Management of Donor-Specific Antibodies in Haploidentical Transplant: Multicenter Experience From the Madrid Group of Hematopoietic Transplant.

Background: Donor specific antibodies (DSAs) can be responsible for graft failure (GF) in the setting of mismatched hematopoietic stem cell transplantation (HSCT). The aim of our study is to report the experience of the Madrid Group of Hematopoietic Transplant (GMTH) in patients with DSAs undergoing haplo-HSCT. Methods: Patients undergoing haplo-HSCT in centers from the GMTH from 2012 to 2020 were included in the study. DSAs were analyzed with a solid-phase single-antigen immunoassay; monitoring was performed during desensitization on days -14, -7, 0 and in a weekly basis until neutrophil engraftment. Desensitization strategies varied depending on center experience, immunofluorescence intensity, complement fixation and type of antibodies. Results: We identified a total of 20 haplo-HSCT in 19 patients performed with DSAs in 5 centers. 10 (53%) patients presented anti-HLA class I DSAs (6 of them with > 5000 mean fluorescence intensity (MFI)), 4 (21%) presented anti-HLA class II (1 with > 5000 MFI) and 5 (26%) presented both anti-HLA class I and II (5 with > 5000 MFI). 90% of patients received at least two treatments as desensitization strategy and all experienced a decrease of MFI after desensitization (mean reduction 74%). Only one patient who developed progressive increase of MFI after infusion developed GF. Desensitization treatments used included rituximab, immunoglobulins, therapeutic plasma exchange, incompatible platelets, buffy coat and immunosuppressors. Seventeen (90%) patients achieved neutrophil engraftment; one patient died before engraftment because of infection and one patient with class I DSAs developed primary GF despite an intensive desensitization. After a median follow-up of 10 months, OS and EFS were 60% and 58%, respectively, cumulative incidence of relapse was 5% and NRM was 32%. Conclusions: Despite the optimal strategy of DSAs desensitization remains unclear, the use of desensitization treatment guided by DSAs intensity kinetics constitute an effective approach with high rates of engraftment for patients with DSAs in need for an haplo-HSCT lacking an alternative suitable donor.

Myeloid-derived suppressor cells as cellular immunotherapy in transplantation and autoimmune diseases.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells, which have been characterized for their immunosuppressive capacity through multiple mechanisms. These cells have been extensively studied in the field of tumor immunity. Emerging evidence has highlighted its essential role in maintaining immune tolerance in transplantation and autoimmunity. Because of their robust immune inhibitory activities, there has been growing interest in MDSC-based cellular therapy. Various pre-clinical studies have demonstrated that the adoptive transfer of MDCS represented a promising therapeutic strategy for immune-related disorders. In this review, we summarize relevant studies of MDSC-based cell therapy in transplantation and autoimmune diseases and discuss the challenges and future directions for clinical application of MDSC-based cell therapy.

NK cells in antibody-mediated rejection - Key effector cells in microvascular graft damage.

Antibody-mediated rejection (ABMR) stands as the major limitation to long-term transplant outcome. The immunologic understanding of ABMR continues to progress and has identified natural killer (NK) cells as key effector cells promoting and coordinating the immune attack on the graft microvascular endothelium. This review discusses the current concepts outlining the different ways that allow for NK cell recognition of graft endothelial cells which includes antibody-dependent as well as independent processes.

Macrophage Proinflammatory Responses to Microorganisms and Transplanted Organs.

Tissue-resident macrophages and those conscripted from the blood/bone marrow are professional phagocytes. They play a role in tissue homeostasis, replacement, and healing, and are the first-line responders to microbial (viral, bacterial, and fungi) infections. Intrinsic ameboid-type motility allows non-resident macrophages to move to the site of inflammation or injury, where, in response to the inflammatory milieu they perform the anti-microbial and/or tissue repair functions. Depending on the need and the signaling from the surrounding tissue and other immune cells, macrophages acquire morphologically and functionally different phenotypes, which allow them to play either pro-inflammatory or anti-inflammatory functions. As such, the macrophages are also the major players in the rejection of the transplanted organs making an excellent target for the novel anti-rejection therapies in clinical transplantation. In this review, we describe some of the less covered aspects of macrophage response to microbial infection and organ transplantation.

