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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., (© 2015 Steunstichting ESOT.)

Background: Ribavirin is efficient at treating chronic hepatitis E virus infection in solid-organ transplant patients. However, the early kinetics of viral replication under therapy and the impact of immunosuppressant regimens on viral replication are unknown: thus, determining the aim of our study., Methods: Thirty-five patients with a solid-organ transplant and chronic hepatitis E virus infection were given ribavirin for 3 months. The hepatitis E virus (HEV) RNA concentrations were determined before treatment, at days 7, 15, and 21 and at months 1, 2, and 3 during therapy and after ribavirin cessation., Results: A sustained virological response (SVR) occurred in 63%. Decreased viral concentration within the first week post-ribavirin therapy was an independent predictive factor for SVR, and a decreased HEV concentration of 0.5 log copies/mL or greater had an 88% positive predictive value. No correlation between ribavirin trough level on day 7 or at month 2 with a virological response or an SVR was observed. Before therapy, HEV RNA concentration was significantly greater in patients receiving mechanistic target of rapamycin inhibitor-based immunosuppression compared to patients given calcineurin inhibitors. The use of mycophenolic acid did not impact on the response to ribavirin., Conclusion: An early response to ribavirin can be used to define the optimal duration of therapy in the setting of HEV infection.

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., (© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Objectives: Few data regarding viral replication in patients receiving belatacept are available. The aim of this single-center study was to compare the incidence of viral infections (cytomegalovirus, Epstein Barr virus, BK virus, and JC virus), in 62 de novo kidney transplant patients enrolled in the BENEFIT studies, receiving either belatacept (n=42) or cyclosporine (n=20)., Materials and Methods: By means of polymerase chain reaction, belatacept-treated patients were tested for cytomegalovirus, Epstein-Barr virus, BK virus, and JC virus infections monthly for 36 months, monthly for the first 6 months, and then quarterly for 36 months in cyclosporine-treated patients. Additional samples were obtained when a viral infection was suspected., Results: The number of positive cytomegalovirus, BK virus, or JC virus viremias over the number of polymerase chain reactions performed through all 3 years was similar in both groups. Conversely, over the 3-year study, the number of positive Epstein-Barr virus viremias over the number of Epstein-Barr virus polymerase chain reactions performed was significantly higher in the belatacept group (76% vs 50%; P = .047). The number of Epstein-Barr virus primary infection was similar in both groups, while the number of Epstein-Barr virus reactivation was higher in the belatacept group., Conclusions: Epstein-Barr virus replication occurs more often in patients receiving belatacept, than it does in those receiving cyclosporine.

Background: Patients with a simultaneous pancreas-kidney transplant (SPKT), especially those with gastroparesis, often have gastro-intestinal (GI) disorders that can modify immunosuppressant pharmacokinetics. We compared the MPA 12-hours area under the curve (AUC(0-12)) in SKPT patients with severe gastroparesis receiving mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS)., Material/methods: Fifteen SKPT patients having a severe gastroparesis were switched, at 182 (69-1523) days post-transplantation, from MMF to EC-MPS because of GI disorders. MPA AUC(0-12) values were obtained before and after the switch, ie, under MMF (500 mg b.i.d.) at 169 (51-1522) days post-transplantation and EC-MPS (360 mg b.i.d.) at 102 (26-355) days after the switch., Results: Mean MPA AUC(0-12) h did not differ significantly under MMF and EC-MPS, ie, 40.13±14 and 38.24±15.5 mg*h/L, respectively. Trough and maximal MPA concentrations were similar with both MPA formulations. Although all patients had GI disorders under MMF (100%), only 3 had persistent GI disorders under EC-MPS (20%) (p<0.001)., Conclusions: In SKPT patients with severe gastroparesis, exposure to MPA is similar under MMF and EC-MPS. However, the incidence of GI disorders is significantly lower when patients are given EC-MPS.

The human polyomavirus BK (BKV) is associated with severe complications, such as ureteric stenosis and polyomavirus-associated nephropathy (PVAN), which often occur in kidney-transplant patients. However, it is unknown if BKV can replicate within bone marrow. The aim of this study was to search for BKV replication within the bone marrow of kidney-transplant patients presenting with a hematological disorder. Seventy-two kidney-transplant patients underwent bone-marrow aspiration for cytopenia. At least one virus was detected in the bone marrow of 25/72 patients (35%), that is, parvovirus B19 alone (n = 8), parvovirus plus Epstein-Barr virus (EBV) (n = 3), cytomegalovirus (n = 4), EBV (n = 2), BKV alone (n = 7), and BKV plus EBV (n = 1). Three of the eight patients who had BKV replication within the bone marrow had no detectable BKV replication in the blood. Neutropenia was observed in all patients with BKV replication in the bone marrow, and blockade of granulocyte maturation was observed. Hematological disorders disappeared in all patients after doses of immunosuppressants were reduced. In conclusion, an association between BKV replication in bone marrow and hematological disorders, especially neutropenia, was observed. Further studies are needed to confirm these findings.

