Multisystemic Effects of Elexacaftor-Tezacaftor-Ivacaftor in Adults with Cystic Fibrosis and Advanced Lung Disease.

RATIONALE: Limited data exist on safety and effectiveness of elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) and advanced lung disease. OBJECTIVE: To evaluate the effects of ETI in an unselected population of pwCF and advanced lung disease. METHODS: A prospective observational study, including all adults, aged 18 years and older, with a percent predicted FEV1 (ppFEV1)≤ 40 who initiated ETI from December 2019 to June 2021 in France was conducted. PwCF were followed until August 8th, 2022. RESULTS: ETI was initiated in 434 pwCF with a median [interquartile range, IQR] ppFEV1=30 [25; 35], including 27 with severe CF liver disease and 183 with diabetes. PwCF were followed for a median [IQR] 587 [396; 728] days after ETI initiation. Discontinuation of ETI occurred in 12 (2.8%) pwCF and was mostly due to lung transplantation (n=5) or death (n=4). Absolute increase in ppFEV1 by a mean +14.2% (95% CI, 13.1-15.4) occurred at 1 month and persisted throughout the study. Increase in ppFEV1 in the younger age quartile was almost twice that of the oldest quartile (P<0.001); body mass index <18.5 kg/m2 was found in 38.6% at initiation vs. 11.3% at 12 months (P=0.0001). Increase in serum concentrations of vitamin A and E, but not 25OHD3, was observed. Significant reduction in the % of pwCF using oxygen therapy, noninvasive ventilation, nutritional support, inhaled and systemic therapies (including antibiotics) were observed; insulin was discontinued in 12% of diabetics. CONCLUSION: ETI is safe in pwCF and advanced lung disease with multisystem pulmonary and extrapulmonary benefits.

The gut microbiota posttranslationally modifies IgA1 in autoimmune glomerulonephritis.

Mechanisms underlying the disruption of self-tolerance in acquired autoimmunity remain unclear. Immunoglobulin A (IgA) nephropathy is an acquired autoimmune disease where deglycosylated IgA1 (IgA subclass 1) auto-antigens are recognized by IgG auto-antibodies, forming immune complexes that are deposited in the kidneys, leading to glomerulonephritis. In the intestinal microbiota of patients with IgA nephropathy, there was increased relative abundance of mucin-degrading bacteria, including Akkermansia muciniphila. IgA1 was deglycosylated by A. muciniphila both in vitro and in the intestinal lumen of mice. This generated neo-epitopes that were recognized by autoreactive IgG from the sera of patients with IgA nephropathy. Mice expressing human IgA1 and the human Fc α receptor I (α1KI-CD89tg) that underwent intestinal colonization by A. muciniphila developed an aggravated IgA nephropathy phenotype. After deglycosylation of IgA1 by A. muciniphila in the mouse gut lumen, IgA1 crossed the intestinal epithelium into the circulation by retrotranscytosis and became deposited in the glomeruli of mouse kidneys. Human α-defensins-a risk locus for IgA nephropathy-inhibited growth of A. muciniphila in vitro. A negative correlation observed between stool concentration of α-defensin 6 and quantity of A. muciniphila in the guts of control participants was lost in patients with IgA nephropathy. This study demonstrates that gut microbiota dysbiosis contributes to generation of auto-antigens in patients with IgA nephropathy and in a mouse model of this disease.

Reversal of cylindrical bronchial dilatations in a subset of adults with cystic fibrosis treated with elexacaftor-tezacaftor-ivacaftor.

BACKGROUND: This study sought to evaluate the impact of elexacaftor-tezacaftor-ivacaftor (ETI) on lung structural abnormalities in adults with cystic fibrosis (awCF) with a specific focus on the reversal of bronchial dilatations. METHODS: Chest computed tomography (CT) performed prior to, and ≥12 months after initiation of ETI were visually reviewed for possible reversal of bronchial dilatations. AwCF with and without reversal of bronchial dilatation (the latter served as controls with 3 controls per case) were selected. Visual Brody score, bronchial and arterial diameters, and lung volume were measured on CT. RESULTS: Reversal of bronchial dilatation was found in 12/235 (5%) awCF treated with ETI. Twelve awCF with and 36 without reversal of bronchial dilatations were further analyzed (male=56%, mean age=31.6±8.5 years, F508del/F508del CFTR =54% and mean %predicted forced expiratory volume in 1 s=58.8%±22.3). The mean±sd Brody score improved overall from 79.4±29.8 to 54.8±32.3 (p<0.001). Reversal of bronchial dilatations was confirmed by a decrease in bronchial lumen diameter in cases from 3.9±0.9 mm to 3.2±1.1 mm (p<0.001), whereas it increased in awCF without reversal of bronchial dilatation (from 3.5±1.1 mm to 3.6±1.2 mm, p=0.002). Reversal of bronchial dilatations occurred in cylindrical (not varicose or saccular) bronchial dilatations. Lung volumes decreased by -6.6±10.7% in awCF with reversal of bronchial dilatation but increased by +2.3±9.6% in controls (p=0.007). CONCLUSION: Although bronchial dilatations are generally considered irreversible, ETI was associated with reversal, which was limited to the cylindrical bronchial dilatations subtype, and occurred in a small subset of awCF. Initiating ETI earlier in life may reverse early bronchial dilatations.

