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BACKGROUND: Congenital hydrocephalus is characterized by ventriculomegaly, defined as a dilatation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. Primary congenital hydrocephalus is a subset of cases with prenatal onset and absence of another primary cause, e.g., brain hemorrhage. Published series report a Mendelian cause in only a minority of cases. In this study, we analyzed exome data of PCH patients in search of novel causal genes and addressed the possibility of an underlying oligogenic mode of inheritance for PCH. MATERIALS AND METHODS: We sequenced the exome in 28 unrelated probands with PCH, 12 of whom from families with at least two affected siblings and 9 of whom consanguineous, thereby increasing the contribution of genetic causes. Patient exome data were first analyzed for rare (MAF < 0.005) transmitted or de novo variants. Population stratification of unrelated PCH patients and controls was determined by principle component analysis, and outliers identified using Mahalanobis distance 5% as cutoff. Patient and control exome data for genes biologically related to cilia (SYScilia database) were analyzed by mutation burden test. RESULTS: In 18% of probands, we identify a causal (pathogenic or likely pathogenic) variant of a known hydrocephalus gene, including genes for postnatal, syndromic hydrocephalus, not previously reported in isolated PCH. In a further 11%, we identify mutations in novel candidate genes. Through mutation burden tests, we demonstrate a significant burden of genetic variants in genes coding for proteins of the primary cilium in PCH patients compared to controls. CONCLUSION: Our study confirms the low contribution of Mendelian mutations in PCH and reports PCH as a phenotypic presentation of some known genes known for syndromic, postnatal hydrocephalus. Furthermore, this study identifies novel Mendelian candidate genes, and provides evidence for oligogenic inheritance implicating primary cilia in PCH.
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Hidrocefalia , Herança Multifatorial , Feminino , Gravidez , Humanos , Mutação , Consanguinidade , Bases de Dados FactuaisRESUMO
BACKGROUND AND HYPOTHESIS: The decision for acceptance or discard of the increasingly rare and marginal brain-dead donor kidneys in Eurotransplant (ET) countries has to be made without solid evidence. Thus, we developed and validated flexible clinicopathological scores called 2-Step Scores for the prognosis of delayed graft function (DGF) and one-year death-censored transplant loss (1y-tl) reflecting the current practice of six ET countries including Croatia and Belgium. METHODS: The training set was n=620 for DGF and n=711 for 1y-tl, with validation sets n=158 and n=162. In step 1, stepwise logistic regression models including only clinical predictors were used to estimate the risks. In step 2, risk estimates were updated for statistically relevant intermediate risk percentiles with nephropathology. RESULTS: Step 1 revealed an increased risk of DGF with increased cold ischaemia time, donor and recipient BMI, dialysis vintage, number of HLA-DR mismatches or recipient CMV IgG positivity. On the training and validation set, c-statistics were 0.672 and 0.704, respectively. At a range between 18% and 36%, accuracy of DGF-prognostication improved with nephropathology including number of glomeruli and Banff cv (updated overall c statistics of 0.696 and 0.701, respectively).Risk of 1y-tl increased in recipients with cold ischaemia time, sum of HLA-A. -B, -DR mismatches and donor age. On training and validation sets, c-statistics were 0.700 and 0.769, respectively. Accuracy of 1y-tl prediction improved (c-statistics = 0.706 and 0.765) with Banff ct. Overall, calibration was good on the training, but moderate on the validation set; discrimination was at least as good as established scores when applied to the validation set. CONCLUSION: Our flexible 2-Step Scores with optional inclusion of time-consuming and often unavailable nephropathology should yield good results for clinical practice in ET, and may be superior to established scores. Our scores are adaptable to donation after cardiac death and perfusion pump use.
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Congenital hydrocephalus is a potentially devastating, highly heterogeneous condition whose genetic subset remains incompletely known. We here report a consanguineous family where three fetuses presented with brain ventriculomegaly and limb contractures and shared a very rare homozygous variant of KIDINS220, consisting of an in-frame deletion of three amino acids adjacent to the fourth transmembrane domain. Fetal brain imaging and autopsy showed major ventriculomegaly, reduced brain mass, and with no histomorphologic abnormalities. We demonstrate that the binding of KIDINS220 to TrkA is diminished by the deletion mutation. This family is the second that associates a KIDINS220 genetic variant with human ventriculomegaly and limb contractures, validating causality of the gene and indicating TrkA as a likely mediator of the phenotype.
