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.

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.

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.

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.

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.

Prevalence of malnutrition in coronavirus disease 19: the NUTRICOV study.

Recent European Society of Parenteral and Enteral Nutrition guidelines highlighted the interest of prevention, diagnosis and treatment of malnutrition in the management of coronavirus disease 19 (COVID-19) patients. The aim of our study was to evaluate the prevalence of malnutrition in patients hospitalised for COVID-19. In a prospective observational cohort study malnutrition was diagnosed according to the Global Leadership Initiative on Malnutrition (GLIM) two-step approach. Patients were divided into two groups according to the diagnosis of malnutrition. Covariate selection for the multivariate analysis was based on P <0·2 in univariate analysis, with a logistic regression model and a backward elimination procedure. A partitioning of the population was realised. Eighty patients were prospectively enrolled. Thirty patients (37·5 %) had criteria for malnutrition. The need for intensive care unit admission (n 46, 57·5 %) was similar in the two groups. Three patients who died (3·75 %) were malnourished. Multivariate analysis exhibited that low BMI (OR 0·83, 95 % CI 0·73, 0·96, P = 0·0083), dyslipidaemia (OR 29·45, 95 % CI 3·12, 277·73, P = 0·0031), oral intake reduction <50 % (OR 3·169, 95 % CI 1·04, 9·64, P = 0·0422) and glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration; CKD-EPI) at admission (OR 0·979, 95 % CI 0·96, 0·998, P = 0·0297) were associated with the occurrence of malnutrition. We demonstrate the existence of a high prevalence of malnutrition in a general cohort of COVID-19 inpatients according to GLIM criteria. Nutritional support in COVID-19 care seems an essential element.

Hepatitis E virus replication in human intestinal cells.

OBJECTIVE: Hepatitis E virus (HEV), one of the most common agent of acute hepatitis worldwide, is mainly transmitted enterically, via contaminated water for HEV genotypes 1 (HEV1) and HEV2, or by eating raw or undercooked infected meat for HEV genotype 3 (HEV3) and HEV4. However, little is known about how the ingested HEV reaches the liver or its ability to replicate in intestinal cells. DESIGN: We developed human primary cultures of small intestine epithelial cells and intestinal explants obtained from small bowel resections. The epithelial cells were also polarised on transwells. Cells were infected with Kernow-p6 strain or clinically derived virions. RESULTS: Primary intestinal cells supported the growth of Kernow-p6 strain and HEV1 and HEV3 clinically derived virions. Polarised enterocytes infected with HEV1 and HEV3 strains released HEV particles vectorially: mostly into the apical compartment with a little basally. Iodixanol density gradient centrifugation of enterocyte-derived HEV virions gave bands at a density of 1.06-1.08 g/cm3, corresponding to that of quasi-enveloped HEV particles. Ribavirin therapy inhibited HEV excretion from the basal surface but not from the apical side of infected human enterocytes. HEV virions also infected intestinal tissue explants. Lastly, HEV RNA and antigen were detected in the intestinal crypts of a chronically infected patient. CONCLUSION: HEV can replicate in intestinal cells and reaches the liver as quasi-enveloped virions.

Ribavirin for Hepatitis E Virus Infection After Organ Transplantation: A Large European Retrospective Multicenter Study.

BACKGROUND: Ribavirin is currently recommended for treating chronic hepatitis E virus (HEV) infection. This retrospective European multicenter study aimed to assess the sustained virological response (SVR) in a large cohort of solid organ transplant (SOT) recipients with chronic HEV infection treated with ribavirin monotherapy (N = 255), to identify the predictive factors for SVR, and to evaluate the impact of HEV RNA mutations on virological response. METHODS: Data from 255 SOT recipients with chronic HEV infection from 30 European centers were analyzed. Ribavirin was given at the median dose of 600 (range, 29-1200) mg/day (mean, 8.6 ± 3.6 mg/kg/day) for a median duration of 3 (range, 0.25-18) months. RESULTS: After a first course of ribavirin, the SVR rate was 81.2%. It increased to 89.8% when some patients were offered a second course of ribavirin. An increased lymphocyte count at the initiation of therapy was a predictive factor for SVR, while poor hematological tolerance of ribavirin requiring its dose reduction (28%) and blood transfusion (15.7%) were associated with more relapse after ribavirin cessation. Pretreatment HEV polymerase mutations and de novo mutations under ribavirin did not have a negative impact on HEV clearance. Anemia was the main adverse event. CONCLUSIONS: This large-scale retrospective study confirms that ribavirin is highly efficient for treating chronic HEV infection in SOT recipients and shows that the predominant HEV RNA polymerase mutations found in this study do not affect the rate of HEV clearance.This large-scale retrospective study that included 255 solid organ transplant recipients confirms that ribavirin is highly efficient for treating chronic hepatitis E virus (HEV) infection and shows that HEV RNA polymerase mutations do not play a role in HEV clearance.

Vectorial Release of Hepatitis E Virus in Polarized Human Hepatocytes.

