Publications by authors named "Philippe Gatault"

71 Publications

Early changes in renal resistive index and mortality in diabetic and nondiabetic kidney transplant recipients: a cohort study.

BMC Nephrol 2021 Feb 19;22(1):62. Epub 2021 Feb 19.

Néphrologie-Immunologie Clinique, Hôpital Bretonneau, CHU Tours, Tours, France.

Background: Renal resistive index (RI) predicts mortality in renal transplant recipients (RTR). However, its predictive value may be different according to the time of measurement. We analysed RI changes between 1 month and 3 months after transplantation and its predictive value for death with a functioning graft (DWFG).

Methods: We conducted a retrospective study in 1685 RTR between 1985 and 2017. The long-term predictive value of changes in RI value from 1 month to 3 months was assessed in diabetic and non-diabetic RTR.

Results: Best survival was observed in RTR with RI < 0.70 both at 1 and 3 months, and the worst survival was found in RTR with RI ≥ 0.70 both at 1 and 3 months (HR = 3.77, [2.71-5.24], p < 0.001). The risk of DWFG was intermediate when RI was < 0.70 at 1 month and ≥ 0.70 at 3 months (HR = 2.15 [1.29-3.60], p = 0.003) and when RI was ≥0.70 at 1 month and < 0.70 at 3 months (HR = 1.90 [1.20-3.03], p = 0.006). In diabetic RTR, RI was significantly associated with an increased risk of death only in those with RI < 0.70 at 1 month and ≥ 0.70 at 3 months (HR = 4.69 [1.07-20.52], p = 0.040). RI considered as a continuous variable at 1 and 3 months was significantly associated with the risk of DWFG in nondiabetic but not in diabetic RTR.

Conclusion: RI changes overtime and this impacts differently diabetic and nondiabetic RTR. RI short-term changes have a strong prognosis value and refines the risk of DWFG associated with RI.
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http://dx.doi.org/10.1186/s12882-021-02263-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893742PMC
February 2021

Rat and human cytomegalovirus ORF116 encodes a virion envelope glycoprotein required for infectivity.

Virology 2021 Feb 9;557:23-33. Epub 2021 Feb 9.

Vaccine & Gene Therapy Institute, Oregon Health & Science University, Portland, OR, 97239, USA. Electronic address:

Herpesviruses encode multiple glycoproteins required for different stages of viral attachment, fusion, and envelopment. The protein encoded by the human cytomegalovirus (HCMV) open reading frame UL116 forms a stable complex with glycoprotein H that is incorporated into virions. However, the function of this complex remains unknown. Herein, we characterize R116, the rat CMV (RCMV) putative homolog of UL116. Two R116 transcripts were identified in fibroblasts with three proteins expressed with molecular weights of 42, 58, and 82 kDa. R116 is N-glycosylated, expressed with late viral gene kinetics, and is incorporated into the virion envelope. RCMV lacking R116 failed to result in productive infection of fibroblasts and siRNA knockdown of R116 substantially reduced RCMV infectivity. Complementation in trans of an R116-deficient virus restored ability of the virus to infect fibroblasts. Finally, UL116 knockdown also decreased HCMV infectivity indicating that R116 and UL116 both contribute to viral infectivity.
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http://dx.doi.org/10.1016/j.virol.2020.12.014DOI Listing
February 2021

Combined Liver-Kidney Transplantation With Preformed Anti-human Leukocyte Antigen Donor-Specific Antibodies.

Kidney Int Rep 2020 Dec 3;5(12):2202-2211. Epub 2020 Oct 3.

Department of Nephrology and Organ Transplantation, Toulouse University Hospital (Centre Hospitalier et Universitaire), Toulouse, France.

Introduction: The impact of preformed donor-specific anti-human leukocyte antigen (HLA) antibodies (pDSAs) after combined liver-kidney transplantation (CLKT) is still uncertain.

Methods: We conducted a retrospective study in 8 European high-volume transplant centers and investigated the outcome of 166 consecutive CLKTs, including 46 patients with pDSAs.

Results: Patient survival was lower in those with pDSAs (5-year patient survival rate of 63% and 78% with or without pDSA, respectively;  = 0.04). The presence of pDSAs with a mean fluorescence intensity (MFI) ≥ 5000 (hazard ratio 4.96; 95% confidence interval: 2.3-10.9;  < 0.001) and the presence of 3 or more pDSAs (hazard ratio 6.5; 95% confidence interval: 2.5-18.8;  = 0.05) were independently associated with death. The death-censored liver graft survival was similar in patients with or without pDSAs. Kidney graft survival was comparable in both groups. (The 1- and 5-year death-censored graft survival rates were 91.6% and 79.5%, respectively, in patients with pDSAs and 93% and 88%, respectively, in the donor-specific antibody [DSA]-negative group,  = not significant). Despite a higher rate of kidney graft rejection in patients with pDSAs (5-year kidney graft survival rate without rejection of 87% and 97% with or without pDSAs, respectively;  = 0.04), kidney function did not statistically differ between both groups at 5 years post-transplantation (estimated glomerular filtration rate 45 ± 17 vs. 57 ± 29 ml/min per 1.73 m, respectively, in patients with and without pDSAs). Five recipients with pDSAs (11.0%) experienced an antibody-mediated kidney rejection that led to graft loss in 1 patient.

