Kidney Transplantation in Patients With AA Amyloidosis: Outcomes in a French Multicenter Cohort.

RATIONALE & OBJECTIVE: Outcomes of kidney transplantation for patients with renal AA amyloidosis are uncertain, with reports of poor survival and high rates of disease recurrence. However, the data are inconclusive and mostly based on studies from the early 2000s and earlier. STUDY DESIGN: Retrospective multicenter cohort study. SETTING & PARTICIPANTS: We searched the French national transplant database to identify all patients with renal AA amyloidosis who underwent kidney transplantation between 2008 and 2018. EXPOSURES: Age, cause of amyloidosis, use of biotherapies, and C-reactive protein levels. OUTCOMES: Outcomes were all-cause mortality and allograft loss. We also reported amyloidosis allograft recurrence, occurrence of acute rejection episodes, as well as infectious, cardiovascular, and neoplastic disease events. ANALYTICAL APPROACH: Kaplan-Meier estimator for mortality and cumulative incidence function method for allograft loss. Factors associated with patient and allograft survival were investigated using a Cox proportional hazards model and a cause-specific hazards model, respectively. RESULTS: 86 patients who received kidney transplants for AA amyloidosis at 26 French centers were included. The median age was 49.4 years (IQR, 39.7-61.1). The main cause of amyloidosis was familial Mediterranean fever (37 cases; 43%). 16 (18.6%) patients received biotherapy after transplantation. Patient survival rates were 94.0% (95% CI, 89.1-99.2) at 1 year and 85.5% (77.8-94.0) at 5 years after transplantation. Cumulative incidences of allograft loss were 10.5% (4.0-17.0) at 1 year and 13.0% (5.8-20.1) at 5 years after transplantation. Histologically proven AA amyloidosis recurrence occurred in 5 transplants (5.8%). An infection requiring hospitalization developed in 55.8% of cases, and there was a 27.9% incidence of acute allograft rejection. Multivariable analysis showed that C-reactive protein concentration at the time of transplantation was associated with patient survival (HR, 1.01; 95% CI, 1.00-1.02; P=0.01) and allograft survival (HR, 1.68; 95% CI, 1.10-2.57; P=0.02). LIMITATIONS: The study lacked a control group, and the effect of biotherapies on transplantation outcomes could not be explored. CONCLUSIONS: This relatively contemporary cohort of patients who received a kidney transplant for AA amyloidosis experienced favorable rates of survival and lower recurrence rates than previously reported. These data support the practice of treating these patients with kidney transplantation for end-stage kidney disease. PLAIN-LANGUAGE SUMMARY: AA amyloidosis is a severe and rare disease. Kidney involvement is frequent and leads to end-stage kidney disease. Because of the involvement of other organs, these patients are often frail, which has raised concerns about their suitability for kidney transplantation. We reviewed all patients with AA amyloidosis nephropathy who underwent kidney transplantation in France in the recent era (2008-2018) and found that the outcomes after kidney transplantation were favorable, with 85.5% of patients still alive 5 years after transplantation, a survival rate that is comparable to the outcomes of patients receiving a transplant for other forms of kidney diseases. Recurrence of amyloidosis in the transplanted kidney was infrequent (5.8%). These data support the practice of kidney transplantation for patients with AA amyloidosis who experience kidney failure.

Diagnostic and management strategies for chronic hepatitis E infection.

INTRODUCTION: Hepatitis E Virus (HEV) was initially thought to cause only acute infections, but the discovery of chronic hepatitis E in immunocompromised patients has profoundly changed our understanding of the virus. AREAS COVERED: We describe the physiopathology, diagnosis, and clinical management of chronic HEV infection. The virus can persist in nearly two-thirds of immunosuppressed patients. Reducing immunosuppression is the first immunomodulatory strategy to cure chronic hepatitis E. But this may not always be feasible or effective. Ribavirin monotherapy for 3 months has been recommended as first-line treatment for chronically infected patients. Ribavirin is around 80% effective at eradicating HEV in retrospective studies. Apart from ribavirin, interferon has been successfully used in liver transplants recipients, but if the patient does not respond, no other alternative drug is available. The vaccine available to prevent HEV infection is one available only in China. EXPERT OPINION: HEV infection is a major concern in immunocompromised patients. But the therapeutic arsenal is limited to ribavirin and interferon. Both produce several side effects and new drugs are urgently needed. Moreover, preventive strategies to limit HEV transmission and/or evolution to a chronic infection are also required.

