hypothermal phannacocooling conservation of a donor kidney after its extraction from the potential organ donor, provides its initial washing from a blood the preserving solutions of relatives on ionic structure to intracellular liquid -Collins's solutions, Saks, SIUT and AO-2, Ross and Marshall, Bredsh-nayder. Despite the above-mentioned actions, measures referred on conservation of a donor organ have the specific features as the task of an organ washing from a blood lays down on the conservating solutions having excess viscosity. As solution with the smallest viscosity in the studied work to conservation of a donor kidney and washing of a lumen of vessels of the finest order from a blood and bloody clots was applied the sequence of solutions - the Heparin divorced in a normal saline solution in the ratio of 1:100 that is 1,0 ml of Solution of the Heparin on 100,0 ml ofNaCl of 0,9% in the temperature range 14-16 C and after that further washing of kidneys Custodiol solution.
The main clinical criteria of quality of the car-ried-out actions at stages of extraction the donor kidneys referred on their «protection» namely at a stage of conditioning and a stage of their conservation were the beginning of excretory function after immediate transplantation and further conservation of these parameters with long-term adequate functioning. The condition of a ncphrositcs, convoluted tubules, vascular glomulus, degree of a dystrophia and a condition of a canaliculus of a kidney, existence of contents and fullness of a vascular glomulus of a kidney were the main morphological data of quality of extraction of donor kidneys, these data were regarded at 400 and 1000 multiple augmentation when coloring by a hematoxylin and cosine and the basal fuchsine of an azur2 methylene blue terms of opportunity to trace such data were at the time of conservation of a donor kidney, for the 5th and 21st days after transplantation of this kidney.
The pathogenesis of acute antibody-mediated rejection includes: subsequent complement activation and adhesion of cells in result of necrosis of endothelial-cells, produced by platelet deposition and coagulation. It is denotes polymorphonuclear cells. Usually mononuclear cells adherence to the endothelium of the glomeruli is prodused, which process is accompanied by C4d deposition in the glomeruli and peritubular capillaries, in the peritubular capillaries between ghost outlines of the tubules.
Chronic allograft rejection - is immune injury of the graft, developed due to a failure to maintain sufficient immunosuppression which controlled by residual antigraft antibodies and lymphocytes. Which is include a progressive decline in renal function, infiltration and invasion of the renal parenchyma by T-cells, and persistent infiltration of the interstitial space by T-cells and macrophages, proliferation of smooth-muscles and hyperplasia vessel walls, with formation a ncointima; focal destruction and nccro-sis of internal elastic lamina, result of which is total vascular occlusion.
Acute antibody-mediated rejection is divided on: acute antibody-mediated rejection (type I: expression of positive C4d, minimal signs of inflammation, type II: expression of positive C4d, leukocytic infiltration, type 111: expression of positive C4d, transmural arteritis), chronic active antibody-medi-ated rejection.
The pathogenesis of second theory mainly includes processing of endogenous and exogenous antigens by class I and class II of major histocompatibility complex pathways. The first one is endog-
Figure 1. A. The glomerulus is presented by the afferent and efferent arterioles forming «Malpigie's» body. Capsule's walls are thin. In canaliculi nephrothelium is high cylindrical, in cytoplasm are visible small vacuole (H&E stain). B. Low magnification of cortex with portions of two glomeruli, tubules, and interstitium and interlobular artery with arteriolar branch (periodic acid-Schiff (PAS) stain). C. Normal glomerulus with surrounding normal
tubules and interstitium (Jones silver stain)
enous antigens are digested by proteosomes into peptides and are leads into class I major histocompatibility complex. Exogenous antigensare degraded by endosomes and are leads into class II major histocompatibility complex. Assembly of the major histocompatibility complex within the cell'sendoplasmic reticulum leads for its transport through the Golgi apparatus and provides its expression on the cellsurface in connection with peptide, where the major histocompatibility complex -peptide complex connects with CD8+ CD4+ T lymphocytes. Next stage is activation and differentiation of T-lymphocytes from dendritic-cell maturation till activation and proliferation of effector T-cells with its active products.
