[Evaluation of the efficacy and safety of HIVEC intravesical thermochemotherapy with intermediate-risk and high-risk non-muscle-invasive bladder cancer]. / Évaluation de l'efficacité et de la tolérance de la thermo-chimiothérapie intravésicale HIVEC pour les tumeurs de vessie non infiltrant la musculeuse de risque intermédiaire et de haut risque.

INTRODUCTION: Non-muscle-infiltrating cancers (NMIBC) represent 75% of bladder tumors. The objective of our study is to report a single-center experience of the efficacy and tolerability of HIVEC on intermediate- and high-risk NMIBC in adjuvant therapy. MATERIAL AND METHOD: Between December 2016 and October 2020, patients with intermediate-risk or high-risk NMIBC were included. They were all treated with HIVEC as an adjuvant therapy to bladder resection. Efficacy was assessed by endoscopic follow-up and tolerance by a standardized questionnaire. RESULTS: A total of 50 patients were included. The median age was 70years (34-88). The median follow-up time was 31 months (4-48). Forty-nine patients had cystoscopy as part of the follow-up. Nine recurred. One patient progressed to Cis. The 24-month recurrence-free survival was 86.6%. There were no severe adverse events (grade 3 or 4). The ratio of delivered instillations to planned instillations was 93%. CONCLUSION: HIVEC with the COMBAT system is well tolerated in adjuvant treatment. However, it is not better than standard treatments, especially for intermediate-risk NMIBC. While waiting for recommendations, it cannot be proposed as an alternative to standard treatment.

[Rituximab immunomonitoring in autoimmune diseases: a support tool in clinical practice?] / Immunomonitoring du rituximab appliqué aux maladies auto-immunes : une aide pour la pratique clinique ?

INTRODUCTION: Immune monitoring of monoclonal antibodies is a helpful tool in optimizing the management of patients treated with TNF blockers, especially in gastroenterology. In contrast, studies evaluating the interest of such monitoring are lacking for other monoclonal antibodies used in autoimmune diseases, including rituximab despite its widespread use in the field for almost 15 years. Hence, we conducted a study whose goal was to describe the clinical and biological characteristics of all patients who had a rituximab immune monitoring. METHODS: All the clinical, biological and therapeutic data attached to the demands (from 2015 onwards) we received for immune monitoring of rituximab (measurements of rituximab serum levels and anti-rituximab antibodies using the drug-sensitive assay LISA-TRACKER Duo Rituximab®), were retrospectively reviewed. Suspected cases of hypersensitivity and secondary non-response were included. RESULTS: Several medical specialities (nephrology, haematology, neurology, rheumatology, internal medicine) were represented among the 18 records included in the study (out of 23 demands), 10 being suspected cases of hypersensitivity and 8 secondary non-responders. All 6 patients whose symptoms were consistent with the classical presentation of serum sickness, as well as half of the secondary non-responders, were positive for antirituximab antibodies. CONCLUSION: This detailed real world case study illustrates the potential benefits of rituximab immune monitoring (especially anti-rituximab antibodies) in autoimmune diseases, suggesting it could be helpful in suspected cases of serum sickness, as well as secondary non-response (B-cell non-depletion being an early red flag). Larger and disease-specific studies are warranted to support these findings.

Hospital-acquired infections documented by repeated annual prevalence surveys over 15 years.

OBJECTIVE: To estimate the benefits of iterative prevalence surveys in detecting trends of hospital-acquired infections (HAIs). METHODS: On the basis of the French protocol for national prevalence studies, HAI data of 15 consecutive annual surveys performed at the same period by the same group of investigators was gathered in a single database to describe the trend of HAIs in a University Hospital over a 15-year period. RESULTS: A total of 20,401 patients were included. Overall, the prevalence of patients presenting with at least one HAI acquired in our University Hospital was 5.1% [95% CI, 4.8-5.4%]. The prevalence of HAIs and antimicrobial drug use significantly decreased over time (P<0.01). CONCLUSION: Despite limitations, repeated prevalence surveys can be a useful tool for promoting control measures to better prevent HAIs.