MAIT cells altered phenotype and cytotoxicity in lupus patients are linked to renal disease severity and outcome.

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease in which circulating immune complexes can cause different types of glomerulonephritis, according to immune deposits and to the type of glomerular cell injury. Proliferative lesions represent the most severe form of lupus nephritis (LN) and often lead to kidney failure and death. Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells that recognize microbial-derived ligands from the riboflavin synthesis pathway. Although abundant in peripheral blood, MAIT cells are enriched in mucosal and inflamed tissues. While previous studies have reported concordant results concerning lower MAIT cell frequencies in the blood of SLE patients, no information is known about MAIT cell function and LN severity and outcome. Methods: In the current study, we analyzed the baseline phenotype and function of peripheral blood MAIT cells by flow cytometry in 26 patients with LN and in a control group of 16 healthy individuals. Results: We observe that MAIT cell frequencies are markedly reduced in blood of LN patients. MAIT cells from patients have an altered phenotype in terms of migration, proliferation and differentiation markers, notably in most severe forms of LN. Frequencies of PMA/ionomycin stimulated MAIT cells secreting effector molecules, such as proinflammatory IL-17 and cytotoxic protein granzyme B, are higher in LN patients. Patients undergoing a complete renal remission after immunosuppressive therapy had higher MAIT cell frequency, lower expression of proliferation marker Ki-67 and granzyme B (GzB) at inclusion. Remarkably, GzB production defines a predictive model for complete remission. Discussion: We report here that blood MAIT cells display proinflammatory and cytotoxic function in severe lupus nephritis which may play a pathogenesis role, but without association with systemic lupus activity. Finally, low cytotoxic profile of MAIT cells may represent a promising prognostic factor of lupus nephritis remission one year after induction therapy.

Theratyping cystic fibrosis patients to guide elexacaftor/tezacaftor/ivacaftor out-of-label prescription.

BACKGROUND: Around 20% of people with cystic fibrosis (pwCF) do not have access to the triple combination elexacaftor/tezacaftor/ivacaftor (ETI) in Europe because they do not carry the F508del allele on the CF transmembrane conductance regulator (CFTR) gene. Considering that pwCF carrying rare variants may benefit from ETI, including variants already validated by the US Food and Drug Administration (FDA), a compassionate use programme was launched in France. PwCF were invited to undergo a nasal brushing to investigate whether the pharmacological rescue of CFTR activity by ETI in human nasal epithelial cell (HNEC) cultures was predictive of the clinical response. METHODS: CFTR activity correction was studied by short-circuit current in HNEC cultures at basal state (dimethyl sulfoxide (DMSO)) and after ETI incubation and expressed as percentage of normal (wild-type (WT)) CFTR activity after sequential addition of forskolin and Inh-172 (ΔI ETI/DMSO%WT). RESULTS: 11 pwCF carried variants eligible for ETI according to the FDA label and 28 carried variants not listed by the FDA. ETI significantly increased CFTR activity of FDA-approved CFTR variants (I601F, G85E, S492F, M1101K, R347P, R74W;V201M;D1270N and H1085R). We point out ETI correction of non-FDA-approved variants, including N1303K, R334W, R1066C, Q552P and terminal splicing variants (4374+1G>A and 4096-3C>G). ΔI ETI/DMSO%WT was significantly correlated to change in percentage predicted forced expiratory volume in 1 s and sweat chloride concentration (p<0.0001 for both). G85E, R74W;V201M;D1270N, Q552P and M1101K were rescued more efficiently by other CFTR modulator combinations than ETI. CONCLUSIONS: Primary nasal epithelial cells hold promise for expanding the prescription of CFTR modulators in pwCF carrying rare mutants. Additional variants should be discussed for ETI indication.