T-cell rejection is divided on: acute T-cell rejection (Type IA: moderate intimal arteriitis;severe intimal arteriitis and moderate tubulitis; type IB: severe tubulitis. Type IIA: mild-moderate intimal ar-
teritis. Type IIB: severe intimal arteritis. Type III: transmural arteritis) Chronic active T-cell rejection.
Results and discussion: it was about 48 cases. 64,58 % (n-31) cases is related transplantations of a kidney. According to Banff-07 classification they have been divided into groups by investigated signs. Diagnostic categories of Banff-07 classifica-tionrenal allograft biopsiaswas following: the norm-51,61 % (n-16), antibodyassociated rejection -3,22 % (n-1), boundary changes - 9,67 % (n-3), acute rejection - 9,67 % (n-3), chronic nephropathy of transplantate - 25,80 % (n-8), with inherent morphological signs.
The antibody-associated rejection, presumably mediated by antibodies is typically characterized by the accumulation of polymorphonuclear leukocytes in glomerular and peritubular capillaries in the early period after transplantation, followed by damage to the endothelium and capillary thrombosis (fig. 2).
Figure 2. A. Humoral rejection, typell. Neutrophils are in peritubular capillaries and glomeruli; interstitial hemorrhage is present. Anti-donor class II antibodies were demonstrable (H&E stain). B. Hyperacute rejection. The cortex shows diffuse hemorrhage and neutrophils in peritubular capillaries with prominent glomerular thrombi 1 day after transplantation (H&E stain). C. Hyperacute rejection due to ABO incompatibility (Immunofluorescence stain shows immunoglobulin M (IgM) in arterial walls)
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However, the histological diagnosis of acute ABMR is still problematic, especially in cases with few outward symptoms [8, 9]. The studies using immunofluorescence to detect immunoglobulins (IgG, IgM and IgA), complement factors (C3, C4 and Clq) and fibrin are not very accurate [10].
Boundary changes - «suspicion'» on acute rejection [11]. This category is used when there is no intimal arteriitis, but the presence of foci of weak tubulitis.
Figure 3. There is an edema in a glomerulus, full-blooded vessels. Canaliculi lumens are stretched, are marked by mononuclear cells: 1 -3 in cross-section (weak tubulitis) (H&E stain)
In grafts undergoing acute rejection, T lymphocytes infiltrate and proliferate within the interstitial space, whence they invade renal tubules, causing tubulitis.Invading CD8 T lymphocytes, which have immunologic specificity for the allograft, cross the basement membrane of the tubule, where they proliferate and induce apoptosis of tubular cells [12]. Sublethally injured tubular cells can also transform from their native epithelial phenotype into primitive
mesenchymal myofibroblasts, promoting interstitial fibrosis [13, 14]. Necrosis of tubular epithelial cells and basementmembrane rupture cause urinary leakage, graft dysfunction, and progressive tubular atrophy [15, 16]. The histologic characteristics of vascular rejection (also termed arteritis or endarteritis) include the infiltration of vessels by mononuclear cells, cndothclial-cell apoptosis, and the synthesis of matrix proteins and collagens by intimal myofibroblasts.
Chronic allograft rejection - ongoing immune injury to the graft - is due to a failure to maintain sufficient immunosuppression to control residual antigraft lymphocytes or antibodies [13]. Its features include a progressive decline in renal function, invasion of the renal parenchyma by T cells, and persistent infiltration of the interstitium by T cells and macrophages [17]. Occasionally, one also sees smooth-muscle proliferation and hyperplasia in vessels, forming a neointima; focal destruction of internal elastic lamina; and finally, vascular occlusion.
Conclusion: future advances in analysis of renal allograft biopsies can already be predicted, and the classification and grading of acute/active rejection will continue to evolve. The significance of specific morphologic findings-including glomcrulitis, arteriolitis, and infiltrates with unusual cellular fea-tures-for acute and chronic allograft function and outcome will continue to be investigated. Emphasis in biopsy assessment will shift from diagnosis to prediction of later allograft function and outcome, potentially enabling early intervention. Results of research have shown that lifetime morphological research of kidney transplant biopsies allows to give full representation about dynamics of a current, a stage of pathological process, a qualitative and quantitative estimation.
