Pharmacometabolomics applied to low-dose interleukin-2 treatment in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The immunosuppressive functions of regulatory T lymphocytes (Tregs) are impaired in ALS, and correlate to disease progression. The phase 2a IMODALS trial reported an increase in Treg number in ALS patients following the administration of low-dose (ld) interleukin-2 (IL-2). We propose a pharmacometabolomics approach to decipher metabolic modifications occurring in patients treated with ld-IL-2 and its relationship with Treg response. Blood metabolomic profiles were determined on days D1, D64, and D85 from patients receiving 2 MIU of IL-2 (n = 12) and patients receiving a placebo (n = 12). We discriminated the three time points for the treatment group (average error rate of 42%). Among the important metabolites, kynurenine increased between D1 and D64, followed by a reduction at D85. The percentage increase of Treg number from D1 to D64, as predicted by the metabolome at D1, was highly correlated with the observed value. This study provided a proof of concept for metabolic characterization of the effect of ld-IL-2 in ALS. These data could present advances toward a personalized medicine approach and present pharmacometabolomics as a key tool to complement genomic and transcriptional data for drug characterization, leading to systems pharmacology.

The effect of pH alterations on TDP-43 in a cellular model of amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. The pathophysiology of ALS is not well understood but TDP-43 proteinopathy (aggregation and mislocalization) is one of the major phenomena described. Several factors can influence TDP-43 behavior such as mild pH alterations that can induce conformational changes in recombinant TDP-43, increasing its propensity to aggregate. However to our knowledge, no studies have been conducted yet in a cellular setting, in the context of ALS. We therefore tested the effect of cellular pH alterations on the localization, aggregation, and phosphorylation of TDP-43. HEK293T cells overexpressing wildtype TDP-43 were incubated for 1 h with solutions of different pH (6.4, 7.2, and 8). Incubation of cells for 1 h in solutions of pH 6.4 and 8 led to an increase in TDP-43-positive puncta. This was accompanied by the mislocalization of TDP-43 from the nucleus to the cytoplasm. Our results suggest that small alterations in cellular pH affect TDP-43 and increase its mislocalization into cytoplasmic TDP-43-positive puncta, which might suggest a role of TDP-43 in the response of cells to pH alterations.

Neutrophil to Lymphocyte Ratio as a Prognostic Marker in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative motor neuron disease and remains misunderstood with a difficult diagnosis and prognosis. The implication of the immune system is recognized in ALS pathophysiology, hence the interest in leucocyte count as lymphocytes and neutrophils. The neutrophil-to-lymphocyte ratio (NLR) has recently been used as a prognosis factor to assess the progression of ALS. Thus, the aim of this study was to analyze the evolution of the NLR during disease evolution in a French cohort of ALS patients and its relation with survival. In this monocentric retrospective study, clinical parameters and NLR were collected in ALS patients followed at the University Hospital of Tours (France). ALS patients were subdivided into three groups regarding their NLR value at inclusion: group 1 (NLR < 2); group 2 (NLR: 2-3); group 3 (NLR > 3). A comparison of qualitative and quantitative clinical and biological variables between NLR groups was performed. Then, Cox regressions were carried out to determine the association of NLR with survival. We observed a significant correlation of NLR with ALSFRS-r score (p < 0.0001) and with vital forced capacity (p = 0.0004) at inclusion. We observed that increased NLR at diagnosis is associated with decreased ALS patients' survival.

Implication of Central Nervous System Barrier Impairment in Amyotrophic Lateral Sclerosis: Gender-Related Difference in Patients.

Central nervous system (CNS) barrier impairment has been reported in amyotrophic lateral sclerosis (ALS), highlighting its potential significance in the disease. In this context, we aim to shed light on its involvement in the disease, by determining albumin quotient (QAlb) at the time of diagnosis of ALS in a large cohort of patients. Patients from the university hospital of Tours (n = 307) were included in this monocentric, retrospective study. In total, 92 patients (30%) had elevated QAlb levels. This percentage was higher in males (43%) than in females (15%). Interestingly, QAlb was not associated with age of onset, age at sampling or diagnostic delay. However, we found an association with ALS functional rating scale-revised (ALSFRS-r) at diagnosis but this was significant only in males. The QAlb levels were not linked to the presence of a pathogenic mutation. Finally, we performed a multivariate survival analysis and found that QAlb was significantly associated with survival in male patients (HR = 2.3, 95% CI = 1.2-4.3, p = 0.009). A longitudinal evaluation of markers of barrier impairment, in combination with inflammatory biomarkers, could give insight into the involvement of CNS barrier impairment in the pathogenesis of the disease. The gender difference might guide the development of new drugs and help personalise the treatment of ALS.