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Feto/patologia , Hidrocefalia/patologia , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Malformações do Sistema Nervoso/patologia , Receptor trkA/metabolismo , Feminino , Feto/metabolismo , Homozigoto , Humanos , Hidrocefalia/etiologia , Hidrocefalia/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Malformações do Sistema Nervoso/etiologia , Malformações do Sistema Nervoso/metabolismo , Linhagem , Receptor trkA/genéticaRESUMO
BACKGROUND: In the general population, the seroconversion rate after primary vaccination with two doses of an anti-severe acute respiratory syndrome coronavirus 2 messenger RNA (mRNA) vaccine reaches nearly 100%, with significantly higher antibody titers after mRNA-1273 vaccination compared to BNT162b2 vaccination. Here we performed a systematic review and meta-analysis to compare the antibody response after two-dose mRNA-1273 versus BNT162b2 vaccination in solid organ transplant (SOT) recipients. METHODS: A systematic literature review was performed using PubMed, Web of Science and the Cochrane Library and original research papers were included for a meta-analysis to calculate vaccine-specific seroconversion rates for each of the mRNA vaccines. Next, the pooled relative seroconversion rate was estimated. RESULTS: Eight studies that described the development of antibodies against receptor-binding domain (RBD) and/or spike protein were eligible for meta-analysis. Two of these studies also reported antibody titers. The meta-analysis revealed lower seroconversion rates in SOT recipients vaccinated with two doses of BNT162b2 {44.3% [95% confidence interval (CI) 34.1-54.7]} as compared with patients vaccinated with two doses of mRNA-1273 [58.4% (95% CI 47.2-69.2)]. The relative seroconversion rate was 0.795 (95% CI 0.732-0.864). CONCLUSIONS: This systematic review and meta-analysis indicates that in SOT recipients, higher seroconversion rates were observed after vaccination with mRNA-1273 compared with BNT162b2.
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COVID-19 , Transplante de Órgãos , Vacinas , Vacina de mRNA-1273 contra 2019-nCoV , Anticorpos Antivirais , Vacina BNT162 , COVID-19/prevenção & controle , Humanos , RNA Mensageiro , Soroconversão , Transplantados , VacinaçãoRESUMO
BACKGROUND: Cytomegalovirus (CMV) remains an important challenge after kidney transplantation. Current Transplantation Society International Consensus Guidelines recommend antiviral prophylaxis or pre-emptive therapy for high-risk CMV-seronegative recipients with a CMV-seropositive donor (D+/R-) and moderate-risk CMV-seropositive recipients (R+). However, a split strategy according to CMV serostatus is not specifically mentioned. METHODS: We evaluated a split strategy to prevent CMV infection after kidney transplantation in which D+/R- patients received valganciclovir (VGC) prophylaxis for 200 days, and R + patients were treated pre-emptively according to CMV DNAemia. Patients were followed until 1-year post-transplant. RESULTS: Between April 2014 and March 2018, 40 D+/R- and 92 R + patients underwent kidney transplantation. Forty-six percent received antithymocyte globulin (ATG) induction, and 98% was treated with calcineurin inhibitors, mycophenolic acid (MPA), and steroids. No D+/R- patient developed CMV disease during prophylaxis (median 200 days), but 15% developed post-prophylaxis or late-onset disease. Fifty-three percent developed neutropenia during prophylaxis, including 16/40 (40%) grade 3 or 4 neutropenia requiring reduction/discontinuation of MPA (30%) and/or VGC (35%), and an occasional need for granulocyte colony-stimulating factor (5%). In the R + group, 40% received antiviral therapy for a median duration of 21 days; 5% developed early-onset CMV disease. Only 5% developed neutropenia. D+/R + status (hazard ratio (HR) 2.09,P = .004) and ATG use (HR 2.81, P < .0001) were risk factors for CMV reactivation. CONCLUSIONS: Prophylaxis leads to acceptable CMV control in high-risk patients but comes with a high risk of neutropenia. Pre-emptive therapy is effective and limits drug exposure in those at lower risk of CMV.