Belatacept has been found to be efficient at preserving good kidney function in maintenance kidney-transplant patients. Herein, we report on the use of belatacept as a rescue therapy for two kidney-transplant patients presenting with severe adverse events after treatment with calcineurin inhibitors (CNIs) and mammalian target-of-rapamycin (mTOR) inhibitors. Two kidney-transplant patients developed severely impaired kidney function after receiving CNIs. The use of everolimus was associated with severe angioedema. Belatacept was then successfully used to improve kidney function in both cases, even though estimated glomerular-filtration rate before conversion was <20 mL/min. These case reports show that belatacept can be used as a rescue therapy, even if kidney function is very low in kidney-transplant patients who cannot tolerate CNIs and/or mTOR inhibitors.

Objectives: Scarce data exist regarding the effect of acute graft pyelonephritis on kidney histology after a kidney transplant. This study sought to assess the kidney histology at 1 month, and kidney function at 1 year, after acute graft pyelonephritis in kidney transplant patients., Materials and Methods: All kidney transplant patients with acute graft pyelonephritis between October 2006, and December 2008, underwent a kidney biopsy 1 month later (n=28). Histologic findings were compared with those observed in a control group (n=28) who underwent a protocol kidney biopsy at 1 year posttransplant and did not present with acute graft pyelonephritis. Patients were matched according to age, sex, and immunosuppressive regimen., Results: Kidney function was impaired by the acute graft pyelonephritis episodes at the time of biopsy. In 40% of patients, the estimated glomerular filtration rate did not return to baseline by 1 month after acute graft pyelonephritis and remained impaired thereafter. Three patients had features of acute rejection. Tubulitis was seen more frequently in the acute graft pyelonephritis group, especially in patients in whom estimated glomerular filtration rate did not completely recover by 1 month after acute graft pyelonephritis. Patients with acute graft pyelonephritis who had inflammatory infiltrate of > 20% 1 month after acute graft pyelonephritis had worse kidney function 1 year later., Conclusions: After transplant, when kidney function remains impaired 1 month after acute graft pyelonephritis, kidney biopsies allowed graft rejection diagnosis and predicted kidney function recovery.

Background and Aim: Liver transplantation remains the best option for treating type-1 hepatorenal syndrome (HRS1). The aim of this retrospective study was to determine whether the molecular adsorbent recirculation system (MARS) can improve renal function in HRS1 patients., Methods: Thirty-two patients with chronic liver disease and HRS1 were treated by MARS sessions which were performed every other day. The endpoint was renal function improvement by 28 days after diagnosis of HRS1 that was defined as a serum-creatinine level of < 133 μmol/L. Partial renal recovery was defined as a 10% decrease in baseline serum-creatinine level., Results: The mean number of MARS sessions required by each patient was 3.5 ± 1.5. The median time between admission and the start of MARS therapy was 3 (0-15) days. Of the total patients, 13 (40%) had improved renal function. Among these, nine (28%) had complete renal recovery. Among the patients that survived, only 40% (6/15) had improved renal function, and among the patients that died within the first month after the initiation of MARS, seven patients had a renal response. The 28-day survival rate was 47%. Seven patients received a liver transplant after diagnosis of HRS. Of these, four had complete or partial recovery after transplantation (57%) versus 9 of the 25 patients who did not undergo liver transplantation (36%), P = not significant., Conclusion: MARS therapy improved renal function in only very few patients with HRS1. Further controlled studies including large number of patients are required., (© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Scarce data exist regarding the incidence of donor-specific antibodies (DSAs) in kidney transplant patients receiving everolimus-based immunosuppression without calcineurin inhibitors (CNIs). The aim of this retrospective case-control study was to compare the incidence of de novo DSAs in patients converted to an everolimus-based regimen without CNIs with that seen in patients maintained on CNIs. Sixty-one DSA-free kidney transplant patients who had been converted to an everolimus-based regimen (everolimus group) were compared to 61 other patients maintained on CNIs-based regimen (control group). Patients were matched according to age, gender, induction therapy, date of transplantation, and being DSA-free at baseline. At last follow-up, the incidence of DSAs was 9.8% in the everolimus group and 5% in the control group (p = ns). In the everolimus group, the increased incidence of DSAs between baseline and last follow-up was statistically significant. Antibody-mediated rejection occurred in 6.5% in the everolimus group and 0% in the CNIs group. The incidence of DSAs is numerically increased in kidney transplant patients treated with an everolimus-based without CNIs. A study including a larger number of patients is required to determine whether a CNI-free everolimus-based immunosuppression significantly increases DSAs formation., (© 2013 John Wiley & Sons A/S.)