Conclusion: Our results suggest that CLKT with pDSAs is associated with a lower patients' survival despite good recipients', liver and kidney grafts' outcome.
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http://dx.doi.org/10.1016/j.ekir.2020.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710847PMC
December 2020

Response to plasma exchange and graft survival in recurrent focal and segmental glomerulosclerosis after transplantation: does the time of recurrence matter? A retrospective study.

Transpl Int 2021 Feb 31;34(2):302-312. Epub 2020 Dec 31.

Department of Nephrology - Hypertension, Dialysis, Transplantation, CHRU, Tours, France.

Recurrence of primary focal and segmental glomerulosclerosis following kidney transplantation (rFSGS) is a frequent and severe disease. We studied the time to recurrence of FSGS and its impact on the response to plasma exchange (PE) and graft survival. Between 1990 and 2013, 2730 kidney transplants were performed, including 52 patients with a primary diagnosis of FSGS. Of these patients with primary FSGS, 34 (67%) developed rFSGS. We retrospectively divided these patients into two groups depending on the time to recurrence: early (up to three months after transplantation, n = 26) or late (more than three months after transplantation, n = 8). Survival did not significantly differ between the two groups. In cases of late recurrence, PE was started later and was performed less frequently, and remission was achieved after more PE sessions and longer PE treatment than for the early group (P = 0.01). In early recurrence, resistance to PE at 40 days was associated with no long-term response to PE. PE should be performed as soon as possible after rFSGS. Patients with late rFSGS need to be offered the same treatment regime as those with early rFSGS.
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http://dx.doi.org/10.1111/tri.13796DOI Listing
February 2021

Among CMV-positive renal transplant patients receiving non-T-cell depleting induction, the absence of CMV disease prevention is a safe strategy: A retrospective cohort of 372 patients.

Transpl Infect Dis 2020 Dec 3:e13541. Epub 2020 Dec 3.

Service de Néphrologie, CHU Pontchaillou, Rennes, France.

Cytomegalovirus (CMV) is the most common opportunistic pathogen affecting renal transplant recipients, especially in the first months. CMV-seropositive renal transplant recipients (CMV R+) are at intermediate risk for CMV disease, but this risk is enhanced among CMV R+ receiving T-cell depleting induction, compared to CMV R+ receiving non-depleting induction. In this second group, data in favor of prophylactic antiviral treatment with valganciclovir to reduce CMV disease is sparse. In this retrospective and multicentric trial, we included 372 CMV R+ transplanted between January 2012 and April 2015 and receiving non-depleting induction. During the first year following transplantation, CMV disease occurred in 5/222 patients (2.25%) in the prophylaxis group and 9/150 (6%) in the no-prophylaxis group (difference +3.7; 95% CI: 0.5-8; P = .002 for non-inferiority). The incidence of allograft rejection and other infectious diseases was similar between the two groups. Graft and patient survival were similar at the end of follow-up. In conclusion, the absence of prophylaxis did not appear to have a deleterious effect for CMV diseases among CMV R+ receiving non-depleting induction.
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http://dx.doi.org/10.1111/tid.13541DOI Listing
December 2020

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

Rat Cytomegalovirus Virion-Associated Proteins R131 and R129 Are Necessary for Infection of Macrophages and Dendritic Cells.

Pathogens 2020 Nov 19;9(11). Epub 2020 Nov 19.

Vaccine & Gene Therapy Institute, Oregon Health & Science University, Portland, OR 97239, USA.

Cytomegalovirus (CMV) establishes persistent, latent infection in hosts, causing diseases in immunocompromised patients, transplant recipients, and neonates. CMV infection modifies the host chemokine axis by modulating chemokine and chemokine receptor expression and by encoding putative chemokine and chemokine receptor homologues. The viral proteins have roles in cellular signaling, migration, and transformation, as well as viral dissemination, tropism, latency and reactivation. Herein, we review the contribution of CMV-encoded chemokines and chemokine receptors to these processes, and further elucidate the viral tropism role of rat CMV (RCMV) R129 and R131. These homologues of the human CMV (HCMV)-encoded chemokines UL128 and UL130 are of particular interest because of their dual role as chemokines and members of the pentameric entry complex, which is required for entry into cell types that are essential for viral transmission and dissemination. The contributions of UL128 and UL130 to acceleration of solid organ transplant chronic rejection are poorly understood, and are in need of an effective in vivo model system to elucidate the phenomenon. We demonstrated similar molecular entry requirements for R129 and R131 in the rat cells, as observed for HCMV, and provided evidence that R129 and R131 are part of the viral entry complex required for entry into macrophages, dendritic cells, and bone marrow cells.
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http://dx.doi.org/10.3390/pathogens9110963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699341PMC
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

Feasibility and safety of tailored dosing schedule for eculizumab based on therapeutic drug monitoring: Lessons from a prospective multicentric study.

Br J Clin Pharmacol 2020 Oct 28. Epub 2020 Oct 28.

EA4245 Transplant Immunology and Inflammation, Université de Tours, Tours, France.

