Hélène Fontaine

MD Laurent Alric

PhD Julien Labreuche

PhD Benjamin Legendre

PhD Alexandre Louvet

MD PhD Corinne Antoine

MD Christophe M Legendre

PhD Marc Hazzan

MD Nassim Kamar

PhD Sebastien Dharancy

PhD Stanislas Pol

MD PhD Alain Duhamel

MD PhD Philippe Mathurin
email: philippe.mathurin@chru-lille.fr

Control of replication of hepatitis B and C virus improves patient and graft survival in kidney transplantation

Keywords: kidney transplant recipients, chronic hepatitis C, chronic hepatitis B, prognosis

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Renal transplantation (RT) is the best treatment of patients with end stage renal disease (ESRD) because of a significant survival benefit as compared to patients who remain on hemodialysis 1 . Although the prevalence of Hepatitis B virus (HBV) and C virus (HCV) infection in patients with ESRD has significantly declined over time, it remains at least 4times higher than in the general population [START_REF] Bagnis | Epidemiology update for hepatitis C virus and hepatitis B virus in end-stage renal disease in France[END_REF][START_REF] Izopet | Incidence of HCV infection in French hemodialysis units: a prospective study[END_REF] . Chronic HCV or HBV infection can result in chronic liver disease, cirrhosis, and hepatocellular carcinoma [START_REF] Lai | Viral hepatitis B[END_REF][START_REF] Poynard | Viral hepatitis C[END_REF][START_REF] Poynard | Natural history of liver fibrosis progression in patients with chronic hepatitis C[END_REF] and increase the risk of chronic kidney disease [START_REF] Fabrizi | Association Between Hepatitis C Virus and Chronic Kidney Disease: A Systematic Review and Meta-Analysis[END_REF][START_REF] Lee | Association of hepatitis C and B virus infection with CKD in an endemic area in Taiwan: a cross-sectional study[END_REF][START_REF] Molnar | Association of hepatitis C viral infection with incidence and progression of chronic kidney disease in a large cohort of US veterans[END_REF][START_REF] Park | Chronic hepatitis C virus (HCV) increases the risk of chronic kidney disease (CKD) while effective HCV treatment decreases the incidence of CKD[END_REF] . Before the use of antiviral therapy, HBV and HCV infection were associated with a poor outcome in kidney transplant recipients (KTR) [START_REF] Fabrizi | HBsAg seropositive status and survival after renal transplantation: meta-analysis of observational studies[END_REF][START_REF] Legendre | Harmful long-term impact of hepatitis C virus infection in kidney transplant recipients[END_REF][START_REF] Mathurin | Impact of hepatitis B and C virus on kidney transplantation outcome[END_REF][START_REF] Morales | Hepatitis C and its impact on renal transplantation[END_REF] . This poorer outcome has been reported in untreated patients [START_REF] Fabrizi | HBsAg seropositive status and survival after renal transplantation: meta-analysis of observational studies[END_REF][START_REF] Legendre | Harmful long-term impact of hepatitis C virus infection in kidney transplant recipients[END_REF][START_REF] Mathurin | Impact of hepatitis B and C virus on kidney transplantation outcome[END_REF][START_REF] Morales | Hepatitis C and its impact on renal transplantation[END_REF] . With the development of new treatments against viral hepatitis, an update of data in large cohorts of KTR with long-term follow-up is warranted.

HBV treatment has improved in the last 2 decades [START_REF]EASL clinical practice guidelines: Management of chronic hepatitis B virus infection[END_REF][START_REF]EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection[END_REF][START_REF] Terrault | AASLD guidelines for treatment of chronic hepatitis B[END_REF] . The probability of undetectability HBV DNA upon therapy has increased from the use of first generation (lamivudine or adefovir) [START_REF] Hadziyannis | Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B[END_REF][START_REF] Liaw | Lamivudine for patients with chronic hepatitis B and advanced liver disease[END_REF][START_REF] Marcellin | Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B[END_REF] treatment to the second generation analogs (tenofovir or entecavir) [START_REF] Lai | Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B[END_REF][START_REF] Marcellin | Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B[END_REF] . Most HBV kidney transplant recipients have received this safe long-term treatment with analogs before and continue long after RT. However, the impact of viral replication on RT remains somewhat controversial [START_REF] Cosconea | Benefits associated with antiviral treatment in kidney allograft recipients with chronic hepatitis B virus infection[END_REF] . Additional studies in HBV-infected RT are needed with longer follow-up, larger sample populations, and prospective designs to provide accurate evaluation.

During the same period, in HCV KTR, interferon based regimens were contraindicated due to the high risk of transplant rejection. KDIGO recommendations were to treat patients on hemodialysis [START_REF]Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease[END_REF] , but interferon-based regimens were associated with a low efficacy [START_REF] Deltenre | Anti-viral therapy in haemodialysed HCV patients: efficacy, tolerance and treatment strategy[END_REF] and poor tolerance in ESRD patients [START_REF] Deltenre | Anti-viral therapy in haemodialysed HCV patients: efficacy, tolerance and treatment strategy[END_REF][START_REF] Fabrizi | Combined antiviral therapy of hepatitis C virus in dialysis patients: meta-analysis of clinical trials[END_REF][START_REF] Fabrizi | Antiviral therapy (pegylated interferon and ribavirin) of hepatitis C in dialysis patients: meta-analysis of clinical studies[END_REF][START_REF] Fabrizi | Pegylated Interferon Mono-Therapy of Chronic Hepatitis C in the Dialysis Population: Systematic Review and Meta-Analysis[END_REF] . Since 2017, the updated KDIGO and international guidelines recommend extensive use of the new direct anti-viral agents (DAAs) because of their good efficacy and safety) [START_REF]EASL Recommendations on Treatment of Hepatitis C[END_REF][START_REF] Hepatitis | Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection[END_REF] .

The aims of the present study were to update on the influence of HBV and HCV on patient and graft survival and to assess the prognostic influence of viral replication in a large prospective French database of KTR.

METHODS

Study Conduct

Both scientific Committees from the ANRS (in charge of the research on viral hepatitis) and the ABM (Agence de Biomédecine in charge of graft allocation), two French governmental agencies, approved the study. The CNIL (Commission Nationale de l'Informatique et des Libertés), the French government agency in charge of the authorization for the use of database, allowed the CRHU of Lille to analyze these data on December, 28 th 2012 (authorization number: 912384).

Data collection and variables

From January 1993 to December 2010 data were extracted from CRISTAL, a national database begun in 1993 and administered by the ABM that prospectively collects data on all organ transplant recipients in France along with their outcomes and donor characteristics.

Recipient and donor data are entered into the CRISTAL registry by transplant and procurement centers, respectively. Recipient deaths are reported prospectively. The study was performed in accordance with the French law indicating that research studies based on the national registry CRISTAL are part of transplant assessment activity and do not require institutional review board approval. Data are entered into the register by each center. Data collection is mandatory. Variables potentially associated with outcomes were analyzed.

Demographic and clinical data were collected at the time of transplantation and annually thereafter. The following variables were analyzed: gender of donors and recipients, age of recipients and donor, duration of dialysis, duration of cold ischemia, underlying nephropathy, year of transplantation, screening of HBsAg, and anti-HCV. Only adult KTR (i.e age ≥18 years) were included.

Random checking of viral replication in infected HBV and HCV recipients

We randomly selected 191 HBV and 511 HCV KTR cases to assess the control of viral replication among the centers with high yearly transplant activities from the CRISTAL database. This numbers were calculated on the basis of the following assumptions: a) for HBV cases, we expected 70% of patients with control viral replication, a relative precision of 20% in the estimation of this rate (corresponding to a width of 95% confidence interval) and 25% with unavailable virological data. b) for HCV KTR cases, we expected 20% of patients with control viral replication, a relative precision of 40% in the estimation of this rate and 25% with unavailable virological data. Between 2014 and 2015, research assistants visited the centers of selected recipients to analyze recipients' medical records and recorded in case report forms the following information: results of quantification of HBV DNA viral and/or HCV RNA, antiviral therapy ("yes" or "no"), the type of regimen in treated patients, data for diagnosis of cirrhosis such as histological data and/or results of Fibrotest® and Fibroscan®.

HBV replication was considered to be controlled in HBV KTR if DNA <20 000 units during follow-up, based on the definition proposed by the EASL Clinical Practice Guidelines published in 2012 to consider antiviral therapy or classify patients as inactive carriers [START_REF]EASL clinical practice guidelines: Management of chronic hepatitis B virus infection[END_REF] . RNA was classified as undetectable in HCV patients in two cases: a/ spontaneous HCV clearance defined as anti-HCV antibodies and negative HCV RNA; b/ sustained virological response defined as undetectable HCV RNA 24 weeks after the end of antiviral therapy in treated patients.

Case-Control Study of HCV recipients with available HCV RNA data

For each HCV KTR with detectable or undetectable HCV RNA (cases), we randomly selected one to four matched controls from the 29797 non-infected RT patients, with the following matching criteria: gender, age of recipients ± 5 years, duration of dialysis in quartiles calculated for the overall population (<40, 41 to 82, 83 to 206, ≥207 months), quartiles of duration of cold ischemia (<15.8, 15.8 to 20.4, 20.5 to 28.4, ≥28.5 hours) and year of transplantation ± 5 years. The control groups were randomly matched to case groups using the global optimal matching algorithm.

Endpoints

The primary endpoint was ten-year overall survival and the secondary endpoint was ten-year graft survival. Overall survival was defined as the time from the date of renal transplantation to the date of death from any cause. Patients with repeat renal transplants were also treated as censored cases at the time of the second renal transplant. Graft survival was defined as the time from the date of renal transplantation to the date of graft loss or death from any cause.

Graft loss was defined as the need for permanent dialysis or repeat transplantation.

For both overall-and graft-survivals, patients with no information at ten years were treated as censored cases at the date of the last follow-up and events that occurred after the ten-year follow-up period were not included in analysis.

Statistical analysis

Quantitative variables were expressed as means (standard deviations) or medians (interquartile range) and categorical variables were expressed in numbers and percentages. 10-year overall and graft survivals were estimated using the Kaplan-Meier method.

Main baseline characteristics were compared in the overall cohort (n=31433 adult KTR) according to viral status (non-infected, HBs Ag positive or anti-HCV positive) using the Chi-Square test, one-way analysis of variance or Kruskal-Wallis test, as appropriate. Comparisons in overall and graft survivals were obtained in relation to viral status using the log-rank test.

