Is ABO-Incompatible Living Donor Liver Transplantation Really a Good Alternative for Pediatric Recipients?

Background: ABO-incompatible (ABOi) living donor liver transplantation (LDLT) has been proposed to compensate for donor shortage. To date, few studies have reported detailed ABOi LDLT results in large series of pediatric patients. C4d complement deposition in graft capillaries has been reported to be associated with antibody-mediated rejection in solid organ transplantation. Methods: A retrospective case–control study was conducted, comparing clinical outcomes of each of 34 consecutive pediatric ABOi LDLT recipients with those of 2 non-ABOi pairs (n = 68), matched according to pre-transplant diagnostic criteria, age, and date of transplantation. In addition, we studied the C4d immunostaining pattern in 22 ABOi and in 36 non-ABOi recipients whose liver biopsy was performed within the first 4 post-transplant weeks for suspected acute rejection. Results: The incidence of biliary complications was higher in ABOi recipients (p < 0.05), as were the incidence of acute humoral rejection (p < 0.01) and the incidence of retransplantation (p < 0.05). All children who required retransplantation were older than 1 year at the time of ABOi LDLT. Positive C4d immunostaining was observed in 13/22 (59%) ABOi recipients versus 3/36 (8.3%) non-ABOi recipients (p < 0.0001). Conclusions: ABOi LDLT is a feasible option for pediatric end-stage liver disease but carries increased risks for the recipient, especially for children older than 1 year, even with a specific preparation protocol. C4d immunostaining may be a hallmark of acute humoral rejection in ABOi liver transplantation.

Az antitestmediált rejekció diagnosztikája és kezelése gyakorlatunkban

Összefoglaló. Bevezetés: Az antitest közvetítette kilökődés a graftvesztés gyakori oka a vesetranszplantáltak körében. Célkitűzés: Célul tűztük ki, hogy ismertetjük a centrumunkban biopsziával igazolt humorális kilökődéssel rendelkező betegeknek a kezelésre (standard kezelés: plazmaferézis, immunglobulin, rituximab) adott válaszát, valamint hogy vizsgáljuk a proteinuria grafttúlélésre kifejtett hatását és azt, hogy ezt a DSA-tól függetlenül teszi-e. Vizsgáltuk az eGFR-, a DSA-MFI-értéknek az antirejekciós terápia hatására bekövetkező változásait is. Módszer: 85 beteg retrospektív analízisét végeztük el. A szövettani elemzésben a Banff-klasszifikációt vettük alapul. A csoportok összehasonlításához kategorikus változók esetén a Fisher-féle egzakt próbát, folyamatos változók esetén a Kruskal–Wallis-próbát használtuk. Eredmények: A biopsziával igazolt humorális rejekciós csoportba (ABMR-csoport) 19, a DSA-pozitív csoportba 14, a DSA-negatív csoportba 52 beteget választottunk be. A DSA-érték az ABMR-csoportban 61,16%-kal csökkent, a DSA-pozitív csoportban 42,86%-kal redukálódott (Fisher-féle egzakt: p = 0,1). Az ABMR-csoportban 9 betegnek a jelentős, 4-nek a nephroticus mértékű proteinuriája csökkenthető volt (az ABMR-csoport 68%-a). A legjobb grafttúlélés a legalacsonyabb fehérjeürítésnél adódott. Az antirejekciós terápiát követően készült biopsziákban: a glomerulitis, az interstitialis gyulladás, az arteritis mértéke csökkent az antihumorális kezelés hatására, azonban krónikus elváltozások jelentek meg. Következtetés: Az ABMR-csoportban az antirejekciós terápiát követően a fehérjeürítés monitorizálása javasolt, hiszen becsülhető vele a grafttúlélés. Orv Hetil. 2021; 162(26): 1029–1037. Summary. Introduction: Antibody-mediated rejection is a common cause of graft loss among kidney transplant recipients. Objective: We aimed to describe the response of patients with biopsy-proven humoral rejection to treatment (standard treatment: plasmapheresis, immunoglobulin, rituximab) in our center. We also analyzed the effect of proteinuria on graft survival and whether this effect is independent of donor-specific antibodies (DSAs). Changes of eGFR and level of DSA following rejection treatment were examined. Method: In this study, laboratory data of 85 patients were analysed. Histological analysis was based on the Banff classification. Fisher’s exact test was used for statistical analysis, and Kruskal–Wallis test was used to compare patient groups per variable. Results: Data from 85 patients were processed retrospectively. 19 patients were selected for the biopsy-confirmed humoral rejection group (ABMR group), 14 for the DSA-positive group, and 52 for the DSA-negative group. DSA titer decreased by 61.16% in the ABMR group after treatment and by 42.86% in the DSA-positive group (Fisher’s exact test: p = 0.1). In the ABMR group, significant nephrotic proteinuria in 4 patients and severe proteinuria in 9 patients were reduced (68% of ABMR group). The patients with the lowest protein excretion had the best graft survival. In biopsies performed after antirejection therapy, the extent of glomerulitis, interstitial inflammation, arteritis decreased with antihumoral treatment, but chronic lesions appeared. Conclusion: Following treatment of biopsy-proven ABMR, reduction of proteinuria predicts graft survival and should be monitored as an important factor-predicting prognosis. Orv Hetil. 2021; 162(26): 1029–1037.

