High Risk Of Rejection Research Articles

Longitudinal changes in corneal leucocyte density in vivo following transplantation

AimsTo prospectively evaluate the changes in corneal leucocyte density with in vivo confocal microscopy (IVCM) following transplantation and to determine if leucocyte density post-transplant is an indicator of graft rejection...

The Results of the PRISM (Prediction of Rejection In Sensitized patient blood saMples) Trial with a Novel Bioassay

Background kSORT, a 17 gene blood biomarker, has been retrospectively validated for detection of BPAR and immune quiescence in kidney tx. This is the first assessment of the predictive accuracy of pre and serial post-tx kSORT in a prospective clinical trial of high immunologic risk tx patients. Methods 113 kidney tx recipients, with cPRA of >50% (median 97%) were enrolled pre-tx and followed for 6 mo post-tx in the PRISM (Prediction of Rejection In Sensitized SaMples) trial. A protocol bx was done at 6 mo and/or at graft dysfunction. kSORT was run pre-tx and 5 times post-tx (0.5, 1, 2, 3, 6 mo). Customized software kSAS generated actionable immune risk scores as High-(HR) or Low-(LR) risk for AR. All patients had induction with Thymoglobulin and maintained on TAC, MMF and prednisone. Statistical analysis used R and Fisher's exact test. Results 98 evaluable patients had kSORT analyzed across 560 blood samples and results correlated with 93 bx (34 for cause), with 12 AR and 20 borderline (BL)-AR. 15.7% of kSORT had a null call of Indeterminate-Risk (IR). The overall predictive accuracy of the pre-tx kSORT (assessed in 54 pts) was 90.3% for no-rejection post-tx. For pre-tx kSORT: 80% wereLR,18% were -HR and did not correlate with cause of sensitization. For post-tx blood samples paired with bx, 51 patients had no-rejection and 47 were correctly classified as LR (specificity 92.2%). Among the 20 BL-AR, kSORT was HR in 93% with definitive kSORT scores (HR in 14; LR in 1, IR in 5). Among the 12 AR, 78% were HR. Combining the AR and BL-AR group as “rejection”, the accuracy of kSORT for matching the same results as the biopsy was 84%. A diagnostic odds ratio of a kSORT+ (HR) call in the AR and BL-AR group, compared to the odds of a LR call in the same group was >27-fold (dOR=27.4), confirming that the kSORT test can discriminate between BPAR outcomes (p<0.0001). After treatment of AR, 42% remained kSORT positive. Conclusions kSORT can be applied both pre-tx and at serial times post-tx to monitor patients at low and high risk of rejection in highly sensitized patients. A LR kSORT score has 90% accuracy for predicting freedom from rejection, either before or after tx. Pre and post-tx kSORT assessment is an important adjunct measure for instituting Precision Medicine in the management of sensitized renal tx recipients and optimizing their outcomes.

Outcomes of antiviral treatment in hepatitis C virus liver transplant patients off immunosuppression in the direct acting antivirals era: A case series.

Clearance of hepatitis C virus (HCV) under antiviral therapy, including direct-acting antivirals (DAAs), has been associated with higher risk of rejection. Whether patients who are not on immunosuppression (IS) during DAA therapy are at higher risk of rejection is unknown. Four transplant recipients who were off IS and treated with DAA therapy were identified. All patients were genotype 1 infection and treated for 12weeks with sofosbuvir/ledipasvir/ribavirin. At the time of DAA therapy, patients were off IS for a median of 9.5years. Time from liver transplant (LT) to treatment was 12.9 years.Median baseline ALT was 70 IU/L, at follow-up week 12 was 18 IU/L. No signs of rejection were observed during DAA therapy or follow-up after the end of therapy. All 4 patients obtained sustained virological response. Direct-acting antivirals therapy in HCV patients off IS post-LT can be successfully undertaken without the need to restart IS.

Immunologic Stromal Rejection After Deep Anterior Lamellar Keratoplasty With Grafts of a Larger Size (9 mm) for Various Stromal Diseases.

