Renal Epidemiology And Information Network Research Articles

Offre de soins

On the occasion of the 20th anniversary of the REIN (French Renal Epidemiology and Information Network), a summary work on the contributions of the French national ESKD register was carried out. On the issue of healthcare provision, the following key messages were retained. France offers diversified, local healthcare that adapts to the patients’ needs with several additional players (public, university, lucrative private, solidarity private). However, the spatial distribution of this offer shows differences between territories as regards the distribution of the different treatment modalities. For several years now, the REIN proposes a new way of representing the provision of care using groups of establishments working together, a granularity that seems more suited to the evaluation of practices than isolated dialysis units.

REIN : un outil au service de la vigilance et de la pharmaco-épidémiologie

On the occasion of the 20th anniversary of the REIN (French Renal Epidemiology and Information Network), a summary work on the contributions of the national French ESKD register was carried out. On the issue of its role in vigilance, the following key messages were retained. The vigilance system consists, among other things, of collecting information that is useful for the surveillance of health products that are drugs for pharmacovigilance, and medical devices for materiovigilance. This includes the reporting of adverse events by health professionals and manufacturers as well as the use of any information concerning the risk of adverse events. Vigilance enables improving and optimising product and patient safety by reducing the risks of adverse events and better understanding the risks and benefits. Using data from the REIN registry, cross-referenced with other external sources, it is possible to conduct post-marketing studies of these products. These studies generate hypotheses, are low-cost and are yet to be confirmed by randomised studies. Following the presentation of a study suggesting an unfavourable role of citrate dialysates on mortality, and thanks to the mobilisation of all the operators of the network, the REIN registry was able to conduct a study in a few months that made it possible to conclude that the use of citric acid in dialysates does not present a risk of excess mortality for the patients. With this example, the REIN registry has shown its adaptability and utility as a vigilance tool.

Trajectoires des patients en suppléance

On the occasion of the 20th anniversary of the REIN (French Renal Epidemiology and Information Network), a summary work on the contributions of the national French ESKD register was carried out. On the issue of trajectory of ESKD patients, the following key messages were retained. Apart from a few rare, absolute or relative contraindications, till date, there is no medical consensus on the indications of one treatment modality as compared to another, and therefore, no recommendations allowing defining criteria for guiding patients, based on their characteristics, to a technique/treatment modality. In addition, the patients’ choices and their changing needs over time must be taken into account. Thus, due to the limitations of each of these modalities, a good number of patients with stage 5 renal failure treated with kidney replacement therapy will move between these different modalities. For many years, the REIN registry has endeavoured to represent the patient flows between the different treatment modalities. In order to better understand and then optimise the trajectories followed by patients who have reached stage 5 of their chronic renal failure, it was necessary to develop tools to model these complex trajectories where the treatment modalities are considered as complementary.

Mortalité des patients avec une maladie rénale chronique stade 5 traités par suppléance

On the occasion of the 20th anniversary of the REIN (French Renal Epidemiology and Information Network), a summary work on the contributions of the national French ESKD register was carried out. On the issue of survival of ESKD patients, the following key messages were retained. The annual mortality rates of ESKD patients are relatively stable even though patients are ageing and increasingly have diabetes or obesity. These changes are probably linked to improved practices. Cardiovascular diseases and infections are the main causes of death. The year 2020 was marked by an increase in mortality due to the SARS-CoV-19 infection that was particularly severe in these patients.

REIN : un outil au service des patients âgés

On the occasion of the 20th anniversary of the REIN (French Renal Epidemiology and Information Network), a summary work on the contributions of the national French ESKD register was carried out. On the issue of elderly CKD patients, the following key messages were retained. The population of elderly dialysis patients continues to grow. These patients have multiple comorbidities including pathologies specific to the elderly like undernutrition, walking and cognitive disorders. The data from the REIN registry has been the subject of numerous studies pertaining to this group showing heterogeneous prognosis and treatment, requiring to be better evaluated to target an individualised treatment. Decision support tools have been developed using the registry data to help nephrologists and patients in deciding whether to start replacement therapy and whether to refer elderly patients for assessment for a renal transplant. Finally, the risk-benefit evaluation of the different replacement therapies in this population should be monitored at the registry level and on a case-by-case basis in clinical practice.

