Publications by authors named "Marc Hazzan"

81 Publications

[Covid-19 in kidney transplantation: Lessons from the French Registry].

Nephrol Ther 2021 Mar 18. Epub 2021 Mar 18.

Service de néphrologie et transplantation, Centre hospitalier universitaire de Lille, Lille, France.

The Covid-19 pandemic hits the French transplant population on March 3, 2020. Very quickly, a French registry was set up on behalf of the French Society of Transplantation allowing the collection of confirmed cases of Covid-19 occurring in kidney transplant recipients in almost all French centers. The analysis of this registry in conjunction with the data from the Agence de la Biomédecine (Cristal) has enabled us to obtain instructive results. We first showed that the incidence of severe forms among transplant patients hospitalized for Covid-19 was 46% and that their mortality was 22.8%. The risk factors for severe forms and mortality are described. Then we showed, by comparing transplant patients with immunocompetent patients matched for the main severity factors of the disease, that mortality among transplant patients was higher (17.9% vs 11.4%; P<0.001). In multivariate analysis, a creatinine level at admission above 115 μmol/L was associated with death, whereas being transplanted was not. Finally, comparing the transplant cohort with patients on the kidney transplant waiting list during the period from February to June 2020, we found that patients on the waiting list had a higher Covid-19-related excess mortality than transplant patients, mainly in areas of low viral circulation. In conclusion, the French Registry of transplant patients with Covid-19, which was rapidly set up at the beginning of the epidemic, has already enabled us to draw several lessons about this initially unknown infection, particularly in kidney transplant patients, a population which appeared to be particularly at risk.
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http://dx.doi.org/10.1016/j.nephro.2021.01.002DOI Listing
March 2021

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

Covid-19 in liver transplant recipients: the French SOT COVID registry.

Clin Res Hepatol Gastroenterol 2021 Jan 28;45(4):101639. Epub 2021 Jan 28.

AP-HP, Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM, Unité 1193, Villejuif, France.

Background: Notwithstanding the ongoing coronavirus disease-2019 (Covid-19) pandemic, information on its clinical presentation and prognosis in organ transplant recipients remains limited. The aim of this registry-based observational study was to report the characteristics and clinical outcomes of liver transplant (LT) recipients included in the French nationwide Registry of Solid Organ Transplant Recipients with Covid-19.

Methods: COVID-19 was diagnosed in patients who had a positive PCR assay for SARS-CoV-2 or in presence of typical lung lesions on imaging or specific SARS-CoV-2 antibodies. 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.

Results: Of the 104 patients, 67 were admitted to hospital and 37 were managed at home (including all 13 children). Hospitalized patients had a median age of 65.2 years (IQR: 58.1 - 73.2 years) and two thirds were men. Most common comorbidities included overweight (67.3%), hypertension (61.2%), diabetes (50.7%), cardiovascular disease (20.9%) and respiratory disease (16.4%). SARS-CoV-2 infection was identified after a median of 92.8 months (IQR: 40.1 - 194.7 months) from LT. During hospitalization, antimetabolites, mTOR inhibitor, and CNIs were withdrawn in 41.9%, 30.0% and 12.5% of patients, respectively. The composite endpoint of severe Covid-19 within 30 days after diagnosis was reached by 33.0% of the adult patients. The 30-day mortality rate was 20.0%, and 28.1% for hospitalized patients. Multivariate analysis identified that age was independently associated with mortality.

Conclusion: In our large nationwide study, Covid-19 in LT recipients was associated with a high mortality rate.
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http://dx.doi.org/10.1016/j.clinre.2021.101639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843027PMC
January 2021

Impact of Covid-19 on kidney transplant and waiting list patients: Lessons from the first wave of the pandemic.

Nephrol Ther 2021 Jan 8. Epub 2021 Jan 8.

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

Background: The first wave of the Covid-19 pandemic resulted in a drastic reduction in kidney transplantation and a profound change in transplant care in France. It is critical for kidney transplant centers to understand the behaviors, concerns and wishes of transplant recipients and waiting list candidates.

Methods: French kidney patients were contacted to answer an online electronic survey at the end of the lockdown.

Results: At the end of the first wave of the pandemic in France (11 May 2020), 2112 kidney transplant recipients and 487 candidates answered the survey. More candidates than recipients left their home during the lockdown, mainly for health care (80.1% vs. 69.4%; P<0.001). More candidates than recipients reported being exposed to Covid-19 patients (2.7% vs. 1.2%; P=0.006). Many recipients and even more candidates felt inadequately informed by their transplant center during the pandemic (19.6% vs. 54%; P<0.001). Among candidates, 71.1% preferred to undergo transplant as soon as possible, 19.5% preferred to wait until Covid-19 had left their community, and 9.4% were not sure what to do.