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Infecções por Citomegalovirus , Transplante de Rim , Antivirais/uso terapêutico , Citomegalovirus , Infecções por Citomegalovirus/tratamento farmacológico , Ganciclovir/uso terapêutico , Humanos , Preparações Farmacêuticas , Valganciclovir/uso terapêuticoRESUMO
Primary microcephaly (PM) is characterized by a small head since birth and is vastly heterogeneous both genetically and phenotypically. While most cases are monogenic, genetic interactions between Aspm and Wdr62 have recently been described in a mouse model of PM. Here, we used two complementary, holistic in vivo approaches: high throughput DNA sequencing of multiple PM genes in human patients with PM, and genome-edited zebrafish modeling for the digenic inheritance of PM. Exomes of patients with PM showed a significant burden of variants in 75 PM genes, that persisted after removing monogenic causes of PM (e.g., biallelic pathogenic variants in CEP152). This observation was replicated in an independent cohort of patients with PM, where a PM gene panel showed in addition that the burden was carried by six centrosomal genes. Allelic frequencies were consistent with digenic inheritance. In zebrafish, non-centrosomal gene casc5 -/- produced a severe PM phenotype, that was not modified by centrosomal genes aspm or wdr62 invalidation. A digenic, quadriallelic PM phenotype was produced by aspm and wdr62. Our observations provide strong evidence for digenic inheritance of human PM, involving centrosomal genes. Absence of genetic interaction between casc5 and aspm or wdr62 further delineates centrosomal and non-centrosomal pathways in PM.
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Centrossomo/metabolismo , Estudos de Associação Genética , Predisposição Genética para Doença , Padrões de Herança , Microcefalia/diagnóstico , Microcefalia/genética , Animais , Bases de Dados Genéticas , Estudos de Associação Genética/métodos , Humanos , Mutação , Fases de Leitura Aberta , Fenótipo , Transdução de Sinais , Sequenciamento do Exoma , Peixe-ZebraRESUMO
A systematic review and meta-analysis were performed to investigate the value of donor-derived cell-free DNA (dd-cfDNA) as a noninvasive biomarker in diagnosing kidney allograft rejection. We searched PubMed, Web of Science and the Cochrane Library for original research papers published between January 1994 and May 2020 on dd-cfDNA fractions in blood of kidney allograft recipients. A single-group meta-analysis was performed by computing pooled estimates for dd-cfDNA fractions using the weighted median of medians or quantile estimation (QE) approach. Weighted median differences in medians (WMDMs) and median differences based on the QE method were used for pairwise comparisons. Despite heterogeneity among the selected studies, the meta-analysis revealed significantly higher median dd-cfDNA fractions in patients with antibody-mediated rejection (ABMR) than patients without rejection or patients with stable graft function. When comparing patients with T cell-mediated rejection (TCMR) and patients with ABMR, our two statistical approaches revealed conflicting results. Patients with TCMR did not have different median dd-cfDNA fractions than patients without rejection or patients with stable graft function. dd-cfDNA may be a useful marker for ABMR, but probably not for TCMR.
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Ácidos Nucleicos Livres , Transplante de Rim , Biomarcadores , Rejeição de Enxerto/diagnóstico , Humanos , Transplante de Rim/efeitos adversos , Doadores de TecidosRESUMO
BACKGROUND: Kidney recipients maintaining a prolonged allograft survival in the absence of immunosuppressive drugs and without evidence of rejection are supposed to be exceptional. The ERA-EDTA-DESCARTES working group together with Nantes University launched a European-wide survey to identify new patients, describe them and estimate their frequency for the first time. METHODS: Seventeen coordinators distributed a questionnaire in 256 transplant centres and 28 countries in order to report as many 'operationally tolerant' patients (TOL; defined as having a serum creatinine <1.7 mg/dL and proteinuria <1 g/day or g/g creatinine despite at least 1 year without any immunosuppressive drug) and 'almost tolerant' patients (minimally immunosuppressed patients (MIS) receiving low-dose steroids) as possible. We reported their number and the total number of kidney transplants performed at each centre to calculate their frequency. RESULTS: One hundred and forty-seven questionnaires were returned and we identified 66 TOL (61 with complete data) and 34 MIS patients. Of the 61 TOL patients, 26 were previously described by the Nantes group and 35 new patients are presented here. Most of them were noncompliant patients. At data collection, 31/35 patients were alive and 22/31 still operationally tolerant. For the remaining 9/31, 2 were restarted on immunosuppressive drugs and 7 had rising creatinine of whom 3 resumed dialysis. Considering all patients, 10-year death-censored graft survival post-immunosuppression weaning reached 85% in TOL patients and 100% in MIS patients. With 218 913 kidney recipients surveyed, cumulative incidences of operational tolerance and almost tolerance were estimated at 3 and 1.5 per 10 000 kidney recipients, respectively. CONCLUSIONS: In kidney transplantation, operational tolerance and almost tolerance are infrequent findings associated with excellent long-term death-censored graft survival.