Evaluation of arterial blood gas parameters as prognostic markers in amyotrophic lateral sclerosis.

BACKGROUND: Forced vital capacity (FVC) remains difficult to determine for some patients suffering from amyotrophic lateral sclerosis (ALS) due to the rapid progression of the disease. Arterial blood gas (ABG) parameters could represent a valuable alternative. The aim of this study was therefore to evaluate the correlation between ABG parameters and FVC, along with the prognostic ability of ABG parameters, in a large cohort of ALS patients. METHODS: ALS patients (n=302) with FVC and ABG parameters available at diagnosis were included. Correlations between ABG parameters and FVC were evaluated. Cox regression was then carried out to determine the association of each parameter (ABG and clinical data) with survival. Finally, receiver operating characteristic (ROC) curves were built to predict the survival of ALS. RESULTS: Bicarbonates (HCO3 - ), oxygen partial pressure (pO2 ), carbon dioxide partial pressure (pCO2 ), base excess (BE), oxygen saturation and oxyhemoglobin were significantly correlated with FVC both in patients with spinal or bulbar onset. Univariate Cox regression showed that HCO3 - and BE were associated with survival but only in spinal forms. ABG parameters predicted the survival of ALS with a similar performance to FVC, HCO3 - being the parameter with the highest area under the curve. CONCLUSIONS: Our results suggest that there is an interest in conducting a longitudinal evaluation throughout disease progression to confirm the equal performances of FVC and ABG. This study highlights the benefits of performing ABG analysis that could be used as an interesting alternative to FVC when spirometry cannot be performed.

Correlation between assessment of cytochrome P450 1A2 activity and enzyme activity scores, and their relation to clozapine exposure.

AIMS: Cytochrome P450 1A2 (CYP1A2) is involved in the metabolism of antipsychotic drugs such as clozapine and olanzapine. Personalization of these treatments requires an accurate estimation of CYP1A2 activity. In this study, we aimed (1) to evaluate the correlation between activity score (AS), covariate-corrected activity score (CCS) and the phenotype of CYP1A2 using a caffeine test probe and (2) to investigate their relationship with dose-adjusted clozapine concentrations in a subgroup of the cohort. METHODS: A multicentric, retrospective and observational study was carried out in the French university hospitals of Marseille and Tours. CYP1A2 activity was calculated by the paraxanthine/caffeine (17X/137X) ratio determined 4 h after an oral intake of 100 mg caffeine. AS was calculated according to the CYP1A2*1F alleles. CCS was calculated according to the CYP1A2*1F alleles, smoking status and the presence of concomitant inhibitors. RESULTS: As expected, among the 89 patients included, the 17X/137X ratio was significantly higher in patients who smoked. We found a significant but modest correlation between the 17X/137X ratio and CCS (R2 = 0.3, P = 1.74 × 10-8 ) but none between the 17X/137X ratio and AS (R2 = -0.007, P = 0.52). AS was not correlated with dose-adjusted clozapine levels, contrary to CCS (R2 = 0.19, P = 0.016) and especially the 17X/137X ratio (R2 = 0.42, P = 1.7 × 10-5 ). CONCLUSIONS: Correlation with clozapine concentrations showed the advantage of the 17X/137X ratio over the CCS in clozapine dose optimization. CYP1A2 activity, especially when determined by the caffeine probe, may be used to personalize clozapine dosing for patients experiencing treatment failure.

Quantitative impact of pre-analytical process on plasma uracil when testing for dihydropyrimidine dehydrogenase deficiency.

AIMS: Determining dihydropyrimidine dehydrogenase (DPD) activity by measuring patient's uracil (U) plasma concentration is mandatory before fluoropyrimidine (FP) administration in France. In this study, we aimed to refine the pre-analytical recommendations for determining U and dihydrouracil (UH2 ) concentrations, as they are essential in reliable DPD-deficiency testing. METHODS: U and UH2 concentrations were collected from 14 hospital laboratories. Stability in whole blood and plasma after centrifugation, the type of anticoagulant and long-term plasma storage were evaluated. The variation induced by time and temperature was calculated and compared to an acceptability range of ±20%. Inter-occasion variability (IOV) of U and UH2 was assessed in 573 patients double sampled for DPD-deficiency testing. RESULTS: Storage of blood samples before centrifugation at room temperature (RT) should not exceed 1 h, whereas cold (+4°C) storage maintains the stability of uracil after 5 hours. For patients correctly double sampled, IOV of U reached 22.4% for U (SD = 17.9%, range = 0-99%). Notably, 17% of them were assigned with a different phenotype (normal or DPD-deficient) based on the analysis of their two samples. For those having at least one non-compliant sample, this percentage increased up to 33.8%. The moment of blood collection did not affect the DPD phenotyping result. CONCLUSION: Caution should be taken when interpreting U concentrations if the time before centrifugation exceeds 1 hour at RT, since it rises significantly afterwards. Not respecting the pre-analytical conditions for DPD phenotyping increases the risk of DPD status misclassification.