Conclusions: During the Covid-19 pandemic in France, the majority of candidates wished to receive a transplant as soon as possible without waiting until Covid-19 had left their community. Communication between kidney transplant centers and patients must be improved to better understand and serve patients' needs.
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http://dx.doi.org/10.1016/j.nephro.2020.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791308PMC
January 2021

Clinical Trial Emulation by Matching Time-dependent Propensity Scores: The Example of Estimating Impact of Kidney Transplantation.

Epidemiology 2021 Mar;32(2):220-229

From the INSERM UMR 1246 -SPHERE, Nantes University, Tours University, Nantes, France.

Background: No study to our knowledge has examined the use of observational data to emulate a clinical trial whereby patients at the time of kidney transplant proposal are randomly assigned to an awaiting transplantation or transplantation group. The main methodologic issue is definition of the baseline for dialyzed patients assigned to awaiting transplantation, resulting in the inability to use common propensity score-based approaches. We aimed to use time-dependent propensity score to better appraise the benefit of transplantation.

Methods: We studied 23,231 patients included in the French registry and on a transplant waiting list from 2005 to 2016. The main outcome was time to death. By matching on time-dependent propensity score, we obtained 10,646 pairs of recipients (transplantation group) versus comparable patients remaining on dialysis (awaiting transplantation group).

Results: The baseline exposure, that is, pseudo-randomization, was matching time. Median follow-up time was 3.5 years. At 10 years' follow-up, the restricted mean survival time was 8.8 years [95% confidence interval (CI) = 8.7, 8.9] in the transplantation group versus 8.2 years (95% CI = 8.1, 8.3) in the awaiting transplantation group. The corresponding life expectancy gain was 6.8 months (95% CI = 5.5, 8.2), and this corresponded to one prevented death at 10 years for 13 transplantations.

Conclusions: Our study has estimated the life expectancy gain due to kidney transplantation. It confirms transplantation as the best treatment for end-stage renal disease. Furthermore, we demonstrated that this simple method should also be considered for estimating marginal effects of time-dependent exposures.
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http://dx.doi.org/10.1097/EDE.0000000000001308DOI Listing
March 2021

Is COVID-19 infection more severe in kidney transplant recipients?

Am J Transplant 2021 03 28;21(3):1295-1303. Epub 2021 Jan 28.

Department of Infectious Diseases, Strasbourg University Hospital, Strasbourg, France.

There are no studies which have compared the risk of severe COVID-19 and related mortality between transplant recipients and nontransplant patients. We enrolled two groups of patients hospitalized for COVID-19, that is, kidney transplant recipients (KTR) from the French Registry of Solid Organ Transplant (n = 306) and a single-center cohort of nontransplant patients (n = 795). An analysis was performed among subgroups matched for age and risk factors for severe COVID-19 or mortality. Severe COVID-19 was defined as admission (or transfer) to an intensive care unit, need for mechanical ventilation, or death. Transplant recipients were younger and had more comorbidities compared to nontransplant patients. They presented with higher creatinine levels and developed more episodes of acute kidney injury. After matching, the 30-day cumulative incidence of severe COVID-19 did not differ between KTR and nontransplant patients; however, 30-day COVID-19-related mortality was significantly higher in KTR (17.9% vs 11.4%, respectively, p = .038). Age >60 years, cardiovascular disease, dyspnea, fever, lymphopenia, and C-reactive protein (CRP) were associated with severe COVID-19 in univariate analysis, whereas transplant status and serum creatinine levels were not. Age >60 years, hypertension, cardiovascular disease, diabetes, CRP >60 mg/L, lymphopenia, kidney transplant status (HR = 1.55), and creatinine level >115 µmol/L (HR = 2.32) were associated with COVID-19-related mortality in univariate analysis. In multivariable analysis, cardiovascular disease, dyspnea, and fever were associated with severe disease, whereas age >60 years, cardiovascular disease, dyspnea, fever, and creatinine level>115 µmol/L retained their independent associations with mortality. KTR had a higher COVID-19-related mortality compared to nontransplant hospitalized patients.
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http://dx.doi.org/10.1111/ajt.16424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753418PMC
March 2021

[Very-old deceased donors in kidney transplantation: How far can we go?]

Nephrol Ther 2020 Dec 14;16(7):408-413. Epub 2020 Nov 14.

Nephrology Department, University of Lille, CHRU Lille, 59000 Lille, France.