Prévalence de l’IRCT et part des différentes modalités de traitement

On the occasion of the 20th anniversary of the REIN (French Renal Epidemiology and Information Network), a summary work on the contributions of the national French ESKD register was carried out. On the issue of ESKD prevalence, the following key messages were retained. While chronic kidney disease affects all age groups, there always are more patients to treat in the older age groups, with a median age of 71.1 years (IIQ 60.3-80.0) under dialysis and 58.7 years (IIQ 47.4-68.3) under renal transplant. Despite an increase in transplant activity and improved survival of grafts, the gap between the number of dialysis patients and transplant patients at the end of each year is only moderately reduced. There has been a moderate decrease in the proportion of in-centre haemodialysis that is explained by a significant increase in medicalised dialysis units (out-centre haemodialysis) and a decrease in self-care haemodialysis. Finally, a stable home-based care has been observed despite the ministerial incentives and the recommendations of the French-speaking scientific society (SFNDT-white paper).

Is there sex disparity in vascular access at dialysis initiation in France? A mediation analysis using data from the Renal Epidemiology and Information Network registry.

This study was conducted to estimate the direct effect of sex on the proportion of hemodialysis (HD) catheters used at dialysis initiation and to investigate whether predialysis care or socioeconomic status acted as a mediator of the sex effect. Patients who started dialysis between January 1, 2017, and June 30, 2018, in France were included using the data of the Renal Epidemiology and Information Network (REIN) registry. We performed logistic regression to study the association between sex and the proportion of HD catheters used. A mediation analysis with a counterfactual approach was carried out to evaluate whether there was an indirect effect of sex through the proxies of predialysis care {hemoglobin, albumin levels, glomerular filtration rate [GFR] at dialysis initiation} and socioeconomic status. Because an interaction between sex and social deprivation has been identified, we performed a subgroup analysis on deprived and nondeprived patients. The study included 16032 patients, and the sex ratio (male to female) was 10405:5627. In the multivariable analysis, women were associated with a greater risk of starting dialysis with a catheter {odds ratio [OR], 1.32 [95% confidence interval (CI): 1.23-1.42]}. There was an indirect effect of sex on the proportion of HD catheters through proxies for predialysis care {albuminemia <30g/L [OR, 1.08 (95% CI: 1.05-1.10)], hemoglobin <11g/dL [OR, 1.03 (95% CI: 1.02-1.04)], glomerular filtration rate <7mL/min [OR, 1.05 (95% CI: 1.04-1.07)]}. Among deprived patients, there was no direct effect of sex on catheter proportion. Women were associated with a higher risk of starting dialysis through an HD catheter. The effect of sex was mediated by predialysis care, particularly for deprived patients.

Association between kidney retransplantation and survival according to age in the French national cohort of dialysis patients

The mean age of patients returning to dialysis after a first kidney transplantation (KT) has increased in the past decades. We aimed to assess the association between second KT (2KT) and survival according to age at the time of return to dialysis. Data of 5334 patients registered in the French Renal Epidemiology and Information Network (REIN) (mean age 56.6 ± 13.6 years) who returned to dialysis after a first KT were collected. The association of 2KT with death was assessed using a propensity score‐based analysis taking into account baseline and follow‐up variables. In relisted patients (3272 patients, 61.3%), retransplantation was associated with better overall survival in comparison with patients who remained in dialysis (adjusted HR 0.75 [0.63–0.89], p = .0009). The survival advantage conferred by retransplantation gradually declined with increasing age (adjusted HR 0.41 [0.24–0.70] in patients <50, HR 0.94 (0.69–1.27) in patients aged 70 or older, p for interaction 0.034 for age considered as a continuous variable). 2KT is associated with better survival as opposed to remaining on dialysis after a first kidney graft failure. Nevertheless, this survival benefit is age dependent and diminishes with increasing age. The risk/benefit ratio should be comprehensively assessed in the oldest patients when relisting is considered.

