Rituximab has shown encouraging results for the treatment of kidney transplantation recipients with focal segmental glomerulosclerosis (FSGS) recurrence. However, the correct, opportune, and safe use ...of rituximab for this indication remains to be determined.
This multicenter retrospective study reports on 19 new cases aged 35 (15-66) years who developed FSGS recurrence at 12 (1.5-27) days posttransplantation. Initial treatment consisted of plasma exchanges (PE), high doses of calcineurin inhibitors, and steroids. Rituximab was introduced either immediately (N = 6) or after failure of the initial treatment (N = 10) or failed attempted weaning from PE (N = 3).
Overall, we observed 9 of 19 complete remissions and 3 of 19 partial remissions. Estimated glomerular filtration rates (Modification of Diet in Renal Disease 4) were significantly higher in the responding patients than in nonresponding patients at month (M)12, M36, and M60. Overall, kidney survival at 5 years was 77.4% (95% range, 41.9-92.7). The 5-year graft survival rates in the responding patients and the nonresponding patients were 100% and 36.5%, respectively (P = 0.01). A further course of rituximab was required for 4 patients as a result of FSGS relapse, with good results. During the first year after renal transplantation, 14 patients developed severe infections (16 bacterial, 4 viral, 1 parasitic).
In kidney transplantation recipients with recurrent FSGS, rituximab therapy may be a recommended treatment for cases that have failed either the initial treatment or weaning from PE.
BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) is one of the major causes of kidney graft dysfunction, and there are no BKPyV-specific antiviral therapies available. BKPyV neutralizing ...antibodies (NAbs) play key roles in protecting against BKPyV replication and represent a potential therapeutic or preventive strategy. In this study, we evaluated NAb titers in intravenous immunoglobulin (i.v. Ig) preparations and in kidney transplant recipients (KTR) before and after i.v. Ig administration. NAb titers directed against major BKPyV genotypes were measured using a BKPyV pseudovirion system. Thirty-three KTR receiving high (1 g/kg of body weight/day;
= 17) or low (0.4 g/kg/day;
= 16) i.v. Ig doses were included. Median NAb titers in i.v. Ig preparations ranged from 5.9 log
50% inhibitory concentration (IC
) for genotype I to 4.1 log
IC
for genotype IV. A mean of 90% of patients (range, 88% to 100%) displaying low or negative BKPyV NAb titers against genotype I reached 4 log
IC
after the first i.v. Ig administration. This value was reached by a mean of 44% (range, 13% to 83%) and 19% (range, 0% to 38%) of patients against genotype II and genotype IV, respectively. The benefit of i.v. Ig administration persisted until the following course of treatment (day 22 ± 7 days) for genotypes I and II, and no cumulative effect was observed through the three doses. Our findings demonstrate that i.v. Ig administration results in a significant increase in BKPyV NAb titers in KTR. These
and
pharmacokinetic data provide the rationale for a proof-of-concept study investigating the efficacy of i.v. Ig for the prevention of BKPyV infection in KTR.
The identity of histocompatibility loci, besides human leukocyte antigen (HLA), remains elusive. The major histocompatibility complex (MHC) class I MICA gene is a candidate histocompatibility locus. ...Here, we investigate its role in a French multicenter cohort of 1,356 kidney transplants. MICA mismatches were associated with decreased graft survival (hazard ratio (HR), 2.12; 95% confidence interval (CI): 1.45-3.11; P < 0.001). Both before and after transplantation anti-MICA donor-specific antibodies (DSA) were strongly associated with increased antibody-mediated rejection (ABMR) (HR, 3.79; 95% CI: 1.94-7.39; P < 0.001; HR, 9.92; 95% CI: 7.43-13.20; P < 0.001, respectively). This effect was synergetic with that of anti-HLA DSA before and after transplantation (HR, 25.68; 95% CI: 3.31-199.41; P = 0.002; HR, 82.67; 95% CI: 33.67-202.97; P < 0.001, respectively). De novo-developed anti-MICA DSA were the most harmful because they were also associated with reduced graft survival (HR, 1.29; 95% CI: 1.05-1.58; P = 0.014). Finally, the damaging effect of anti-MICA DSA on graft survival was confirmed in an independent cohort of 168 patients with ABMR (HR, 1.71; 95% CI: 1.02-2.86; P = 0.041). In conclusion, assessment of MICA matching and immunization for the identification of patients at high risk for transplant rejection and loss is warranted.
Abstract
Background
Neurological manifestations are common in patients with coronavirus disease 2019 (COVID-19), but little is known about pathophysiological mechanisms. In this single-center study, ...we examined neurological manifestations in 58 patients, including cerebrospinal fluid (CSF) analysis and neuroimaging findings.