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Rejeição de Enxerto/epidemiologia , Sobrevivência de Enxerto/imunologia , Tolerância Imunológica/imunologia , Terapia de Imunossupressão/métodos , Transplante de Rim , Transplantados , Adulto , Europa (Continente)/epidemiologia , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Incidência , Masculino , Inquéritos e Questionários , Taxa de Sobrevida/tendências , Transplante HomólogoRESUMO
BACKGROUND: Kidney disease Improving Global Outcomes (KDIGO) guidelines strongly recommend administering an anti-IL-2R mAb (i.e., basiliximab) for induction in all kidney transplant recipients. We describe a life-threatening episode of shock following basiliximab injection and review the literature. METHODS AND RESULTS: A 20-year-old male was given tacrolimus, methylprednisolone, mycophenolate, and basiliximab, 20 mg in the context of living-related kidney transplantation. On post-operative Day 1 (POD 1), he developed acute respiratory distress syndrome (ARDS), shock, multiple organ failure, and had a cardiac arrest. After effective resuscitation, he received rescue therapies (NO inhalation, extra-corporeal membrane oxygenation, and CVVHD) but lost the graft as the result of cortical necrosis. We conducted PubMed searches that yielded 7 similar cases; 6 required invasive ventilation. Three patients developed cardiac arrest, 3 required major inotropic support, and 2 developed MOF and myocardial depression. All but 1 patient recovered rapidly within a few days. There was no evidence for infectious, allergic, or over-hydration concerns. Although the direct causal role of basiliximab cannot be formally proven, the fact that ARDS at the time of induction therapy with other immunosuppressive agents is otherwise extremely rare suggests a direct role for basiliximab. CONCLUSIONS: Basiliximab could be associated with shock and ARDS.
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Anticorpos Monoclonais/efeitos adversos , Imunossupressores/efeitos adversos , Transplante de Rim/métodos , Proteínas Recombinantes de Fusão/efeitos adversos , Síndrome do Desconforto Respiratório/induzido quimicamente , Choque/induzido quimicamente , Anticorpos Monoclonais/administração & dosagem , Basiliximab , Pré-Escolar , Oxigenação por Membrana Extracorpórea , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/administração & dosagem , Masculino , Proteínas Recombinantes de Fusão/administração & dosagem , Síndrome do Desconforto Respiratório/terapia , Choque/terapiaRESUMO
BACKGROUND: The 2009 KDIGO (Kidney Disease: Improving Global Outcomes) chronic kidney disease-mineral and bone disorder clinical practice guideline suggests correcting 25-hydroxyvitamin D3 (25[OH]D) levels<30ng/mL in patients treated with maintenance hemodialysis, but does not provide a specific treatment protocol. STUDY DESIGN: 2-center, double-blind, randomized, 13-week, controlled trial followed by a 26-week open-label study. SETTING & PARTICIPANTS: 55 adult maintenance hemodialysis patients with 25(OH)D levels<30ng/mL were recruited from June 2008 through October 2009. INTERVENTION: Cholecalciferol, 25,000IU, per week orally versus placebo for 13 weeks, then 26 weeks of individualized cholecalciferol prescription based on NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) guidelines. OUTCOMES: Primary end point was the percentage of patients with 25(OH)D levels≥30ng/mL at 13 weeks. Secondary outcomes included the percentage of patients with normal calcium, phosphorus, and intact parathyroid hormone (iPTH) blood levels. Safety measures included incidence of hypercalcemia and hypervitaminosis D. MEASUREMENTS: Blood calcium and phosphate were measured weekly; iPTH, 25(OH)D, 1,25-dihydroxyvitamin D3 (1,25[OH]2D), and bone turnover markers, trimonthly; fetuin A and fibroblast growth factor 23 (FGF-23) serum levels and aortic calcification scores were determined at weeks 0 and 39. RESULTS: The primary end point significantly increased in the treatment group compared with the placebo group (61.5% vs 7.4%; P<0.001), as well as 1,25(OH)2D levels (22.5 [IQR, 15-26] vs 11 [IQR, 10-15]pg/mL; P<0.001) and the proportion of patients achieving the target calcium level (76.9% vs 48.2%; P=0.03). Incidence of hypercalcemia and phosphate and iPTH levels were similar between groups. The second 26-week study phase did not significantly modify the prevalence of 25(OH)D level≥30ng/mL in patients issued from the placebo group. LIMITATIONS: Small size of the study population. CONCLUSIONS: Oral weekly administration of 25,000IU of cholecalciferol for 13 weeks is an effective, safe, inexpensive, and manageable way to increase 25(OH)D and 1,25(OH)2D levels in hemodialysis patients. Further evaluation of clinical end points is suggested.
