Adaptative Strategy of Immunosuppressive Drugs Dosage Adjustments When Combined With Nirmatrelvir/Ritonavir in Solid Organ Transplant Recipients With COVID-19.

Nirmatrelvir/ritonavir is a promising option for preventing severe COVID-19 in solid organ transplant recipients with SARS-CoV-2 infection. However, concerns have arisen regarding potential drug interactions with calcineurin inhibitors (CNI). This two-phase multicentre retrospective study, involving 113 patients on tacrolimus and 13 on cyclosporine A, aimed to assess the feasibility and outcomes of recommendations issued by The French societies of transplantation (SFT) and pharmacology (SFPT) for CNI management in this context. The study first evaluated adherence to recommendations, CNI exposure, and clinical outcomes. Notably, 96.5% of patients on tacrolimus adhered to the recommendations, maintaining stable tacrolimus trough concentrations (C0) during nirmatrelvir/ritonavir treatment. After reintroduction, most patients experienced increased C0, with 42.9% surpassing 15 ng/mL, including three patients exceeding 40 ng/mL. Similar trends were observed in cyclosporine A patients, with no COVID-19-related hospitalizations. Moreover, data from 22 patients were used to refine the reintroduction strategy. Modelling analyses suggested reintroducing tacrolimus at 50% of the initial dose on day 8, and then at 100% from day 9 as the optimal approach. In conclusion, the current strategy effectively maintains consistent tacrolimus exposure during nirmatrelvir/ritonavir treatment, and a stepwise reintroduction of tacrolimus may be better suited to the low CYP3A recovery.

Laboratory Testing for Endocrine Hypertension: Current and Future Perspectives.

BACKGROUND: Secondary hypertension (SH) is a form of high blood pressure caused by an identifiable underlying condition. Although, it accounts for a small fraction of the overall hypertensive population, detection and management of SH is of utmost importance, because SH phenotypes carry a high cardiovascular risk and can possibly be cured by timely treatment. CONTENT: This review focuses on the endocrine causes of SH, such as primary aldosteronism, Cushing syndrome, thyroid disease, pheochromocytoma and paraganglioma, acromegaly, and rare monogenic forms. It discusses current biomarkers, analytical methods, and diagnostic strategies, highlighting advantages and limitations of each approach. It also explores the emerging -omics technologies that can provide a comprehensive and multidimensional assessment of SH and its underlying mechanisms. SUMMARY: Endocrine SH is a heterogeneous and complex condition that requires proper screening and confirmatory tests to avoid diagnostic delays and improve patient outcomes. Careful biomarker interpretation is essential due to potential interferences, variability, and method-dependent differences. Liquid chromatography-tandem mass spectrometry is a superior method for measuring low-concentration hormones and metabolites involved in SH, but it requires expertise. Omics approaches have great potential to identify novel biomarkers, pathways, and targets for SH diagnosis and treatment, especially considering its multifactorial nature.

Tacrolimus Pharmacokinetics is Associated with Gut Microbiota Diversity in Kidney Transplant Patients: Results from a Pilot Cross-Sectional Study.

Clinical use of tacrolimus (TAC), an essential immunosuppressant following transplantation, is complexified by its high pharmacokinetic (PK) variability. The gut microbiota gains growing interest but limited investigations have evaluated its contribution to TAC PKs. Here, we explore the associations between the gut microbiota composition and TAC PKs. In this pilot cross-sectional study (Clinicaltrial.gov NCT04360031), we recruited 93 CYP3A5 non-expressers stabilized kidney transplant recipients. Gut microbiota composition was characterized by 16S rRNA gene sequencing, TAC PK parameters were computed, and additional demographic and medical covariates were collected. Associations between PK parameters or diabetic status and the gut microbiota composition, as reflected by α- and ß-diversity metrics, were evaluated. Patients with higher TAC area under the curve AUC/(dose/kg) had higher bacterial richness, and TAC PK parameters were associated with specific bacterial taxa (e.g., Bilophila) and amplicon sequence variant (ASV; e.g., ASV 1508 and ASV 1982 (Veillonella/unclassified Sporomusaceae); ASV 664 (unclassified Oscillospiraceae)). Building a multiple linear regression model showed that ASV 1508 (co-abundant with ASV 1982) and ASV 664 explained, respectively, 16.0% and 4.6% of the interindividual variability in TAC AUC/(dose/kg) in CYP3A5 non-expresser patients, when adjusting for hematocrit and age. Anaerostipes relative abundance was decreased in patients with diabetes. Altogether, this pilot study revealed unprecedented links between the gut microbiota composition and diversity and TAC PKs in stable kidney transplant recipients. It supports the relevance of studying the gut microbiota as an important contributor to TAC PK variability. Elucidating the causal relationship will offer new perspectives to predict TAC inter- and intra-PK variability.

Flecainide-induced pneumonitis: a case report.