To evaluate the rate and outcomes of immunologic stromal rejection occurring after large deep anterior lamellar keratoplasty (DALK) and the effect of the underlying disease on the cumulative probability of rejection. This was a retrospective chart review of all eyes that underwent a 9-mm DALK at Ospedali Privati Forlì (Forlì, Italy). On the basis of preoperative diagnosis, eyes were assigned to group 1: keratoconus, group 2: stromal disease with a low risk for rejection, or group 3: stromal disease with a high risk for rejection. The cumulative probability of experiencing a rejection episode over time was assessed by Kaplan-Meier analysis and was compared among the 3 groups using the log-rank test. Values of corrected distance visual acuity, central corneal thickness, and endothelial cell density before and 6 months after rejection were compared. Twenty of 377 eyes (5.3%) experienced an episode of stromal rejection [17/265 (6.4%) in group 1, 2/71 (2.8%) in group 2, and 1/41 (2.4%) in group 3]. The mean time interval between DALK and the rejection onset was 11.8 months (range 1-24). The cumulative probability of rejection episodes did not differ significantly among the 3 groups. All episodes resolved within 6 months after the onset, with no significant differences between prerejection and 6-month postrejection values of corrected distance visual acuity, central corneal thickness, and endothelial cell density. The rate of immunologic stromal rejection after large 9-mm DALK is within the range reported in the literature for conventional DALK, regardless of the indication for surgery.

Biomaterials-enabled cornea regeneration in patients at high risk for rejection of donor tissue transplantation

The severe worldwide shortage of donor organs, and severe pathologies placing patients at high risk for rejecting conventional cornea transplantation, have left many corneal blind patients untreated. Following successful pre-clinical evaluation in mini-pigs, we tested a biomaterials-enabled pro-regeneration strategy to restore corneal integrity in an open-label observational study of six patients. Cell-free corneal implants comprising recombinant human collagen and phosphorylcholine were grafted by anterior lamellar keratoplasty into corneas of unilaterally blind patients diagnosed at high-risk for rejecting donor allografts. They were followed-up for a mean of 24 months. Patients with acute disease (ulceration) were relieved of pain and discomfort within 1–2 weeks post-operation. Patients with scarred or ulcerated corneas from severe infection showed better vision improvement, followed by corneas with burns. Corneas with immune or degenerative conditions transplanted for symptom relief only showed no vision improvement overall. However, grafting promoted nerve regeneration as observed by improved touch sensitivity to near normal levels in all patients tested, even for those with little/no sensitivity before treatment. Overall, three out of six patients showed significant vision improvement. Others were sufficiently stabilized to allow follow-on surgery to restore vision. Grafting outcomes in mini-pig corneas were superior to those in human subjects, emphasizing that animal models are only predictive for patients with non-severely pathological corneas; however, for establishing parameters such as stable corneal tissue and nerve regeneration, our pig model is satisfactory. While further testing is merited, we have nevertheless shown that cell-free implants are potentially safe, efficacious options for treating high-risk patients.

Efficacy and safety of sofosbuvir-based antiviral therapy to treat hepatitis C virus infection after kidney transplantation.

ABSTRACTBackgroundThe objectives of this pilot study were to assess the efficacy and safety of an interferon-free sofosbuvir and ribavirin combination regimen to treat chronic hepatitis C virus (HCV) infection in kidney transplant recipients and to study the impact of sofosbuvir on calcineurin inhibitor (CNI) drug levels.MethodsA total of 10 kidney transplant recipients with chronic HCV infection were included in the study. All received sofosbuvir and ribavirin combination therapy. The virological response to therapy and the adverse effects of the drugs were studied. The area under the curve (AUC) and pharmacokinetic data of levels of CNI were compared while the patients were receiving sofosbuvir and ribavirin drugs and when they were no longer on these drugs.ResultsIn all, 9 of 10 patients (90%) achieved rapid virological response (RVR) with undetectable HCV RNA at 4 weeks and the remaining patient achieved undetectable HCV RNA at 8 weeks. A sustained virological response was seen at 3, 6 and 12 months and was maintained in all 10 patients (100%). The important aspect of the study is the effect of treatment with the sofosbuvir–ribavirin combination regimen on the CNI AUC levels, which resulted in a reduction in the CNI AUC. While used as part of triple-drug immunosuppression, no change in the dose of CNI (tacrolimus and cyclosporine) was required based on measurement of C0 levels.ConclusionsThe sofosbuvir and ribavirin combination therapy is effective and safe to treat HCV infection in the post-renal transplant setting. There is a need for close CNI level monitoring while these patients are on sofosbuvir therapy. With therapy and viral clearance, there could be reduction in CNI levels due to increased clearance of CNI drugs, which is shown by the AUC measurements. This could be important for patients at high risk for rejection.