Amotosalen-inactivated plasma is as equally well tolerated as quarantine plasma in patients undergoing large volume therapeutic plasma exchange.

A retrospective - single center - survey compared tolerance of individual donor therapeutic plasma in a series of 88 patients principally presenting with thrombotic microangiopathy; all patients underwent therapeutic plasma exchange (TPE) performed with more than 90% of either of two types of plasma preparations. One plasma type used in TPE was prepared with pathogen reduction by amotosalen addition and UVA illumination, and the other one was non-manipulated (quarantine plasma). Both types of plasma were single donor. Occurrences of adverse reactions were equally low in either arm (amotosalen: 9 in 4689 bags of ∼200mL [0.019] versus quarantine: 2 in 828 bags [0.024]), confirming the safe use of amotosalen inactivated therapeutic plasma for TPE.

CKD-EPI equation: A suitable Glomerular Filtration Rate estimate for drug dosing in HIV-infected patients.

OBJECTIVES: To evaluate concordance between glomerular filtration rate (GFR) estimates (Cockcroft and Gault, modification of diet in renal diseases, chronic kidney disease epidemiology study group equations) for drug dosing in HIV-infected patients. PATIENTS AND METHODS: We performed a monocentric study. GFR was measured using the gold standard method (plasma clearance of iohexol) in 230 HIV-infected patients. Concordance rate was evaluated between measured GFR (mGFR) and estimated GFR (eGFR) for different GFR categories (GFR>90 mL/min, GFR<90 mL/min, GFR>70 mL/min, and GFR<70 mL/min). MDRD and CKD-EPI were used with and without indexation to body surface area (BSA). RESULTS: Mean age was 48±10 years, mean mGFR was 101±26 mL/min. Concordance between mGFR and eGFR estimated with CG, CKD-EPI (indexed and not indexed to BSA), or MDRD equations (not indexed to BSA) was similar (73%, 73%, 74%, and 73% respectively) for a breakpoint value of 90 mL/min for GFR. At this value, the concordance rate between mGFR and MDRD indexed to BSA was significantly lower (65%, P<0.05). Using 70 mL/min of GFR as the breakpoint value, all equations had similar concordance rates with mGFR (with or without indexation to BSA). CONCLUSION: CKD-EPI equation has the same concordance with GFR and with CG when used for drug dosing.

Preventing healthcare-associated infections: Residents and attending physicians need better training in advanced isolation precautions.

OBJECTIVE: Compliance with advanced isolation precautions (IPs) is crucial to reduce healthcare-associated infections. Our aim was to evaluate physician's knowledge and attitudes related to IPs. METHODS: An online questionnaire was sent to our hospital's physicians (attending physicians and residents). RESULTS: A total of 111 physicians completed the questionnaire: 60 (54%) attending physicians and 51 (46%) residents. Overall, respondents had a poor knowledge of the three types of IPs, especially droplet precautions (13 correct answers, 11.7%) and airborne IP (17 correct answers, 16.3%). We observed a statistically significant difference between attending physicians and residents for the type of IP to prescribe to a patient presenting with multidrug-resistant urinary infection: 44 residents (86%) gave the correct answer vs 42 attending physicians (70%), P=0.04. Physicians (both residents and attending physicians) who were already familiar with the dedicated webpage available on the hospital's intranet (n=40) obtained a score of 4.75/10 (±2.0) compared with 4.03/10 (±1.7) for those who had never used that tool (n=71). The difference was statistically significant (P=0.04). The average score for both residents and attending physicians was 4.3/10 (±1.9, range: 1-10). Attending physicians' and residents' scores were 4/10 (±1.8) and 4.5/10 (±1.9), respectively, but the difference was not statistically significant (P=0.14). CONCLUSION: Physicians' knowledge of IPs was insufficient. Improvement in medical training is needed. The use of a dedicated webpage on hospitals' intranet could help physicians acquire better knowledge on that matter.

