Anti-CTLA4 antibody-induced lupus nephritis Fadel, Fouad; El Karoui, Khalil; Knebelmann, Bertrand
The New England journal of medicine,
2009-Jul-09, Letnik:
361, Številka:
2
Journal Article
Vaccination and COVID-19 Dynamics in Dialysis Patients El Karoui, Khalil; Hourmant, Maryvonne; Ayav, Carole ...
Clinical journal of the American Society of Nephrology,
03/2022, Letnik:
17, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Dialysis patients have a high mortality risk after coronavirus disease 2019 (COVID-19) and an altered immunologic response to vaccines, but vaccine clinical effectiveness remains unknown in this ...population.
Using Bayesian multivariable spatiotemporal models, we estimated the association between vaccine exposure and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) severe infections (with hospital admission) in dialysis patients from simultaneous incidence in the general population. For dialysis patients, cases were reported within the French end-stage kidney disease REIN registry from March 11, 2020, to April 29, 2021, and vaccine exposure (first dose) was reported in weekly national surveys since January 2021. Cases in the general population were obtained from the national exhaustive inpatient surveillance system (SI-VIC database), and vaccination coverage (first dose) was obtained from the national surveillance system (VAC-SI database).
During the first wave, incidence in dialysis patients was approximately proportional to the general population. However, we showed a lower relative incidence for dialysis patients during the second wave (compared with that observed in nondialysis patients), suggesting an effect of prevention measures. Moreover, from the beginning of the vaccination rollout, incidence in dialysis patients was lower compared with predictions based on the first and second waves. Adding vaccination coverages in dialysis and nondialysis patients as predictors allowed the reported cases to be fit correctly (3685 predicted cases, 95% confidence interval, 3552 to 3816, versus 3620 reported). Incidence rate ratios were 0.37 (95% confidence interval, 0.18 to 0.71) for vaccine exposure in dialysis patients and 0.50 (95% confidence interval, 0.40 to 0.61) per 10% higher in vaccination coverage in the same-age general population, meaning that vaccine exposure in dialysis patients and the general population was independently associated with lower hospitalization rate of dialysis patients.
Our findings suggest that vaccination may yield a protective effect against severe forms of COVID-19 in dialysis patients, despite altered immunologic vaccine responses.
Mechanisms of progression of chronic kidney disease (CKD), a major health care burden, are poorly understood. EGFR stimulates CKD progression, but the molecular networks that mediate its biological ...effects remain unknown. We recently showed that the severity of renal lesions after nephron reduction varied substantially among mouse strains and required activation of EGFR. Here, we utilized two mouse strains that react differently to nephron reduction--FVB/N mice, which develop severe renal lesions, and B6D2F1 mice, which are resistant to early deterioration--coupled with genome-wide expression to elucidate the molecular nature of CKD progression. Our results showed that lipocalin 2 (Lcn2, also known as neutrophil gelatinase-associated lipocalin NGAL), the most highly upregulated gene in the FVB/N strain, was not simply a marker of renal lesions, but an active player in disease progression. In fact, the severity of renal lesions was dramatically reduced in Lcn2-/- mice. We discovered that Lcn2 expression increased upon EGFR activation and that Lcn2 mediated its mitogenic effect during renal deterioration. EGFR inhibition prevented Lcn2 upregulation and lesion development in mice expressing a dominant negative EGFR isoform, and hypoxia-inducible factor 1α (Hif-1α) was crucially required for EGFR-induced Lcn2 overexpression. Consistent with this, cell proliferation was dramatically reduced in Lcn2-/- mice. These data are relevant to human CKD, as we found that LCN2 was increased particularly in patients who rapidly progressed to end-stage renal failure. Together our results uncover what we believe to be a novel function for Lcn2 and a critical pathway leading to progressive renal failure and cystogenesis.