Validation of metabolomic and lipidomic analyses of human tears using ultra-high-performance liquid chromatography tandem mass spectrometry.

To facilitate application in ophthalmological and systemic diseases, there is a need to standardize preanalytical and analytical steps for metabo-lipidomics in human tears. We assessed different methods for each step of the workflow, from sampling to omics profiles acquisition, to provide the largest metabo-lipidomic coverage with the most robust analytical criteria in human tears. We compared reproducibility according to different extraction methods, two sampling techniques, three volumes (2 µL, 5 µL, 10 µL) and eye laterality using ultra-high-performance liquid chromatography coupled with tandem high-resolution mass spectrometry for metabolomic and lipidomic application. The effect of age on the tear metabo-lipidome was also investigated in healthy subjects. The extraction method using methanol/water provided the best results for Schirmer strip metabolomics, while Folch extraction was superior for lipidomics, whatever the sampling method used. When comparing both sampling methods, microcapillary glass tube was superior to Schirmer strip for metabolomics but comparable for lipidomics. The 5 µL volume provided a satisfying metabo-lipidomic coverage. There was no significant difference in tear metabo-lipidome between both eyes in healthy subjects. While most metabolites and lipids where not influenced by age, the phenylalanine-tyrosine-tryptophan pathway, aminoacyl t-RNA biosynthesis, and alanine-aspartate-glutamate metabolism were the 3 principal pathways associated with the 15 most variable metabolites according to age. The current findings will contribute to improve metabo-lipidomic workflow in human tears for the identification of new biomarkers. Preanalytical and analytical standardization is mandatory in order to perform better between-study comparisons and increase the chances of transferring laboratory findings into clinical practice.

Taking Advantages of Blood-Brain or Spinal Cord Barrier Alterations or Restoring Them to Optimize Therapy in ALS?

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that still lacks an efficient therapy. The barriers between the central nervous system (CNS) and the blood represent a major limiting factor to the development of drugs for CNS diseases, including ALS. Alterations of the blood-brain barrier (BBB) or blood-spinal cord barrier (BSCB) have been reported in this disease but still require further investigations. Interestingly, these alterations might be involved in the complex etiology and pathogenesis of ALS. Moreover, they can have potential consequences on the diffusion of candidate drugs across the brain. The development of techniques to bypass these barriers is continuously evolving and might open the door for personalized medical approaches. Therefore, identifying robust and non-invasive markers of BBB and BSCB alterations can help distinguish different subgroups of patients, such as those in whom barrier disruption can negatively affect the delivery of drugs to their CNS targets. The restoration of CNS barriers using innovative therapies could consequently present the advantage of both alleviating the disease progression and optimizing the safety and efficiency of ALS-specific therapies.

Triad of diabetic ketoacidosis-acute pancreatitis-hypertriglyceridaemia: interest of genetic exploration / Triade acidocétose-pancréatite aiguë-hypertriglycéridémie : cas où l'exploration génétique peut s'avérer utile

A 16-year-old child with no medical history was admitted to the hospital emergency for abdominal pain associated with polyuria-polydipsia and weight loss (baseline BMI: 25,4 kg/m2). Diagnosis of severe ketoacidosis was quickly raised regarding major metabolic acidosis, high ketonemia and glycemia. Acute pancreatitis was then diagnosed according to a plasmatic lipase more than tenfold normal values associated with a severe hypertriglyceridemia superior to 100 mmol/L. The triad composed of diabetic ketoacidosis-acute pancreatitis-hypertriglyceridemia is rarely found in childhood and can have deleterious consequences. The etiology of this disease is still enigmatic, as one can be both, cause and consequence of the other. Genetic investigation of familial chylomicronemia legitimated to invalidate the dyslipidemia etiology of this event. On the other hand, the association of a genetic variant of lipoprotein lipase leading to a decrease in its activity, with the insulinopenia of type 1 diabetes most certainly triggered this episode of hypertriglyceridemia.