Aims: Eculizumab is an anti-C5 monoclonal antibody approved for rare diseases including atypical haemolytic-uraemic syndrome. The maintenance phase dosing regimen is identical for all adult patients: 1200 mg every 2 weeks. Recent studies reported an overexposure in many patients when considering a target trough concentration range of 50-100 mg/L. The aim of the present work was to validate the feasibility of therapeutic drug monitoring of eculizumab in atypical haemolytic-uraemic syndrome patients.

Methods: We performed a 2-step prospective multicentre study. In the first phase, we developed a pharmacokinetic population model using data from 40 patients and identified patients for whom a 1-week lengthening of interval between infusions would lead to a trough concentration above 100 mg/L. In the second phase, selected patients were allocated a 1-week extension and eculizumab trough concentrations were monitored.

Results: The model confirmed the previously reported influence of bodyweight on elimination clearance and predicted that 36 (90%) patients would be eligible for interval extension. In the second phase of the study, a 1-week lengthening of interval between infusions was performed in 15 patients whose trough concentration at the next visit was predicted with a Bayesian model to be above 100 mg/L. After interval extension, 10 patients (67%) presented measured trough concentrations over 100 mg/L. No biological or clinical recurrence of disease was observed, even in the 5 patients with concentrations below 100 mg/L in whom the initial dosing regimen was resumed.

Conclusion: Safe eculizumab interval adjustment is feasible with a PK monitoring.
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http://dx.doi.org/10.1111/bcp.14627DOI Listing
October 2020

Major Bleeding and Risk of Death after Percutaneous Native Kidney Biopsies: A French Nationwide Cohort Study.

Clin J Am Soc Nephrol 2020 Nov 15;15(11):1587-1594. Epub 2020 Oct 15.

Service de Cardiologie, Centre Hospitalier Universitaire Trousseau et Faculté de Médecine, Equipe d'Accueil 7505, University of Tours, Tours, France.

Background And Objectives: The risk of major bleeding after percutaneous native kidney biopsy is usually considered low but remains poorly predictable. The aim of the study was to assess the risk of major bleeding and to build a preprocedure bleeding risk score.

Design, Setting, Participants, & Measurements: Our study was a retrospective cohort study in all 52,138 patients who had a percutaneous native kidney biopsy in France in the 2010-2018 period. Measurements included major bleeding (, blood transfusions, hemorrhage/hematoma, angiographic intervention, or nephrectomy) at day 8 after biopsy and risk of death at day 30. Exposures and outcomes were defined by diagnosis codes.

Results: Major bleeding occurred in 2765 of 52,138 (5%) patients (blood transfusions: 5%; angiographic intervention: 0.4%; and nephrectomy: 0.1%). Nineteen diagnoses were associated with major bleeding. A bleeding risk score was calculated (Charlson index [2-4: +1; 5 and 6: +2; >6: +3]; frailty index [1.5-4.4: +1; 4.5-9.5: +2; >9.5: +3]; women: +1; dyslipidemia: -1; obesity: -1; anemia: +8; thrombocytopenia: +2; cancer: +2; abnormal kidney function: +4; glomerular disease: -1; vascular kidney disease: -1; diabetic kidney disease: -1; autoimmune disease: +2; vasculitis: +5; hematologic disease: +2; thrombotic microangiopathy: +4; amyloidosis: -2; other kidney diagnosis: -1) + a constant of 5. The risk of bleeding went from 0.4% (lowest score group =0-4 points) to 33% (highest score group ≥35 points). Major bleeding was an independent risk of death (500 of 52,138 deaths: bleeding: 81 of 2765 [3%]; no bleeding: 419 of 49,373 [0.9%]; odds ratio, 1.95; 95% confidence interval, 1.50 to 2.54; <0.001).

Conclusions: The risk of major bleeding after percutaneous native kidney biopsy may be higher than generally thought and is associated with a twofold higher risk of death. It varies widely but can be estimated with a score useful for shared decision making and procedure choice.
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http://dx.doi.org/10.2215/CJN.14721219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646233PMC
November 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

Renal arteriography with endovascular ultrasound for the management of renal infarction patients.

BMC Nephrol 2020 07 14;21(1):273. Epub 2020 Jul 14.

EA 4245 T2I & Loire Valley Cardiovascular Collaboration, Université de Tours, Tours, France.

Background: Renal infarction (RI) is a rare disease with poor prognosis. Appropriate secondary prevention treatment is essential and requires an exhaustive etiological assessment. We aimed to determine whether invasive endovascular explorations may improve the diagnostic process and change the secondary prevention treatment strategy in RI patients.

Methods: We report a retrospective observational study of 25 RI patients referred to Tours University Hospital between 2011 and 2018 for etiological investigation including renal arteriography and intravascular ultrasonography (IVUS). We sought for antithrombotic treatment regimen, vital status, bleeding and ischemic outcomes during the median follow-up of 59 months.

Results: Invasive explorations showed local arterial disease in 14 patients (56%). This led to a diagnosis or change in diagnosis in 9 patients (36%) and to a change in antithrombotic strategy in 56% of cases, with an increased prescription of antiplatelet therapy. No patient died, only two patients (8%) had persistent mild renal insufficiency. One IVUS complication was reported and treated without any significant long-term consequences.

