RESUMO
BACKGROUND: Pharmacokinetic monitoring is insufficient to estimate the intensity of immunosuppression after transplantation. Virus-specific T cells correlate with both virus-specific and general cellular immune defense. Additional steering of immunosuppressive therapy by virus-specific T cell levels might optimize dosing of immunosuppressants. METHODS: In a multicenter, randomized, controlled trial, we randomized 64 pediatric kidney recipients to a control group with trough-level monitoring of immunosuppressants or to an intervention group with additional steering of immunosuppressive therapy by levels of virus-specific T cells (quantified by cytokine flow cytometry). Both groups received immunosuppression with cyclosporin A and everolimus in the same target range of trough levels. Primary end point was eGFR 2 years after transplantation. RESULTS: In the primary analysis, we detected no difference in eGFR for the intervention and control groups 2 years after transplantation, although baseline eGFR 1 month after transplantation was lower in the intervention group versus the control group. Compared with controls, patients in the intervention group received significantly lower daily doses of everolimus and nonsignificantly lower doses of cyclosporin A, resulting in significantly lower trough levels of everolimus (3.5 versus 4.5 µg/L, P<0.001) and cyclosporin A (47.4 versus 64.1 µg/L, P<0.001). Only 20% of patients in the intervention group versus 47% in the control group received glucocorticoids 2 years after transplantation (P=0.04). The groups had similar numbers of donor-specific antibodies and serious adverse events. CONCLUSIONS: Steering immunosuppressive therapy by virus-specific T cell levels in addition to pharmacokinetic monitoring seems safe, results in a similar eGFR, and personalizes immunosuppressive therapy by lowering exposure to immunosuppressive drugs, likely resulting in lower drug costs. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: IVIST trial, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2009-012436-32 and ISRCTN89806912.
Assuntos
Ciclosporina/administração & dosagem , Everolimo/administração & dosagem , Rejeição de Enxerto/prevenção & controle , Imunossupressores/administração & dosagem , Falência Renal Crônica/cirurgia , Transplante de Rim , Adolescente , Contagem de Linfócito CD4 , Criança , Pré-Escolar , Esquema de Medicação , Monitoramento de Medicamentos , Feminino , Rejeição de Enxerto/sangue , Rejeição de Enxerto/diagnóstico , Humanos , Lactente , Falência Renal Crônica/sangue , Falência Renal Crônica/etiologia , MasculinoRESUMO
After pediatric kidney transplantation, immunosuppressive therapy causes an increased risk of severe viral complications, especially from cytomegalovirus (CMV), BK polyomavirus (BKPyV) or Epstein-Barr virus (EBV), and less frequent from adenovirus (ADV). However, suitable predictive markers for the individual outcome of viral infections are missing and the therapeutic management remains a challenge to the success of pediatric kidney transplantation. Virus-specific T cells are known for controlling viral replication and there is growing evidence that virus-specific T cells may serve as a prognostic marker to identify patients at risk for viral complications. This review provides an overview of the usability of virus-specific T cells for improving diagnostic and therapeutic management of viral infections with reference to the necessity of antiviral prophylaxis, timing of pre-emptive therapy, and dosing of immunosuppressive medication after pediatric kidney transplantation. Several studies demonstrated that high levels of virus-specific T cells are associated with decrease of virus load and favorable outcome, whereas lack of virus-specific T cells coincided with virus-induced complications. Accordingly, the additional monitoring of virus-specific T cells aims to personalize the management of antiviral therapy, identify overimmunosuppression, and avoid unnecessary therapeutic interventions. Prospective randomized trials in pediatric kidney recipients comparing standard antiviral and immunosuppressive regimens with T cell-guided therapeutic interventions are needed, before monitoring of virus-specific T cells is implemented in the routine care of pediatric kidney graft recipients.
