Publications by authors named "Nicolas Bouvier"

32 Publications

Living kidney donor evaluation for all candidates with normal estimated GFR for age.

Transpl Int 2021 Mar 27. Epub 2021 Mar 27.

Nephrology, Dialysis and Renal Transplantation Department, Hôpital Nord, CHU de Saint-Etienne, Jean Monnet University, COMUE Université de Lyon, France.

Background: Multiple-days-assessments is frequent for the evaluation of candidates to living kidney donation, combined with an early GFR estimation (eGFR). Living kidney donation is questionable when eGFR is <90mL/min/1.73m (KDIGO guidelines) or 80mL/min/1.73m (most US centers). However, age-related GFR decline results in a lower eGFR for older candidates. That may limit the number of older kidney donors. Yet, continuing the screening with a GFR measure increases the number of eligible donors. We hypothesized that in-depth screening should be proposed to all candidates with a normal eGFR for age.

Methods: We compared the evolution of eGFR after donation between three groups of pre-donation eGFR: normal for age (S ) higher than 90 or 80 mL/min/1.73m (S and S respectively); across three age groups (<45, 45-55, >55 years) in a population of 1825 French living kidney donors with a median follow-up of 5.9 years.

Results: In donors younger than 45, post-donation eGFR, absolute- and relative-eGFR variation were not different between the three groups. For older donors post-donation eGFR was higher in S than in S or S but other comparators were identical. Post-donation eGFR slope was comparable between all groups.

Conclusions: Our results are in favor of in-depth screening for all candidates to donation with a normal eGFR for age.
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http://dx.doi.org/10.1111/tri.13870DOI Listing
March 2021

Rituximab for recurrence of primary focal segmental glomerulosclerosis after kidney transplantation: Results of a nationwide study.

Am J Transplant 2021 Jan 29. Epub 2021 Jan 29.

Department of Nephrology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France.

Rituximab (RTX) therapy for primary focal segmental glomerulosclerosis recurrence after kidney transplantation (KT) has been extensively debated. We aimed to assess the benefit of adding RTX to plasmapheresis (PP), corticosteroids, and calcineurin inhibitors (standard of care, SOC). We identified 148 adult patients who received KT in 12/2004-12/2018 at 21 French centers: 109 received SOC (Group 1, G1), and 39 received immediate RTX along with SOC (Group 2, G2). In G1, RTX was introduced after 28 days of SOC in the event of failure (G1a, n = 19) or PP withdrawal (G1b, n = 12). Complete remission (CR) was achieved in 46.6% of patients, and partial remission (PR) was achieved in 33.1%. The 10-year graft survival rates were 64.7% and 17.9% in responders and nonresponders, respectively. Propensity score analysis showed no difference in CR+PR rates between G1 (82.6%) and G2 (71.8%) (p = .08). Following the addition of RTX (G1a), 26.3% of patients had CR, and 31.6% had PR. The incidence of severe infections was similar between patients treated with and without RTX. In multivariable analysis, infection episodes were associated with hypogammaglobulinemia <5 g/L. RTX could be used in cases of SOC failure or remission for early discontinuation of PP without increasing the risk of infection.
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http://dx.doi.org/10.1111/ajt.16504DOI Listing
January 2021

Paternity in male kidney transplant recipients: a French national survey, the PATeRNAL study.

BMC Nephrol 2020 11 16;21(1):483. Epub 2020 Nov 16.

Centre Universitaire des Maladies Rénales, CHU de Caen, Avenue de la côte de Nacre, 14033, Caen, Cedex 9, France.

Background: There is concern about the impact of immunosuppressive agents taken by male kidney transplant (KT) recipients on the risk of foetal malformations. The aim of our survey was to estimate the paternity rate and the outcomes of pregnancies fathered by kidney transplanted males.

Methods: This survey analysed 1332 male KT recipients older than 18 years, followed in 13 centres in France. A self-reported questionnaire was used to collect data on the patients, treatments at the time of conception and the pregnancy outcomes.

Results: The study included data on 349 children from 404 pregnancies fathered by 232 male KT recipients. The paternity rate was 17% (95% CI [15-20]). There were 37 (9%, 95% CI [7-12]) spontaneous abortions, 12 (3%, 95% CI [2-5]) therapeutic abortions, 2 (0.5%, 95% CI [0.1-1]) still births, and 13 (4%, 95% CI [2-6]) malformations reported. Compared to the general population, there was no difference in the proportion of congenital malformations nor unwanted outcomes whether the father was exposed or not to immunosuppressive agents.

Conclusions: This survey does not provide any warning signal that pregnancies fathered by male patients exposed to immunosuppressive agents, notably the debated MMF/MPA, have more complications than pregnancies in the general population.
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http://dx.doi.org/10.1186/s12882-020-02115-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667842PMC
November 2020

Opportunistic Infections and Efficacy Following Conversion to Belatacept-Based Therapy after Kidney Transplantation: A French Multicenter Cohort.

J Clin Med 2020 Oct 28;9(11). Epub 2020 Oct 28.

Nephrology, Hemodialysis, Apheresis and Kidney Transplantation Department, University Hospital Grenoble, 38000 Grenoble, France.

Conversion from calcineurin-inhibitors (CNIs) to belatacept can help kidney-transplant (KT) recipients avoid CNI-related nephrotoxicity. The risk of associated opportunistic infections (OPIs) is ill-defined. We conducted a multicentric cohort study across 15 French KT-centers in a real-life setting. Between 07-2010 and 07-2019, 453 KT recipients were converted from CNI- to belatacept-based therapy at 19 [0.13-431] months post-transplantation. Most patients, i.e., 332 (79.3%), were converted after 6-months post-transplantation. Follow-up time after conversion was 20.1 +/- 13 months. OPIs developed in 42(9.3%) patients after 14 +/- 12 months post-conversion. Eight patients (19%) had two OPI episodes during follow-up. Incidences of CMV DNAemia and CMV disease were significantly higher in patients converted before 6-months post-KT compared to those converted later (i.e., 31.6% vs. 11.5%; < 0.001; and 11.6% vs. 2.4%, < 0.001, respectively). Cumulative incidence of OPIs was 6.5 OPIs/100 person-years. Incidence of CMV disease was 2.8/100 person-years, of pneumocystis pneumonia 1.6/100 person-years, and of aspergillosis 0.2/100 person-years. Multivariate analyses showed that estimated glomerular filtration (eGFR) < 25 mL/min/1.73 m at conversion was independently associated with OPIs (HR = 4.7 (2.2 - 10.3), < 0.001). The incidence of EBV DNAemia was 17.3 events /100 person-years. At 1-year post-conversion, mean eGFR had significantly increased from 32.0 +/- 18 mL/min/1.73 m to 42.2 +/- 18 mL/min/1.73 m ( < 0.0001). Conversion to belatacept is an effective strategy with a low infectious risk.
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http://dx.doi.org/10.3390/jcm9113479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693007PMC
October 2020

An initial report from the French SOT COVID Registry suggests high mortality due to COVID-19 in recipients of kidney transplants.