The French Compassionate Program of elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis with advanced lung disease and no F508del CFTR variant.

BACKGROUND: The European Medicines Agency has approved the cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination elexacaftor-tezacaftor-ivacaftor (ETI) for people with cystic fibrosis (pwCF) carrying at least one F508del variant. The United States Food and Drug Administration (FDA) also approved ETI for pwCF carrying one of 177 rare variants. METHODS: An observational study was conducted to evaluate the effectiveness of ETI in pwCF with advanced lung disease that were not eligible to ETI in Europe. All patients with no F508del variant and advanced lung disease (defined as having a percent predicted forced expiratory volume (ppFEV1)<40 and/or being under evaluation for lung transplantation) and enrolled in the French Compassionate Program initiated ETI at recommended doses. Effectiveness was evaluated by a centralized adjudication committee at 4-6 weeks in terms of clinical manifestations, sweat chloride concentration and ppFEV1. RESULTS: Among the first 84 pwCF included in the program, ETI was effective in 45 (54%) and 39 (46%) were considered to be non-responders. Among the responders 22/45 (49%) carried a CFTR variant that is not currently approved by FDA for ETI eligibility. Important clinical benefits, including suspending the indication for lung transplantation, a significant decrease in sweat chloride concentration by a median [IQR] -30 [-14;-43]mmol·l-1 (n=42; p<0.0001) and an improvement in ppFEV1 by+10.0 [6.0; 20.5] (n=44, p<0.0001), were observed in those for whom treatment was effective. CONCLUSION: Clinical benefits were observed in a large subset of pwCF with advanced lung disease and CFTR variants not currently approved for ETI.

CFTR Modulators: Current Status and Evolving Knowledge.

In the past decade, the medical management of people with cystic fibrosis (pwCF) has changed with the development of small molecules that partially restore the function of the defective CF transmembrane conductance regulator (CFTR) protein and are called CFTR modulators. Ivacaftor (IVA), a CFTR potentiator with a large effect on epithelial ion transport, was the first modulator approved in pwCF carrying gating mutations. Because IVA was unable to restore sufficient CFTR function in pwCF with other mutations, two CFTR correctors (lumacaftor and tezacaftor) were developed and used in combination with IVA in pwCF homozygous for F508del, the most common CFTR variant. However, LUM/IVA and TEZ/IVA were only moderately effective in F508del homozygous pwCF and had no efficacy in those with F508del and minimal function mutations. Elexacaftor, a second-generation corrector, was thus developed and combined to tezacaftor and ivacaftor (ELX/TEZ/IVA) to target pwCF with at least one F508del variant, corresponding to approximately 85% of pwCF. Both IVA and ELX/TEZ/IVA are considered highly effective modulator therapies (HEMTs) in eligible pwCF and are now approved for nearly 90% of the CF population over 6 years of age. HEMTs are responsible for rapid improvement in respiratory manifestations, including improvement in symptoms and lung function, and reduction in the rate of pulmonary exacerbations. The impact of HEMT on extrapulmonary manifestations of CF is less well established, although significant weight gain and improvement in quality of life have been demonstrated. Recent clinical trials and real-world studies suggest that benefits of HEMT could even prove greater when used earlier in life (i.e., in younger children and infants). This article shortly reviews the past 10 years of development and use of CFTR modulators. Effects of HEMT on extrapulmonary manifestations and on CF demographics are also discussed.

Bats (Mammalia, Chiroptera) and bat flies (Diptera, Streblidae) from the Cazumbá-Iracema and Chico Mendes Reserve, Western Brazilian Amazon.

Bats belong to the order Chiroptera and are composed of 18 families, 202 genera, and 1420 species. Cosmopolitans, they have a high diversity of trophic and behavioral guilds, several ecosystem services, and intraspecific associations with ectoparasites. In Brazil, 68 species of Streblidae have already been recorded, although knowledge about the bat fauna and their ectoparasites is still low. Thus, the objective was to present a list of bat species, and to relate parasites with hosts, for two extractive reserves in the state of Acre, western Brazilian Amazon. The collections took place in ten nights, five in each RESEX, both carried out in August 2019. At each point, 10 mist nets (9 m × 2.5 m) were used, remaining open for 6 h. The captured bats were stored in cotton bags and had their data collected. Subsequently, the search for ectoparasites was carried out throughout the individual's body and extracted with brushes moistened with 96% ethyl alcohol and fine-tipped tweezers. Species of flies were identified to the lowest taxonomic level through specific bibliography. Thirty-three bats from six trophic guilds and 46 ectoparasitic dipterans were sampled, all from the Streblidae family. The most abundant bat family was Phyllostomidae, a recurring result in several studies carried out in the neotropical region. This is related to the selectivity of the mist net in bat sampling, in addition to a close correlation between Phyllostomidae bats and ectoparasitic flies of the Streblidae family.

