Nicolas Congy-Jolivet

Prevalence, incidence and risk factors for donor-specific anti-HLA antibodies in maintenance liver transplant patients.

Although large retrospective studies have identified the presence of donor‐specific antibodies (DSAs) to be a risk factor for rejection and impaired survival after liver transplantation, the long‐term predicted pathogenic potential of individual DSAs after liver transplantation remains unclear. We investigated the incidence, prevalence and consequences of DSAs in maintenance liver transplant (LT) recipients. Two hundred sixty‐seven LT recipients, who had undergone transplantation at least 6 months previously and had been screened for DSAs at least twice using single‐antigen bead technology, were included and tested annually for the presence of DSAs. At a median of 51 months (min–max: 6–220) after an LT, 13% of patients had DSAs. At a median of 36.5 months (min–max: 2–45) after the first screening, 9% of patients have developed de novo DSAs. The sole predictive factor for the emergence of de novo DSAs was retransplantation (OR 3.75; 95% CI 1.28–11.05, p = 0.025). Five out of 21 patients with de novo DSAs (23.8%) developed an antibody‐mediated rejection. Fibrosis score was higher among patients with DSAs. In conclusion, monitoring for the development of DSAs in maintenance LT patients is useful in case of graft dysfunction and to identify patients with a high risk of developing liver fibrosis.

Donor-Specific Antibodies after Ceasing Immunosuppressive Therapy, with or without an Allograft Nephrectomy

BACKGROUND AND OBJECTIVES Within the last few years, anti-human leukocyte antigen detection assays have significantly improved. This study asked, using the Luminex single-antigen assay, whether an allograft nephrectomy allowed donor-specific alloantibodies to appear that were not previously detected in the serum when the failed kidney was still in place. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS After losing the kidney allograft and stopping immunosuppressive therapy, the proportions of donor-specific alloantibodies and nondonor-specific alloantibodies were compared in patients who had (n=48; group I) and had not (n=21; group II) undergone an allograft nephrectomy. Allograft nephrectomies were performed at 150 days after kidney allograft loss, and the time between allograft nephrectomy and last follow-up was 538 ± 347 days. RESULTS At kidney allograft loss, donor-specific alloantibodies were detected in three group II patients (14.2%) and six group I patients (12.5%). At last follow-up, donor-specific alloantibodies were detected in 11 patients (52.4%) without and 39 patients (81%) with an allograft nephrectomy (P=0.02). Anti-human leukocyte antigen class I donor-specific alloantibodies were positive in 23.8% of group II and 77% of group I patients (P<0.001); anti-human leukocyte antigen class II donor-specific alloantibodies were positive in 42.8% of group II and 62.5% of group I patients. Independent predictive factors for developing donor-specific alloantibodies after losing kidney allograft and stopping immunosuppressants were number of anti-human leukocyte antigen A/B mismatches at transplantation (zero versus one or more) and allograft nephrectomy. CONCLUSIONS The development of donor-specific alloantibodies was significantly greater in patients with a failed kidney who had undergone an allograft nephrectomy compared with those patients who had not undergone allograft nephrectomy.

De novo donor-specific anti-HLA antibodies mediated rejection in liver-transplant patients.

The incidence and consequences of de novo donor‐specific anti‐HLA antibodies (DSAs) after liver transplantation (LT) are not well known. We investigated the incidence, risk factors, and complications associated with de novo DSAs in this setting. A total of 152 de novo liver‐transplant patients, without preformed anti‐HLA DSAs, were tested for anti‐HLA antibodies, with single‐antigen bead technology, before, at transplantation, at 1, 3, 6 and 12 months after transplantation, and thereafter annually and at each time they presented with increased liver‐enzyme levels until the last follow‐up, that is, 34 (1.5–77) months. Twenty‐one patients (14%) developed de novo DSAs. Of these, five patients had C1q‐binding DSAs (24%). Younger age, low exposure to calcineurin inhibitors, and noncompliance were predictive factors for de novo DSA formation. Nine of the 21 patients (43%) with de novo DSAs experienced an acute antibody‐mediated rejection (AMR). Positive C4d staining was more frequently observed in liver biopsies of patients with AMR (9/9 vs. 1/12, P < 0.0001). Eight patients received a B‐cell targeting therapy, and one patient received polyclonal antibodies. Only one patient required retransplantation. Patient‐ and graft‐survival rates did not differ between patients with and without DSAs. In conclusion, liver‐transplant patients with liver abnormalities should be screened for DSAs and AMR.

Impact of Early Blood Transfusion After Kidney Transplantation on the Incidence of Donor-Specific Anti-HLA Antibodies.