Preemptive HLA Antibody Screening Prior to Episodic Transplant Renal Biopsy Enables Early Diagnosis and Therapeutic Response in Asymptomatic Chronically Active Antibody-Related Rejection: A Case Report.

Common management of renal transplant recipients includes episodic renal biopsy based on clinical findings such as an increase in proteinuria or serum creatinine. When antibody-related rejection is suspected from the renal biopsy, subsequent testing for donor-specific antibodies (DSAs) is performed. We instead performed preemptive screening of asymptomatic post-renal transplant recipients for DSAs prior to renal biopsy. In this case, a 30-year-old woman with a secondary transplant was positive for 61 anti-HLA antibodies of class I and class II, among which DQ2 was a DSA with a mean fluorescence index of 2039. The patient had a living kidney transplant 9 years earlier. She had never been diagnosed with rejection, her serum creatinine was around 1.0 mg/dL, and her proteinuria was negative. Following the positive DSA result, a renal biopsy was performed, and she was diagnosed as C4d-negative chronic-active antibody-mediated rejection (CAABMR) with a Banff score of cg1b, (g + ptc) ≥ 2, and C4d 0. Intravenous steroid pulse, deoxyspagarin, antithymocyte globulin, rituximab, and oral everolimus were administrated. The treatment resulted in a gradual decrease in the DSA, which became negative 1 year later. The patient's serum creatinine remains around 1.0 mg/dL, and proteinuria remains negative. Treatments for advanced CAABMR are often expensive and ineffective. Our present case suggests that early detection and treatment through preemptive HLA antibody screening could improve the prognosis of renal transplants.

Increased CD200 expression in post-transplant lymphoproliferative disorders correlates with an increased frequency of FoxP3(+) regulatory T cells.

CD200 is a membrane protein with immunosuppressive function and is expressed in many hematopoietic neoplasms, including acute myeloid leukemia (AML), plasma cell myeloma (PCM), and B-cell lymphoproliferative disorders, but is mostly negative in diffuse large cell lymphoma (DLBCL). CD200 has been shown to be a poor prognostic marker in AML and PCM; in AML, its immunomodulatory effect was linked to its ability to induce FoxP3(+) regulatory T cells (Tregs). Post-transplant lymphoproliferative disorders (PTLDs) arise in the setting of immune dysregulation, and tumor-infiltrating T cells, including Tregs, have been shown to correlate with outcome in these disorders. Because there is no literature data and CD200 is a potentially useful diagnostic and prognostic marker, we studied the expression of CD200 in a series of 38 PTLDs by immunohistochemistry (ICH), and found that 23.7% PTLDs were CD200(+) and showed strong membrane and cytoplasmic positivity in the neoplastic cells. All CD200(+) monomorphic PTLDs were DLBCLs and the median FoxP3(+) Treg count/hpf was higher in CD200(+) than in CD200(-) PTLDs: 22.6 vs. 0.30 (p < 0.001). These results indicated that almost a quarter of PTLDs in our series are CD200(+) by IHC, and CD200 expression correlates with the frequency of immunosuppressive Tregs. This is novel data and supports a pathophysiologic link between CD200 activity and Tregs. In our series, the 5-year overall survival was shorter in CD200(+) PTLDs, compared to CD200(-) patients, although this difference did not reach statistical significance. In addition, we find a higher proportion of CD200(+) monomorphic PTLD-DLBCLs (31.0%), as compared to de novo DLBCLs (7-8%, as found here and in other studies). This may indicate differential expression of CD200 in B-cell lymphomas arising in the setting of immune dysregulation, and raises the possibility of anti-CD200 immunotherapy for these cases.

Association of Pretransplant BK Polyomavirus Antibody Status with BK Polyomavirus Infection After Kidney Transplantation: A Prospective Cohort Pilot Study of 47 Transplant Recipients.