Recurrent and de novo glomerulonephritis following renal transplantation: higher rates of rejection and lower graft survival.

In this retrospective study with case-control design, we aimed to determine the clinical and pathological characteristics of post-transplant glomerulonephritis (GN), and their effects on transplant recipients. One hundred and twenty renal transplant recipients with biopsy-proven recurrent or de novo primary GN were compared with two matched control groups including 120 transplant recipients with nonrecurrent primary GN (nonrecurrent GN group) and 120 transplant recipients with non-GN etiology (non-GN group). Primary outcome was allograft loss, and secondary outcomes were biopsy-confirmed cellular or antibody-mediated rejection. In recurrent/de novo GN, nonrecurrent GN and non-GN groups, 54.2% (n=65), 16.7% (n=20) and 8.3% (n=10) of patients reached primary outcome after a median follow-up of 96 (IQR: 56-149) months, respectively. Allograft loss was significantly higher in recurrent/de novo GN group compared to nonrecurrent GN and non-GN groups (p<0.001). At 10years, allograft loss rates in recurrent/de novo GN group were 54.2% for focal segmental glomerulosclerosis, 53.2% for membranoproliferative glomerulonephritis, and 33.4% for IgA nephropathy cases. Biopsy-confirmed rejection rate was significantly higher in the recurrent/de novo GN group (n=25, 20.8%) compared to non-GN (n=8, 6.7%) group (p=0.001). Recurrent/de novo GN is associated with higher risk of rejection and worse allograft survival.

Kidney transplant outcomes in HIV serodiscordant recipient pairs

Kidney transplant outcomes in HIV serodiscordant recipient pairs

The challenging management of pediatric corneal transplantation: an overview of surgical and clinical experiences.

Pediatric keratoplasty is an immense challenge because of the technical complexity of the procedure and the high risk of rejection in young graft recipients. Our aim is to describe the major indications and appropriate timing of corneal transplantation intervention, including a report of our experience and surgical tips, in conjunction with the current literature. Review of the literature on indications for keratoplasty in pediatric patients classified as: congenital, traumatic and acquired non-traumatic opacities. We additionally explored the challenges corneal surgeons face in performing this type of surgery and review the most pressing transplant-related problems and their management. Outcomes after pediatric keratoplasty, in terms of visual development, restoration and clarity of the graft, are influenced by peri-operative local and systemic conditions and factors, and by intraoperative management of the transplantation procedure itself. Pediatric corneal transplantation is a critical tool for visual restoration and development in young patients with corneal opacities, particularly during the critical period of visual development. Successful management of the significant challenges associated with pediatric keratoplasty requires customized clinical and surgical management of each patient with particular attention paid to proper post-operative rehabilitation.

Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients.

Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients.

Impaired Function of Peripherally Induced Regulatory T Cells in Hosts at High Risk of Graft Rejection.

Regulatory T cells (Tregs) are crucial for allograft survival. Tregs can be divided into thymus-derived natural Tregs (tTregs) and peripherally-derived induced Tregs (pTregs). Here, we determine whether the suppressive function of Treg subsets is hampered in hosts who are at high risk for rejecting their graft. To induce graft beds that promote high risk of transplant rejection, intrastromal corneal sutures were placed two weeks prior to the transplant procedure in mice. We demonstrate that in high-risk recipients the frequencies and function of pTregs (but not tTregs) are suppressed. Reduced function of pTregs correlated with decreased expression of CTLA-4, interleukin-10, and transforming growth factor-β. Adoptive transfer of pTregs from mice at low risk of subsequent graft rejection is able to rescue graft survival in recipients that are at high risk of rejecting their grafts. Our data suggest that impaired function of pTregs, but not tTregs, mediates the loss of immune tolerance and promotes allograft rejection.