Kidney Int 2020 12 24;98(6):1549-1558. Epub 2020 Aug 24.

Department of Nephrology and Transplantation, University of Lille, Lille, France.

Notwithstanding the ongoing coronavirus disease-2019 (Covid-19) pandemic, information on its clinical presentation and prognosis in recipients of a kidney transplant remain scanty. The aim of this registry-based observational study was to explore characteristics and clinical outcomes of recipients of kidney transplants included in the French nationwide Registry of Solid Organ Transplant Recipients with Covid-19. Covid-19 was diagnosed in symptomatic patients who had a positive PCR assay for SARS-CoV-2 or having typical lung lesions on imaging. Clinical and laboratory characteristics, management of immunosuppression, treatment for Covid-19, and clinical outcomes (hospitalization, admission to intensive care unit, mechanical ventilation, or death) were recorded. Risk factors for severe disease or death were determined. Of the 279 patients, 243 were admitted to hospital and 36 were managed at home. The median age of hospitalized patients was 61.6 years; most had comorbidities (hypertension, 90.1%; overweight, 63.8%; diabetes, 41.3%; cardiovascular disease, 36.2%). Fever, cough, dyspnea, and diarrhea were the most common symptoms on admission. Laboratory findings revealed mild inflammation frequently accompanied by lymphopenia. Immunosuppressive drugs were generally withdrawn (calcineurin inhibitors: 28.7%; antimetabolites: 70.8%). Treatment was mainly based on hydroxychloroquine (24.7%), antiviral drugs (7.8%), and tocilizumab (5.3%). Severe Covid-19 occurred in 106 patients (46%). Forty-three hospitalized patients died (30-day mortality 22.8%). Multivariable analysis identified overweight, fever, and dyspnea as independent risk factors for severe disease, whereas age over 60 years, cardiovascular disease, and dyspnea were independently associated with mortality. Thus, Covid-19 in recipients of kidney transplants portends a high mortality rate. Proper management of immunosuppression and tailored treatment of this population remain challenging.
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http://dx.doi.org/10.1016/j.kint.2020.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444636PMC
December 2020

Protocol Biopsies in Patients With Subclinical De Novo Donor-specific Antibodies After Kidney Transplantation: A Multicentric Study.

Transplantation 2020 08;104(8):1726-1737

Nephrology Kidney Transplantation Dialysis, CHU Rouen, Rouen, France.

Background: De novo donor-specific antibodies (DSAs) are associated with antibody-mediated rejection (AMR) and allograft loss. Whether monitoring of de novo DSA (dnDSA) paired with systematic kidney biopsy should become routine remains to be established.

Methods: A retrospective multicentric study (9 French kidney transplant units of the Spiesser group) included patients without graft dysfunction biopsied because of the presence of dnDSA (One Lambda, mean fluorescence intensity [MFI], >1000).

Results: One hundred twenty-three patients (85 male/38 female; mean age, 49.5 ± 13.1 y old) were biopsied after the detection of a dnDSA, 65.3 months (median) after kidney transplantation. Graft function was stable within 3 months before biopsy (estimated glomerular filtration rate, 55.3 ± 18.9 mL/min/1.73 m). Fifty-one subclinical AMRs (sAMRs) (41.4%) were diagnosed, of which 32 (26%) active and 19 (15.5%) chronic active sAMR. Seventy-two biopsies revealed no AMR (58.5%). Predictive factors associated with the diagnosis of active sAMR were MFI of immunodominant DSA >4000, MFI of the sum of DSA >6300, age of the recipient <45 years old, and the absence of steroids at biopsy. The presence of proteinuria >200 mg/g was predictive of chronic active sAMR. The decrease of estimated glomerular filtration rate at 5 years post-biopsy was significantly higher in patients with acute sAMR (-25.2 ± 28.3 mL/min/1.73 m) and graft survival significantly lower.

Conclusions: Performing a kidney graft biopsy for the occurrence of dnDSA without renal dysfunction leads to the diagnosis of a sAMR in over 40% of cases. Nevertheless, we did not observe any effect of standard treatment in acute sAMR.
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http://dx.doi.org/10.1097/TP.0000000000003055DOI Listing
August 2020

Chronic Hepatitis C Virus Infection After Kidney Transplantation With or Without Direct-Acting Antivirals in a Real-Life Setting: A French Multicenter Experience.

Transplant Proc 2020 Dec 5;52(10):3179-3185. Epub 2020 Jul 5.

Department of Nephrology and Clinical Immunology, CHU Tours, Tours, France.

Purpose: Kidney transplant recipients (KTRs) are frequently infected with chronic hepatitis C virus (HCV), which can increase the risk of graft loss. Active HCV infections among KTRs are associated with shorter survival times. The emergence of very efficient interferon-free treatments (direct-acting antivirals [DAAs]) has revolutionized prognoses for chronic viral hepatitis. We performed a multicenter study where HCV (+)/RNA (+) KTRs were followed up and either received DAAs (group A) or not (group B) according to the transplant center. The aim was to assess, in a real-life setting, the impact of DAA therapy and to compare these results with those from HCV RNA (+) KTRs where HCV infection was not treated during the same period.

Methods: This study included 66 patients from 11 centers: 44 patients (66.7%; group A) received DAAs, whereas 22 patients did not (group B); the 2 groups were comparable according to baseline data. Most patients (88.6%) received sofosbuvir, 50% received ledipasvir, and 34.7% received daclatasvir. The duration of treatments ranged from 8 to 24 weeks.