BACKGROUND: Prevention and early detection of BK polyomavirus (BKV) infection is important for long-term kidney graft survival; hence, pretransplant screening methods are essential to identify recipients at high risk for BKV infection. This study investigated the association of pretransplant donor and recipient BKV antibody status with the occurrence of post-transplant BKV infection. METHODS: We prospectively enrolled 47 adult living donor kidney transplant pairs from December 2014 to January 2016. Recipient and donor pretransplant BKV antibody titer was measured by hemagglutination inhibition (HI) test. Donor and recipient median HI titer of 1:20 was used as a cutoff to define seropositivity. Recipients were divided into 2 groups (BKV antibody donor-seropositive/recipient-seronegative (D+/R-) and non-D+/R-). Urinary cytology was used to screen for BKV infection. Plasma polymerase chain reaction testing for BKV DNA was used when decoy cells in urine were persistently detected. RESULTS: Nine (19.2%) of 47 patients belonged to the D+/R- group. Decoy cells were observed in 32 recipients (68.1%) during follow-up. BK viremia occurred in 3 (6.4%) cases. The maximum decoy cell count was significantly higher in the D+/R- group than in the non-D+/R- group (P = .0002). Decoy-cell-free survival was significantly shorter in the D+/R- group (P = .0220). Multivariate analysis identified only BKV antibody serostatus as an independent risk factor for decoy cell appearance (P = .0491). CONCLUSIONS: Pretransplant donor and recipient BKV antibody status was associated with higher maximum decoy cell count and shorter decoy-cell-free survival after kidney transplantation.

Transplanting Marginal Organs in the Era of Modern Machine Perfusion and Advanced Organ Monitoring.

Organ transplantation is undergoing profound changes. Contraindications for donation have been revised in order to better meet the organ demand. The use of lower-quality organs and organs with greater preoperative damage, including those from donation after cardiac death (DCD), has become an established routine but increases the risk of graft malfunction. This risk is further aggravated by ischemia and reperfusion injury (IRI) in the process of transplantation. These circumstances demand a preservation technology that ameliorates IRI and allows for assessment of viability and function prior to transplantation. Oxygenated hypothermic and normothermic machine perfusion (MP) have emerged as valid novel modalities for advanced organ preservation and conditioning. Ex vivo prolonged lung preservation has resulted in successful transplantation of high-risk donor lungs. Normothermic MP of hearts and livers has displayed safe (heart) and superior (liver) preservation in randomized controlled trials (RCT). Normothermic kidney preservation for 24 h was recently established. Early clinical outcomes beyond the market entry trials indicate bioenergetics reconditioning, improved preservation of structures subject to IRI, and significant prolongation of the preservation time. The monitoring of perfusion parameters, the biochemical investigation of preservation fluids, and the assessment of tissue viability and bioenergetics function now offer a comprehensive assessment of organ quality and function ex situ. Gene and protein expression profiling, investigation of passenger leukocytes, and advanced imaging may further enhance the understanding of the condition of an organ during MP. In addition, MP offers a platform for organ reconditioning and regeneration and hence catalyzes the clinical realization of tissue engineering. Organ modification may include immunological modification and the generation of chimeric organs. While these ideas are not conceptually new, MP now offers a platform for clinical realization. Defatting of steatotic livers, modulation of inflammation during preservation in lungs, vasodilatation of livers, and hepatitis C elimination have been successfully demonstrated in experimental and clinical trials. Targeted treatment of lesions and surgical treatment or graft modification have been attempted. In this review, we address the current state of MP and advanced organ monitoring and speculate about logical future steps and how this evolution of a novel technology can result in a medial revolution.

Assessment of Organ Quality in Kidney Transplantation by Molecular Analysis and Why It May Not Have Been Achieved, Yet.

Donor organ shortage, growing waiting lists and substantial organ discard rates are key problems in transplantation. The critical importance of organ quality in determining long-term function is becoming increasingly clear. However, organ quality is difficult to predict. The lack of good measures of organ quality is a serious challenge in terms of acceptance and allocation of an organ. The underlying review summarizes currently available methods used to assess donor organ quality such as histopathology, clinical scores and machine perfusion characteristics with special focus on molecular analyses of kidney quality. The majority of studies testing molecular markers of organ quality focused on identifying organs at risk for delayed graft function, yet without prediction of long-term graft outcome. Recently, interest has emerged in looking for molecular markers associated with biological age to predict organ quality. However, molecular gene sets have not entered the clinical routine or impacted discard rates so far. The current review critically discusses the potential reasons why clinically applicable molecular quality assessment using early kidney biopsies might not have been achieved yet. Besides a critical analysis of the inherent limitations of surrogate markers used for organ quality, i.e., delayed graft function, the intrinsic methodological limitations of studies assessing organ quality will be discussed. These comprise the multitude of unpredictable hits as well as lack of markers of nephron mass, functional reserve and regenerative capacity.