Little is known about the impact of posttransplant blood transfusion on the sensitization of anti‐HLA antibodies and the formation of donor‐specific antibodies (DSAs). The aims of our study were to determine the 1‐year incidence of DSAs (assessed using a solid‐phase assay) and antibody‐mediated rejection (AMR) in kidney transplant patients who had or had not received a blood transfusion during the first year after transplantation. Included were 390 non–HLA‐sensitized patients who had received an ABO‐compatible kidney transplant and had not previously or simultaneously received a nonkidney transplant. Overall, 64% of patients received a red blood cell transfusion within the first year after transplantation, most within the first month. The overall 1‐year incidence of DSAs was significantly higher in patients that had undergone transfusion (7.2% vs. 0.7% in patients with no transfusion, p < 0.0001). AMR occurred more often in the transfusion group (n = 15, 6%) compared with the nontransfusion group (n = 2, 1.4%; p = 0.04). Blood transfusion was an independent predictive factor for de novo DSA formation but not for AMR. Patients who had a transfusion and developed DSAs were more often treated with cyclosporin A (n = 10, 55.5%) rather than tacrolimus (n = 45, 19.4%; p = 0.0001). In conclusion, early posttransplant blood transfusion may increase immunological risk, especially in underimmunosuppressed patients.

Pregnancy after kidney transplantation: outcome and anti-human leucocyte antigen alloimmunization risk

BACKGROUND Kidney transplantation increases the chances for pregnancy and live birth for women with end-stage kidney disease. The aims of this study were to describe the outcomes of pregnancies in women with a kidney transplant and to evaluate the impact on anti-human leucocyte antigen (HLA) alloimmunization. METHODS We analysed 61 pregnancies that occurred in 46 patients after having excluded 10 miscarriages during the first trimester and 10 other pregnancies from which important data were missing. Anti-HLA antibodies were screened using the Luminex assay. RESULTS Overall, the live birth rate was 83% (94% after exclusion of miscarriages during the first trimester). Pre-eclampsia and gestational diabetes occurred in 26 and 21% of cases, respectively. The use of tacrolimus was an independent predictive factor for gestational diabetes. Twenty-four newborns (42%) were premature (<37 weeks). The median birth weight was 2720 (1040-3730) g. Nine newborns (15%) had low birth weights (<2.5 kg). At least one severe complication occurred in 56% of pregnancies. A high glomerular-filtration rate (GFR) before pregnancy was the sole independent protective factor that avoided a severe complication. Death-censored kidney-allograft survival was 80.4% at 6 years. De novo donor-specific anti-HLA antibodies were detected after only 5.9% of pregnancies: for two women, the father had the same HLA antigens as those from the deceased organ donor. The determination of the HLA of the father before pregnancy can better inform the woman about the possible impact of pregnancy on her kidney-allograft function. CONCLUSIONS Despite many complications, the outcomes for pregnancy and kidney allografts are good. The risk of anti-HLA alloimmunization was low.

Donor-specific antibodies and liver transplantation.

In contrast to other types of organ transplantation, liver-transplant recipients used to be considered highly resistant to donor-specific antibodies (DSAs). Consequently, most transplant programs did not consider the presence of DSAs at transplantation or during the follow-up. However, since the early 1990s, antibody-mediated pathological lesions have been recognized in ABO-incompatible liver-transplant recipients. Recent data confirm the detrimental effect of preformed and de novo DSAs in ABO-compatible liver transplantation, with inferior clinical outcomes in patients presenting with circulating antibodies. Acute antibody-mediated rejection (AMR), plasma-cell hepatitis, biliary stricture, but also long-term complications, such as chronic rejection, liver ductopenia, and graft fibrosis, are now recognized to be associated with DSAs. Moreover, some non-HLA DSAs are suspected to induce graft dysfunction. Clinical, biological, and histological patterns within AMR need to be clarified. Treatment of these complications has yet to be defined. This article summarizes recent advances concerning the impact of preformed and de novo DSAs in liver transplantation, it defines the complications associated with DSAs, and discusses the potential strategies to manage patients with such complications.

Immunoglobulin IgA, IgD, IgG, IgM and IgG subclass reference values in adults

*Corresponding author: Pr. Antoine Blancher, Laboratoire d’Immunologie du CHU de Toulouse, Hôpital Rangueil, TSA 50032, 31059 Toulouse Cedex 9, France, Phone: +33 5 61 323432, Fax: +33 5 61 323424, E-mail: blancher.a@chu-toulouse.fr; and Laboratoire d’Immunogénétique Moléculaire, EA 3034, Université Paul Sabatier, Toulouse III, France Bénédicte Puissant-Lubrano, Pol-André Apoil and Nicolas CongyJolivet: Laboratoire d’Immunogénétique Moléculaire, EA 3034, Université Paul Sabatier, Toulouse III, France; and Laboratoire d’Immunologie, CHU de Toulouse, France Michael Peres: Laboratoire d’Immunologie, CHU de Toulouse, France Francis Roubinet: EFS Pyrénées-Méditerranée, Toulouse, France Letter to the Editor

Allelic and Epitopic Characterization of Intra-Kidney Allograft Anti-HLA Antibodies at Allograft Nephrectomy.