Results: HCV RNA clearance (ie, a sustained virologic response) was observed in 95.4% of treated patients. Eradication of HCV led to a significant decrease in liver enzymes (50% reduction for alanine aminotransferase [P ≤ .001] and 41% for gamma glutamyl transpeptidase [P < .001]). Conversely, liver enzymes did not decrease in group B. Death occurred significantly more frequently in nontreated than treated patients (3 in group B vs none in group A, P = .003). Of the 10 treated patients with severe renal impairment before DAA therapy, 6 experienced graft loss.

Conclusion: DAAs are very effective at treating chronic HCV and have an excellent tolerance profile.
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http://dx.doi.org/10.1016/j.transproceed.2020.06.005DOI Listing
December 2020

The FcγRIIIA-158 VV genotype increased the risk of post-transplant lymphoproliferative disorder in T-cell-depleted kidney transplant recipients - a retrospective study.

Transpl Int 2020 08 14;33(8):936-947. Epub 2020 May 14.

EA7501 « Groupe Innovation et Ciblage Cellulaire » team « Fc Receptors, Antibodies and Microenvironment », University of Tours, Tours, France.

Post-transplantation lymphoproliferative disorder (PTLD) is a severe complication in organ transplant recipients. The use of T lymphocyte-depleting antibodies (TLDAb), especially rabbit TLDAb, contributes to PTLD, and the V158F polymorphism of Fc gamma receptor IIIA (FcγRIIIA) also named CD16A could affect the concentration-effect relationship of TLDAb. We therefore investigated the association of this polymorphism with PTLD in kidney transplant recipients. We characterized the V158F polymorphism in two case-control cohorts (discovery, n = 196; validation, n = 222). Then, we evaluated the binding of rabbit IgG to human FcγRIIIA-158V and FcγRIIIA-158F. The V158F polymorphism was not linked to PTLD in the overall cohorts, but risk of PTLD was increased in VV homozygous recipients receiving TLDAb compared with F carriers in both cohorts, especially in recipients receiving TLDAb without muromonab (discovery: HR = 2.22 [1.03-4.76], P = 0.043, validation: HR = 1.75 [1.01-3.13], P = 0.049). In vitro, we found that the binding of rabbit IgG to human NK-cell FcγRIIIA was increased when cells expressed the 158-V versus the 158-F allotype. While the 158-V allotype of human FcγRIIIA binds rabbit immunoglobulin-G with higher affinity, the risk of PTLD was increased in homozygous VV kidney transplant recipients receiving polyclonal TLDAb.
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http://dx.doi.org/10.1111/tri.13624DOI Listing
August 2020

Opportunistic infections after conversion to belatacept in kidney transplantation.

Nephrol Dial Transplant 2020 02;35(2):336-345

Department of Nephrology, Rouen University Hospital, Rouen, France.

Background: Belatacept (bela) rescue therapy seems to be a valuable option for calcineurin inhibitor chronic toxicity in kidney transplantation. Nevertheless, the risk of infection associated with bela is not well reported.

Methods: We report the rate of opportunistic infections (OPI) after a switch to bela in a multicentric cohort of 280 kidney transplant patients.

Results: Forty-two OPI occurred in 34 patients (12.1%), on average 10.8 ± 11.3 months after the switch. With a cumulative exposure of 5128 months of bela treatment, we found an incidence of 0.008 OPI/month of exposure, and 9.8 OPI/100 person-years. The most common OPI was cytomegalovirus (CMV) disease in 18/42 OPI (42.9%) and pneumocystis pneumonia in 12/42 OPI (28.6%). Two patients presented a progressive multifocal leucoencephalopathy and two patients developed a cerebral Epstein-Barr virus-induced post-transplant lymphoproliferative disease. OPI led to death in 9/34 patients (26.5%) and graft failure in 4/34 patients (11.8%). In multivariate analysis, estimated glomerular filtration rate <25/mL/min/1.73 m2 on the day of the switch and the use of immunosuppressive agents before transplantation were associated with the occurrence of OPI. We found a higher rate of infection-related hospitalization (24.1 versus 12.3/100 person-years, P = 0.0007) and also a higher rate of OPI (13.2 versus 6.7/100 person-years, P = 0.005) in the early conversion group (within 6 months).

Conclusions: The risk of OPI is significant post-conversion to bela and may require additional monitoring and prophylactic therapy, particularly regarding pneumocystis pneumonia and CMV disease. These data need to be confirmed in a larger case-control study.
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http://dx.doi.org/10.1093/ndt/gfz255DOI Listing
February 2020

Temporal trends in living kidney donation in France between 2007 and 2017.

Nephrol Dial Transplant 2021 Mar;36(4):730-738

Nephrology and Renal Transplantation Department, Necker Hospital, Paris, France.

Background: Long-term studies have demonstrated a slight increased risk for end-stage renal disease (ESRD) for living kidney donors (LKD). In France, living kidney donation doubled within the past 10 years. We investigated the change in characteristics of LKD between 2007 and 2017 and the adequacy of follow-up.

Methods: Data were obtained from the national registry for LKD. We compared characteristics of LKD between two study periods: 2007-11 and 2012-17, and stratified donors by age and relation to recipient. We aggregated four characteristics associated with higher ESRD risk [young age, first-degree relation to recipient, obesity, low glomerular filtration rate (GFR) for age] in a single risk indicator ranging from 0 to 4.

Results: We included 3483 donors. The proportion of unrelated donors >56 years of age increased significantly. The proportion of related donors <56 years of age decreased significantly. The body mass index and proportion of obese donors did not change significantly. The proportion of donors with low estimated GFR for age decreased significantly from 5% to 2.2% (P < 0.001). The proportion of donors with adequate follow-up after donation increased from 19.6% to 42.5% (P < 0.001). No donor had a risk indicator equal to 4, and the proportion of donors with a risk indicator equal to 0 increased significantly from 19.2% to 24.9% (P < 0.001).

Conclusions: An increase in living kidney donation in France does not seem to be associated with the selection of donors at higher risk of ESRD and the proportion of donors with adequate annual follow-up significantly increased.
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http://dx.doi.org/10.1093/ndt/gfz229DOI Listing
March 2021

Clinical utility of leflunomide for BK polyomavirus associated nephropathy in kidney transplant recipients: A multicenter retrospective study.

Transpl Infect Dis 2019 Apr 1;21(2):e13058. Epub 2019 Mar 1.

Nephrology and Transplantation Department, Universitary Hospital, Strasbourg, France.