Methods
The study included 58 patients with COVID-19 and neurological manifestations in whom severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse-transcription polymerase chain reaction screening and on CSF analysis were performed. Clinical, laboratory, and brain magnetic resonance (MR) imaging data were retrospectively collected and analyzed.
Results
Patients were mostly men (66%), with a median age of 62 years. Encephalopathy was frequent (81%), followed by pyramidal dysfunction (16%), seizures (10%), and headaches (5%). CSF protein and albumin levels were increased in 38% and 23%, respectively. A total of 40% of patients displayed an elevated albumin quotient, suggesting impaired blood-brain barrier integrity. CSF-specific immunoglobulin G oligoclonal band was found in 5 patients (11%), suggesting an intrathecal synthesis of immunoglobulin G, and 26 patients (55%) presented identical oligoclonal bands in serum and CSF. Four patients (7%) had a positive CSF SARS-CoV-2 reverse-transcription polymerase chain reaction. Leptomeningeal enhancement was present on brain MR images in 20 patients (38%).
Conclusions
Brain MR imaging abnormalities, especially leptomeningeal enhancement, and increased inflammatory markers in CSF are frequent in patients with neurological manifestations related to COVID-19, whereas SARS-CoV-2 detection in CSF remained scanty.
Cerebrospinal fluid abnormalities were frequent in patients with neurological manifestations related to coronavirus disease 2019, whereas severe acute respiratory syndrome coronavirus 2 detection in cerebrospinal fluid remained scanty.
Post-transplantation lymphoproliferative disorder (PTLD) is associated with significant mortality in kidney transplant recipients. We conducted a prospective survey of the occurrence of PTLD in a ...French nationwide population of adult kidney recipients over 10 years.
A French registry was established to cover a nationwide population of transplant recipients and prospectively enroll all adult kidney recipients who developed PTLD between January 1, 1998, and December 31, 2007. Five hundred patient cases of PTLD were referred to the French registry. The prognostic factors for PTLD were investigated using Kaplan-Meier and Cox analyses.
Patients with PTLD had a 5-year survival rate of 53% and 10-year survival rate of 45%. Multivariable analyses revealed that age > 55 years, serum creatinine level > 133 μmol/L, elevated lactate dehydrogenase levels, disseminated lymphoma, brain localization, invasion of serous membranes, monomorphic PTLD, and T-cell PTLD were independent prognostic indicators of poor survival. Considering five variables at diagnosis (age, serum creatinine, lactate dehydrogenase, PTLD localization, and histology), we constructed a prognostic score that classified patients with PTLD as being at low, moderate, high, or very high risk for death. The 10-year survival rate was 85% for low-, 80% for moderate-, 56% for high-, and 0% for very high-risk recipients.
This nationwide study highlights the prognostic factors for PTLD and enables the development of a new prognostic score. After validation in an independent cohort, the use of this score should allow treatment strategies to be better tailored to individual patients in the future.
The COVID-19 pandemic affects the transplant recipients since March 2020. Transplant centers quickly organized themselves to optimize the management of the immunocompromised patients and to progress ...in the knowledge of this new disease. To this end, a French Registry was created, which includes all solid organ transplant patients who have developed a SARS Cov2 infection. Numerous studies have been carried out using these data to describe this new disease in transplant patients, to characterize its clinical and biological risk factors and to define its prognosis. The 60 days-mortality of transplant patients hospitalized for COVID-19 was evaluated at 23% and renal failure plays a major role in the poor prognosis in addition to the classical risk factors described in the general population. The advent of vaccination has been a great relief but transplanted patients have shown a poor vaccine response keeping them at risk of severe disease even after an adapted vaccination scheme. Specific strategies was proposed in this particularly fragile population like increasing vaccine doses or using anti SARS Cov-2 monoclonal antibodies.
Published data describing the efficacy and safety of autologous stem-cell transplantation (autoSCT) in post-transplant lymphoproliferative disorders (PTLD) is limited to case reports. This is a ...retrospective analysis of 21 patients reported to the EBMT registry who received an autoSCT for PTLD post solid organ transplant (SOT). Median age at autoSCT was 47 (range: 22-71) years. The commonest SOTs were kidney (48%) and liver (24%). Commonest histologies included DLBCL-type PTLD (14/21) and plasmacytoma-like PTLD (3/21). Patients received a median of two lines of therapy (range: 1-4) pre-autoSCT. ECOG performance status pre-autoSCT was 0 in 14% and 1 in 86%. Remission status pre-autoSCT was CR 47% and PR 38%. BEAM conditioning was used in 57% and high-dose melphalan in 10%. The median follow-up post-autoSCT was 64 months for alive patients. 3-year PFS was 62% 95% confidence interval (CI) 44-87% and 3-year OS was 61% 95% CI:43-86. There were 12 deaths, including four related to autoSCT. 100-day non-relapse-mortality (NRM) was 14% and 1-year NRM was 24%. This study suggests that autoSCT, although feasible and with potential therapeutic activity, is associated with a high NRM, primarily driven by infectious toxicity. A multi-disciplinary approach, expert microbiological input and stringent patient selection are required to optimise outcomes.