To identify independent predictors of ten-year overall and graft survivals, we performed univariate and multivariate Cox proportional hazards regression models by including viral status and other main baseline characteristics (gender, age of recipients and donors, duration of dialysis, duration of cold ischemia, and year of transplantation). For each candidate predictor, the proportional hazards assumption was assessed by examining Schoenfeld residuals plots. The log-linearity assumption for continuous predictors was assessed by examining Martingale residual plots. Since the log-linearity assumption for the age of recipients and donors was satisfied after including both linear and quadratic terms, the effect of both ages was modelled using a polynomial function. All candidate predictors associated with survival at a level of significance of p<0•10 were included in the multivariate Cox regression models. We derived hazard ratios (HRs) from Cox regression models as effect size measures with the 95% confidence intervals (CIs).

The percentage of patients treated by antiviral therapy and the percentage of responders to antiviral therapy were compared from random samples of available viral data from HBV and HCV KTR between HBV patients with viral replication and HCV patients with detectable RNA using the Chi-square test.

Finally, comparisons of overall and graft-survivals between HCV KTR and their matched non-infected controls were performed separately based on detectable HCV RNA using Cox regression models with the robust sandwich variable estimate to take into account the matched sets.

Statistical testing was performed at the 2-tailed α-level of 0.05. Data were analyzed using SAS software (version 9.4, SAS Institute Inc., Cary, NC, USA).

RESULTS

Between January 1993 and December 2010, 32,249 KTR were entered into the Cristal database, and 816 who were < 18 years old were excluded from the study (figure 1). A total of 31,433 adult KTR (19,580 men and 11,853 women) were included with a median age, duration of dialysis, and cold ischemia of 49.4 years, 28.1 months, and 18.8 hours, respectively. Patients were grouped according to virological status (table 1): 575 HBV KTR (HBs antigen positive) (1.83%), 1,060 HCV KTR (anti-HCV positive) (3.37%), and 29,798 non-infected patients (without anti-HCV antibodies or HBs antigen) (94.8%). The 3 groups differed significantly for sex ratio, age, duration of dialysis and cold ischemia, year of transplantation, and causes of underlying nephropathy (table 1). The prevalence of HBV decreased after 2003 (the median year of transplantation) from 2.26% to 1.4% (p<0.0001), while the prevalence of HCV remained stable (3.38% vs 3.36%).

Ten-year patient survival (primary outcome)

Ten-year patient survival in HCV KTR (71.3%, 95% CI: 67.5-75.2%) was significantly lower than in the HBV KTR (81.2%, 95% CI: 77.1-85.2%, p=0.0004) and non-infected (82.7%, 95% CI: 82.1-83.2%, p<0.0001) groups (figure 2a). There was no difference in ten-year survival between the HBV and non-infected groups (p=0.6). In multivariate analysis, male sex, age of KTR, duration of dialysis, anti-HCV antibodies, age of donor, duration of cold ischemia, and year of transplantation were independently associated with mortality at ten years (table 2). The proportion of liver-related deaths were significantly higher in HBV (6.85%, p=0.01) and HCV (7.29%, p<0.0001) KTR than in non-infected KTR (2.33%).

Ten-year graft survival (secondary outcome)

Ten-year graft survival in HCV KTR (50.6%, 95% CI: 46.8-54.4%) was significantly lower than in the HBV (62.3%, 95% CI: 57.6-67%, p<0.0001) or non-infected (64.7%, 95% CI: 64-65.4%, p<0.0001) groups (figure 2b). There was no difference in ten-year survival between HBV and non-infected groups (p=0.7). In multivariate analysis, male sex, age of recipient, duration of dialysis, anti-HCV antibodies, age of donor, duration of cold ischemia, and the year of transplantation were independently associated with graft loss at ten years (table 3).

Random checking of viral replication in infected HBV and HCV recipients

Virological data were available in 167 out of 191 medical records from HBV KTR patients (87.4%). Viral replication was controlled in 157 out of 167 HBV KTR (94%), including 21 inactive carriers and 136 treated with NAs. In the ten HBV KTR with viral replication, three were not treated and seven insufficiently controlled by antiviral therapy.

Virological data were available in 441 out of 511 medical records from HCV KTR patients (86.3%) (figure 1). HCV RNA was undetectable in 155 out of 441 HCV KTR (35%), including 75 with spontaneous HCV clearance and 80 with a SVR after antiviral therapy.

HCV RNA was detectable in 286 out of 441 HCV KTR (64.9%), including 140 untreated patients and 146 non-responders to antiviral therapy. In patients with viral hepatitis who were candidates for antiviral therapy (i.e with viral replication before initiation of antiviral therapy), HBV KTR were more frequently treated than HCV KTR (85.6% (143/167) vs 61.7% (226/366), p<0.0001) with greater success (95.8% (137/143) vs 35.4% (80/226), p<0.0001). Using the cut off of 2000 IU/ml, the percentage of patients with control of viral replication was lower but not so different than the percentage of patients with control of viral replication using the cutoff of 20 000 IU: 83% vs 94%. The proportion of liver-related deaths among all deaths in HCV KTR patients was 0% in HCV KTR with undetectable RNA and 8.93% in HCV KTR with detectable RNA. A sensitivity analysis was performed in patients with fibrosis assessment. Assessment of fibrosis was available in in 374 out of 702 (53.2%) medical records of infected patients: 93 out of 191 (48.7%) of HBV KTR and 281 out of 511 (55%) HCV KTR. Assessment of liver fibrosis was performed in 293 (78.3%) cases with histological analysis, in 12 (3.2%) with Fibrotest and in 69 (18.4%) with liver stiffness.

Diagnosis of cirrhosis was based on histological analysis or according to cut-offs of non-

invasive methods indicating the diagnosis of cirrhosis (0.74 for Fibrotest and 14.6 KPa for Fibroscan). There were no significant differences between patients with fibrosis assessment and those without fibrosis assessment in terms of: male sex (67% vs. 62.6%), virological status (21.5% HBV and 78.5% HCV vs. 24.7% HBV and 75.3% HCV), duration of dialysis (76.8 vs. 87.9 months), duration of cold ischemia (20 vs 20.8 hours) age of donors (44 vs.

45.1 years), patient (78.9% vs 73.8%) and graft (57.1% vs 52%) survival. Infected patients with fibrosis assessment were younger than those without fibrosis assessment (46.9 vs. 49.1 years, p=0.01). In infected KTR patients with fibrosis evaluation, 29 (7.8%) were classified as cirrhotic and 345 (92.2%) as non-cirrhotic. Ten-year patient survival in cirrhotic (16.4%, 95% CI: 0-36.2%) was significantly lower than in non-cirrhotic (84.7%, 95% CI: 79.6-89.9%, p<0.0001) with an HR of 7.30 (95% CI 2.3-23.3). Ten-year graft survival in cirrhotic (12%, 95% CI: 0-27%) was also lower than in non-cirrhotic (61%, 95% CI: 54.5-67.6%, p<0.0001) with an HR of 3.24 (95% CI: 1.5-6.9). The proportion of liver-related deaths was higher in infected KTR with cirrhosis than in infected KTR without cirrhosis: 64.7% vs 1.8%, p<0.0001. In non-cirrhotic infected patients, ten-year patient survival in KTR with viral replication (79.9%, 95% CI: 72.1-87.6%) was lower than in in those without viral replication (89.4%, 95% CI: 81.8-96.9%, p=0.02) with an HR of 2.5 (95% CI: 1.3-4.9). Ten-year graft survival in KTR with viral replication (54.1%, 95% CI: 45.1-63.1%) was also lower than in in those without viral replication (70.4%, 95% CI: 60.5-80.2%, p=0.02) with an HR of 1.69 (95% CI:1.1-2.6).

Case-control study

Use of the global optimal algorithm resulted in the random selection of 935 matched noninfected controls for 263 HCV KTR with detectable RNA and 482 matched non-infected controls for 137 HCV KTR with undetectable RNA. The global optimal algorithm could not identify matched controls for 23 HCV with detectable RNA and 18 HCV with undetectable RNA. The baseline characteristics of the two cases-control studies of HCV KTR (detectable and undetectable RNA) are provided in supplementary tables 1 and 2. Ten-year patient survival in HCV KTR with detectable RNA (66.1%, 95% CI: 61.1-77.1%) was significantly lower than in their matching non-infected controls (81.5%, 95% CI: 78.1-84.9%, p=0.003) with an HR of 1.61 (95%CI, 1.18-2.21) (figure 3a). Ten-year graft survival in HCV KTR with detectable RNA (45.7%, 95% CI: 38.2-53.2%) was significantly lower than in their matching non-infected controls (59.2%, 95% CI: 55.3-63.1%, p=0.01) with an HR of 1.31 (95% CI, 1.06-1.61) (figure 3b). Ten-year patient survival in HCV KTR with undetectable RNA (86.5%, 95% CI: 77.8-95.3%) was significantly higher than in their matching non-infected controls (77.9%, 95% CI: 72.5-83.4%, p=0.04) with an HR of 0.50 (95% CI, 0.25 to 0.98) (figure 4a). Ten-year graft survival in HCV KTR with undetectable RNA (63.8%, 95% CI: 52.8-74%) was not significantly different than in their matching non-infected controls (61.5%, 95% CI: 55.7-67.3%, p=0.3) with an HR of 0.84 (0.57 to 1.22) (figure 4b). In HCV KTR, we conducted a post-hoc secondary analysis adjusted for diabetes as primary cause of end-stage renal disease (table 1) and for smoking (31.5% of former or current smokers) showing that the deleterious effect of HCV replication remained significant on 10-year patient (HR 2.3, 95% CI: 1.11-4.8, p=0.03) and graft survival (HR 1.63, 95%CI:1.04-2.54, p=0.03).

DISCUSSION

This study evidences that HBV chronic infection, which had previously a negative impact on patient and survival in KT, no longer influences ten-year patient or graft survival due to the control of viral replication in 90% of cases, related to the extensive use of nucleos(t)ides analogues [START_REF]EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection[END_REF][START_REF] Terrault | AASLD guidelines for treatment of chronic hepatitis B[END_REF] . By contrast, HCV chronic infection still negatively impact ten-year patient and graft survival, while this negative influence of HCV is removed by sustained viral suppression, since no longer observed in KTR with undetectable HCV RNA. The present results suggest, in line with the international and KDIGO guidelines, that antiviral therapy should be systematically proposed to HBV-and/or HCV-infected kidney recipients or RT candidates to prevent the deleterious hepatic and extra-hepatic impact of chronic viral replication [START_REF]EASL Recommendations on Treatment of Hepatitis C[END_REF][START_REF] Hepatitis | Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection[END_REF] .