Background: BK polyomavirus associated nephropathy (BKPyVAN) is a significant clinical issue in kidney transplant (KT) recipients. No specific therapy is currently available, although treatment with leflunomide may be part of the therapeutic strategy. Here, we sought to examine the impact of leflunomide on the evolution of BKPyVAN.

Methods: This was an observational retrospective study conducted in 3 French transplant centers. KT recipients who developed BKPyVAN and received leflunomide after failure of other treatment approaches were deemed eligible. Graft function, viral clearance, patient survival, rejection rates, treatment tolerability, and immunosuppression levels served as the main outcome measures.

Results: A total of 55 patients were included. Treatment with leflunomide was started after a mean of 1.4 ± 4.1months  after BKPyVAN diagnosis. Between the introduction of leflunomide and the end of follow-up, creatinine levels increased by 31 ± 118% (P = 0.04), whereas viremia decreased by 79 ± 37% (P < 0.001). Blood viral clearance was observed in 76% of the study patients. Rejection episodes occurred in 33% of the participants. Eleven patients lost their graft (9 of which because of BKPyVAN). Ten patients developed adverse effects and 3 discontinued leflunomide.

Conclusion: We cannot conclude about the exact place of leflunomide in the therapeutic strategy of BKPyVAN. It may be a part of the therapy to promote BK polyomavirus clearance in cases of BKPyVAN who fail to improve after immunosuppression lowering alone. Unfortunately, a significant decline in renal function and high rejection rates remain major clinical challenges.
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http://dx.doi.org/10.1111/tid.13058DOI Listing
April 2019

Pharmacokinetics of 300 mg/d Intraperitoneal Daptomycin: New Insight from the DaptoDP Study.

Perit Dial Int 2018 Nov-Dec;38(6):463-466

Nephrology Department, CHU de Caen, Caen, FRANCE.

The DaptoDP (NCT 2012-005699-33) study aimed to evaluate the pharmacokinetic parameters of daptomycin (DAP) in peritoneal dialysis-related peritonitis (PDRP) patients following intraperitoneal (IP) administration. The authors have already reported the findings on the 200-mg dosing and present here the follow-up results of the 300-mg dosing. The primary endpoint was a dialysate concentration of DAP above the effective concentration during 6 hours of dwell time i.e., 16 mg/L. Secondary endpoints were to avoid the toxic threshold of 120 mg/L DAP and to be above 16 mg/L DAP for 2 hours in plasma. Pharmacokinetic parameters were evaluated on days 1 and 5. Safety data were evaluated on days 1 to 14 based on clinical and biological parameters. Daptomycin was administered in Nutrineal during 6 hours of dwell time for 14 days plus the usual antibiotic therapy in a separate dwell. Because the 200-mg dosing objectives were not reached, a higher DAP dose of 300 mg was tested in the next 3 patients. Effective dialysate and plasma concentrations were achieved at the 300-mg DAP dose with the plasma concentration well below the toxic threshold, even at steady state, during which the accumulation factor never exceeded 3. The optimal DAP dose of 300 mg daily by the IP route, as determined by the pharmacokinetic data, needs to be clinically confirmed prior to routine use. The peritoneal bioavailability of DAP supports using the IP route as an alternative to the intravenous route for peritonitis and systemic infections.
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http://dx.doi.org/10.3747/pdi.2017.00256DOI Listing
March 2019

[Outcome of living kidney donors for transplantation].

Nephrol Ther 2017 Nov 12;13(6):448-459. Epub 2017 Oct 12.

Service de néphrologie, dialyse et transplantation, CUMR, CHU de Caen, avenue de la Côte-de-Nacre, 14033 Caen cedex 9, France; Normandie université, Unicaen, UFR de médecine, 2 rue des rochambelles, 14032 Caen cedex, France.

Nowadays, several treatments exist to treat terminal chronic renal failure. Best results for the recipients are obtained with kidney transplantation concerning mortality and quality of life. Transplantation is also the cheaper option for society. Living kidney donation raises the issue of the becoming of the donor, an absolutely healthy subject who gets to a surgical procedure. The becoming of living kidney donors has been compared with the one of controls subjects in several studies. The evaluations focused on the complications of nephrectomy in the short and long-term: kidney failure, hypertension, proteinuria, possibility of pregnancy, quality of life, and mortality. The first results did not show any risk linked to kidney donation, compared to general population. However, since 2013, kidney donors were found at higher risk for kidney failure and even for mortality, compared with controls selected like donor candidates. The risk of kidney donation is nevertheless acceptable and minimal, on the condition of rigorous selection of candidates and regular follow-up.
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http://dx.doi.org/10.1016/j.nephro.2017.02.011DOI Listing
November 2017

[Encapsulating peritoneal sclerosis].

Nephrol Ther 2017 Jun 30;13(4):211-219. Epub 2017 May 30.

Service de néphrologie, dialyse et transplantation, CUMR, CHU de Caen, 14033 Caen cedex, France.

Encapsulating peritoneal sclerosis is a rare but devastating complication of long-term peritoneal dialysis with a high mortality rate. The incidence is between 0.5 and 2.5%, decreasing with time. PSE is defined as a clinical syndrome with signs of gastrointestinal obstruction, inflammation parameters, radiological and macroscopic changes. The duration of treatment and the cessation of peritoneal dialysis are the main risks. About 75% occured in patients on hemodialysis or after kidney transplantation. Morphological alterations are disappearance of mesothelial layer, submesothelial fibrosis, interstitial sclerosis and vasculopathy. Ultrafiltration failure, fast transport status of the peritoneal membrane and loss of sodium sieving, the most powerful predictor, are the functional abnormalities. Biomarkers in peritoneal effluent include cancer antigen 125, interleukin-6. The pathophysiology is probably a consequence of a multiple-hit process in which expression of growth factors and cytokines play a central role. Medical strategies (corticosteroids, tamoxifen) in association with parenteral nutrition and/or surgery (enterolysis) are discussed. Prevention is the use of physiological peritoneal dialysis solutions, icodextrine instead of high glucose concentration solutions and peritoneal lavage after peritoneal dialysis stopping.
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http://dx.doi.org/10.1016/j.nephro.2017.01.020DOI Listing
June 2017

Anti-TNFα therapy for chronic inflammatory disease in kidney transplant recipients: Clinical outcomes.

