Late Allograft Loss Research Articles

Pretransplant IgG Reactivity to Apoptotic Cells Correlates With Late kidney Allograft Loss

Preexisting serum antibodies have long been associated with graft loss in transplant recipients. While most studies have focused on HLA-specific antibodies, the contribution of non-HLA-reactive antibodies has been largely overlooked. We have recently characterized mAbs secreted by B cell clones derived from kidney allograft recipients with rejection that bind to apoptotic cells. Here, we assessed the presence of such antibodies in pretransplant serum from 300 kidney transplant recipients and examined their contribution to the graft outcomes. Kaplan-Meier survival analysis revealed that patients with high pretransplant IgG reactivity to apoptotic cells had a significantly increased rate of late graft loss. The effect was only apparent after approximately 1 year posttransplant. Moreover, the association between pretransplant IgG reactivity to apoptotic cells and graft loss was still significant after excluding patients with high reactivity to HLA. This reactivity was almost exclusively mediated by IgG1 and IgG3 with complement fixing and activating properties. Overall, our findings support the view that IgG reactive to apoptotic cells contribute to presensitization. Taking these antibodies into consideration alongside anti-HLA antibodies during candidate evaluation would likely improve the transplant risk assessment.

Pre-Transplant IgG Reactivity to Apoptotic Cells Correlates With Late Kidney Allograft Loss.

Pre-existing antibodies in patient serum have long been associated with rejection and graft loss. While most studies have focused on characterizing HLA-specific abs, the contribution of non-HLA-reactive abs has been largely overlooked. Recently, we characterized polyreactive monoclonal abs derived from kidney graft recipients amidst rejection. These abs react to a broad range of common self-antigens as well as HLA for some of them. Their one constant was a capacity to bind to apoptotic cells (AC). Here we assessed the presence of such abs reactive to AC in pre-transplant patients and examined their contribution to graft outcomes. Pre-transplant sera from 300 patients along with sera from 20 healthy subjects were used in this study. IgG reactivity to HLA was assessed by Luminex. IgM and IgG reactivity to generic AC and complement activation was measured by flow cytometry. Overall, serum IgG but not IgM reactivity to AC was significantly higher in pre-transplant patients compared to healthy subjects. This reactivity was predominantly mediated by IgG1 and IgG3 with complement activating capacity. Pre-transplant IgG reactivity to AC significantly increased the risk of graft loss.Figure: No Caption available.The effect on graft loss was only apparent after approximately 1 year post-transplant. IgG reactivity to AC as an explanatory factor remained significantly associated to graft loss even when the reactivity to HLA and demographic variables were included. Based on our previous studies, we propose that this reactivity results in part from polyreactive abs. Overall, our findings support the view that abs cross-reactive to apoptotic cells contribute to “pre-sensitization” in patients on the kidney transplant waiting list.

Interstitial Fibrosis and Tubular Atrophy (IFTA), Antibody Mediated Rejection (ABMR) and Recurrent Disease as the Major Causes of Late Renal Allograft Loss.

Interstitial Fibrosis and Tubular Atrophy (IFTA), Antibody Mediated Rejection (ABMR) and Recurrent Disease as the Major Causes of Late Renal Allograft Loss.

Experimental rat models of chronic allograft nephropathy: a review.

Chronic allograft nephropathy (CAN) is the leading cause of late allograft loss after renal transplantation (RT), which continues to remain an unresolved problem. A rat model of CAN was first described in 1969 by White et al. Although the rat model of RT can be technically challenging, it is attractive because the pathogenesis of CAN is similar to that following human RT and the pathological features of CAN develop within months as compared with years in human RT. The rat model of RT is considered as a useful investigational tool in the field of experimental transplantation research. We have reviewed the literature on studies of rat RT reporting the donor and recipient strain combinations that have investigated resultant survival and histological outcomes. Several different combinations of inbred and outbred rat combinations have been reported to investigate the multiple aspects of transplantation, including acute rejection, cellular and humoral rejection mechanisms and their treatments, CAN, and potential targets for its prevention.

Donor-specific human leukocyte antigen antibodies in intestinal transplantation.