In this study of 31,433 French patients with renal transplantation performed between 1993 and 2010, the prevalence of HBV and HCV chronic infection was 1.8 % and 3.37 %, respectively. HBV prevalence decreases from 2.26% before 2003 to 1.4% thereafter; the HCV prevalence remains stable at approximately 3.4%. These prevalences of HCV and HBV are significantly lower than the 30% and 15% reported in our 2 studies of cohorts transplanted before 1990 [START_REF] Legendre | Harmful long-term impact of hepatitis C virus infection in kidney transplant recipients[END_REF][START_REF] Mathurin | Impact of hepatitis B and C virus on kidney transplantation outcome[END_REF] . This decrease is related to universal hygienic precautions in hemodialysis units and systematic anti-HBV vaccination in patients with end-stage renal disease. However, the current prevalence of both infection in patients with CKD, including KTR, is still higher compared to the general population.

In the sensitivity analysis restricted to infected patients with available assessment of fibrosis, cirrhotic infected patients had the worst outcome and the value of controlling viral replication was confirmed even in patients with less severe liver injury. However, the results of this sensitivity analysis should be treated with caution because of the limited sample size of the cohort of patients with available evaluation of fibrosis, the a posteriori analysis, the important variability in the delay to perform the assessment of fibrosis according to the date of transplantation and the risk of inflated false positive (Type I) errors because of multiplicity of comparison. We did not adjust for multiple comparison given the exploratory nature of this sensitivity analysis restricted to patients with fibrosis assessment. Therefore we couldn't exclude false positive findings.

Before the era of NAs, HBV KTR ten-year patient and graft survival was the worst [START_REF] Mathurin | Impact of hepatitis B and C virus on kidney transplantation outcome[END_REF] . In the present study, there was no significant difference in patient and graft survival between HBV and non-infected KTR, thanks to the extensive use of NAs [START_REF] Hadziyannis | Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B[END_REF][START_REF] Liaw | Lamivudine for patients with chronic hepatitis B and advanced liver disease[END_REF][START_REF] Marcellin | Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B[END_REF][START_REF] Lai | Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B[END_REF] , as shown by the random checking of recipient's medical records. Thus, these data support the benefit of NAs in HBV KTR.

By opposition with HBV, HCV continues to negatively influence KTR. These results are similar to those observed more than 20 years ago [START_REF] Legendre | Harmful long-term impact of hepatitis C virus infection in kidney transplant recipients[END_REF][START_REF] Mathurin | Impact of hepatitis B and C virus on kidney transplantation outcome[END_REF] . However, to further clarify this observation, we checked a large number of patient files to classify KTR according to viral replication. KTR with undetectable RNA had higher ten-year patient survival and similar tenyear graft survival than non-infected. Conversely, the case-control study clearly shows that KTR with detectable RNA have lower ten-year patient and graft survivals than non-infected. These data strongly support the control of viral replication in HCV KTR as the best approach to improve patient and graft survivals. It should be emphasized that the applicability of antiviral treatment was limited during the era of interferon-based regimens. The use of several DAA regimens in CKD patients including KTR with renal impairment represents major progress that will allow extensive use of antiviral therapy in RT candidates and KTR patients with HCV [START_REF] Morales | Hepatitis C and its impact on renal transplantation[END_REF] . HCV therapies with DAAs are being constantly improved. Three DAAs combination have been approved in dialyzed patients or in patients with ESRD [START_REF] Bruchfeld | Elbasvir plus grazoprevir in patients with hepatitis C virus infection and stage 4-5 chronic kidney disease: clinical, virological, and health-related quality-of-life outcomes from a phase 3, multicentre, randomised, double-blind, placebo-controlled trial[END_REF][START_REF] Pockros | Efficacy of Direct-Acting Antiviral Combination for Patients With Hepatitis C Virus Genotype 1 Infection and Severe Renal Impairment or End-Stage Renal Disease[END_REF][START_REF] Roth | Grazoprevir plus elbasvir in treatmentnaive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study[END_REF][START_REF] Gane | Glecaprevir and Pibrentasvir in Patients with HCV and Severe Renal Impairment[END_REF] . Only the new combination of glecaprevir and pibrentasvir has shown pan-genotypic HCV activity achieved SVR rate of more than 95% [START_REF] Gane | Glecaprevir and Pibrentasvir in Patients with HCV and Severe Renal Impairment[END_REF] with negligible renal excretion. Other DAA regimens may be used in KTR patients when the glomerular filtration rate is > 30 ml/mn [START_REF] Afdhal | Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection[END_REF][START_REF] Feld | Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection[END_REF] . DAA treatment should be systematically proposed before and after RT in KTR with HCV replication.

Future studies are needed to confirm what has been previously reported in high-risk population for HCV (intravenous drugs user and men who have sex with men), namely whether systematic anti-viral treatment can decrease or even eliminate the incidence of viral hepatitis in dialysis patients and KTR. An European initiative for HCV elimination (European Hepatology -EASL-and Nephrology association -ERA/EDTA) proposed a program for "micro-elimination" of HCV in CKD patients.

The limit of this study was the absence of data concerning the anti-viral treatment and its efficacy on the viral replication in all patients collected in the Cristal database. We try to overcome this limit by performing a case-control study in which virological data and antiviral therapies were collected, by research assistance who analyze recipients' medical records.

In conclusion, HBV and HCV KTR without viral replication have similar patient and graft survivals than non-infected patients. Recent access to DAA regimens in HCV patients with renal dysfunction provides exciting perspectives. and in their matching non-infected controls were estimated using the Kaplan-Meier method

Legends of the tables

Figure legends : Figure 1 .

 :1 Figure legends: Figure 1. Flow shart of the study: 32,249 KTR were entered into the Cristal database; 816 who were < 18 years old were excluded from the study. A total of 31,433 adult KTR were included.

Figure 2a .

 2a Figure 2a. Ten-year patient survival in HCV, HBV and non-infected KTR were estimated using the Kaplan-Meier method.

Figure 2b .

 2b Figure 2b. Ten-year graft survival in HCV, HBV and non-infected KTR were estimated using the Kaplan-Meier method.

Figure 3a .

 3a Figure 3a. Ten-year patient survival in HCV KTR with viral replication (detectable RNA) and in their matching non-infected controls were estimated using the Kaplan-Meier method.

Figure 3b .

 3b Figure 3b. Ten-year graft survival in HCV KTR with viral replication (detectable RNA) and in their matching non-infected controls were estimated using the Kaplan-Meier method Figure4a. Ten-year patient survival in HCV KTR without viral replication (undetectable RNA) and in their matching non-infected controls were estimated using the Kaplan-Meier method.

Figure 4b .

 4b Figure 4b. Ten-year graft survival in HCV KTR without viral replication (undetectable RNA)

Table 1 .

 1 : Clinical characteristics according to virological status

Table 2 .

 2 Multivariate Analysis of Factors Associated with 10-year patient mortality in overall cohort

Table 3 .

 3 Multivariate analysis of factors associated with 10-year graft failure in overall cohort Supplementary Table 1. Results of case-control comparisons of undetectable HCV RNA patients and their randomly selected matched controls Supplementary

Table 2 :

 2 Results of case-control comparisons of detectable HCV RNA patients and their randomly selected matched controls

Table 1 . Clinical characteristics according to virological status

 1

	Virological status

a including mainly hypertensive nephropathy in addition others causes. Abbreviations: IQR=Interquartile range

Acknowledgement to french kidney transplantation network (for adult patients): Dr Gabriel Choukroun and Dr Fabien Saint (Amiens), Dr Thibault Culty et Dr Jean-François Subra (Angers), Dr Didier Ducloux et Dr François Kleinclauss (Besançon), Dr Jean-Marie Ferrière, Dr Pierre Merville, Dr Eric Dobremez (Bordeaux), Dr Georges Fournier, Dr Yannick Le Meur (Brest), Dr Xavier Tillou, Dr Thierry Lobbedez (Caen), Dr Jean-Paul Boiteux, Dr Anne-Elisabeth Heng (Clermont-Ferrand), Dr Philippe Grimbert, Dr Alaexandre de la Taille (Créteil), Dr Luc Cormier, Dr Christiane Mousson (Dijon), Dr Bénédicte Janbon, Dr Jean-Jacques Rambeaud (Grenoble), Dr Antoine Durbach, Dr Jacques Irani (Le Kremlin-Bicêtre), Dr Sébastien Bouye, Dr Christian Noël (Lille), Dr Aurélien Descazeaud, Dr Marie Essig (Limoges), Dr Lionel Badet, Dr Emmanuel Morelon (Lyon), Dr Yvon Berland, Dr Valérie Moal, Dr Eric Lechevallier (Marseille), Dr Georges Mourad, Dr Rodolphe Thuret

Grant support : This study was supported by a grant from ANRS (Agence Française de Recherches sur le VIH/Sida et les Hépatites virales) without any role. This work was supported by a Hospital-Based Clinical Research Program and a grant from ANRS (France Recherche Nord&Sud Sida-HIV Hépatites) 3


Caroline Charlier
email: caroline.charlier@aphp.fr

Julien Dang

Paul-Louis Woerther

Prise en charge hospitalière des infections urinaires complexes In-hospital management of acute complicated urinary tract infections

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Les infections urinaires hospitalisées correspondent soit à des infections urinaires sévères, définies par la présence d'un sepsis, ou d'un recours à la chirurgie pour drainer un obstacle ou une collection, soir des infections urinaires à risque de complication du fait d'un terrain particulier : infection masculine, sujet âgé, femme enceinte, insuffisance rénale définie par une clearance de la créatinine inférieure à 30 ml/min , anomalie de l'arbre urinaire, ou des infections à risque de bactérie multirésistante. La prise en charge de ces infections a récemment fait l'objet d'une conférence de consensus [START_REF] Caron | Practice guidelines for the management of adult community-acquired urinary tract infections[END_REF]. Certaines situations complexes justifient d'une attention particulière. Nous en détaillons quatre dans cette revue : infections sévères, infections survenant chez la femme enceinte, infections à bactéries multirésistantes, infections de kystes rénaux. Nous nous limiterons le propos aux infections hautes de l'adulte.

Infections urinaires graves : recommandations de la conférence de consensus

Les signes de gravité comportent la présence d'un score quick sequential organ failure assessment score (qSOFA) de 2 ou plus, d'un sepsis (anciennement appelé sepsis sévère, défini par la présence d'une dysfonction d'organe), d'un choc septique ou d'une indication chirurgicale de drainage (hors drainage vésical simple) [START_REF] Caron | Practice guidelines for the management of adult community-acquired urinary tract infections[END_REF][START_REF] Singer | The Third International Consensus definitions for sepsis and septic shock (Sepsis-3)[END_REF].