Impact of imlifidase treatment on immunoglobulins in an HLA-hypersensitized lupus nephritis patient with anti-SSA/SSB antibodies after kidney transplantation: A case report.

Bacterial recombinant cysteine protease Ides (imlifidase, Idefirix®, Hansa Biopharma) is used to prevent humoral transplant rejection in highly HLA-sensitized recipients, and to control IgG-mediated autoimmune diseases. We report the case of a 51 years old woman suffering from lupus nephritis with end stage kidney disease, grafted for the second time and pre-treated with imlifidase. The patient was HLA-hypersensitized (calculated Panel Reactive Antibodies [Abs], cPRA>99 %) and has three preformed Donor Specific Antibodies (DSA). Circulating immunoglobulins were monitored at initiation (0, 6, 36, 72 and 96 h), and at Ab recovery one and two months following imlifidase injection. From baseline, the higher depletion was reported after 36h for total IgG (-75 %) and IgG subclasses (-87 % for IgG1, IgG2 and IgG3, -78 % for IgG4), while no significant impact on IgA and IgM was observed. Anti-SSA 60 kDa and anti-SSB auto-Abs quickly decreased after imlifidase injection (-96 % for both after 36 h) as well as post-vaccinal specific IgG (-95 % for tetanus toxoid, -97 % for pneumococcus and -91 % for Haemophilus influenzae Abs after 36 h). At the Ab recovery phase, total IgG and anti-SSA60/SSB Abs reached their initial level at two months. Regarding alloreactive Abs, anti-HLA Abs including the three DSA showed a dramatic decrease after injection with 100 % depletion from baseline after 36 h as assessed by multiplex single bead antigen assay, leading to negative crossmatches using both lymphocytotoxicity (LCT) and flow cell techniques. DSA rebound at recovery was absent and remained under the positivity threshold (MFI = 1000) after 6 months. The findings from this case report are that imlifidase exerts an early depleting effect on all circulating IgG, while IgG recovery may depend in part from imlifidase's capacity to target memory B cells.

[Infectious risks after solid organ transplantation]. / Risques infectieux après transplantation d'organes solides.

INFECTION AFTER SOLID-ORGAN-TRANSPLANTATION. Infections is one the most cause for hospitalization after solid-organ-transplantation. We distinguish donor-derived infections, reactivation of latent infection in recipients, nosocomial infections and community infections. The first three types are observed mainly in the early period post-transplantation, while community infections can occur at any time after transplantation. Opportunistic infections and some specific infections should be assessed systematically and rapidly. This often requires invasive diagnostic procedures. Prevention altered the incidence and severity of post-transplant infections. It included vaccination, use of universal prophylaxis, systematic monitoring of some agents after transplantation and safer living.

RISQUES INFECTIEUX APRÈS TRANSPLANTATION D'ORGANES SOLIDES. Les infections sont une des premières causes d'hospitalisation après transplantation d'organes solides. On distingue celles liées au donneur, celles dues à une réactivation d'une infection latente chez le receveur, les infections nosocomiales et les infections communautaires. Les trois premières sont observées le plus souvent dans une période précoce suivant la transplantation, alors que les infections communautaires peuvent survenir à tout moment. Les infections opportunistes et certaines infections spécifiques doivent être systématiquement recherchées, rapidement et activement, en ayant recours, si nécessaire, à des méthodes invasives. La prévention permet de diminuer significativement l'incidence et la sévérité des infections. Elle comprend la vaccination, la prophylaxie universelle, la surveillance régulière et les précautions en rapport avec le mode de vie.

Humoral and Cellular Responses to a Delayed Fourth SARS-CoV-2 mRNA-Based Vaccine in Weak Responders to 3 Doses Kidney Transplant Recipients.

While kidney transplant recipients (KTRs) represent a high-risk population for severe SARS-CoV-2 infection, almost half of them do not develop adequate levels of antibodies conferring clinical protection despite 3 doses of the mRNA vaccine. In the present study we retrospectively analyzed the humoral and cellular responses resulting from a fourth dose of vaccine administered to KTRs having an anti-SARS-CoV-2 antibody titer below 142 binding antibody unit (BAU)/mL at 3 months post-third-dose. We observed a significant increase in anti-SARS-CoV-2 antibody concentration from 6.1 (Q1 4.3; Q3 12.7) BAU/mL on the day of the fourth dose to 1054.0 (Q1 739.6; Q3 1649.0) BAU/mL one month later (p = 0.0007), as well as neutralizing antibody titers (from 0.0 (Q1 0.0; Q3 2.0) to 8 (4; 16) IU/mL, p = 0.01) and CD3+ T cell response (from 37.5 (Q1 12.5; Q3 147.5) to 170.0 (Q1 57.5; Q3 510.0) SFUs per 106 PBMCs, p = 0.001). Hence, delaying the fourth dose seems to improve vaccine immunogenicity in KTRs, compared with previously reported data obtained in respect of a fourth dose one month after the third dose. Nevertheless, antibody concentrations seem to remain insufficient to confer clinical protection, especially for Omicron, for which breakthrough infections occur even at very high concentrations.