In order to increase the pool of organ donors, kidney transplantation from very old-donors, notably aged more than 70, is increasing. Compared to the United States, where the use of these grafts does not reach 5%, in France it reaches over 20%. Kidney aging is determined by a progressive glomerusclerosis, interstitial fibrosis, and nephrosclerosis, responsible of a linear decrease of glomerular filtration rate with time. Aging in kidney transplantation goes along also with an increased immunogenicity and risk of ischemia-reperfusion injuries. Hence, the prognosis of these transplantations is worse than those from younger donors, even though it remains better than dialysis. Data is lacking on risk factors of graft loss in this specific population. Hypothermic perfusion machine, pre-implantation kidney biopsy, dual kidney transplantation and immunosuppressive strategies have been evaluated to improve the long-term prognosis of these grafts.
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http://dx.doi.org/10.1016/j.nephro.2020.06.002DOI Listing
December 2020

IMPact of the COVID-19 epidemic on the moRTAlity of kidney transplant recipients and candidates in a French Nationwide registry sTudy (IMPORTANT).

Kidney Int 2020 12 31;98(6):1568-1577. Epub 2020 Oct 31.

Department of Nephrology and Transplantation, Strasbourg University Hospital, Strasbourg, France.

End stage kidney disease increase the risk of COVID-19 related death but how the kidney replacement strategy should be adapted during the pandemic is unknown. Chronic hemodialysis makes social distancing difficult to achieve. Alternatively, kidney transplantation could increase the severity of COVID-19 due to therapeutic immunosuppression and contribute to saturation of intensive care units. For these reasons, kidney transplantation was suspended in France during the first epidemic wave. Here, we retrospectively evaluated this strategy by comparing the overall and COVID-19 related mortality in kidney transplant recipients and candidates over the last three years. Cross-interrogation of two national registries for the period 1 March and 1 June 2020, identified 275 deaths among the 42812 kidney transplant recipients and 144 deaths among the 16210 candidates. This represents an excess of deaths for both populations, as compared with the same period the two previous years (mean of two previous years: 253 in recipients and 112 in candidates). This difference was integrally explained by COVID-19, which accounted for 44% (122) and 42% (60) of the deaths in recipients and candidates, respectively. Taking into account the size of the two populations and the geographical heterogeneity of virus circulation, we found that the excess of risk of death due to COVID-19 was similar for recipients and candidates in high viral risk area but four-fold higher for candidates in the low viral risk area. Thus, in case of a second epidemic wave, kidney transplantation should be suspended in high viral risk areas but maintained outside those areas, both to reduce the excess of deaths of candidates and avoid wasting precious resources.
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http://dx.doi.org/10.1016/j.kint.2020.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604114PMC
December 2020

The authors reply.

Kidney Int 2020 12 13;98(6):1618-1619. Epub 2020 Oct 13.

Department of Nephrology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2020.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550975PMC
December 2020

Antibiotics versus no therapy in kidney transplant recipients with asymptomatic bacteriuria (BiRT): a pragmatic, multicentre, randomized, controlled trial.

Clin Microbiol Infect 2021 Mar 10;27(3):398-405. Epub 2020 Sep 10.

Department of Nephrology, Universitair Ziekenhuis Antwerpen, Universiteit Antwerpen, Antwerp, Belgium.

Objectives: Many transplant physicians screen for and treat asymptomatic bacteriuria (ASB) during post-kidney-transplant surveillance. We investigated whether antibiotics are effective in reducing the occurrence of symptomatic urinary tract infection (UTI) in kidney transplant recipients with ASB.

Methods: We performed this multicentre, randomized, open-label trial in kidney transplant recipients who had ASB and were ≥2 months post-transplantation. We randomly assigned participants to receive antibiotics or no therapy. The primary outcome was the incidence of symptomatic UTI over the subsequent 12 months.

Results: One hundred and ninety-nine kidney transplant recipients with ASB were randomly assigned to antibiotics (100 participants) or no therapy (99 participants). There was no significant difference in the occurrence of symptomatic UTI between the antibiotic and no-therapy groups (27%, 27/100 versus 31%, 31/99; univariate Cox model: hazard ratio 0.83, 95%CI: 0.50-1.40; log-rank test: p 0.49). Over the 1-year study period, antibiotic use was five times higher in the antibiotic group than in the no-therapy group (30 antibiotic days/participant, interquartile range 20-41, versus 6, interquartile range 0-15, p < 0.001). Overall, 155/199 participants (78%) had at least one further episode of bacteriuria during the follow-up. Compared with the participant's baseline episode of ASB, the second episode of bacteriuria was more frequently caused by bacteria resistant to clinically relevant antibiotics (ciprofloxacin, cotrimoxazole, third-generation cephalosporin) in the antibiotic group than in the no-therapy group (18%, 13/72 versus 4%, 3/83, p 0.003).