Une jeune adolescente de 16 ans, sans antécédent médical, s'est présentée aux urgences pour douleurs abdominales dans un contexte de polyuro-polydipsie avec amaigrissement (IMC initial : 25,4 kg/m2). Une acidocétose sévère a rapidement été évoquée devant une acidose métabolique majeure, ainsi qu'une cétonémie et glycémie élevées. Une pancréatite aiguë a ensuite été diagnostiquée devant une lipase plasmatique supérieure à 10 fois les valeurs normales associée à une hypertriglycéridémie majeure de plus de 100 mmol/L. La triade acidocétose-pancréatite aiguë-hypertriglycéridémie est un phénomène très rarement retrouvé dans l'enfance et qui peut avoir des conséquences dramatiques. Il s'agit d'une pathologie à l'étiologie encore énigmatique, l'une pouvant être la cause et la conséquence de l'autre. L'exploration génétique d'une hyperchylomicronémie a pu permettre d'infirmer l'étiologie dyslipidémique de cet épisode. En revanche, l'association d'un variant génétique de la lipoprotéine lipase conduisant à une diminution de son activité, à l'insulinopénie du diabète de type 1 a très certainement déclenché cet épisode d'hypertriglycéridémie.

Problematic rise of vitamin B6 supplementation overuse and potential risk to bariatric surgery patients.

OBJECTIVES: Due to the increased prevalence of obesity in the world, bariatric surgeries are on the rise and necessitate life-long surveillance for deficiencies; hence the recommended vitamin supplementation in these patients. However, inadequate multivitamin supplementation may induce vitamin B6 overload. METHODS: We reviewed all vitamin B6 dosages at the university hospitals of Poitiers, Tours, Bordeaux, and Limoges for the past 5 to 8 years. Analyses were performed by high-performance liquid chromatography, coupled with a fluorescence detector on whole blood samples. RESULTS: During the study period, there was an increase in the number of vitamin B6 dosages. Deficiencies were detected early in Poitiers and Limoges, but were negligible by 2020. However, during the same time period, the number of overdoses increased, reaching close to 40% of dosages at all centers. CONCLUSIONS: Pyridoxin overload is not possible through food-derived pyridoxin; hence, combined with the fact that most vitamin supplements contain vitamin B6, inadequate vitamin supplementation is likely the cause of the observed increase in overdoses. High doses of vitamin B6 can induce polyneuropathy, particularly targeting motor neurons; thus, the increase of overdoses is worrying. In light of the possible risks and the ease with which these could be averted (better formulation of supplements), the precaution principle requires a definition of clear guidelines for vitamin supplementation, especially in patients undergoing bariatric surgery.

Inflammatory mediators, lipoproteins and apolipoproteins in early diagnosis of amyotrophic lateral sclerosis.

There is currently no diagnostic or prognostic biomarker available in clinical practice for Amyotrophic Lateral Sclerosis (ALS). The objective of this study was to monitor a combination of various inflammatory markers, lipids, and apolipoproteins alterations in ALS patients at the time of diagnosis, to assess their role as early diagnostic or prognostic biomarker candidates. C-reactive protein, orosomucoid, prealbumin, calprotectin, lipids and apoliproteins were determined in the blood of all subjects (25 ALS patients, 23 controls) as routinely performed in our laboratory. Inflammatory mediators were evaluated by a bead-based multiplex assay. A two-step approach was used for each analytical strategy: univariate analysis followed by multivariate analysis. Eight features were significantly different between ALS patients and controls, sometimes with important fold changes. The supervised Partial least Squares Discriminant Analysis separated ALS and controls with great accuracy (94 %) and the permutation test was significant (p < 0.01), ensuring the robustness of the model. The prediction model leads to a mean sensitivity and specificity of 90 (+/- 10) and 78 (+/- 10) %, respectively, with a mean predictive positive value and negative predictive value of 80 (+/- 8.9) and 89 (+/- 11.8) %, respectively. However, the models did not discriminate subgroups of ALS patients based on ALS characteristics. This study highlights the usefulness of evaluating a combination of multiple pathways rather than focusing on a single target. These promising results suggest the need for the longitudinal monitoring of these candidates to determine their role in disease evolution.

TAR DNA-binding protein of 43 kDa (TDP-43) and amyotrophic lateral sclerosis (ALS): a promising therapeutic target.

INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that lacks an effective treatment. Aggregates of the TAR DNA-binding protein-43 (TDP-43) are observed in 97% of all ALS cases, thus making this protein a major therapeutic target in ALS. . AREAS COVERED: The authors describe the major cellular functions of TDP-43 and the features and consequences of TDP-43 proteinopathy. Drawing from fundamental and preclinical studies on cellular and animal TDP-43 models of ALS and selected clinical trials, the major pathways that have been targeted for the mitigation of TDP-43 pathology in ALS are discussed. The authors provide insights on the approaches targeting the tendency of TDP-43 for aggregation, defective nucleocytoplasmic transport, dysfunctional proteostasis, abnormal stress granule dynamics, and pathological post-translational modifications of TDP-43. EXPERT OPINION: The complexity of ALS and TDP-43 proteinopathy generates challenges for the development of novel therapeutic approaches. However, the critical involvement of TDP-43 in the initiation and progression of ALS, makes it a promising therapeutic target. Further research should be centered on the development of precision strategies, consideration of patient subgroups, the prevention of the mislocalization of TDP-43 and restoration of the lost functions of TPD-43. .

Perfusate Metabolomics Content and Expression of Tubular Transporters During Human Kidney Graft Preservation by Hypothermic Machine Perfusion.

BACKGROUND: Ischemia-related injury during the preimplantation period impacts kidney graft outcome. Evaluating these lesions by a noninvasive approach before transplantation could help us to understand graft injury mechanisms and identify potential biomarkers predictive of graft outcomes. This study aims to determine the metabolomic content of graft perfusion fluids and its dependence on preservation time and to explore whether tubular transporters are possibly involved in metabolomics variations. METHODS: Kidneys were stored on hypothermic perfusion machines. We evaluated the metabolomic profiles of perfusion fluids (n = 35) using liquid chromatography coupled with tandem mass spectrometry and studied the transcriptional expression of tubular transporters on preimplantation biopsies (n = 26), both collected at the end of graft perfusion. We used univariate and multivariate analyses to assess the impact of perfusion time on these parameters and their relationship with graft outcome. RESULTS: Seventy-two metabolites were found in preservation fluids at the end of perfusion, of which 40% were already present in the native conservation solution. We observed an increase of 23 metabolites with a longer perfusion time and a decrease of 8. The predictive model for time-dependent variation of metabolomics content showed good performance (R 2 = 76%, Q 2 = 54%, accuracy = 41%, and permutation test significant). Perfusion time did not affect the mRNA expression of transporters. We found no correlation between metabolomics and transporters expression. Neither the metabolomics content nor transporter expression was predictive of graft outcome. CONCLUSIONS: Our results call for further studies, focusing on both intra- and extratissue metabolome, to investigate whether transporter alterations can explain the variations observed in the preimplantation period.

Specific changes of erythroid regulators and hepcidin in patients infected by SARS-COV-2.

Iron metabolism is tightly linked to infectious and inflammatory signals through hepcidin synthesis. To date, iron homeostasis during SARS-CoV-2 infection has not yet been described. The aim of this study is to characterize the hepcidin and erythroid regulators (growth differentiation factor 15 (GDF-15) and erythroferrone (ERFE)) by measuring concentrations in plasma in context of COVID-19 disease.We performed a single-center observational study of patients with COVID-19 to evaluate concentrations of main regulatory proteins involved in iron homeostasis, namely: hepcidin, ERFE and GDF-15. SARS-CoV-2 infection (COVID-19+) was defined by a positive RT-PCR. Sixteen patients with COVID-19+ were gender-matched and age-matched to 16 patients with a sepsis unrelated to SARS-CoV-2 (COVID-19-) and were compared with non-parametric statistic test.Clinical and hematological parameters, plasma iron, transferrin, transferrin saturation, ferritin, soluble transferrin receptor and C reactive protein were not statistically different between both groups. Median plasma hepcidin concentrations were higher in the COVID-19+ group (44.1 (IQR 16.55-70.48) vs 14.2 (IQR 5.95-18.98) nmol/L, p=0.003), while median ERFE and GDF-15 concentrations were lower in the COVID-19+ group (0.16 (IQR 0.01-0.73) vs 0.89 (IQR 0.19-3.82) ng/mL, p=0.035; 2003 (IQR 1355-2447) vs 4713 (IQR 2082-7774) pg/mL, p=0015), respectively) compared with the COVID-19- group.This is the first study reporting lower ERFE and GDF-15 median concentrations in patients with COVID-19+ compared with patients with COVID-19-, associated with an increased median concentration of hepcidin in the COVID-19+ group compared with COVID19- group.

