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1.
Am J Transplant ; 24(7): 1205-1217, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38320731

RESUMEN

De novo thrombotic microangiopathy (dnTMA), after renal transplantation may significantly alter graft outcomes. However, its pathogenesis and the role of complement alternative pathway dysregulation remain elusive. We studied all consecutive adult patients with a kidney allograft biopsy performed between January 2004 and March 2016 displaying dnTMA. Ninety-two patients were included. The median time of occurrence was 166 (IQR 25-811) days. The majority (82.6 %) had TMA localized only in the graft. Calcineurin inhibitor toxicity and antibody-mediated rejection (ABMR) were the 2 most frequent causes (54.3% and 37.0%, respectively). However, etiological factors were multiple in 37% patients. Interestingly, pathogenic variants in the genes of complement alternative pathway were significantly more frequent in the 42 tested patients than in healthy controls (16.7% vs 3.7% respectively, P < .008). The overall graft survival after biopsy was 66.0% at 5 years and 23.4% at 10 years, significantly worse than a matched cohort without TMA. Moreover, graft survival of patients with TMA and ABMR was worse than a matched cohort with ABMR without TMA. The 2 main prognostic factors were a positive C4d staining and a lower estimated glomerular filtration rate at diagnosis. DnTMA is a severe and multifactorial disease, induced by 1 or several endothelium-insulting conditions, mostly calcineurin inhibitor toxicity and ABMR.


Asunto(s)
Tasa de Filtración Glomerular , Rechazo de Injerto , Supervivencia de Injerto , Trasplante de Riñón , Microangiopatías Trombóticas , Humanos , Microangiopatías Trombóticas/etiología , Microangiopatías Trombóticas/genética , Trasplante de Riñón/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Pronóstico , Estudios de Seguimiento , Adulto , Factores de Riesgo , Complicaciones Posoperatorias , Pruebas de Función Renal , Fallo Renal Crónico/cirugía , Estudios Retrospectivos , Proteínas del Sistema Complemento/genética , Estudios de Casos y Controles
2.
Br J Clin Pharmacol ; 90(5): 1312-1321, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38373846

RESUMEN

AIMS: Eculizumab is a monoclonal antibody targeting complement protein C5 used in renal diseases. As recommended dosing regimen leads to unnecessarily high concentrations in some patients, tailored dosing therapeutic drug monitoring was proposed to reduce treatment cost. The objectives of the present work were (i) to investigate the target-mediated elimination of eculizumab and (ii) whether a pharmacokinetic model integrating a nonlinear elimination allows a better prediction of eculizumab concentrations than a linear model. METHODS: We analysed 377 eculizumab serum concentrations from 44 patients treated for atypical haemolytic uraemic syndrome and C3 glomerulopathy with a population pharmacokinetic approach. Critical concentrations (below which a non-log-linear decline of concentration over time is evidenced) were computed to estimate the relevance of the target-mediated elimination. Simulations of dosing regimens were then performed to predict probabilities of target attainment (i.e. trough >100 mg/L). RESULTS: Pharmacokinetics of eculizumab was nonlinear and followed a mixture of first-order (CL = 1.318 mL/day/kg) and Michaelis-Menten elimination (Vmax = 26.07 mg/day, Km = 24.06 mg/L). Volume of distribution (72.39 mL/kg) and clearance were weight-dependent. Critical concentrations (Vmax/CL) ranged from 144.7 to 759.7 mg/L and were inversely related to body weight (P = .013). Nonlinearity was thus noticeable at therapeutic concentrations. Simulations predicted that 1200 mg of eculizumab every 21 days would allow 85% and 76% of patients to maintain a therapeutic exposure, for 50 or 90 kg body weight, respectively. CONCLUSIONS: Our study investigates the nonlinear elimination of eculizumab and discusses the importance of accounting for eculizumab target-mediated elimination in therapeutic drug monitoring.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Síndrome Hemolítico Urémico Atípico , Monitoreo de Drogas , Modelos Biológicos , Dinámicas no Lineales , Humanos , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Adulto , Monitoreo de Drogas/métodos , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Anciano , Relación Dosis-Respuesta a Droga , Adulto Joven , Inactivadores del Complemento/farmacocinética , Inactivadores del Complemento/administración & dosificación , Simulación por Computador , Adolescente
3.
Clin Transplant ; 38(8): e15424, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39136236