Early outcomes following intestinal transplantation (ITx) have markedly improved in recent years. However, there has been a lack of improvement in long-term outcomes. Increasing amounts of data suggest the humoral immune system is a major contributor to rejection and late allograft loss. This review will summarize the available data on donor-specific human leukocyte antigen antibodies (DSAs) in ITx, with a focus on the clinical significance of DSAs, diagnosis of antibody-mediated rejection (AMR), and available treatment modalities. Areas requiring further investigation will also be identified. Mounting evidence shows that pre- and/or posttransplant DSAs are associated with rejection and allograft loss following ITx. Preformed DSAs are present in nearly one-third of ITx recipients, and de-novo DSAs develop in up to 40% of patients. Diagnosis and treatment of AMR remains challenging, but reports indicate that when optimal induction and maintenance immunosuppressive agents are used, the impact of DSAs may be negligible. Although data are limited due to center differences with regard to patient population, induction and maintenance immunosuppression protocols, and monitoring strategies, DSAs are associated with poor outcomes following ITx. A consensus to define AMR and optimal treatment strategies is needed.

Monoclonal antibody therapy and renal transplantation: focus on adverse effects.

A series of monoclonal antibodies (mAbs) are commonly utilized in renal transplantation as induction therapy (a period of intense immunosuppression immediately before and following the implant of the allograft), to treat steroid-resistant acute rejections, to decrease the incidence and mitigate effects of delayed graft function, and to allow immunosuppressive minimization. Additionally, in the last few years, their use has been proposed for the treatment of chronic antibody-mediated rejection, a major cause of late renal allograft loss. Although the exact mechanism of immunosuppression and allograft tolerance with any of the currently used induction agents is not completely defined, the majority of these medications are targeted against specific CD proteins on the T or B cells surface (e.g., CD3, CD25, CD52). Moreover, some of them have different mechanisms of action. In particular, eculizumab, interrupting the complement pathway, is a new promising treatment tool for acute graft complications and for post-transplant hemolytic uremic syndrome. While it is clear their utility in renal transplantation, it is also unquestionable that by using these highly potent immunosuppressive agents, the body loses much of its innate ability to mount an adequate immune response, thereby increasing the risk of severe adverse effects (e.g., infections, malignancies, haematological complications). Therefore, it is extremely important for clinicians involved in renal transplantation to know the potential side effects of monoclonal antibodies in order to plan a correct therapeutic strategy minimizing/avoiding the onset and development of severe clinical complications.

Current Issues in the Treatment of Chronic Antibody-Mediated Rejection in Kidney Transplantation

Circulating alloantibodies are found in a substantial number of renal allograft recipients, and can induce chronic allograft injury, which is represented microscopically as transplant glomerulopathy and diffuse C4d deposition in peritubular capillaries (PTCs). Development of these injuries is significantly correlated with late allograft loss, and in this regard, it was included as a new disease entity named chronic antibody-mediated rejection (cAMR) in the updated Banff 05 classification. Usually, the prognosis of cAMR is poor and conventional immunosuppressants mainly targeting T cell-mediated immunity cannot prevent or reverse it. Therefore, some researchers have suggested that therapies directed at the humoral response may be required for the treatment of cAMR. Recently, some reports have suggested that the combined use of rituximab and intravenous immunoglobulin (IVIg) therapy may be useful for the treatment of cAMR. Our previous study also showed that rituximab and IVIg combination therapy effectively delayed the progression of cAMR. We administered rituximab and IVIg combination therapy to 18 biopsy-proven cAMR patients and found that it significantly slowed the decline of the estimated glomerular filtration rate. However, this effect was limited in patients with heavy proteinuria, and dissipated in all patients by 1 year post-treatment. Recently, new drugs targeting the humoral immune system, such as bortezomib and eculizumab, have been tested for the treatment of cAMR. However, the studies still lack definitive data in terms of successful treatment of cAMR. We speculate that those therapies will compensate for the limitation of previous anti-humoral therapies for cAMR.

A clinical and pathological variant of acute transplant glomerulopathy.

Acute transplant glomerulopathy transplant glomerulopathy (TG) is a common cause of late renal allograft loss. We describe a unique case of a renal transplant recipient who developed rapid-onset nephrotic-range proteinuria and acute kidney injury secondary to C4d negative acute TG. Two courses of intravenous Rituximab resulted in significant improvement in proteinuria and allograft function. In the setting of acute nephrotic-range proteinuria postrenal allograft, both renal biopsy with electron microscopy and screening for de novo donor-specific antibody should be performed to distinguish atypical presentations of TG from other diagnoses.