Le bilan doit comporter, outre l'examen cytobactériologique des urines et la réalisation systématique d'hémocultures, une évaluation de la fonction rénale et une imagerie morphologique des voies urinaires (en priorité un uroscanner) dans les 24 heures suivant le début de la prise en charge.

Le traitement probabiliste doit comporter l'association parentérale d'une bêta-lactamines et d'un aminoside. L'aminoside retenu est l'amikacine, qui conserve la meilleure activité sur les entérobactéries productrices de bêtalactamase à spectre étendu (E-BLSE), dont le taux de portage communautaire est actuellement estimé entre 5 et 10% en France, avec des disparités importantes selon les régions [START_REF] Woerther | Trends in human fecal carriage of extended-spectrum beta-lactamases in the community: toward the globalization of CTX-M[END_REF]. Le choix de la bêtalactamine prend en compte deux critères : la gravité clinique

Infections urinaires de la femme enceinte

Les infections du tractus urinaires sont une des complications infectieuses les plus fréquentes pendant la grossesse, elles sont rapportées, selon les séries, dans 2 à 10% des cas grossesses. Ses conséquences sont potentiellement graves pour la mère et la grossesse :

•

Les bactériuries asymptomatiques ont été rapportées dans 2 à 10% des grossesses [START_REF] Nicolle | Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults[END_REF]. Jusqu'à 40% des bactériuries asymptomatiques non traitées évoluent vers une pyélonéphrite chez la femme enceinte, dans un délai médian de 2 à 3 semaines (6, 7). Dans plusieurs séries et métaanalyses, les bactériuries étaint associées à un excès de prématurité, de petit poids pour l'âge gestationnel et de mortalité périnatale [START_REF] Smaill | Antibiotics for asymptomatic bacteriuria in pregnancy[END_REF][START_REF] Romero | Meta-analysis of the relationship between asymptomatic bacteriuria and preterm delivery/low birth weight[END_REF][START_REF] Naeye | Causes of the excessive rates of perinatal mortality and prematurity in pregnancies complicated by maternal urinary-tract infections[END_REF].

•

Les pyélonéphrites ont été rapportées dans 0,5 à 1% des grossesses [START_REF] Wing | Acute pyelonephritis in pregnancy: an 18-year retrospective analysis[END_REF]. Elles ont été associées à un risque de bactériémie de 17% dans une série américaine prospective publiée par Hill et al. [START_REF] Hill | Acute pyelonephritis in pregnancy[END_REF]. Dans une étude prospective menée par

Infections urinaires à entérobactérie multirésistante

Entérobactéries productrices de bêtalactamase à spectre étendu (E-BLSE)

Les infections urinaires à E-BLSE sont actuellement les situations d'infections à bactéries multirésistantes les plus souvent rencontrées. Du fait de l'augmentation régulière de leur fréquence, les dernières recommandations tiennent compte du risque associé à leur présence.

Dans les infections urinaires basses, les traitements de première intention sont la fosfomycine et le pivmécillinam, deux molécules habituellement actives sur la majorité des souches d'E. coli BLSE. En effet, bien qu'il s'agisse d'une bêtalactamine, le pivmécillinam (précurseur du mécillinam qui en est la molécule active) n'est pas hydrolysé par les bêtalactamase à spectre étendu et présente une bonne efficacité clinique dans ces situations [START_REF] Jansaker | Clinical and bacteriological effects of pivmecillinam for ESBL-producing Escherichia coli or Klebsiella pneumoniae in urinary tract infections[END_REF].

Dans les infections urinaires hautes graves et/ou en présence de facteurs de risque (voir plus haut), un traitement empirique par carbapénème est indiqué et le relais adapté aux résultats de l'antibiogramme. Cette famille de bêtalactamine reste constamment active en l'absence de mécanisme de résistance associé.

Il est important de savoir que certains tests rapides et simples à mettre en place sont disponibles dans certains laboratoires permettent de détecter avec d'excellentes valeurs prédictives la production d'une BLSE par une souche avant l'obtention de l'antibiogramme. Cette stratégie, qui permet une adaptation précoce de l'antibiothérapie peut être appliquée au culot urinaire à partir d'un échantillon positif à l'examen direct ou plus fréquemment à partir de la culture [START_REF] Gallah | The beta-Lacta test for direct detection of extendedspectrum-beta-lactamase-producing Enterobacteriaceae in urine[END_REF][START_REF] Renvoise | Evaluation of the betaLacta test, a rapid test detecting resistance to third-generation cephalosporins in clinical strains of Enterobacteriaceae[END_REF].

Entérobactéries productrices de céphalosporinases hyperproduites

Les souches avec céphalosporinases hyperproduites par dérépression chromosomique (chez les espèces Enterobacter spp.et Morganella morganii principalement) ou acquisition plasmidique (chez E. coli et K. pneumoniae) sont moins fréquentes que celles productrices de bêtalactamase à spectre étendu ; ce mécanisme de résistance peut conférer une résistance aux céphalosporines de troisième génération et constitue généralement une indication à un traitement par céfépime, une céphalosporine de quatrième génération, en particulier en cas de fort inoculum (lésions abcédées).

Entérobactéries productrices de carbapénémases

Après la dissémination de bêtalactamase à spectre étendu chez les entérobactéries (principalement E. [START_REF] Shortridge | Antimicrobial activity of ceftolozanetazobactam tested against enterobacteriaceae and Pseudomonas aeruginosa collected from patients with bloodstream infections isolated in United States hospitals (2013-2015) as part of the Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS) surveillance program[END_REF]. A la posologie de 1,5g trois fois par jour par voie intraveineuse, cet antibiotique bien toléré a démontré sa non-infériorité comparée à la ciprofloxacine dans le traitement des infections urinaires et présente une élimination urinaire sous forme inchangée supérieure à 90% [START_REF] Wagenlehner | Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI)[END_REF][START_REF] Scott | Ceftolozane/tazobactam: a review in complicated intra-abdominal and urinary tract infections[END_REF].

Ceftazidime-avibactam (disponible)

Cette association combine la classique ceftazidime à l'avibactam, un nouvel inhibiteur de bêtalactamase qui la protège contre l'hydrolyse des enzymes appartenant aux classes A et C d'Ambler.

De ce fait, cette association permet d'assurer une activité non seulement contre la plupart des E-BLSE mais aussi contre les entérobactéries productrices de carbapénémase KPC [START_REF] Mendes | Molecular beta-lactamase characterization of Gram-negative pathogens recovered from patients enrolled in the ceftazidime-avibactam phase 3 trials (RECAPTURE 1 and 2) for complicated urinary tract infections: Efficacies analysed against susceptible and resistant subsets[END_REF]. Enfin, cette association est également efficace contre la majorité des entérobactéries productrices d'OXA-48, carbapénémase la plus prévalente en France et qui a la particularité de ne pas hydrolyser la ceftazidime. Elle a également montré son intérêt dans le traitement des infections urinaires dues aux entérobactéries résistantes à la ceftazidime à la dose de 2g trois fois par jour par voie intraveineuse [START_REF] Carmeli | Ceftazidimeavibactam or best available therapy in patients with ceftazidime-resistant enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study[END_REF]. Son excrétion est également essentiellement urinaire à 90% (25).

Imipénème/cilastatine-relebactam (phase 3)

Le relebactam est un inhibiteur de bêtalactamase proche de l'avibactam du point de vue de sa structure ainsi que de sa capacité à inhiber les enzymes appartenant aux classes A et C d'Ambler. En association avec l'imipénème qui est en soi actif sur l'ensemble des bêtalactamase à spectre étendu, ce nouvel antibiotique permet donc d'inclure dans son spectre les bacilles à Gram négatif producteurs de carbapénémase KPC [START_REF] Zhanel | Imipenemrelebactam and meropenem-vaborbactam: two novel carbapenem-beta-lactamase inhibitor combinations[END_REF]. De façon intéressante, cette association est également active sur de nombreuses souches de P. aeruginosa résistantes à l'imipénème par hyperproduction de la céphalosporinase chromosomique associée à une perte de la porine D2 (27).

Méropénème-vaborbactam (phase 3)

Le vaborbactam est un inhibiteur de bêtalactamase, qui associé au méropénème -qui présente une excellente activité sur les bêtalactamases à spectre étendu -permet d'être actif sur les entérobactéries productrices de carbapénémase KPC. En revanche, cette association n'apporte pas d'avantage significatif sur les souches de P. aeruginosa résistantes au méropénème [START_REF] Zhanel | Imipenemrelebactam and meropenem-vaborbactam: two novel carbapenem-beta-lactamase inhibitor combinations[END_REF][START_REF] Castanheira | Meropenem-vaborbactam tested against contemporary Gram-negative isolates collected worldwide during 2014, including carbapenem-resistant, KPC-producing, multidrug-resistant, and extensively drug-resistant enterobacteriaceae[END_REF].

Céfidérocol (phase 2)

Il

Infections urinaires sur kyste

La polykystose hépatorénale autosomique dominante est la maladie rénale héréditaire la plus fréquente, avec une incidence de 1/400 à 1/1000 naissances [START_REF] Torres | Autosomal dominant polycystic kidney disease[END_REF] Ces données sont en cours de réévaluation [START_REF] Sallee | Cyst infections in patients with autosomal dominant polycystic kidney disease[END_REF][START_REF] Lantinga | Management of renal cyst infection in patients with autosomal dominant polycystic kidney disease: a systematic review[END_REF].

Liens d'intérêts :

PLW : honoraires pour la réalisation de conférences et invitations à des congrès par le laboratoire MSD.