Conclusion: Invasive endovascular investigations of RI may modify the secondary prevention treatment through a better assessment of the aetiology of RI. Multicentric randomized studies are necessary to advocate the hypothesis that invasive exploration of renal artery can improve long-term prognosis.
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http://dx.doi.org/10.1186/s12882-020-01929-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362568PMC
July 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 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

The Presence of Renal IgG Deposits in Necrotizing Crescentic Glomerulonephritis Associated with ANCA Is Not Related to Worse Renal Clinical Outcomes.

Kidney Dis (Basel) 2020 Mar 21;6(2):98-108. Epub 2019 Nov 21.

Department of Nephrology - Hypertension, Dialysis, Transplantation, CHRU, Tours, France.

Introduction: Classical pauci-immune necrotizing crescentic glomerulonephritis (CGN) associated with antineutrophil cytoplasmic autoantibodies (ANCA) is characterized by the absence of renal immunoglobulin (Ig) deposits. However, IgG deposits can sometimes be present. We wanted to assess whether necrotizing CGN with IgG deposits is associated with a more severe presentation and outcome than necrotizing CGN without IgG deposits.

Methods: Between November 2008 and August 2013, we retrospectively identified 158 patients from four centers who had necrotizing CGN due to primary ANCA-associated systemic vasculitis. Glomerular IgG deposits were found in 18 (11%) patients (group 1). For each patient in group 1, we selected 2 patients with classical pauci-immune necrotizing CGN with the nearest date of diagnosis in the same center (group 2, = 36). We assessed clinical, biological, and pathological characteristics in both groups.

Results: Baseline characteristics were similar in both groups, and most patients had ANCA-associated vasculitis with antibodies to myeloperoxidase (74%). Deposits displayed moderate to strong staining in 9 patients. As compared with group 2, group 1 exhibited a higher frequency of interstitial fibrosis/tubular atrophy lesions ( = 0.024) and lower frequency of acute tubular necrosis ( = 0.046). Nevertheless, after a mean follow-up of 30 and 26 months for group 1 and group 2, respectively, IgG deposits did not affect the renal prognosis or probability of relapse. Finally, the groups did not differ in renal or patient survival.

Conclusions: IgG deposits, detected in 11% of patients with ANCA-associated necrotizing CGN, did not affect renal or patient outcomes.
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http://dx.doi.org/10.1159/000503969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154286PMC
March 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

Specific impact of past and new major cardiovascular events on acute kidney injury and end-stage renal disease risks in diabetes: a dynamic view.

Clin Kidney J 2020 Feb 16;13(1):17-23. Epub 2019 Apr 16.

Service de Néphrologie-Hypertension, Dialyses, Transplantation Rénale, Hôpital Bretonneau, CHU Tours, Tours, France.

Background: Interconnections between major cardiovascular events (MCVEs) and renal events are recognized in diabetes, however, the specific impact of atrial fibrillation (AF), heart failure (HF) and acute coronary syndrome (ACS) on the risk of end-stage renal disease (ESRD) on top of established renal risk factors is unclear in type 2 diabetes mellitus.

Methods: We conducted a retrospective study in 861 consecutive patients followed in a nephrology setting during the 2000-13 period.

Results: The mean age was 70 ± 10 years, 65.1% were men and the estimated glomerular filtration rate (eGFR) was 42.4 ± 21.0 mL/min/1.73 m. During follow-up (median 59 months), 194 patients reached ESRD. A history of AF, HF or ACS was associated with an increased risk of reduced baseline eGFR. In turn, reduced baseline eGFR resulted in a greater risk of new MCVE (especially HF) during follow-up. Finally, all new MCVEs were risk factors for subsequent acute kidney injury (AKI) {HF: hazard ratio [HR] 8.99 [95% confidence interval (CI) 7.06-11.4]; AF: HR 5.42 (3.91-7.52); ACS: HR 8.82 (6.24-12.5); all P < 0.0001} and ESRD [HF: HR 5.52 (95% CI 4.01-7.60), P < 0.0001; AF: HR 3.48 (2.30-5.21), P < 0.0001; ACS: HR 2.31 (1.43-3.73), P = 0.0006]. The AF- and HF-associated risks of ESRD were significant after adjustments on all renal risks of ESRD (gender, blood pressure, eGFR, albuminuria, renin-angiotensin blockers, retinopathy and AKI), but the association was less strong for ACS. Importantly, no association was noted between other major events such as stroke or infections and the risk of ESRD.

Conclusions: Past and new cardiovascular events (more HF and AF than ACS) have a strong, independent impact on the development of ESRD above and beyond established risk factors in diabetes.
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http://dx.doi.org/10.1093/ckj/sfz028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025370PMC
February 2020

Serum tenascin-C is independently associated with increased major adverse cardiovascular events and death in individuals with type 2 diabetes: a French prospective cohort.

Diabetologia 2020 05 10;63(5):915-923. Epub 2020 Feb 10.

INSERM, Centre d'Investigation Clinique CIC1402, Université de Poitiers, CHU de Poitiers, Poitiers, France.