Clinicopathologic Analyses of Chronic Vascular Rejection After Kidney Transplantation.

AIM: We discuss the clinicopathologic analyses of cases of biopsy specimens (BS) after renal transplantation and clarify the mechanisms underlying the development and prognostic significance of chronic vascular rejection (CVR). PATIENTS: CVR was diagnosed in 30 renal allograft BS obtained from 23 renal transplant patients being followed up at the Department of Urology and Transplant Surgery, Toda Chuo General Hospital, between January 2010 and August 2017. RESULTS: CVR was diagnosed at a median of 33.1 months post-transplantation. Among the 23 patients, 14 had a history of rejection. Among the 30 BS showing evidence of CVR, the CVR was mild (cv1 on Banff's classification) in 19, moderate (cv2) in 6, and severe (cv3) in 5. We then classified the 30 BS showing evidence of CVR by their overall histopathologic features as follows: cv alone was seen in 9 (30%), cv + antibody-mediated rejection (AMR) in 11 (37%), and cv + T-cell-mediated rejection (TCMR) in 8 (27%). Loss of the renal allograft occurred during the observation period in 2 patients (9%). Of the remaining patients with functioning grafts, deterioration of the renal allograft function after the biopsies occurred in 6 (26%). CONCLUSIONS: Our study results suggest that AMR contributes to CVR in 30% to 40% of cases, TCMR in 20% to 30% of cases, isolated v lesions in 10% of cases, and cv lesions alone in 30%. The prognosis of the graft exhibiting CVR was not too poor even under the present immunosuppressive protocol.

Early Steroid Withdrawal Protocol With Basiliximab and Rituximab in ABO-Incompatible Kidney Transplant Recipients.

OBJECTIVES: Corticosteroids remain an important component of immunosuppressive regimens in high-risk kidney transplants. In this study, we investigated the efficacy of early steroid withdrawal with basiliximab and rituximab in ABO-blood type incompatible (ABO-i) recipients of kidney transplants. METHODS: Between 2008 and 2019, 15 patients underwent ABO-i kidney transplantation. Seven of the 15 patients were treated with a steroid maintenance protocol and the remaining 8 with an early steroid withdrawal protocol. The immunosuppressive protocol consisted of tacrolimus, mycophenolate mofetil, and methylprednisolone (MP), with basiliximab administered as induction therapy. Rituximab was administered as a single 200-mg dose 1 to 4 weeks before kidney transplantation. Two to 4 sessions of either double-filtration plasmapheresis or regular plasmapheresis or both were performed to remove anti-AB antibodies before transplantation. During surgery, MP was administered at a dose of 500 mg; thereafter, the dosage was tapered rapidly, and the drug was discontinued on day 14 post transplant. RESULTS: In the steroid maintenance group, 2 patients experienced acute antibody-mediated rejection (AMR). One patient with severe AMR had graft loss on postoperative day 4. Patient and graft survival rates in the steroid maintenance group were 100% and 86%, respectively. MP was successfully withdrawn in the steroid withdrawal group. In this group, there was no biopsy-proven rejection. Patient and graft survival rates were 100%, and when last measured, serum creatinine level ± SD was 1.6 ± 0.8 mg/dL. CONCLUSIONS: Our protocol successfully enabled the early withdrawal of steroids in recipients of ABO-i grafts; however, further follow-up is necessary to confirm our results.

Angiotensin II Type 1 Receptor Expression in Renal Transplant Biopsies and Anti-AT1R Antibodies in Serum Indicates the Risk of Transplant Loss.

