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BACKGROUND AND OBJECTIVES: Children with multi-drug resistant idiopathic nephrotic syndrome (MDR-INS) usually progress to end-stage kidney disease with a consistent risk of disease recurrence after transplantation. New therapeutic options are needed for these patients. Mesenchymal stromal cells (MSCs) are multipotential non-hematopoietic cells with several immunomodulatory properties and growing clinical applications. Cord blood-derived MSC have peculiar anti-inflammatory and immunosuppressive properties. We aimed at assessing safety and efficacy of cord-blood-derived MSCs (CB-MSCs) in children with MDR-INS. DESIGN, SETTING, PARTICIPANTS: Prospective, open-label, single arm phase I-II pilot study. Pediatric patients with MDR-INS, resistant to at least two lines of therapy, were enrolled. Allogenic CB-MSCs were administered intravenously on days 0, 14, and 21 at a dose of 1.5 × 106 cells/kg. Patients were followed for at least 12 months. The primary outcomes were safety and toxicity. The secondary outcome was remission at 12 months evaluated by urinary protein/urinary creatinine ratio (uPr/uCr). Circulating regulatory T cells (Tregs) were monitored. RESULTS: Eleven pediatric patients with MDR-INS (10 females, median age 13 years) resistant to a median of 3 previous lines of therapy were enrolled. All patients completed the CB-MSC infusion schedule. No patient experienced any infusion-related adverse event or toxicity. Nine patients were assessable for efficacy. At the 12 months follow-up after the treatment, the median uPr/uCr did not change significantly from baseline (8.13 vs. 9.07; p = 0.98), while 3 patients were in partial or complete remission. A lower baseline uPr/uCr was a predictor of remission (2.55 vs. 8.74; p = 0.0238). Tregs count was not associated with CB-MSCs therapy. CONCLUSIONS: CB-MSCs are safe and may have a role in the immunosuppressive therapy of pediatric patients with MDR-INS. This preliminary experience paves the way toward further phase II studies addressing MSC efficacy in immune-mediated kidney diseases.
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Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Síndrome Nefrótico , Adolescente , Niño , Femenino , Sangre Fetal , Humanos , Trasplante de Células Madre Mesenquimatosas/efectos adversos , Síndrome Nefrótico/etiología , Síndrome Nefrótico/terapia , Proyectos Piloto , Estudios ProspectivosRESUMEN
Background: A great majority of children with idiopathic nephrotic syndrome will relapse after successful treatment of the initial episode. The possibility that different steroid dosing regimens at onset, adjusted for risk factors, can reduce the rate of relapse represents an interesting option to investigate. Objectives: To evaluate the effect of the initial steroid regimen, adjusted for time to remission (TTR), on the frequency of relapses and steroid dependence, and to verify the influence of prognostic factors on disease course. Methods: A multicentre, prospective, cohort study. Children with nephrotic syndrome, with TTR ≤ 10 days (Group A), were given a 20-week prednisone regimen (2,828 mg/m2) and those with a TTR >10 days, a 22-week regimen (3,668 mg/m2) (Group B). Previously published retrospective data from the same centers were also evaluated. Main outcomes were: relapse rate, number of frequent relapsers + steroid dependent children and total prednisone dose after induction. Results: 143 children were enrolled. Rate of relapsed subjects (77 vs. 79%) and frequent relapsers + steroid dependent subjects (40 vs. 53%) did not differ between Groups A and B, or between the retrospective and prospective cohorts. The cumulative prednisone dose taken after the induction treatment was similar in both groups and in the retrospective and prospective cohorts. TTR was not associated with relapse risk. Age at onset and total serum protein were significantly lower in relapsing patients. At ROC analysis, the best cut-off was 5.3 years for age at onset and 4.2 g/dL for total serum protein. According to these cut-offs, older children with higher total serum protein had a higher relapse free survival rate (58%) than younger children with lower total serum protein (17%). Conclusions: TTR was not found to be a prognostic factor of relapse; because of this, different steroid regimens, adjusted for TTR, did not modify the relapse rate in any relevant measure. Conversely, younger age and low total serum protein were independent predictors of relapse risk, however this outcome was not modified by higher prednisone regimens. Clinical Trial Registration:https://www.ClinicalTrials.gov/, identifier: NCT01386957 (www.nefrokid.it).