Abstract 13110: Pediatric Heart Transplantation in Pre-Sensitized Recipients: A Current Perspective

Introduction: Anti-HLA antibodies (Ab) are increasingly prevalent in pediatric patients (pts) awaiting heart transplant (HT) and may result in a significant delay in time to HT because of the need to wait for a negative prospective donor HLA crossmatch (XM). Methods: Data from pts in the Pediatric HT Study transplanted between 2010-2014 were analyzed to determine the association of pre-HT percent reactive anti-HLA Ab (PRA) detected by flow cytometry with retrospective donor XM results and outcomes after HT. Sensitization was defined as a PRA &gt;20%. Results: HT was performed in 1,596 pts, 1,459 had a PRA calculated and 1,419 had XM results available. Sensitization was present in 32% of pts; 25% were sensitized against Class I and 20% were sensitized against Class II Ab (p&lt;0.01). Sensitization was more common in pts with congenital heart disease (CHD) compared to cardiomyopathy (CM), 28% vs. 15%, respectively, p&lt;0.01). Sensitization was similar between pts with and without ventricular assist device support, 20% vs. 25%, respectively, p=0.07. The level of sensitization was significantly associated with a +XM (p&lt;0.01, Table). Sensitized pts who had a +XM were at higher risk for rejection than those who had a - XM and those who were not sensitized (p&lt;0.01, Figure). There was no difference in post-HT survival between sensitized and nonsensitized pts, p=0.11, or those with and without a +XM, p=0.06. Conclusions: In the current era, 32% of pediatric HT pts are sensitized, with a higher incidence seen in pts with CHD compared to those with CM. Although, increasing PRA levels were associated with a higher likelihood of a positive retrospective XM, 68% of pts with a pre-HT PRA &gt;50% had a negative XM. XM was positive in 9% of pts with a PRA between 1-20%. Sensitized pts with a positive XM had a higher incidence of rejection than all other pts. Better methods of identifying pts at risk for a positive XM are needed to refine the indications for a prospective XM in pediatric pts listed for HT.

Protocol Biopsies: Utility and Limitations.

As both T cell and antibody-mediated rejection can have a subclinical phase, protocol biopsies provide an early opportunity to intervene before the onset of clinical allograft dysfunction. Protocol biopsies are usually done after reperfusion to establish baseline, between 3 and 6months to identify subclinical rejection, and at 6-12months to assess chronicity and persistent inflammation that have prognostic implication. Treatment of both subclinical T cell and antibody-mediated rejection prevents progression of rejection and development of interstitial fibrosis/tubular atrophy or transplant glomerulopathy. Although subclinical rejection has become less frequent in low-risk patients on triple immunosuppression containing tacrolimus, protocol biopsies may still be useful in selected population. Protocol biopsies are more likely to benefit patients at higher risk for rejection, including those who are highly sensitized, transplanted across donor-specific antibody barriers, or on calcineurin inhibitor/corticosteroids sparing regimens. Interstitial fibrosis on protocol biopsies, especially in conjunction with persistent inflammation, predicts lower allograft survival.

Deep anterior lamellar keratoplasty in dematiaceous keratomycosis

Deep anterior lamellar keratoplasty is a technique which has been used effectively to treat anterior stromal corneal opacities, with the obvious benefit of preserving host endothelium. This report documents its use in a case of dematiaceous keratomycosis resistant to conservative management. Therapeutic penetrating keratoplasty, although a gold standard, has a high risk of rejection and poor graft survival. In our patient, careful case selection and meticulous dissection ensured elimination of infection, restoration of vision, and absence of recurrence of infection.

Corneal Immunosuppressive Mechanisms, Anterior Chamber-Associated Immune Deviation (ACAID) and Their Role in Allograft Rejection.

Corneal transplantation is the most frequently performed transplant procedure in humans. Human leukocyte antigen matching, while imperative for other types of organ transplants, is usually not performed before cornea transplantation. With the use of topical steroid immunosuppressants, which are subsequently tailed off to almost zero, most corneal transplants will not be rejected in recipients with low risk of graft rejection. This phenomenon has been described as immune privilege by Medawar many years ago. However, this immune privilege is relative and can be easily eroded, e.g. by postoperative nonspecific inflammation or other causes of corneal or ocular inflammation. Interestingly, corneas that are at high risk of rejection have a higher failure rate than other organs. Considerable progress has been made in recent years to provide a better understanding of corneal immune privilege. This chapter will review current knowledge on ocular immunosuppressive mechanisms including anterior chamber-associated immune deviation and discuss their role(s) in corneal allograft rejection. Ultimately, this evolving information will be of benefit in developing therapeutic strategies to prevent corneal transplant rejection.