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Colecalciferol/administração & dosagem , Colecalciferol/sangue , Diálise Renal/métodos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/terapia , Idoso , Método Duplo-Cego , Feminino , Fator de Crescimento de Fibroblastos 23 , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Vitamina D/sangueRESUMO
BACKGROUND: Patients undergoing kidney transplantation are sometimes being treated with antiplatelet agents such as ticlopidine or clopidogrel. Some teams refuse to wait-list these patients for fear of bleeding during transplant surgery. METHODS: We retrospectively reviewed the records of 702 adult patients with a kidney transplant alone between 2000 and 2010. Nineteen (2.7%) patients were taking clopidogrel or ticlopidine when called in for transplantation. Furthermore, 10 of these 19 patients were also taking low-dose aspirin (ASA). We compared the risk of bleeding peri- and postoperatively, and the occurrence of cardiovascular complications within 30 days after renal transplantation between 19 cases and 39 controls randomly selected within the cohort. RESULTS: Platelets were administered to 7 cases (37%) versus 0 controls (P<0.001). A single case (5.3%) presented with significant bleeding during surgery following an implantation biopsy, and required 4 red bood cell (RBC) units. During the first day, 3 of the 19 cases (16%) and 1 of the 39 controls required RBC (P=0.1). No reoperation was performed for bleeding. After the transplant, clopidogrel or ticlopidine was resumed in only two patients. The platelet count and haemoglobin were similar between cases and controls at Day 30. No cardiovascular event occurred in cases or controls during the first month post-transplantation. At 5 years, graft and patient survival was similar in cases and controls. CONCLUSIONS: Clopidogrel and ticlopidine, sometimes in combination with ASA, are associated with a low risk of bleeding during renal transplantation and does not seem to be a contraindication for renal transplant surgery.
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Aspirina/administração & dosagem , Perda Sanguínea Cirúrgica/prevenção & controle , Falência Renal Crônica/cirurgia , Transplante de Rim , Complicações Pós-Operatórias/prevenção & controle , Ticlopidina/análogos & derivados , Ticlopidina/administração & dosagem , Estudos de Casos e Controles , Clopidogrel , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Seguimentos , Sobrevivência de Enxerto , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/administração & dosagem , Complicações Pós-Operatórias/epidemiologia , Prognóstico , Estudos Retrospectivos , Risco , Fatores de Risco , Taxa de Sobrevida/tendências , Fatores de TempoAssuntos
Nefropatias , Transplante de Rim , Estudo de Associação Genômica Ampla , Rejeição de Enxerto , Humanos , RimRESUMO
BACKGROUND/AIMS: Intradialytic hypotension is the most common complication of modern day haemodialysis (HD). Convective modalities, including haemodiafiltration (HDF) are reported to result in greater cardiovascular stability compared to standard HD, which has been suggested to be due to improved solute transport between compartments. We therefore investigated the effect of treatment on body water by bioimpedance. METHODS: We measured the change in extracellular water (ECW) and intracellular water (ICW) in 263 outpatients attending for HD using cooled dialysate and 134 patients for HDF. RESULTS: Patient cohorts were matched for demographics, dialysate composition, ultrafiltration rate, and session duration. The fall in systolic blood pressure following HD was -11.8 mm Hg (-25.3 to 2.3) and not different from that following HDF -12 mm Hg (-27 to 6). Similarly there were no differences in pretreatment serum sodium and dialysate sodium gradient [HD 1 mmol/l (-1 to 3) vs. HDF 2 mmol/l (1 to 4)], or change in serum sodium posttreatment [HD 0 mmol/l (-2 to 2) vs. HDF 1 mmol/l (-1 to 3)]. There were no differences in ICW or ECW pretreatment, and following treatment the reduction in ICW and ECW did not differ [ICW HD -3.5% (-5.7 to -1.8) vs. -4.1% (-6.0 to -1.7), ECW HD -7.1% (-9.4 to -4.7) vs. HDF -7.1% (-9.7 to -4.9)]. CONCLUSION: We were unable to demonstrate any advantage for HDF over HD using cooled dialysate in terms of changes in blood pressure during a treatment session, or differences in the relative changes in ICW or ECW volumes.