RESUMEN

BACKGROUND: Epstein-Barr virus (EBV) is a herpesvirus linked to nine different human tumors and lymphoproliferative disorders. Immunosuppression promotes EBV-driven malignancies. The most frequent EBV-induced malignancies are lymphomas and nasopharyngeal carcinoma. By promoting smooth muscle proliferation, EBV can induce EBV-associated smooth muscle tumors (EBV-SMT). EBV-SMT is a rare oncological entity for which no current guideline for diagnosis or management exists. Data on posttransplant EBV-SMT (PT-SMT) are scarce in kidney transplant recipients. METHODS: We conducted a national multicentric retrospective study and collected cases among transplantation centers in France. Kidney transplant recipients experiencing histologically proven PT-SMT were included. We collected data on demographic characteristics of patient, history of kidney transplantation, history of PT-SMT, evolution of graft function, and patient survival. RESULTS: Eight patients were included. The median age at PT-SMT diagnosis was 31 years (range 6.5-40). PT-SMT occurred after a median delay of 37.8 months after transplantation (range 6-175). PT-SMT management consisted in immunosuppressive regimen minimization in all patients. Introduction of mTOR inhibitors was performed in two patients. Four patients (50%) needed chemotherapy. Surgical resection was performed in four patients. At last follow-up after PT-SMT diagnosis (median 33 months (range 17-132)), five patients were considered in complete remission, and two patients had died. Two patients experienced graft rejection; two resumed dialysis (25%). All patients with available data presented with impaired graft function at last follow-up. CONCLUSION: PT-SMT is a subacute and progressive disease during kidney transplantation. Even if the risk of developing PT-SMT is low in kidney transplant recipients (0.07% in our cohort), PT-SMT is associated with significant graft loss, possibly due to reduced immunosuppression. Developing guidelines could help transplantation teams better manage these patients.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Trasplante de Riñón , Complicaciones Posoperatorias , Tumor de Músculo Liso , Humanos , Trasplante de Riñón/efectos adversos , Estudios Retrospectivos , Masculino , Femenino , Tumor de Músculo Liso/virología , Tumor de Músculo Liso/etiología , Tumor de Músculo Liso/patología , Tumor de Músculo Liso/diagnóstico , Adulto , Estudios de Seguimiento , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/aislamiento & purificación , Pronóstico , Francia/epidemiología , Adolescente , Adulto Joven , Niño , Complicaciones Posoperatorias/diagnóstico , Rechazo de Injerto/etiología , Fallo Renal Crónico/cirugía , Supervivencia de Injerto , Factores de Riesgo , Pruebas de Función Renal , Tasa de Filtración Glomerular , Tasa de Supervivencia
4.
Am J Transplant ; 23(3): 366-376, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36695682

RESUMEN

Vitamin D sufficiency is associated with a reduced risk of fractures, diabetes mellitus, cardiovascular events, and cancers, which are frequent complications after renal transplantation. The VITALE (VITamin D supplementation in renAL transplant recipients) study is a multicenter double-blind randomized trial, including nondiabetic adult renal transplant recipients with serum 25-hydroxy vitamin D (25(OH) vitamin D) levels of <30 ng/mL, which is randomized 12 to 48 months after transplantation to receive high (100 000 IU) or low doses (12 000 IU) of cholecalciferol every 2 weeks for 2 months and then monthly for 22 months. The primary outcome was a composite endpoint, including diabetes mellitus, major cardiovascular events, cancer, and death. Of 536 inclusions (50.8 [13.7] years, 335 men), 269 and 267 inclusions were in the high-dose and low-dose groups, respectively. The serum 25(OH) vitamin D levels increased by 23 versus 6 ng/mL in the high-dose and low-dose groups, respectively (P < .0001). In the intent-to-treat analysis, 15% versus 16% of the patients in the high-dose and low-dose groups, respectively, experienced a first event of the composite endpoint (hazard ratio, 0.94 [0.60-1.48]; P = .78), whereas 1% and 4% of patients in the high-dose and low-dose groups, respectively, experienced an incident symptomatic fracture (odds ratio, 0.24 [0.07-0.86], P = .03). The incidence of adverse events was similar between the groups. After renal transplantation, high doses of cholecalciferol are safe but do not reduce extraskeletal complications (trial registration: ClinicalTrials.gov; identifier: NCT01431430).