Assuntos
Vírus BK , Infecções por Vírus Epstein-Barr , Transplante de Rim , Infecções por Polyomavirus , Antivirais/uso terapêutico , Criança , Herpesvirus Humano 4 , Humanos , Transplante de Rim/efeitos adversos , Estudos Prospectivos , Linfócitos TRESUMO
BACKGROUND: After kidney transplantation, immunosuppressive therapy increases risk of BK polyomavirus-associated nephropathy (BKPyVAN). Outcomes of BKPyV viremia are various and prognostic markers are missing. The impact of different immunosuppressive regimens on BKPyV infections is currently under discussion. METHODS: We analyzed immunosuppressive therapy and BKPyV-specific cellular immunity to distinguish patients at risk of BKPyVAN from those with self-limiting viremia for purposes of risk-stratified BKPyV management. In a retrospective analysis, 46 pediatric kidney recipients with BKPyV viremia were analyzed with regard to duration of BKPyV viremia and immunosuppressive therapy; in addition, in 37/46 patients, BKPyV-specific CD4 and CD8 T cells were measured. RESULTS: Nine patients showed persistent BKPyV viremia and BKPyVAN, and required therapeutic intervention, while 37 patients had asymptomatic, self-limiting viremia. At onset of viremia, 78% of patients with persistent viremia and BKPyVAN were treated with tacrolimus, whereas tacrolimus therapy was significantly less frequent in patients with self-limiting viremia (14%). The majority of patients with transient, self-limiting viremia received cyclosporine A (81%) and/or mTOR inhibitors (81%). Patients with persistent BKPyV viremia and BKPyVAN showed lack of BKPyV-specific CD4 and CD8 T cells (6/6), whereas the majority of patients with self-limiting viremia (27/31) had detectable BKPyV-specific CD4 and/or CD8 T cells ≥ 0.5 cells/µl (p < 0.001). CONCLUSIONS: These results indicate that tacrolimus enhances risk of BKPyVAN with need of therapeutic intervention, whereas under cyclosporine A and mTOR inhibitors, the majority of pediatric kidney recipients showed self-limiting viremia. In patients at risk of BKPyV infections, combination of cyclosporine A and mTOR inhibitor may be advantageous.
Assuntos
Terapia de Imunossupressão/métodos , Transplante de Rim/efeitos adversos , Infecções por Polyomavirus/diagnóstico , Adolescente , Vírus BK/isolamento & purificação , Criança , Pré-Escolar , Ciclosporina/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Terapia de Imunossupressão/efeitos adversos , Imunossupressores/uso terapêutico , Lactente , Estudos Longitudinais , Masculino , Infecções por Polyomavirus/etiologia , Estudos Retrospectivos , Tacrolimo/uso terapêutico , Transplantados , Viremia/diagnóstico , Viremia/etiologiaRESUMO
After pediatric kidney transplantation BK polyomavirus (BKPyV) infections are associated with an increased risk of graft loss by BKPyV-associated nephropathy (BkPyVAN). However, suitable prognostic markers for the individual outcome of BKPyV infections are missing and the management of therapeutic interventions remains a challenge to the success of pediatric kidney transplantation. This review gives an overview on current diagnostic and therapeutic strategies in the field of BKPyV infections after pediatric kidney transplantation. Methods determining the individual immune response to BKPyV are described and their usability is discussed. There is growing evidence that BKPyV-specific T cells (BKPyV-Tvis) may serve as prognostic markers in order to steer immunosuppressive therapy in pediatric kidney recipients with BKPyV viremia in future. Prospective randomized trials in viremic kidney recipients comparing Tvis-steered therapeutic intervention with standard reduction of immunosuppression are needed before implementation of BKPyV-Tvis monitoring in routine care of BKPyV infections.