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Água Corporal/fisiologia , Líquido Extracelular/fisiologia , Hemodiafiltração , Líquido Intracelular/fisiologia , Diálise Renal , Adulto , Pressão Sanguínea , Temperatura Baixa , Impedância Elétrica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Renal/métodosRESUMO
INTRODUCTION: Haemodialysis dosing is traditionally based on urea clearance (Kt/V). Aiming for the same Kt/V target, some racial groups have better survival. We investigated whether body composition differs with ethnicity and may lead to differences in Kt/V delivered. METHODS: We compared total body water (TBW) measured by multifrequency bioelectrical impedance analysis (MF-BIA) that calculated from standard anthropometric equations. RESULTS: Three hundred and seventy-one adult patients, with a mean age of 58.2 ± 16.6 years, 60.6% of whom were male, 29.1% diabetic, 38.5% Caucasoid, 29.4% African/Afro-Caribbean, 24.8% South Asian and 5.4% East Asian, were studied. TBW measured by MF-BIA differed significantly from that predicted by anthropometric equations. Body fat of women and diabetics was greater, and muscle mass in South Asians was reduced. The difference between the TBW MF-BIA measurement and that of the equation by Watson et al. [11] was associated with % muscle mass (ß -10.8, p < 0.001), age (ß 0.23, p < 0.001), serum albumin (ß -0.24, p < 0.001), body mass index (ß 0.91, p = 0.001) and racial origin (ß -9.86, p = 0.04). CONCLUSIONS: Variation in body composition between ethnic groups potentially leads to over-estimation of delivered dose for some ethnic groups and underestimation for others when using anthropometric equations. MF-BIA assessments of body water should be evaluated as a method for dosing dialysis patients.
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Antropometria/métodos , Composição Corporal , Água Corporal/química , Soluções para Hemodiálise/química , Grupos Raciais/estatística & dados numéricos , Diálise Renal/métodos , Ureia/urina , Espectroscopia Dielétrica/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Reino UnidoRESUMO
BACKGROUND: BK polyomavirus-associated nephropathy (PVAN) is a frequent complication in the early phase after kidney transplantation. The most important risk factor for PVAN is the intensity of immunosuppression. A recent study suggests that exposure to valganciclovir (VGC) could also be a risk factor. METHODS: We performed a retrospective, single-center study to investigate the effect of valganciclovir exposure on the risk for PVAN during the first 100 days post transplant. Cytomegalovirus (CMV) seronegative recipients of a CMV seropositive donor kidney received VGC prophylaxis, whereas CMV seropositive recipients were managed by a pre-emptive CMV strategy. Cox regression analysis was used to identify risk factors for PVAN development with VGC treatment and strength of immunosuppressive therapy as time-dependent variables. RESULTS: A total of 211 adults who received a kidney transplant between 2014 and 2019 were included. Eighteen (9%) developed PVAN. Multivariate regression analysis showed that women have a lower risk of developing PVAN (hazard ratio [HR] 0.08 (confidence interval [CI] 0.01-0.58), P = .013), whereas age was associated with an increased risk for PVAN (HR 1.04 for every additional year [CI 1.00-1.08], P = .029). There was a trend toward a lower risk of PVAN for patients on reduced immunosuppressive therapy (HR 0.44 [CI 0.15-1.24], P = .12). VGC use was not associated with the risk for PVAN (HR 0.99 [CI 0.35-2.78], P = .98). CONCLUSIONS: In our study, VGC exposure was not associated with the risk for PVAN. Our study is the first to reassess in depth the hypothesis that VGC treatment increases the risk of PVAN. The unique strength of this study is the correction for the degree of immunosuppression and the statistical use of time-dependent covariates. This methodological approach can provide a foundation for further studies needed to confirm our findings.