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Idiopathic nephrotic syndrome (INS) is the most frequent primary glomerular disease in children, displaying high grade proteinuria and oedema. The mainstay of therapy are steroids, and patients are usually classified according to the treatment response (sensitive vs. resistant). The mechanisms involved in INS pathogenesis and treatment responsiveness have not yet been identified. In this context, the analysis of urinary extracellular vesicles (UEv) is interesting, since they represent a molecular snapshot of the parental cells, offering a "fingerprint" for monitoring their status. Therefore, the aim of this study is to verify the feasibility of using UEv of INS patients as indicators of therapy response and its prediction. UEv were isolated from the urine of pediatric patients in remission after therapy; they showed characteristic electrophoresis profiles that matched specific patient subgroups. We then built a statistical model to interpret objectively each patient UEv protein profile: in particular, steroid-resistant patients cluster together with a very distinct pattern from other INS patients and controls. In conclusion, the evaluation of the UEv protein profile looks promising in the investigation of INS, showing a disease signature that might predict clinical evolution.
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BACKGROUND: We evaluated the role of CYP3A5, ABCB1 and SXR gene polymorphisms in the occurrence of acute kidney rejection in a cohort of pediatric renal transplant recipients. METHODS: Forty-nine patients were genotyped for CYP3A5, ABCB1 and SXR polymorphisms and evaluated with tacrolimus through levels in a retrospective monocenter study. RESULTS: Patients with the A allele of CYP3A5 treated with tacrolimus had a higher risk of acute rejection than those without the A allele, while patients carrying the homozygous GG variant for SXR A7635GG did not show any episode of acute rejection. CONCLUSION: Genetic analysis of polymorphisms implicated in drug metabolism and tacrolimus trough levels may help to forecast the risk of acute rejection and individualize drug dosage in children undergoing renal transplantation.
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Trasplante de Riñón , Niño , Genotipo , Humanos , Inmunosupresores/uso terapéutico , Trasplante de Riñón/efectos adversos , Polimorfismo de Nucleótido Simple , Estudios Retrospectivos , TacrolimusRESUMEN
Steroid-sensitive nephrotic syndrome is an immunological disorder mediated by still poorly defined circulating factor(s) that target the podocyte and damage the filtration barrier. Fatty acids (FA) have several biological roles and, in particular, are strictly involved in cell to cell communication, inflammatory processes and regulation of lymphocyte pools. Studies of FAs during INS have been mainly focused on biochemical changes during the phase of proteinuria; while no information is available about FA profile in patients with idiopathic nephrotic syndrome (INS) on stable remission. Aim of this study is to assess differences in blood FA profile between pediatric patients with INS during the phase of stable remission. Blood fatty acid profile of 47 pediatric patients on stable remission and 47 matched healthy controls were evaluated with gas chromatography. Patients with INS on stable remission had significantly higher levels of PUFA and omega-6 than controls (40.17 vs. 37.91% and 36.95 vs. 34.79%), lower levels of SFA and MUFA. Considering the single fatty acids, levels of omega-6 18:2n6 linoleic acid and omega-6 20:4n6 arachidonic acid were significantly higher in patients with INS than in controls (23.01 vs. 21.55%, p-value 0.003 and 10.37 vs. 9.65%, p-value 0.01). Moreover, patients with INS showed lower levels of SFA 14:0 (0.74 vs. 0.92%) and 18:0 (10.74 vs. 11.74%) and MUFA 18:1n9 oleic acid (18.50 vs. 19.83%). To the best of our knowledge this is the first study assessing FAs profile in children with INS in stable remission. In a population of 47 patients, we were able to demonstrate a higher blood level of linoleic and arachidonic acid, and consequently of omega-6 and PUFA, compared to controls. Persistently higher than normal levels of either linoleic or arachidonic acid, could be viewed as candidate biomarker for a state of risk of relapse in children with idiopathic nephrotic syndrome.