Aims/hypothesis: Tenascin-C (TN-C) is an extracellular matrix glycoprotein highly expressed in inflammatory and cardiovascular (CV) diseases. Serum TN-C has not yet been specifically studied in individuals with type 2 diabetes, a condition associated with chronic low-grade inflammation and increased CV disease risk. In this study, we hypothesised that elevated serum TN-C at enrolment in participants with type 2 diabetes would be associated with increased risk of death and major adverse CV events (MACE) during follow-up.

Methods: We used a prospective, monocentric cohort of consecutive type 2 diabetes participants (the SURDIAGENE [SUivi Rénal, DIAbète de type 2 et GENEtique] cohort) with all-cause death as a primary endpoint and MACE (CV death, non-fatal myocardial infarction or stroke) as a secondary endpoint. We used a proportional hazard model after adjustment for traditional risk factors and the relative integrated discrimination improvement (rIDI) to assess the incremental predictive value of TN-C for these risk factors.

Results: We monitored 1321 individuals (58% men, mean age 64 ± 11 years) for a median of 89 months. During follow-up, 442 individuals died and 497 had MACE. Multivariate Cox analysis showed that serum TN-C concentrations were associated with an increased risk of death (HR per 1 SD: 1.27 [95% CI 1.17, 1.38]; p < 0.0001) and MACE (HR per 1 SD: 1.23 [95% CI 1.13, 1.34]; p < 0.0001). Using TN-C concentrations on top of traditional risk factors, prediction of the risk of all-cause death (rIDI: 8.2%; p = 0.0006) and MACE (rIDI: 6.7%; p = 0.0014) improved significantly, but modestly.

Conclusions/interpretation: In individuals with type 2 diabetes, increased serum TN-C concentrations were independently associated with death and MACE. Therefore, including TN-C as a prognostic biomarker could improve risk stratification in these individuals.
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http://dx.doi.org/10.1007/s00125-020-05108-5DOI Listing
May 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

Assessment of the glomerular filtration rate (GFR) in kidney transplant recipients using Bayesian estimation of the iohexol clearance.

Clin Chem Lab Med 2020 03;58(4):577-587

Laboratoire de Biochimie et de Biologie Moléculaire, CHU de Tours, Tours, France.

Background Plasma iohexol clearance (CLiohexol) is a reference technique for glomerular filtration rate (GFR) determination. In routine practice, CLiohexol is calculated using one of several formulas, which have never been evaluated in kidney transplant recipients. We aimed to model iohexol pharmacokinetics in this population, evaluate the predictive performance of three simplified formulas and evaluate whether a Bayesian algorithm improves CLiohexol estimation. Methods After administration of iohexol, six blood samples were drawn from 151 patients at various time points. The dataset was split into two groups, one to develop the population pharmacokinetic (POPPK) model (n = 103) and the other (n = 48) to estimate the predictive performances of the various GFR estimation methods. GFR reference values (GFRref) in the validation dataset were obtained by non-compartmental pharmacokinetic (PK) analysis. Predictive performances of each method were evaluated in terms of bias (ME), imprecision (root mean square error [RMSE]) and number of predictions out of the ±10% or 15% error interval around the GFRref. Results A two-compartment model best fitted the data. The Bayesian estimator with samples drawn at 30, 120 and 270 min allowed accurate prediction of GFRref (ME = 0.47%, RMSE = 3.42%), as did the Brøchner-Mortensen (BM) formula (ME = - 0.0425%, RMSE = 3.40%). With both methods, none of the CL estimates were outside the ±15% interval and only 2.4% were outside the ±10% for the BM formula (and none for the Bayesian estimator). In patients with GFR ≤30 mL/min/1.73 m2, the BM formula performed very well, while the Bayesian method could not be evaluated in depth due to too small a number of patients with adequate sampling times. Conclusions GFR can be estimated with acceptable accuracy in kidney transplant patients using the BM formula, but also using a Bayesian algorithm.
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http://dx.doi.org/10.1515/cclm-2019-0904DOI Listing
March 2020

Prevention of parvovirus B19-induced repetitive acute kidney failure by subcutaneous immunoglobulins.

Fundam Clin Pharmacol 2020 Apr 12;34(2):296-298. Epub 2019 Nov 12.

Department of Nephrology and Clinical Immunology, University Hospital of Tours, Tours, France.

Human parvovirus B19 has been associated with various cases of kidney injuries with different glomerular phenotypes. In immunocompromised individuals, insufficient production of neutralizing antibodies can lead to chronic PVB19 carriage and manifestations. However, PVB19 DNA has been detected in bone marrow and peripheral blood for months or years in seemingly immunocompetent individuals, despite the presence of neutralizing antibodies. We report here PVB19-induced recurrent anuric acute kidney failures in a 57-year-old man over a 7-year period with persistent PVB19 infection and then PVB19-associated cryoglobulinemia. Acute renal failures were preceded by influenza-like syndrome associated with arthralgia, skin rash, and low-grade fever. Serum, bone marrow, renal, and digestive PVB19 replication was found in the different episodes. Endocapillary proliferative glomerulonephritis evolved into membranoproliferative glomerulonephritis. Complete renal recovery occurred after each bout. Off-label subcutaneous immunoglobulin therapy resulted in disappearance of blood and bone marrow PVB19 viral load and stopped the glomerulonephritis recurrence. Subcutaneous immunoglobulin therapy withdrawal resulted in renal relapse with cryoglobulin-associated manifestations.
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http://dx.doi.org/10.1111/fcp.12511DOI Listing
April 2020

Use of Highly Individualized Complement Blockade Has Revolutionized Clinical Outcomes after Kidney Transplantation and Renal Epidemiology of Atypical Hemolytic Uremic Syndrome.