Medicine (Baltimore) 2016 Oct;95(41):e5108

CHU Clermont-Ferrand, Department of Nephrology, Clermont-Ferrand Necker Hospital, Assistance Publique-Hôpitaux de Paris, Department of Nephrology and Kidney Transplantation, Paris CHU Rangueil, Nephrology, Dialysis, Transplantation, Toulouse CHU Pontchaillou, Department of Nephrology, Rennes CHU Clermont-Ferrand, Biostatistics Unit (DRCI), Clermont-Ferrand University Hospital, Nephrology-Transplantation Department, Strasbourg CHRU and FHU Transplantation, Department of Nephrology and Clinical Immunology, Tours CHU Clermont-Ferrand, Department of Rheutamology, Clermont-Ferrand Service de Néphrologie-Dialyse-Transplantation, CHU Angers, Angers Hôpital Maison Blanche-CHU Reims, Department of Nephrology, Reims Gastroenterology Department, University Hospital Estaing, Clermont-Ferrand Nephrology Department, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris Department of Nephrology, CHU de Caen, Caen, France.

Anti-tumor necrosis factor-α (TNFα) therapy has improved the prognosis of many chronic inflammatory diseases. It appears to be well-tolerated by liver-transplant patients. However, their use and their safety in kidney-transplant patients have yet to be determined.In this retrospective study, we identified 16 adult kidney-transplant patients aged 46.5 years (34-51.8) who received anti-TNFα therapy from 7 kidney transplantation centers. The indications for this treatment included: chronic inflammatory bowel disease (n = 8), inflammatory arthritis (n = 5), AA amyloidosis (n = 1), psoriasis (n = 1), and microscopic polyangiitis (n = 1).Anti-TNFα therapies resulted in a clinical response in 13/16 patients (81%). Estimated glomerular filtration rates (MDRD-4) were similar on day 0 and at 24 months (M24) after anti-TNFα treatment had been initiated (41 [12-55] and 40 [21-53] mL/min/1.73 m, respectively). Two allograft losses were observed. The 1st case was due to antibody-mediated rejection (M18), while the 2nd was the result of AA amyloidosis recurrence (M20). There were several complications: 8 patients (50%) developed 23 serious infections (18 bacterial, 4 viral, and 1 fungal) and 4 developed cancer. Five patients died (infection n = 2, cardiac AA amyloidosis n = 1, intraalveolar hemorrhage following microscopic polyangiitis n = 1, and acute respiratory distress syndrome n = 1). On univariate analysis, recipient age associated with death (P = 0.009) and infection development (P = 0.06).Using anti-TNFα therapies, remission can be achieved in chronic inflammatory diseases in kidney-transplant patients. However, concommitant anti-TNFα and immunosuppresive therapies must be used with caution due to the high risk of infection, particularly after the age of 50.
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http://dx.doi.org/10.1097/MD.0000000000005108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5072954PMC
October 2016

Successful renal retransplantation after graft loss from BK polyomavirus infection in a human immunodeficiency virus-positive patient.

Transpl Infect Dis 2016 Dec 10;18(6):946-949. Epub 2016 Nov 10.

Department of Nephrology, CHU de Caen, Caen, France.

We report the case of a human immunodeficiency virus-seropositive patient whose initial kidney transplant failed because of BK polyomavirus-induced nephropathy, and who underwent a second transplantation 3 years later. BK viruria was detected 1 day after transplantation. After 1 month, BK viremia developed along with a donor-specific antibody. After decreasing tacrolimus and mycophenolic acid and 2 courses of intravenous immunoglobulins, BK viremia and donor-specific antibody permanently disappeared, with stable renal function.
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http://dx.doi.org/10.1111/tid.12615DOI Listing
December 2016

Pharmacokinetics of Intraperitoneal Daptomycin in Patients with Peritoneal Dialysis-Related Peritonitis.

Perit Dial Int 2017 01 28;37(1):44-50. Epub 2016 Sep 28.

Nephrology Department, CHU de Caen, France.

♦ BACKGROUND: Antibiotics are preferentially delivered via the peritoneal route to treat peritoneal dialysis-related peritonitis (PDRP) to ensure that maximal concentrations are delivered to the site of infection. Our study focused on the pharmacokinetics of daptomycin (DAP) administered via the intraperitoneal (IP) route in patients with PDRP. ♦ METHODS: According to the DaptoDP protocol (Clinical Trial No. 2012-005699-33), IP DAP was administered daily, i.e., during the 6-h Nutrineal (Baxter Healthcare Corporation, Deerfield, IL, USA) dwell time period, for 14 days, in addition to administration of the antibiotics used for the usual care of patients with PDRP. The plasma and IP levels of DAP were measured on days 1 and 5. The tested dose was 200 mg/day. The principal endpoint was the dialysate concentration after 6 hours of dwell time > 16 mg/L (corresponding to 4 x minimum inhibitory concentration [MIC] for E. faecalis). ♦ RESULTS: Three participants were evaluated. On day 5, the IP concentrations after 6 hours of dwell time were between 6.3 and 23.4 mg/L, and the peak plasma concentrations were between 13.0 and 15.3 mg/L. ♦ CONCLUSION: The results suggest that 200 mg/day is very likely sufficient for the treatment of PDRP by Staphylococci or Streptococci whereas it could be insufficient to treat PRDP by Enterococci. The good peritoneal bioavailability of DAP was quantitatively established, suggesting that IP administration could also be used as an alternate route for patients with damaged venous access. No DAP accumulation that could lead to toxic concentrations after repeated administration is expected, even in anuric patients. The protocol will further continue to assess whether a higher dose achieves the pharmacokinetic objectives.
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http://dx.doi.org/10.3747/pdi.2016.00028DOI Listing
January 2017

[BK virus infections in kidney transplantation].

Nephrol Ther 2016 Apr 28;12(2):76-85. Epub 2016 Jan 28.