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.

Introduction: The occurrence of de novo anti-human leukocyte antigen (HLA) antibodies and donor-specific antibodies (DSAs) after early graft loss is not well known. The aims of this single-center study were to evaluate the incidence of de novo DSAs and non-DSA anti-HLA antibodies after allograft nephrectomy for early graft loss and to seek the predictive factors for the development of DSAs., Materials and Methods: Thirty-two patients, who experienced an early graft loss (<3 months after transplantation) and required an allograft nephrectomy, and who were considered for retransplantation, were included in the study. Anti-HLA antibodies were assessed, using the Luminex assay, before transplantation, on day 15 and at months 1, 3, 6, and 9 after the nephrectomy, and then every 3 to 6 months until the last follow-up., Results: The median time between transplantation and allograft nephrectomy was 2.5 (0-81) days. The median follow-up was 335 (30-1441) days. At month 9, postallograft nephrectomy, the incidence of DSAs was 56.6% (17/30). Anti-HLA class I and class II DSAs were detected, respectively, in 33.3% (10/30) and 30% (9/30) of patients. The incidence of de novo non-DSA anti-HLA antibodies was 64% (19/30): of these, 83.3% reacted to the donors' epitopes. Induction therapy (type and dose) and the time between transplantation and allograft nephrectomy did not influence the incidence of DSAs. No independent predictive factor for the development of DSAs was identified., Conclusion: Even after a short transplantation period, DSAs and non-DSA anti-HLA antibodies may develop in more than 50% of patients whose immunosuppression has been stopped after an allograft nephrectomy.

Preventive treatment of focal and segmental glomerulosclerosis (FSGS) allograft recurrence in high risk recipients having a prior history of graft loss caused by FSGS recurrence is still a challenging question. We retrospectively identified four patients who underwent a second renal transplantation because of recurrent FSGS and who received Rituximab therapy as a prophylactic treatment. Loss of their first allograft was directly related to an early (<3 months) recurrence of FSGS that was either resistant to plasmapheresis therapy in two cases or had escaped to this therapeutic management in the two others. After the second renal transplantation, all patients were free of FSGS recurrence during follow-ups that were between 12 and 54 months long. These preliminary results demonstrate for the first time that Rituximab therapy may constitute an attractive prophylactic option for patients being considered for a second renal transplantation because of recurrent FSGS in their first graft., (© 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.)

Background: Hepatitis E virus (HEV) infection is an emerging disease in industrialized countries. Few data regarding genotype 3 HEV extrahepatic manifestations exist., Methods: We assessed kidney function and histology in solid-organ transplant patients during HEV infection. In all, 51 cases of genotype 3 HEV infections were diagnosed (34 kidney, 14 liver, and 3 kidney-pancreas transplant patients). Of these, 43.2% were cleared of the virus spontaneously within 6 months of infection, whereas 56.8% evolved to chronic hepatitis. Twelve of these patients completed a 3-month antiviral therapy and were followed up for 6 months posttreatment. Kidney function (estimated glomerular filtration rate [eGFR] obtained by the Modification of Diet in Renal Disease equation) and proteinuria were assessed before infection, during HEV infection and during follow-up. Kidney biopsies were obtained from patients with high proteinuria and decreased eGFR levels., Results: During HEV infection, there was a significant decrease in eGFR in both kidney- and liver-transplant patients. Glomerular diseases were observed in kidney biopsies obtained during the acute and chronic phases. This included membranoproliferative glomerulonephritis and relapses in IgA nephropathy. The majority of patients had cryoglobulinemia that became negative after HEV clearance. Kidney function improved and proteinuria decreased after HEV clearance., Conclusion: HEV-associated glomerulonephritis seems to be an HEV-related extrahepatic manifestation. Further studies are required to confirm these observations.