Características Socioeconômicas do Assentamento Banco da Terra, Nova Xavantina (MT): uma análise sob a ótica da adoção ou construção de conhecimentos

Resumo: O presente trabalho analisa as formas pelas quais as características socioeconômicas dos produtores familiares influenciam o processo de adoção ou construção de conhecimentos, no Assentamento Banco da Terra, em Nova Xavantina (MT). O enfoque deste estudo, de caráter qualitativo, incluiu, além da pesquisa bibliográfica, observações de campo e a aplicação de 25 questionários junto aos produtores assentados. Os resultados obtidos demonstraram que 40% dos agricultores pesquisados têm entre 41 e 50 anos de idade e 24% mais de 60 anos, a maioria não possui o Ensino Fundamental completo (68%) e a faixa de renda bruta mensal de 64% das famílias é de até dois salários mínimos por mês. A principal fonte de renda apresentada foi o arrendamento, mas também são importantes a renda resultante de trabalho externo ao estabelecimento e a proveniente de aposentadorias/pensões. Dessa forma, conclui-se que essas características apontadas servem como um alerta aos extensionistas locais, pois a promoção de conhecimentos altamente dependentes de mão de obra ou habilidades de maior complexidade apresentaria um alto risco de rejeição ou insucesso. Assim, o caminho mais assertivo a ser seguido pela extensão rural é partir desta realidade socioeconômica para estabelecer um diálogo com as famílias assentadas.

Long-Term Outcomes of High-Risk Keratoplasty in Patients Receiving Systemic Immunosuppression.

Immunological graft rejection after corneal transplantation remains the leading cause of graft failure. Systemic immunosuppression is used for keratoplasty at a high risk of rejection to improve graft survival. We examined the long-term outcomes of high-risk corneal grafts in patients receiving systemic immunosuppression. Thirty-five corneal transplants with a high risk of rejection were identified from 29 patients within a regional immunosuppression service in the United Kingdom. Definition of keratoplasty at "high risk" of rejection included one or more of the following: a history of ipsilateral graft rejection and/or failure, 2 or more quadrants of stromal vascularization, perforation or ocular inflammation at the time of surgery, presence of atopy, and a large-diameter (≥9 mm) graft. Median follow-up duration was 5 years after transplantation. Graft survival at 5 years in patients receiving systemic immunosuppression was 73.5%. Rejection episodes occurred in 14 grafts (40%); these episodes were reversible in 10 grafts (71%). Indications for transplantation were mostly visual (n = 19; 54%) and tectonic (n = 14; 40%). Eighteen grafts (51%) had 2 or more high-risk characteristics. Most patients (n = 20; 69%) received monotherapy, commonly with tacrolimus (n = 15; 52%) or mycophenolate mofetil (n = 8; 28%). Three patients (10%) experienced severe systemic side effects. Median "day-to-day" logMAR visual acuity was 0.5 in grafts for all indications and 0.2 for visual indications. Systemic immunosuppression in patients with high-risk keratoplasty seems to improve graft survival with a median follow-up duration of 5 years and is tolerated by most patients. Despite rejection episodes occurring in 40% of grafts, these were mostly reversible.

C1q Binding Activity of De Novo Donor-specific HLA Antibodies in Renal Transplant Recipients With and Without Antibody-mediated Rejection.