Service de néphrologie, dialyse et transplantation, CUMR, CHU de Caen, avenue de la Côte-de-Nâcre, 14033 Caen cedex, France. Electronic address:

BK virus is near ubiquitous, with a seroprevalence of around 80% in the general population. Subsequent to an asymptomatic primary infection, BK virus then remains dormant in healthy subjects. Reactivation occurs in immunocompromised people. BKv is pathogenic mainly among patients who have received a kidney transplant, in whom the virus can cause specific tubulo-interstitial nephritis and even result in graft failure among approximately 20 to 30% of nephritic cases. Since the mid 90 s, incidence has increased with the use of new powerful immunosuppressor treatments. The cornerstone of BK virus infection or BK virus-associated nephropathy treatment is a decrease of the immunosuppressive regimen, which must then be offset with the risk of rejection. The use of several adjuvant therapies has been submitted (fluoroquinolones, leflunomide, intravenous immunoglobulins, cidofovir), with no sufficient proof enabling the recommendation of first-line prescription. The high frequency of this infection and its potential harmfulness argue for the use of prevention strategies, at least among patients presenting risk factors. Retransplantation is safe after a first kidney allograft loss caused by BK-virus nephropathy, on condition that a screening for viremia is frequently conducted.
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http://dx.doi.org/10.1016/j.nephro.2015.11.003DOI Listing
April 2016

A Novel Extrinsic Pathway for the Unfolded Protein Response in the Kidney.

J Am Soc Nephrol 2016 09 28;27(9):2670-83. Epub 2016 Jan 28.

Institut National de la Santé et de le Recherche Médicale (INSERM) U1147, Centre Universitaire des Saints Pères, Paris, France; Université Paris Descartes, Paris, France; Service de Biochimie, Service de Néphrologie, Hôpital Européen Georges Pompidou, Paris, France;

The ribonuclease angiogenin is a component of the mammalian stress response, and functions in both cell-autonomous and non-cell-autonomous ways to promote tissue adaptation to injury. We recently showed that angiogenin regulates tissue homeostasis during AKI associated with endoplasmic reticulum (ER) stress through the production of transfer RNA fragments that interfere with translation initiation and thereby alleviate ER stress. However, whether the paracrine signaling mediated by angiogenin secretion is a genuine component of the ER stress response to kidney injury is unknown. Here, we explored the molecular mechanisms by which angiogenin is secreted upon ER stress, and determined how it modulates the inflammatory microenvironment. In cultured renal epithelial cells, ER stress specifically induced angiogenin secretion under the selective control of inositol-requiring enzyme 1α, a key activator of the unfolded protein response. The transcription factors spliced X-box-binding protein 1 and p65, which are activated by inositol-requiring enzyme 1α upon ER stress, each bound the angiogenin promoter and controlled the amount of angiogenin secreted. Furthermore, p65 promoted angiogenin transcription in an ER stress-dependent manner. Similar to secretion of the ER stress-induced proinflammatory cytokine IL-6, secretion of angiogenin required the ER-Golgi pathway. Notably, incubation of human macrophages with angiogenin promoted macrophage reprogramming toward an activated and proinflammatory phenotype. In patients, angiogenin expression increased upon renal inflammation, and the urinary concentration of angiogenin correlated with the extent of immune-mediated kidney injury. Collectively, our data identify angiogenin as a mediator of the ER stress-dependent inflammatory response and as a potential noninvasive biomarker of AKI.
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http://dx.doi.org/10.1681/ASN.2015060703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004651PMC
September 2016

Minimization of maintenance immunosuppressive therapy after renal transplantation comparing cyclosporine A/azathioprine or cyclosporine A/mycophenolate mofetil bitherapy to cyclosporine A monotherapy: a 10-year postrandomization follow-up study.

Transpl Int 2016 Jan;29(1):23-33

Service de Néphrologie-Hémodialyse-Transplantation rénale, CHU de Poitiers, Poitiers, France.

Long-term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post-transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients' survival was 100%, 94.2%, and 95.8% (P = 0.25), and death-censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m(2), respectively (P = 0.16). The incidence of biopsy-proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus-associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody-mediated rejection (n = 6). De novo donor-specific antibodies were detected in 13% of AZA-, 21% of MMF-, and 14% of CsA-treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well-selected renal transplant recipient (ClinicalTrials.gov number: 980654).
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http://dx.doi.org/10.1111/tri.12627DOI Listing
January 2016

[PRETAGREF study: Prevalence of tobacco use and factors associated with smoking cessation in kidney transplant recipients].

Nephrol Ther 2016 Feb 23;12(1):48-55. Epub 2015 Nov 23.

Service de néphrologie, CHU Clémenceau, avenue de la Côte-de-Nacre, 14033 Caen cedex, France.

Introduction: Tobacco use increases the risk of mortality, cancers and cardiovascular diseases in transplanted patients. Transplanted patients are encouraged to quit tobacco use before and after renal transplantation. This study was carried out to evaluate the prevalence of tobacco consumption in transplanted patients in one French region. This survey was also conducted to identify factors associated with failure in smoking cessation.

Materials And Method: A questionnaire was sent by mail to transplanted patients followed in our center between the 1/01/95 and the 31/12/10. A second mail was sent to increase the response rate.

Results: During the study period, 544 questionnaires were sent to kidney transplant recipients. Among these 544 patients, there were 362 responders. Of these 362 patients, 121 patients (33.4%) were past smokers, and 21 (5.8%) were active smokers. Among the smokers, 20% were exposed to second-hand smoke, 48% had criteria for tobacco moderate to high dependency, and 13.4% were addicted to alcohol. In the multivariate analysis, exposure to second-hand smoke and living alone at home were associated with failure in smoking cessation.

Conclusion: This study shows that the prevalence of tobacco use is not high in transplanted patients. Only 6% of our patients report tobacco use at the study time. Environmental factors are associated with failure in tobacco cessation. Living alone and exposure to second-hand smoke are associated with smoking. Therefore, in transplantation centers, programs devoted to tobacco cessation should be implemented and should take care of patients' lifestyle.
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http://dx.doi.org/10.1016/j.nephro.2015.08.001DOI Listing
February 2016

Angiogenin Mediates Cell-Autonomous Translational Control under Endoplasmic Reticulum Stress and Attenuates Kidney Injury.

J Am Soc Nephrol 2016 Mar 20;27(3):863-76. Epub 2015 Jul 20.