Alloantibody and Complement Promote T Cell–Mediated Cardiac Allograft Vasculopathy Through Noncanonical Nuclear Factor-κB Signaling in Endothelial Cells

Cardiac allograft vasculopathy is the major cause of late allograft loss after heart transplantation. Cardiac allograft vasculopathy lesions contain alloreactive T cells that secrete interferon-γ, a vasculopathic cytokine, and occur more frequently in patients with donor-specific antibody. Pathological interactions between these immune effectors, representing cellular and humoral immunity, respectively, remain largely unexplored. We used human panel reactive antibody to form membrane attack complexes on allogeneic endothelial cells in vitro and in vivo. Rather than inducing cytolysis, membrane attack complexes upregulated inflammatory genes, enhancing the capacity of endothelial cells to recruit and activate allogeneic interferon-γ--producing CD4(+) T cells in a manner dependent on the activation of noncanonical nuclear factor-κB signaling. Noncanonical nuclear factor-κB signaling was detected in situ within endothelial cells both in renal biopsies from transplantation patients with chronic antibody-mediated rejection and in panel-reactive antibody--treated human coronary artery xenografts in immunodeficient mice. On retransplantation into immunodeficient hosts engrafted with human T cells, panel-reactive antibody--treated grafts recruited more interferon-γ--producing T cells and enhanced cardiac allograft vasculopathy lesion formation. Alloantibody and complement deposition on graft endothelial cells activates noncanonical nuclear factor-κB signaling, initiating a proinflammatory gene program that enhances alloreactive T cell activation and development of cardiac allograft vasculopathy. Noncanonical nuclear factor-κB signaling in endothelial cells, observed in human allograft specimens and implicated in lesion pathogenesis, may represent a target for new pharmacotherapies to halt the progression of cardiac allograft vasculopathy.

Role of bone marrow-derived stem cells, renal progenitor cells and stem cell factor in chronic renal allograft nephropathy

IntroductionChronic allograft nephropathy (CAN) is a poorly understood clinico-pathological entity associated with chronic allograft loss due to immunologic and non-immunologic causes. It remains the leading cause of late allograft loss. Bone marrow derived stem cells are undifferentiated cells typically characterized by their capacity for self renewal, ability to give rise to multiple differentiated cellular population, including hematopoietic (HSCs) and mesenchymal stem cells (MSCs). Characterization of HSCs includes their multipotency, expression of typical surface markers such as CD34 and CD45, while characterization of MSC includes their multipotency, expression of typical surface markers such as CD90 and CD105, and the absence of hemopoietic lineage markers. Aim & methodsThe aim of the present work was to study the role of bone marrow-derived HSCs and MSCs, renal progenitor cells and SCF in chronic renal allograft nephropathy in relation to renal hemodynamics and histopathological changes. We studied 30 patients with kidney transplantation for more than 6 months, divided into 15 patients with stable serum creatinine and 15 patients who developed CAN. Detection of HSCs and MSCs in the peripheral blood using flow cytometry via detection of CD34, CD45, CD117 and CD106, as well as immunohistochemical detection of CD34, CD133, VEGF and αSMA in transplanted kidney biopsies of patients with CAN were done. ResultsThere was a significant increase in the levels of SCF, number of peripheral blood HSCs and MSCs in both transplanted patient groups than the controls and they were higher in patients of group Ia than patients of group Ib, (F = 39.73, P < 0.001), (F = 13.28, P < 0.001), (F = 11.94, P < 0.001), respectively and this was accompanied by evident expression of markers of renal repair. ConclusionStem cells might have a role in renal regeneration in CAN and this may pave the way toward the use of stem cells in correction of CAN.

Update on the Treatment of Acute and Chronic Antibody-mediated Rejection

Antibody-mediated rejection (AMR) by preformed and/or de novo human leukocyte antigen alloantibodies is a leading cause of early and late allograft loss. In this review, we describe strategic approaches to various forms of AMR in clinical settings that are not based on pathologic classification, which is controversial for atypical AMR (C4d-, DSA-, subclinical etc.). For acute AMR, a variety of modalities like plasmapheresis, intravenous immunoglobulin, and anti-CD20 antibodies have been utilized singly, or in combination, with variable results; however, no established treatment for chronic AMR is known. Significant research efforts are being made for developing new and novel therapies. Improvements in clinical outcomes can be expected from studies evaluating innovative therapeutic concepts, such as proteasome inhibition or complement-blocking agents.

