Clinicopathological relevance of granular C4d deposition in peritubular capillaries of kidney allografts.

While linear C4d staining in peritubular capillaries (PTC) is established as a marker of antibody-mediated rejection, the significance of a distinct granular C4d deposition pattern has not yet been clarified. In this study, 329 renal allograft recipients who underwent indication biopsies were analysed for immunohistochemical C4d staining characteristics. Fifty-six (17%) recipients showed granular C4d in PTC, without any relationship to conventional risk factors and morphological features of rejection.

Pretransplant risk stratification for early survival of renal allograft recipients.

Background: Baseline comorbidities influence patient outcomes in renal transplantation. Identification of high-risk recipients for patient death and early allograft loss might lead to superior stratification.

Material And Methods: In this retrospective study, risk stratification models were developed in a cohort of 392 kidney transplant recipients and validated in an independent cohort to predict short-term (2 year) outcomes.

Donor specific transplant tolerance is dependent on complement receptors.

The complement system has recently been described as a crucial component for transplant tolerance induction, but the underlying mechanisms are poorly understood. Using a rodent model of donor lymphocyte infusion-induced male histocompatibility antigen-specific transplant tolerance, we demonstrate that tolerance induction is dependent on the complement receptors decay accelerating factor, complement receptor 3, and complement component 3a receptor (C3aR). Furthermore, we have provided evidence that complement dependent tolerance is mediated through C3aR on infused donor splenocytes and on recipient cells.

Solid phase detection of C4d-fixing HLA antibodies to predict rejection in high immunological risk kidney transplant recipients.

Protocols for recipient desensitization may allow for successful kidney transplantation across major immunological barriers. Desensitized recipients, however, still face a considerable risk of antibody-mediated rejection (AMR), which underscores the need for risk stratification tools to individually tailor treatment. Here, we investigated whether solid phase detection of complement-fixing donor-specific antibodies (DSA) has the potential to improve AMR prediction in high-risk transplants.

Transplantation of the broadly sensitized patient: what are the options?

Purpose Of Review: Recipient sensitization to a wide variety of human leukocyte antigens (HLA) represents a major barrier to transplantation. We discuss the options for the challenging group of broadly sensitized kidney transplant candidates.

Recent Findings: Transplantation by way of kidney-paired donation (KPD) represents a preferable way to bypass immunological barriers.

Prevention and treatment of alloantibody-mediated kidney transplant rejection.

Antibody-mediated rejection (AMR), which is commonly caused by preformed and/or de novo HLA alloantibodies, has evolved as a leading cause of early and late kidney allograft injury. In recent years, effective treatment strategies have been established to counteract the deleterious effects of humoral alloreactivity. One major therapeutic challenge is the barrier of a positive pretransplant lymphocytotoxic crossmatch.

Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse.

In individuals with mammary carcinoma, the most relevant prognostic predictor of distant organ metastasis and clinical outcome is the status of axillary lymph node metastasis. Metastases form initially in axillary sentinel lymph nodes and progress via connecting lymphatic vessels into postsentinel lymph nodes. However, the mechanisms of consecutive lymph node colonization are unknown.

Significance of peritubular capillary, glomerular, and arteriolar C4d staining patterns in paraffin sections of early kidney transplant biopsies.

Background: Although diffuse linear C4d deposition in peritubular capillaries (PTCs) is a well-established criterion of alloantibody-mediated kidney transplant rejection, the actual relevance of focal or granular C4d deposits or staining outside PTC (glomeruli and arterioles) has yet to be established.

Methods: This study was designed to evaluate the diagnostic significance of such nontypical C4d staining patterns. A total of 539 early indication biopsies (329 kidney transplants) were analyzed by immunohistochemistry using a polyclonal anti-C4d antibody.

Prevalence and qualitative properties of circulating anti-human leukocyte antigen alloantibodies after pregnancy: no association with unexplained recurrent miscarriage.

In pregnant women, circulating alloantibodies, triggered by exposure to paternal HLA antigens, are frequently detectable. The finding of lower alloantibody levels in women who experience spontaneous abortion (miscarriage) has led to the speculation that antipaternal antibodies could favor maintenance of pregnancy, whereas their lack poses a risk of miscarriage. Postulating a role of alloantibodies in the pathogenesis of unexplained abortion, we examined whether different categories of recurrent miscarriage (RM) can be distinguished according to prevalence or distinct qualitative properties of anti-human leukocyte antigen (HLA) antibody patterns.

