Adaptative Strategy of Immunosuppressive Drugs Dosage Adjustments When Combined With Nirmatrelvir/Ritonavir in Solid Organ Transplant Recipients With COVID-19.

Nirmatrelvir/ritonavir is a promising option for preventing severe COVID-19 in solid organ transplant recipients with SARS-CoV-2 infection. However, concerns have arisen regarding potential drug interactions with calcineurin inhibitors (CNI). This two-phase multicentre retrospective study, involving 113 patients on tacrolimus and 13 on cyclosporine A, aimed to assess the feasibility and outcomes of recommendations issued by The French societies of transplantation (SFT) and pharmacology (SFPT) for CNI management in this context. The study first evaluated adherence to recommendations, CNI exposure, and clinical outcomes. Notably, 96.5% of patients on tacrolimus adhered to the recommendations, maintaining stable tacrolimus trough concentrations (C0) during nirmatrelvir/ritonavir treatment. After reintroduction, most patients experienced increased C0, with 42.9% surpassing 15 ng/mL, including three patients exceeding 40 ng/mL. Similar trends were observed in cyclosporine A patients, with no COVID-19-related hospitalizations. Moreover, data from 22 patients were used to refine the reintroduction strategy. Modelling analyses suggested reintroducing tacrolimus at 50% of the initial dose on day 8, and then at 100% from day 9 as the optimal approach. In conclusion, the current strategy effectively maintains consistent tacrolimus exposure during nirmatrelvir/ritonavir treatment, and a stepwise reintroduction of tacrolimus may be better suited to the low CYP3A recovery.

Anti-SARS-CoV-2 spike protein and neutralizing antibodies at 1 and 3 months after three doses of SARS-CoV-2 vaccine in a large cohort of solid organ transplant patients.

The immunogenicity of the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccine was improved by the administration of a third dose. The aim of our retrospective study was to assess the evolution of binding and neutralizing antibody concentration until 3 months after the third dose in a large cohort of solid organ transplant (SOT) patients (n = 872). At 1 month after the third dose, anti-SARS-CoV-2 antibodies were detected by means of enzyme-linked immunosorbent assay tests in 578 patients (66.3%). In a subgroup of patients, 70% (180 out of 257) had anti-SARS-CoV-2 antibody concentrations ranging from 1.2 to 18 411 binding antibody units (BAU)/ml and 48.5% (115 out of 239) had a neutralizing antibodies titer that can confer clinical protection against SARS-CoV-2. Three-hundred ninety-three patients out of the 416 (94.5%) who were seropositive at month 1 and were tested at 3 months after vaccination remained seropositive. Between months 1 and 3 after vaccination, binding and neutralizing antibodies concentrations decreased significantly. The proportion of protected patients against the SARS-CoV-2 also slightly decreased. In conclusion, this study shows that although two-third of SOT develop anti-SARS-CoV-2 antibodies after three doses, one-third of them remain weak or non-protected. It is important to measure anti-SARS-CoV-2 antibodies to define the strategy that can optimize SOT protection against SARS-CoV-2.

Do anti-IL-6R blockers have a beneficial effect in the treatment of antibody-mediated rejection resistant to standard therapy after kidney transplantation?

Antibody-mediated rejection (AMR) that resists to standard of care (SOC) therapy remains a major challenge after kidney transplantation and leads to graft failure in a majority of cases. The use of anti-IL6 receptor antibodies was suggested to treat chronic antibody-mediated rejection (cAMR) after failure of classical treatments. We treated nine patients with AMR resistant to apheresis, rituximab, and intravenous immunoglobulins, with a monthly infusion of tocilizumab and compared them with a historical cohort of 37 patients with similar clinical, immunological, and histological characteristics. The 1-year graft survival and the decline in renal function did not differ between patients who received tocilizumab and those who did not. Histological follow-up showed that despite a decrease in inflammation and tubulitis scores after tocilizumab, the course of antibody-mediated lesions and chronic glomerulopathy were similar in both groups. In our study, the addition of monthly infusions of tocilizumab did not alter the course of AMR that resist to SOC therapy. Large randomized studies are urgently needed to assess the effect of tocilizumab in this context.

Therapeutic education as a tool to improve patient-reported and clinical outcomes after renal transplantation: results of the EPHEGREN multicenter retrospective cohort study.