Incremental and Personalized Hemodialysis Start: A New Standard of Care

IntroductionIncremental hemodialysis (iHD) may attenuate “dialysis shock” and reduce costs, preserving quality of life. It is considered difficult to reconcile with HD wards’ routine; fear of underdialysis and increasing mortality are additional concerns. The aim of this study was to evaluate mortality, morbidity, and costs in a large HD ward where iHD is the standard of HD start.MethodsThis observational study included all incident HD patients in 2017 to 2021, stratified according to HD start: iHD (1–2 sessions/wk), decremental HD (dHD, 3 sessions/wk at start, later reduced), or standard (3 sessions/wk). Results were compared with data recorded in the same unit before the incremental program (2015–2017) and with a propensity score-matched cohort from the French Renal Epidemiology and Information Network (REIN) registry.ResultsA total of 158 patients started HD in 2017 to 2021, 57.6% on iHD, 8.9% dHD, and 33.5% standard HD schedule. Patients on the standard schedule had lower initial estimated glomerular filtration rate (eGFR) (5 vs. 7 ml/min per 1.72 m2, P = 0.003). We found no survival differences according to period of start (same center) and propensity score matching (REIN). Patients intensively followed in the pre-HD period were more likely to start on iHD-dHD. Persistence on iHD-dHD was about 50% at 1 year and 35% at 2 years. Hospitalization rates and time to first hospitalization or death did not differ between the schedules. The iHD-dHD policy allowed a 16% cost saving, even accounting for supplemental biochemical tests.ConclusionOur study reveals that iHD can be a new standard of care, as it is safe and feasible in up to two-thirds of patients on incident HD.

A prospective observational study for justification, safety, and efficacy of a third dose of mRNA vaccine in patients receiving maintenance hemodialysis

The level of protection achieved by the standard two doses of COVID-19 mRNA vaccines in patients receiving maintenance hemodialysis (MHD) remains unclear. To study this we used the French Renal Epidemiology and Information Network (REIN) Registry to compare the incidence and severity of 1474 cases of COVID-19 diagnosed in patients receiving MHD after none, one or two doses of vaccine. Vaccination significantly reduce COVID-19 incidence and severity, but 11% of patients infected after two doses still died. Lack of vaccinal protection in patients naïve for SARS-CoV-2 could be due to defective Tfh response [38% of patients with negative spike-specific CD4+ T-cell interferon gamma release assay] and failure to generate viral neutralizing titers of anti-spike receptor binding domain (RBD) IgGs (63% of patients with titer at or under 997 BAU/ml, defining low/no responders) after two doses of vaccine. To improve protection, a third dose of vaccine was administered to 75 patients [57 low/no responders, 18 high responders after two doses] from the ROMANOV cohort that prospectively enrolled patients receiving MHD vaccinated with BNT162b2 (Pfizer). Tolerance to the third dose was excellent. High responders to two doses did not generate more anti-RBD IgGs after three doses but had more side effects. Importantly, 31 (54%) of low/no responders to two doses reached neutralizing titers of anti-RBD IgGs after three doses. A positive interferon gamma release assay and/or suboptimal titer of anti-RBD IgGs after two doses were the only predictive variables for response to three doses in multivariate analysis. Thus, the standard scheme of vaccination insufficiently protects patients receiving MHD. Anti-RBD IgG and specific CD4+ T-cell response after two doses can guide personalized administration of the third dose, which improves the humoral response of SARS-CoV-2–naïve patients receiving MHD.

Comorbidity Profiles among Obese–Diabetic End-Stage Renal Disease Patients: Data from REIN Registry of PACA Region of France

IntroductionThe proportion of new dialysis patients with comorbidities increased by an average of 5.6% per year in the Provence-Alpes-Côte d’Azur (PACA) region, with major increases in obese, cancer, and diabetic patients. This study aimed to describe comorbidity profiles among obese–diabetic end-stage renal disease (ESRD) patients in the Renal Epidemiology and Information Network (REIN) registry of the PACA region of France on December 31, 2018.MethodsData for this retrospective cross-sectional study were retrieved from the REIN registry of the PACA region. Data were analyzed using two models. Firstly, the ESRD patients were divided into two groups and binary logistic regression model used for the analysis of the data. Secondly, ESRD patients were divided into four groups and multinomial logistic regression model used. Univariate analysis was performed for group comparison using x2 and t-tests, while binary logistic and multinomial logistic regression models were used for multivariate analysis to derive ORs and 95% CIs.ResultsAmong the 4,491 ESRD patients in this study, 623 were obese–diabetic and 3,868 nonobese–nondiabetic and obese only/ diabetic only. Obese–diabetic ESRD patients were younger (<75 years, OR 0.46, p<0.001), smoked less (OR 0.51, p<0.001), were mainly dialyzed at centers (OR 1.29, p=0.014), and less likely to be on the renal transplant waiting list (OR 0.46, p<0.001) compared to the other group. Obese–diabetic ESRD patients also had more comorbidities, including cardiovascular diseases (OR 1.38, p=0.028), coronary insufficiency (OR 1.49, p=0.001) and chronic obstructive pulmonary disease (OR 1.75, p<0.001), but had fewer cases of cancer (OR 0.68, p=0.024) compare to the other group.ConclusionObese–diabetic patients with ESRD have many specific characteristics. These patients were younger, but had more cardiovascular comorbidities and were less likely to be on the waiting list for transplantation. They should receive special attention and be the subject of prevention and therapeutic education.