J Am Soc Nephrol 2019 12 1;30(12):2449-2463. Epub 2019 Oct 1.

French Study Group of Atypical Hemolytic Uremic Syndrome, France.

Background: Atypical hemolytic uremic syndrome (HUS) is associated with high recurrence rates after kidney transplant, with devastating outcomes. In late 2011, experts in France recommended the use of highly individualized complement blockade-based prophylaxis with eculizumab to prevent post-transplant atypical HUS recurrence throughout the country.

Methods: To evaluate this strategy's effect on kidney transplant prognosis, we conducted a retrospective multicenter study from a large French nationwide registry, enrolling all adult patients with atypical HUS who had undergone complement analysis and a kidney transplant since January 1, 2007. To assess how atypical HUS epidemiology in France in the eculizumab era evolved, we undertook a population-based cohort study that included all adult patients with atypical HUS (=397) between 2007 and 2016.

Results: The first study included 126 kidney transplants performed in 116 patients, 58.7% and 34.1% of which were considered to be at a high and moderate risk of atypical HUS recurrence, respectively. Eculizumab prophylaxis was used in 52 kidney transplants, including 39 at high risk of recurrence. Atypical HUS recurred after 43 (34.1%) of the transplants; in four cases, patients had received eculizumab prophylaxis and in 39 cases they did not. Use of prophylactic eculizumab was independently associated with a significantly reduced risk of recurrence and with significantly longer graft survival. In the second, population-based cohort study, the proportion of transplant recipients among patients with ESKD and atypical HUS sharply increased between 2012 and 2016, from 46.2% to 72.3%, and showed a close correlation with increasing eculizumab use among the transplant recipients.

Conclusions: Results from this observational study are consistent with benefit from eculizumab prophylaxis based on pretransplant risk stratification and support the need for a rigorous randomized trial.
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http://dx.doi.org/10.1681/ASN.2019040331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900783PMC
December 2019

Comparison of Tacrolimus Starting Doses Based on CYP3A5 Phenotype or Genotype in Kidney Transplant Recipients.

Prog Transplant 2019 12 12;29(4):300-308. Epub 2019 Sep 12.

CHRU de Tours, Service de Néphrologie-Hypertension artérielle, Dialyses et Transplantation Rénale, FHU SUPORT, Tours, France.

Background: Selection of expected phenotypes (ie, expressers/non-expressers) is currently used in CYP3A5*3 genotype-based tacrolimus dosing. The authors assessed whether a dosing regimen based on the 3 CYP3A5 genotypes may reduce the occurrence of inadequate exposure.

Methods: Tacrolimus whole blood trough levels () were retrieved from a retrospective cohort of 100 kidney transplant recipients treated with a starting dose of 0.15 (non-expressers) or 0.30 (expressers) mg/kg/d. The authors evaluated the occurrence of overexposures (12 < < 20 ng/mL) or toxic concentrations ( ≥ 20 ng/mL). These results were used to set up a new strategy based on the 3 distinct CYP3A5 genotypes, which relevance was evaluated in a prospective cohort of 107 patients.

Results: In the retrospective cohort, non-expressers exhibited frequent overexposure (63.6%) or toxic (20.8%). Among expressers, none of the homozygous *1 carriers exhibited overexposure contrary to 25% of the heterozygotes. Based on these results, new tacrolimus starting doses were set at 0.10, 0.20, and 0.30 mg/kg/d for CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1 genotypes, respectively. Tacrolimus overexposure was reduced in the CYP3A5*3/*3 group (63.6% vs 40%, = .0038). None of the heterozygous patients exhibited toxic tacrolimus . Clinical outcomes were not different between the 2 periods, whatever the genotype. Our results indicate that the best tacrolimus exposure was obtained for doses of 0.10, 0.20, and 0.20 mg/kg/d for CYP3A5*3/3, CYP3A5*1/*3, and CYP3A5*1/*1, respectively.

Conclusions: Our results confirm that selecting tacrolimus dosing regimen according to the expected phenotype is appropriate, but that lower than currently recommended doses may be preferable.
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http://dx.doi.org/10.1177/1526924819873905DOI Listing
December 2019

A Prognostic Tool for Individualized Prediction of Graft Failure Risk within Ten Years after Kidney Transplantation.

J Transplant 2019 8;2019:7245142. Epub 2019 Apr 8.

INSERM, U1248, F-87000 Limoges, France.