CC, JD : aucun conflit d'intérêts.

  du malade et le risque d'E-BLSE. En l'absence de choc septique, d'antécédent d'infection urinaire/colonisation à E-BLSE dans les 6 mois, la bêtalactamine choisie est une céphalosporine de troisième génération (ceftriaxone ou céfotaxime). Dans un contexte de choc septique, un traitement par carbapénème est indiqué, notamment en cas de notion de colonisation ou d'infection urinaire à E-BLSE dans les 6 derniers mois, mais aussi en cas de prise récente d'amoxicilline/acide clavulanique, fluoroquinolones, céphalosporines de deuxième et troisième génération, de retour de voyage dans une zone de forte endémie (sous-continent indien, Asie du Sud-Est et Afrique notamment) ou un hébergement en long séjour ou en maison de retraite. En cas d'allergie grave aux bêtalactamines ou d'allergie documentée aux céphalosporines, l'aztréonam est une alternative intéressante car cette bêtalactamine de la famille des monobactames ne présente pas d'allergie croisée avec les autres bêtalactamines et peut ainsi être prescrite dans cette situation (hormis en cas d'antécédent de syndrome d'hypersensibilité médicamenteuse (syndrome drug reaction with eosinophilia and systemic symptoms [DRESS]) aux bêtalactamines, combinant toxidermie avec éosinophilie et signes systémiques) (4). La gravité de l'infection ou la présence d'une bactériémie associée ne sont pas en eux-mêmes une indication à prolonger la durée totale antibiothérapie, qui doit être de 10 jours.

  plus haut.). Ces résultats sont cependant à nuancer. D'abord, ils ont été obtenus chez des patients pour la plupart indemnes d'infection de kyste (parfois même décédés), et l'inflammation locale pourrait augmenter la diffusion des antibiotiques, comme cela a été constaté pour l'amikacine dont la concentration intrakystique indétectable en l'absence d'infection, est évaluée à environ 50% de la valeur sérique au cours d'une infection de kyste[START_REF] Ohkawa | Biochemical and pharmacodynamic studies of simple renal cyst fluids in relation to infection[END_REF]. Certains antibiotiques, notamment les bêtalactamines peuvent également pénétrer lentement la paroi kystique, justifiant de traitement prolongés pour atteindre de bonnes concentrations in situ (5 à 8 jours pour les bêtalactamines (54)).Enfin, un gradient kyste/sérum faible n'exclut pas d'atteindre une concentration antibiotique intra kystique supérieure à la concentration minimale inhibitrice vis-à-vis des germes identifiés, donc efficace. En l'absence de documentation microbiologique, il est primordial de proposer une antibiothérapie active sur les entérobactéries, qui repose en première intention sur les fluoroquinolones en l'absence d'exposition dans les 3 à 6 mois précédents. En l'absence de données issus d'essai, il n'existe toujours aucune recommandation concernant les modalités du traitement antimicrobien (nombre d'antibiotiques, voie d'administration, durée) ni sur les indications à un drainage éventuel[START_REF] Davison | Executive summary of the KDIGO Controversies Conference on Supportive Care in Chronic Kidney Disease: developing a roadmap to improving quality care[END_REF]. Des échecs de traitement antibiotique ont été rapportés dans 29% des cas, et seraient liés (i) à la taille du kyste (plus de 5 cm) (ii) au germe incriminé (plus d'échecs en cas d'infections impliquant une autre bactérie que E. coli).

  Pour faire face à cette nouvelle menace, de nouvelles molécules (dont les principales sont brièvement développées plus bas) ont été développées ou sont encore en cours de développement. Il s'agit le plus souvent d'associations combinant une bêtalactamine à un inhibiteur de bêtalactamase qui visent non seulement à créer des alternatives aux carbapénèmes pour le traitement des bacilles à Gram négatif producteurs de bêtalactamase à spectre étendu mais aussi de pouvoir disposer de molécules efficaces pour les traitements des bacilles à Gram négatif producteurs de carbapénémases.Cette association combine le ceftolozane, une nouvelle céphalosporine dérivée de la ceftazidime qui a l'avantage de présenter une très grande stabilité vis-à-vis des céphalosporinases produites par les entérobactéries du groupe 3 et Pseudomonas aeruginosa, et le tazobactam qui est un inhibiteur de bêta-lactamases actif sur les bêtalactamase à spectre étendu. Il en résulte que l'association de ceftolozane et de tazobactam reste active non seulement sur la plupart des bacilles à Gram négatif

	4.3.1. Ceftolozane-tazobactam (disponible)
	génétiques appelés plasmides, qui ont la caractéristique de diffuser facilement non seulement entre les
	différentes souches d'une même espèce, mais également d'une espèce à l'autre. Comme toutes les
	bêta-lactamases, les carbapénémases répondent à la classification d'Ambler. Chez les entérobactéries,
	les carbapénémases les plus fréquentes sont KPC (classe A d'Ambler), les métalloenzymes comme

coli et K. pneumoniae), la dernière décennie a vu l'émergence de nouveaux mécanismes capables de conférer aux bactéries qui les acquièrent une résistance aux carbapénèmes

[START_REF] Logan | The epidemiology of carbapenem-resistant enterobacteriaceae: the impact and evolution of a global menace[END_REF]

.

Comme la plupart des mécanismes de résistance des bacilles à Gram négatif aux bêtalactamines, il s'agit quasiexclusivement de bêtalactamases, c'est-à-dire d'enzymes capables d'hydrolyser les carbapénèmes en composés inactifs. Si cette diffusion touche aujourd'hui à des degrés variables l'ensemble des pays du globe, c'est en grande partie dû au fait que les gènes codant ces enzymes sont portées par des éléments NDM, IMP ou VIM (classe B d'Ambler) ou OXA-48 et ses dérivées (classe D d'Ambler). Les enzymes de la classe C, composé des céphalosporinases ne comportent pas d'enzyme susceptible d'hydrolyser les carbapénèmes à ce jour. producteurs de céphalosporinase à haut niveau (y compris P. aeruginosa) mais également sur un grand nombre d'E-BLSE

  s'agit d'un antibiotique sidérophore composé d'une céphalosporine comportant un résidu catéchol capable de chélater le fer. L'ion fer est capté par la bactérie, et la molécule antibiotique qui lui est

attachée est transportée à travers la membrane externe grâce à un système de transport actif, indépendant du système des porines qui sont les transporteurs habituels de toutes les autres classes antibiotiques. Le céfidérocol est par ailleurs stable vis-à-vis de l'ensemble des enzymes connues ce qui permet à cet antibiotique d'échapper à l'ensemble des mécanismes de résistance connus chez les bacilles à Gram négatif, y compris P. aeruginosa, Acinetobacter baumannii et Stenotrophomonas maltophilia, ce qui en fait une molécule extrêmement prometteuse. Les résultats de l'étude de phase 2 comparant l'efficacité du céfidérocol à la dose de 2g trois fois par jour par voie intraveineuse à celle du méropénème pour le traitement des infections urinaires viennent de démontrer sa non-infériorité et sa bonne tolérance

[START_REF] Portsmouth | Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial[END_REF]

.