Specific circulating neutrophils subsets are present in clinically stable adults with cystic fibrosis and are further modulated by pulmonary exacerbations.

The progressive lung destruction in cystic fibrosis (CF) is tightly associated with chronic bacterial infection and neutrophil-dominated airway inflammation. CF pulmonary disease is complicated by episodes of acute exacerbations, contributing to irreversible lung damage. We hypothesized that circulating subsets of neutrophils from clinically stable adults with CF present some phenotypic specificities that could amplify their activation during an infectious episode. The aim of the present study was to examine the different neutrophil subsets in whole blood and in the low density neutrophils (LDN) that co-purify with peripheral blood mononuclear cells (PBMC) in clinically stable adults with CF and in CF adults during pulmonary exacerbations compared to healthy donors. Blood samples were obtained from 22 adults with CF (16 in stable state and 6 during pulmonary exacerbations) and from 20 healthy donors. Flow cytometry analysis of 13 different markers related to lineage (CD45, CD15), maturity (CD16, CD10, and CD33), activation (CD62L, CD11b, CD66b, and CD114), metabolism (GLUT-1, LOX1) and immunosuppression (PD1, PD-L1) was carried out within whole blood and within the LDN fraction. Unsupervised analysis of flow cytometry data was performed using visual t-distributed stochastic neighbor embedding (vi-tSNE). A significant increase in the CD11b expression in neutrophils from CF patients during exacerbations was observed compared to neutrophils from stable CF patients or to healthy donors, indicative of a circulating activation state due to an infectious status. The percentage of LDN was not increased in stable CF patients but increased during exacerbations. Analysis of neutrophil subsets using the double CD16/CD62L labeling revealed a significant increase in the CD16high/CD62Llow subset in all CF patients compared to healthy donors. In contrast, an increase in the CD16low/CD62Lhigh subset was observed only in CF patients during exacerbations. Unsupervised analysis identified a PD-L1high/CD114high population that was present in stable CF patients and as well as in CF patients during exacerbations.

CFTR Modulators in People with Cystic Fibrosis: Real-World Evidence in France.

Cystic fibrosis (CF) is a rare genetic multisystemic disease, the manifestations of which are due to mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein and can lead to respiratory insufficiency and premature death. CFTR modulators, which were developed in the past decade, partially restore CFTR protein function. Their clinical efficacy has been demonstrated in phase 3 clinical trials, particularly in terms of lung function and pulmonary exacerbations, nutritional status, and quality of life in people with gating mutations (ivacaftor), homozygous for the F508del mutation (lumacaftor/ivacaftor and tezacaftor/ivacaftor), and in those with at least one F508del mutation (elexacaftor/tezacaftor/ivacaftor). However, many questions remain regarding their long-term safety and effectiveness, particularly in patients with advanced lung disease, liver disease, renal insufficiency, or problematic bacterial colonization. The impact of CFTR modulators on other important outcomes such as concurrent treatments, lung transplantation, chest imaging, or pregnancies also warrants further investigation. The French CF Reference Network includes 47 CF centers that contribute patient data to the comprehensive French CF Registry and have conducted nationwide real-world studies on CFTR modulators. This review seeks to summarize the results of these real-world studies and examine their findings against those of randomized control trials.

Sustained effectiveness of elexacaftor-tezacaftor-ivacaftor in lung transplant candidates with cystic fibrosis.