The reasons for the increased incidence of de novo anti–human leukocyte antibody (HLA) donor‐specific antibodies (DSAs) observed after kidney allograft nephrectomy are not fully understood. One advocated mechanism suggests that at graft loss, DSAs are not detected in the serum because they are fixed on the nonfunctional transplant; removal of the kidney allows DSAs to then appear in the blood circulation. The aim of our study was to compare anti‐HLA antibodies present in the serum and in the graft at the time of an allograft nephrectomy. Using solid‐phase assays, anti‐HLA antibodies were searched for in the sera of 17 kidney transplant patients undergoing allograft nephrectomy. No anti‐HLA antibodies were detected in the graft if they were not also detected in the serum. Eleven of the 12 patients who had DSAs detected in their sera also had DSAs detected in the grafts. Epitopic analysis revealed that most anti‐HLA antibodies detected in removed grafts were directed against the donor. In summary, our data show that all anti‐HLA antibodies that were detected in grafts were also detected in the sera. These intragraft anti‐HLA antibodies are mostly directed against the donor at an epitopic level but not always at an antigenic level.

Histological long‐term outcomes from acute antibody‐mediated rejection following ABO‐compatible liver transplantation

Acute antibody‐mediated rejection (aAMR) is an unusual complication after orthotopic ABO‐compatible liver transplantation. To date, the clinical and histological long‐term outcomes after aAMR are not well known.

Maintaining immunosuppressive treatment after early allograft nephrectomy does not reduce the risk of anti-HLA allosensitization.

Dear Sir, Early loss of a kidney allograft within the first days or weeks after transplantation occurs in 3–5% of kidney transplant patients [1,2]. It is mainly caused by artery and/or vein allograft thrombosis [2] and requires a rapid allograft nephrectomy. We have previously shown that, even after a short transplant period, donor-specific antibodies (DSAs) and non-DSA anti-HLA antibodies develop in up to 50% of patients who stop immunosuppressive treatments immediately after an early allograft nephrectomy [3]. Mechanisms leading to sensitization are incompletely explained, but could involve the persistence of the donor’s antigens after allograft removal, particularly in the vascular patches. The presence of preformed anti-HLA DSAs is associated with a poor kidney allograft outcome [4]. Hence, avoiding the development of anti-HLA antibodies is mandatory to allow rapid access to kidney transplantation without DSAs. Therefore, we have speculated that maintaining immunosuppressive therapy for 3 months after kidney allograft nephrectomy might reduce the occurrence of anti-HLA immunization. Between July 2007 and December 2013, 925 kidney transplantations were performed in our institution. Among these, 43 (4.6%) experienced an early allograft loss, defined by graft loss within the first week after transplantation and that required rapid allograft nephrectomy. Only patients who were eligible for retransplantation and were screened for anti-HLA antibodies after an allograft nephrectomy were included in this study (n = 33). Arterial and/or venous thromboses were the main causes of graft loss. Between July 2007 and November 2012, 21 early graft losses occurred. At that time, the policy in our institution was to stop all immunosuppressive drugs immediately after a kidney allograft nephrectomy. At transplantation, all patients had received mycophenolate mofetil (1 g) and a steroid pulse (10 mg/kg). Fifteen of the 21 patients had also received an induction therapy with polyclonal antibodies (n = 3) or anti-CD25 monoclonal antibodies (n = 12). After transplantation, all patients were given calcineurin inhibitors, mycophenolic acid, and steroids. Between November 2012 and December 2013, there were 12 early losses of kidney allografts. Continued immunosuppressive therapy was proposed for all patients but one. This latter patient had a full HLA match with his donor. Hence, the 11 remaining patients were given immunosuppressive therapy for 3 months after having given their written informed consent. Before transplantation, all patients had received mycophenolate mofetil (1 g) and a steroid pulse (10 mg/kg). Ten of the 11 patients also received an induction therapy of polyclonal antibodies (n = 2) or anti-CD25 monoclonal antibodies (n = 8). After transplantation, all patients were given calcineurin inhibitors, mycophenolic acid, and steroids. After the kidney allograft nephrectomy, all patients were given tacrolimus (target trough level of 4–6 ng/ml), mycophenolate mofetil (500 mg b.i.d.), and low-dose steroids (5 mg/day) for 3 months. Anti-HLA antibodies were assessed for class I HLAs in A/ B and class II in DR/DQ IgG before and after transplantation, using Labscreen single Ag HLA detection tests (One Lambda, Canoga Park, CA, USA). After allograft nephrectomy, anti-HLA antibodies were tested on day 15 and at months 1, 3, 6, 9, and 12 postnephrectomy. A baseline mean fluorescence intensity value of >500 was considered positive. Before transplantation, complement-dependent cytotoxicity cross-matches were negative for all patients. The median time between transplantation and allograft nephrectomy was 1 day (range: 0–2) in the group that continued immunosuppressive therapy and 1 day (range: 0–5) in the group that promptly stopped immunosuppressive therapy after allograft nephrectomy, termed the controls (P = ns). None of the graft losses were related to an acute rejection episode. One patient from the immunosuppression group had psychiatric complications at 1 week after the allograft nephrectomy and stopped all immunosuppressive drugs. Another patient from the same group presented