[Therapeutic drug monitoring of cyamemazine: How to interpret a concentration? A review of literature]. / Suivi thérapeutique pharmacologique de la cyamémazine : comment interpréter une concentration ? Une revue de la littérature.

Cyamemazine is the most prescribed antipsychotic drug in France, often in combination with another antipsychotic, for its sedative and anxiolytic component. Providing to physicians serum concentrations of cyamemazine in different contexts (compliance checking, ineffectiveness, adverse effects, intoxication, modification of pharmacokinetic parameters…) requires to interpret them correctly. This article presents an update on how to interpret a concentration of cyamemazine, wich remains poorly documented. The anxiolysis occurs at steady-state serum trough concentrations of 4 to 5µg/L; the antipsychotic effect from 18-20µg/L. Cyamemazine is not a drug with a narrow therapeutic window and concentrations up to 400µg/L may be sought in cases of partial efficacy; concentrations of 1800µg/L might be fatal; lower concentrations might be fatal if association with high others concentrations of drugs.

Some CSF Kynurenine Pathway Intermediates Associated with Disease Evolution in Amyotrophic Lateral Sclerosis.

The aim of this study was to evaluate the kynurenine pathway (KP) and amino acids profile, using mass spectrometry, in the cerebrospinal fluid (CSF) of 42 amyotrophic lateral sclerosis (ALS) patients at the diagnosis and 40 controls to detect early disorders of these pathways. Diagnostic and predictive ability (based on weight loss, forced vital capacity, ALS Functional Rating Scale-Revised evolution over 12 months, and survival time) of these metabolites were evaluated using univariate followed by supervised multivariate analysis. The multivariate model between ALS and controls was not significant but highlighted some KP metabolites (kynurenine (KYN), kynurenic acid (KYNA), 3-Hydroxynurenine (3-HK)/KYNA ratio), and amino acids (Lysine, asparagine) as involved in the discrimination between groups (accuracy 62%). It revealed a probable KP impairment toward neurotoxicity in ALS patients and in bulbar forms. Regarding the prognostic effect of metabolites, 12 were commonly discriminant for at least 3 of 4 disease evolution criteria. This investigation was crucial as it did not show significant changes in CSF concentrations of amino acids and KP intermediates in early ALS evolution. However, trends of KP modifications suggest further exploration. The unclear kinetics of neuroinflammation linked to KP support the interest in exploring these pathways during disease evolution through a longitudinal strategy.

Effects of Ischemia-Reperfusion on Tubular Cell Membrane Transporters and Consequences in Kidney Transplantation.

Ischemia-reperfusion (IR)-induced acute kidney injury (IRI) is an inevitable event in kidney transplantation. It is a complex pathophysiological process associated with numerous structural and metabolic changes that have a profound influence on the early and the late function of the transplanted kidney. Proximal tubular cells are particularly sensitive to IRI. These cells are involved in renal and whole-body homeostasis, detoxification processes and drugs elimination by a transporter-dependent, transcellular transport system involving Solute Carriers (SLCs) and ATP Binding Cassettes (ABCs) transporters. Numerous studies conducted mainly in animal models suggested that IRI causes decreased expression and activity of some major tubular transporters. This could favor uremic toxins accumulation and renal metabolic alterations or impact the pharmacokinetic/toxicity of drugs used in transplantation. It is of particular importance to understand the underlying mechanisms and effects of IR on tubular transporters in order to improve the mechanistic understanding of IRI pathophysiology, identify biomarkers of graft function or promote the design and development of novel and effective therapies. Modulation of transporters' activity could thus be a new therapeutic opportunity to attenuate kidney injury during IR.

[Pharmacogenetics for patient care in France: A discipline that evolves!] / La pharmacogénétique au service du soin en France : une discipline qui évolue !

Pharmacogenetics, which concepts are known for a long time, is entering a new period at least as far as its practical applications for patients are concerned. In recent years there have been more and more initiatives to promote widespread dissemination, and health authorities are increasingly incorporating these concepts into drug labels. In France, the national network of pharmacogenetics (RNPGx) works to promote these activities, both with health actors (biologists, clinicians) and health authorities. This article reviews the current situation in France and the milestones of the year 2018. It highlights recent advances in this field, in terms of currently recommended analyses, sharing of information or technological developments, and the prospects for future developments in the near future from targeted pharmacogenetics to eventually preemptive approaches.