Identification of patients at risk of kidney graft loss relies on early individual prediction of graft failure. Data from 616 kidney transplant recipients with a follow-up of at least one year were retrospectively studied. A joint latent class model investigating the impact of serum creatinine (Scr) time-trajectories and onset of donor-specific anti-HLA antibody (DSA) on graft survival was developed. The capacity of the model to calculate individual predicted probabilities of graft failure over time was evaluated in 80 independent patients. The model classified the patients in three latent classes with significantly different Scr time profiles and different graft survivals. Donor age contributed to explaining latent class membership. In addition to the SCr classes, the other variables retained in the survival model were proteinuria measured one-year after transplantation (HR=2.4, p=0.01), pretransplant non-donor-specific antibodies (HR=3.3, p<0.001), and DSA in patient who experienced acute rejection (HR=15.9, p=0.02). In the validation dataset, individual predictions of graft failure risk provided good predictive performances (sensitivity, specificity, and overall accuracy of graft failure prediction at ten years were 77.7%, 95.8%, and 85%, resp.) for the 60 patients who had not developed DSA. For patients with DSA individual risk of graft failure was not predicted with a so good performance.
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http://dx.doi.org/10.1155/2019/7245142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476124PMC
April 2019

The association between renal resistive index and premature mortality after kidney transplantation is modified by pre-transplant diabetes status: a cohort study.

Nephrol Dial Transplant 2020 09;35(9):1577-1584

Néphrologie-Immunologie Clinique, Hôpital Bretonneau, CHU Tours, Tours, France.

Background: Renal resistive index (RI) predicts mortality in renal transplant recipients, but we do not know whether this is true in diabetic patients. The objective of this study was to analyse the long-term predictive value of RI for death with a functioning graft (DWFG) in renal transplant recipients with or without pre-transplant diabetes.

Methods: We conducted a retrospective study in 1800 renal transplant recipients between 1985 and 2017 who were followed for up to 30 years (total observation period: 14 202 patient years). Donor and recipient characteristics at time of transplantation and at 3 months were reviewed. The long-term predictive value of RI for DWFG and the age-RI and arterial pressure-RI relationships were assessed.

Results: A total of 284/1800 (15.7%) patients had diabetes mellitus before transplantation. RI was <0.75 in 1327/1800 patients (73.7%). High RI was associated with a higher risk of DWFG in non-diabetic patients [hazard ratio (HR) = 3.39, 95% confidence interval 2.50-4.61; P < 0.001], but not in patients with pre-transplant diabetes (HR = 1.25, 0.70-2.19; P = 0.39), even after multiple adjustments. There was no interaction between diabetes and age. In contrast, there was an interaction between RI and pulse pressure.

Conclusion: Our study indicates that RI is not a predictor of DWFG in diabetic renal transplant recipients, in contrast to non-diabetic recipients. These findings could be due to a different age-RI or pulse pressure-RI relationship.
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http://dx.doi.org/10.1093/ndt/gfz067DOI Listing
September 2020

Increased risk of rejection after basiliximab induction in sensitized kidney transplant recipients without pre-existing donor-specific antibodies - a retrospective study.

Transpl Int 2019 Aug 12;32(8):820-830. Epub 2019 Apr 12.

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

Depleting induction therapy is recommended in sensitized kidney transplant recipients (KTRs), though the detrimental effect of nondonor-specific anti-HLA antibodies is not undeniable. We compared the efficacy and safety of basiliximab and rabbit anti-thymocyte globulin (rATG) in sensitized KTRs without pre-existing donor-specific antibodies (DSAs). This monocentric retrospective study involved all sensitized KTR adults without pre-existing DSAs (n = 218) who underwent transplantation after June 2007. Patients with basiliximab and rATG therapy were compared for risk of biopsy-proven acute rejection (BPAR) and a composite endpoint (BPAR, graft loss and death) by univariate and multivariate analysis. Patients with basiliximab (n = 60) had lower mean calculated panel reactive antibody than those with rATG (n = 158; 23.7 ± 24.2 vs. 63.8 ± 32.3, P < 0.0001) and more often received a first graft (88% vs. 54%, P < 0.0001) and a transplant from a living donor (13% vs. 2%, P = 0.002). Risks of BPAR and of reaching the composite endpoint were greater with basiliximab than rATG [HR = 3.63 (1.70-7.77), P = 0.0009 and HR = 1.60 (0.99-2.59), P = 0.050, respectively]. Several adjustments did not change those risks [BPAR: 3.36 (1.23-9.16), P = 0.018; composite endpoint: 1.83 (0.99-3.39), P = 0.053]. Infections and malignancies were similar in both groups. rATG remains the first-line treatment in sensitized KTR, even in the absence of pre-existing DSAs.
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http://dx.doi.org/10.1111/tri.13428DOI Listing
August 2019

Transplant center characteristics associated with living-donor kidney transplantation: a cohort study with a hierarchical modeling approach.

Transpl Int 2019 Aug 2;32(8):865-875. Epub 2019 Apr 2.

Service de Néphrologie et Transplantation, Hôpital Civil, Strasbourg, France.