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BACKGROUND: Steroid resistant nephrotic syndrome (SRNS) is a frequent cause of end stage renal disease in children and post-transplant disease recurrence is a major cause of graft loss. METHODS: We identified all children with SRNS who underwent renal transplantation in Italy, between 2005 and 2017. Data were retrospectively collected for the presence of a causative gene mutation, sex, histology, duration of pre-transplant dialysis, age at onset and transplant, HLA matching, recurrence, therapy for recurrence, and graft survival. RESULTS: 101 patients underwent a first and 22 a second renal transplant. After a median follow-up of 58.5 months, the disease recurred on the first renal transplant in 53.3% of patients with a non-genetic and none with a genetic SRNS. Age at transplant > 9 years and the presence of at least one HLA-AB match were independent risk factors for recurrence. Duration of dialysis was longer in children with relapse, but did not reach statistical significance. Overall, 24% of patients lost the first graft, with recurrence representing the commonest cause. Among 22 patients who underwent a second transplant, 5 suffered of SRNS recurrence. SRNS relapsed in 5/9 (55%) patients with disease recurrence in their first transplant and 2 of them lost the second graft. CONCLUSIONS: Absence of a causative mutation represents the major risk factor for post-transplant recurrence in children with SRNS, while transplant can be curative in genetic SRNS. A prolonged time spent on dialysis before transplantation has no protective effect on the risk of relapse and should not be encouraged. Retransplantation represents a second chance after graft loss for recurrence.
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Trasplante de Riñón , Síndrome Nefrótico , Niño , Preescolar , Femenino , Humanos , Italia , Masculino , Síndrome Nefrótico/terapia , Recurrencia , Estudios Retrospectivos , EsteroidesRESUMEN
PURPOSE: Idiopathic nephrotic syndrome (INS) is the most frequent form of childhood nephrotic syndrome. Steroids represent the best therapeutic option; however, inter-individual differences in their efficacy and side effects have been reported. To date, there is no way to predict patients' resistance and/or dependence. Alterations in the cytokine profile of INS patients might contribute to proteinuria and glomerular damage and affect drug sensitivity. METHODS: The cytokine plasma levels were measured in 21 INS children at diagnosis to investigate the association among cytokines pattern and clinical response. Patients were selected on the basis of their clinical response: 7 steroid sensitive (SS), 7 dependent (SD), and 7 resistant (SR). Significant results were then analyzed in 41 additional pediatric INS patients. RESULTS: Within the 48 cytokines analyzed, macrophage migration inhibitory factor (MIF) was a good predictor of steroid response. Indeed, SR patients showed significantly higher MIF plasma levels compared with all others (p = 0.022; OR = 4.3, 95%CI = 1.2-25.4): a cutoff concentration of MIF > 501 pg/ml significantly discriminated SR patients (sensitivity = 85.7%, specificity = 71.4%). On the contrary, SD patients showed lower MIF plasma levels compared with others (p = 0.010; OR = 0.12, 95%CI = 9.2 × 10-3-6.7 × 10-1). Significant results were confirmed in the entire cohort. CONCLUSIONS: Our comprehensive cytokine analysis indicates that assessing MIF plasma levels at diagnosis could predict response to glucocorticoids in children with INS.
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Oxidorreductasas Intramoleculares/sangre , Factores Inhibidores de la Migración de Macrófagos/sangre , Síndrome Nefrótico/sangre , Síndrome Nefrótico/tratamiento farmacológico , Esteroides/uso terapéutico , Adolescente , Niño , Preescolar , Citocinas/sangre , Resistencia a Medicamentos , Femenino , Humanos , Oxidorreductasas Intramoleculares/genética , Factores Inhibidores de la Migración de Macrófagos/genética , Masculino , Síndrome Nefrótico/genética , Polimorfismo Genético , Valor Predictivo de las PruebasRESUMEN
This consensus document is aimed at providing an updated, multidisciplinary overview on the diagnosis and treatment of pediatric nephrotic syndrome (NS) at first presentation. It is the first consensus document of its kind to be produced by all the pediatric nephrology centres in Italy, in line with what is already present in other countries such as France, Germany and the USA. It is based on the current knowledge surrounding the symptomatic and steroid treatment of NS, with a view to providing the basis for a separate consensus document on the treatment of relapses. NS is one of the most common pediatric glomerular diseases, with an incidence of around 2-7 cases per 100000 children per year. Corticosteroids are the mainstay of treatment, but the optimal therapeutic regimen for managing childhood idiopathic NS is still under debate. In Italy, shared treatment guidelines were lacking and, consequently, the choice of steroid regimen was based on the clinical expertise of each individual unit. On the basis of the 2015 Cochrane systematic review, KDIGO Guidelines and more recent data from the literature, this working group, with the contribution of all the pediatric nephrology centres in Italy and on the behalf of the Italian Society of Pediatric Nephrology, has produced a shared steroid protocol that will be useful for National Health System hospitals and pediatricians. Investigations at initial presentation and the principal causes of NS to be screened are suggested. In the early phase of the disease, symptomatic treatment is also important as many severe complications can occur which are either directly related to the pathophysiology of the underlying NS or to the steroid treatment itself. To date, very few studies have been published on the prophylaxis and treatment of these early complications, while recommendations are either lacking or conflicting. This consensus provides indications for the prevention, early recognition and treatment of these complications (management of edema and hypovolemia, therapy and prophylaxis of infections and thromboembolic events). Finally, recommendations about the clinical definition of steroid resistance and its initial diagnostic management, as well as indications for renal biopsy are provided.