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Figure 4. A. Acute cellular rejection (type I). A diffuse mononuclear infiltrate is present with edema and tubulitis (periodic acid-Schiff (PAS) stain). B. Acute allograft glomerulopathy. This pattern of glomerular injury can occur as a feature of cellular or humoral rejection (PAS stain). C. There was no graft function. Tubules show severe acute damage, with a heavy infiltrate of neutrophils in intertubular capillaries (H&E stain)
REFERENCES
1 Hoffmann SC, Hale DA, Kleiner DE, et al. Functionally significant renal allograft rejection is defined by transcriptional criteria. Am J Transplant 2005; 5: 573-81.
2 LiXC, Rothstein DM, Sayegh MH. Costimulatory pathways in transplantation: challenges and new developments. Immunol Rev 2009; 229: 271-93.
3 Stratta R J, Sundberg AK, Rohr MS, et al. Optimal use of older donors and recipients in kidney transplantation. Surgery 2006; 139: 324-33.
4 Cornell LD, Smith RN, Colvin RB. Kidney transplantation: mechanisms of rejection and acceptance. Annu Rev Pathol. 2008; 3: 189-220.
5 Fiirness PN, Taub N, Assmann KJ et al. International variation in histologic grading is large, and persistent feedback does not improve reproducibility. Am J Surg Pathol 2003; 27: 805-810.
6 Terasaki PI. Antibody response to homograft. I. Preliminary studies of the time of appearance of lymphoagglutinins upon homografting. Am Surg 1959; 11: 896-9. [Pubmed]
7 Howie AJ. Problems with BANFF. Transplantation. 2002; 73(9): 1383-4, a comment on McCarthy GP, Roberts IS. Diagnosis of acute renal allograft rejection: evaluation of the Banff 97 Guidelines for Slide Preparation. Transplantation 2002; 73: 1518-1521
8 Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004; 351:2715-29.
9 Sis B, Mengel M, Haas M, Colvin RB, Halloran PF, Racusen LC, et al. Banff '09 Meeting Report: antibody mediated graft deterioration and implementation of Banff working groups. Am J Transplant 2010; 10: 464-71. [Pubmed]
10 Stegall MD, Gloor JM. Deciphering antibody-mediated rejection: new insights into mechanisms and treatment. Curr Opin Organ Transplant 2010; 15: 8-10.
11 De Freitas DG, Sellare Is J, Mengel M et al. The nature of biopsies with 'borderline rejection' and prospects for eliminating this categoiy. Am J Transplant 2012; 12: 191-201.
12 Bestard O. Nickel P, Cruzado JM. et al. Circulating alloreactive T cells correlate with graft function in longstanding renal transplant recipients. J Am Soc Nephrol 2008; 19: 1419-29.
13 Bonsib SM, Abul-Ezz SR. Ahmad I, et al. Acute rejection-associated tubular basement membrane defects and chronic allograft nephropathy. Kidney Int 2000; 58: 2206-14.
14 Kalluri R. EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest 2009;119:1417-9.
15 Elshafie M, Furness PN. Identification of lesions indicating rejection in kidney transplant biopsies: tubulitis is severely under-detected by conventional microscopy. Nephrol Dial Transplant 2012; 27: 1252-1255.
16 Robertson H.. Kirby JA. Post-transplant renal tubulitis: the recruitment, differentiation and persistence of intra-epithelial T cells. Am J Transplant 2003;3: 3-10.
17 Nankivell BJ, Borrows RJ. Fung CL. O'Connell PJ. Allen RD. Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med 2003; 349: 2326-33.
ТУЙ1Н
Жакын туыстык донор буйрепнщ аллотрансплантатынын патологиясы кезшде бергпген классификациям! тэяфибелк туршда колдану жэне клиникалык, процесс динамикасын даморфологиялык, зерттеу-лердщ жиынтышньщ машнасын аныктау. 5 жылаукымындаш, 2012 ж. кантарынан 2016 ж. акдан айын коса апгандагы, ретроспектива сипаттамалыкзерттеулер. Сурыптау - тутас. Ерекше критери1 - буйректщ кадаверлж трансплантациясы. Жумыс А.Н.Сызганов атындаш улттык шлыми хирургия орталыгыньщ патоморфология зертханасынын мурагатында жургЫлдк Буйрек трансплантациясыньщ 48жагдайы кара-стырылды. 64,58% (п-31) жагдай туыстык трансплантация. Banff-07 классификациясына байланысты олар зерттеу белплерЫе байланысты топтарга белЫдК Banff-07 классификациясына байланысты буйрек аллот-рансплантациясыньщ биоптаттары келеа морфологиялык ерекшел1ктер1мен керЫдк калыпты - 51,61 % (п-16), антидене-ассоциирленген кабылдамаушылык - 3,22% (п-1), шеткер1 езгерютер - 9,67% (п-3), жедел кабылдамаушылык;- 9,67% (п-3), трансплантанттын созылмалы нефропатиясы - 25,80% (п-8).