Transplant center organization, that is a modifiable factor, may affect the access to living-donor kidney transplantation (LDKT). The objective of this study was to identify the center characteristics associated with LDKT using a hierarchical analysis. This was a retrospective multicenter observational study of 8701 patients who received a first renal graft between 2010 and 2014 in 32 transplantation centers of France. Hierarchical modeling was used to estimate the center effect and organization associated with LDKT. Among 8507 patients, 1225 (12%) were transplanted with a LD kidney. There was a transplant center effect on the proportion of LDKT. After adjustment for patient and center characteristics, the random effect variance decreased by 47%. Patients transplanted at a center with more than four nephrologists [1.81 (95% CI: 1.10-2.95)] and more than 1.5 nurse transplant coordinators [1.98 (95% CI: 1.26-3.13)] were more likely to be transplanted with a LD kidney. ABO-incompatible program was associated with LDKT [2.23 (95% CI: 1.22-4.06)]. There was a transplant center effect on the proportion of LDKT that could be decreased by modifiable center characteristics. Our study suggests the importance of the transplant team organization on the LDKT utilization.
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http://dx.doi.org/10.1111/tri.13429DOI Listing
August 2019

Evaluation of outcomes in renal transplantation with hypothermic machine perfusion for the preservation of kidneys from expanded criteria donors.

Clin Transplant 2019 05 10;33(5):e13536. Epub 2019 Apr 10.

Agence de la Biomédecine, Direction Prélèvement Greffe Organes-Tissus, Saint-Denis La Plaine, France.

In 2012, an expert working group from the French Transplant Health Authority recommended the use of hypothermic machine perfusion (HMP) to improve kidney preservation and transplant outcomes from expanded criteria donors, deceased after brain death. This study compares HMP and cold storage (CS) effects on delayed graft function (DGF) and transplant outcomes. We identified 4,316 kidney transplants from expanded criteria donors (2011-2014) in France through the French Transplant Registry. DGF occurrence was analyzed with a logistic regression, excluding preemptive transplants. One-year graft failure was analyzed with a Cox regression. A subpopulation of 66 paired kidneys was identified: one preserved by HMP and the other by CS from the same donor. Kidneys preserved by HMP (801) vs CS (3515) were associated with more frequent recipient comorbidities and older donors and recipients. HMP had a protective effect against DGF (24% in HMP group and 38% in CS group, OR = 0.49 [0.40-0.60]). Results were similar in the paired kidneys (OR = 0.23 [0.04-0.57]). HMP use decreased risk for 1-year graft failure (HR = 0.77 [0.60-0.99]). Initial hospital stays were shorter in the HMP group (P < 0.001). Our results confirm the reduction in DGF occurrence among expanded criteria donors kidneys preserved by HMP.
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http://dx.doi.org/10.1111/ctr.13536DOI Listing
May 2019

Etiology and Outcomes of Thrombotic Microangiopathies.

Clin J Am Soc Nephrol 2019 04 12;14(4):557-566. Epub 2019 Mar 12.

Service de Néphrologie-hypertension, Dialyses, Transplantation Rénale, Hôpital Bretonneau et hôpital Clocheville,

Background And Objectives: Thrombotic microangiopathies constitute a diagnostic and therapeutic challenge. Secondary thrombotic microangiopathies are less characterized than primary thrombotic microangiopathies (thrombotic thrombocytopenic purpura and atypical hemolytic and uremic syndrome). The relative frequencies and outcomes of secondary and primary thrombotic microangiopathies are unknown.

Design, Setting, Participants, & Measurements: We conducted a retrospective study in a four-hospital institution in 564 consecutive patients with adjudicated thrombotic microangiopathies during the 2009-2016 period. We estimated the incidence of primary and secondary thrombotic microangiopathies, thrombotic microangiopathy causes, and major outcomes during hospitalization (death, dialysis, major cardiovascular events [acute coronary syndrome and/or acute heart failure], and neurologic complications [stroke, cognitive impairment, or epilepsy]).

Results: We identified primary thrombotic microangiopathies in 33 of 564 patients (6%; thrombotic thrombocytopenic purpura: 18 of 564 [3%]; atypical hemolytic and uremic syndrome: 18 of 564 [3%]). Secondary thrombotic microangiopathies were found in 531 of 564 patients (94%). A cause was identified in 500 of 564 (94%): pregnancy (35%; 11 of 1000 pregnancies), malignancies (19%), infections (33%), drugs (26%), transplantations (17%), autoimmune diseases (9%), shiga toxin due to (6%), and malignant hypertension (4%). In the 31 of 531 patients (6%) with other secondary thrombotic microangiopathies, 23% of patients had sickle cell disease, 10% had glucose-6-phosphate dehydrogenase deficiency, and 44% had folate deficiency. Multiple causes of thrombotic microangiopathies were more frequent in secondary than primary thrombotic microangiopathies (57% versus 19%; <0.001), and they were mostly infections, drugs, transplantation, and malignancies. Significant differences in clinical and biologic differences were observed among thrombotic microangiopathy causes. During the hospitalization, 84 of 564 patients (15%) were treated with dialysis, 64 of 564 patients (11%) experienced major cardiovascular events, and 25 of 564 patients (4%) had neurologic complications; 58 of 564 patients (10%) died, but the rates of complications and death varied widely by the cause of thrombotic microangiopathies.

Conclusions: Secondary thrombotic microangiopathies represent the majority of thrombotic microangiopathies. Multiple thrombotic microangiopathies causes are present in one half of secondary thrombotic microangiopathies. The risks of dialysis, neurologic and cardiac complications, and death vary by the cause of thrombotic microangiopathies.
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http://dx.doi.org/10.2215/CJN.11470918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450353PMC
April 2019