Hepatitis B Virus Reactivation in Kidney Transplant Recipients Treated With Belatacept.

Introduction: Hepatitis B virus (HBV) reactivation in kidney transplant recipients has been reported in 3% to 9% of anti-HBc antibody (HBcAb)-positive HBs antigen (HBsAg)-negative patients. It has not been studied in patients receiving belatacept, a selective costimulation blocker. Methods: We performed a retrospective study of all transplant recipients receiving belatacept in 2 kidney transplantation centers in France. Among HBcAb-positive patients, we analyzed HBV reactivation rate, outcomes, and risk factors. Results: A total of 135 patients treated with belatacept were included: 32 were HBcAb-positive and 2 were HBsAg-positive. Seven patients reactivated HBV (21.9% of HBcAb-positive patients), including 5 HBsAg-negative patients (16.7% of HBcAb-positive HBsAg-negative patients). Reactivation occurred 54.8 (± 70.9) months after transplantation. One patient presented with severe hepatitis and 1 patient developed cirrhosis. There was no significant difference in survival between patients that reactivated HBV and patients that did not: 5-year patient survival of 100% (28.6; 100) and 83.4% (67.6; 100), respectively (P = 0.363); and 5-year graft survival of 100% (28.6; 100) and 79.8% (61.7; 100), respectively (P = 0.335). No factor, including HBsAb positivity and antiviral prophylaxis, was statistically associated with the risk of HBV reactivation. Conclusion: HBV reactivation rate was high in patients treated with belatacept when compared with previous transplantation studies. HBV reactivation did not impact survival. Further studies are needed to confirm these results. A systematic antiviral prophylaxis for these patients should be considered and evaluated.

Apixaban Prophylactic Anticoagulation in Patients with Nephrotic Syndrome.

Background Nephrotic syndrome (NS) is associated with an increased risk of thromboembolic events (TEs), due to hemostatic derangements. The use of direct oral anticoagulants (DOACs) in the prevention of TE has not been studied intensively in patients suffering from NS. Methods The method included retrospective analysis of consecutive incident patients with NS due to glomerular disease, receiving apixaban for thromboprophylaxis. It is an uncontrolled, single-center study. Results We identified 27 patients treated with apixaban for the prevention of TEs, in the context of NS. During follow-up, apixaban minimal blood concentration (trough level; Cmin) and maximum blood concentration (Cmax) levels were measured. The mean duration of the anticoagulant treatment was 153 days (±132). Patients were followed for a mean of 14.7 months (±8.4) since the introduction of apixaban. Three patients had a TE at the time of NS diagnosis. Two patients had pulmonary embolism (PE) and one patient presented a stroke in a lupus membranous nephropathy context. One patient developed PE approximately 2 months after the introduction of apixaban treatment. No minor or major bleeding events were noticed. Conclusion The present study shows that patients, suffering from severe NS under anticoagulant therapy with apixaban had a reduced risk of venous and arterial TEs compared with patients previously described in the literature, without increased risk of bleeding.

Long-term health-related quality of life outcomes of adults with pediatric onset of frequently relapsing or steroid-dependent nephrotic syndrome.

BACKGROUND: Long-term psychosocial outcomes and health-related quality of life (HRQOL) in adults with pediatric onset of frequently relapsing or steroid-dependent idiopathic nephrotic syndrome (FRNS or SDNS) remain to be determined. METHODS: In this prospective cohort study, 59 adults with pediatric onset of FRNS/SDNS and persistent active glomerular disease in adulthood completed the GEDEPAC-2 questionnaire exploring 11 well-being domains. Data were compared to the French general population (FGP) with standardized incidence ratio ([SIR]; adjusted for period, age, gender). Regression models were performed to identify predictive factors of psychosocial well-being. RESULTS: In 82% of cases, the questionnaire was completed while the participants (n = 59; 47 men; median age = 32 years; median number of relapses = 13) were in complete remission (under specific therapy in 76% of cases). Participants had higher educational degree than in the FGP (SIR = 6.3; p < 0.01) and more frequently a managerial occupation (SIR = 3.1; p < 0.01). Social integration was acceptable with regard to marital status and experience of sexual intercourse, but experiences of discrimination were far more frequent (SIR = 12.5; p < 0.01). The SF-12 mental component summary (MCS) score was altered (Z-score = - 0.6; p < 0.01) and mean multidimensional fatigue inventory (MFI-20) global fatigue score appeared high (12). Transfer from pediatric to adult healthcare was followed by a period of discontinued care for 33% of participants. Multivariate analysis revealed a close relationship between MFI-20, physical health, and MCS. CONCLUSIONS: This study shows that pediatric onset FRNS and SDNS may have a long-term negative impact on mental HRQOL and highlights the impact of fatigue, which is often not adequately considered in routine care.