[Review of the current use of rituximab during 4 years in a French university hospital]. / Le rituximab dans la vraie vie: revue d'utilisation du rituximab de 2010 à 2013 au CHU de Saint-Étienne.

PURPOSE: Rituximab is a human/murine chimeric monoclonal antibody primarily used for treating non-Hodgkin's B-cell lymphoma. Recently, it has also been used in the treatment of several autoimmune diseases. PATIENTS AND METHODS: We conducted a retrospective analysis of patients treated at least once with rituximab between 2010 and 2013 in a French university hospital, to provide a panoramic view of rituximab use including FDA or off-labels uses, its efficacy and safety. RESULTS: Eighty-seven patients were included with 20 different indications: cryoglobulinemic vasculitis (16%) and anti-PLA2R idiopathic membranous nephropathy (13%) were the most frequent. Rituximab use was off-labels in 50% of cases. Eleven percent of patients experienced severe adverse events, mostly infections. After rituximab, 17% of patients were in complete response (CR), 41% in partial response (PR), and 39% non-responding (NR). Relapse was observed in 65% (33/51) of responding patients. CONCLUSION: Further investigation with randomized controlled trials will provide more insight into the specifics of the role of RTX in the overall management of each disease. Identifying clear objectives and strict outcome measures, associated with long term clinical and biological follow-up would help deciding when, how and in which therapeutic regimen will rituximab most benefit a disease or a patient.

Common hepatic artery as inflow in kidney transplantation.

Kidney transplantation originating from the hepatic artery has not previously been reported. Herein, we report a third kidney transplantation with the common hepatic artery as inflow. A 62-year-old male with chronic renal failure due to polycystic kidney disease was proposed to a third kidney transplantation. CT-scan showed diffuse calcification of the aorto-iliac axis and the splenic artery. The common hepatic artery was the only artery suitable for anastomosis and as such was chosen as the inflow for retransplantation. The operation was performed through a right subcostal laparotomy. A saphenous bypass was interposed between the common hepatic artery and the graft, then the renal vein was anastomosed to the suprarenal inferior vena cava. Duration of warm ischemia was 27 min. Postoperative course was complicated with delayed graft function of 17 days and pulmonary infection. Patient was discharged at day 30. With a follow-up of 40 months, serum creatinine level and eGFR are, respectively, 191 µmol/L and 32 mL/min. Hepato-renal bypass technique can be used in kidney retransplantation when patient anatomy is not compatible with other classical options.

KDIGO Guidelines and Kidney Transplantation: Is the Cystatin-C Based Recommendation Relevant?

The KDIGO guidelines propose a new approach to diagnose chronic kidney disease (CKD) based on estimated glomerular filtration rate (GFR). In patients with a GFR value comprised between 45 and 59 mL/min/1.73 m(2) as estimated by the CKD-EPI creatinine equation (eGFRcreat ), it is suggested to confirm the diagnosis with a second estimation using the CKD-EPI cystatin C-based equations (eGFRcys /eGFRcreat-cys) . We sought to determine whether this new diagnostic strategy might extend to kidney transplant recipients (KTR) and help to identify those with decreased GFR. In 670 KTR for whom a measured GFR was available, we simulated the detection of CKD using the two-steps approach recommended by the guidelines in comparison to the conventional approach relying on creatinine equation. One hundred forty-five patients with no albuminuria had eGFRcreat between 45 and 59 mL/min/1.73 m(2) . Among them, 23% had inulin clearance over 60 mL/min/1.73 m(2) and were thus incorrectly classified as CKD patients. When applying the Kidney Disease: Improving Global Outcomes (KDIGO) strategy, 138 patients were confirmed as having a GFR below 60 mL/min with eGFRcreat-cys . However, 21% of them were misclassified in reference to measured GFR. Our data do no not support the use of cystatin C as a confirmatory test of stage 3 A CKD in KTR.

Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.

BACKGROUND: Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. METHODS: We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). RESULTS: A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. CONCLUSIONS: Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]).

Rate of renal graft function decline after one year is a strong predictor of all-cause mortality.

The slope of GFR associates with an increased risk for death in patients with native CKD but whether a similar association exists in kidney transplantation is not known. We studied an inception cohort of 488 kidney transplant recipients (mean follow-up of 12 ± 4 years) for whom GFR was longitudinally measured by inulin clearance (mGFR) at 1 year and then every 5 years. Association of mGFR at 1 year posttransplant and GFR slope after the first year with all-cause mortality was studied with a Cox regression model and a Fine and Gray competing risk model. While in Crude analysis, the mGFR value at 1 year posttransplant and the rate of mGFR decline were both associated with a higher risk of all-cause mortality, only the slope of mGFR remained a significant and strong predictor of death in multivariate analysis. Factors independently associated with a more rapid mGFR decline were feminine gender, higher HLA mismatch, retransplantation, longer duration of transplantation, CMV infection during the first year and higher rate of proteinuria. Our data suggest that the rate of renal graft function decline after 1 year is a strong predictor of all-cause mortality in kidney transplantation.

Kidney biopsy in the critically ill patient, results of a multicentre retrospective case series.

BACKGROUND: The impact of a contributive result of kidney biopsy on the management of patients in the intensive care unit (ICU) has not been extensively investigated yet. METHODS: This was a retrospective study conducted between 2000 and 2011 in five French ICUs. The study included 56 patients. They had at least one non-renal organ failure, as defined by a Sequential Organ Failure Assessment (SOFA) score ≥3 on ICU admission, and kidney biopsy was performed during ICU stay. Kidney samples were obtained by percutaneous (N.=55) or transjugular biopsy (N.=1). RESULTS: The mean Simplified Acute Physiology Score II and total SOFA scores on ICU admission were 52±19 years and 10.3±3.6, respectively. ICU mortality was 23%. The median (interquartile range) time between ICU admission and kidney biopsy was 9 days (5-21). Pathologic findings in the 54 analyzable kidney biopsies were acute tubular necrosis (N.=26), glomerulonephritis (N.=14), acute vascular nephritis (N.=11), acute interstitial nephritis (N.=6), and deposit disease (N.=3). Kidney biopsy was contributive to the management of 40 patients. In 23 of these, new treatments were started, in 13 ongoing treatments were stopped, including four life-sustaining therapies, and in 13 it was decided to start chronic renal replacement. Severe bleeding was observed in 7 patients, with fatal outcome in one case. CONCLUSION: Kidney biopsy may have a significant impact on the management of critically ill patients. Further studies should be done to identify the groups of ICU patients likely to benefit from the procedure with minimum risk.

Renal transplantation in patients with AA amyloidosis nephropathy: results from a French multicenter study.

Although end-stage renal disease related to AA amyloidosis nephropathy is well characterized, there are limited data concerning patient and graft outcome after renal transplantation. We performed a multicentric retrospective survey to assess the graft and patient survival in 59 renal recipients with AA amyloidosis. The recurrence rate of AA amyloidosis nephropathy was estimated at 14%. The overall, 5- and 10-year patient survival was significantly lower for the AA amyloidosis patients than for a control group of 177 renal transplant recipients (p = 0.0001, 0.028 and 0.013, respectively). In contrast, we did not observe any statistical differences in the 5- and 10- year graft survival censored for death between two groups. AA amyloidosis-transplanted patients exhibited a high proportion of infectious complications after transplantation (73.2%). Causes of death included both acute cardiovascular events and fatal septic complications. Multivariate analysis demonstrated that the recurrence of AA amyloidosis on the graft (adjusted OR = 14.4, p = 0.01) and older recipient age (adjusted OR for a 1-year increase = 1.06, p = 0.03) were significantly associated with risk of death. Finally, patients with AA amyloidosis nephropathy are eligible for renal transplantation but require careful management of both cardiovascular and infectious complications to reduce the high risk of mortality.

