Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide

The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk

Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism

Author’s Reply to Peverill: “Predictors of Left Ventricular Dysfunction in Friedreich’s Ataxia in a 16-Year Observational Study”

International audienc

Significance of NT-proBNP and High-Sensitivity Troponin in Friedreich Ataxia

International audienceackground: Friedreich's ataxia (FA) is a rare autosomal recessive mitochondrial disease resulting of a triplet repeat expansion guanine-adenine-adenine (GAA) in the frataxin (FXN) gene, exhibiting progressive cerebellar ataxia, diabetes and cardiomyopathy. We aimed to determine the relationship between cardiac biomarkers, serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and serum cardiac high-sensitivity troponin (hsTnT) concentrations, and the extent of genetic abnormality and cardiac parameters.Methods: Between 2013 and 2015, 85 consecutive genetically confirmed FA adult patients were prospectively evaluated by measuring plasma hsTnT and NT-proBNP concentrations, electrocardiogram, and echocardiography.Results: The 85 FA patients (49% women) with a mean age of 39 ± 12 years, a mean disease onset of 17 ± 11 years had a mean SARA (Scale for the Assessment and Rating of Ataxia) score of 26 ± 10. The median hsTnT concentration was 10 ng/L (3 to 85 ng/L) and 34% had a significant elevated hsTnT ≥ 14 ng/L. Increased septal wall thickness was associated with increased hsTnT plasma levels (p < 0.001). The median NT-proBNP concentration was 31 ng/L (5 to 775 ng/L) and 14% had significant elevated NT-proBNP ≥ 125 ng/L. Markers of increased left ventricular filling pressure (trans mitral E/A and lateral E/E' ratio) were associated with increased NT-proBNP plasma levels (p = 0.01 and p = 0.01). Length of GAA or the SARA score were not associated with hsTnT or NT-proBNP plasma levels.Conclusion: hsTnT was increased in 1/3 of the adult FA and associated with increased septal wall thickness. Increased NT-proBNP remained a marker of increased left ventricular filling pressure. This could be used to identify patients that should undergo a closer cardiac surveillance

Significance of NT-proBNP and High-Sensitivity Troponin in Friedreich Ataxia

Background: Friedreich’s ataxia (FA) is a rare autosomal recessive mitochondrial disease resulting of a triplet repeat expansion guanine-adenine-adenine (GAA) in the frataxin (FXN) gene, exhibiting progressive cerebellar ataxia, diabetes and cardiomyopathy. We aimed to determine the relationship between cardiac biomarkers, serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and serum cardiac high-sensitivity troponin (hsTnT) concentrations, and the extent of genetic abnormality and cardiac parameters. Methods: Between 2013 and 2015, 85 consecutive genetically confirmed FA adult patients were prospectively evaluated by measuring plasma hsTnT and NT-proBNP concentrations, electrocardiogram, and echocardiography. Results: The 85 FA patients (49% women) with a mean age of 39 ± 12 years, a mean disease onset of 17 ± 11 years had a mean SARA (Scale for the Assessment and Rating of Ataxia) score of 26 ± 10. The median hsTnT concentration was 10 ng/L (3 to 85 ng/L) and 34% had a significant elevated hsTnT ≥ 14 ng/L. Increased septal wall thickness was associated with increased hsTnT plasma levels (p &lt; 0.001). The median NT-proBNP concentration was 31 ng/L (5 to 775 ng/L) and 14% had significant elevated NT-proBNP ≥ 125 ng/L. Markers of increased left ventricular filling pressure (trans mitral E/A and lateral E/E’ ratio) were associated with increased NT-proBNP plasma levels (p = 0.01 and p = 0.01). Length of GAA or the SARA score were not associated with hsTnT or NT-proBNP plasma levels. Conclusion: hsTnT was increased in 1/3 of the adult FA and associated with increased septal wall thickness. Increased NT-proBNP remained a marker of increased left ventricular filling pressure. This could be used to identify patients that should undergo a closer cardiac surveillance.</jats:p

Low Incidence of Hepatic Veno-Occlusive Disease after Fractionated Doses of Mylotarg and Autologous or Allogeneic Stem Cell Transplantation.