The manifestation of anti-angiotensin II type 1 receptor (AT1R) antibodies is considered a risk factor for transplant injury; however, the occurrence of angiotensin II type 1 (AT1)-Receptor expression in renal transplant biopsy may help to predict transplant loss. The aim of our study was to evaluate the expression of AT1-Receptors together with their antibodies and assess the risk of transplant loss in patients who had a renal transplant indication biopsy. METHODS: AT1-Receptor immunoreactivity was analyzed in renal transplant biopsies. Additionally, we analyzed the presence of anti-AT1R antibodies in these patients using the enzyme-linked immunosorbent assay (ELISA) method. A result ≥ 10 was assessed as positive. An immunohistochemical evaluation of AT1-Receptor expression was performed on 4 µm-thick paraffin sections mounted on salinized slides. RESULTS: We checked 156 samples of biopsies for the immunoreactivity of the AT1-Receptor. Additionally, we analyzed the presence of anti-AT1R antibodies in these patients using the ELISA method. A group of 67 patients had positive AT1-Receptor expression, and 16 patients had positive anti-AT1R antibodies (R+Ab+) results. A group of 89 patients had no expression of AT1-Receptor, among which 51 had also no anti-AT1R (R-Ab-). One-year postbiopsy graft loss in the R+Ab+ patients was 37% (6/16) compared to 10% (7/69) in the R-Ab- patients (P = .006). Two-year and 3-year graft loss was 43% versus 17% and 50% versus 21%, respectively. CONCLUSIONS: The presence of anti-AT1R antibodies in serum together with the expression of AT1-Receptor in transplant biopsies was associated with a significantly higher graft loss. The relevance of AT1-Receptor expression analyzed together with anti-AT1R antibodies should be considered for better transplant immunologic risk assessment.

Outcome of ABO Blood Type-Incompatible Living-Related Donor Kidney Transplantation Under a Contemporary Immunosuppression Strategy in Japan.

BACKGROUND: Because of the serious donor shortage in Japan, there is an increasing need for ABO blood type-incompatible kidney transplantation (ABOi-KT) in living-related donor kidney transplantation. We evaluated the outcomes of ABOi-KT performed at our hospitals using a contemporary immunosuppression strategy with low-dose rituximab. PATIENTS AND METHODS: Between June 2006 and April 2019, 107 patients underwent living-related donor kidney transplantation at our hospitals. The patients were divided into ABO-compatible (ABOc) and ABOi groups. The basic immunosuppression regimen differed between the 2 groups in the use of low-dose rituximab and therapeutic apheresis in the ABOi group. We compared graft survival, patient survival, rejection, viral infection, and posttransplant renal function between the 2 groups. RESULTS: Of 107 recipients, 37 (35%) underwent ABOi-KT. The 5-year graft survival rates in the ABOc and ABOi group were 91% and 100%, respectively. The Kaplan-Meier analyses showed no difference in graft survival (P = .168) or patient survival (P = .873) between the groups. Biopsy-proven rejection in the ABOc and ABOi groups was observed in 13 (19%) and 7 (19%) patients, respectively (P = .965), and viral infection was observed in 21 (30%) and 10 (27%) patients (P = .747), respectively. Renal function by estimated glomerular filtration rate from 1 week to 5 years after transplantation was similar in both groups. CONCLUSIONS: The outcomes of ABOi-KT with low-dose rituximab were comparable with those of ABOc-KT at our hospitals. ABOi-KT with proper immunosuppression may be an option to help resolve the severe donor shortage in Japan.

Low Immunologic Risk Living Related Renal Transplant Using Very Low-Dose Antithymocyte Globulin as Induction Therapy: A Single Tertiary Hospital Experience.