Institut National de la Sante et de la Recherche Médicale (INSERM) U1147, Saints-Pères Research Center Paris, France; Paris Descartes University Paris, France; Clinical Chemistry and Nephrology Departments, Georges Pompidou European Hospital Paris, France;

Endoplasmic reticulum (ER) stress is involved in the pathophysiology of kidney disease and aging, but the molecular bases underlying the biologic outcomes on the evolution of renal disease remain mostly unknown. Angiogenin (ANG) is a ribonuclease that promotes cellular adaptation under stress but its contribution to ER stress signaling remains elusive. In this study, we investigated the ANG-mediated contribution to the signaling and biologic outcomes of ER stress in kidney injury. ANG expression was significantly higher in samples from injured human kidneys than in samples from normal human kidneys, and in mouse and rat kidneys, ANG expression was specifically induced under ER stress. In human renal epithelial cells, ER stress induced ANG expression in a manner dependent on the activity of transcription factor XBP1, and ANG promoted cellular adaptation to ER stress through induction of stress granules and inhibition of translation. Moreover, the severity of renal lesions induced by ER stress was dramatically greater in ANG knockout mice (Ang(-/-)) mice than in wild-type mice. These results indicate that ANG is a critical mediator of tissue adaptation to kidney injury and reveal a physiologically relevant ER stress-mediated adaptive translational control mechanism.
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http://dx.doi.org/10.1681/ASN.2015020196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769205PMC
March 2016

Access to preemptive registration on the waiting list for renal transplantation: a hierarchical modeling approach.

Transpl Int 2015 Sep 28;28(9):1066-73. Epub 2015 Apr 28.

Service de Néphrologie, CHU Clémenceau, Caen, France.

Preemptive kidney transplantation is associated with both longer patient and graft survival. This study was carried out to estimate the association between the renal units and preemptive registration on the waiting list for first deceased donor renal transplantation in a French network of care. From 2008 to 2012, 1529 adult patients followed in 48 units of the French North-West network and registered on the waiting list for a first deceased donor renal allograft were included. We used a mixed logistic regression with renal units as random-effects term for statistical analysis. Of the 1529 patients included, 407 were placed on the waiting list preemptively. There was a significant variability across renal units (variance 0.452). In multivariate analysis, factors independently associated with preemptive registration were cardiovascular disease (odds ratio (OR) 0.57, [95% CI: 0.42-0.79]), social deprivation (OR 0.73, [95% CI 0.57-0.94]), and renal units' characteristics (ownership of the facility: academic hospital, reference-community hospital, OR 0.44, [95% CI 0.24-0.80]-private hospital, OR 0.35, [95% CI 0.18-0.69] and transplant center; P < 0.10]. Variability between renal units was reduced after taking into account their characteristics but was not influenced by patient characteristics. Preemptive registration is associated with renal units, transplant centers, and social deprivation and can be partly explained by disparities in practices.
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http://dx.doi.org/10.1111/tri.12592DOI Listing
September 2015

The unfolded protein response regulates an angiogenic response by the kidney epithelium during ischemic stress.

J Biol Chem 2012 Apr 8;287(18):14557-68. Epub 2012 Mar 8.

INSERM U775, Centre Universitaire des Saints Peres, Paris, France.

Ischemic injuries permanently affect kidney tissue and challenge cell viability, promoting inflammation and fibrogenesis. Ischemia results in nutrient deprivation, which triggers endoplasmic reticulum stress, ultimately resulting in the unfolded protein response (UPR). The aim of this study was to test whether the UPR could promote an angiogenic response independently of the HIF-1α pathway during ischemic stress in the human kidney epithelium. Glucose deprivation induced the secretion of vascular endothelial growth factor A (VEGFA), basic fibroblast growth factor (bFGF) and angiogenin (ANG) in human kidney epithelial cells independently of HIF-1α. Glucose deprivation, but not hypoxia, triggered endoplasmic reticulum stress and activated the UPR. RNA interference-mediated inhibition of the gene encoding the kinase PERK decreased VEGFA and bFGF expression, but neither gene was affected by the inhibition of IRE1α or ATF6. Furthermore, we show that the expression of angiogenin, which inhibits protein synthesis, is regulated by both IRE1α and PERK, which could constitute a complementary function of the UPR in the repression of translation. In a rat model of acute ischemic stress, we show that the UPR is activated in parallel with VEGFA, bFGF, and ANG expression and independently of HIF-1α.
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http://dx.doi.org/10.1074/jbc.M112.340570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340272PMC
April 2012

The unfolded protein response regulates an angiogenic response by the kidney epithelium during ischemic stress.

J Biol Chem 2012 Apr 8;287(18):14557-68. Epub 2012 Mar 8.

INSERM U775, Centre Universitaire des Saints Peres, Paris, France.

Ischemic injuries permanently affect kidney tissue and challenge cell viability, promoting inflammation and fibrogenesis. Ischemia results in nutrient deprivation, which triggers endoplasmic reticulum stress, ultimately resulting in the unfolded protein response (UPR). The aim of this study was to test whether the UPR could promote an angiogenic response independently of the HIF-1α pathway during ischemic stress in the human kidney epithelium. Glucose deprivation induced the secretion of vascular endothelial growth factor A (VEGFA), basic fibroblast growth factor (bFGF) and angiogenin (ANG) in human kidney epithelial cells independently of HIF-1α. Glucose deprivation, but not hypoxia, triggered endoplasmic reticulum stress and activated the UPR. RNA interference-mediated inhibition of the gene encoding the kinase PERK decreased VEGFA and bFGF expression, but neither gene was affected by the inhibition of IRE1α or ATF6. Furthermore, we show that the expression of angiogenin, which inhibits protein synthesis, is regulated by both IRE1α and PERK, which could constitute a complementary function of the UPR in the repression of translation. In a rat model of acute ischemic stress, we show that the UPR is activated in parallel with VEGFA, bFGF, and ANG expression and independently of HIF-1α.
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http://dx.doi.org/10.1074/jbc.M112.340570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340272PMC
April 2012

Antiapoptotic properties of recombinant human erythropoietin protects against tubular cyclosporine toxicity.

Pharmacol Res 2010 Jan 18;61(1):71-5. Epub 2009 Sep 18.

INSERM U775 and Université Paris Descartes, Paris, France.