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor induces rapid clinical improvement in patients with cystic fibrosis (CF) and advanced pulmonary disease, often leading to suspend the indication for lung transplantation. Yet no long-term data is available in lung transplant candidates. METHODS: Lung transplant candidates (defined as being waitlisted for lung transplantation or considered for listing within 3 months) who have initiated elexacaftor-tezacaftor-ivacaftor were identified in the French cohort of patients with CF and advanced pulmonary disease. Patients were prospectively followed to evaluate treatment safety and effectiveness from initiation to July 20th, 2021. RESULTS: Among the 331 patients with advanced CF pulmonary disease who initiated elexacaftor-tezacaftor-ivacaftor, 65 were lung transplant candidates (17 listed for transplantation, 48 considered for listing within 3 months). Median [IQR] follow-up time was 363 [329; 377] days. At the end of the follow-up period, two patients were transplanted five and 11 days following treatment initiation, two were listed for transplantation, and 61 no longer met transplantation criteria. Improvement in percent predicted forced expiratory volume in 1 s (ppFEV1) at one month was +13.4% (95% confidence interval, 10.3%-16.5%; P < 0.0001) and remained stable thereafter. Treatment burden decreased substantially, with an 86% decrease in the need for intravenous antibiotics, 59% for oxygen therapy and 62% for non-invasive ventilation. CONCLUSION: In lung transplant candidates eligible for elexacaftor-tezacaftor-ivacaftor, the rapid improvement following initiation of treatment persisted over one year with a reduction in treatment burden and lung transplantation could be safely deferred in most patients.

Real-world assessment of LCI following lumacaftor-ivacaftor initiation in adolescents and adults with cystic fibrosis.

Lung clearance index (LCI) is a biomarker of ventilation inhomogeneity. Data are scarce on its usefulness in daily practice for monitoring the effects of treatments in older children and adults with CF. In this French observational study of lumacaftor-ivacaftor, 63 of 845 patients (7.5%) had available LCI performed at baseline and at six (M6; n=34) or 12 months (M12; n=46) after lumacaftor-ivacaftor initiation. At inclusion, median [IQR] age was 16 years [13-17], ppFEV1 was 72.8 [59.6-80.7], and LCI was 12.3 [10.3-15.0]. At both M6 and M12, no statistically significant LCI increases of 0.13 units or 1.34% (95% CI: -4.85-7.53) and 0.6 units or 6.66% (95% CI: -0.03-13.5) were observed. Discordant results between LCI and ppFEV1 were observed in one-third of the patients. In daily practice, LCI monitoring in adolescents and young adults with moderate lung disease gives results that are more heterogenous than those reported in children with milder disease.

Soluble CD89 is a critical factor for mesangial proliferation in childhood IgA nephropathy.

Childhood IgA nephropathy (IgAN) includes a wide spectrum of clinical presentations, from isolated hematuria to acute nephritis with rapid loss of kidney function. In adults, IgAN is an autoimmune disease and its pathogenesis involves galactose deficient (Gd) IgA1, IgG anti-Gd-IgA1 autoantibodies and the soluble IgA Fc receptor (CD89). However, implication of such factors, notably soluble CD89, in childhood IgAN pathogenesis remains unclear. Here, we studied these biomarkers in a cohort of 67 patients with childhood IgAN and 42 pediatric controls. While Gd-IgA1 was only moderately increased in patient plasma, levels of circulating IgA complexes (soluble CD89-IgA and IgG-IgA) and free soluble CD89 were markedly increased in childhood IgAN. Soluble CD89-IgA1 complexes and free soluble CD89 correlated with proteinuria, as well as histological markers of disease activity: mesangial, endocapillary hypercellularity and cellular crescents. Soluble CD89 was found in patient's urine but not in urine from pediatric controls. Mesangial deposits of soluble CD89 were detected in biopsies from patients with childhood IgAN. Serum chromatographic fractions containing covalently linked soluble CD89-IgA1 complexes or free soluble CD89 from patients induced mesangial cell proliferation in vitro in a soluble CD89-dependent manner. Recombinant soluble CD89 induced mesangial cell proliferation in vitro which was inhibited by free soluble recombinant CD71 (also a mesangial IgA receptor) or mTOR blockers. Interestingly, injection of recombinant soluble CD89 induced marked glomerular proliferation and proteinuria in mice expressing human IgA1. Thus, free and IgA1-complexed soluble CD89 are key players in mesangial proliferation. Hence, our findings suggest that soluble CD89 plays an essential role in childhood IgAN pathogenesis making it a potential biomarker and therapeutic target.

Using chest CT scan and unsupervised machine learning for predicting and evaluating response to lumacaftor-ivacaftor in people with cystic fibrosis.