Asunto(s)
Enfermedades Cardiovasculares , Trasplante de Riñón , Deficiencia de Vitamina D , Masculino , Adulto , Humanos , Colecalciferol/efectos adversos , Trasplante de Riñón/efectos adversos , Vitamina D/uso terapéutico , Vitaminas/efectos adversos , Método Doble Ciego , Suplementos Dietéticos , Enfermedades Cardiovasculares/etiología , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/tratamiento farmacológico
5.
Am J Hematol ; 98 Suppl 4: S44-S56, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36683290

RESUMEN

Overactivation of the complement alternative pathway drives the pathogenesis of primary atypical hemolytic uremic syndrome (aHUS). Genetically-determined or acquired dysregulation of the complement is frequently identified in patients with aHUS, pregnancy-related hemolytic uremic syndrome (HUS), and severe hypertension-associated HUS. In contrast, it is still unclear whether self-limited complement activation, which frequently occurs in other forms of HUS, provides key mechanistic clues or results from endothelial damage. Development of novel biomarkers is underway to firmly establish complement-driven pathogenesis. C5 blockade therapy has revolutionized the management of aHUS patients, resulting in a halving of the subpopulation under chronic dialysis over the course of a few years. On the other hand, the efficacy of C5 blockade in secondary forms of HUS, as assessed by small and uncontrolled case series, is less compelling and should be investigated through properly designed prospective clinical trials. The increased risk of meningococcal infection, related to C5 inhibition, must be rigorously addressed with suitable prophylaxis. Treatment duration should be determined based on an individualized benefit/risk assessment.


Asunto(s)
Síndrome Hemolítico Urémico Atípico , Humanos , Estudios Prospectivos , Síndrome Hemolítico Urémico Atípico/terapia , Activación de Complemento , Factores de Riesgo , Biomarcadores
6.
Transpl Int ; 36: 11328, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37554319

RESUMEN

The first COVID-19 stay-at-home order came into effect in France on 17 March 2020. Immunocompromised patients were asked to isolate themselves, and outpatient clinic visits were dramatically reduced. In order to avoid visits to the hospital by belatacept-treated kidney transplant recipients (KTRs) during the initial period of the pandemic, we promptly converted 176 KTRs at two French transplant centers from once-monthly 5 mg/kg in-hospital belatacept infusion to once-weekly 125 mg subcutaneous abatacept injection. At the end of follow-up (3 months), 171 (97.16%) KTRs survived with a functioning graft, 2 (1.14%) had died, and 3 (1.70%) had experienced graft loss. Two patients (1.1%) experienced acute T cell-mediated rejection. Nineteen patients (10.80%) discontinued abatacept; 47% of the KTRs found the use of abatacept less restrictive than belatacept, and 38% would have preferred to continue abatacept. Mean eGFR remained stable compared to baseline. Seven patients (3.9%) had COVID-19; among these, two developed severe symptoms but survived. Only one patient had a de novo DSA. Side effects of abatacept injection were uncommon and non-severe. Our study reports for the first time in a large cohort that once-weekly injection of abatacept appears to be feasible and safe in KTRs previously treated with belatacept.