Increased Urinary CCL2

Early noninvasive markers that identify patients at risk of renal allograft loss may stratify patients for more intensive monitoring or therapy. CCL2 is a CCR2 receptor chemokine that is a chemoattractant protein for monocytes/macrophages, T cells, and natural killer cells. We have previously demonstrated in a multicenter cohort that urinary CCL2 at 6 months is an independent predictor for the development of IFTA at 24 months. The goal of this study was to determine if early urinary CCL2 is a predictor of graft loss in an independent patient cohort. A prospective, observational cohort study was conducted in the Transplant Manitoba Adult Kidney Program (n=231 patients) from 1997 to 2008. Six-month urinary CCL2 was measured by ELISA, corrected for urinary creatinine, and correlated with long-term graft outcomes. Urine CCL2: Cr at 6 months was significantly associated with death-censored graft loss (HR, 2.42; 95% CI, 1.54-3.82, P<0.0001). On multivariate analysis, urinary CCL2: Cr at 6 months remained an independent predictor of death-censored graft loss (HR, 2.20; 95% CI, 1.18-4.10, P=0.01) after adjustment for pretransplant/de novo donor-specific antibody and delayed graft function. An early posttransplant (≤6 months) multivariate model of CCL2, recipient age, and delayed graft function yielded an AUC 0.87 for prediction of death-censored graft loss. A cutoff value of urinary CCL2: Cr 34.8 ng/mmol yielded a strong positive predictive value of 0.96. This study confirms in an independent prospective cohort that early urinary CCL2 at 6 months is a noninvasive, independent predictor for late renal allograft loss.

Clinical and histological predictors of long-term kidney graft survival

Renal transplantation is the best option for patients with end-stage renal disease (ESRD), but its half-life is limited to a decade. Clinical and histological markers measurable within the first year of transplantation can be used to predict its outcome. These markers are important for selecting kidneys for transplantation, for identifying the main causes of late allograft loss, for therapeutic decisions and as surrogate markers in therapeutic trials. 'Basal state' markers, such as age, glomerular filtration rate and fibrotic lesions, are highly predictive of allograft loss, showing that early and stable pathological mechanisms contribute considerably to this loss. On the other hand, some more dynamic predictors such as treatment, recurrence of the initial disease, inflammation and epithelial phenotypic changes offer clinicians and researchers opportunities to influence the fate of allografts.

Safety and efficacy of everolimus in chronic allograft nephropathy

Chronic allograft nephropathy (CAN) is a major cause of late kidney allograft loss. Everolimus, a novel proliferation signal inhibitor, ameliorates CAN by its antiproliferative or apoptosis-enhancing effects. This study aims to evaluate the safety and efficacy of everolimus in renal transplant recipients with calcineurin inhibitor (CNI) withdrawal either due to CAN or cal-cineurin inhibitor toxicity (CNIT). A total 21 patients with CAN or CNIT converted from CNI to everolimus were prospectively studied from 2006 to 2009. There were 19 males and two females, with a mean age of 32.9 ± 10.7 years. Eight patients had chronic interstitial nephritis, three had diabetes mellitus, nine had end-stage renal disease and one had focal segmental glomerulosclerosis as native kidney disease. The mean duration of dialysis was 10.7 ± 7 months. 57.2% of the patients had CAN and 42.8% had CNIT. Everolimus was started within six months of post-transplantation in six patients, within 6-12 months in two patients, within 1-2 years in four patients and after more than 2 years in nine patients. The mean dose at first month was 1.25 mg/day, at six month was 1.028 ± 0.3 mg/day and at 12 th month was 0.97 ± 0.2 mg/day, with a mean trough level of 6.35 ± 3 ng/dL, 5.18 ± 3 ng/dL and 6.43 ± 1.7 ng/dL, respectively. At the 12 th month, serum creatinine declined from 2.07 ± 0.58 mg/dL to 1.65 ± 0.81 mg/dL. The mean calculated glomerular filtration rate improved from 40.85 ± 8.8 mL/min to 56.84 ± 11.4 mL/min. No major side-effects were observed. Everolimus along with mycophenolate mofetil or azathioprine and prednisolone as a maintenance immunosuppressive therapy was found to be effective and safe in patients with CNIs withdrawal either due to CAN or CNIT.