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Corticoesteroides/administración & dosificación , Síndrome Nefrótico/diagnóstico , Síndrome Nefrótico/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Niño , Preescolar , Consenso , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Italia , Masculino , Síndrome Nefrótico/mortalidad , Pronóstico , Recurrencia , Retratamiento , Sociedades Médicas , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Plasma-exchange (PEX) has been well described in pediatrics, but most of the current indications are derived from adult experience. Aim of the study was to review the PEX treatments in our Unit over a six-year period. METHODS: Three hundred and seventy-seven PEX sessions were performed in 38 patients (median age 12.1 years, range 0.6-20.5). Double-needle and single-needle PEX combined with hemodialysis and PEX combined with ultrafiltration were performed in 9, 1 and 3 patients respectively. The most common indications to PEX were atypical hemolytic uremic syndrome (aHUS, 9 patients), focal segmental glomerulosclerosis (FSGS, 9 cases), antibody mediated rejection (AMR) in renal transplant (rTx) recipients (8 patients) and hyperimmunization in patients waiting for rTx (4 cases). RESULTS: We treated five patients with aHUS on native kidneys with PEX only, with complete remission in 4/6 recurrences; PEX was also successfully used to prevent HUS relapse in three patients undergoing rTx. Only one partial remission was obtained in four patients with FSGS on native kidneys, by means of treatment protocols based on PEX and immunosuppressants; conversely, a partial remission was observed in 6/6 patients with recurrence of FSGS on rTx. Immunosuppressive protocols combined with PEX proved useful in sensitized cadaveric rTx recipients (2/4 successfully transplanted), but failed in 6 patients with chronic AMR. As regards complications, two severe adverse reactions occurred: an anaphylactic shock after the use of albumin and an abdominal hemorrhage. CONCLUSIONS: PEX is a relatively safe procedure in children. Pediatric patients with aHUS, recurrent FSGS and sensitized rTx recipients seem to benefit from treatment strategies including PEX.
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Enfermedades Renales/terapia , Intercambio Plasmático/métodos , Diálisis Renal/métodos , Ultrafiltración/métodos , Adolescente , Niño , Preescolar , Femenino , Humanos , Inmunosupresores/administración & dosificación , Lactante , Enfermedades Renales/fisiopatología , Trasplante de Riñón/métodos , Masculino , Intercambio Plasmático/efectos adversos , Inducción de Remisión , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Background: High levels of preformed anti-HLA antibodies dramatically diminish renal transplant outcomes. Most desensitization programmes guarantee good intermediate outcomes but quite disappointing long-term prognosis. The search for a fully compatible kidney increases time on the waiting list. Methods: In February 2011, a nationwide hyperimmune programme (NHP) was begun in Italy: all available kidneys are primarily proposed to highly sensitized patients with a panel reactive antibody above 80%. In this manuscript, we evaluate the outcome of paediatric patients transplanted with this approach. Results: Twenty-one patients were transplanted. Complete data are available for 20 patients. Mean age at transplantation was 14.5 years [standard deviation (SD) ± 5.5)]. Mean time on the waiting list was 29.3 months (SD ± 27.5). Median follow-up was 29.2 months (range: 11.2-59.3). The average number of HLA mismatches in these patients was 2.3 versus 3.7 in 48 standard patients transplanted in the same period (P < 0.001). Only one graft was lost. Two cases of humoral rejection occurred and were successfully treated. No cellular rejection was reported. Median creatinine clearance was 84, 88, 77 and 77 mL/min/1.73 m 2 respectively 1, 6, 12 and 24 months after transplant. Conclusions: Transplantation of sensitized patients avoiding prohibited antigens is feasible, at least in a selected cohort of patients. In order to be able to further improve this approach, which in our opinion is very successful, it would be necessary to expand the donor pool, possibly increasing the number of countries participating in the programme. In this series, time on the waiting list did not increase significantly. This allocation policy should ideally lead to an outcome comparable to that expected in standard patients, which is particularly desirable in young patients who have the longest life expectancy. Since long-term results of desensitization programmes are not (yet) convincing, we suggest that these programmes should be reserved for selected cases where compatible organs cannot be found within a reasonable time span.