Asunto(s)
COVID-19 , Trasplante de Riñón , Humanos , Abatacept/uso terapéutico , Inmunosupresores/efectos adversos , Trasplante de Riñón/efectos adversos , Inhibidores de la Calcineurina/uso terapéutico , Rechazo de Injerto/prevención & control , Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto , COVID-19/etiología , Receptores de Trasplantes
7.
Am J Transplant ; 21(7): 2448-2458, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33283406

RESUMEN

Belatacept may increase cytomegalovirus (CMV) disease risk after conversion from CNI-based therapy. We analyzed CMV disease characteristics after belatacept conversion. Propensity score matching was used to compare CMV disease incidence in belatacept- and CNI-treated kidney transplant recipients (KTRs). CMV disease characteristics and risk factors under belatacept were analyzed. In total, 223 KTRs (median age [IQR] 59.2 years [45.4-68.5]) were converted to belatacept (median of 11.5 months [2.5-37.0] post-transplantation); 40/223 (17.9%) developed CMV disease. Independent risk factors included increased age (p = .0164), D+/R- CMV serostatus (p = .0220), and low eGFR at conversion (p = .0355). Among 181 belatacept-treated patients matched to 181 controls, 32/181 (17.7%) experienced CMV disease (vs. 5/181 controls [2.8%]). CMV disease cumulative incidences were 6.33 and 0.91/100 person-years (p-y) in belatacept and control groups, respectively. CMV disease risk was particularly high in elderly patients (converted >70 years) and those with eGFR <30 ml/min; cumulative incidences were 18.4 and 5.2/100 p-y, respectively. CMV diseases under belatacept were atypical, with late-onset disease (24/40 patients [60%]), high CMV seropositivity (27/40, 67%), increased severe and tissue-invasive disease rates (gastrointestinal involvement in 32/40 [80%]) and life-threatening diseases (4/40 [10%]). These findings should stimulate further research to secure the use of belatacept as a valuable rescue therapy in KTRs.


Asunto(s)
Infecciones por Citomegalovirus , Trasplante de Riñón , Abatacept , Anciano , Preescolar , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/epidemiología , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/epidemiología , Rechazo de Injerto/etiología , Supervivencia de Injerto , Humanos , Inmunosupresores/efectos adversos , Incidencia , Trasplante de Riñón/efectos adversos , Estudios Retrospectivos , Receptores de Trasplantes
8.
Am J Transplant ; 21(12): 4043-4051, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34431207

RESUMEN

Poor responses to mRNA COVID-19 vaccine have been reported after 2 vaccine injections in kidney transplant recipients (KTRs) treated with belatacept. We analyzed the humoral response in belatacept-treated KTRs without a history of SARS-CoV-2 infection who received three injections of BNT162b2-mRNA COVID-19 vaccine. We also investigated vaccine immunogenicity in belatacept-treated KTRs with prior COVID-19 and characterized symptomatic COVID-19 infections after the vaccine in belatacept-treated KTRs. Among the 62 belatacept-treated KTRs (36 [58%] males), the median age (63.5 years IQR [51-72]), without COVID-19 history, only four patients (6.4%) developed anti-SARS-CoV-2 IgG with low antibody titers (median 209, IQR [20-409] AU/ml). 71% were treated with mycophenolic acid and 100% with steroids in association with belatacept. In contrast, in all the 5 KTRs with prior COVID-19 history, mRNA vaccine induced a strong antibody response with high antibody titers (median 10 769 AU/ml, IQR [6410-20 069]) after two injections. Seroprevalence after three-vaccine doses in 35 non-belatacept-treated KTRs was 37.1%. Twelve KTRs developed symptomatic COVID-19 after vaccination, including severe forms (50% of mortality). Breakthrough COVID-19 occurred in 5% of fully vaccinated patients. Administration of a third dose of BNT162b2 mRNA COVID-19 vaccine did not improve immunogenicity in KTRs treated with belatacept without prior COVID-19. Other strategies aiming to improve patient protection are needed.