Hepatitis E virus (HEV) is a common cause of acute viral hepatitis worldwide. Most HEV infections are asymptomatic, but immunocompromised patients infected with HEV genotype 3 (HEV3), HEV4, or HEV7 may develop chronic infections. The HEV particles in stools are naked (nHEV), while those in the serum and culture supernatants (eHEV) are associated with lipids. Hepatocytes are polarized epithelial cells that have basolateral (oriented toward the blood) and apical (oriented toward the bile) exosomal pathways. We isolated a subclone, F2, from the human hepatocarcinoma cell line HepG2/C3A that grew as a polarized monolayer culture and had better HEV production than HepG2/C3A cells. F2 cells cultured on semipermeable collagen inserts and infected basolaterally with nHEV3 released 94.6% of virus particles apically, those infected with eHEV3 released 96.8% apically, and eHEV1-infected cells released 99.3% apically. Transcytosis was not involved. Density gradient centrifugation and NP-40 treatment showed that HEV particles released both apically and basolaterally were lipid associated. The apically released HEV3 and HEV1 particles were six and nine times more infectious than those released basolaterally, respectively. Confocal microscopy indicated that the open reading frame 2 (ORF2) capsid protein colocalized apically with ORF3 virus protein, the apical marker DPP4, and the recycling endosome GTPase Rab27a. The amounts of soluble glycosylated ORF2 secreted apically and basolaterally were similar. These polarized-hepatocyte data suggest that infectious HEV particles are mainly released into bile, while the small fraction released into blood could spread HEV throughout the host.IMPORTANCE Hepatitis E virus (HEV) in stools is naked, while that in culture supernatants and patients' blood is lipid associated. Its life cycle in hepatocytes, polarized cells with a basolateral side communicating with blood and an apical side connected with bile, is incompletely understood. We have developed a polarized hepatocyte model and used the cells to analyze the supernatants bathing the apical and basolateral sides and HEV subcellular distribution. HEV particles from both sides were lipid associated, and most infectious HEV particles left the cell via its apical side. Similar amounts of the open reading frame 2 (ORF2) soluble capsid protein were secreted from both sides of the hepatocytes. This model mimicking physiological conditions should help clarify the HEV cell cycle in polarized hepatocytes.

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.

Direct-acting antivirals and hepatitis B virus (HBV) reactivation in co-infected HBV/HCV kidney-transplant recipients.

Direct-acting agents (DAAs) are highly efficient at treating hepatitis C virus (HCV) infections after kidney transplantation. Although drug agencies have recently warned of the risk of hepatitis B virus (HBV) reactivation after patients have received DAAs, reports have discrepant results in HBsAg-positive and HBsAg-negative patients. We report on 3 cases of HBV reactivation that were detected after achieving a DAA-associated sustained virological response in 3 kidney-transplant recipients initially HBsAg-negative. In the first case, retrospective virological analysis revealed that HBsAgs had become positive and HBV DNA was detectable before initiating DAA therapy. In the second and third cases, HBV reactivation occurred 2 months and more than 1 year after stopping anti-HCV therapy. These cases underline the discrepancies and highlight the need for comprehensive information before making definitive conclusions regarding the causal link between DAAs and HBV reactivation.

[Hepatitis E virus infection]. / Hépatite E.

Hepatitis E virus infection. Hepatitis E virus (HEV) infection is currently recognized as an endemic pathogen in developed countries, especially in Western Europe. In these regions, HEV is a zoonotic agent and is mainly transmitted by the consumption of under cooked pig or game meat. HEV infection is generally a self-limiting illness in immunocompetent subjects. Conversely, in immunocompromised patients, i.e., solid-organ-transplant recipients, human immunodeficiency virus-infected patients with a low CD4 cell count, hematological patients receiving chemotherapy, and patients given immune suppressive therapy, HEV can lead to chronic hepatitis and cirrhosis. In this case, if viral replication persists despite immunosuppressive regimen decrease, ribavirin therapy has to be initiated to allow viral clearance. Recently, some extra-hepatic manifestations associated with HEV infection have been observed, suggesting a broader tropism than initially considered.

Hépatite E. Après avoir été longtemps considéré comme un pathogène d'importation au retour de zones à faible niveau d'hygiène, le virus de l'hépatite E (VHE) est désormais reconnu comme endémique dans de nombreux pays développés. Sa transmission y est alors zoonotique à partir d'un réservoir animalier domestique et sauvage. Le VHE est ainsi la principale cause d'hépatite aiguë d'origine virale en France et en Europe de l'Ouest. Bien que l'infection soit généralement asymptomatique chez les sujets immunocompétents, les patients immunodéprimés, à savoir les transplantés d'organes solides, les patients infestés par le virus de l'immunodéficience humaine avec un taux de lymphocytes CD4 bas, les patients d'oncohématologie traités par chimiothérapie ou les patients recevant une biothérapie immunosuppressive, peuvent développer une infection chronique, avec un risque élevé d'évolution vers la cirrhose. Si la réplication virale persiste malgré la réduction de l'immunosuppression, un traitement par ribavirine doit être instauré. Récemment, des manifestations extrahépatiques associées aux infections par le VHE ont été caractérisées, laissant envisager un tropisme non restreint au compartiment hépatique.

[Hepatitis E virus: from the infected organism to the cellular response]. / Virus de l'hépatite E : de l'organisme infecté à la réponse cellulaire.

Hepatitis E virus (HEV) presents a worldwide distribution. In developing countries, hepatitis E, related to HEV1 and HEV2, is a waterborne disease. In developed countries, hepatitis E is a zoonotic disease due to HEV3 and HEV4. It is mainly transmitted through meat consumption from animal reservoirs such as pig, boar, deer and rabbit. New clinical forms include neurological manifestations that are now clearly associated with HEV3 infection. Recent studies showed that ORF1 polyprotein was able to disrupt the innate immune response. It was also shown that ORF2 protein exists at least in two forms: a free, glycosylated form and a non-glycosylated form, which assembles to form the capsid. Lastly, it was shown that ORF3 protein, involved in the virus egress, acts as a viroporin. New culture systems and animal models have been developed recently, and will be very helpful to complete our understanding of HEV life cycle and pathogenesis.

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.