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Desensibilización Inmunológica/métodos , Supervivencia de Injerto/inmunología , Antígenos HLA/inmunología , Fallo Renal Crónico/inmunología , Trasplante de Riñón , Adolescente , Adulto , Niño , Preescolar , Femenino , Antígenos HLA/sangre , Prueba de Histocompatibilidad , Humanos , Isoanticuerpos/sangre , Masculino , Adulto JovenRESUMEN
AIM: of the study was to analyse the impact of SXR rs3842689 polymorphism on the response to corticosteroids in pediatric idiopathic nephrotic syndrome. PATIENTS & METHODS: 66 children (56 steroid-sensitive, ten steroid-resistant) were studied for SXR gene polymorphism distribution. RESULTS: Steroid sensitive patients accounted for 96% of cases with In/In polymorphism, but only for 53% of cases with Del/Del polymorphism At odds ratio analysis, Del/Del represented a clear risk factor of steroid resistance (OR: 20.57; p = 0.009), while In/In was a favourable prognostic factor of steroid sensitivity. CONCLUSION: The analysis of SXR polymorphism is a promising tool to predict both the favourable response to corticosteroids and the risk of developing steroid resistance.
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Corticoesteroides/uso terapéutico , Síndrome Nefrótico/tratamiento farmacológico , Síndrome Nefrótico/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Niño , Preescolar , Resistencia a Medicamentos/genética , Femenino , Humanos , Masculino , Polimorfismo Genético/genética , Valor Predictivo de las Pruebas , Pronóstico , Factores de RiesgoRESUMEN
AIM: The activity of several key enzymes involved in the metabolism of many drugs is subject to change closely related to the age of patients. This possibility must also be considered in the case of tacrolimus, the most important calcineurins inhibitor, which is widely used in pediatric kidney transplantation. As well as in the liver and intestine, some of the enzymes involved in the metabolism of tacrolimus were also isolated in the peripheral blood mononuclear cells (PBMCs), where also appear to play an important regulatory action. Therefore, the influence of some external factors on the expression of specific mRNA can be determined noninvasively. PATIENTS & METHODS: The correlation between the levels of mRNA specific for key enzymes SXR, CYP3A and ABCB1 involved in the metabolism of tacrolimus was evaluated in PBMCs obtained from a selected population of 29 young kidney transplant recipients. A possible correlation between the expression of these specific mRNAs and tacrolimus pharmacokinetics was also investigated. RESULTS: The patients' age and their blood concentrations of SXR mRNA were directly correlated with the expression of CYP3A4, CYP3A5 mRNAs, but not of ABCB1 mRNA in the PBMCs. tacrolimus-normalized daily dose was strongly correlated with patient's age and multivariable regression indicates the CYP3A4-specific mRNA as the sole independent variable influencing tacrolimus concentration-to-dose ratio. CONCLUSION: Aging and SXR mRNA significantly affect the expression of CYP3A4- and CYP3A5-specific mRNA as measured by their concentration in PBMC.