Effects of the dialysate calcium concentrations and mineral bone disease treatments on mortality in The French Renal Epidemiology and Information Network (REIN) registry.

In patients on hemodialysis (HD), the various chemical elements in the dialysate may influence survival rates. In particular, calcium modifies mineral and bone metabolism and the vascular calcification rate. We studied the influence of the dialysate calcium concentration and the treatments prescribed for mineral bone disease (MBD) on survival. All patients in REIN having initiated HD from 2010 to 2013 were classified according to their exposure to the different dialysate calcium concentrations in their dialysis unit. Data on the individual patients' treatments for MBD were extracted from the French national health database. Cox proportional hazard models were used to estimate mortality hazard ratios (HR) associated with time-dependent exposure to dialysate calcium concentrations and MBD therapies, adjusted for comorbidities, laboratory and technical data. Dialysate calcium concentration of 1.5 mmol/L was used by 81% of the dialysis centers in 2010 and in 83% in 2014. Most centers were using several formulas in up to 78% for 3 formulas in 2010 to 86% in 2014. In full adjusted Cox survival analyses, the percentage of calcium >1.5 mmol/L and <1.5 mmol/l by center and the number of formula used per center were not associated with survival. Depending on the daily dose used, the MBD therapies were associated with survival improvement for calcium, native vitamin D, active vitamin D, sevelamer, lanthanum and cinacalcet in the second and third tertiles of dose. No influence of the dialysate calcium concentration was evidenced on survival whereas all MBD therapies were associated with a survival improvement depending on the daily dose used.

Systemic sclerosis and end-stage renal disease: study of patient characteristics, follow-up and outcomes in France.

Scleroderma renal crisis (SRC), the most frequent renal complication of Systemic Sclerosis (SSc), can lead to end-stage renal disease (ESRD),most frequently, but not exclusively, because ofscleroderma renal crisis (SRC). The main objectives of our study using data extracted from the French renal epidemiology and information network (REIN) registry, were to describe the characteristics and outcomes in an incident French cohort of SSc patients requiring renal replacement therapy (RRT) compared with a matched RRT patient sample. Between 2002 and 2014, 120 incident SSc patients started RRT in France. SSc was significantly associated with higher mortality (HR 1.95; 95% CI 1.41-2.71; p = 0.001) in comparison with matched controls. Among SSc patients in dialysis, besides age, the only risk factor independently associated with mortality was the inability to walk without help (HR 2.34, CI 95% 1.37-4.02, p = 0.002). Dialysis withdrawal was reported for 22 (18.3%) of the SSc patients compared to 15 (6.3%) for the controls. Patients with SSc have less access to transplantation waiting list (HR 0.21; CI 95% 0.11-0.41, p < 0.001) and to kidney transplantation (KTR) (HR 0.22; 95% CI 0.12-0.43; p < 0.001). During the follow-up, 6 of the 27 patients (22.2%) registered on KTR waiting list died compared to 69 of the 93 (74.2%) patients who were not on the waiting list. The prognosis for SSc patients requiring RRT is still poor, with a significantly higher mortality and lower registration on kidney transplant waiting-list compared to matched controls.