Asunto(s)
COVID-19 , Trasplante de Riñón , Abatacept/uso terapéutico , Anciano , Formación de Anticuerpos , Vacunas contra la COVID-19 , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , SARS-CoV-2 , Estudios Seroepidemiológicos , Vacunas Sintéticas , Vacunas de ARNm
9.
Am J Transplant ; 21(3): 1285-1294, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33252201

RESUMEN

Higher rates of severe COVID-19 have been reported in kidney transplant recipients (KTRs) compared to nontransplant patients. We aimed to determine if poorer outcomes were specifically related to chronic immunosuppression or underlying comorbidities. We used a 1:1 propensity score-matching method to compare survival and severe disease-free survival (defined as death and/or need for intensive care unit [ICU]) incidence in hospitalized KTRs and nontransplant control patients between February 26 and May 22, 2020. Patients were matched for risk factors of severe COVID-19: age, sex, body mass index, diabetes mellitus, preexisting cardiopathy, chronic lung disease, and basal renal function. We included 100 KTRs (median age [interquartile range (IQR)]) 64.7 years (55.3-73.1) in three French transplant centers. After a median follow-up of 13 days (7-30), transfer to ICU was required for 34 patients (34%) and death occurred in 26 patients (26%). Overall, 43 patients (43%) developed a severe disease during a median follow-up of 8.5 days (2-14). Propensity score matching to a large French cohort of 2017 patients hospitalized in 24 centers, revealed that survival was similar between KTRs and matched nontransplant patients with respective 30-day survival of 62.9% and 71% (p = .38) and severe disease-free 30-day survival of 50.6% and 47.5% (p = .91). These findings suggest that severity of COVID-19 in KTRs is related to their associated comorbidities and not to chronic immunosuppression.


Asunto(s)
COVID-19/epidemiología , Huésped Inmunocomprometido , Trasplante de Riñón , SARS-CoV-2 , Receptores de Trasplantes , Anciano , Comorbilidad , Femenino , Humanos , Unidades de Cuidados Intensivos/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Pandemias , Estudios Retrospectivos
10.
Br J Clin Pharmacol ; 87(5): 2236-2246, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33118186

RESUMEN

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.


Asunto(s)
Monitoreo de Drogas , Adulto , Anticuerpos Monoclonales Humanizados , Teorema de Bayes , Estudios de Factibilidad , Humanos , Estudios Prospectivos
11.
Transpl Infect Dis ; 23(3): e13552, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33352001

RESUMEN

EBV-positive mucocutaneous ulcer (EBV-MCU) is a rare EBV-positive B-cell lymphoproliferative disorder occurring in immunocompromised patients such as patients with solid organ or hematopoietic stem cells transplantation. EBV-MCU often consists of an isolated and circumscribed cutaneous or mucosal ulcerative lesion with a self-limited growth potential and a high regression rate upon immunosuppressive treatment withdrawal or rituximab therapy. Nevertheless, the pathophysiology of this latent infection leading to clonal lymphoproliferation is not well established. We report here two cases of EBV-MCU in kidney transplant recipients with a dissociated immune response to EBV with the absence of EBV-related antibodies and a positive T-cell response to EBV suggesting a potential specific oncogenic mechanism in this lymphoproliferative disorder.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Trasplante de Riñón , Herpesvirus Humano 4 , Humanos , Inmunidad Celular , Trastornos Linfoproliferativos , Receptores de Trasplantes , Úlcera
12.
Am J Transplant ; 20(5): 1365-1374, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31883413

RESUMEN

Anti-denatured HLA-Cw antibodies are highly prevalent, whereas anti-native HLA-Cw antibodies seem to lead to random flow cytometry crossmatch results. We aimed to reassess crossmatch prediction for anti-HLA-Cw using 2 types of single antigen flow beads (classical beads and beads with diminished expression of denatured HLA), and to compare the pathogenicity of preformed anti-denatured and anti-native HLA-Cw antibodies in kidney transplantation. We performed 135 crossmatches with sera reacting against donor HLA-Cw (classical beads fluorescence ≥500); only 20.6% were positive. Forty-three (31.6%) were anti-denatured HLA antibodies (beads with diminished expression of denatured HLA fluorescence <300); all were crossmatch negative. The correlation between classical beads fluorescence and the crossmatch ratio was low (ρ = 0.178), and slightly higher with beads with diminished expression of denatured HLA (ρ = 0.289). We studied 52 kidney recipients with preformed anti-HLA-Cw donor-specific antibodies. Those with anti-native HLA antibodies experienced more acute and chronic antibody-mediated rejections (P = .006 and .03, respectively), and displayed a lower graft survival (P = .04). Patients with anti-native HLA-Cw antibodies more frequently had previous sensitizing events (P < .000001) or plausibility of their antibody profile according to known anti-native HLA-Cw eplets (P = .0001). Anti-native but not anti-denatured HLA-Cw antibodies are deleterious, which underscores the need for reagents with diminished expression of denatured HLA.


