Renal transplantation outcomes in obese patients: a French cohort-based study.

BACKGROUND: Whilst there are a number of publications comparing the relationship between body mass index (BMI) of kidney transplant recipients and graft/patient survival, no study has assessed this for a French patient cohort. METHODS: In this study, cause-specific Cox models were used to study patient and graft survival and several other time-to-event measures. Logistic regressions were performed to study surgical complications at 30 days post-transplantation as well as delayed graft function. RESULTS: Among the 4691 included patients, 747 patients were considered obese with a BMI level greater than 30 kg/m2. We observed a higher mortality for obese recipients (HR = 1.37, p = 0.0086) and higher risks of serious bacterial infections (HR = 1.24, p = 0.0006) and cardiac complications (HR = 1.45, p < 0.0001). We observed a trend towards death censored graft survival (HR = 1.22, p = 0.0666) and no significant increased risk of early surgical complications. CONCLUSIONS: We showed that obesity increased the risk of death and serious bacterial infections and cardiac complications in obese French kidney transplant recipients. Further epidemiologic studies aiming to compare obese recipients versus obese candidates remaining on dialysis are needed to improve the guidelines for obese patient transplant allocation.

Utility of anaerobic bottles for the diagnosis of bloodstream infections.

BACKGROUND: Obligate anaerobes usually account for less than 10% of bacteria recovered from blood cultures (BC). The relevance of routine use of the anaerobic bottle is under debate. The aim of this study was to evaluate the utility of anaerobic bottles for the diagnosis of bloodstream infections (BSI). METHODS: We conducted a 6-month, retrospective, monocentric study in a tertiary hospital. All positive BC were grouped into a single episode of bacteremia when drawn within 7 consecutive days. Bacteremia were classified into contaminants and BSI. Charts of patients with BSI due to obligate anaerobes were studied. RESULTS: A total of 19,739 blood cultures were collected, 2341 of which (11.9%) were positive. Anaerobic bottles were positive in 1528 (65.3%) of all positive BC but were positive alone (aerobic bottles negative) in 369 (15.8%). Overall 1081 episodes of bacteremia were identified, of which 209 (19.3%) had positive anaerobic bottles alone. The majority 126/209 (60.3%) were contaminants and 83 (39.7%) were BSI. BSI due to facultative anaerobes, obligate aerobes and obligate anaerobes were identified in 67 (80.7%), 3 (3.6%) and 13 (15.7%) of these 83 episodes, respectively. BSI due to obligate anaerobic bacteria were reported in 9 patients with gastro-intestinal disease, in 3 with febrile neutropenia and in 1 burned patient. CONCLUSIONS: Anaerobic bottles contributed to the diagnosis of a significant number of episodes of bacteremia. Isolated bacteria were mostly contaminants and non-obligate anaerobic pathogens. Rare BSI due to obligate anaerobes were reported mainly in patients with gastro-intestinal disorders and during febrile neutropenia.

The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials.

The kidney sessions of the 2017 Banff Conference focused on 2 areas: clinical implications of inflammation in areas of interstitial fibrosis and tubular atrophy (i-IFTA) and its relationship to T cell-mediated rejection (TCMR), and the continued evolution of molecular diagnostics, particularly in the diagnosis of antibody-mediated rejection (ABMR). In confirmation of previous studies, it was independently demonstrated by 2 groups that i-IFTA is associated with reduced graft survival. Furthermore, these groups presented that i-IFTA, particularly when involving >25% of sclerotic cortex in association with tubulitis, is often a sequela of acute TCMR in association with underimmunosuppression. The classification was thus revised to include moderate i-IFTA plus moderate or severe tubulitis as diagnostic of chronic active TCMR. Other studies demonstrated that certain molecular classifiers improve diagnosis of ABMR beyond what is possible with histology, C4d, and detection of donor-specific antibodies (DSAs) and that both C4d and validated molecular assays can serve as potential alternatives and/or complements to DSAs in the diagnosis of ABMR. The Banff ABMR criteria are thus updated to include these alternatives. Finally, the present report paves the way for the Banff scheme to be part of an integrative approach for defining surrogate endpoints in next-generation clinical trials.