Patients are not always aware of the inconveniences associated with renal transplantation, which they compare with a « rebirth ¼, and from which they expect complete recovery. Therapeutic education is proposed to prepare patients for their life after transplantation. This study evaluated the impact of pretransplant therapeutic education on patient-reported outcomes and rejection-free survival over the first year. We collected data from 383 renal transplant patients followed-up in seven centers. Patients who benefited from therapeutic education before transplantation (N = 182) were compared with patients who did not (N = 139) for quality-of-life, adherence and adverse events using the Pearson's chi-square test, one-way ANOVA or t-test. The association between therapeutic education and time to acute rejection was investigated using Cox models. The patients who benefited from therapeutic education reported adverse events less frequently (e.g., tremor: 9% vs. 32.4%, P = 0.01) and better quality-of-life (MCS-QOL: 50.7 ± 8.1 vs. 47.7 ± 9.5, P = 0.02; PCS-QOL: 49.1 ± 7.1 vs. 46.0 ± 9.2, P = 0.013). No difference was found on adherence. Rejection-free survival was slightly better in the therapeutic education group (HR = 0.44, 95% CI = [0.19-1.01]). This multicenter retrospective cohort study suggests that integrating therapeutic education to care pathways entails clinical benefit, in terms of quality-of-life, self-reported adverse events and rejection-free survival. Randomized clinical trials are necessary to confirm this.

Outcomes of solid organ transplant recipients with invasive aspergillosis and other mold infections.

OBJECTIVES: To characterize the clinical presentation and outcomes of invasive mold infections (IMI) in solid organ transplant (SOT) recipients. METHODS: Inclusion of all SOT recipients with IMI diagnosed between 2008 and 2016 at a referral center for SOT. Univariable analyses identified factors associated with death at one year, and logistic regression models retained independent predictors. RESULTS: Of the 1739 patients that received a SOT during this period, 68 developed IMI (invasive aspergillosis [IA] in 58). Cumulative incidence of IMI at 1 year ranged from 1.2% to 18.8% (kidney and heart transplantation, respectively). At baseline, compared with other IMI, the need for vasoactive drugs was more frequent in patients with IA. During follow-up, 35 patients (51%) were admitted to the ICU and required mechanical ventilation (n = 27), vasoactive drugs (n = 31), or renal replacement therapy (n = 31). The need for vasoactive drugs (OR 7.34; P = .003) and a positive direct examination (OR 10.1; P = .004) were independently associated with the risk of death at 1 year in patients with IA (n = 33; 57%) CONCLUSIONS: Characteristics of IMI at presentation varied according to the underlying transplanted organ and the mold species. Following IA, one-year mortality may be predicted by the need for hemodynamic support and initial fungal load.

Anti-IL-2R blockers comparing with polyclonal antibodies: Higher risk of rejection without negative mid-term outcomes after ABO-incompatible kidney transplantation.

There is no recommendation regarding the type of induction therapy to use in ABO-incompatible (ABOi) kidney transplantation. The aim of this retrospective study was to compare the outcome of ABOi living donor kidney transplant (LDKT) recipients who received either polyclonal antibodies or anti-interleukin-2 receptor (IL-2R) blockers as an induction agent. All ABOi HLA-compatible patients that received a LDKT between 03/11 and 03/18 in three French transplantation center (Paris Saint-Louis, Paris Necker, and Toulouse) were included in the study. Fifty-eight patients were given polyclonal antibodies and 39 patients received anti-IL-2R blockers. We identified by a Cox proportional hazard model the use of polyclonal antibodies as a protective factor against acute rejection (HR = 0.4, 95%CI [0-0.9], P < .05). However, pathological findings on protocol biopsies at 1 year were similar in both groups, as were patient and graft survivals, renal function, and complications. We conclude that the acute rejection rate was significantly higher in patients given anti-IL-2R blockers compared to polyclonal antibodies. However, in our series, there was no negative impact on mid-term outcome.

Outcomes of kidney transplant recipients admitted to the intensive care unit: a retrospective study of 200 patients.