Conclusions: Applying a screen-and-treat strategy for ASB does not reduce the occurrence of symptomatic UTI in kidney transplant recipients who are more than 2 months post-transplantation. Furthermore, this strategy increases antibiotic use and promotes the emergence of resistant organisms.
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http://dx.doi.org/10.1016/j.cmi.2020.09.005DOI Listing
March 2021

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

New visceral manifestations of fibrinogen alpha-chain amyloidosis.

Amyloid 2020 Dec 24;27(4):281-282. Epub 2020 Jun 24.

Centre Hospitalier Regional Universitaire de Lille, Service de Néphrologie et transplantation rénale, Lille, France.

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http://dx.doi.org/10.1080/13506129.2020.1782373DOI Listing
December 2020

A simple score to predict early death after kidney transplantation.

Eur J Clin Invest 2020 Nov 29;50(11):e13312. Epub 2020 Jun 29.

INSERM, UMR1098, Federation hospitalo-universitaire INCREASE, Besançon, France.

Background: Few studies have focused on risk stratification for premature death after transplantation. However, stratification of individual risk is an essential step in personalized care.

Material And Methods: We have developed a risk score of early post-transplant death (ORLY score) in a prospective multicentre cohort including 942 patients and validated our model in a retrospective independent replication cohort including 874 patients.

Results: 60 patients (6.4%) from the prospective cohort died during the first three-year post-transplant. Age, male gender, diabetes, dialysis duration and chronic respiratory failure were associated with early post-transplant death. The multivariable model exhibited good discrimination ability (C-index = 0.78, 95%CI [0.75-0.81]). ORLY score highly predicted early death after transplantation (1.34; 95%CI, 1.22 to 1.48 for each increase of 1 point in score; P < .001). The predictive value of the score in the validation cohort was close to that observed in the experimental cohort (1.41; 95%CI, 1.27 to 1.56 for each increase of 1 point in score; P < .001). Merging the two cohorts, four categories of risk could be individualized: low, 0-5 (n = 522, mean risk, 1%); intermediate, 6-7 (n = 739, mean risk 4.7%); moderate, 8-10 (n = 429, mean risk 10%); and high risk 11-15 (n = 132, mean risk 19%).

Conclusions: The ORLY score discriminates patients with high risk of early death.
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http://dx.doi.org/10.1111/eci.13312DOI Listing
November 2020

Donor-to-recipient transmission and reactivation in a kidney transplant recipient of an inherited chromosomally integrated HHV-6A: Evidence and outcomes.

Am J Transplant 2020 12 28;20(12):3667-3672. Epub 2020 Jun 28.

Service de Néphrologie, CHU Lille, Lille, France.

Human herpesvirus (HHV)-6A can be inherited and chromosomally integrated (iciHHV-6A), and donor-to-recipient transmission has been reported in solid organ transplant. However, when HHV-6A reactivation happens after transplant, the source of HHV-6A is often not evident and its pathogenicity remains unclear. Here, we present an exhaustive case of donor-to-recipient transmission and reactivation of iciHHV-6A through kidney transplant. The absence of HHV-6A genome from the nails of the recipient excluded a recipient-related iciHHV-6A. Viral loads > 7 log copies/10 cells in donor blood samples and similarities of U38, U39, U69, and U100 viral genes between donor, recipient, and previously published iciHHV-6A strains are proof of donor-related transmission. Detection of noncoding HHV-6 snc-RNA14 using fluorescence in situ hybridization analysis and immunofluorescence staining of HHV-6A gp82/gp105 late proteins on kidney biopsies showed evidence of reactivation in the transplanted kidney. Because HHV-6A reactivation can be life threatening in immunocompromised patients, we provide several tools to help during the complete screening and diagnosis.
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http://dx.doi.org/10.1111/ajt.16067DOI 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 Aug 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

An extension of the RITUX-ERAH study, multicenter randomized clinical trial comparing rituximab to placebo in acute antibody-mediated rejection after renal transplantation.

Transpl Int 2020 Jul 5;33(7):786-795. Epub 2020 May 5.

Department of Nephrology, Hypertension, Dialysis and Kidney Transplantation, University hospital of Tours, Tours, France.