MO065DIAGNOSTIC CRITERIA OF HUMORAL REJECTION IN RENAL TRANSPLANT RECIPIENTS WITH PRE-EXISTING ANTI-HLA ANTIBODIES BASED ON SENTINEL SKIN FLAP BIOPSY

Background and Aims Twenty years of transplantation of composite vascularised allografts have revealed the high immunogenicity of the constituent parts, especially the skin.Several researchers have proposed the use of vascular stalk flaps, which allow to performe skin biopsy and diagnose rejection without biopsy of the transplanted solid organ.Pre-existing anti-HLA antibodies represent a serious immunological barrier to successful kidney transplantation.We are not aware of any studies on the diagnosis of antibody-associated acute kidney allograft rejection from deceased donors in recipients with pre-existing antibodies, based on morphological examination of a sentinel skin flap on a vascular stalk. The Aim: To determine the morphological features of humoral rejection in renal transplant recipients with pre-existing anti-HLA antibodies based on sentinel skin flap biopsy. Method Three skin-kidney allografts recipients underwent skin flap biopsy on 2nd day after transplantation. A kidney allograft biopsy was performed on day 7, 30, 60, 90.The results of morphological studies are presented using the Banff classification of renal allograft and skin allograft pathology. All recipients were female; 35, 44, and 57 years old. Two patients were re-transplanted and the main cause of CKD was chronic glomerulonephritis. The third patient, with congenital abnormality of the urinary tract, received her first graft.Pre-existing anti-HLA antibody levels before transplantation were 50%, 60%, 80%, respectively. Results All recipients showed signs of humoral rejection of the skin flap with thrombosis of the feeding vascular bundle, phlebitis, predominantly intimal arteritis with median necrosis, detachment and areactive necrosis of epidermis and epithelium of skin appendages. Clinical rejection, similar to the algorithm proposed by Etra J.W. et al. to assess preclinical skin rejection in an animal model (2019), was interpreted as G2 in two cases and G3 in one case. The Banff classification of the skin flap offers a qualitative assessment of certain biopsy parameters, while the kidney graft has qualitative-quantitative criteria for assessing rejection. When comparing the two classifications, a quantitative gradation of pathological changes in the skin flap according to the parameter of intimal arteritis (v) and immunoreactivity of the C4d marker similar to renal rejection was possible. In histological examination of skin flap biopsies, the degree of vasculitis was assessed in a large feeding artery: in all three cases this parameter was equal to v3. C4d expression was analyzed in the endothelium of microcirculatory blood vessels of the dermis and hypodermis: C4d1 in one case and C4d3 in the other two. The analysis of renal allograft biopsies revealed signs of humoral rejection (v1) only at day 30 in two recipients whose C4d expression in the skin and hypodermis was strong (C4d3). Conclusion Antibody-mediated rejection of a vascularized sentinel skin flap in recipients with combined skin-kidney transplantation is characterized by vasculitis affecting a core vascular bundle in the form of endarteritis with necrosis of media,phlebitis and associated thrombosis.Further studies are required to determine the feasibility of using a vascular stalked skin flap in the diagnosis of humoral rejection after renal transplantation.