BACKGROUND: Risk of over-immunosuppression or immunization may mitigate the overall and long-term renal outcomes of kidney transplant recipients (KTR) admitted to the ICU in the modern era but remain poorly described. Thus, there is an unmet need to better characterize the survival of KTR admitted to the ICU, but also the renal and immunological outcomes of survivors. METHODS: Retrospective observational study that included 200 KTR admitted between 2010 and 2016 to the ICU of a teaching hospital (median age 61 years [IQR 50.7-68]; time from transplantation 41 months [IQR 5-119]). Survival curves were compared using the Log-rank test. RESULTS: Mortality rates following admission to the ICU was low (26.5% at month-6), mainly related to early mortality (20% in-hospital), and predicted by the severity of the acute condition (SAPS2 score) but also by Epstein Barr Virus proliferation in the weeks preceding the admission to the ICU. Acute kidney injury (AKI) was highly prevalent (85.1%). Progression toward chronic kidney disease (CKD) was observed in 45.1% of survivors. 15.1% of survivors developed new anti-HLA antibodies (donor-specific antibodies 9.2% of cases) that may impact the long-term renal transplantation function. CONCLUSIONS: Notwithstanding the potential biases related to the retrospective and monocentric nature of this study, our findings obtained in a large cohort of KTR suggest that survival of KTR admitted in ICU is good but in-ICU management of these patients may alter both survival and AKI to CKD transition, as well as HLA immunization. Further interventional studies, including systematic characterization of the Epstein Barr virus proliferation at the admission (i.e., a potential surrogate marker of an underlying immune paralysis and frailty) will need to address the optimal management of immunosuppressive regimen in ICU to improve survival but also renal and immunological outcomes.

Hepatitis E virus-associated cryoglobulinemia in solid-organ-transplant recipients.

BACKGROUND & AIMS: An association between hepatitis E virus (HEV) infection and cryoglobulinemia has been suggested. The aims of this study were to assess the prevalence of cryoglobulinemia during HEV infection in solid-organ-transplant (SOT) recipients, to describe its outcomes under ribavirin therapy and to evaluate its effects on kidney function and histology. METHODS: Between November 2005 and June 2016, 128 cases of HEV infection were diagnosed among SOT recipients followed in our institution. Cryoglobulinemia data obtained from 66 patients during acute-phase HEV and 51 patients during chronic-phase HEV were compared to a historical control group of 89 SOT recipients without HEV markers. Cryoglobulins were also monitored in a group of 43 patients treated by ribavirin. RESULTS: The prevalence of cryoglobulinemia was increased in HEV-infected SOT patients during a chronic phase (52.9%) compared to HEV-infected SOT patients at acute phase (36.4%) (P = .1) and to HEV-negative SOT patients (23.6%) (P < .001). HEV infection was identified as an independent predictive factor for cryoglobulinemia (OR 2.3, CI 95%: 1.17-4.55, P = .02). After ribavirin therapy and HEV clearance, the prevalence of cryoglobulin was significantly decreased from 53.5% to 20.9% (P = .003). Kidney function was significantly worse and proteinuria tended to be higher in chronically HEV-infected patients with cryoglobulinemia compared to those without cryoglobulinemia. Membranoproliferative glomerulonephritis was diagnosed in 2 patients, of which 1 had detectable cryoglobulinemia. CONCLUSIONS: In conclusion, a relationship between HEV and cryoglobulin formation seems to exist. However, the clinical impact of cryoglobulinemia in SOT patients infected with HEV has to be confirmed.

Impact of donor BK polyomavirus replication on recipient infections in living donor transplantation.

BACKGROUND: Multiple risk factors for BK polyomavirus (BKPyV) replication after kidney transplantation have been described. Here, we investigated the impact of living donors' urinary BKPyV shedding and recipients' BKPyV antibody status pre-transplant on BKPyV replication during the first year post-transplantation. METHODS: We assessed a cohort of living kidney donors and their paired recipients (n = 121). All donors were tested before transplantation, and recipients were tested before and after transplantation for BKPyV viruria and viremia. BKPyV-specific serology was assessed in all recipients at transplantation. RESULTS: Ten of 121 donors (8.3%) had urinary BKPyV shedding pre-transplant, none had viremia. Overall, 33 (27.3%) recipients developed viruria after transplantation: 7 had received a kidney from a donor with BK viruria (7/10 positive donors) and 26 had received a kidney from a donor without BK viruria (26/111 negative donors; P = .0015). Fifteen (12.4%) recipients developed BK viremia after transplantation: 3 received a kidney from a donor with viruria (3/10 positive donors, 30%) and 12 received a kidney from a donor without viruria (12/111 negative donors, 11%; P = .08). One patient developed proven nephropathy. Ninety-one percent of recipients were seropositive for BKPyV. No relationship between recipients' sero-reactivity at transplantation and post-transplant BKPyV replication was observed. Pre-transplant donor urinary shedding was an independent risk factor for post-transplant BKPyV replication. CONCLUSION: Screening living kidney donors for BKPyV can identify recipients at higher risk for BKPyV replication after transplantation who may benefit from intensified post-transplant screening and treatment strategies.