Complement fixation by donor-specific HLA antibodies (DSA) is a primary mechanism for antibody-mediated damage of organ allografts. Using a recently developed kit that measures C1q binding to distinguish complement fixing and nonfixing antibodies, studies showed that C1q + DSAs have a higher risk of rejection and graft loss compared to C1q-DSA. The objective of this study was to assess the ability of the C1q-binding assay to identify clinically significant de novo DSA in renal transplant recipients and to define the properties of DSA that confer C1q binding ability. The DSA-positive sera from 34 kidney recipients, 19 with biopsy-proven antibody-mediated rejection (AMR) + and 15 who were AMR-, were assayed in C1q-binding assays (C1q Screen; One Lambda, Inc. Canoga Park, CA). The correlation between C1q-binding activity, presence of AMR, DSA mean fluorescence intensity (MFI) values, and immunoglobulin G isotype was determined. Fifty-three percent (10/19) of sera from AMR+ patients had C1q + DSA, whereas only 13% (2/15) of sera from AMR- patients contained C1q + DSA. C1q + DSA exhibited significantly higher MFI values regardless of whether they were from AMR+ or AMR- patients (16,118 ± 6698 vs 6429 ± 4003; P < 0.0001). C1q + DSA converted to C1q - when diluted to a comparable MFI level as the C1q - DSA from AMR- patients, and some C1q - antibodies converted to C1q + when concentrated to MFI levels comparable to those observed for AMR+/C1q + sera. The C1q binding activity by de novo DSA in patients with AMR largely reflects differences in antibody strength. The C1q assay does not appear to distinguish functionally distinct DSA with clinical significance.

Athymic rat model for studying acellular human allograft

BackgroundAlthough human acellular nerve allograft is a promising nerve repair tool, optimizing graft application and understanding effective graft dimensions has been hampered by lack of an appropriate animal model. Rodent nerve acellular allograft can be tested in the utilitarian rodent nerve repair model, but testing different size options is limited by the size of the rodent donor animal. Human acellular nerve allograft offers the variety of sizes desired for more complete study but poses a high risk of rejection as xenograft tissue in the rodent model. Athymic nude rats are less prone to reject xenograft tissue due to their immunocompromised state and may offer an animal model for testing human acellular allograft. MethodsFifteen athymic nude and 15 Sprague-Dawley rats underwent unilateral excision and repair of a 10mm tibial nerve segment using 10mm of human acellular nerve graft. Testing at 3 months consisted of muscle force measurements, wet muscle weight, and histological assessment from the middle of the nerve grafts. ResultsAthymic rats repaired with human acellular xenograft demonstrated higher reinnervated muscle weight Gross inspection of the xenograft in euthymic rats revealed a brown and scarred center and histological inspection demonstrated larger axon diameters, and higher midgraft axon counts in the grafts of athymic rats.Comparison with existing methods: The athymic rat has been used in many studies that require an immunocompromised host, including implantation of foreign nervous tissue. Previous attempts at implanting acellular nerve xenograft into immunocompetent rats have yielded suboptimal results when compared to allograft. This study is the first to test acellular human nerve allograft in an athymic rat. ConclusionThe nerve regeneration was better in human acellular nerve allograft implanted into immunocompromised athymic rats when compared to euthymic rats supporting a potential role of this model in studying acellular human nerve tissue.

Adipose-derived mesenchymal stem cell administration does not improve corneal graft survival outcome.

The effect of local and systemic injections of mesenchymal stem cells derived from adipose tissue (AD-MSC) into rabbit models of corneal allograft rejection with either normal-risk or high-risk vascularized corneal beds was investigated. The models we present in this study are more similar to human corneal transplants than previously reported murine models. Our aim was to prevent transplant rejection and increase the length of graft survival. In the normal-risk transplant model, in contrast to our expectations, the injection of AD-MSC into the graft junction during surgery resulted in the induction of increased signs of inflammation such as corneal edema with increased thickness, and a higher level of infiltration of leukocytes. This process led to a lower survival of the graft compared with the sham-treated corneal transplants. In the high-risk transplant model, in which immune ocular privilege was undermined by the induction of neovascularization prior to graft surgery, we found the use of systemic rabbit AD-MSCs prior to surgery, during surgery, and at various time points after surgery resulted in a shorter survival of the graft compared with the non-treated corneal grafts. Based on our results, local or systemic treatment with AD-MSCs to prevent corneal rejection in rabbit corneal models at normal or high risk of rejection does not increase survival but rather can increase inflammation and neovascularization and break the innate ocular immune privilege. This result can be partially explained by the immunomarkers, lack of immunosuppressive ability and immunophenotypical secretion molecules characterization of AD-MSC used in this study. Parameters including the risk of rejection, the inflammatory/vascularization environment, the cell source, the time of injection, the immunosuppression, the number of cells, and the mode of delivery must be established before translating the possible benefits of the use of MSCs in corneal transplants to clinical practice.