BACKGROUND: We report a case of acute respiratory distress associated with a histological pattern of acute fibrinous and organizing pneumonia, and discuss the possible responsibility of flecainide therapy. CASE PRESENTATION: A 61-year-old African woman developed a rapidly progressive dyspnea and required admission in the intensive care unit for orotracheal intubation and mechanical ventilation. Chest X-ray examination revealed bilateral infiltrates predominating in the basal part of both lungs. Lung computed tomography disclosed bilateral ground-glass opacities and septal thickening. After exclusion of the most common causes of infectious or immune pneumonia, a toxic origin was investigated and flecainide toxicity was considered. Lung biopsy was consistent with the unusual pattern of acute fibrinous and organizing pneumonia. Clinical and radiological improvement was noted after corticosteroid therapy, but the patient died from septic complications. CONCLUSION: Flecainide-induced lung injury has rarely been reported in the literature and remains a diagnosis of exclusion. The histological pattern of acute fibrinous and organizing pneumonia has been previously observed with amiodarone. There are no firm guidelines for the treatment of acute fibrinous and organizing pneumonia, but some patients may positively respond to corticosteroids.

Safety, Efficacy, and Relapse of Nirmatrelvir-Ritonavir in Kidney Transplant Recipients Infected With SARS-CoV-2.

Introduction: The efficacy of nirmatrelvir-ritonavir (NR; Paxlovid, Pfizer, New York, NY) to decrease the risk of progression to severe COVID-19 in high-risk patients has been demonstrated. However, evidence in infected kidney transplant recipients (KTRs) is lacking. Moreover, NR has significant and potentially harmful interactions with calcineurin inhibitors (CNIs). Methods: In this single-center retrospective study, we included all KTRs treated with NR from April 28 to June 3, 2022. A standard management strategy of CNI dose adaptation (discontinuation of tacrolimus 12 hours before the start of NR and administration of 20% of the cyclosporine dose) and laboratory follow-up was applied. Results: A total of 14 patients were included. Compared with day-0 (day before NR initiation), day-7 plasma creatinine concentrations and SARS-CoV-2 viral loads were similar (P = 0.866) and decreased (P = 0.002), respectively. CNI trough concentrations at the end of the treatment were satisfactory, nonetheless, with high individual variability. After a median follow-up time of 34 days, no death or viral pneumonia were observed. Nevertheless, 2 patients experienced early SARS-CoV-2 infection relapses (at day-10 and day-21) associated with an increase in SARS-CoV-2 viral loads. Conclusion: NR can be used in KTRs but requires a strict protocol of drug adaptation. We observed 2 cases of early relapse after NR treatment that need further investigations.

Unexplained Metabolic Acidosis: Alcoholic Ketoacidosis or Propylene Glycol Toxicity.

INTRODUCTION: Severe metabolic acidosis with elevated anion and osmol gap is suggestive of toxic alcohol ingestion. The absence of detectable methanol or ethylene glycol in the serum could mean that metabolism is complete or that other hypotheses have to be considered. Ingestion of less common alcohol or alcoholic ketoacidosis should be investigated as illustrated by the present observation. CASE REPORT: A 46-year-old woman was admitted with altered consciousness in the Emergency Department. In the presence of a high anion gap (peak value 39 mEq/L) metabolic acidosis with mildly increased osmol gap (peak value 19 mOsm/kg), there was a high suspicion of toxic alcohol ingestion in an individual with alcohol use disorder (AUD). Serum arterial lactate concentration was particularly high at 27 mmol/L. Urinalysis failed to reveal the presence of ketone bodies or oxalate crystals. The results of the serum determination of ethanol, methanol, ethylene glycol, and isopropanol were obtained within 2 h and were negative. Due to the severity of lactic metabolic acidosis and the persisting suspicion of intoxication by a less common toxic alcohol, antidotal therapy with ethanol was initiated together with hemodialysis. Correction of lactic metabolic acidosis was obtained. Results of urinalysis obtained later revealed the presence not only of propylene glycol and D-lactate but also of significant concentrations of ß-hydroxybutyrate as a marker of alcoholic ketoacidosis. DISCUSSION: The combination of propylene glycol ingestion and alcoholic ketoacidosis may have contributed to the severity of lactic acidosis.

Two-site evaluation of a new workflow for the detection of malignant cells on the Sysmex XN-1000 body fluid analyzer.