The aim of induction therapy in the management of kidney transplant is to reduce the incidence of acute rejection and delayed graft function after kidney transplant. The agent for induction therapy differs depending on the recipient risks. The regimen can be either polyclonal (rabbit antithymocyte globulin [rATG]) or monoclonal antibody (basiliximab). Basiliximab is commonly used in patients with low immunologic risk. However, to date we know that the use of rATG on T cell depletion is dose dependent and more potent antirejection therapy. Therefore, we would like to look at 1-year graft function of very low-dose rATG in low immunologic risk recipients. All low immunologic risk patients who received low-dose rATG (0.5 mg/kg of body weight daily) during transplant (day 0) and on days 1 and 2 were recruited. Their renal function, HLA donor-specific antibodies, lymphocyte counts, protocol biopsy results, and cytomegalovirus (CMV) polymerase chain reaction were monitored as per clinical practice. All 10 patients had immediate graft function. Low-dose rATG caused lymphocyte counts to deplete immediately on day 0, and the effect lasted about 1 month post-transplant. All the patients had stable graft function without any significance episode of rejection. Only one patient had de novo HLA-DQ antibody. It is good to know that without prophylaxis antiviral in CMV+ donor to CMV+ recipient, the incidence of CMV viremia is considerably low in our cohort. Very low-dose rATG is an effective induction immunosuppression in low immunologic risk patients with acceptable infection risk.

Extracellular Vesicles as Mediators of Cellular Crosstalk Between Immune System and Kidney Graft.

Extracellular vesicles (EVs) are known immune-modulators exerting a critical role in kidney transplantation (KT). EV bioactive cargo includes graft antigens, costimulatory/inhibitory molecules, cytokines, growth factors, and functional microRNAs (miRNAs) that may modulate expression of recipient cell genes. As paracrine factors, neutrophil- and macrophage-derived EVs exert immunosuppressive and immune-stimulating effects on dendritic cells, respectively. Dendritic cell-derived EVs mediate alloantigen spreading and modulate antigen presentation to T lymphocytes. At systemic level, EVs exert pleiotropic effects on complement and coagulation. Depending on their biogenesis, they can amplify complement activation or shed complement inhibitors and prevent cell lysis. Likewise, endothelial- and platelet-derived EVs can exert procoagulant/prothrombotic effects and also promote endothelial survival and angiogenesis after ischemic injury. Kidney endothelial- and tubular-derived EVs play a key role in ischemia-reperfusion injury (IRI) and during the healing process; additionally, they can trigger rejection by inducing both alloimmune and autoimmune responses. Endothelial EVs have procoagulant/pro-inflammatory effects and can release sequestered self-antigens, generating a tissue-specific autoimmunity. Renal tubule-derived EVs shuttle pro-fibrotic mediators (TGF-ß and miR-21) to interstitial fibroblasts and modulate neutrophil and T-lymphocyte influx. These processes can lead to peritubular capillary rarefaction and interstitial fibrosis-tubular atrophy. Different EVs, including those from mesenchymal stromal cells (MSCs), have been employed as a therapeutic tool in experimental models of rejection and IRI. These particles protect tubular and endothelial cells (by inhibition of apoptosis and inflammation-fibrogenesis or by inducing autophagy) and stimulate tissue regeneration (by triggering angiogenesis, cell proliferation, and migration). Finally, urinary and serum EVs represent potential biomarkers for delayed graft function (DGF) and acute rejection. In conclusion, EVs sustain an intricate crosstalk between graft tissue and innate/adaptive immune systems. EVs play a major role in allorecognition, IRI, autoimmunity, and alloimmunity and are promising as biomarkers and therapeutic tools in KT.

Plasma Cell-Rich Acute Rejection in Renal Transplantation: A Case Report.

Plasma cell-rich acute rejection (PCAR) is a rare type of allograft rejection in renal transplantation. It is characterized by the presence of mature plasma cells that compromise more than 10% of inflammatory cells infiltrating the renal graft. The pathogenesis of PCAR is unknown, appears late, and has been related mainly to insufficient immunosuppression or infections. The treatment is not clearly defined, and the graft survival is poor. Here, we report a case series of 3 Spanish patients diagnosed with PCAR accompanied by donor-specific antibodies (DSA) after kidney transplantation. Mean to diagnosis was 2-12 years post-transplantation, and they began with abrupt deterioration of renal function. All patients were women and had preceding viral infection. In addition, two of the three patients recognize a doubtful adherence to immunosuppression. About treatment, 2 of the 3 patients, because the biopsy of the renal graft showed signs suggestive of incipient antibody-mediated rejection (ABMR) (glomerulitis, capilaritis, transplant glomerulopathy), were started with corticosteroids, anti-thymoglobulin, plasmapheresis, and intravenous immunoglobulins. The last patient, who only showed PCAR at biopsy, was treated with corticosteroids and anti-thymoglobulin. After treatment, graft function improved in all of them, but one patient developed an ABMR and another required a dialysis program, all of which indicates the difficulty in management and treatment of PCAR.