OBJECTIVES: Lumacaftor-ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator known to improve clinical status in people with cystic fibrosis (CF). This study aimed to assess lung structural changes after one year of lumacaftor-ivacaftor treatment, and to use unsupervised machine learning to identify morphological phenotypes of lung disease that are associated with response to lumacaftor-ivacaftor. METHODS: Adolescents and adults with CF from the French multicenter real-world prospective observational study evaluating the first year of treatment with lumacaftor-ivacaftor were included if they had pretherapeutic and follow-up chest computed tomography (CT)-scans available. CT scans were visually scored using a modified Bhalla score. A k-mean clustering method was performed based on 120 radiomics features extracted from unenhanced pretherapeutic chest CT scans. RESULTS: A total of 283 patients were included. The Bhalla score significantly decreased after 1 year of lumacaftor-ivacaftor (-1.40±1.53 points compared with pretherapeutic CT; p<0.001). This finding was related to a significant decrease in mucus plugging (-0.35±0.62 points; p<0.001), bronchial wall thickening (-0.24±0.52 points; p<0.001) and parenchymal consolidations (-0.23±0.51 points; p<0.001). Cluster analysis identified 3 morphological clusters. Patients from cluster C were more likely to experience an increase in percent predicted forced expiratory volume in 1 sec (ppFEV1) ≥5 under lumacaftor-ivacaftor than those in the other clusters (54% of responders versus 32% and 33%; p=0.01). CONCLUSION: One year treatment with lumacaftor-ivacaftor was associated with a significant visual improvement of bronchial disease on chest CT. Radiomics features on pretherapeutic CT scan may help in predicting lung function response under lumacaftor-ivacaftor.

Fishway in hydropower dams: a scientometric analysis.

Building dams for hydroelectric use causes several negative effects on the aquatic fauna with special attention to fish communities. In fact, among other impacts, dams act as a barrier for migratory fish, causing discontinuities in rivers and not allowing fish to move to the headwaters to breed and back to the lower portions of rivers, to grow. For more than 300 years, fishways have been used to minimize the impact of dams. Here, we assess the worldwide knowledge about fishways, identifying the temporal and spatial pattern and the situation of Brazil in this global pattern. For this, we conducted scientometric research on the Web of Science repository with the following words: weir, fish, facilities, ladder, pass, dam, fish ladder, fish pass, fishway, hydropower, Petromyzon, and salmon between 1985 and 2019. Initially, we obtained 1282 articles. After a selection, 324 articles aimed to describe fishway efficiency and the relationship with the fish fauna remained. Most of the articles on dams, fishways, and fish are from North America and Europe. Among the articles in South America, most are from Brazil. Nonetheless, information on the topic is incipient in Brazil, since the country has one of the biggest hydropower in the world and 42 scientific articles about fishways published in the international scientific database. Ecology is the area of knowledge with most articles, with continuous growth in the last 10 years. Studies in the field of ecology are strategical, as this field can integrate different areas of knowledge to test the efficiency of fishways in fish conservation and may be able to answer the question: "Are fishways an ecological trap?" Research focusing on this question is important to understand the efficiency of fishways to better evaluate solutions to minimize the negative effects of dams on fish and increase the effectiveness of fishways.

Rifaximin as a Potential Treatment for IgA Nephropathy in a Humanized Mice Model.

IgA Nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by the mesangial deposition of abnormally glycosylated IgA1 (Gd-IgA). The production of Gd-IgA occurs in mucose-associated lymphoid tissue (MALT). The microbiota plays a role in MALT modulation. Rifaximin (NORMIX®), a non-absorbable oral antibiotic, induces positive modulation of the gut microbiota, favoring the growth of bacteria beneficial to the host. Here, we evaluate the effect of rifaximin on a humanized mice model of IgAN (α1KI-CD89Tg). Methods: The α1KI-CD89Tg mice were treated by the vehicle (olive oil) or rifaximin (NORMIX®). Serum levels of hIgA, hIgA1-sCD89, and mIgG-hIgA1 immune complexes were determined. Glomerular hIgA1 deposit and CD11b+ cells recruitment were revealed using confocal microscopy. Furthermore, the mRNA of the B-Cell Activating Factor (BAFF), polymeric immunoglobulin receptor (pIgR), and Tumor Necrosing Factor-α (TNF-α) in gut samples were detected by qPCR. Results: Rifaximin treatment decreased the urinary protein-to-creatinine ratio, serum levels of hIgA1-sCD89 and mIgG-hIgA1 complexes, hIgA1 glomerular deposition, and CD11b+ cell infiltration. Moreover, rifaximin treatment decreased significantly BAFF, pIgR, and TNF-α mRNA expression. Conclusions: Rifaximin decreased the IgAN symptoms observed in α1KI-CD89Tg mice, suggesting a possible role for it in the treatment of the disease.