  Des complications telles que des saignements intrakystiques ou des surinfections bactériennes ont été rapportées à une fréquence de 0,01 épisodes par patient par an. Les infections de kyste sont et K. pneumoniae (respectivement 11 cas et deux cas sur 19, soit 58% et 11%) puis des cocci à Gram positif (entérocoques et Staphylococcus epidermidis)[START_REF] Suwabe | Cyst infection in autosomal dominant polycystic kidney disease: causative microorganisms and susceptibility to lipidsoluble antibiotics[END_REF]. La prévalence de la résistance des souches d'E. coli aux fluoroquinolones et au cotrimoxazole était élevée dans ce travail, (respectivement 46 et 36%), corrélée au nombre d'infections antérieures, et donc à l'exposition aux antibiotiques. Les difficultés posées par les infections de kyste sont diagnostiques et thérapeutiques, et elles n'ont pas fait l'objet de beaucoup d'études à ce jour : les plus grandes séries sont celles publiées par Sallée et al. (travail rétrospectif sur 31 cas entre 1998 et 2008), Suwabe et al. (travail rétrospectif sur 29 cas entre 2004 et 2014), et Lantinga et al. (85 cas issus de plus de 60 séries et cas cliniques entre 1948 et 2014)[START_REF] Sallee | Cyst infections in patients with autosomal dominant polycystic kidney disease[END_REF][START_REF] Lantinga | Management of renal cyst infection in patients with autosomal dominant polycystic kidney disease: a systematic review[END_REF][START_REF] Suwabe | Cyst infection in autosomal dominant polycystic kidney disease: causative microorganisms and susceptibility to lipidsoluble antibiotics[END_REF]. Les symptômes sont non spécifiques et associent fièvre et douleur abdominale ou lombaire. Des signes fonctionnels urinaires, tels qu'une pollakiurie ou des brûlures mictionnelles, ont parfois été rapportés, ainsi que des troubles digestifs non spécifiques. Au plan biologique, on note fréquemment un syndrome inflammatoire ainsi qu'une leucocyturie. Rien ne permet de différencier une infection de kyste rénal d'une infection rénale parenchymateuse, ni d'une hémorragie intra-kystique non surinfectée. Dans au moins 25% des cas, la culture bactériologique des urines et les hémocultures sont négatives[START_REF] Sallee | Cyst infections in patients with autosomal dominant polycystic kidney disease[END_REF][START_REF] Suwabe | Cyst infection in autosomal dominant polycystic kidney disease: causative microorganisms and susceptibility to lipidsoluble antibiotics[END_REF].Des critères permettant d'établir le diagnostic d'infection probable ont été établis par Sallée et al. qui ont été depuis repris et adaptés dans d'autres études[START_REF] Sallee | Cyst infections in patients with autosomal dominant polycystic kidney disease[END_REF]. Le diagnostic nécessitait alors la présence de tous les critères suivants : fièvre définie par une température de plus de 38,5°C pendant plus de 3 jours, douleur abdominale ou lombaire, augmentation de la concentration sérique de CRP de plus de 50 mg/L, absence de saignement intrakystique récent au scanner ou d'autre explication de syndrome fébrile. Ces critères soulignent les caractéristiques du diagnostic d'infection de kyste, porté sur un faisceau d'arguments cliniques et sur l'exclusion des autres causes de fièvre aigue. Aucune étude n'a pu notamment discerner les infections kystiques et celles du parenchyme rénal, ce qui a amené à exclure des séries étudiées les cas d'hémorragies intrakystiques possiblement surinfectées. L'apport de l'imagerie au diagnostic est incertain : aucun signe radiologique n'est spécifique d'une infection de kyste rénal, et la sensibilité d'une imagerie est impossible à déterminer en en raison de l'impossibilité de ponctionner tous les kystes rénaux et d'évaluer le taux de faux-négatifs radiologiques. L'échographie ne permet pas d'évaluer les gros volumes rénaux, a une rentabilité faible et reste opérateur-dépendant. La tomodensitométrie (TDM) abdominale est l'examen le plus pratiqué, mais nécessite l'injection de produit de contraste iodé, contre-indiquée chez les patients en insuffisance rénale chronique. Oh et al. ont mené une analyse radiologique de 51 infections de kyste prouvées par ponction, dont 31 infections de kyste rénal et 20 infections de kyste hépatique. Quatre-6%)[START_REF] Oh | Infected cyst in patients with autosomal dominant polycystic kidney disease: Analysis of computed tomographic and ultrasonographic imaging features[END_REF]. L'absence de bras contrôle ne permettait pas de conclure à la spécificité de ces signes radiologiques. L'IRM rénale peut montrer les mêmes caractéristiques, et également un hyper signal en séquence de diffusion au niveau des kystes infectés[START_REF] Suwabe | Cyst infection in autosomal dominant polycystic kidney disease: causative microorganisms and susceptibility to lipidsoluble antibiotics[END_REF]. La rentabilité de ces deux examens est faible dans toutes les études[START_REF] Sallee | Cyst infections in patients with autosomal dominant polycystic kidney disease[END_REF][START_REF] Jouret | Diagnosis of cyst infection in patients with autosomal dominant polycystic kidney disease: attributes and limitations of the current modalities[END_REF]. La tomographie par émission de positons (PET) couplée à la TDM, avec comme traceur le fluorodésoxyglucose ([ 18 F]-FDG) a été évaluée plus récemment[START_REF] Sallee | Cyst infections in patients with autosomal dominant polycystic kidney disease[END_REF][START_REF] Jouret | Positron-emission computed tomography in cyst infection diagnosis in patients with autosomal dominant polycystic kidney disease[END_REF][START_REF] Neuville | Diagnostic algorithm in the management of acute febrile abdomen in patients with autosomal dominant polycystic kidney disease[END_REF][START_REF] Piccoli | Positron emission tomography in the diagnostic pathway for intracystic infection in ADPKD and "cystic" kidneys. a case series[END_REF][START_REF] Bobot | Diagnostic performance of ( 18 F)-fluorodeoxyglucose positron emission tomography-computed tomography in cyst infection in patients with autosomal dominant polycystic kidney disease[END_REF][START_REF] Bleeker-Rovers | Diagnosis of renal and hepatic cyst infections by 18-F-fluorodeoxyglucose positron emission tomography in autosomal dominant polycystic kidney disease[END_REF]. Elle permet d'identifier un hyper métabolisme en regard d'un kyste ou de ses parois, avec l'avantage d'être réalisable chez l'insuffisant rénal chronique sévère, et possiblement de suivre l'efficacité du traitement et d'exclure une autre cause de syndrome inflammatoire. Plusieurs limites doivent cependant être rappelées : la valeur de la PET-TDM n'a Sur la base de ces données, les antibiotiques recommandés dans ce contexte sont les quinolones, le cotrimoxazole, le métronidazole, les macrolides, le linézolide ou la clindamycine tandis que les bêtalactamines et les aminosides, souvent utilisés en pratique lipophobes, devraient être moins efficaces. Ces recommandations sont appuyées par plusieurs études de petite taille ayant mesuré la diffusion intrakystique de différents antibiotiques. Les fluoroquinolones et le cotrimoxazole semblent se concentrer dans les kystes (ratio kyste/sérum de 2,5 pour la ciprofloxacine dans une série de sept patients, de 3,9 pour le triméthoprime, et de 0,43 pour le sulfaméthoxazole dans une série de huit patients), tandis que la concentration atteinte par les aminosides semble plus faible (ratio kyste/sérum de 0,26 [n = 3]) pour la gentamicine, ou indétectable après une dose d'amikacine (n=2), comme celle de certaines bêtalactamines (ratio kyste/sérum de 0,12 pour la ticarcilline [n=1], de 0,04 à 0,13 pour le méropénème [n=2], concentration de 0 à 9 µg/ml de pipéracilline après une dose [n=8], et concentration indétectable de céfotaxime [n=3])[START_REF] Bennett | Cyst fluid antibiotic concentrations in autosomal-dominant polycystic kidney disease[END_REF][START_REF] Muther | Cyst fluid antibiotic concentrations in polycystic kidney disease: differences between proximal and distal cysts[END_REF][START_REF] Elzinga | Ciprofloxacin activity in cyst fluid from polycystic kidneys[END_REF][START_REF] Elzinga | Trimethoprim-sulfamethoxazole in cyst fluid from autosomal dominant polycystic kidneys[END_REF][START_REF] Ohkawa | Biochemical and pharmacodynamic studies of simple renal cyst fluids in relation to infection[END_REF][START_REF] Hamanoue | Cyst infection in autosomal dominant polycystic kidney disease: penetration of meropenem into infected cysts[END_REF][START_REF] Bonadio | Penetration of piperacillin into renal cysts[END_REF]. Il n'existe pas encore donnée à notre connaissance sur les nouveaux antibiotiques actifs sur les bactéries productrices de carbapénémase (cf.

	vingt-six pour cent des TDM avaient bénéficié d'une injection de produit de contraste iodé (39). Les
	kystes infectés étaient le plus souvent sous-capsulaires (90%), avec un diamètre médian de 5,5 cm
	(extrêmes : 2,3 -18,8 cm), à contours irréguliers ou lobulés (94%). La paroi des kystes était souvent
	épaissie de plus de 3 mm (84%), rehaussée par le produit de contraste, et entourée d'une infiltration de
	la graisse périkystique (53%). Le contenu kystique présentait rarement un niveau liquide-liquide (6%)
	et des bulles d'air (Au plan thérapeutique, il n'existe que très peu de données permettant de guider la prise en
	charge. La pénétration des antibiotiques dans le kyste est un facteur majeur à prendre en compte. Elle
	est liée à deux paramètres : filtration glomérulaire de la molécule et transport transépithélial à travers
	responsables de 10% des hospitalisations des patients avec polykystose (31). Elles peuvent accélérer la paroi kystique (46). Les kystes développés à partir des cellules tubulaires proximales ont un
	l'évolution vers l'insuffisance rénale terminale et ont été associées à une mortalité pouvant aller épithélium avec des jonctions cellulaires lâches et une composition ionique proche du plasma ; les
	jusqu'à 7% dans des séries historiques (32-34). antibiotiques y diffusent par passage transcellulaire selon un gradient de concentration. Les kystes
	développés à partir des cellules tubulaires distales ont un épithélium étanche avec des jonctions Sur le plan physiopathologique, l'infection peut se faire par voie ascendante urinaire, par voie hématogène, ou rarement par inoculation iatrogène. Il existe peu de données sur l'écologie des serrées ; les mécanismes de traversée y sont plus complexes (47, 48). On peut retenir que les

. Cette pathologie est caractérisée par le développement de nombreux kystes rénaux et hépatiques. Les kystes rénaux se développent à partir de tous les segments tubulaires du néphron ; ils peuvent perdre leur communication avec le tractus urinaire. infections de kyste, dont le gold standard diagnostique repose sur la mise en culture du liquide de ponction du kyste infecté. Sur les 19 cas confirmés rapportés par Suwabe et al. les bactéries les plus fréquemment mises en évidence étaient des entérobactéries dans 15 cas sur 19 (79%), notamment E. coli Le diagnostic de certitude repose donc sur l'identification de micro-organisme ou de débris de polynucléaires neutrophiles dans le liquide de kyste, mais cette ponction est rarement pratiquée, car les examens d'imagerie ne permettent pas toujours d'identifier avec certitude le kyste infecté, qui n'est pas toujours accessible à un geste de ponction percutanée. Le risque potentiel de complication hémorragique doit être également pris en compte, même s'il semble faible d'après les données très limitées disponibles dans la littérature : aucune complication n'était observée sur 16 patients avec des kystes de 3 à 8 cm dans l'étude de Akinci et al., sur 24 patients dans l'étude de Monville et al., ou 15

patients avec des kystes de 6 à 12 cm dans l'étude de Kovacevic et al.

[START_REF] Monville | Sclérothérapie percutanée à l'éthanol des kystes rénaux symptomatiques : résultats à 4 ans[END_REF][START_REF] Akinci | Percutaneous treatment of pyocystis in patients with autosomal dominant polycystic kidney disease[END_REF][START_REF] Kovacevic | Ultrasound-guided percutaneous sclerotherapy of simple renal cysts: primary success and procedure safety[END_REF]

. jamais été comparée à celle de la culture d'un liquide kyste, sa sensibilité dépend de la précocité de sa réalisation par rapport à l'instauration de l'antibiothérapie et l'imagerie, et sa spécificité est débattue, dans la mesure où un hyper métabolisme pourrait également refléter une hémorragie très récente ou une lésion tumorale, ou une infection parenchymateuse adjacente au kyste. Enfin, la PET-TDM est un examen coûteux et difficilement accessible dans beaucoup de centres hospitaliers. molécules liposolubles traversent plus facilement l'épithélium kystique, tandis qu'un pH kystique acide, comme cela est rapporté au niveau de ces kystes distaux, aide à l'ionisation complète de certaines molécules comme la clindamycine, et diminuerait leur capacité à ressortir du kyste

[START_REF] Schwab | PH-dependent accumulation of clindamycin in a polycystic kidney[END_REF]

.


Maxime Coutrot
email: maxime.coutrot@aphp.fr

Jona Joachim

François Dépret

Sandrine Millasseau

Hélène Nougué

Joaquim Matéo

Alexandre Mebazaa

Etienne Gayat

Fabrice Vallée

Noninvasive continuous detection of arterial hypotension during induction of anaesthesia using a photoplethysmographic signal: proof of concept

Keywords: General anaesthesia, Arterial hypotension, Pulse oximetry, Intraoperative monitoring, Haemodynamics, Photoplethysmography, Perfusion Index ClinicalTrials.gov NCT03756935

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

EDITOR'S KEY POINTS

• Photoplethysmography may be used to assess the dicrotic notch height and perfusion index during anaesthesia • This study sought to investigate whether relative variations in the photoplethysmographic dicrotic notch height and perfusion index are predictive for intra-operative hypotension during anaesthesia induction.

• A combination of the relative variations in dicrotic notch height and perfusion index showed a high predictive power for intra-operative hypotension.

• Photoplethysmography may be used as additional haemodynamic detection method in patients at risk of intra-operative hypotension during anaesthesia induction.