The treatment of active antibody-mediated rejection (ABMR) is still a matter of debate, the place of rituximab remaining controversial. The French multicenter double-blind RITUX-ERAH study included 38 patients with ABMR in the first year of renal transplantation. All patients received plasma exchanges, intravenous immunoglobulins, and corticosteroids and were randomly assigned rituximab or placebo infusion at day 5. Additional rituximab infusions were allowed. In the intention-to-treat analysis, 12-month graft survival and renal function were not different between the rituximab and placebo groups. Long-term data are needed to conclude. Evaluation of the 7-year outcomes of the RITUX-ERAH study patients according to the rituximab or placebo treatment received. Eleven patients received placebo and 27 at least one infusion of rituximab. Seven years after ABMR, death-censored kidney allograft survival and renal function were not different between the groups. The evolution of anti-HLA sensitization was similar. There was no statistically significant difference in the incidence of infectious or neoplastic complications, but to be noted, seven cancers developed in six patients treated with rituximab (mean period of 44 months post-ABMR). In this cohort, there was no benefit 7 years after ABMR of rituximab in addition to plasma exchanges, intravenous immunoglobulins, and steroids.
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http://dx.doi.org/10.1111/tri.13613DOI Listing
July 2020

Severe Infection in Anti-Glomerular Basement Membrane Disease: A Retrospective Multicenter French Study.

J Clin Med 2020 Mar 4;9(3). Epub 2020 Mar 4.

Department of Nephrology, Dialysis, and Transplantation, University of Picardie Jules Verne, Amiens University Hospital, F-80054 Amiens, France.

In patients presenting with anti-glomerular basement membrane (GBM) disease with advanced isolated kidney involvement, the benefit of intensive therapy remains controversial due to adverse events, particularly infection. We aim to describe the burden of severe infections (SI) (requiring hospitalization or intravenous antibiotics) and identify predictive factors of SI in a large cohort of patients with anti-GBM disease. Among the 201 patients (median [IQR] age, 53 [30-71] years) included, 74 had pulmonary involvement and 127 isolated glomerulonephritis. A total of 161 SI occurred in 116 patients during the first year after diagnosis. These infections occurred during the early stage of care (median [IQR] time, 13 [8-19] days after diagnosis) with mainly pulmonary (45%), catheter-associated bacteremia (22%) and urinary tract (21%) infections. In multivariable analysis, positive ANCA (HR [95\% CI] 1.62 [1.07--2.44]; = 0.02) and age at diagnosis (HR [95% CI] 1.10 [1.00-1.21]; = 0.047) remained independently associated with SI. Age-adjusted severe infection during the first three months was associated with an increased three-year mortality rate (HR [95% CI] 3.13 [1.24-7.88]; = 0.01). Thus, SI is a common early complication in anti-GBM disease, particularly in the elderly and those with positive anti-neutrophil cytoplasmic antibodies (ANCA). No significant association was observed between immunosuppressive strategy and occurrence of SI.
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http://dx.doi.org/10.3390/jcm9030698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141378PMC
March 2020

External Validation of the DynPG for Kidney Transplant Recipients.

Transplantation 2021 02;105(2):396-403

INSERM UMR 1246 - SPHERE, Nantes University, Tours University, Nantes, France.

Background: In kidney transplantation, dynamic prediction of patient and kidney graft survival (DynPG) may help to promote therapeutic alliance by delivering personalized evidence-based information about long-term graft survival for kidney transplant recipients. The objective of the current study is to externally validate the DynPG.

Methods: Based on 6 baseline variables, the DynPG can be updated with any new serum creatinine measure available during the follow-up. From an external validation sample of 1637 kidney recipients with a functioning graft at 1-year posttransplantation from 2 European transplantation centers, we assessed the prognostic performance of the DynPG.

Results: As one can expect from an external validation sample, differences in several recipient, donor, and transplantation characteristics compared with the learning sample were observed. Patients were mainly transplanted from deceased donors (91.6% versus 84.8%; P < 0.01), were less immunized against HLA class I (18.4% versus 32.7%; P < 0.01) and presented less comorbidities (62.2% for hypertension versus 82.7%, P < 0.01; 25.1% for cardiovascular disease versus 33.9%, P < 0.01). Despite these noteworthy differences, the area under the ROC curve varied from 0.70 (95% confidence interval [CI], 0.64-0.76) to 0.76 (95% CI, 0.64-0.88) for prediction times at 1 and 6 years posttransplantation respectively, and calibration plots revealed reasonably accurate predictions.

Conclusions: We validated the prognostic capacities of the DynPG in terms of both discrimination and calibration. Our study showed the robustness of the DynPG for informing both the patient and the physician, and its transportability for a cohort presenting different features than the one used for the DynPG development.
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http://dx.doi.org/10.1097/TP.0000000000003209DOI Listing
February 2021

Description of a transient proximal tubulopathy induced by amino acids perfusion in peptide receptor radionuclide therapy: A case report.