Contribution of medico-administrative data to the development of a comorbidity score to predict mortality in End-Stage Renal Disease patients

Comorbidity scores to predict mortality are very useful to facilitate decision-making for personalized patient management. This study aim was to assess the contribution of medico-administrative data in addition to French Renal Epidemiology and Information Network (REIN) data to the development of a risk score to predict the 1-year all-cause mortality in patients with End Stage Renal Disease (ESRD), and to compare it with previous scores. Data from a derivation sample (n = 6336 patients who started dialysis in 2015 in France) obtained by linking the REIN and the French National Health Insurance Information System databases were analyzed with multivariate Cox models to select risk factors to establish the score. A randomly chosen validation sample (n = 2716 patients who started dialysis in 2015) was used to validate the score and to compare it with the comorbidity indexes developed by Wright and Charlson. The ability to predict one-year mortality of the score constructed using REIN data linked to the medico-administrative database was not higher than that of the score constructed using only REIN data (i.e., Rennes score). The Rennes score included five comorbidities, albumin, and age. This score (AUC = 0.794, 95%CI: 0.768–0.821) outperformed both the Wright (AUC = 0.631, 95%CI: 0.621–0.639; p < 0.001) and Charlson (AUC = 0.703, 95%CI: 0.689–0.716; p < 0.001) indexes. Data from the REIN registry alone, collected at dialysis start, are sufficient to develop a risk score that can predict the one-year mortality in patients with ESRD. This simple score might help identifying high risk patients and proposing the most adapted care.

From tuberous sclerosis complex to end stage renal disease: who are these patients?

In patients with tuberous sclerosis complex (TSC), renal complications are not limited to bleeding angiomyolipoma (AML); although rare, end-stage renal disease (ESRD) may occur. New treatments (e.g., mammalian target of rapamycin (m-Tor) inhibitors) for AML might influence the epidemiology of ESRD in patients with TSC. In France, 99 patients with TSC from the Renal Epidemiology and Information Network (REIN) registry and having undergone renal replacement therapy (RRT) between 2002 and 2016 were included in the present study. Additional data were collected from the patients' medical charts. The mean ± standard deviation age at RRT initiation was 48.4 ± 16.4 and 73.8% had a neurologic impairment. Fifty-four patients underwent kidney transplantation after an average of 23 ± 12.3months on dialysis. Among the 61 patients with additional data the most common renal lesion was AML: 26.2% of the patients had isolated AML, and 26.2% had AML and renal cysts, 65.6% of patients had undergone nephrectomy, and 16.4% had undergone at least one embolization. None of the patients had been treated with an m-Tor inhibitor before dialysis. The graft survival rate was 92.5% at 5years and 70.2% at 10years. The present cohort study is the first to have assessed TSC patients on RRT from a national registry. Nephrectomy or embolization due to AML was the leading cause of ESRD in our cohort. By reducing the size of the AML, m-tor inhibitors might lower the risk of complications and thus reduce the number of patients with TSC requiring RRT.

Linking disease registries and nationwide healthcare administrative databases: the French renal epidemiology and information network (REIN) insight

BackgroundRecord linkage is increasingly used in health research worldwide. Combining the patient information available in healthcare, administrative and clinical databases broadens the research perspectives, particularly for chronic diseases. Recent guidelines highlight the need for transparency on the used record linkage processes and the extracted data to be used by researchers.MethodsTherefore, the aim of this study was to describe the deterministic iterative approach used to link the French Epidemiology and Information Network (REIN), a French national End-Stage Renal Disease registry, with the Système National des Données de Santé (SNDS), a French nationwide medico-administrative healthcare database.ResultsAmong the 22,073 patients included in the REIN registry who started renal replacement therapy between 2014 and 2015 in France, 19,223 (87.1%) were matched with patients in the SNDS database. Comparison of matched and unmatched patients confirmed the absence of any major selection bias. Then, the record linkage was evaluated using the comorbidity status (diabetes).ConclusionsThis fast and efficient method of record linkage with pseudonymized data and without unique and direct identifier might inspire other research teams. It also opens the path for new research on chronic kidney disease.

Effects of the dialysate calcium concentrations and mineral bone disease treatments on mortality in The French Renal Epidemiology and Information Network (REIN) registry

Effects of the dialysate calcium concentrations and mineral bone disease treatments on mortality in The French Renal Epidemiology and Information Network (REIN) registry

Access to the waiting list and to kidney transplantation for people living with HIV: A national registry study.