Harnessing Scientific and Technological Advances to Improve Equity in Kidney Allocation Policies.

We reported that current assignment of HLA-DQ is a barrier to organ allocation. Here we simulated the impact of incorporating HLA-DQ antigens and antibodies as A/B and αß allelic variants, respectively, on calculated panel reactive antibody (cPRA) and probability of finding potential compatible donors (PCD). A cohort of 1224 donors and 2075 sensitized candidates was analyzed using HLA-DQαß allelic (study) versus serologic (current practice) nomenclature. A significant (p < 10-4 ) decrease in cPRA was observed with higher impact for male versus female, and first transplant versus retransplant (p < 10-4 ), affecting mostly patients with moderate cPRA (30-80%). Consequently, the number of patients qualifying for 100% cPRA points according to the United Network for Organ Sharing-Kidney Allocation System decreased by 37%. More critically, by using allelic versus serologic nomenclature for HLA-DQ, the number of PCDs for all patients was increased, with male and first-transplant patients showing a higher expansion compared with female and retransplants. Patients of blood group O showed the highest benefit. The goal of reporting unacceptable antigens is to improve accuracy of virtual crossmatching and increase the likelihood of finding immunologically compatible donors. Our simulation provides strong support for the need to re-evaluate the use of allele typing and how HLA-DQ antigens and antibodies are incorporated into allocation policies to ensure equity.

The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology.

The XIII Banff meeting, held in conjunction the Canadian Society of Transplantation in Vancouver, Canada, reviewed the clinical impact of updates of C4d-negative antibody-mediated rejection (ABMR) from the 2013 meeting, reports from active Banff Working Groups, the relationships of donor-specific antibody tests (anti-HLA and non-HLA) with transplant histopathology, and questions of molecular transplant diagnostics. The use of transcriptome gene sets, their resultant diagnostic classifiers, or common key genes to supplement the diagnosis and classification of rejection requires further consensus agreement and validation in biopsies. Newly introduced concepts include the i-IFTA score, comprising inflammation within areas of fibrosis and atrophy and acceptance of transplant arteriolopathy within the descriptions of chronic active T cell-mediated rejection (TCMR) or chronic ABMR. The pattern of mixed TCMR and ABMR was increasingly recognized. This report also includes improved definitions of TCMR and ABMR in pancreas transplants with specification of vascular lesions and prospects for defining a vascularized composite allograft rejection classification. The goal of the Banff process is ongoing integration of advances in histologic, serologic, and molecular diagnostic techniques to produce a consensus-based reporting system that offers precise composite scores, accurate routine diagnostics, and applicability to next-generation clinical trials.

C1 Inhibitor in Acute Antibody-Mediated Rejection Nonresponsive to Conventional Therapy in Kidney Transplant Recipients: A Pilot Study.

Complement inhibitors have not been thoroughly evaluated in the treatment of acute antibody-mediated rejection (ABMR). We performed a prospective, single-arm pilot study to investigate the potential effects and safety of C1 inhibitor (C1-INH) Berinert added to high-dose intravenous immunoglobulin (IVIG) for the treatment of acute ABMR that is nonresponsive to conventional therapy. Kidney recipients with nonresponsive active ABMR and acute allograft dysfunction were enrolled between April 2013 and July 2014 and received C1-INH and IVIG for 6 months (six patients). The primary end point was the change in eGFR at 6 months after inclusion (M+6). Secondary end points included the changes in histology and DSA characteristics and adverse events as evaluated at M+6. All patients showed an improvement in eGFR between inclusion and M+6: from 38.7 ± 17.9 to 45.2 ± 21.3 mL/min/1.73 m(2) (p = 0.0277). There was no change in histological features, except a decrease in the C4d deposition rate from 5/6 to 1/6 (p = 0.0455). There was a change in DSA C1q status from 6/6 to 1/6 positive (p = 0.0253). One deep venous thrombosis was observed. In a secondary analysis, C1-INH patients were compared with a similar historical control group (21 patients). C1-INH added to IVIG is safe and may improve allograft function in kidney recipients with nonresponsive acute ABMR.