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Infecções por Citomegalovirus , Nefropatias , Transplante de Rim , Infecções por Polyomavirus , Polyomavirus , Adulto , Humanos , Feminino , Valganciclovir , Transplante de Rim/efeitos adversos , Estudos Retrospectivos , Citomegalovirus , Infecções por Polyomavirus/complicações , Antivirais/uso terapêutico , TransplantadosRESUMO
Tacrolimus (Tac) has a narrow therapeutic range. Dosing is generally targeted at Tac trough levels (C 0), notwithstanding conflicting reports on the correlation between Tac C 0 and systemic exposure measured by the area-under-the-concentration-over-time curve (AUC). The Tac dose required to meet the target C 0 varies highly among patients. We hypothesized that patients requiring a relatively high Tac dose for a certain C 0 may show a higher AUC. Methods: We retrospectively analyzed data from 53 patients in which a 24-h Tac AUC24 estimation was performed at our center. Patients were divided into those taking a low (≤0.15 mg/kg) or high (>0.15 mg/kg) once-daily Tac dose. Multiple linear regression models were used to investigate if the association between C 0 and AUC24 changes according to dose level. Results: Despite the large difference in mean Tac dose between the low- and high-dose group (7 versus 17 mg/d), C 0 levels were similar. However, the mean AUC24 was substantially higher in the high-dose group (320 ± 96 h·µg/L versus 255 ± 81 h·µg/L, P < 0.001). This difference remained significant after adjusting for age and race. For a same C 0, every 0.01 mg/kg increase in Tac dose resulted in an AUC24 increase of 3.59 h·µg/L. Conclusions: This study challenges the general belief that C 0 levels are sufficiently reliable to estimate systemic drug exposure. We demonstrated that patients requiring a relatively high Tac dose to attain therapeutic C 0 levels have higher drug exposure and could therefore potentially be overdosed.
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BACKGROUND: Post-transplant diabetes mellitus occurs in 10-40% of kidney transplant recipients and is associated with increased risk of developing cardiovascular diseases. Early identification of patients with a higher risk of developing diabetes could allow to take timely measures. However, no validated model exists to predict the risk of post-transplant diabetes mellitus. METHODS: This retrospective study includes 267 adult patients who underwent kidney transplantation at the Antwerp University Hospital between January 2014 and August 2021. Post-transplant diabetes mellitus was diagnosed based on the American Diabetes Association definition at 3 months post-transplant. First, a logistic regression analysis was used to identify predictors for post-transplant diabetes mellitus. Second, criteria to identify patients with a high risk (> 35%) of developing post-transplant diabetes mellitus at 3 months were established. RESULTS: At 3 months post-transplantation, 54 (20.2%) patients developed post-transplant diabetes mellitus. Univariable analysis showed that age, body mass index and HbA1c on the day of transplantation were associated with post-transplant diabetes mellitus. However, in a multivariable model with the same parameters, only HbA1c remained statistically significant. An absolute increase in HbA1c of 0.1% increases the odds for developing post-transplant diabetes mellitus by 28% (95% confidence interval 1.15-1.42). An HbA1c level ≥ 5.3% at transplantation, regardless of age or body mass index, is sufficient to identify patients with a post-transplant diabetes mellitus risk of ≥ 35% with a positive predictive value of 39% and a negative predictive value of 88%. CONCLUSIONS: The HbA1c value at transplantation was the strongest predictor for post-transplant diabetes mellitus at 3 months post-transplant. Furthermore, at least in our population, a pre-transplant HbA1c of ≥ 5.3% can be used as an easy tool to identify patients at high risk of early post-transplant diabetes mellitus.
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Diabetes Mellitus , Transplante de Rim , Adulto , Humanos , Estudos Retrospectivos , Hemoglobinas Glicadas , Transplante de Rim/efeitos adversos , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Transplantados , Fatores de RiscoRESUMO
INTRODUCTION: Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) often caused by alternative complement dysregulation. Patients with aHUS can present with malignant hypertension (MHT), which may also cause TMA. METHODS: This analysis of the Global aHUS Registry (NCT01522183) assessed demographics and clinical characteristics in eculizumab-treated and not-treated patients with aHUS, with (n = 71) and without (n = 1026) malignant hypertension, to further elucidate the potential relationship between aHUS and malignant hypertension. RESULTS: While demographics were similar, patients with aHUS + malignant hypertension had an increased need for renal replacement therapy, including kidney transplantation (47% vs 32%), and more pathogenic variants/anti-complement factor H antibodies (56% vs 37%) than those without malignant hypertension. Not-treated patients with malignant hypertension had the highest incidence of variants/antibodies (65%) and a greater need for kidney transplantation than treated patients with malignant hypertension (65% vs none). In a multivariate analysis, the risk of end-stage kidney disease or death was similar between not-treated patients irrespective of malignant hypertension and was significantly reduced in treated vs not-treated patients with aHUS + malignant hypertension (adjusted HR (95% CI), 0.11 [0.01-0.87], P = 0.036). CONCLUSIONS: These results confirm the high severity and poor prognosis of untreated aHUS and suggest that eculizumab is effective in patients with aHUS ± malignant hypertension. Furthermore, these data highlight the importance of accurate, timely diagnosis and treatment in these populations and support consideration of aHUS in patients with malignant hypertension and TMA. TRIAL REGISTRATION DETAILS: Atypical Hemolytic-Uremic Syndrome (aHUS) Registry. Registry number: NCT01522183 (first listed 31st January, 2012; start date 30th April, 2012).