First Successful Delivery after Uterus Transplantation in MHC-Defined Cynomolgus Macaques

Delivery following uterus transplantation (UTx)—an approach for treating uterine factor infertility—has not been reported in nonhuman primate models. Here, six female major histocompatibility complex (MHC)-defined cynomolgus macaques that underwent allogeneic UTx were evaluated. Antithymocyte globulin and rituximab were administered to induce immunosuppression and a triple maintenance regimen was used. Menstruation resumed in all animals with long-term survival, except one, which was euthanized due to infusion associated adverse reaction to antithymocyte globulin. Donor-specific antibodies (DSA) were detected in cases 2, 4, and 5, while humoral rejection occurred in cases 4 and 5. Post-transplant lymphoproliferative disorder (PTLD) developed in cases 2 and 3. Pregnancy was attempted in cases 1, 2, and 3 but was achieved only in case 2, which had haploidentical donor and recipient MHCs. Pregnancy was achieved in case 2 after recovery from graft rejection coincident with DSA and PTLD. A cesarean section was performed at full-term. This is the first report of a successful livebirth following allogeneic UTx in nonhuman primates, although the delivery was achieved via UTx between a pair carrying haploidentical MHCs. Experimental data from nonhuman primates may provide important scientific knowledge needed to resolve unsolved clinical issues in UTx.

Beyond the Superficial: Disseminated Trichophyton rubrum Infection in a Kidney Transplant Recipient

Superficial dermatophyte infections are common in the general population and are readily treated with topical antifungals. Deeper invasion is rare, and dissemination to visceral organs is extremely uncommon. We describe a 66-year-old renal transplant recipient who developed disseminated Trichophyton rubrum infection while undergoing treatment for acute humoral rejection. The infection presented as a facial rash with subsequent dissemination to the lungs and chest wall. All sites of infection improved with combination administration of oral posaconazole and terbinafine. In this work, we review the available literature regarding management of disseminated Trichophyton infection and discuss therapeutic interventions for disseminated dermatophytosis in immunosuppressed hosts.

P0290THERAPEUTIC PLASMAPHERESIS EXPERIENCE DUE TO NEPHROLOGICAL INDICATIONS

Background and Aims Therapeutic plasma exchange (PEX) has an increasingly long list of indications in recent years, in addition to immunosuppressive therapies in many life-threatening immune activations, it provides significant improvements in mortality and morbidity. In this study, we aimed to investigate the laboratory and clinical effects of PEX performed with nephrologic indication in our clinic. Method The records of 67 patients (36 females, 31 males; mean age, 45.7±15.8 years) who underwent PEX with nephrological indication between 2012 and 2017 in our clinic were retrospectively reviewed. Characteristics of the patients such as, indications of PEX, laboratory values and number of PEX sessions were recorded. In addition, clinical responses were also evaluated. Results When a total 398 PEX sessions were examined, the most common indication (40.3%) was acute humoral rejection after renal transplantation, followed by granulomatosis with polyangiitis (19.4%) and thrombotic microangiopathy (9%), respectively. The average of the PEX sessions was 5.94. There was a statistically significant increase in the bicarbonate value when the arterial blood gas of the patients was evaluated after PEX (p=0.002). However, no significant difference was observed in the pH and ionized calcium values (p=0.135, p=0.969, respectively) (Table 1). When all the patients were evaluated, there was no significant change in hemoglobin values (p=0.174), but platelet values decreased significantly (p=0.011) after PEX. However, when the patient group admitted with thrombotic microangiopathy was examined, it was observed that platelet count increased and LDH level decreased significantly (p=0.063, p=0.028, respectively). When the serum creatinine values of all patients were evaluated, a significant decrease was observed in the serum creatinine values after PEX (p=0.001). In addition, after 2 years following PEX treatment, 70.1% of patients were still alive and 12.5% of patients undergoing PEX for acute humoral rejection were undergoing on hemodialysis treatment. Conclusion According to the results of our study, patients should be followed up especially for acid-base and electrolyte changes after PEX. In addition, therapeutic PEX might be effective in terms of improving morbidity and 2 year-mortality of these patients.