While either pancreas or pancreatic islet transplantation can restore endogenous insulin secretion in patients with diabetes, no beta-cell replacement strategies are recommended in the literature. ...For this reason, the aim of this national expert panel statement is to provide information on the different kinds of beta-cell replacement, their benefit-risk ratios and indications for each type of transplantation, according to type of diabetes, its control and association with end-stage renal disease. Allotransplantation requires immunosuppression, a risk that should be weighed against the risks of poor glycaemic control, diabetic lability and severe hypoglycaemia, especially in cases of unawareness. Pancreas transplantation is associated with improvement in diabetic micro- and macro-angiopathy, but has the associated morbidity of major surgery. Islet transplantation is a minimally invasive radiological or mini-surgical procedure involving infusion of purified islets via the hepatic portal vein, but needs to be repeated two or three times to achieve insulin independence and long-term functionality. Simultaneous pancreas-kidney and pancreas after kidney transplantations should be proposed for kidney recipients with type 1 diabetes with no surgical, especially cardiovascular, contraindications. In cases of high surgical risk, islet after or simultaneously with kidney transplantation may be proposed. Pancreas, or more often islet, transplantation alone is appropriate for non-uraemic patients with labile diabetes. Various factors influencing the therapeutic strategy are also detailed in this report.
De novo donor-specific antibodies (dnDSA) are associated with antibody-mediated rejection (ABMR) and allograft loss. We tested Immucor* (IM) Luminex Single-antigen beads (LSAB) assay and C3d-fixing ...antibodies in the setting of dnDSA and subclinical (s) ABMR. This retrospective multicentric study included 123 patients biopsied because of the presence of subclinical de novo DSA detected by One Lamda* Labscreen (MFI > 1000). In 112 patients, sera of the day of the biopsy were available and tested in a central lab with IM Lifecodes LSAB and C3d fixing antibodies assays. In 16 patients (14.3%), no DSA was detected using Immucor test. In 96 patients, at least one DSA was determined with IM. Systematic biopsies showed active sABMR in 30 patients (31.2%), chronic active sABMR in 17 patients (17.7%) and no lesions of sABMR in 49 KT recipients (51%). Intensitity criteria (BCM, BCR and AD-BCR) of DSA were not statistically different between these 3 histological groups. The proportion of patients with C3d-fixing DSA was not statistically different between the 3 groups and did not offer any prognostic value regarding graft survival. Performing biopsy for dnDSA could not be guided by the intensity criteria of IM LSAB assay. C3d-fixing DSA do not offer added value.
Therapeutic monoclonal antibodies have been successful in protecting vulnerable populations against SARS-CoV-2. However, their effectiveness has been hampered by the emergence of new variants. To ...adapt the therapeutic landscape, health authorities have based their recommendations mostly on in vitro neutralization tests. However, these do not provide a reliable understanding of the changes in the dose-effect relationship and how they may translate into clinical efficacy. Taking the example of EvusheldTM (AZD7442), we aimed to investigate how in vivo data can provide critical quantitative results and project clinical effectiveness. We used the Golden Syrian hamster model to estimate 90 % effective concentrations (EC90) of AZD7442 in vivo against SARS-CoV-2 Omicron BA.1, BA.2 and BA.5 variants. While our in vivo results confirmed the partial loss of AZD7442 activity for BA.1 and BA.2, they showed a much greater loss of efficacy against BA.5 than that obtained in vitro. We analyzed in vivo EC90s in perspective with antibody levels measured in a cohort of immunocompromised patients who received 300 mg of AZD7442. We found that a substantial proportion of patients had serum levels of anti-SARS-CoV-2 spike protein IgG above the estimated in vivo EC90 for BA.1 and BA.2 (21 % and 92 % after 1 month, respectively), but not for BA.5. These findings suggest that AZD7442 is likely to retain clinical efficacy against BA.2 and BA.1, but not against BA.5. Overall, the present study illustrates the importance of complementing in vitro investigations by preclinical studies in animal models to help predict the efficacy of monoclonal antibodies in humans.
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•AZD7442 retains significant in vitro activity against the Omicron BA.5 strain•AZD7442 no longer exhibits activity against the BA.5 strain in a hamster model•Patient serum anti-spike IgG levels were below the in vivo EC90 against BA.5 strain•Relevance of in vivo models when mAb efficacy against a new variant is reduced
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