Identification of Non-HLA antigens targeted by alloreactive antibodies in patients undergoing chronic hemodialysis.

The only treatment of end-stage renal disease patients undergoing chronic dialysis is kidney transplantation. However, about half of graft recipients encounter organ loss within ten years after renal transplantation. There is emerging evidence that the presence of alloreactive antibodies against non-HLA antigens in the serum of the recipient prior transplantation is associated with higher incidence of chronic rejection.

Clinical relevance of preformed C4d-fixing and non-C4d-fixing HLA single antigen reactivity in renal allograft recipients.

Donor-specific alloantibodies (DSA), especially those fixing complement, may pose a particular immunologic risk to transplant recipients. To assess the clinical impact of C4d- or non-C4d-fixing (IgG) HLA sensitization, pretransplant sera obtained from 338 kidney allograft recipients prescreened by FlowPRA were retrospectively evaluated by Luminex single antigen (SA) testing using a novel fluorescent-labeled anti-C4d reagent for detection of antibody-triggered C4d deposition in addition to IgG binding. Recipients with [IgG]DSA (n = 39) showed a substantially higher rate of C4d positive rejection (33%) than 16 patients with [IgG] non-DSA (0%) or 283 antibody-negative patients (4%, multivariate analysis excluding retransplantation because of high co-linearity: P < 0.

Prospects and limitations of post-transplantation alloantibody detection in renal transplantation.

Antibody-mediated immunity is generally accepted to be a major cause of kidney allograft injury and loss. Post-transplantation monitoring for circulating alloantibodies was proposed to represent a useful noninvasive diagnostic approach to assess individual immunologic risks and to guide the implementation of specific therapeutic measures. This was supported by the recent establishment of highly sensitive and specific solid phase immunoassays for detailed characterisation of reactivity patterns.

Antibodies, isotypes and complement in allograft rejection.

Purpose Of Review: Classical complement activation is a key step in the process of antibody-mediated rejection. Emphasizing novel diagnostic strategies, this study will discuss recent studies highlighting the particular relevance of alloantibodies with complement-fixing ability.

Recent Findings: Reinforcing the pivotal role of complement, numerous studies have shown tight associations of capillary C4d deposition, a 'footprint' of alloantibody-triggered complement activation, with the occurrence of allograft injury.

Ingested matter affects intestinal lesions in Crohn's disease.

Background: Environmental factors of the modern Western lifestyle may trigger Crohn's disease (CD) in susceptible individuals. Because such factors could be part of ingested matter, we intended to improve intestinal Crohn's lesions by exclusion thereof.

Methods: At first we tested a highly restricted diet (based on spelt bread and red meat, both derived from intensively monitored organic farming) in 5 pilot cases.

Determinants of the complement-fixing ability of recipient presensitization against HLA antigens.

Background: The presence of preformed alloantibodies with the ability to activate complement may pose a particular risk for kidney allograft rejection. The aim of this study was to evaluate variables that determine the complement-fixing capability of human leukocyte antigen (HLA) sensitization.

Methods: Sixty-five sensitized patients with > or =10% pretransplant panel-reactive antibody (PRA) levels uncovered by immunoglobulin G [IgG]FlowPRA HLA class I and/or class II screening were included.

Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants.

De novo lymphangiogenesis influences the course of different human diseases as diverse as chronic renal transplant rejection and tumor metastasis. The cellular mechanisms of lymphangiogenesis in human diseases are currently unknown, and could involve division of local preexisting endothelial cells or incorporation of circulating progenitors. We analyzed renal tissues of individuals with gender-mismatched transplants who had transplant rejection and high rates of overall lymphatic endothelial proliferation as well as massive chronic inflammation.

Tetrahydrobiopterin corrects Escherichia coli endotoxin-induced endothelial dysfunction.

Acute inflammation causes endothelial dysfunction, which is partly mediated by oxidant stress and inactivation of nitric oxide. The contribution of depletion of tetrahydrobiopterin (BH(4)), the cofactor required for nitric oxide generation, is unclear. In this randomized, double-blind, three-way crossover study, forearm blood flow (FBF) responses to ACh and glyceryltrinitrate (GTN) were measured before and 3.