Background. Diffuse peritubular capillary (PTC) C4d deposition has been shown to be associated with relatively poor graft outcome. The significance of focal PTC C4d staining in the early ...post-transplant period is uncertain. Methods. Sixty-five biopsies from 53 patients with acute rejection were graded (Banff ’97 criteria), stained for C4d, monocytes and T cells, and divided into three groups according to PTC C4d: (i) focal C4d (F) (14 biopsies, 14 patients), (ii) diffuse C4d (D) (23 biopsies, 15 patients) and (iii) no C4d (N) (28 biopsies, 24 patients). The three groups were compared with respect to a variety of biopsy and clinical parameters including outcome. Results. The incidence of transplant glomerulitis and glomerular monocyte infiltration were significantly greater in F (64% and 2.0±2.0) and D (57% and 3.4±2.0) than in N (11% and 0.2±0.2). A significantly higher proportion of F (93%) demonstrated acute cellular rejection (Banff ’97 grade ≥1A) than did D (35%). The F and D groups included significantly more females (50 and 67%, respectively) than did N (21%). The percentage of patients with a second or third transplant was higher in F (29%) and D (40%) than in N (8%) (P = 0.0589). The proportion of patients with glomerular filtration rate <30 ml/min at 12, 24 and 48 months was higher in the D and F groups than in the N, and there was a statistically significant increasing trend in odds of this outcome occurring at 48 months across the three groups (D>F>N group) (P = 0.0416). Conclusion. The results suggest that the biopsy findings and clinical course in patients with focal PTC C4d staining are similar to those associated with diffuse C4d.
We examined the prevalence and severity of renal artery stenosis (RAS) in patients undergoing cardiac catheterization who were deemed at risk for RAS based on clinical or laboratory criteria for ...study entry, but who had not previously been suspected of having RAS.
The diagnosis of atherosclerotic RAS remains problematic because its clinical manifestations are nonspecific.
Consecutive patients undergoing non-emergent cardiac catheterization at a single institution during a 12-month period were evaluated using standardized clinical, laboratory, and angiographic criteria. Patients exhibiting at least one of four predefined selection criteria (severe hypertension, unexplained renal dysfunction, acute pulmonary edema with hypertension, or severe atherosclerosis) were prospectively registered and underwent coincident diagnostic renal angiography.
Renal angiography was performed in 851 patients and was diagnostic in 837. Angiographically evident renal atherosclerosis was present in 39% of the population, with RAS ≥50% in 120 (14.3%) and severe stenosis (≥70%) in 61 (7.3%). Severe stenosis was present in 48 (7%) patients with severe atherosclerosis, 38 (16%) with renal dysfunction, 25 (9%) with hypertension, and 2 (22%) with acute pulmonary edema with hypertension. The prevalence was higher in those exhibiting multiple selection criteria. In a multivariate model, severe RAS was associated with age, female gender, reduced creatinine clearance, increased systolic blood pressure, and peripheral or carotid artery disease.
In a population at risk of, but not previously suspected of having RAS, severe RAS is associated with simple and readily determined clinical and laboratory patient characteristics. These data facilitate focused application of diagnostic renal angiography.
The objective of this study was to evaluate systemic immunosuppression regimens used for patients undergoing ocular surface stem cell transplantation, including their benefits and adverse effects in ...the adjunctive management of limbal stem cell deficiency (LSCD). A systematic literature review was conducted using the MEDLINE and EMBASE databases (1980–2015). Data were collected on surgical intervention(s), type of immunosuppressive agent(s), duration of immunosuppression, percentage with stable ocular surface at last follow-up, mean follow-up time, and demographics. Data were also collected on adverse ocular and systemic outcomes. Sixteen reports met the inclusion criteria. There were no randomized controlled studies. Three studies were noncomparative prospective case series, whereas the majority were retrospective case series. Bilateral severe LSCD was the most common disease (50%), and keratolimbal allograft was the most common intervention (80%). Immunosuppressive regimens showed a progression from early studies using oral cyclosporine to later studies using combinations of mycophenolate mofetil and tacrolimus. Most studies included a course of high-dose systemic corticosteroids. For patients adherent to long-term systemic immunosuppression, stable ocular surface rates of 70%–80% at last follow-up were reported. Adverse effects included hypertension, diabetes mellitus, and biochemical abnormalities managed with pharmacotherapy or discontinuation of offending agents. There were no cases of mortality related to immunosuppression. However, the current literature does not elucidate which immunosuppressive regimen is most efficacious for different categories of LSCD or graft types. Evidence-based guidelines for systemic immunosuppression in limbal allograft therapy would benefit from randomized controlled and/or additional prospective studies. Long-term immunosuppression would benefit from close collaboration between ophthalmologists and transplant specialists to individualize treatments.