Rituximab in Patients With Phospholipase A2 Receptor-Associated Membranous Nephropathy and Severe CKD.

INTRODUCTION: Patients with phospholipase A2 receptor (PLA2R)-associated membranous nephropathy and stage 4 or 5 chronic kidney disease are at high risk of end-stage kidney disease. In recent years, rituximab (RTX) emerged as a safe and efficient treatment for patients with PLA2R-associated membranous nephropathy. Whether its use is also appropriate in patients with an estimated glomerular filtration rate <30 ml/min per 1.73 m2 has not been investigated. METHODS: We retrospectively reviewed characteristics and outcome of 13 patients with PLA2R-associated membranous nephropathy and stage 4 or 5 chronic kidney disease who received a total of 14 consecutive RTX treatments from January 2012 to March 2018. The treatment regimen consisted of either 2 weekly infusions of 375 mg/m2 or 2 RTX infusions of 1 g/d two weeks apart. When needed, the regimen was repeated to achieve immunological remission. RESULTS: The mean estimated glomerular filtration rate, serum albumin level, and urinary protein level at the first RTX infusion were 18 ± 7 ml/min per 1.73 m2, 25.2 ± 5.4 g/l, and 13.2 ± 7.5 g/d, respectively, with all patients being tested positive for serum PLA2R antibodies. Ten treatment courses led to an increase in estimated glomerular filtration rate and remission of nephrotic syndrome after a median follow-up of 40.8 months (interquartile range, 14.8-46.8). Conversely, 4 RTX treatments were unsuccessful, with patients requiring chronic hemodialysis within 1 year. The urinary albumin-to-protein ratio before treatment was predictive of renal response. Immunological remission occurred after 11 treatment courses and was associated with clinical response in 10 of 11 patients. Three patients experienced severe adverse events. CONCLUSION: RTX seems effective and reasonably safe in PLA2R-associated membranous nephropathy with stage 4 or 5 chronic kidney disease. Immunological remission is associated with a good clinical outcome.

Hepatitis B virus reactivation during belatacept treatment after kidney transplantation.

We report a case of HBV reactivation following belatacept treatment in a patient who underwent kidney transplantation in 2015 for HIV-associated nephropathy (HIVAN). Human immunodeficiency virus viral load was undetectable prior to transplantation, and CD4+ lymphocyte count was greater than 300/mL. Baseline HBV serology at transplantation was HBsAg negative, anti-HBcAb positive, anti-HBsAb 312 UI/L, and HBeAg negative/anti-HBeAb positive. Liver function tests were normal, and viral DNA was undetectable. Two years later, the patient presented with severe acute hepatitis after a progressive disappearance of anti-HbsAb, quickly followed by HBV reactivation. Immunosuppressive treatment was drastically reduced, and treatment with entecavir was started. The outcome was favorable, and HBV DNA became undetectable after 9 weeks of treatment. This is the first report of acute hepatitis related to HBV reactivation in a kidney transplant recipient treated with belatacept. The risk for HBV reactivation in patients treated with belatacept should not be underestimated, especially in those with resolved HBV infection.

Survival and specific outcome of sickle cell disease patients after renal transplantation.

The prognosis of sickle cell disease (SCD) patients who need dialysis is poor, but experience with kidney transplantation is limited. This study assessed the characteristics of 36 SCD patients undergoing renal transplantation. Immediate post-surgical complications occurred in 25% of cases. Cytomegalovirus and bacterial infections were frequently observed. Twelve patients died after a median follow-up period of 17·4 months. Overall patient survival was significantly lower in SCD than in the control group without significant difference for overall death-censored graft survival. Our data suggest that renal transplantation should be systematically considered in SCD patients with end-stage renal disease.

High-Dose Rituximab and Early Remission in PLA2R1-Related Membranous Nephropathy.