Abstract Background. Gemtuzumab ozogamicin (GO, Mylotarg®) is a humanized calicheamicin-conjugated monoclonal antibody targeted to the CD33 antigen present on myeloblasts. A 28% response rate in acute myeloblastic leukaemia (AML) in first relapse was reported in phase 2 single agent trials using Mylotarg at a dose of 9 mg/m2 for two doses at 14 days interval. Significant hepatotoxicity was observed and an increased risk (up to 60%) of developing veno-occlusive disease (VOD) was also reported in patients receiving stem cell transplantation (SCT) after GO exposure. Risk of VOD was correlated with a short interval, less than 3,5 months from GO administration to SCT. We report here the feasibility of an intensive consolidation therapy followed by autologous or allogeneic SCT in patients with AML in complete remission after a reduced and fractionated salvage therapy with GO. Patients and methods. We retrospectively collected the results from 10 consecutive patients (median age 47 years; 18 years to 62 years) treated in 4 haematological centers. All patients received 3 infusions of GO 3 mg/m2/d at day 1, day 4 and day 7 during the induction course. Consolidation modalities and conditioning regimens before HSCT were adapted in each center. Results. Eight patients were in relapse (first relapse, n=4; second and subsequent relapses, n=4) and 2 were primary refractory to induction therapy. After GO salvage therapy, 6 patients achieved a complete remission (CR) and 4 a CR without normalization of the platelets counts (CRp). A grade 1 toxicity and a non severe VOD were recorded during salvage therapy. Consolidation therapy was administered in 6 cases (based on Ara-C chemotherapy in 5 cases and GO administration (3 mg/m2 day 1) in 1 case). Five patients received an allogeneic SCT (genoidentical donors n=2, phenoidentical donors n=3, one of those after a non myeloablative conditioning regimen) and five patients received an autologous SCT after a conditioning regimen with busulfan and melphalan. Median interval between the last chemotherapy and the graft was 47 days (16 to 61 days) and median interval from the last dose of GO and the graft was 108 days (16 to 221 days). Three cases (30%) of hepatic toxicity were recorded (grade 1, n=1; grade 2, n=1; grade 3, n=1), including 2 cases with VOD (20%), one of them confirmed by liver biopsy. The two patients with VOD were successfully treated with defibrotide and normalization of the hepatic tests was obtained. In both cases, the conditioning regimen was TBI/EDX and the interval from the last GO infusion to SCT was short (30 days and 16 days). Of note, the patient who experienced hepatic toxicity during the fractionated induction course did not experienced hepatic toxicity during the intensive SCT phase. Overall, median DFS and OS post SCT were 6.4 months and 8.6 months respectively. Conclusion. This retrospective study argues in favour of a lower hepatotoxicity with fractionated doses of GO leading to a lower risk of VOD when stem cell transplant is used as post remission therapy.</jats:p

Arsenic Trioxide (AS2O3) Therapy for Relapsed Acute Promyelocytic Leukemia (APL): Comparison with a Historic Control Combining All-Trans Retinoic Acid (ATRA) Plus Intensive Chemotherapy.

Abstract AS2O3 has shown great promise in the treatment of patients with relapsed/refractory APL. We evaluated the results of an As2O3 (Trisenox®)-based treatment strategy proposed to French patients with relapsed APL over the last few years and compared these results to those of our previous strategy combining ATRA with EMA (etoposide + mitoxantrone + AraC) intensive timed-sequential chemotherapy (Thomas et al., Leukemia14:1006, 2000), particularly in the setting of hematopoietic stem cell transplantation (HSCT). 28 consecutive patients (median age, 52 years; range, 21 – 80) with relapsed (relapse 1, R1 = 22 of whom 2 in molecular relapse; R2, R3 or R4 = 6) APL (25 M3, 3 M3v) were treated with AS2O3 between 2002 and 2005. The time from the last complete remission (CR) was 20.5 months (range, 0.9 – 74). Initial treatment was AS2O3 (0.15 mg/kg/day iv) administered alone (n = 25) or combined with ATRA (n = 3) ± idarubicin (n = 1) until CR. Median time to CR was 47 days. Severe toxicities included infection (24%) and APL differentiation syndrome (20%). Median time for granulocytes &amp;gt; 0.5 x 109/l was 15 days (range, 0 – 52). 24 patients (86%) achieved CR after initial AS2O3 treatment. Early death was observed in 2 cases and resistance in 2. CR was followed in 11 patients by at least a second cycle of AS2O3 ± consolidation chemotherapy + maintenance therapy (including ± AS2O3 ± ATRA). The 13 other remitters received HSCT (median time to transplant, 4.7 months): 9 underwent unpurged autologous SCT and 4 genoidentical allogeneic SCT, after at least a second cycle of AS2O3 ± one course of consolidation chemotherapy (n = 5). At a median follow-up of 2.5 years, 22 patients are alive. 4 (16%) have relapsed (median time to relapse, 8.1 months). 80% of patients in continuous CR were PML-RARα negative on sensitive nested RT-PCR. Median LFS was not reached. AS2O3-based therapy resulted in a 2-year LFS of 84%. 2-year OS was 73%. Prognostic factors were HSCT as postremission therapy (p = 0.01) and less than 3 therapeutic lines (p = 0.002). While CR proportions were comparable, 2-year LFS (84% vs 47%) and 2-year OS (79% vs 51%) increased in patients receiving AS2O3-based therapy as compared to the historic control. Severe infections were significantly lower with AS2O3-based regimen (24% vs 54%). When considering only patients receiving HSCT, results showed a benefit with AS2O3-based regimen in terms of 2-year LFS (100% vs 54%) and 2-year OS (100% vs 61%), the historic control showing a high mortality associated with the allogeneic SCT procedure. Our data shows that AS2O3-based therapy induces durable remission in a high proportion of patients with relapsed APL with no major toxicity. The results appear more favorable than those of our previous therapy based on ATRA and intensive timed-sequential chemotherapy particularly in the setting of HSCT. Combination AS2O3 and HSCT regimens are anticipated to further extend survival in relapsed APL.</jats:p