Asunto(s)
Trasplante de Riñón , Citometría de Flujo , Rechazo de Injerto/etiología , Supervivencia de Injerto , Antígenos HLA , Prueba de Histocompatibilidad , Humanos , Isoanticuerpos , Donantes de Tejidos
13.
J Inherit Metab Dis ; 43(2): 348-356, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31444911

RESUMEN

Little is known about the long-term progression of adult nephropathic cystinosis patients. Our objective was to study central nervous system complications in cystinosis patients in the era of early cysteamine treatment, using advanced neuroimaging techniques. Neurological examination and multimodal brain 3 Tesla MRI were performed in 21 adult cystinosis patients, including 18 infantile cystinosis patients, 20 controls matched for age and renal function, and 12 healthy controls. Differences in gray matter volume and rest cerebral blood flow (CBF) using arterial spin labeling sequence were investigated using whole-brain voxel-based approach. Median age was 33.8 years (18.7-65.8). Seven patients (38.9%) presented with at least one central nervous system clinical abnormality: two (11.1%) with seizures, three (16.7%) with memory defects, five (27.8%) with cognitive defect, and one (5.5%) with stroke-like episode. These patients had a worse compliance to treatment (compliance score 2 vs 1, P = .03) and received a lower median cysteamine dose (0.9 g/day vs 2.1 g/day, P = .02). Among patients with infantile cystinosis, 13 (72.2%) showed cortical atrophy, which was absent in controls, but it was not correlated with symptoms. Cystinosis patients showed a significant gray matter decrease in the middle frontal gyrus compared with healthy controls and a significant negative correlation between the cystine blood level and rest CBF was observed in the right superior frontal gyrus, a region associated with executive function. Compliance to cysteamine treatment is a major concern in these adult patients and could have an impact on the development of neurological and cognitive complications.


Asunto(s)
Enfermedades del Sistema Nervioso Central/etiología , Cisteamina/administración & dosificación , Cistinosis/tratamiento farmacológico , Síndrome de Fanconi/complicaciones , Sustancia Gris/patología , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Enfermedades del Sistema Nervioso Central/diagnóstico por imagen , Circulación Cerebrovascular , Cistina/sangre , Cistinosis/complicaciones , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Adulto Joven
14.
J Am Soc Nephrol ; 30(12): 2449-2463, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31575699

RESUMEN

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 (n=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.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Inactivadores del Complemento/uso terapéutico , Trasplante de Riñón , Adulto , Síndrome Hemolítico Urémico Atípico/epidemiología , Síndrome Hemolítico Urémico Atípico/genética , Síndrome Hemolítico Urémico Atípico/cirugía , Proteínas Inactivadoras del Complemento C3b/genética , Proteínas del Sistema Complemento/análisis , Femenino , Francia , Supervivencia de Injerto/efectos de los fármacos , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Proteínas Mutantes Quiméricas/genética , Cuidados Preoperatorios , Modelos de Riesgos Proporcionales , Recurrencia , Sistema de Registros , Estudios Retrospectivos , Prevención Secundaria
15.
Nephrol Dial Transplant ; 34(9): 1597-1604, 2019 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-30608553