HLA Class II Antibody Activation of Endothelial Cells Promotes Th17 and Disrupts Regulatory T Lymphocyte Expansion.

Kidney transplantation is the most successful treatment option for patients with end-stage renal disease, and chronic antibody-mediated rejection is the principal cause of allograft loss. Predictive factors for chronic rejection include high levels of HLA alloantibodies (particularly HLA class II) and activation of graft endothelial cells (ECs). The mechanistic basis for this association is unresolved. We used an experimental model of HLA-DR antibody stimulation of microvascular ECs to examine the mechanisms underlying the association between HLA class II antibodies, EC activation and allograft damage. Activation of ECs with the F(Ab')2 fragment of HLA-DR antibody led to phosphorylation of Akt, ERK and MEK and increased IL-6 production by ECs cocultured with allogeneic peripheral blood mononuclear cells (PBMCs) in an Akt-dependent manner. We previously showed that HLA-DR-expressing ECs induce polarization of Th17 and FoxP3(bright) regulatory T cell (Treg) subsets. Preactivation of ECs with anti-HLA-DR antibody redirected EC allogenicity toward a proinflammatory response by decreasing amplification of functional Treg and by further increasing IL-6-dependent Th17 expansion. Alloimmunized patient serum containing relevant HLA-DR alloantibodies selectively bound and increased EC secretion of IL-6 in cocultures with PBMCs. These data contribute to understanding of potential mechanisms of antibody-mediated endothelial damage independent of complement activation and FcR-expressing effector cells.

Assessing Antibody Strength: Comparison of MFI, C1q, and Titer Information.

The presence of donor-specific HLA antibodies before or after transplantation may have different implications based on the antibody strength. Yet, current approaches do not provide information regarding the true antibody strength as defined by antigen-antibody dissociation rate. To assess currently available methods, we compared between neat mean fluorescence intensity (MFI) values, C1q MFI values, ethylenediaminetetraacetic acid (EDTA)-treated samples, as well as titration studies and peak MFI values of over 7000 Luminex-based single-antigen HLA antibody data points. Our results indicate that neat MFI values do not always accurately depict antibody strength. We further showed that EDTA treatment (6%) does not always remove all inhibitory factors compared with C1q or titration studies. In this study of patients presenting with multiple antibody specificities, a prozone effect was observed in 71% of the cohort (usually not affecting all antibody specificities within a single serum sample, though). Similar to titration studies, the C1q assay was able to address the issue of potential inhibition; however, its limitation is its low sensitivity and inability to detect the presence of weak antibodies. Titration studies are the only method among the approaches used in this study to provide information suggesting antigen-antibody dissociation rates and are, therefore, likely to provide better indication of true antibody strength.

Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions.

The 12th Banff Conference on Allograft Pathology was held in Comandatuba, Brazil, from August 19-23, 2013, and was preceded by a 2-day Latin American Symposium on Transplant Immunobiology and Immunopathology. The meeting was highlighted by the presentation of the findings of several working groups formed at the 2009 and 2011 Banff meetings to: (1) establish consensus criteria for diagnosing antibody-mediated rejection (ABMR) in the presence and absence of detectable C4d deposition; (2) develop consensus definitions and thresholds for glomerulitis (g score) and chronic glomerulopathy (cg score), associated with improved inter-observer agreement and correlation with clinical, molecular and serological data; (3) determine whether isolated lesions of intimal arteritis ("isolated v") represent acute rejection similar to intimal arteritis in the presence of tubulointerstitial inflammation; (4) compare different methodologies for evaluating interstitial fibrosis and for performing/evaluating implantation biopsies of renal allografts with regard to reproducibility and prediction of subsequent graft function; and (5) define clinically and prognostically significant morphologic criteria for subclassifying polyoma virus nephropathy. The key outcome of the 2013 conference is defining criteria for diagnosis of C4d-negative ABMR and respective modification of the Banff classification. In addition, three new Banff Working Groups were initiated.