Glomerular Disease Recurrence in the Renal Allograft: A Hurdle But Not a Barrier for Successful Kidney Transplantation

Almost all forms of primary as well as secondary glomerulonephritides may recur after renal transplantation. Recurrence of the original disease is now the third most common cause of late allograft loss. Nevertheless, in most cases it is difficult to assess the true impact of primary disease recurrence in the allograft; histological recurrence with mild features does not necessarily implicate clinically severe disease. Moreover it is often difficult to distinguish recurrent from de novo disease as in membranous glomerulopathy. Because recurrence occurs late, histological lesions of recurrent glomerulonephritis may be unmasked by chronic damage from other causes such as chronic rejection. Beside the difficulties to interpret renal histology due to the variety of allograft lesions, there are no well-established options to prevent clinically severe disease recurrence nor the therapeutic approaches to the problem. The purpose of this review was mainly to underline that almost all primary and secondary glomerulonephritides represent a contraindication to transplantation. For the majority of patients with end-stage renal disease due to glomerulonephritis, transplantation still represents the treatment of choice.

VEGF-C, VEGF-A and related angiogenesis factors as biomarkers of allograft vasculopathy in cardiac transplant recipients

Cardiac allograft vasculopathy (CAV), the major cause of late allograft loss after cardiac transplantation, results from donor-directed cellular and humoral alloimmune responses. Graft vascular endothelial cells (EC) are primary targets of these destructive responses, suggesting that factors associated with endothelial injury and repair could serve as biomarkers of CAV. Using a protein profiler array platform, we measured the levels of 55 angiogenesis-related proteins in sera from 33 adult heart transplant recipients, including 17 with angiographically documented CAV and 16 age- and gender-matched controls without CAV. All patients were >2 years after heart transplant. The study population was 75% male with a mean age of 62 ± 11 years. On average, patients were 12 ± 5 years after heart transplantation. We found that vascular endothelial growth factor (VEGF)-C, VEGF-A, angiopoietin-2, artemin, urokinase-type plasminogen activator and vasohibin were strongly associated with established CAV (all p < 0.01). Multivariable modeling identified VEGF-C, VEGF-A and platelet factor-4 (PF-4) as significant independent biomarkers of CAV. Furthermore, receiver-operating characteristic curve analysis demonstrated that the combination of all 3 molecules provided outstanding performance for the diagnosis of CAV (area under the curve [AUC] = 0.98; p < 0.001). Serum levels of VEGF-C, VEGF-A and PF-4 demonstrate strong associations with established CAV and, together with related angiogenesis factors, may serve as a reliable, non-invasive diagnostic test for CAV in cardiac transplant recipients.

IVIG and Rituximab for Treatment of Chronic Antibody-Mediated Rejection in Pediatric Renal Transplantation: A Prospective Pilot Study with a 2 Year Follow-Up

Background: Chronic antibody-mediated rejection (AMR) is the major cause of late renal allograft loss. There is, however, no established treatment for this condition. Here we report an update of our prospective study on an antihumoral regimen consisting of high-dose intravenous immunoglobulin G (IVIG) and rituximab in paediatric renal transplant recipients. Methods: Twenty patients with chronic AMR were treated with four weekly doses of IVIG (1 g/kg body weight per dose), followed by a single dose of rituximab (375 mg/m2 body surface area) 1 week after the last IVIG infusion. Response to antihumoral therapy was defined as a reduction of the rate of loss of GFR by at least 30%. Calculated eGFR (Schwartz) were smoothed by LOESS procedure (SAS 9.2) to reduce bias due to outliers. At least one serum creatinine value per month and patient was available. Donor-specific HLA antibodies (HLA DSA) were quantified with Luminex-based bead array technology. Results: Loss of eGFR decreased significantly from 7.6 ml/min/1.73 m2 (range, -29.2 to 1.9) during the 6 months prior to antihumoral therapy to 2.1 ml/min/1.73 m2 (range, -15.0 to 7.6; P=0.006) during the 6 months after intervention. Fourteen patients (70%) responded: 9 of 9 patients (100%) without and 5 of 11 (45%) with transplant glomerulopathy (P=0.014). During 2 years of follow-up, the respective median loss of eGFR in each of the four 6-month periods remained significantly lower than that prior to intervention.[Fig. 1]No patients had pre-existing anti-HLA DSA. At the time of index biopsy de novo anti-HLA DSA were found in 16 of 20 (80%) patients. In 13 of 20 patients (65%) the immunodominant DSA was directed against HLA class II antigens. HLA class I DSA declined in response to antihumoral therapy by 54.4% (p=0.027) and HLA class II DSA by 47% (p=0.040) at 12 months after intervention. The percentage of C4d positivity in peritubular capillaries decreased from 40 ± 18.5% in the index biopsy to 11.6 ± 12.2% (P=0.002) in the follow-up biopsy. In four of nine biopsies (44%) C4d staining turned completely negative. Conclusions: Antihumoral treatment with IVIG and rituximab significantly reduces or stabilizes the progressive loss of transplant function in paediatric patients with chronic AMR over an observation period of 2 years, apparently by lowering circulating DSA and reducing intrarenal complement activation. This treatment protocol may represent a significant advance in the management of this common and often difficult-to-treat posttransplant complication.