Impact of transplant accessibility for sensitized patients by avoiding unacceptable antigens.

Recent data have confirmed the negative impact of preformed donor-specific antibodies (pDSAs) after liver transplantation (LT). In order to reduce the risk of developing lesions associated with acute and chronic antibody-mediated rejection in LT recipients, we evaluated the consequences in terms of transplant accessibility, associated with avoiding pDSAs according to several mean fluorescence intensity (MFI) titer thresholds that have been previously reported to be relevant in LT. Among the 484 included LT candidates, 99 (20.5%) presented with anti-human leukocyte antibodies (HLAs). The predictive factors for anti-HLA sensitization were a history of previous kidney transplantation (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.30-1.9; P = 0.05), a history of previous LT (OR, 1.9; 95% CI, 1.6-2.1; P = 0.01), a history of blood transfusion (OR, 2.5; 95% CI, 2.2-4.1; P = 0.01), and a history of pregnancy (OR, 2.9; 95% CI, 2.4-3.3; P = 0.04). By applying a strategy of unacceptable mismatches for recipients with an antibody (Ab) MFI of > 5000, only 35 patients were affected (7% of the cohort), but 22 of these (63%) would have been considered incompatible with >50% of the donors. Using a MFI threshold of >10,000, only 16 patients were affected (1.4% of the cohort), but half of these would have been considered incompatible with >50% of the proposed donors. Considering only those with anti-class II Ab and a MFI >5000 and >10,000, respectively, 10/14 and 4/8 patients were considered incompatible with >50% of the donors. In conclusion, avoiding pDSAs affects a small but not negligible proportion of LT candidates. However, in these sensitive patients, avoiding pDSAs has the potential to significantly reduce the donor pool and, consequently, transplant accessibility. Liver Transplantation 23 880-886 2017 AASLD.

Pregnancy outcomes in simultaneous pancreas and kidney transplant recipients: a national French survey study.

Simultaneous pancreas and kidney transplantation (SPK) is currently the best therapeutic option for patients with type 1 diabetes and terminal renal failure. Renal transplantation restores fertility enabling women to pursue pregnancies. However, scarcity of available data on pregnancy outcomes in SPK impedes fair medical counseling. Medical files of all pregnancies that lasted ≥3 months among recipients of functional SPK performed between 1990 and 2015 in France were retrospectively analyzed. Twenty-six pregnancies in 22 SPK recipients were identified. Main maternal complications included gestational hypertension (53.8%) and infections (50%). Cesarean section was performed in 73% of cases. Overall fetal survival was 92.6% with a mean gestational age of 34.2 ± 3 weeks. Four children (16.7% of live births) had a birth weight <10th percentile. Endocrine pancreas graft function remained stable during pregnancy. An acute kidney rejection occurred in two patients, one of which resulting in graft loss. Kidney and pancreas graft survival was, respectively, 96% and 100% at 1 year postconception and did not differ from controls. Pregnancy in SPK is feasible, but patients should be informed of the risks for the fetus, the mother, and the grafts. Planning of pregnancy in SPK women is key to allow a personalized multidisciplinary monitoring, which represents the most straightforward approach to optimize outcomes.

Malignancies in hepatitis C virus-positive and -negative kidney transplant recipients: A case-controlled study.