Medicine (Baltimore) 2019 Dec;98(52):e18478

Department of Nephrology.

Rationale: Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs is a targeted internal radiotherapy method used to treat tumors expressing somatostatin receptors. Concomitant amino acids perfusion is systematically performed in order to inhibit the proximal tubular uptake of the radionuclide and thus prevent nephrotoxicity. PATIENT CONCERNS:: a 67-year-old woman with an intestinal neuroendocrine tumor with multiple lymphadenopathies and liver metastases. The patient displayed a carcinoid syndrome with flushes including facial erythrosis and paresthesia. During the treatment, the patient exhibited emesis and severe cramps.

Diagnosis: We describe incomplete proximal tubulopathy induced by an amino acid therapy with [177Lu]-DOTA0-Tyr3-octreotate, which was reversible after treatment discontinuation. This diagnosis relies on metabolic acidosis, hypophosphatemia due to renal loss, tubular proteinuria and generalized aminoaciduria. Serum creatinine remained stable during and after the procedure.

Interventions: PRRT with radiolabeled somatostatin analog ([177Lu]-DOTA0-Tyr3-octreotate). In order to prevent PRRT induced nephrotoxicity, we used a solution of 20 amino acids including 22 g/L Lysine and 16.8 g/L Arginine. Metoclopramide was successfully used to control vomiting. During the treatment and at the time of cramps, the blood sample showed hypophosphatemia at 0.3 mmol/L justifying intravenous phosphate supplementation. The cramps disappeared after this infusion.

Outcomes: Hypophosphatemia with low TmPO4/GFR was observed as well as an increase in β2-microglobulinuria, urinary polyclonal light chains, and amino aciduria involving all amino acids. All these disturbances disappeared the day after the treatment and there was no acute kidney injury after 5 PRRT sessions. Six months after PRRT discontinuation, the patient had neither renal failure nor proximal tubulopathy. Aminoacid induced tubulopathy involves the main ligands of the megalin receptor. It has recently been demonstrated that cilastatin is a megalin inhibitor in the proximal tubule and therefore could represent an attractive alternative to amino acids for this purpose.

Lessons: This case report is a description of a nephroprotective strategy in which partial, and transient tubulopathy is induced, in order to decrease proximal absorption of a tubulotoxic molecule. This little known strategy could be used to prevent proximal tubular injury caused by others megalin-mediated nephrotoxicity medication.
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http://dx.doi.org/10.1097/MD.0000000000018478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946443PMC
December 2019

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

[Kidney disease care for the elderly].

Nephrol Ther 2019 Dec 9;15(7):533-552. Epub 2019 Nov 9.

Service de néphrologie, hôpital Huriez, CHRU de Lille, 59037 Lille, France. Electronic address:

In our aging population, kidney disease management needs to take into account the frailty of the elderly. Standardized geriatric assessments can be proposed to help clinicians apprehend this dimension in their daily practice. These tools allow to better identify frail patients and offer them more personalized and harmless treatments. This article aims to focus on the kidney diseases commonly observed in elderly patients and analyze their specific nephrogeriatric care modalities. It should be noticed that all known kidney diseases can be also observed in the elderly, most often with a quite similar clinical presentation. This review is thus focused on the diseases most frequently and most specifically observed in elderly patients (except for monoclonal gammopathy associated nephropathies, out of the scope of this work), as well as the peculiarities of old age nephrological care.
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http://dx.doi.org/10.1016/j.nephro.2019.10.001DOI Listing
December 2019

Caveolin-1 rs4730751 single-nucleotide polymorphism may not influence kidney transplant allograft survival.

Sci Rep 2019 10 29;9(1):15541. Epub 2019 Oct 29.

University Lille, EA4483, F-59000, Lille, France.

Caveolin-1 is a protein (encoded by the CAV1 gene) supposedly harboring a protective effect against fibrosis. CAV1 rs4730751 single nucleotide polymorphism (SNP) AA genotype was initially associated with lower graft survival compared to non-AA. However, subsequent studies could not find the same effect. CAV1 rs4730751 SNP was investigated on 918 kidney donors. Multivariate Cox-model analyses were performed to evaluate risk factors for graft loss. Longitudinal changes on long-term estimated glomerular filtration rate (eGFRs) were evaluated with a linear mixed model. Histopathological findings from protocolled biopsies after 3 months post transplantation were also analyzed. Donor CAV1 rs4730751 genotyping proportions were 7.1% for AA, 41.6% for AC and 51.3% for CC. The AA genotype, compared to non-AA, was not associated with lower graft survival censored or not for death (multivariate analysis: HR = 1.23 [0.74-2.05] and HR = 1.27 [0.84-1.92]). Linear mixed model on long-term eGFRs revealed also no significant difference according to the genotype, yet we observed a trend. AA genotype was also not associated with a higher degree of fibrosis index on protocolled kidney biopsies at 3 months. To conclude, donor CAV1 rs4730751 SNP may impact on kidney transplantation outcomes, but this study could not confirm this hypothesis.
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http://dx.doi.org/10.1038/s41598-019-52079-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820546PMC
October 2019

Ten-Year Outcome of Islet Alone or Islet After Kidney Transplantation in Type 1 Diabetes: A Prospective Parallel-Arm Cohort Study.