Cette étude avait pour objectif d’évaluer les schémas d’immunosuppression systémique chez les patients qui subissent une greffe de cellules souches de la surface oculaire et d’examiner leurs effets bénéfiques et indésirables à titre de traitement d’appoint de l’insuffisance en cellules souches limbiques (ICSL). Pour ce faire, on a procédé à une revue systématique de la littérature médicale dans les bases de données MEDLINE et EMBASE (de 1980 à 2015). On a ainsi recueilli des données sur les interventions chirurgicales, les types d’immunosuppresseurs, la durée de l’immunosuppression, le pourcentage de patients présentant une surface oculaire stable lors du dernier suivi, la durée moyenne du suivi et les caractéristiques démographiques. On a également compilé des données sur les effets indésirables oculaires et systémiques. Seize rapports répondaient aux critères d’inclusion. Aucun ne portait sur une étude comparative randomisée. Trois des études étaient des séries de cas prospectives non comparatives, mais la majorité était des séries rétrospectives. L’ICSL bilatérale grave représentait l’affection la plus fréquente (50 %), tandis que l’allogreffe kératolimbique était l’intervention la plus fréquente (80 %). On a observé une évolution au chapitre des schémas d’immunosuppression : les premières études faisaient appel à la cyclosporine orale, tandis que les études plus récentes portaient sur des associations de mycophénolate mofétil et de tacrolimus. La plupart des études comportaient l’administration de corticostéroïdes systémiques fortement dosés. Les patients qui faisaient l’objet d’une immunosuppression systémique à long terme présentaient des taux de surface oculaire stable de 70 à 80 % lors du dernier suivi. Au nombre des effets indésirables, citons l’hypertension, le diabète sucré et des anomalies biochimiques; ces effets ont été pris en charge par une pharmacothérapie ou la cessation de l’administration des médicaments responsables. On ne déplore aucun décès lié à l’immunosuppression. Cela dit, la littérature médicale actuelle ne permet pas de déterminer le schéma d’immunosuppression le plus efficace en fonction des différents types d’ICSL ou de greffes. La tenue d’études comparatives randomisées et (ou) d’autres études prospectives permettrait de rédiger des lignes directrices factuelles sur le recours à l’immunosuppression systémique dans l’allogreffe limbique. Une collaboration étroite entre ophtalmologistes et spécialistes des greffes permettrait de contribuer à personnaliser le traitement immunosuppressif à long terme.
There is a paucity of population-level data on the long-term outcomes of kidney transplants from deceased donors with a history of diabetes mellitus (DM).
We examined the association of donor DM with ...graft and patient survival in 66,654 deceased donor kidney transplant recipients (KTR) from January 1, 1994, to December 31, 2003, in the United States. KTR receiving kidneys from DM versus non-DM donors were compared in the total study population and in a 1:1 propensity score-matched cohort.
A total of 2302 KTR received kidneys from DM donors over the study period. Older and female recipients, increased donor age, longer cold ischemia time, and transplants after 2000 were associated with a greater odds of receiving a DM donor. After propensity score matching, Cox proportional hazards models revealed hazard ratios of 1.11 (95% CI: 1.02-1.22), 1.17 (95% CI: 1.04-1.33), and 1.06 (95% CI: 0.94-1.18) for graft failure, death-censored graft failure, and patient mortality, respectively. No significant effect measure modification was seen across various patient subgroups. Longer duration of donor DM was generally associated with an increased risk of adverse outcomes. The results were robust to several sensitivity analyses.
The long-term graft survival of KTR with DM donors is significantly inferior to non-DM donors, but the absolute difference is small. DM donors do not adversely impact patient survival. This suggests that DM donors may be effectively used to expand the donor pool, but evidence-based guidelines on the appropriate selection of these donors are needed.
New onset diabetes mellitus (NODM) and acute rejection (AR) are important causes of morbidity and risk factors for allograft failure after kidney transplantation.
In this multi-center, open label, ...single-arm pilot study, 49 adult (≥18 years of age), low immunologic risk, non-diabetic recipients of a first deceased or living donor kidney transplant received early steroid reduction to 5 mg/day combined with Thymoglobulin® (Genzyme Transplant, Cambridge, MA, USA) induction, low dose cyclosporine (2-hour post-dose (C2) target of 600 to 800 ng/ml) and mycophenolic acid (MPA) therapy.
Six months after transplantation, two patients (4%) developed NODM and one patient (2%) developed AR. Four patients had impaired fasting glucose tolerance based on 75-g oral glucose tolerance testing (OGTT). There was one patient death. There were no episodes of cytomegalovirus (CMV) infection or BK virus nephritis. In contrast, in a historical cohort of n = 27 patients treated with Thymoglobulin induction, and conventional doses of cyclosporine and corticosteroids, the incidence of NODM and AR was 18% and 15%.
The pilot study results suggest that Thymoglobulin induction combined with early steroid reduction, reduced cyclosporine exposure and MPA, may reduce the incidence of both NODM and AR in low immunological risk patients. A future controlled study enriched for patients at high risk for NODM is under consideration.
ClinicalTrials.gov: http://NCT00706680.