INTRODUCTION

Haemodynamic stability is a major issue in the management of patients during general anaesthesia. Anaesthetic drugs may induce a rapid and deep systemic arterial blood pressure drop, which leads to intra-operative hypotension episodes. Intra-operative hypotension can contribute to complications, such as myocardial infarction, cerebral hypoperfusion or acute kidney injury. [START_REF] Lienhart | Survey of anesthesia-related mortality in France[END_REF][START_REF] Nair | Anesthesia information management system-based near real-time decision support to manage intraoperative hypotension and hypertension[END_REF][START_REF] Futier | Effect of Individualized vs Standard Blood Pressure Management Strategies on Postoperative Organ Dysfunction Among High-Risk Patients Undergoing Major Surgery: A Randomized Clinical Trial[END_REF][START_REF] Wesselink | Intraoperative hypotension and the risk of postoperative adverse outcomes: a systematic review[END_REF] These adverse events may induce higher postsurgery mortality risk , result in extended hospital stay, and are thus a source of higher hospital costs. [START_REF] Willingham | Concurrence of Intraoperative Hypotension, Low Minimum Alveolar Concentration, and Low Bispectral Index Is Associated with Postoperative Death[END_REF][START_REF] Reich | Predictors of Hypotension After Induction of General Anesthesia[END_REF][START_REF] Kork | Association of comorbidities with postoperative in-hospital mortality: a retrospective cohort study[END_REF] Standard haemodynamic monitoring in the operating room includes electrocardiography, assessment of the arterial oxygenation saturation by pulse oximetry, and non-invasive blood pressure measurements from an oscillometric blood pressure cuff. The major drawback of the oscillometric cuff is that it measures blood pressure at intermittent intervals only. As the blood pressure may vary quickly, especially during induction of anaesthesia, intra-operative hypotension should be detected in real-time, as even a short hypotensive period may have deleterious consequences on vital organs. 8 9 Digital photoplethysmography is a non-invasive signal produced by light absorption variations due to pulsatile blood volume variations. Similarities in the photoplethysmographic and invasive blood pressure waveforms have been described since the 1940s. 10 11 Indices derived from photoplethysmographic signals have been used successfully to characterise the cardiovascular status in patients. Dicpleth, representing the relative height of the dicrotic wave compared to the maximum peak of the waveform (Figure 1, Panel A), has been described as the amount of reflected wave, dependent of the vascular tone. Reduction in Dicpleth has been shown to be related to the reduction of vascular tone due to vasodilator drugs such as salbutamol or glyceryl trinitrate. [START_REF] Chowienczyk | Photoplethysmographic assessment of pulse wave reflection: blunted response to endothelium-dependent beta2-adrenergic vasodilation in type II diabetes mellitus[END_REF] The perfusion index (PI) represents the ratio of the pulsatile light absorption (i.e the amount of blood ejected at each systole) on the continuous absorption (corresponding to the nonpulsatile vessels, bones and soft tissues) (Figure 1, Panel A). The perfusion index has been described as a reliable tool for vascular tone assessment and monitoring. 13 14 As Dicpleth and PI are both related to vascular tone and are easily derived from the photoplethysmographic signal, we aimed to explore whether the combined analysis of Dicpleth and PI variations would allow for early detection of intra-operative hypotension during the induction of general anaesthesia.

MATERIAL AND METHODS:

Patients

We conducted a single-centre, prospective and observational study in the neuroradiology unit of the department of Anaesthesiology and Intensive Care of Lariboisière University Hospital (Paris, France). The study has been approved by local ethics committee (n°CE SRLF 11-356). Inclusion criteria were patients with age over 18-year-old undergoing elective neuroradiological procedures. All patients were included after oral informed consent was obtained. Exclusion criteria from the study were cardiac arrhythmia (i.e auricular fibrillation) and pregnancy. The study was registered in ClinicalTrials.gov (NCT03756935).

Anaesthesia protocol

Before induction of anaesthesia, standard monitoring was initiated with electrocardiography, non-invasive brachial arterial blood pressure measurements (PHILIPS FRANCE, Suresnes, France) set to inflate every minute and digital pulse oximetry (PHILIPS FRANCE, Suresnes, France) placed on the second finger of the contralateral side to the blood pressure cuff. Bispectral index (BIS; BIS™quatro sensor, Medtronic France, Boulogne-Billancourt, France) and neuromuscular blockade monitoring (TOF Watch®, ALSEVIA PHARMA, Paris, France) were also used to monitor anaesthesia. All monitoring parameters were available on a PHILIPS Intellivue MP 60 monitor (PHILIPS FRANCE, Suresnes, France). Induction of anaesthesia was conducted according to our local standard of care with Target Controlled Anaesthesia (TCA) using remifentanil and propofol with a starting dose of 5 ng mL -1 and 5 µg mL -1 , and adjusted to reach a BIS between 40 and 60. After the BIS decreased below 60 and loss of consciousness was observed, neuromuscular blockade was conducted by intravenous injection of 0.5 mg kg -1 of atracurium. Patients were then mechanically ventilated with tracheal intubation via direct laryngoscopy (end-tidal volume = 6 mL kg-1 of ideal body weight, positive end-expiratory pressure = 5 cmH2O, respiratory rate and oxygen fraction to reach an end-tidal CO2=4.7 kPa and an O2 saturation >95%).

In agreement with our local protocol for neuroradiological patients, arterial pressure was measured every minute during induction and every 5 minutes after tracheal intubation and stabilization. The anaesthetist in charge of the patient could at any time modify the frequency of the measurements, and treat hypotensive episodes with fluid load and/or vasopressor administration (phenylephrine and/or noradrenaline). After induction, some patients were subjected to invasive and continuous blood pressure monitoring, following our standard department management guidelines or by decision of the anaesthetist in charge of the patient.

Data collection

All monitoring parameters and curves displayed on the monitor were recorded on a computer with ixTrend© software (ixellence, Wildau, Germany). Haemodynamic parameters (heart rate, systolic arterial pressure [SAP], mean arterial pressure [MAP] and diastolic arterial pressure [DAP]), and photophlethysmographic parameters (Dicpleth, PI and SpO2) were then retrospectively sampled every minute during induction. The induction period was arbitrarily defined from pre-oxygenation to 3 minutes after connection to mechanical ventilation. "Baseline" values were obtained by averaging of the two measures (1 minute apart) prior to the anaesthetic drug injection during the preoxygenation period.

We defined "pre-pressor" values as the measures prior to the vasopressor bolus during intra-operative episodes. "Peak-pressor" values were defined as the maximum effects of vasopressor bolus, when the highest MAP was reached. In agreement with most studies, intra-operative hypotension was defined as a MAP drop of more than 20% from baseline MAP. [START_REF] Bijker | Incidence of intraoperative hypotension as a function of the chosen definition: literature definitions applied to a retrospective cohort using automated data collection[END_REF]

Dicpleth and perfusion index measurements

Dicpleth was obtained from the recorded photoplethysmographic waveforms by an operator who was blinded from arterial blood pressure values. The Dicpleth was defined as the ratio of the height of the dicrotic notch (from nadir point of the complex to the notch) to the height of the systolic peak (from same nadir point of the complex to the pic), measured at endexpiratory time in patients under mechanical ventilation (average of 3 consecutive complexes) (Figure 1, Panel B). The perfusion index was provided by the manufacturer and is calculated as the ratio of the pulsatile component of the photoplethysmographic signal and the continuous component.

We calculated the ∆MAP, ∆Dicpleth, and ∆PI during the induction period as their relative variations (in percent) from their baseline values. During vasopressor boluses, respective parameter variations were calculated between "pre-pressor" and "peak-pressor" measurements.

Dicradial measurements

In patients with invasive monitoring during maintenance of anaesthesia, Dicradial was also measured from the arterial pressure signal using the same methodology as Dicpleth. The last 3 heart beats of the end-expiratory period were used to calculate Dicradial, from the height of the dicrotic notch to the height of the systolic peak. In those patients, Dicpleth, Dicradial and their relative variations (∆Dicpleth and ∆Dicradial) during vasoconstrictors administration were also analysed.

Statistical analysis

Values were expressed as median and interquartile range [25 th ; 75th percentiles]. Changes of the parameters were analysed using Wilcoxon rank test. Concordance percentages between delta ∆MAP, and ∆Dicpleth and ∆PI were calculated during induction period. Areas under the curve (AUC) of Receiver Operating Characteristic (ROC) curve (with 95% confidence interval) of ΔDicpleth and ΔPI to detect a hypotensive episode were estimated and eventually compared using DeLong test. Youden method was used to determine the optimal ΔDicpleth and ΔPI cut-off values to detect hypotensive episodes. ROC curve of combination of ∆Dicpleth and ∆PI was built using logistic model. Correlation tests were performed using Spearman test. P<0.05 was considered as statistically significant.

The primary aim of the study was to estimate the AUC of the ROC curve of both ΔDicpleth and ΔPI to track hypotension during induction. Sample size was determined with an expected AUC at 0.85, an expected incidence of hypotension of 80% and the width of the confidence interval of 1. With a power of 80%, the number of patients to include was then 62. [START_REF] Obuchowski | Sample size calculations in studies of test accuracy[END_REF] Secondary objective was to evaluate AUC of the ROC curve for the combination of ΔDicpleth and ΔPI.

Statistical analysis was performed using Prism 6.00© (Graphpad Software, Inc, La Jolla, CA, USA) and R 3.3.0 software (R foundation for Statistical Computing, Vienna, Austria).

Patients who had non-measurable Dicpleth at baseline before induction of anaesthesia were excluded from the analysis.

RESULTS

Patients

From November 2014 to May 2015, 65 patients were included in the study. Before induction of anaesthesia, Dicpleth was non-measurable in 4 patients (6.2%) due to the absence of detectable dicrotic notch on the photoplethysmographic signal (class IV waveform according to Dawber et al.). [START_REF] Dawber | Characteristics of the dicrotic notch of the arterail pulse wave in coronary heart disease[END_REF] Characteristics of the 61 remaining patients are listed in Table 1. Most patients were ASA II, with a mean age of 54 [39; 64] years. Arterial hypertension, smoking, and dyslipidaemia were the most common co-morbidity encountered. Reason for Neuroradiology procedures was mainly aneurysm or arteriovenous malformation scheduled embolization. ∆Dicpleth and ∆PI over induction time is described in Figure 2. We found 89% concordance between ΔDicpleth and ΔMAP and 90% between ∆PI and ∆MAP (Supplemental file 1). 2. The best threshold value of ∆Dicpleth and ∆PI for detecting intra-operative hypotension were -19% and 51%, respectively. AUC of ∆Dicpleth and ∆PI were not significantly different (p=0.22). Combining ∆Dicpleth and ∆PI to detect hypotensive episodes improved the detection performance with an AUC of ROC curve (0.91, (95%CI 0.88-0.95, p<0.001) statistically better than ∆Dicpleth and ∆PI separately (p=0.026 and p<0.001, respectively) (Table 2, Supplemental file 2 and 3). ∆Dicpleth and ∆PI under the effect of vasopressors were strongly related to ∆MAP (r=+0.73, 95%CI 0.48-0.87, p<0.001 and r = -0.62 95%CI -0.81 to -0.32, p<0.001; respectively) (Supplemental file 4).