Diabetes Care 2019 11;42(11):2042-2049

University of Lille, U1190-EGID, Lille, France

Objective: The long-term outcome of allogenic islet transplantation is unknown. The aim of this study was to evaluate the 10-year outcome of islet transplantation in patients with type 1 diabetes and hypoglycemia unawareness and/or a functioning kidney graft.

Research Design And Methods: We enrolled in this prospective parallel-arm cohort study 28 subjects with type 1 diabetes who received islet transplantation either alone (ITA) or after a kidney graft (IAK). Islet transplantation consisted of two or three intraportal infusions of allogenic islets administered within (median [interquartile range]) 68 days (43-92). Immunosuppression was induced with interleukin-2 receptor antibodies and maintained with sirolimus and tacrolimus. The primary outcome was insulin independence with A1C ≤6.5% (48 mmol/mol). Secondary outcomes were patient and graft survival, severe hypoglycemic events (SHEs), metabolic control, and renal function.

Results: The primary outcome was met by (Kaplan-Meier estimates [95% CI]) 39% (22-57) and 28% (13-45) of patients 5 and 10 years after islet transplantation, respectively. Graft function persisted in 82% (62-92) and 78% (57-89) of case subjects after 5 and 10 years, respectively, and was associated with improved glucose control, reduced need for exogenous insulin, and a marked decrease of SHEs. ITA and IAK had similar outcomes. Primary graft function, evaluated 1 month after the last islet infusion, was significantly associated with the duration of graft function and insulin independence.

Conclusions: Islet transplantation with the Edmonton protocol can provide 10-year markedly improved metabolic control without SHEs in three-quarters of patients with type 1 diabetes, kidney transplanted or not.
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http://dx.doi.org/10.2337/dc19-0401DOI Listing
November 2019

Hypercalcemia is common during Pneumocystis pneumonia in kidney transplant recipients.

Sci Rep 2019 08 29;9(1):12508. Epub 2019 Aug 29.

University of Lille, Regional University Hospital Centre of Lille, Nephrology Dialysis and Kidney Transplantation Department, F-59000, Lille, France.

A few cases of hypercalcemia related to Pneumocystis jirovecii pneumonia (PJP) have previously been described, supposedly associated with an 1α-hydroxylase enzyme-dependent mechanism. The prevalence and significance of hypercalcemia in PJP remain unclear, especially in kidney transplant recipients (KTR) who frequently display hypercalcemia via persisting hyperparathyroidism. We here retrospectively identified all microbiologically-proven PJP in adult KTR from 2005 to 2017 in the Lille University Hospital, and studied the mineral and bone metabolism parameters during the peri-infectious period. Clinical features of PJP-patients were analyzed according to their serum calcium level. Hypercalcemia (12.6 ± 1.6 mg/dl) was observed in 37% (18/49) of PJP-patients and regressed concomitantly to specific anti-infectious treatment in all cases. No other cause of hypercalcemia was identified. In hypercalcemic patients, serum levels of 1,25-dihydroxyvitamin D were high at the time of PJP-diagnosis and decreased after anti-infectious treatment (124 ± 62 versus 28 ± 23 pg/mL, p = 0.006) while PTH serum levels followed an inverse curve (35 ± 34 versus 137 ± 99 pg/mL, p = 0.009), suggesting together a granuloma-mediated mechanism. Febrile dyspnea was less frequent in hypercalcemic PJP-patients compared to non-hypercalcemic (29 versus 67%). In summary, hypercalcemia seems common during PJP in KTR. Unexplained hypercalcemia could thus lead to specific investigations in this particular population, even in the absence of infectious or respiratory symptoms.
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http://dx.doi.org/10.1038/s41598-019-49036-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715728PMC
August 2019

Prevention of Cisplatin-Induced Acute Kidney Injury: A Systematic Review and Meta-Analysis.

Drugs 2019 Sep;79(14):1567-1582

Nephrology Department, CHRU Lille, University of Lille, 59000, Lille, France.