Increasing number of Janus kinase (JAK) inhibitors have been approved for chronic haematopoietic neoplasms and inflammatory/autoimmune diseases. We aimed to assess safety of the first three approved ...JAK inhibitors: ruxolitinib, tofacitinib and baricitinib. In this retrospective observational study, pharmacovigilance data were extracted from the World Health Organization database. Adverse events are classified according to Medical Dictionary for Regulatory Activities hierarchy. Until February 28, 2021, all Individual Case Safety Reports ICSRs with the suspected drug ruxolitinib, tofacitinib or baricitinib were included. Disproportionality analysis was performed and the information component (IC) was estimated. Adverse events were considered a significant signal if the lower end of the 95% credibility interval of the IC (IC025) was positive. We identified 126,815 ICSRs involving JAK inhibitors. Ruxolitinib, tofacitinib and baricitinib were associated with infectious adverse events (IC025 1.7, especially with viral herpes and influenza, fungal, and mycobacterial infectious disorders); musculoskeletal and connective tissue disorders (IC025 1.1); embolism and thrombosis (IC025 0.4); and neoplasms (IC025 0.8, especially malignant skin neoplasms). Tofacitinib was associated with gastrointestinal perforation events (IC025 1.5). We did not find a significant increase in the reporting of major cardiovascular events. We identified significant association between adverse events and ruxolitinib, tofacinitib and baricitinib in international pharmacovigilance database.
A typical hemolytic uremic syndrome (aHUS) is a prototypic thrombotic microangiopathy attributable to complement dysregulation. Hypertensive emergency, characterized by elevation of systolic (>180 ...mmHg) or diastolic (>120 mmHg) blood pressure together with end-organ damage, can cause thrombotic microangiopathy which may mimic aHUS. We retrospectively evaluated the clinical, biological and complement genetic characteristics of 76 and 61 aHUS patients with and without hypertensive emergency, respectively. Patients with hypertensive emergency-aHUS were more frequently males, with neurological involvement, and a slightly higher hemoglobin level. At least one rare complement variant was identified in 51.3% (39/76) and 67% (41/61) patients with or without hypertensive emergency, respectively (
=0.06). In both groups, renal prognosis was severe with 23% and 40% of patients reaching end-stage renal disease after a 5-year follow-up (
=0.1). The 5-year renal survival was 77% in patients without hypertensive emergency or a complement variant, and below 25% in the three groups of patients with hypertensive emergency and/or a complement variant (
=0.02). Among patients without hypertensive emergency, the 5-year renal survival was 100%
40% in those treated or not with eculizumab, respectively (
<0.001). Conversely, the 5-year renal survival of patients with hypertensive emergency was 46%
23% in those treated or not with eculizumab, respectively (
=0.18). In conclusion, information on the presence or absence of hypertensive emergency and rare complement variants is essential to stratify the long-term renal prognosis of patients with aHUS.
Atypical hemolytic uremic syndrome (HUS) is associated with high recurrence rates after kidney transplant, with devastating outcomes. In late 2011, experts in France recommended the use of highly ...individualized complement blockade-based prophylaxis with eculizumab to prevent post-transplant atypical HUS recurrence throughout the country.
To evaluate this strategy's effect on kidney transplant prognosis, we conducted a retrospective multicenter study from a large French nationwide registry, enrolling all adult patients with atypical HUS who had undergone complement analysis and a kidney transplant since January 1, 2007. To assess how atypical HUS epidemiology in France in the eculizumab era evolved, we undertook a population-based cohort study that included all adult patients with atypical HUS (
=397) between 2007 and 2016.
The first study included 126 kidney transplants performed in 116 patients, 58.7% and 34.1% of which were considered to be at a high and moderate risk of atypical HUS recurrence, respectively. Eculizumab prophylaxis was used in 52 kidney transplants, including 39 at high risk of recurrence. Atypical HUS recurred after 43 (34.1%) of the transplants; in four cases, patients had received eculizumab prophylaxis and in 39 cases they did not. Use of prophylactic eculizumab was independently associated with a significantly reduced risk of recurrence and with significantly longer graft survival. In the second, population-based cohort study, the proportion of transplant recipients among patients with ESKD and atypical HUS sharply increased between 2012 and 2016, from 46.2% to 72.3%, and showed a close correlation with increasing eculizumab use among the transplant recipients.