RESUMEN

BACKGROUND: Diarrhoea is one of the most frequent complications after kidney transplantation (KT). Non-infectious diarrhoea has been associated with reduced graft survival in kidney transplant recipients. However, the risk factors for renal allograft loss following diarrhoea remain largely unknown. METHODS: Between January 2010 and August 2011, 195 consecutive KT recipients who underwent standardized microbiological workups for diarrhoea at a single centre were enrolled in this retrospective study. RESULTS: An enteric pathogen was readily identified in 91 patients (47%), while extensive microbiological investigations failed to find any pathogen in the other 104. Norovirus was the leading cause of diarrhoea in these patients, accounting for 30% of the total diarrhoea episodes. The baseline characteristics were remarkably similar between non-infectious and infectious diarrhoea patients, with the exception that the non-infectious group had significantly lower graft function before diarrhoea (P = 0.039). Infectious diarrhoea was associated with a longer duration of symptoms (P = 0.001) and higher rates of acute kidney injury (P = 0.029) and hospitalization (P < 0.001) than non-infectious diarrhoea. However, the non-infectious group had lower death-censored graft survival than the infectious group (Gehan-Wilcoxon test, P = 0.038). Multivariate analysis retained three independent predictors of graft failure after diarrhoea: diarrhoea occurring ≥5 years after KT [hazard ratio (HR) 4.82; P < 0.001], re-transplantation (HR 2.38; P = 0.001) and baseline estimated glomerular filtration rate <30 mL/min/1.73 m2 (HR 11.02; P < 0.001). CONCLUSION: Our study shows that pre-existing conditions (re-transplantation, chronic graft dysfunction and late occurrence) determine the primary functional long-term consequences of post-transplant diarrhoea.


Asunto(s)
Diarrea/epidemiología , Rechazo de Injerto/diagnóstico , Fallo Renal Crónico/diagnóstico , Trasplante de Riñón/efectos adversos , Complicaciones Posoperatorias/diagnóstico , Adulto , Diarrea/patología , Femenino , Francia/epidemiología , Tasa de Filtración Glomerular , Rechazo de Injerto/etiología , Supervivencia de Injerto , Humanos , Incidencia , Fallo Renal Crónico/etiología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo
16.
Kidney Int ; 94(5): 1013-1022, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30348286

RESUMEN

Monogenic forms of Steroid-Resistant Nephrotic Syndrome (SRNS) have been widely characterized, but genetic screening paradigms preferentially address congenital, infantile onset, and familial cases. Our aim was to characterize the distribution of disease-causing gene mutations in adults with sporadic SRNS or focal segmental glomerulosclerosis (FSGS). We selected adult patients with non-syndromic, biopsy-proven FSGS or SRNS in the absence of known family history. Strict clinical criteria included lack of response to glucocorticoids and cyclosporine, and no recurrence after kidney transplantation. Mutations in SRNS genes were detected using a targeted gene panel. Sixteen of 135 tested participants (11.8%) carried pathogenic mutations in monogenic SRNS genes, and 14 others (10.4%) carried two APOL1 high-risk alleles. Autosomal recessive disease was diagnosed in 5 participants, autosomal dominant disease in 9, and X-linked disease in 2. Four participants carried a de novo heterozygous mutation. Among the 16 participants with identified mutations in monogenic SNRS genes, 7 (43.7%) had type IV collagen mutations. Mutations in monogenic SNRS genes were identified primarily in participants with proteinuria onset before 25 years of age, while the age at disease onset was variable in those with APOL1 high-risk genotype. Mean age at diagnosis was lower and renal survival was worse in participants with identified mutations in SNRS genes than in those without mutations. We found a significant rate of pathogenic mutations in adults with SRNS, with Type IV collagen mutations being the most frequent. These findings may have immediate impact on clinical practice.


Asunto(s)
Glucocorticoides/uso terapéutico , Mutación , Síndrome Nefrótico/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Apolipoproteína L1/genética , Autoantígenos/genética , Colágeno Tipo IV/genética , Proteínas del Citoesqueleto/genética , Resistencia a Medicamentos , Femenino , Humanos , Riñón/patología , Masculino , Persona de Mediana Edad , Síndrome Nefrótico/tratamiento farmacológico , Adulto Joven
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