7th International Immunoglobulin Conference: Transplantation.

In transplantation, harnessing the immune system is essential for allograft survival and function. This session explores different aspects of the immune system during transplantation, including the effect of donor-specific anti-human leucocyte antigen (HLA) antibodies (DSAs), antibody-mediated rejection (AMR), B cell modulation and the role of immunoglobulin (Ig) therapy. It is well known that DSAs play a key role in the failure of allografts. Identifying and characterizing DSAs provides information that can aid in risk stratification of transplant recipients. The ability to bind complement provides additional information regarding the cytotoxic potential of these antibodies and can therefore potentially guide individualized treatment strategies. AMR presents as several phenotypes, which vary in severity. As such, potentially different treatment strategies are required, emphasizing the importance of accurate diagnosis. In patients with elevated anti-HLA antibodies, waiting times for a compatible organ are often prolonged. Desensitization protocols using intravenous immunoglobulin (IVIg), in combination with other therapies, have been developed to enhance the availability of compatible donors. Another important aspect of transplantation is the role of B cells. While B cells may be involved in AMR and forms of cellular rejection, there is evidence to suggest that regulatory B cells may also have a positive impact upon long-term graft survival. Hypogammaglobulinaemia (HGG) has been reported after solid organ transplantation and is associated with an increased risk of infections. Monitoring immunoglobulin G (IgG) levels post-transplantation may identify patients at risk for infections who could potentially benefit from pre-emptive treatment with IVIg.

7th International Immunoglobulin Conference: Transplantation.

The data presented highlight the complexity of the immune response during transplantation. Early identification and characterization of donor-specific anti-HLA antibodies (DSAs) allows for identification of patients at high risk of transplant rejection and offers information regarding appropriate intervention strategies. The availability of new diagnostic tools can also detect the presence of complement-binding antibodies, providing further information as to the cytotoxic potential of these antibodies. It is particularly encouraging to note that monitoring transplant recipients for the presence of various immune cells or immunoglobulin G (IgG) levels can provide detailed information regarding those at high risk for complications and therefore increased morbidity and mortality. Intervention strategies, either before or after transplantation, may potentially increase the long-term survival of allografts, thus enhancing patient outcomes. Future trials are warranted to assess these strategies in more detail.

Acute enteritis associated with Coxsackievirus A19 in a kidney transplant patient.

Diarrhea is a frequent complication after kidney transplantation, with an incidence rate between 22% and 51%. In many cases, the cause remains unknown. We describe here the first case, to our knowledge, of persistent diarrhea associated with Coxsackievirus A19 (CVA19) in a kidney transplant recipient. The patient was a 46-year-old man who received a deceased-donor kidney. He experienced delayed graft function because of donor kidney donation after circulatory determination of death. Maintenance immunosuppression consisted of low-dose cyclosporine, high-dose mycophenolate mofetil (MMF) (3 g/day), and prednisone (10 mg/day). He had severe diarrhea for 2 weeks associated with acute renal failure. No pathogens were found in the stool cultures. Enterovirus detection was positive by real-time polymerase chain reaction, and sequence analysis found CVA19 (from Enterovirus C group). Area under the curve of MMF was 48 mg.h/L. Because of the persistence of diarrhea, MMF was stopped and replaced by azathioprine. The diarrhea disappeared, but serum creatinine did not return to baseline. CVA19 rarely causes gastroenteritis. This case illustrates that MMF is not always the direct cause of diarrhea, and that new clinical infectious diseases will be detected with the expansion of molecular-based DNA diagnostics.

Low body mass index is associated with a positive response during a head-up tilt test.