The Leeds hand transplant programme: Review of the laboratory management of the first six cases.

The UK hand transplantation programme is hosted by the Department of Plastic and Reconstructive Surgery at Leeds Teaching Hospitals under the leadership of Professor Simon Kay. Since programme launch in 2013, ten procedures in six individuals have been performed involving unilateral or bilateral transplants. The multi-disciplinary team that delivers the programme includes the transplant immunology service. The laboratory experience in programme support is reported here.

Life-supporting Kidney Xenotransplantation From Genetically Engineered Pigs in Baboons: A Comparison of Two Immunosuppressive Regimens.

BACKGROUND: The aims of this study were to evaluate the efficacy of US Food and Drug Administration-approved drugs in genetically engineered pig-to-baboon kidney xenotransplantation and compare the results with those using an anti-CD40 monoclonal antibody (mAb)-based regimen. METHODS: Ten life-supporting kidney transplants were carried out in baboons using α1,3-galactosyltransferase gene-knockout/CD46 pigs with various other genetic manipulations aimed at controlling coagulation dysregulation. Eight transplants resulted in informative data. Immunosuppressive therapy consisted of induction with antithymocyte globulin and anti-CD20mAb, and maintenance based on either (1) CTLA4-Ig and/or tacrolimus (+rapamycin or mycophenolate mofetil) (GroupA [US Food and Drug Administration-approved regimens], n = 4) or (2) anti-CD40mAb + rapamycin (GroupB, n = 4). All baboons received corticosteroids, interleukin-6R blockade, and tumor necrosis factor-α blockade. Baboons were followed by clinical and laboratory monitoring of kidney function, coagulation, and immune parameters. At euthanasia, morphological and immunohistochemical studies were performed on the kidney grafts. RESULTS: The median survival in GroupB was 186 days (range 90-260), which was significantly longer than in GroupA; median 14 days (range 12-32) (P < 0.01). Only GroupA baboons developed consumptive coagulopathy and the histopathological features of thrombotic microangiopathic glomerulopathy and interstitial arterial vasculitis. CONCLUSIONS: Recognizing that the pig donors in each group differed in some genetic modifications, these data indicate that maintenance immunosuppression including anti-CD40mAb may be important to prevent pig kidney graft failure.

Can endoscopists differentiate cytomegalovirus esophagitis from herpes simplex virus esophagitis based on gross endoscopic findings?

Differential diagnosis between herpes simplex virus (HSV) esophagitis and cytomegalovirus (CMV) esophagitis is challenging because there are many similarities and overlaps between their endoscopic features. The aims of this study were to investigate the implications of the endoscopic findings for the diagnosis of HSV and CMV esophagitis, and to develop a predictive model for differentiating CMV esophagitis from HSV esophagitis.Patients who underwent endoscopic examination and had pathologically-confirmed HSV or CMV esophagitis were eligible. Clinical characteristics and endoscopic features were retrospectively reviewed and categorized. A predictive model was developed based on parameters identified by logistic regression analysis.During the 8-year study period, HSV and CMV esophagitis were diagnosed in 85 and 63 patients, respectively. The endoscopic features of esophagitis were categorized and scored as follows: category 1 (-3 points): discrete ulcers or ulcers with vesicles, bullae, or pseudomembranes, category 2 (-2 points): coalescent or geographic ulcers, category 3 (1 points): ulcers with an uneven base, friability, or with a circumferential distribution, category 4 (2 points): punched-out, serpiginous, or healing ulcers with yellowish exudates. And previous history of transplantation (2 point) was included in the model as a discriminating clinical feature. The optimal cutoff point of the prediction model was 0 (area under receiver operating characteristic curve: 0.967), with positive scores favoring CMV esophagitis. Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 96.8%, 89.4%, 92.6%, 87.3%, and 97.5%, respectively.The predictive model based on endoscopic and clinical findings appears to be accurate and useful in differentiating CMV esophagitis from HSV esophagitis.