Can the COVID-19 Pandemic Improve the Management of Solid Organ Transplant Recipients?

Increased mortality due to SARS-CoV-2 infection was observed among solid organ transplant patients. During the pandemic, in order to prevent and treat COVID-19 infections in this context, several innovative procedures and therapies were initiated within a short period of time. A large number of these innovations can be applied and expanded to improve the management of non-COVID-19 infectious diseases in solid organ transplant patients and in the case of a future pandemic. In this vein, the present paper reviews and discusses medical care system adaptation, modification of immunosuppression, adjuvant innovative therapies, the role of laboratory expertise, and the prevention of infections as examples of such innovations.

Humoral and Cellular Immune Responses of Solid Organ Transplant Patients on Belatacept to Three Doses of mRNA-Based Anti-SARS-CoV-2 Vaccine.

BACKGROUND: Two doses of anti-SARS-CoV-2 mRNA-based vaccines are poorly immunogenic in solid organ transplant recipients (SOT). METHODS: In total, 68 belatacept-treated SOT recipients followed at the Toulouse University Hospital were investigated. They were given three injections of the BNT162b2 mRNA COVID-19 vaccine. Their humoral response was assessed by determining anti-spike antibodies and neutralizing antibodies. The T-cell responses were assessed using an enzyme-linked immunospot assay that measured the interferon-γ produced by specific SARS-CoV-2 T-cells in a subgroup of 17 patients. RESULTS: Only 23.5% of these patients developed a detectable anti-spike response. Moreover, the cellular and the humoral responses were well correlated. Patients with no humoral response were also without a detectable cellular response. Those belatacept-treated patients who developed an Anti-SARS-CoV-2 humoral response were younger, had been transplanted for longer, and had a higher lymphocyte count and a better glomerular filtration rate than those with no response. Finally, patients on tacrolimus plus belatacept produced a lower immune response. CONCLUSIONS: Belatacept-treated SOT recipients have a reduced immune response to anti-SARS-CoV-2 mRNA vaccination. The vaccine should be given quite separately from the belatacept infusion to improve immunogenicity. Studies to assess whether switching to another immunosuppressive regimen can improve the post-vaccination immune response would be useful.

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.

Predictive Factors for Humoral Response After 2-dose SARS-CoV-2 Vaccine in Solid Organ Transplant Patients.

BACKGROUND: A weak immunogenicity has been reported in solid organ transplant (SOT) recipients after 2 doses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. The aim of this retrospective study was to identify the predictive factors for humoral response in SOT patients. METHODS: Three hundred and ninety-three SOT patients from our center with at least 4 wk of follow-up after 2 doses of mRNA-based vaccine were included in this study. Anti-SARS-Cov-2 spike protein antibodies were assessed before and after vaccination. RESULTS: Anti-SARS-CoV-2 antibodies were detected in 34% of the patients: 33.7% of kidney transplant patients, 47.7% of liver transplant patients, and 14.3% of thoracic transplant patients (P = 0.005). Independent predictive factors for humoral response after vaccination were male gender, a longer period between transplantation and vaccination, liver transplant recipients, a higher lymphocyte count at baseline, a higher estimated glomerular filtration rate and receiving the tacrolimus + everolimus ± steroids combination. Conversely, the nondevelopment of anti-SARS-CoV-2 antibodies after vaccination was associated with younger patients, thoracic organ recipients, induction therapy recipients, and tacrolimus + mycophenolic acid ± steroids recipients. CONCLUSIONS: The immunosuppressive regimen is a modifiable predictive factor for humoral response to SARS-CoV-2 vaccine.

Hemodynamic and Metabolic Tolerance of Acetate-Free Biofiltration in Mechanically Ventilated Critically Ill Patients: A Real-Life Study.