BACKGROUND AND OBJECTIVES: Different rituximab protocols are used to treat membranous nephropathy. We compared two rituximab protocols in patients with membranous nephropathy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twenty-eight participants from the NICE cohort received two infusions of 1-g rituximab at 2-week intervals, whereas 27 participants from the Prospective Randomized Multicentric Open Label Study to Evaluate Rituximab Treatment for Membranous Nephropathy (GEMRITUX) cohort received two infusions of 375 mg/m2 at 1-week interval. We measured serum rituximab levels and compared remission at month 6 and before any treatment modification and analyzed factors associated with remission and relapses. RESULTS: Remissions occurred in 18 (64%) versus eight (30%) from the NICE and GEMRITUX cohort (P=0.02) at month 6, respectively, and in 24 (86%) versus 18 (67%) participants (P=0.12) before treatment modification, respectively. Median time to remission was 3 [interquartile range (IQR), 3-9] and 9 [IQR, 6-12] months for NICE and GEMRITUX cohorts respectively (P=0.01). Participants from the NICE cohort had higher circulating level of rituximab and lower CD19 counts (3.3 µg/L [IQR, 0.0-10.8] versus 0.0 [IQR, 0.0-0.0] P<0.001 and 0.0 [IQR, 0.0-2.0] versus 16.5 [IQR, 2.5-31.0] P<0.001) at month 3, lower level of anti-PLA2R1 antibodies at month 6 (0.0 [IQR, 0.0-8.0] versus 8.3 [IQR, 0.0-73.5] P=0.03). In the combined study population, lower epitope spreading at diagnosis and higher rituximab levels at month 3 were associated with remissions at month 6 (13/26 (50%) versus 22/29 (76%) P=0.05 and 2.2 µg/ml [IQR, 0.0-10.9] versus 0.0 µg/ml [IQR, 0.0-0.0] P<0.001 respectively). All non-spreaders entered into remission whatever the protocol. Eight of the 41 participants who reached remission had relapses. Epitope spreading at diagnosis (8/8 (100%) versus 16/33 (48%) P=0.01) and incomplete depletion of anti-PLA2R1 antibodies at month 6 (4/8 (50%) versus 5/33 (9%) P=0.05) were associated with relapses. CONCLUSIONS: Our work suggests that higher dose rituximab protocol is more effective on depletion of B-cells and lack of epitope spreading is associated with remission of membranous nephropathy.

Functional classification of ATM variants in ataxia-telangiectasia patients.

Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.

Urinary transcriptomics reveals patterns associated with subclinical injury of the renal allograft.

AIM: Subclinical pathological features in renal allograft biopsies predict poor outcomes, and noninvasive biomarkers are wanted. RNA quantification in urine predicts overt rejection. We hypothesized that a whole transcriptome analysis would be informative, even for discrete injury. PATIENTS & METHODS: We performed an mRNA microarray with an optimized normalization method on 26 urinary cell pellets to study renal partial epithelial to mesenchymal transition (pEMT) in stable kidney allografts. RESULTS & CONCLUSION: Unbiased pathway analysis revealed immune response as the main underlying biological process. In a subgroup of pristine biopsies, isolated pEMT was associated with reduced metabolic functions. Thus, pEMT translates into specific urinary mRNA patterns, in other words, increased inflammation and decreased metabolic functions. Deposited in Gene Expression Omnibus (GSE89652).

Urinary mRNA analysis of biomarkers to epithelial mesenchymal transition of renal allograft.

Renal allograft loss is most often a chronic process, irrespective of the mechanism at stake. In this prospective study, we studied the expression of epithelial to mesenchymal transition (EMT) markers vimentin and ß-catenin by immunohistochemistry in the surveillance biopsy and measured the mRNA encoding vimentin (VIM), CD45, GAPDH and uroplakin 1a (UPK) by quantitative PCR in urinary cells in 75 renal transplant patients. The aim is to establish a simple screening test for chronic renal allograft dysfunction. We found that the value of the mRNA of vimentin and CD45 relative to the uroplakin 1a (UPK) mRNA is correlated with the score in vimentin immunostaining in routine biopsies. These biomarkers could be used as a noninvasive tool to monitor the renal graft fibrogenesis. This test could be used for early detection of fibrotic diseases of the kidney transplant.

Phospholipase A2 Receptor 1 Epitope Spreading at Baseline Predicts Reduced Likelihood of Remission of Membranous Nephropathy.

The phospholipase A2 receptor (PLA2R1) is the major autoantigen in primary membranous nephropathy. Several PLA2R1 epitopes have been characterized, and a retrospective study identified PLA2R1 epitope spreading as a potential indicator of poor prognosis. Here, we analyzed the predictive value of anti-PLA2R1 antibody (PLA2R1-Ab) titers and epitope spreading in a prospective cohort of 58 patients positive for PLA2R1-Ab randomly allocated to rituximab (n=29) or antiproteinuric therapy alone (n=29). At baseline, the epitope profile (CysR, CysRC1, CysRC7, or CysRC1C7) did not correlate with age, sex, time from diagnosis, proteinuria, or serum albumin, but epitope spreading strongly correlated with PLA2R1-Ab titer (P<0.001). Ten (58.8%) of the 17 patients who had epitope spreading at baseline and were treated with rituximab showed reversal of epitope spreading at month 6. In adjusted analysis, epitope spreading at baseline was associated with a decreased remission rate at month 6 (odds ratio, 0.16; 95% confidence interval, 0.04 to 0.72; P=0.02) and last follow-up (median, 23 months; odds ratio, 0.14; 95% confidence interval, 0.03 to 0.64; P=0.01), independently from age, sex, baseline PLA2R1-Ab level, and treatment group. We propose that epitope spreading at baseline be considered in the decision for early therapeutic intervention in patients with primary membranous nephropathy.