Immunohistochemical profile of mononuclear infiltrate in the myocardium of transplanted heart. Computer morphometry data

Aim. To carry out a quantitative immunophenotypic characterisation of cellular corporations in a mononuclear inflammatory myocardial infiltrate in the cell and humoral forms of heart transplant rejection using the computer morphometry of endomyocardial biopsy samples.Materials and methods. Endomyocardial biopsy samples (n = 226) were obtained from 56 heart recipients who underwent transplantation in 2018–2019. Sections with a thickness of 5 μm after the paraffin infiltration were stained with hematoxylin and eosin according to the standard procedure. The expression of CD3 T-lymphocyte, CD20 B-lymphocyte and CD68 macrophage markers was determined by the immunohistochemical streptavidin-biotin method. Using computer morphometry, the staining area coefficient (SAC) was calculated as the percentage of the total area of the stained objects to the area of the biopsy. The statistical processing of the results included verification of the distribution nature by the Kolmogorov-Smirnov method and the calculation of the Cramer — Welch criterion.Results. Lymphocytes and macrophages were found in the inflammatory infiltrate of all heart transplants. The expression of CD3 T-lymphocyte marker in the absence of rejection (0R) was at SAC = 0.99 ± 0.02%. In comparison with 0R cases, this coefficient increased 2.1 times (p <0.05), 3.4 times (p <0.05), 5.5 times (p <0.05) and 4.8 times (p <0.05) in 1R, 2R, 3R and humoral rejection, respectively. The expression of the CD20 B-lymphocyte marker in 0R cases was characterised by SAC = 0.19 ± 0.01%. In comparison with 0R cases, this coefficient increased 2.7 times (p <0.05), 3.4 times (p < 0.05), 4.4 times (p <0.05) and 9.5 times (p <0.05) in 1R, 2R, 3R and humoral rejection, respectively. The value of the CD68-positive macrophage region for 0R was only 0.34 ± 0.01%. This parameter increased 2.7 times (p <0.05), 4.0 times (p <0.05), 9.6 times (p <0.05) and 4.1 times (p <0.05) in 1R, 2R, 3R and humoral rejection, respectively.Conclusion. Cellular corporations in the mononuclear inflammatory infiltrate of transplanted heart are characterised by the predominance of T-lymphocytes in the cases of both cellular and humoral rejection. The expression of the B-lymphocyte marker is most pronounced in an antibody-mediated form. The maximum presence of macrophages in the infiltrate characterises severe cell rejection. An increase in the severity of cell rejection leads to an increase in the relative content of B-lymphocytes and macrophages in the infiltrate.

Current status of imaging diagnosis in the transplanted kidney. A review of the literature with a special focus on contrast-enhanced ultrasonography

Objectives. Ultrasonographic scanning is currently the most widespread imaging diagnostic procedure. The method provides real-time morphological, vascular and elastographic information in a non-invasive manner. In recent years, harmonic vascular examination has become accessible using intravenous contrast agents. In urological pathology, this procedure is used in the detection and evaluation of vascular and ischemic complications, in the classification of complex cysts according to the Bosniak system, also in the renal lesions with uncertain etiology and in acute pyelonephritis for the detection of abscesses. The contrast agent (SonoVue) is angiospecific and can be used in patients transplanted immediately after surgery without adverse effects or impaired renal function. Thus, it is desirable to be used in the nephrological pathology of the renal graft and to develop diagnostic models based on the evaluation of renal microvascularization, as well as the quantitative data resulting from the graphical representation of the specific parameters. The purpose of this review is to evaluate the current state of the literature regarding the place and role of contrast substance ultrasound in the early diagnosis of acute renal graft dysfunction and to make a differential diagnosis of this pathological entity. Method. This review quantifies the role of contrast ultrasound in the diagnosis of acute complications of the renal graft. The research was conducted based on the databases PubMed, MedScape, Cochrane , according to the search criteria such as contrast-enhanced ultrasound + kidney transplant, "time intensity curves" + "kidney transplant”, filtered for the period 2004-2018. Results. In the nephrological pathology of the renal graft, contrast-enhanced ultrasound is a valuable tool, superior to Doppler ultrasound in predicting the evolution of the renal graft, identifying very small early defects in renal microvascularization. A number of studies succeeded in identifying acute graft dysfunction, some of which establish its etiology - humoral rejection versus acute tubular necrosis. On the other hand, the contrast-enhanced ultrasound parameters do not have the ability to distinguish between cellular and humoral rejection. Conclusions. If, at present, the histopathological examination is the only one that can differentiate with certainty the cause of acute renal graft dysfunction, we consider that contrast-enhanced ultrasound, as a non-invasive imaging technique, opens a favorable perspective for increasing the survival of the renal graft and decreasing the complications in the renal transplant. The combination of other ultrasound techniques, together with contrast-enhanced ultrasound, could lead to the development of new diagnostic models.