INTRODUCTION: The presence of high fluorescent cells (HF-BF) on the Sysmex XN-1000 hematology analyzers has gained interest regarding the prediction of malignant cells in body fluids, but lacks sensitivity. We aimed to increase this sensitivity by combining HF-BF value, automated results, and clinical information. METHODS: We evaluated a new workflow for the management of body fluids in the hematology laboratory, including the HF-BF criterion and clinical information. In two laboratories, 1623 serous fluids were retrospectively analyzed on the XN-1000 BF mode. All samples were morphologically screened for malignant cells. Optimal HF-BF cutoffs were determined to predict their presence. Thereafter, the added value of clinical information was evaluated. Other reflex testing rules (eosinophilic count >5% and presence of the WBC Abnormal Scattergram flag) were also used to refine our workflow. RESULTS: Optimal HF-BF cutoffs in the two hematology centers were 108 and 45 cells/µL, yielding a sensitivity/specificity of 66.7/93.6% and 86.8/66.6% for malignant cell detection. When adding clinical information, sensitivity/specificity evolved to 100.0/68.9% and 100.0%/not determined. Of 104 samples containing malignant cells, 97 had positive clinical information; the remainder had a HF-BF > cutoff. CONCLUSION: Combining clinical information and HF-BF reached 100% sensitivity for malignant cell detection in body fluid analysis. Lack of robustness of the optimal HF-BF cutoff deserves the use of local cutoffs. Rapid automated results reporting from the XN-1000 BF mode are also feasible in clinical practice. Prospective evaluation of the workflow is needed before its implementation in clinical practice.

Rapid antimicrobial susceptibility testing on positive blood cultures through an innovative light scattering technology: performances and turnaround time evaluation.

BACKGROUND: A bacteremia diagnosis with speeded-up identification and antimicrobial susceptibility testing (AST) is mandatory to adjust empirical broad-spectrum antibiotherapy and avoid the emergence of multi-resistant bacteria. Alfred 60AST (Alifax, Polverara, PD, Italy) is an innovative automated system based on light scattering measurements allowing direct AST from positive blood cultures with rapid results. In this study we aimed to evaluate the system's performances and turnaround time (TAT) compared to routine AST. METHODS: The study was conducted during 2 non-consecutive 3-month periods at the microbiology laboratory of the Cliniques universitaires Saint-Luc. All blood cultures detected positive in the 0 AM-10 AM time frame with a pure Gram-positive cocci or Gram-negative bacilli stain were included for Alfred 60AST testing. Two customized EUCAST antibiotic panels were set up composed of 1) a "Gram-negative" panel including cefuroxime, ceftazidime Enterobacteriaceae, piperacillin-tazobactam Enterobacteriaceae, ciprofloxacine, and ceftazidime Pseudomonas 2) a "Gram-positive" panel including cefoxitin Staphylococcus aureus, cefoxitin coagulase-negative (CNS) Staphylococci and ampicillin Enterococci. Categorical agreement (CA), very major errors (VME), major errors (ME), minor errors (mE) and TAT to Alfred 60AST results were calculated in comparison with AST results obtained from direct testing on positive blood cultures with the Phoenix system (Becton Dickinson, Franklin Lakes, NJ, USA). RESULTS: Five hundred seventy and one hundred nine antibiotics were evaluated on respectively 166 Gram-negative bacilli and 109 Gram-positive cocci included in the studied population. During the first study period regarding Gram-negative strains a CA of 89.5% was obtained with a high rate of VME (19 and 15.4% respectively) for cefuroxime and piperacillin-tazobactam Enterobacteriaceae. Considering this, Alifax reviewed these antibiotics' formulations improving Gram-negative bacilli total CA to 92.2% with no VME during the second study period. For Gram-positive cocci, total CA was 88.1% with 2.3% VME, 13.8% ME (mainly cefoxitin CNS) and 12% mE rates both study periods combined. Median TAT to AST results was 5 h with Alfred versus 12 h34 with Phoenix. CONCLUSION: The Alfred 60AST system shows correct yet improvable microbiological performances and a major TAT reduction compared to direct automated AST testing. Clinical studies measuring the impact of the approach on antibiotic management of patients with bacteremia are recommended.

Subcellular mechanisms involved in apoptosis induced by aminoglycoside antibiotics: Insights on p53, proteasome and endoplasmic reticulum.

Gentamicin, an aminoglycoside used to treat severe bacterial infections, may cause acute renal failure. In the renal cell line LLC-PK1, gentamicin accumulates in lysosomes, induces alterations of their permeability, and triggers the mitochondrial pathway of apoptosis via activation of caspase-9 and -3 and changes in Bcl-2 family proteins. Early ROS production in lysosomes has been associated with gentamicin induced lysosomal membrane permeabilization. In order to better understand the multiple interconnected pathways of gentamicin-induced apoptosis and ensuing renal cell toxicity, we investigated the effect of gentamicin on p53 and p21 levels. We also studied the potential effect of gentamicin on proteasome by measuring the chymotrypsin-, trypsin- and caspase-like activities, and on endoplasmic reticulum by determining phopho-eIF2α, caspase-12 activation and GRP78 and 94. We observed an increase in p53 levels, which was dependent on ROS production. Accumulation of p53 resulted in accumulation of p21 and of phospho-eIF2α. These effects could be related to an impairment of proteasome as we demonstrated an inhibition of trypsin-and caspase-like activities. Moderate endoplasmic reticulum stress could also participate to cellular toxicity induced by gentamicin, with activation of caspase-12 without change in GRP74 and GRP98. All together, these data provide new mechanistic insights into the apoptosis induced by aminoglycoside antibiotics on renal cell lines.