BACKGROUND: To describe the association between body mass index (BMI) and a positive response during a head-up tilt test (HUT) in patients referred for an investigation of syncope. METHODS: Observational study of patients referred for the diagnostic evaluation of syncope. Patients were divided into four groups according to their BMI: <18.5 kg/m(2), 18.5-24.9 kg/m(2), 25-29.9 kg/m(2), and > 30 kg/m(2). RESULTS: A total of 419 patients were evaluated. The mean age was 43 ± 22 years, and 62% were female. The prevalence of a positive tilt test was different between groups when stratified by BMI (P = 0.01), with a higher proportion of patients with positive tests among those with BMI <18.5 kg/m(2) compared with other groups (P = 0.05). Multivariate analysis also showed that underweight patients had a 3.9 times higher risk for a positive HUT response (P = 0.01); additionally, the use of contraceptive drugs was associated with a protective effect during HUT (odds ratio: 0.35, confidence interval: 0.19-0.45, P = 0.001). CONCLUSION: In our sample, changes in BMI are associated with a positive response for HUT, and oral contraceptives seemed to protect against this response. Further studies are needed with larger numbers of patients to corroborate this finding.

Banff 2011 Meeting report: new concepts in antibody-mediated rejection.

The 11th Banff meeting was held in Paris, France, from June 5 to 10, 2011, with a focus on refining diagnostic criteria for antibody-mediated rejection (ABMR). The major outcome was the acknowledgment of C4d-negative ABMR in kidney transplants. Diagnostic criteria for ABMR have also been revisited in other types of transplants. It was recognized that ABMR is associated with heterogeneous phenotypes even within the same type of transplant. This highlights the necessity of further refining the respective diagnostic criteria, and is of particular significance for the design of randomized clinical trials. A reliable phenotyping will allow for definition of robust end-points. To address this unmet need and to allow for an evidence-based refinement of the Banff classification, Banff Working Groups presented multicenter data regarding the reproducibility of features relevant to the diagnosis of ABMR. However, the consensus was that more data are necessary and further Banff Working Group activities were initiated. A new Banff working group was created to define diagnostic criteria for ABMR in kidneys independent of C4d. Results are expected to be presented at the 12th Banff meeting to be held in 2013 in Brazil. No change to the Banff classification occurred in 2011.

How many times can parvovirus B19-related anemia recur in solid organ transplant recipients?

Parvovirus B19 (PB19) infection is known to cause acute erythroblastopenia-mediated anemia in solid organ transplant (SOT) recipients. Intravenous immunoglobulins (IVIg) and the decrease of immunosuppression level are supposed to induce a long-term remission, although no consensus exists about the dose and the schedule of IVIg administrations. However, a few reports have shown that PB19-related anemia can recur despite this treatment, with a maximum of 3 recurrences reported. In this report, we describe in detail the cases of 2 kidney recipients with PB19 infection. They experienced, respectively, 9 and 7 PB19-related anemia recurrences. Immunosuppression level was decreased and IVIg were administered at each recurrence followed by a transitory normalization of hemoglobin level and a decrease of serum PB19 viral load. Episodes were separated by several months. These patients raise an original therapeutic management question about a frequent viral infection in SOT recipients. One patient is currently receiving IVIg every 3 months as a secondary prophylaxis without recurrence to date. These 2 case reports are followed by a review of the literature.

Mastering the risk of HLA antibodies in kidney transplantation: an algorithm based on pretransplant single-antigen flow bead techniques.

The utilization of sensitive techniques of detection of HLA antibodies to define and measure sensitization has greatly evolved in recent years. We present here an approach to minimize the risk of HLA antibodies in kidney transplantation based on the evaluation of graft accessibility of sensitized patients by calculated PRA (cPRA) and estimation of potential matched donors (PMD) using a national simulation software program. This study included all registered patients on our waiting list (WL) for deceased donor (DD) kidney transplants. All patients were screened by single-antigen flow bead (SAFB) techniques. Of the 502 registered patients, 174 (34.7%) were sensitized. Among these, 48.3% (84 pts) had a cPRA>85%. For 75.3% of sensitized patients (90 pts with cPRA≤85% and 41 pts with cPRA>85%), the flow of PMD was considered sufficient to allow a transplant avoiding all unacceptable antigens. The 41 patients with a cPRA>85% (48.8%) had a satisfactory donor flow in the framework of the national prioritization program for highly sensitized patients. Finally, 43 sensitized patients (24.7%) were deemed eligible for a strategy of higher immunological risk through desensitization protocols or transplantation against HLA-DSAs. This approach provides a logical and systematic strategy to rationalize the access of sensitized patients to kidney transplantation minimizing the risk of HLA antibodies.