BACKGROUND: Malignancies and lymphoma are common complications after kidney transplantation. However, no link has been made between the incidence of malignancies and hepatitis C virus (HCV) infection in this setting. This case-controlled study compared the incidence of malignancies, including lymphoma, between kidney transplant (KT) patients with or without HCV replication. PATIENTS AND METHODS: A total of 99 HCV-positive RNA-positive KT patients were matched with 198 (1:2) anti-HCV-negative patients according to age, gender, and date of transplantation, and were followed for 145.8±78.4 months. RESULTS: During the follow-up period, 28 HCV-positive (28%) cases developed at least one cancer, and 64 (32%) patients developed cancer in the HCV-negative group (P=not significant [ns]). Survival without a cancer was similar between both groups. Thirteen HCV-positive patients (13%) developed at least one solid cancer vs 29 (15%) HCV-negative patients (P=ns). Survival without a solid cancer was similar between both groups. Three patients from the HCV-positive and 4 from the HCV-negative group developed a lymphoma. Only 2 patients from the HCV group died from hepatocellular carcinoma. Survival without a skin cancer was similar between both groups. Patient and death-censored graft survival rates were significantly lower in the HCV group. CONCLUSION: The incidences and types of malignancies were similar in the HCV-positive and HCV-negative KT patients.

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

BACKGROUND AND AIM: 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. METHOD: Herein, we describe nine cases of aAMR that occurred in our liver-transplant center between 2008 and 2016, with an initial and reevaluation liver biopsy available for reexamination. RESULTS: Two patients presented with aAMR at 10.5 (10, 11) days post-transplantation, caused by preformed donor-specific antibodies. Seven other recipients developed de novo donor-specific antibodies and aAMR at 11.2 (3-24) months post-transplantation. Eight of the nine patients received a B-cell targeting agent (rituximab, with or without plasma exchange), associated with polyclonal antibodies (three patients) or intravenous immunoglobulins (three patients). At the last follow up (i.e. 21 [4-90] months post-aAMR), seven patients were alive, including two patients with normal liver tests. Grafts' survival was 66%. A liver biopsy performed at 11.5 (5-48.5) months after the first biopsy showed no significant improvement in aAMR score (from 2 ± 1.3 to 1.6 ± 1.5, P = 0.6), a significant improvement in chronic AMR score (from 37 ± 9 to 25 ± 8, P = 0.003) and an increase in the Metavir score (1.2 ± 0.6 to 2.1 ± 0.9, P = 0.03). CONCLUSION: In this study, a B-cell-depleting agent seemed to improve the prognosis of aAMR in selected cases, but several patients kept active lesions antibody-mediated rejection.

Pilot conversion trial from mycophenolic acid to everolimus in ABO-incompatible kidney-transplant recipients with BK viruria and/or viremia.

Immunosuppression using everolimus (EVR) plus low-dose tacrolimus (Tac) is commonly used in organ transplantation. EVR has potential antiviral effects. Herein, the long-term outcomes and impacts of Tac-EVR on the BK virus are reported in ABO-incompatible kidney-transplant recipients. The initial immunosuppressive regimen combined steroids, Tac, and mycophenolic acid (MPA). At a median of 141 (34-529) days post-transplantation, seven stable ABO-incompatible kidney-transplant recipients were converted from MPA to EVR because of active BK replication, and compared with a reference group of fourteen ABO-incompatible patients receiving classical Tac plus MPA. At 1 month before conversion, at 1, 3 months after, and at last follow-up, clinical and biological parameters were monitored. The median time from conversion to the last follow-up was 784 (398-866) days. Conversion to EVR caused no change to rejection episodes or immunological status (isoagglutinin titers, anti-HLA antibodies). At last follow-up, median eGFR was similar in the Tac-MPA versus Tac-EVR group (40 [range: 14-56] vs. 54.5 ml/min/1.73 m(2) [range: 0-128], P = 0.07). The major adverse event was dyslipidemia. Interestingly, conversion from MPA to EVR decreased BK viral load in five patients. ABO-incompatible kidney-transplant recipients with an active BK virus infection may benefit from conversion to EVR.

[Therapeutic education in the transplant patient's pathway]. / L'éducation thérapeutique dans le parcours du patient greffé.

The success of a transplant in the long term depends to a large extent on the taking of immunosuppressant treatments and its follow-up. Therapeutic education plays an important role in the follow-up of transplant patients and in nurses' daily practice. It is integrated into the patient's pre-transplant care.