IVIG and rituximab for treatment of chronic antibody-mediated rejection: a prospective study in paediatric renal transplantation with a 2-year follow-up

Chronic antibody-mediated rejection (AMR) is the major cause of late renal allograft loss. There is, however, no established treatment for this condition. We report the results of a prospective pilot study on an antihumoral therapy (AHT) consisting of high-dose intravenous immunoglobulin G (IVIG) and rituximab in 20 paediatric renal transplant recipients. Donor-specific HLA antibodies (HLA DSA) were quantified by Luminex-based bead array technology. Loss of eGFR decreased significantly from 7.6 ml/min/1.73 m² during 6 months prior to AHT to 2.1 ml/min/1.73 m² (P = 0.0013) during 6 months after AHT. Fourteen patients (70%) responded: nine of nine patients (100%) without and five of 11 (45%) with transplant glomerulopathy (P = 0.014). C4d positivity in PTC decreased from 40 ± 18.5% in the index biopsy to 11.6 ± 12.2% (P = 0.002) in the follow-up biopsy. In four of nine biopsies (44%) C4d staining turned negative. During 2 years of follow-up, the median loss of eGFR in each of the four 6-month periods remained significantly lower compared with prior to AHT. Class I DSA declined in response to AHT by 61% (p = 0.044), class II DSA by 63% (p = 0.033) 12 months after intervention. AHT with IVIG and rituximab significantly reduces or stabilizes the progressive loss of transplant function in paediatric patients with chronic AMR over an observation period of 2 years, apparently by lowering circulating DSA and reducing intrarenal complement activation.

Vascular Smooth Muscle Cell Apoptosis Promotes Transplant Arteriosclerosis Through Inducing the Production of SDF-1α

Transplant arteriosclerosis is a leading cause of late allograft loss. Medial smooth muscle cell (SMC) apoptosis is considered to be an important event in transplant arteriosclerosis. However, the precise contribution of medial SMC apoptosis to transplant arteriosclerosis and the underlying mechanisms remain unclear. We transferred wild-type p53 to induce apoptosis of cultured SMCs. We found that apoptosis induces the production of SDF-1α from apoptotic and neighboring viable cells, resulting in increased SDF-1α in the culture media. Conditioned media from Ltv-p53-transferred SMCs activated PI3K/Akt/mTOR and MAPK/Erk signaling in a SDF-1α-dependent manner and thereby promoted mesenchymal stem cell (MSC) migration and proliferation. In a rat aorta transplantation model, lentivirus-mediated BclxL transfer selectively inhibits medial SMC apoptosis in aortic allografts, resulting in a remarkable decrease of SDF-1α both in allograft media and in blood plasma, associated with diminished recruitment of CD90(+)CD105(+) double-positive cells and impaired neointimal formation. Systemic administration of rapamycin or PD98059 also attenuated MSC recruitment and neointimal formation in the aortic allografts. These results suggest that medial SMC apoptosis is critical for the development of transplant arteriosclerosis through inducing SDF-1α production and that MSC recruitment represents a major component of vascular remodeling, constituting a relevant target and mechanism for therapeutic interventions.

Antibody-mediated rejection after intestinal transplantation

In spite of impressive improvements in short-term outcomes for intestine transplant recipients, late allograft loss continues to plague the field. Attention has mostly been focused on T-cell-mediated cellular mechanisms of allograft rejection to explain these losses; however, as in other forms of solid-organ transplantation, especially kidney and heart, antibody-mediated mechanisms of acute and chronic allograft injury are increasingly being implicated. In this review, the mechanisms of B-cell- and humoral-mediated allograft injury will be briefly discussed along with the limited evidence that exist for invoking antibody-mediated rejection (AMR) as important in intestine transplantation. The presence of donor-specific antibody has been reported to increase the incidence and severity of intestine allograft rejection and to worsen the overall prognosis for graft and patient. C4d staining in intestine biopsies is unreliable, and currently it is not possible to diagnose AMR with certainty in intestine transplantation. Treatment of presumed AMR in intestine recipients is purely anecdotal at this time. Further basic and clinical research needs to be conducted to more confidently diagnose and treat AMR in intestinal transplantation.