Results from this observational study are consistent with benefit from eculizumab prophylaxis based on pretransplant risk stratification and support the need for a rigorous randomized trial.
After two doses of mRNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients on dialysis show a defective humoral response, but a third dose could increase ...anti-SARS-CoV-2 spike IgG titers. Responses could be different in virus-naive and SARS-CoV-2-recovered patients on dialysis. However, characterization of memory B cell response after three doses is lacking.
We evaluated the dynamics of antireceptor binding domain IgG titers and antireceptor binding domain memory B cells until 6 months after two and three doses (administered within 6 months after the second dose) of mRNA vaccine in SARS-CoV-2-recovered and virus-naive dialysis populations. Results were analyzed by ordinary one-way ANOVA, the Kruskal-Wallis test, or the Wilcoxon matched-pairs test as appropriate.
In total, 108 individuals (59 patients on dialysis and 49 controls) were included. In virus-naive patients on dialysis, antireceptor binding domain IgG response was quantitatively lower after two doses compared with healthy controls, but IgG titers increased by three-fold after three doses (
=0.008). In SARS-CoV-2-recovered patients on dialysis, antireceptor binding domain IgG titers after two doses were significantly higher compared with virus-naive patients on dialysis but did not significantly increase after a third dose. Regarding memory B cell response, we detected receptor binding domain-specific memory B cells at similar proportions in virus-naive patients on dialysis and vaccinated controls after two doses. Moreover, a strong receptor binding domain-specific memory B cell expansion was observed after the third dose in virus-naive patients on dialysis (5.5-fold;
<0.001). However, in SARS-CoV-2-recovered patients on dialysis, antireceptor binding domain memory B cells remained unchanged after the third dose.
The third dose of mRNA vaccine given within 6 months after the second dose boosts serologic and memory response in virus-naive patients but not in SARS-CoV-2-recovered patients on dialysis.
COVID-19: SARS-CoV-2 Specific Memory B and T-CD4+ Cells (MEMO-COV2), NCT04402892.
Aims
Hereditary (ATTRv) and wild‐type (ATTRwt) transthyretin amyloidosis are severe and fatal systemic diseases, characterised by amyloid fibrillar accumulation principally in the heart or peripheral ...nerves (or both). Since 2012, tafamidis has been used in France to treat patients with ATTRv with neuropathy (alone or combined with cardiomyopathy). Recently, the Phase III ATTR‐ACT trial showed that tafamidis decreased the relative risk of mortality in ATTR amyloidosis with cardiomyopathy. The aims of this study were to assess the clinical characteristics of ATTR amyloidosis in a real‐life population in comparison to the population included in the ATTR‐ACT trial and to assess the impact of tafamidis treatment on major cardiovascular outcome (MCO)‐free survival time without cardiac decompensation, heart transplant, or death.
Methods and results
From June 2008 to November 2018, 648 patients with ATTR amyloidosis (423 ATTRwt and 225 ATTRv) consecutively referred to the French Referral Center for cardiac amyloidosis were included. A total of 467 (72%) patients matched the inclusion criteria of the ATTR‐ACT trial. For the 631 patients with cardiomyopathy, tafamidis treatment was
associated with a longer median MCO‐free survival time (n = 98): 1565 (1010–2400) days vs. 771 (686–895) days without treatment (log‐rank P < 0.001). This association was confirmed after considering confounding factors (age at inclusion, N‐terminal pro‐B‐type natriuretic peptide and amyloidosis type) with a propensity score (hazard ratio 0.546; P = 0.0132).
Conclusion
In a large cohort of ATTRwt and ATTRv patients, representative of the inclusion criteria of the ATTR‐ACT trial, the present results show an association between tafamidis treatment and a lower occurrence of cardiovascular outcomes in a real‐life population.
Schematic representation of the main results describing the correspondence of ATTRACT trial selection with real‐life cohort and the impact of tafamidis treatment on major cardiovascular outcome‐free survival time in a cohort of patients with transthyretin amyloidosis.
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