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Envejecimiento/genética , Citocromo P-450 CYP3A/biosíntesis , Citocromo P-450 CYP3A/genética , Inmunosupresores/farmacocinética , Trasplante de Riñón , Monocitos/enzimología , Receptores de Esteroides/biosíntesis , Receptores de Esteroides/genética , Tacrolimus/farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP/biosíntesis , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adolescente , Femenino , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Masculino , Receptor X de Pregnano , ARN Mensajero/biosíntesis , Tacrolimus/efectos adversos , Tacrolimus/uso terapéuticoRESUMEN
BACKGROUND: Polyomavirus (PyV) infection is common, ranging from 60% to 100% depending on the virus. The urinary excretion rates of JC virus (JCV) and BK virus (BKV) have been extensively studied, but less is known about the more recently discovered PyVs. OBJECTIVES: To investigate the urinary excretion of Merkel cell PyV (MCPyV), which is associated with Merkel cell carcinoma (MCC), in kidney transplant recipients and healthy subjects, as well as those of lymphotropic polyomavirus (LPV), which was isolated from the B-cells of African green monkeys but has also been found in human blood, JCV and BKV. STUDY DESIGN: Urine samples were collected from 62 adult (ATP) and 46 pediatric (PTP) kidney transplant recipients and from 67 adult (AHC) and 40 pediatric (PHC) healthy controls. DNA was isolated and analyzed using real-time PCR (Q-PCR) to determine the viral loads of MCPyV, LPV, JCV and BKV. RESULTS: MCPyV DNA was more frequently detected (p<0.05) in the PTP (36.9%) and PHC (30.0%) groups compared to JCV (8.7% in PTP, 12.5% in PHC), BKV (6.5% in PTP, 2.5% in PHC), and LPV (2.2% in PTP, 5% in PHC) and in the AHC (47.8%) group compared to BKV (13.4%) and LPV (0%). CONCLUSIONS: Based on the results, it could be concluded that: (a) Despite the rarity of MCC, MCPyV is a common infection; (b) MCPyV demonstrates an excretion pattern similar to those of JCV and BKV, persisting in the kidney and infecting skin cells upon reactivation, with subsequent integration and transformation.
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ADN Viral/aislamiento & purificación , Trasplante de Riñón , Poliomavirus/aislamiento & purificación , Receptores de Trasplantes , Orina/virología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , ADN Viral/genética , Femenino , Voluntarios Sanos , Humanos , Lactante , Masculino , Persona de Mediana Edad , Poliomavirus/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Carga Viral , Adulto JovenRESUMEN
AIM: To clarify the immunogenicity and safety of influenza vaccine in patients with end-stage kidney disease (ESKD) on dialysis or who have received a kidney transplant. METHODS: Sixty adolescents and young adults with ESKD (25 on hemodialysis and 35 kidney transplant recipients) were randomized 1:1 to receive a traditional trivalent split virion vaccine (TIIV) or a virosome-adjuvanted trivalent inactivated influenza vaccine (VATIIV). The immunogenicity and safety of the two vaccines was evaluated and compared with the findings observed in 30 healthy subjects of similar age and gender distribution who received TIIV. RESULTS: The results indicate that the immune response of the patients to TIIV and VATIIV were similar. The administered vaccines were safe and well tolerated, and no advantage was found with the use of VATIIV. CONCLUSION: Given the potential clinical relevance of influenza in patients with ESKD, these findings support the official recommendation that they should receive annual influenza vaccinations.
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Inmunización/métodos , Vacunas contra la Influenza/administración & dosificación , Gripe Humana/prevención & control , Trasplante de Riñón , Diálisis Renal , Insuficiencia Renal , Adolescente , Anticuerpos Antivirales/sangre , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Humanos , Inmunización/efectos adversos , Vacunas contra la Influenza/efectos adversos , Vacunas contra la Influenza/inmunología , Masculino , Estudios Prospectivos , Método Simple Ciego , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/inmunología , Vacunas de Virosoma/administración & dosificación , Vacunas de Virosoma/inmunología , Adulto JovenRESUMEN
The three yr results of a multicenter trial in de novo pediatric KT treated with a proliferative signal inhibitor and low dose CNI are presented. Thirty-seven children (9.1 ± 5 yr old) received basiliximab, cyclosporine A (CyA C2:1400 ng/mL), (MMF C0:1.5-3 µg/mL), and prednisone. Three wk later everolimus was started (C0:5-10 ng/mL), CyA was reduced (C2:600 ng/mL after 90 days 300 ng/mL), and MMF discontinued. During the three-yr period patient and graft survivals were 96%. One patient died for causes unrelated to the immunosuppression. Cumulative acute rejection rate including protocol and indication biopsies was 21.9%. None of the patients had signs of chronic humoral rejection. Incidence of dnDSA was 5%, 11%, and 22% at one, two, and three yr post-transplant, respectively. Mean glomerular filtration rate measured at one yr and three yr post-transplant was 105.5 ± 31 and 110.7 ± 27 mL/min/1.73 m(2), respectively. A growth velocity of 7.7 ± 6.7 cm/yr was achieved with positive catch-up growth. No malignancy or post-transplant lymphoproliferative diseases were diagnosed. In conclusion, the treatment based on basiliximab induction, everolimus, low-dose cyclosporine, and low-dose prednisone leads to good long-term efficacy in de novo pediatric KT recipients.