Importance of the Field: Kidney transplantation is the best treatment for end-stage kidney-disease patients. However, despite major breakthroughs in the last decades, and the progresses made with immunosuppressants, the long-term results still need to be improved. This is related to the increased risk of cardiovascular mortality, de novo post-transplant malignancies, and chronic kidney disease within the allograft. The last is multifactorial and includes immunological and non-immunological factors. Amongst the last is the calcineurin inhibitor (CNI) (cyclosporine A (CsA) and tacrolimus)-related nephrotoxicity. Kidney-allograft function at 1-year post-transplantation is a good surrogate marker of long-term allograft survival., Areas Covered in This Review: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4)-Ig, a fusion protein, presents as abatacept, which conserves the natural structure of CTLA4, and belatacept, which has enhanced activity thanks to two amino-acid substitutions. Abatacept and belatacept block CD86-CD28 interaction, but belatacept blocks them more powerfully. Abatacept is already approved for the treatment of rheumatoid arthritis and is marketed as Orencia(®) (Bristol-Myers Squibb, Princeton, NJ, USA), whereas belatacept is not yet approved. Herein, we review the current data available on the use of belatacept in Phase II and III kidney-transplantation trials. Note, though, that data from belatacept Phase II liver transplantation trials are not yet available., What the Reader Will Gain: The results show in de novo kidney transplant patients that as compared to CsA-treated patients, belatacept-treated patients showed: i) a significant better allograft function both at 1- and 2- year post-transplantation and ii) better cardiovascular and metabolic profiles. Regarding the safety data, Epstein-Barr virus (EBV) seronegative belatacept-treated patients experience more post-transplant lymphoproliferative disorders than the EBV seropositive belatacept-treated patients and the CsA-treated patients., Take Home Message: CNIs are potent immunosuppressants but have some degree of nephrotoxicity. Therefore, it is important to have strong data showing that belatacept-based therapy is as efficient as CsA-based therapy, but displaying at both 1- and 2-year post-transplantation a better allograft function, which might translate in the long-term into longer allograft survival.

This sequential study evaluated two strategies regarding human cytomegalovirus (HCMV) infection/disease in HCMV-seropositive de novo kidney-transplant patients. The first cohort of patients (group 1; n = 132) was monitored sequentially for HCMV DNAemia; if it was positive (a cut-off at 3 log(10) copies/ml), the patient was given pre-emptive IV ganciclovir therapy (10 mg/kg/day for 3 weeks). The second cohort consisted of 150 patients (group 2) who were given valganciclovir (VGC) prophylaxis (900 mg/day) for the first 3 months posttransplantation. During the mean follow-up of at least 2 years for both cohorts, VGC prophylaxis resulted in a significant decrease in both CMV infection (68.9% vs. 33.3%; P < 0.001) and disease (9.8% vs. 2.68%, P = 0.021). Factors associated with HCMV reactivation in multivariate analysis were (i) no HCMV prophylaxis; (ii) recipient's age; (iii) being placed on ciclosporine A and mycophenolic acid from the beginning of transplantation (iv) donor HCMV-seropositivity; and (v) being a male recipient. No cases of ganciclovir resistance were detected in the prophylactic group. HCMV prophylaxis had no impact on 2-year patient/graft survival or on kidney-allograft function. We conclude that VGC-prophylaxis can be reasonably used to treat HCMV-seropositive kidney-transplant recipients., (© 2010 The Authors. Journal compilation © 2010 European Society for Organ Transplantation.)

After kidney transplantation, occurrence of anemia in the early post-transplant period (<1 month) is high and arises out of issues that are multifactorial. We performed a retrospective single-center study to assess whether delivery of high doses of erythropoietin-stimulating agents (ESA) within the first week of kidney transplantation, translates at 1 month post-transplant, in to causing less anemia and whether it has an impact on allograft function. Ninety-nine patients were not given ESA (group I), whereas 82 were (250 IU/kg/week; group II). All patients had similar pretransplant and baseline (day 0) variables. Similar numbers of group II patients were still receiving ESA by day 14 (97.5%) and day 30 (89%). Respective figures for group I were 27% and 27%. Independent factors for anemia at 1 month post-transplant included: being male subject, treatment for hypertension at pretransplant, anemia at transplant, a higher mean corpuscular volume at transplant, and an induction therapy using antithymocyte globulins. Independent predictive factors for lower creatinine clearance included being female subjects, having a donor aged >50 years, being a recipient aged >50 years, not treated for hypertension at pretransplant, and no post-transplant ESA therapy. High doses of ESA within the first month of kidney transplantation have no impact on anemia or renal function by 1 month post-transplant.

This study assessed the effect of a 3-month course of pegylated interferon-alpha-2a (Peg-IFN-alpha-2a) in 3 liver transplant patients with chronic active hepatitis E. A virological response was sustained for 6 and 5 months in 2 patients after Peg-IFN-alpha-2a therapy was completed. A relapse was observed in the third patient.

Hepatitis C virus (HCV) infection is a blood-borne infection and its prevalence used to be elevated in hemodialysis (HD) patients. Its main mode of contamination relies on nosocomial transmission. HCV infection is frequently associated in HD patients with normal liver enzymes whereas liver histology can display some degree of HCV-related lesions. The assessment of HCV-related lesions, even in HD dialysis patients, can be done via noninvasive tests. After kidney transplantation, HCV-related lesions can worsen; however, in this setting antiviral treatment harbors the risk of acute rejection. Therefore, it is recommended to implement antiviral treatment while the patient is receiving dialysis therapy. In this setting, the rate of viral clearance is usually high. In case of sustained virological response, no relapse occurs after kidney transplantation, despite heavy immunosuppression.