Anti-human histocompatibility antigen antibodies (HLA-Ab) are deleterious after kidney transplant and may be increased after T-cell depleting agents are given. A retrospective case control study was ...conducted to evaluate increase in HLA-Ab in 27 kidney transplant recipients who had received antithymocyte globulin (ATG) induction compared with 27 control subjects. A greater than 10% increase in class I or class II HLA-Ab was found in 6 (22.2%) of ATG subjects versus only 1 (3.7%) of non-ATG subjects (
p = 0.05). In females, 6/14 ATG subjects developed increased HLA-Ab ≥10% compared with none of the control subjects (
p = 0.016). In sensitized subjects, 4/10 in the ATG group developed increased HLA-Ab ≥10% versus none of the controls (
p = 0.043). There was no difference in number or severity of acute rejection episodes or estimated glomerular filtration rate 6 months after transplant between the two treatment groups. We conclude that ATG induction may result in increased posttransplant HLA-Ab, particularly in subjects at higher immunologic risk. Further studies are necessary to determine the natural history, clinical consequences, appropriate therapy, and mechanisms responsible for HLA-Ab in this setting.
: Clinical transplantation tolerance has remained an elusive goal in the 50 yr since it was first described in experimental animals. Greater understanding of the molecular mechanisms responsible for ...allorecognition have allowed for the development of promising immunosuppressive strategies that may bring us closer to reproducible induction of tolerance; consideration of past successes and failures from both clinical and basic science is required to define future challenges facing this field. This article reviews mechanisms of self and transplantation tolerance, translation of basic science research to clinical protocols in animals and human beings, the changing role of immunosuppression, complications following tolerance induction and controversies surrounding the choice of patients for tolerance trials with a focus on issues relevant to pediatric patients. The role of the Immune Tolerance Network is discussed along with realistic goals for tolerance induction in human beings over the next decade.
The presence of preexisting (memory) or de novo donor‐specific HLA antibodies (DSAs) is a known barrier to successful long‐term organ transplantation. Yet, despite the fact that laboratory tools and ...our understanding of histocompatibility have advanced significantly in recent years, the criteria to define presence of a DSA and assign a level of risk for a given DSA vary markedly between centers. A collaborative effort between the American Society for Histocompatibility and Immunogenetics and the American Society of Transplantation provided the logistical support for generating a dedicated multidisciplinary working group, which included experts in histocompatibility as well as kidney, liver, heart, and lung transplantation. The goals were to perform a critical review of biologically driven, state‐of‐the‐art, clinical diagnostics literature and to provide clinical practice recommendations based on expert assessment of quality and strength of evidence. The results of the Sensitization in Transplantation: Assessment of Risk (STAR) meeting are summarized here, providing recommendations on the definition and utilization of HLA diagnostic testing, and a framework for clinical assessment of risk for a memory or a primary alloimmune response. The definitions, recommendations, risk framework, and highlighted gaps in knowledge are intended to spur research that will inform the next STAR Working Group meeting in 2019.
This meeting report from an AST‐ASHI expert workgroup provides recommendations on the definition and utilization of HLA diagnostic testing, as well as a framework for clinical assessment of risk for a memory or a primary alloimmune response.
Autoantibodies directed against endogenous proteins including contractile proteins and endothelial antigens are frequently detected in patients with heart failure and after heart transplantation. ...There is evidence that these autoantibodies contribute to cardiac dysfunction and correlate with clinical outcomes. Currently, autoantibodies are detected in patient sera using individual ELISA assays (one for each antigen). Thus, screening for many individual autoantibodies is laborious and consumes a large amount of patient sample. To better capture the broad-scale antibody reactivities that occur in heart failure and post-transplant, we developed a custom antigen microarray technique that can simultaneously measure IgM and IgG reactivities against 64 unique antigens using just five microliters of patient serum. We first demonstrated that our antigen microarray technique displayed enhanced sensitivity to detect autoantibodies compared to the traditional ELISA method. We then piloted this technique using two sets of samples that were obtained at our institution. In the first retrospective study, we profiled pre-transplant sera from 24 heart failure patients who subsequently received heart transplants. We identified 8 antibody reactivities that were higher in patients who developed cellular rejection (2 or more episodes of grade 2R rejection in first year after transplant as defined by revised criteria from the International Society for Heart and Lung Transplantation) compared with those who did have not have rejection episodes. In a second retrospective study with 31 patients, we identified 7 IgM reactivities that were higher in heart transplant recipients who developed antibody-mediated rejection (AMR) compared with control recipients, and in time course studies, these reactivities appeared prior to overt graft dysfunction. In conclusion, we demonstrated that the autoantibody microarray technique outperforms traditional ELISAs as it uses less patient sample, has increased sensitivity, and can detect autoantibodies in a multiplex fashion. Furthermore, our results suggest that this autoantibody array technology may help to identify patients at risk of rejection following heart transplantation and identify heart transplant recipients with AMR.
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