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Ciclosporina/uso terapéutico , Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Sirolimus/análogos & derivados , Adolescente , Anticuerpos Monoclonales/uso terapéutico , Basiliximab , Niño , Preescolar , Esquema de Medicación , Quimioterapia Combinada , Everolimus , Femenino , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/epidemiología , Supervivencia de Injerto , Humanos , Estimación de Kaplan-Meier , Trasplante de Riñón/mortalidad , Masculino , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapéutico , Prednisona/uso terapéutico , Estudios Prospectivos , Proteínas Recombinantes de Fusión/uso terapéutico , Sirolimus/uso terapéutico , Resultado del TratamientoRESUMEN
AIM: Cyclosporine is characterized by a wide interindividual variability in its pharmacokinetics. The objective of this study was to evaluate the effects of ABCB1 and SXR SNPs on cyclosporine exposure in a group of kidney transplant patients followed up from childhood to adulthood. PATIENTS & METHODS: Recipients were genotyped for ABCB1 C1236T, G2677T/A and C3435T, and for SXR RS3842689 and A7635G. Dose-adjusted trough levels and weight-adjusted daily doses were compared among patients according to allelic status by a generalized estimation equation approach that allows longitudinal data analyses. RESULTS: A genotype-dependent effect was found in all ABCB1 genotypes and in one of the SXR SNPs. This effect was particularly evident for the TT genotype of the ABCB1 G2677T/A SNP, the TT genotype of the ABCB1 C3435T SNP and for heterozygotes of the deletion of 6 bp in the promoter region of SXR. CONCLUSION: The presence of specific ABCB1 and SXR SNPs could significantly affect cyclosporine exposure during a kidney transplant patient's development from childhood to adulthood in a time-dependent fashion.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Polimorfismo de Nucleótido Simple/genética , Receptores de Esteroides/genética , Subfamilia B de Transportador de Casetes de Unión a ATP , Adolescente , Adulto , Alelos , Niño , Femenino , Genotipo , Humanos , Trasplante de Riñón/métodos , Masculino , Receptor X de Pregnano , Regiones Promotoras Genéticas/genética , Estudios Retrospectivos , Adulto JovenRESUMEN
Focal segmental glomerulosclerosis (FSGS) is the most frequent acquired renal condition resulting in end stage kidney disease in children. We describe a cell therapy treatment with human allogeneic bone marrow mesenchymal stem cells (MSC) in a 13-year-old patient developing recurrent FSGS after renal transplantation, which was not responding to conventional therapy. This treatment relied on the following measurements:clinical and laboratory evaluation of renal function, proteome array, biopsy, short tandem repeat assay. Before MSC treatment, the patient needed weekly plasmapheresis to achieve proteinuria-to-creatininuria ratio below 5. After three MSC infusions without adverse events, the patient has a stable renal function and the proteinuria target was reached without plasmapheresis. In addition, some circulating inflammatory factors decreased and their levels were still low after one year. This is the first report of an MSC treatment in an FSGS patient. Even though different factors may have contributed to the clinical results, after MSC infusion a stable reduction in the serum level of several inflammatory factors has been registered and the patient does not need anymore plasmapheresis to keep proteinuria under control. In addition, this encouraging single case let us identify some putative efficacy biomarkers that could be of clinical interest in chronic kidney diseases.