Буйрек аллотрансплантанттарыньщбиопсияларын талдау аймагында келеииектеп жетютттер1 алдын ала болжамдалып,жедел/ белсенд1 кабылдамаушылыктын ж1ктемес1 мен градирлену1 жаксарады. Нак,ты морфологиялык KepiHicTepiHin мацыздылыгы, жедел жэне созылмалы аллотранспланттарыньщ бузылы-
/ КАЗАХСКИЙ МЕДИЦИНСКИЙ IУНИВЕРСИТЕТ НЕПРЕРЫВНОГО ОБРАЗОВАНИЯ
сы, соныц ¡шЫде, гломерулонефрит, артериолит жэне эдеттен тыс жасушалык, керЫка бар инфильтратта-ры, олардыц нэтижеа зерттелетЫ болады. Ерте к,ол сугу максатында, аллотрансплантант кызметш анык-тау ушш диагноз к,оюдан бастап, болжамы мен нэтижеан багалауга ерекше назар аударылады. Зерттеу нэтижеа бойынша, буйрек трансплантантыньщ биопсиясын т1ршт1к жагдайында морфологиялык зерттеу, оньщ динамикалык агымын, патологиялык урдю дэрежесш, езгергстердщ сандык, жэне сапалык, касиетш толык, керсетедг
Туйжд1 сездер: буйрек трансплантантыньщ биопсиясы, туыстык, трансплантация, буйрек трансплантантыньщ кризд1к к,абылдамаушылыгы, т1ршт1к жаедайындагы морфологиялык диагностика.
Практическое применение данной классификации при патологии аллотрансплантатапочек близкородственного донора и выявление значения комплекса морфологических исследований в динамике клинического процесса. Ретроспективное описательное исследование, глубиной 5 лет в период с января 2012 г. по февраль 2016 г. включительно. Выборка - сплошная. Критерии исключения - кадаверная трансплантация почки. Работа проводилась в архиве лаборатории патоморфологии национального научного центра хирургии им. А.Н.Сызганова. 48 случаев трансплантации почки. 64,58% (п-31) случаев родственной трансплантации. Согласно ВапА-07 классификации они были разделены на группы по исследуемым признакам. Диагностические категории Вап[(-07 классификации биоптатоваллотрансплантации почки с присущими морфологическими признаками были следующими: норма - 51,61 % (п-16), антитело-ассоциированное отторжение - 3,22% (п-1), пограничные изменения - 9,67% (п-3), острое отторжение - 9,67% (п-3), хроническая нефропатия трансплантата - 25,80 % (п-8).
Будущие достижения в области анализа биопсий почечных аллотрансплантатов может быть предсказаны, а также классификация и градирование острого / активного отторжения будет продолжать улучшаться. Значимость конкретных морфологических признаков, в том числе гломерулит, артериолит и инфильтраты с необычными клеточные признаками, при острых и хронических дисфункциях аллотрансплантата, а также исход будут исследованы. Особое внимание при оценке биопсии будет сдвигаться от постановки диагноза до прогнозирования поздней функции аллотрансплантата и исход, потенциально позволяя раннее вмешательство. Результаты исследования показали, что прижизненное морфологическое исследование биопсий почечного трансплантата позволяет дать полное представление о динамике течения, стадии патологического процесса, качественную и количественную оценку изменений.
Ключевые слова: биопсия почечного трансплантата, родственная трансплантация, кризы отторжения почечного трансплантата, прижизненная морфологическая диагностика.
АННОТАЦИЯ