Intradialytic hypotension can lead to superimposed organ hypoperfusion and ultimately worsens long-term kidney outcomes in critically ill patients requiring kidney replacement therapy. Acetate-free biofiltration (AFB), an alternative technique to bicarbonate-based hemodialysis (B-IHD) that does not require dialysate acidification, may improve hemodynamic and metabolic tolerance of dialysis. In this study, we included 49 mechanically ventilated patients requiring 4 h dialysis (AFB sessions n = 66; B-IHD sessions n = 62). Whereas more AFB sessions were performed in patients at risk of hemodynamic intolerance, episodes of intradialytic hypotension were significantly less frequent during AFB compared to B-IHD, whatever the classification used (decrease in mean blood pressure ≥ 10 mmHg; systolic blood pressure decrease >20 mmHg or absolute value below 95 mmHg) and after adjustment on the use of vasoactive agent. Diastolic blood pressure readily increased throughout the dialysis session. The use of a bicarbonate zero dialysate allowed the removal of 113 ± 25 mL/min of CO2 by the hemofilter. After bicarbonate reinjection, the global CO2 load induced by AFB was +25 ± 6 compared to +80 ± 12 mL/min with B-IHD (p = 0.0002). Thus, notwithstanding the non-controlled design of this study, hemodynamic tolerance of AFB appears superior to B-IHD in mechanically ventilated patients. Its use as a platform for CO2 removal also warrants further research.

Adaptive lymphocyte profile analysis discriminates mild and severe forms of COVID-19 after solid organ transplantation.

Solid organ transplant recipients are at high risk for the development of severe forms of COVID-19. However, the role of immunosuppression in the morbidity and mortality of the immune phenotype during COVID-19 in transplant recipients remains unknown. In this retrospective study, we compared peripheral blood T and B cell functional and surface markers, as well as serum antibody development during 29 cases of mild (World Health Organization 9-point Ordinal Scale (WOS) of 3-4) and 22 cases of severe COVID-19 (WOS 5-8) in solid organ transplant (72% kidney transplant) recipients hospitalized in our center. Patients who developed severe forms of COVID-19 presented significantly lower CD3+ (median 344/mm3 (inter quartile range 197; 564) vs. 643/mm3 (397; 1251)) and CD8+ T cell counts (124/mm3 (76; 229) vs. 240/mm3 (119; 435)). However, activated CD4+ T cells were significantly more frequent in severe forms (2.9% (1.37; 5.72) vs. 1.4% (0.68; 2.35)), counterbalanced by a significantly higher proportion of Tregs (3.9% (2.35; 5.87) vs. 2.7% (1.9; 3.45)). A marked decrease in the proportion of NK cells was noted only in severe forms. In the B cell compartment, transitional B cells were significantly lower in severe forms (1.2% (0.7; 4.2) vs. 3.6% (2.1; 6.2)). Nonetheless, a majority of transplant recipients developed antibodies against SARS-CoV-2 (77% and 83% in mild and severe forms, respectively). Thus, our data revealed immunological differences between mild and severe forms of COVID-19 in solid organ transplant recipients, similar to previous reports in the immunocompetent population.

High immunogenicity of a messenger RNA-based vaccine against SARS-CoV-2 in chronic dialysis patients.

BACKGROUND: Patients with chronic kidney disease, dialysis patients and kidney transplant patients are at high risk of developing severe coronavirus disease 2019 (COVID-19). Data regarding the immunogenicity of anti-severe acute respiratory syndrome coronavirus 2 messenger RNA (anti-SARS-CoV-2 mRNA) vaccines in dialysis patients were published recently. We assessed the immunogenicity of anti-SARS-CoV-2 mRNA vaccine in dialysis patients. PATIENTS AND METHODS: One hundred and nine patients on haemodialysis (n = 85) or peritoneal dialysis (n = 24) have received two injections of 30-µg doses of BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech) that were administered intramuscularly 28 days apart. Those who were still seronegative after the second dose were given a third dose 1 month later. Anti-SARS-CoV-2 antibodies were tested before and after vaccination. RESULTS: Ninety-one out of the 102 patients who had at least a 1-month follow-up after the second (n = 97) or the third (n = 5) vaccine doses had anti-SARS-CoV-2 antibodies. The seroconversion rate was 88.7% (86 out of 97 patients) among SARS-CoV-2 seronegative patients at the initiation of vaccination. Receiving immunosuppressive therapy was an independent predictive factor for non-response to vaccination. CONCLUSION: Due to high immunogenicity and safety of mRNA vaccines, we strongly recommend prioritizing a two-dose vaccination of dialysis patients. A third dose can be required in non-responders to two doses. When possible, patients waiting for a kidney transplantation should be offered the vaccine before transplantation.