Evolution of MAP, Dicpleth and perfusion index during the induction period

Diagnosis performances of ∆Dicpleth and ∆PI for detection of arterial hypotension

Evolution of MAP, Dicpleth and PI during vasoconstrictor administration

DISCUSSION

In our study, we describe during induction of anaesthesia the variations of two parameters issued from photoplethysmographic curves, namely Dicpleth and PI, and their performance to detect intra-operative hypotension under the vasoactive effects of anaesthetic drugs. ∆MAP and ∆Dicpleth vary in parallel during induction of anaesthesia, while ∆MAP and ∆PI vary inversely, with good concordance (89% and 90% respectively). Our study also found correlations between variations of Dicpleth and MAP on one hand, and PI and MAP on the other hand, under the influence of vasoconstrictors. The main result of our study is that ∆Dicpleth and ∆PI were accurate and presented similar performances to detect intra-operative hypotension induced by general anaesthesia. Moreover, a combined analysis of these two parameters enhanced diagnostic performance for detecting intra-operative hypotension under actions of vasoactive effect of anaesthetics. Dicrotic waveform variations have been described on invasive ABP and photoplethysmographic curves with changes of haemodynamic status in various clinical conditions. At the aortic level, the dicrotic notch represents the closure of aortic valve, i.e the end-systolic pressure, which is then followed by the dicrotic wave and the aortic elastic recoil (Windkessel effect). End-systolic pressure is dependent on afterload, which can vary quickly with changes in vascular tone, as during induction of anaesthesia due to the vasoactive effect of anaesthetic drugs. [START_REF] Hébert | Relation between aortic dicrotic notch pressure and mean aortic pressure in adults[END_REF] A linear relationship has been described between central dicrotic notch pressure and MAP. [START_REF] Hébert | Relation between aortic dicrotic notch pressure and mean aortic pressure in adults[END_REF] A similar relationship at the photoplethysmography level has been suggested between Dicpleth and MAP. [START_REF] Millasseau | Determination of age-related increases in large artery stiffness by digital pulse contour analysis[END_REF] But to our knowledge, no study quantified Dicpleth variations to detect arterial hypotension. The photoplethysmography curve represents the pulsatile variations of light absorption measured on a tissue. It is an indirect measurement of arteriolar dilatation and hence of arteriolar transmural pressure variations at each cardiac cycle. It seems that ABP and photoplethysmographic waveforms have the same determinants as confirmed in a subanalysis we performed that shows high correlation between dicrotic notch height on the photoplethysmographic signal and radial invasive ABP (ESM 5). Indeed a transfer function has been previously described between invasive ABP and photoplethysmographic curves. [START_REF] Millasseau | Noninvasive assessment of the digital volume pulse. Comparison with the peripheral pressure pulse[END_REF] This suggests that Dicpleth could be used as a surrogate parameter for the non-invasive and continuous monitoring of MAP during induction of anaesthesia. Furthermore, as the dicrotic notch pressure at the aortic level, Dicpleth, could be used to assess vascular tone and MAP variations under vasoactive drugs effect as reported in several previous studies. [START_REF] Millasseau | Contour analysis of the photoplethysmographic pulse measured at the finger[END_REF] [START_REF] Chowienczyk | Photoplethysmographic assessment of pulse wave reflection: blunted response to endothelium-dependent beta2-adrenergic vasodilation in type II diabetes mellitus[END_REF] Our results confirm this hypothesis, as we found a strong correlation between ∆Dicpleth and ∆MAP under the action of vasoconstrictors. A drop of 19% of Dicpleth had good performances to detect intra-operative hypotension with a sensitivity of 79% and a specificity of 84%. PI represents the ratio between pulsatile and continuous components of light absorption. Lima et al. showed a strong correlation between PI and core-to-toe temperature gradient, a parameter strongly dependent on vascular tone. [START_REF] Lima | Use of a peripheral perfusion index derived from the pulse oximetry signal as a noninvasive indicator of perfusion[END_REF] Some studies have described increase of PI during reduction of vascular tone due to sympathectomy during the onset of peripheral or epidural anaesthesia. 20 21 PI has also been described to increase with vasoconstriction induced by central hypovolemia during lower body negative pressure. [START_REF] Lima | Perfusion index as a predictor for central hypovolemia in humans[END_REF] Most available pulse oximeter in operating room already displays PI. Our results showed a negative correlation between ∆PI and ∆MAP under vasopressors. ∆PI was also accurate to detect intra-operative hypotension, but was probably less reliable than ∆Dicpleth to inform about the depth of hypotension, probably because of the complex influence of vascular tone and stroke volume on PI. Finally, our results suggest than combining both parameters could improve the detection of hypotension with a specificity and sensitivity of 84%.

Our study has some limitations. On first, our study included mainly ASA I or II patients, for neurosurgical or neuroradiology elective procedures. None of them had cardiac failure or severe arterial diseases. However, most of patients in our study were free of medication that may influence arterial compliance and proprieties. Our results need to be validated in patients with higher ASA score and cardiovascular risk. However, patients with higher ASA status are more likely to require continuous invasive ABP monitoring and hence will not require such a simple and easy alternative to detect intra-operative hypotension.

Secondly, we used the standard intermittent oscillometric method for ABP measurements which might be less reliable than invasive ABP. 23 24 A study comparing the performance of ∆Dicpleth and ∆PI to detect hypotension based on accurate continuous ABP reference would be useful. Our patients did not have cardiac output monitoring. In further studies, it would be useful to study relationships between PI, MAP and stroke volume to evaluate the influence of stroke volume on PI variations. These interconnected parameters are complex and a potential drop of stroke volume may influence variations of PI by other mechanisms than changes in vascular tone alone as during induction of anaesthesia. Finally, all the patients received total intravenous anaesthesia (propofol and remifentanil), and the vasoconstrictor drugs used were noradrenaline and phenylephrine. Our result may not be similar with other drugs, such as Ephedrine. Also our study is based on fingertip photoplethysmographic signals. As photoplethysmographic waveforms contour depend on measurement site, our conclusion might not be applicable if photoplethysmographic signals are recorded from another site. [START_REF] Allen | Age-related changes in the characteristics of the photoplethysmographic pulse shape at various body sites[END_REF][START_REF] Cannesson | Pleth variability index to monitor the respiratory variations in the pulse oximeter plethysmographic waveform amplitude and predict fluid responsiveness in the operating theatre[END_REF] The relative height of the dicrotic notch and the perfusion index, both measured from a standard pulse oximetry signal (photoplethysmography signal), could be used to detect hypotensive episodes during induction of anaesthesia. The combined analysis of the variations of these two indices could represent a new non-invasive, simple and easy-to-use tool to follow arterial blood pressure variations during general anaesthesia.

  Median duration of anaesthetic induction was 11 [10; 13.5] minutes. Overall, we recorded 720 haemodynamic data points: 61 at baseline values, and 659 after anaesthetic injection, hence representing 659 variations from baseline. The MAP baseline value was 86 [79; 93] mmHg giving an individual limit of intra-operative hypotension at 69 [62; 74] mmHg. MAP decreased to 54 [48; 60] mmHg before laryngoscopy, and rose to 72 [64; 82] mmHg after tracheal intubation. The mean MAP on the overall induction period was 70 [64; 71] mmHg. Fifty-four patients (88%) suffered from at least one hypotensive episode during anaesthesia induction, representing 323 measurements (49% of haemodynamic points). Twenty-eight patients (46%) received one bolus of vasopressor during induction (2 phenylephrine and 26 noradrenaline). Dicpleth was at 0.54 [0.45; 0.65] at baseline, dropped to 0.36 [0.19; 0.45] (p<0.001) and increased to 0.46 [0.41; 0.56] after tracheal intubation. PI baseline values were 1.7 [0.9; 3] and increased to 4.4 [2.8; 6.6] (p<0.001) before laryngoscopy, and then decreased to 3.6 [2.1; 5.4] after tracheal intubation. A visual representation of ∆MAP,

Figure 3 represents

 3 Figure 3 represents ROC curves to assess ∆Dicpleth and ∆PI performances to detect

  Twenty-eight patients (46%) received a bolus of vasopressors during induction (2 phenylephrine and 26 noradrenaline). After vasopressors, MAP increased from 59 [50; 67] mmHg to 76 [68; 79] mmHg (relative variation: 30 % [14; 45], p<0.001). Dicpleth increased from 0.34 [0.25; 0.39] to 0.48 [0.35; 0.55] (relative variation: 44% [17; 63], p<0.001) and PI decreased from 4.0 [3.3; 5.4] to 3.2 [1.8; 5.4] (relative variation: -28% [-44;-13], p<0.001).

Figure 1 -

 1 Figure 1-Definition of Dicpleth and PI (panel A) and an example of Dicpleth measurement on a real-life photoplethysmographic curve (panel B)

Figure 2 -

 2 Figure 2-Median ∆MAP and ∆Dicpleth (panel A) and median ∆MAP and ∆PI (panel B) during induction of anaesthesia

Figure 3 -

 3 Figure 3-Receiver operator characteristic curves for ∆PI and ∆Dicpleth performance to detect IOH.

Acknowledgements:

The authors thank all the paramedical staff of the operating room, the doctors of Neuroradiology as well as the whole clinical research team of the "Le Temple".

Disclosure:

Alexandre Mebazaa has received speaker honoraria from Abbott, Novartis, Orion, Roche and Servier and fee as member of advisory board and/or steering committee from Cardiorentis, Adrenomed, MyCartis, ZS Pharma and Critical Diagnostics. Etienne Gayat has received consulting fees from Magnisense, research support from Sphingotec, Deltex Medical and Retia Medical. Fabrice Vallée has received research support from Radiometer, Deltex Medical and Retia Medical. Sandrine Millasseau has received consulting fees from Alam Medical, AtCor Medical, Mesi Medical and Omron. Funding: None

Evolution Dicpleth and Dicradial during vasoconstrictor administration

During maintenance of anaesthesia, 48 boluses of noradrenaline were administered to 10 patients (5 [4; 6]

AUTHORS CONTRIBUTION:

Study design and supervision: MC, JM, FV Data collection: MC, JJ, FD, FV Data analysis and interpretation: MC, SM, HN, EG, FV Drafting and writing paper: MC, SM, EG, FV Revision and approval for final manuscript: MC, JJ, FD, SM, HN, JM, AM, EG, FV.