During the early post transplant period, the tubular epithelium is the main target of injuries including ischemia reperfusion and toxicity effects from calcineurin inhibitors. Taking into account the tissue protective effects of erythropoietin mediated through its antiapoptotic properties, we tested whether administration of recombinant human erythropoietin protects against acute cyclosporine nephrotoxicity. Four groups of five rats were intraperitoneally treated over 28 days with 100UI/Kg/48h Epoetin beta (15mg/kg/day CsA diluted in olive oil, 100UI/Kg/48h Epoetin beta+15mg/kg/day CsA, or olive oil. Histological changes due to tubular necrosis were evaluated with Masson'Trichrome staining. Apoptotic nuclei in kidneys were detected using the Terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling (TUNEL) method. Phospho-Akt, Akt, cleaved caspase 3 and non cleaved caspase 3 expression were evaluated using immunblotting. We demonstrate that recombinant human erythropoietin (epoetin beta) improves renal function and protects against acute tubular injury. Our data suggest that this nephroprotective effect is mediated by Akt activation and inhibition of tubular apoptosis. Indeed, western blotting analysis of caspase 3 cleavage and Akt phosphorylation demonstrates that rhEPO activate Akt signaling and inhibits caspase 3 cleavage induced by CsA. TUNEL staining confirms that rhEPO inhibits CsA-induced tubular apoptosis. In conclusion, we describe here a new potential target of recombinant human erythropoietin and our results provide an interesting framework for further nephroprotective therapies based on recombinant human erythropoietin.
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http://dx.doi.org/10.1016/j.phrs.2009.08.010DOI Listing
January 2010

[Endoplasmic reticulum stress in kidney diseases: a question of life and death?].

Nephrol Ther 2009 Jun 13;5(3):173-80. Epub 2008 Dec 13.

Inserm U775, centre universitaire des Saints-Pères, université Paris Descartes, 45, rue des Saints-Pères, 75006 Paris, France.

Increasing our understanding of the cellular and molecular mechanisms of acute and chronic kidney diseases will lead to the development of new biomarkers of early kidney injury and to the discovery of new therapeutic strategies to prevent the initiation of renal failure or to promote the renal regeneration after injury. The implication of the endoplasmic reticulum stress in kidney diseases is not well recognized, but increasing experimental evidences suggest its implication in a wide array of kidney insults. Beside its role in the regulation of cell death, the UPR response induced by the endoplasmic reticulum stress alters many cellular functions and constitutes an important mediator of inflammation and/or epithelial to mesenchymal transition. The purpose of this review is to summarize the existing data concerning the role of the endoplasmic reticulum stress during kidney injury and to clarify its precise role in chronic kidney disease.
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http://dx.doi.org/10.1016/j.nephro.2008.10.007DOI Listing
June 2009

Regional discrepancies in peritoneal dialysis utilization in France: the role of the nephrologist's opinion about peritoneal dialysis.

Nephrol Dial Transplant 2009 Apr 25;24(4):1293-7. Epub 2008 Nov 25.

Department of Nephrology, CHU Clemenceau, Avenue Georges Clemenceau, 14033 Caen CEDEX 9, France.

Background: Peritoneal dialysis (PD) is underused in France compared with other countries. In addition, there are tremendous regional discrepancies concerning the utilization rate of PD. This study was carried out to evaluate the opinion of French nephrologists regarding the optimal rate of PD utilization and to determine which factors limit PD development in France.

Methods: Of the 22 French regions, 2 regions with a high rate of PD utilization (prevalence >15%) and 3 regions with a low rate of PD utilization (prevalence <10%) were selected. In June 2007, nephrologists from the five regions were surveyed by questionnaire. Responses were compared between 'low-prevalence' and 'high-prevalence' groups.

Results: The response rate was 70% and there was no significant difference between the two groups regarding the response rate. In the two groups, a majority of nephrologists were in charge of PD patients (30/34 in 'high-prevalence' group versus 61/80 in 'low-prevalence' group, P = 0.14). Information about PD in the predialysis clinics was provided by nephrologists from high- and low-prevalence regions (32/34 versus 65/80, P = 0.08). Opinions on the optimal rate of PD for prevalent and incident dialysis patients were significantly different between 'high-prevalence' and 'low-prevalence' groups [31 +/- 15% versus 25 +/- 14% (P < 0.03) and 25 +/- 14% versus 19 +/- 9% (P < 0.02)]. There was a significant difference concerning the optimal rate of PD in incident dialysis patients between nephrologists working in public centres (29 +/- 15%), those working in non- profit clinics (27 +/- 12%) and nephrologists working in the private sector (14 +/- 8%). Lack of nurses available for the patient care (48%), low reimbursement of PD (25%), limited training (23%) and hospital care facilities (23%) were the main barriers limiting PD utilization.

Conclusions: In France, like in other countries, there are factors limiting PD development; however, regional discrepancies regarding PD utilization seem to be linked to the nephrologist's opinion.
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http://dx.doi.org/10.1093/ndt/gfn648DOI Listing
April 2009

Cyclosporine triggers endoplasmic reticulum stress in endothelial cells: a role for endothelial phenotypic changes and death.

Am J Physiol Renal Physiol 2009 Jan 5;296(1):F160-9. Epub 2008 Nov 5.

Unité INSERM U775, Centre Universitaire des Saints Pères, 45, rue des saints Pères, 75006 Paris, France.

Calcineurin inhibitors cyclosporine and tacrolimus are effective immunosuppressants, but both substances have the same intrinsic nephrotoxic potential that adversely affects allograft survival in renal transplant patients and causes end-stage renal disease in other solid organ or bone marrow transplant recipients. Endothelial cells are the first biological interface between drugs and the kidney, and calcineurin inhibitors may influence endothelial function and viability in a number of ways. Notably, endothelial cells have recently been shown to contribute to the accumulation of interstitial fibroblasts in nonrenal models, through endothelial-to-mesenchymal transition. Here we demonstrate that cyclosporine, but not tacrolimus or its metabolites, induces morphological and phenotypic endothelial changes suggestive of a partial endothelial-to-mesenchymal transition in human umbilical arterial endothelial cells. We identify for the first time a contingent of interstitial myofibroblasts that coexpress endothelial markers in rat kidneys treated with cyclosporine, suggesting that endothelial-to-mesenchymal transition could occur in vivo. Finally, our findings suggest that endoplasmic reticulum stress triggered by cyclosporine induces endothelial cells to undergo endothelial phenotypic changes suggestive of a partial endothelial-to-mesenchymal transition, whereas salubrinal partially preserves the endothelial phenotype. Inversely, tacrolimus does not induce endothelial-to-mesenchymal transition or endoplasmic reticulum stress. In conclusion, this study demonstrates for the first time that cyclosporine, and not tacrolimus, induces endoplasmic reticulum stress in endothelial cells. Our findings also suggest that endoplasmic reticulum stress contributes to endothelial cell death and phenotypic changes similar to a partial endothelial-to-mesenchymal transition.
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http://dx.doi.org/10.1152/ajprenal.90567.2008DOI Listing
January 2009