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Glomeruloesclerosis Focal y Segmentaria/cirugía , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/citología , Adolescente , Supervivencia Celular , Células Cultivadas , Citometría de Flujo , Glomeruloesclerosis Focal y Segmentaria/etiología , Glomeruloesclerosis Focal y Segmentaria/fisiopatología , Humanos , Inmunofenotipificación , Trasplante de Riñón/efectos adversos , Masculino , Células Madre Mesenquimatosas/metabolismo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
In children with idiopathic nephrotic syndrome, rituximab can maintain short-term remission with withdrawal of prednisone and calcineurin inhibitors. Long-term effects including the number of repeated infusions to maintain remission are unknown. To test this, we treated 46 consecutive children with idiopathic nephrotic syndrome lasting for at least 1 year (mean 6.3 years), maintained in remission with oral prednisone and calcineurin inhibitors. They received 1-5 rituximab courses during a median follow-up of 3 years. Oral agents were tapered after each infusion, and completely withdrawn within 45 days. Rituximab was well tolerated. Six-month probabilities of remission were 48% after the first infusion and 37% after subsequent infusions. One- and 2-year-remission probabilities were, respectively, 20 and 10%. Median time intervals between complete oral-agent withdrawal and relapse were 5.6 and 8.5 months, respectively, following the first and subsequent courses. The time to reconstitution of CD20 cells correlated with the duration of remission, but was not associated with variation in FcyR, CD20, or SMPDL-3B polymorphisms. Podocyte Src phosphorylation was normal. Thus, rituximab can be safely and repeatedly used as a prednisone and calcineurin inhibitor-sparing therapy in a considerable proportion of children with dependent forms of idiopathic nephrotic syndrome. Further study is needed to identify patients who will benefit most from rituximab therapy.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Inhibidores de la Calcineurina , Glucocorticoides/uso terapéutico , Inmunosupresores/uso terapéutico , Riñón/efectos de los fármacos , Síndrome Nefrótico/tratamiento farmacológico , Prednisona/uso terapéutico , Administración Oral , Adolescente , Factores de Edad , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Antígenos CD20/genética , Antígenos CD20/metabolismo , Calcineurina/metabolismo , Niño , Preescolar , Esquema de Medicación , Femenino , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Riñón/inmunología , Riñón/metabolismo , Masculino , Síndrome Nefrótico/diagnóstico , Síndrome Nefrótico/genética , Síndrome Nefrótico/inmunología , Fosforilación , Podocitos/efectos de los fármacos , Podocitos/inmunología , Podocitos/metabolismo , Polimorfismo Genético , Prednisona/administración & dosificación , Prednisona/efectos adversos , Estudios Prospectivos , Receptores de IgG/genética , Recurrencia , Inducción de Remisión , Factores de Riesgo , Rituximab , Esfingomielina Fosfodiesterasa/genética , Factores de Tiempo , Resultado del Tratamiento , Familia-src Quinasas/metabolismoRESUMEN
The polyomavirus (PyV), JC virus (JCV), is a small nonenveloped DNA virus that asymptomatically infects about 80% of healthy adults and establishes latency in the kidney tissue. In case of immunodeficient hosts, JCV can lytically infect the oligodendrocytes, causing a fatal demyelinating disease, known as progressive multifocal leukoencephalopathy (PML). Although the reactivation of another human PyV, BK virus (BKV), is relatively common and its association with the polyomavirus associated nephropathy (PyVAN) following renal transplantation is proven, JCV replication and its impact on graft function and survival are less well studied. Here we describe the biology of JCV and its pathological features and we review the literature regarding the JCV infection analyzed in the setting of transplantations.
Asunto(s)
Rechazo de Injerto/virología , Virus JC/fisiología , Trasplante de Riñón , Leucoencefalopatía Multifocal Progresiva/virología , Infecciones por Polyomavirus/inmunología , Complicaciones Posoperatorias/virología , Infecciones Tumorales por Virus/inmunología , Animales , Enfermedades Asintomáticas , Rechazo de Injerto/etiología , Humanos , Huésped Inmunocomprometido , Riñón/patología , Riñón/virología , Leucoencefalopatía Multifocal Progresiva/etiología , Infecciones por Polyomavirus/complicaciones , Inmunología del Trasplante , Infecciones Tumorales por Virus/complicaciones , Latencia del VirusRESUMEN
The steroids and xenobiotics receptor (SXR) up-regulates the expression and the synthesis of key enzymes in CyA metabolism. In this study, we examined the possible interactions between CyA exposure and SXR polymorphisms during the first year after renal transplantation. The study involved 66 pediatric renal transplant recipients (25 women and 41 men, mean age 13.9 ± 7.4 yr). All patients were genotyped for two sequence variations in the NR1I2 gene: g.-205_-200delGAGAAG and 7635 A>G. CyA trough levels and CyA weight-adjusted daily dose were recorded at 30, 90, 180, and 360 days after transplantation and compared between the different genotypes. A third newly discovered SXR polymorphism was characterized and also included in the study. CyA trough levels and CyA weight-adjusted daily dose were comparable on four time points throughout the first year post-transplant in all three groups. GEE showed a significant reduction in weight-adjusted CyA daily dose in patients carrying the deletion of 6 bp in SXR with a significant group-by-time effect that persisted also when analysis was corrected for age, prednisone dose, and acute rejection episodes. In our group of patients, only the g.-205_-200delGAGAAG SXR polymorphism was able to influence the metabolism of CyA continuously, during the first year after transplantation.