We compared access to a kidney transplantation (KT) waiting list (WL) and to KT between people living with HIV (PLHIV) and HIV-uninfected controls. Using the REIN (the national Renal Epidemiology and Information Network registry), we included all PLHIV initiating dialysis in France throughout 2006-2010 and HIV-uninfected controls matched for age, sex, year of dialysis initiation, and the existence of a diabetic nephropathy. Patients were prospectively followed until December 2015. We used a competitive risk approach to assess the cumulative incidence of enrollment on WL and of KT, with death as a competing event (subdistribution hazard ratio adjusted on comorbidities, asdHR). There were 255 PLHIV in the REIN (median age 47years) of whom 180 (71%) were also found in the French Hospital Database on HIV (FHDH-ANRS CO4) including 126 (70%) known to be on antiretroviral therapy with HIV viral suppression (VS). Five years after dialysis initiation, 65%, and 76%, of treated PLHIV with VS, and of HIV-uninfected controls were enrolled on a WL (asdHR 0.68; 95% CI 0.50-0.91). Access to KT was also less frequent and delayed for treated PLHIV with VS (asdHR 0.75, 95% CI, 0.52-1.10). PLHIV continue to face difficulties to access KT.

2017 Annual Report Digest of the Renal Epidemiology Information Network (REIN) registry.

The French Renal Epidemiology and Information Network (REIN) registry started in 2002 with the goal to provide a tool to evaluate renal replacement therapy (RRT) practices and outcomes, to provide data for research and to support public health decisions related to end-stage renal disease ESRD. This summary presents the incidence and prevalence of RRT including kidney transplantation and wait-listing activity in 2017, and patients' survival and trends over 5years. In 2017, 11543 patients started RRT for ESRD, that is, incidence of 172 pmp. Between 2012 and 2017, the incidence of RRT increased by 1% per year [CI 95% (0.0; +2.0)]. On 31 December 2017, 87275 patients were receiving RRT, that is, prevalence of 1294 pmp, 55% on dialysis, 45% with a functioning transplant. In 2017, 3782 kidney transplantations have been performed including 16% from a living donor, 13% being retransplantations and 15% pre-emptive transplantations. The median time on the waiting list was 19.7months when only taking into account active waiting periods on the list. In 2017, 5280 new patients were registered on the renal transplant waiting list (i.e. 78.7 pmp). The number of patients considered as 'inactive' represented 45% of the patients on the list.

SUN-060 PNEUMOCOCCAL VACCINATION COVERAGE AT THE INITIATION OF CHRONIC DIALYSIS, AND ITS ASSOCIATION WITH MORTALITY DURING THE FIRST YEAR

Limited data are available on the impact of pneumococcal immunization in hemodialysis patients. The purpose of this study was to estimated vaccination coverage among incident patients who initiated chronic dialysis in France in 2015 and its association with mortality according to patient characteristics and vaccination schedule. Data were extracted from two national data-bases, merged using a deterministic linkage method: Renal Epidemiology and Information Network (REIN) registry, which includes all dialysed and transplanted patients in France, and the French National Health Insurance Information System (SNIIRAM) which includes individual data on health expenditure reimbursement, including vaccines. Data on health status at dialysis initiation, dialysis modalities, and all pneumococcal vaccine prescribed from 2 years before to 1 year after dialysis starting were collected. Univariate and multivariate Cox proportional hazard models were used to assess one-year all-cause mortality. Among the 8,294 incident patients included, 1,849 (22.3%) patients received at least one pneumococcal vaccine: 542 (6.5%) during the two years before dialysis start, and 1,307 (15.8%) after dialysis start, in 2015 or 2016. Among them, 35.1% received 23 valent-pneumococcal polysaccharide vaccine (PPSV23) alone, 50.7% 13 valent-pneumococcal conjugated vaccine (PCV13), followed by PPSV23, and 14.1% only PCV13. Vaccinated patients were younger, more likely to have a glomerulonephritis and less likely to start a dialysis in emergency start. Adjusted on age, sex, bio-clinical data and context of dialysis start (planned vs emergency), patients who received PCV13 and PPSV23 or only PCV13 were less likely to die (respectively, HR=0.37; 95%CI: 0.28-0.51, and HR=0.35; 95%CI: 0.19-0.65). Pneumococcal immunization with PCV13 and PPSV23, or only PCV13 but not with PPSV23, is associated with decreased one year-mortality in patients who start dialysis. Patients who initiate hemodialysis should receive pneumococcal immunization, preferably with PCV13 followed by PPSV23.