Antibody-mediated rejection--an ounce of prevention is worth a pound of cure.

The presence of preformed, donor-specific alloantibodies inpatients undergoing renal transplantation is associated with a high risk of hyperacute and acute antibody-mediated rejection (ABMR), and often limits potential recipients' access to organs from living and deceased donors. Over the last decade, understanding of ABMR has improved markedly and given rise to numerous, diverse strategies for the transplantation of allosensitized recipients. Antibody desensitization programs have been developed to allow renal transplant recipients with a willing but antibody-incompatible living donor to undergo successful transplantation, whereas kidney paired exchange schemes circumvent the antibody incompatibility altogether by finding suitable pairs to donors and recipients. Recognizing the complexity of ABMR and the recent developments that have occurred in this important clinical research field, the Roche Organ Transplantation Research Foundation (ROTRF) organized a symposium during the XXIII Congress of The Transplantation Society in Vancouver, Canada, to discuss current understanding in ABMR and ways to prevent it. This Meeting Report summarizes the presentations of the symposium, which addressed key areas that included the interactions between alloantibodies and the complement system in mediating graft injury, technological advancements for assessing antibody-mediated immune responses to HLA antigens, and the potential benefits and challenges of desensitization and kidney paired donation schemes.

Fumagillin for treatment of intestinal microsporidiosis in renal transplant recipients.

We report 10 cases of intestinal microsporidiosis due to Enterocytozoon bieneusi in renal transplant (RT) recipients who were treated with fumagillin. All patients presented with afebrile subacute diarrhea (median of 2 weeks), associated with abdominal cramps (n = 5), and weight loss (n = 6), a mean of 68 months after RT. The diagnosis was made by the identification of microsporidial spores in stools with the use of appropriate staining and confirmed by a specific polymerase chain reaction assay for E. bieneusi in 7 patients. Median CD4 cell count was 292 cells/mm(3). All patients received a median of 14 days of oral fumagillin (20 mg tid), and four patients also discontinued or tapered their immunosuppressive regimen (mycophenolate mofetil in 3, and azathioprine in 2). Clinical symptoms resolved rapidly with the clearance of microsporidial spores from stools in all patients. A severe but reversible thrombocytopenia was observed in one patient during fumagillin therapy, and another patient presented with abdominal cramps. Trough levels of tacrolimus measured in seven patients dropped below 5 ng/mL in six of them after 7-14 days of fumagillin. Intestinal microsporidiosis can cause subacute diarrhea in RT recipients. Fumagillin is an effective treatment with an acceptable safety profile, but monitoring of tacrolimus levels is warranted.

Renal transplantation in HIV-infected patients: the Paris experience.

Kidney transplantation is now considered as a reasonable option for HIV-infected patients with end-stage renal disease. We describe here a retrospective study conducted in five transplantation centers in Paris. Twenty-seven patients were included. Immunosuppressive protocol associated an induction therapy and a long-term treatment combining mycophenolate mofetil, steroids and either tacrolimus or cyclosporine. All the patients had protocol biopsies at 3 months and 1 year. Patient's survival was 100% at 1 year and 98% at 2 years. Graft survival at 1 and 2 years is 98% and 96% at 1 and 2 years, respectively. The mean glomerular filteration rate values at 12 and 24 months were 60.6 mL/min/1.73 m² (range 23-98) and 65.4 mL/min/1.73 m² (range 24-110), respectively. Acute cellular rejection was diagnosed in four cases (15%). Because of high trough levels of calcineurin inhibitor, protease-inhibitor therapies were withdrawn in 11 cases. HIV disease progression was not observed. One patient developed B-cell lymphoma. In conclusion, our study confirms the safety of renal transplantation in HIV-infected patients with few adverse events and a low incidence of acute rejection.