Purpose: Cisplatin-induced acute kidney injury (CIA) is a serious adverse event that affects 20-40% of exposed patients, despite any implemented precaution to avoid it. The aim of this work was therefore to identify a relevant nephroprotective method for CIA.

Methods: We searched Pubmed, Embase, and Web of Science from 1 January 1978 to 1 June 2018, without language restriction. All studies (observational and interventional) assessing a CIA prevention method for adults receiving at least one course of cisplatin were eligible. The primary outcome was acute nephrotoxicity, as defined by the AKI-KDIGO classification (2012). The odds ratio and corresponding 95% confidence interval were used to assess the associations. We used narrative synthesis in case of heterogeneity regarding intervention, population, or outcome. When possible, a random-effects model was used to pool studies. The heterogeneity between studies was quantified (I), and multiple meta-regressions were carried out to identify potential confounders.

Results: Within 4520 eligible studies, 51 articles fulfilling the selection criteria were included in the review, assessing 21 different prevention methods. A meta-analysis could only be performed on the 15 observational studies concerning magnesium supplementation (1841 patients), and showed a significant nephroprotective effect for all combined grades of CIA (OR 0.24, [0.19-0.32], I = 0.0%). This significant nephroprotective effect was also observed for grades 2 and 3 CIA (OR 0.22, [0.14-0.33], I = 0.0% and OR 0.25, [0.08-0.76], I = 0.0%, respectively).

Conclusion: While no method of prevention had so far demonstrated its indisputable efficacy, our results highlight the potential protective effect of magnesium supplementation on cisplatin-induced acute nephrotoxicity.

Trial Registration: This study is registered in PROSPERO, CRD42018090612.
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http://dx.doi.org/10.1007/s40265-019-01182-1DOI Listing
September 2019

BK polyomavirus and valganciclovir: Evidence is still lacking.

Am J Transplant 2019 12 9;19(12):3432-3433. Epub 2019 Sep 9.

Department of Nephrology, University of Lille, CHU Lille, F-59000, Lille, France.

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http://dx.doi.org/10.1111/ajt.15562DOI Listing
December 2019

Extracorporeal photopheresis for the treatment of graft rejection in 33 adult kidney transplant recipients.

Transfus Apher Sci 2019 Aug 22;58(4):515-524. Epub 2019 Jul 22.

Service de Néphrologie, CHU Clermont-Ferrand, Clermont-Ferrand, France; Université Clermont Auvergne, Clermont-Ferrand, France.

Background - Extracorporeal photopheresis (ECP) has shown encouraging results in the prevention of allograft rejection in heart transplantation. However, the role of ECP in kidney transplant (KT) rejection needs to be determined. Methods - This multicentre retrospective study included 33 KT recipients who were treated with ECP for allograft rejection (23 acute antibody-mediated rejections (AMRs), 2 chronic AMRs and 8 acute cellular rejections (ACRs)). The ECP indications were KT rejection in patients who were resistant to standard therapies (n = 18) or in patients for whom standard therapies were contraindicated because of concomitant infections or cancers (n = 15). Results - At 12 months (M12) post-ECP, 11 patients (33%) had a stabilization of kidney function with a graft survival rate of 61%. The Banff AMR score (g + ptc + v) was a risk factor for graft loss at M12 (HR 1.44 [1.01-2.05], p < 0.05). The factorial mixed data analysis identified 2 clusters. Patients with a functional graft at M12 tended to have cellular and/or chronic rejections. Patients with graft loss at M12 tended to have acute rejections and/or AMR; higher serum creatinine levels; DSA levels and histologic scores of AMR; and a longer delay between the rejection and ECP start than those of patients with functional grafts. Conclusions - ECP may be helpful to control ACR or moderate AMR in KT recipients presenting concomitant opportunistic infections or malignancies when it is initiated early.
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http://dx.doi.org/10.1016/j.transci.2019.06.031DOI Listing
August 2019

Editorial: when cirrhosis deserves haemodialysis-rethinking strategies. Authors' reply.

Aliment Pharmacol Ther 2019 08;50(4):457-458

Hôpital Claude Huriez, Service Maladies de l'Appareil Digestif and INSERM Unité 995, Lille, France.

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http://dx.doi.org/10.1111/apt.15366DOI Listing
August 2019

Adjusting on kidney donor profile index may lead to collinearity.

Kidney Int 2019 08;96(2):519-520

Department of Nephrology, University of Lille, Centre Hospitalier Régional Universitaire de Lille, Lille, France.

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http://dx.doi.org/10.1016/j.kint.2019.03.029DOI Listing
August 2019