Assuntos
Síndrome Hemolítico-Urêmica Atípica , Hipertensão Maligna , Falência Renal Crônica , Microangiopatias Trombóticas , Humanos , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Proteínas do Sistema Complemento , Sistema de RegistrosRESUMO
BACKGROUND: The power to predict kidney allograft outcomes based on non-invasive assays is limited. Assessment of operational tolerance (OT) patients allows us to identify transcriptomic signatures of true non-responders for construction of predictive models. METHODS: In this observational retrospective study, RNA sequencing of peripheral blood was used in a derivation cohort to identify a protective set of transcripts by comparing 15 OT patients (40% females), from the TOMOGRAM Study (NCT05124444), 14 chronic active antibody-mediated rejection (CABMR) and 23 stable graft function patients ≥15 years (STA). The selected differentially expressed transcripts between OT and CABMR were used in a validation cohort (n = 396) to predict 3-year kidney allograft loss at 3 time-points using RT-qPCR. FINDINGS: Archetypal analysis and classifier performance of RNA sequencing data showed that OT is clearly distinguishable from CABMR, but similar to STA. Based on significant transcripts from the validation cohort in univariable analysis, 2 multivariable Cox models were created. A 3-transcript (ADGRG3, ATG2A, and GNLY) model from POD 7 predicted graft loss with C-statistics (C) 0.727 (95% CI, 0.638-0.820). Another 3-transcript (IGHM, CD5, GNLY) model from M3 predicted graft loss with C 0.786 (95% CI, 0.785-0.865). Combining 3-transcripts models with eGFR at POD 7 and M3 improved C-statistics to 0.860 (95% CI, 0.778-0.944) and 0.868 (95% CI, 0.790-0.944), respectively. INTERPRETATION: Identification of transcripts distinguishing OT from CABMR allowed us to construct models predicting premature graft loss. Identified transcripts reflect mechanisms of injury/repair and alloimmune response when assessed at day 7 or with a loss of protective phenotype when assessed at month 3. FUNDING: Supported by the Ministry of Health of the Czech Republic under grant NV19-06-00031.
RESUMO
BACKGROUND: Shipment of organs during the allocation process aims to improve human leucocyte antigen (HLA) matching but can also have a detrimental effect by prolonging cold ischaemia. The overall effect of organ exchange on post-transplant outcomes in the Eurotransplant (ET) region has not been investigated. METHODS: This is a retrospective single-centre cohort study to investigate the effect of shipment of renal allografts on cold ischaemia times and the incidence of acute rejection (AR) and graft survival in 661 transplantations of deceased donor kidneys. RESULTS: Forty-six per cent (N = 301) of the patients received a locally procured and 54% (N = 360) a shipped donor kidney. Locally procured donors tended to be older, more often hypertensive and had less frequently died from trauma. Recipients of shipped kidneys were at higher immunological risk, being younger, more frequently retransplanted and immunized against HLA antigens. Shipped kidneys had a 2.2-h prolongation of cold ischaemia time (18.0 versus 20.2 h; P < 0.0001) but significantly less HLA A, B and DR mismatches (2.20 versus 2.84; P < 0.0001). Recipients of shipped kidneys had an increased incidence of first-year AR [19 versus 13%; odds ratio 1.62 (1.06-2.49); P = 0.026] and death-censored graft loss [hazard ratio 1.6 (1.1-2.4); P = 0.01] that was no longer statistically significant after adjustments for risk factors by multivariable modelling. CONCLUSIONS: Shipment of kidneys in the ET region is associated with a modest increase in cold ischaemia time and significantly better HLA matching. This allows for successful transplantation of higher risk patients with no significant penalty with regard to AR rates or death-censored graft survival.