Differential effect of cyclosporine and mycophenolic acid on the human regulatory T cells and TH-17 cells balance.

BACKGROUND: Beyond the usual TH1/TH2 polarization, a reciprocal pathway between FoxP3+ regulatory T cells (Tregs) and interleukin (IL)-17-secreting effector T cells (TH-17) has recently been identified. We have investigated the effects of two immunosuppressive drugs, cyclosporine (CsA) and mycophenolic acid (MPA) on the development of Treg/TH-17 cell responses. METHODS: We compared the influence of CsA and MPA on the transcription levels of FOXP3 (Treg marker) and IL17 (TH-17 marker) in activated human peripheral blood mononuclear cells (PBMC). RESULTS: After 48 hours of activation, IL17 transcription was rapidly induced, remaining stable over 96 hours, whereas only a transient increase in FOXP3 was noted, suggesting that the Treg/TH-17 cell balance was tipped toward TH-17 during PBMC activation. The addition of either CsA or MPA did not affect the level of transcription of FOXP3. MPA but not CsA was found to significantly inhibit IL17 expression by activated PBMC. This effect of MPA seemed to result from its capacity to hamper (1) the production of IL1beta by monocytes and (2) the expression of TIM-1 by CD4+ T cells, two key signals involved in human TH-17 differentiation. CONCLUSION: Through a preferential inhibition of IL17, MPA might favorably influence the Treg/TH- 17 balance. Our results suggest that the immunosuppressive drugs used in the clinic may differentially influence lymphocyte polarization, including the newly identified TH-17 pathway.

[Detection and estimation of chronic kidney disease]. / Détection et estimation du niveau de la maladie rénale chronique.

The prevalence of chronic kidney disease is increasing. An early and precise diagnosis of renal insufficiency requires a measurement of the glomerular filtration rate. Formulas based on serum creatinine to determine the glomerular filtration rate have brought, compared to serum creatinine alone, an improvement in this precision. However, in many clinical conditions, they may give incorrect information. Using 24 h urine collection, calculation of creatinine clearance can be more adequate and accurate in conditions where patient's anthropometric characteristics are far from the normal range. However, this 24 h urine collection is often variable and its validity could be criticized. When a very precise determination of glomerular filtration rate is needed, a method of reference is required such as that using chrome EDTA or iohexol. Each nephrological exploration also needs a urine analysis for detection of proteinuria. When a positive urine dipstick test is noted, a quantification of proteinuria must be done either after 24 h urine collection or more easily by determining the proteinuria/creatininuria ratio on an urine sample.

Significant risk factors for occurrence of cancer after renal transplantation: a single center cohort study of 1265 cases.

Occurrence of cancer after renal transplantation remains a major problem, and the second cause of death. We performed a retrospective analysis of first cancer, first skin cancer, and first organ cancer (including posttransplant lymphoproliferative disease [PTLD]) among 1265 cases from 1979 to 2006. The occurrence of cancer was clearly a time-dependent event justifiying the use of Kaplan-Meier survival and Cox regression methods. The 10-year cumulative incidences of first cancer, first skin cancer, and first organ cancer were 24.6%, 14.5%, and 14.5%, respectively. Recipient age was a major, independent risk factor for the 3 endpoints with a 6% increased relative risk for each year increment (P < .0001). Female gender was also a major, independent risk factor, but only for skin cancer (P = .0002). We could not demonstrate any difference between the immunosuppressive drugs used for induction or maintenance therapy, especially between antithymocyte globulin (ATG) vs anti-CD25, cyclosporine vs tacrolimus, and azathioprine vs mycophenolate mofetil. Large cohorts are needed with strict stratifications for recipient age and gender to detect any difference, if any, among the drugs.