Assuntos
Vírus BK/imunologia , Rejeição de Enxerto/diagnóstico , Transplante de Rim/efeitos adversos , Infecções por Polyomavirus/diagnóstico , Linfócitos T/imunologia , Infecções Tumorais por Vírus/diagnóstico , Aloenxertos/imunologia , Aloenxertos/virologia , Antivirais/uso terapêutico , Vírus BK/isolamento & purificação , Criança , DNA Viral/isolamento & purificação , Fluoroquinolonas/uso terapêutico , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/virologia , Humanos , Terapia de Imunossupressão/efeitos adversos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Rim/imunologia , Rim/virologia , Infecções por Polyomavirus/imunologia , Infecções por Polyomavirus/terapia , Infecções por Polyomavirus/virologia , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Serina-Treonina Quinases TOR/antagonistas & inibidores , Resultado do Tratamento , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/terapia , Infecções Tumorais por Vírus/virologia , Replicação Viral/imunologiaRESUMO
BACKGROUND: Infantile oxalosis, the most devastating form of primary hyperoxaluria type 1 (PH1), often leads to end-stage renal disease (ESRD) during the first weeks to months of life. CASE-DIAGNOSIS: Here, we report the outcome of the therapeutic use of Oxalobacter formigenes (Oxabact OC5; OxThera AB, Stockholm, Sweden) in a female infant with PH1 who exhibited severely elevated plasma oxalate (Pox) levels, pronounced nephrocalcinosis, anuretic end-stage renal disease, and retinal oxalate deposits. Following the diagnosis of PH1 at an age of 8 weeks, a combined regimen of daily peritoneal dialysis, daily pyridoxine treatment and hemodialysis (3 times a week) was unable to reduce the pronounced hyperoxalemia. After the addition of Oxalobacter formigenes therapy to the otherwise unchanged treatment regimen, Pox levels first stabilized and subsequently declined from 130 µmol/L to around 80 µmol/L. Nephrocalcinosis and retinal deposits stabilized. Oxalobacter formigenes treatment was well-tolerated and no related adverse events were observed. The patient showed nearly age-appropriate growth and development and received successful combined liver-kidney transplantation at the age of two years. CONCLUSIONS: Treatment with O. formigenes combined with intensive dialysis led to reduction of Pox, stabilization of systemic oxalosis, and improvement in the clinical disease course. O. formigenes treatment may be an option for reduction of oxalosis in infantile patients with insufficient response to conservative treatments until combined liver-kidney transplantation can be performed.
Assuntos
Hiperoxalúria/terapia , Oxalobacter formigenes/metabolismo , Diálise Renal/métodos , Insuficiência Renal Crônica/complicações , Oxalato de Cálcio/sangue , Progressão da Doença , Feminino , Humanos , Hiperoxalúria/etiologia , Lactente , Transplante de Rim , Transplante de Fígado , Insuficiência Renal Crônica/diagnósticoRESUMO
BACKGROUND/AIMS: Whether the immunosuppressive regimen is associated with micro- and macro-vascular status in pediatric kidney transplant recipients (KTx) is unknown. METHODS: We performed a cross-sectional, case-control study in 44 pediatric KTx patients on either everolimus (EVR) plus calcineurin inhibitor or standard treatment, i.e. mycophenolate mofetil plus calcineurin inhibitor. Measurement of carotid intima-media thickness (cIMT) via ultrasound, central pulse wave velocity (PWV) by a cuff-based oscillometric technique, and skin microvascular blood flow during local heating via laser-Doppler-fluximetry (LDF) served as marker of subclinical vascular disease. Serum concentrations of angiopoietin-1 and -2, fibroblast-growth factor 23 (FGF23) and soluble klotho were measured. RESULTS: EVR-treated patients exhibited a similar degree of hypertension, increased cIMT, elevated pro-inflammatory angiopoietin-2, and diminished endothelial survival factor angiopoietin-1 compared to healthy children but presented with a twofold more reduced skin micro-vascular function compared to standard treatment (each p< 0.001). By contrast, PWV and soluble klotho levels were normal in both groups. CONCLUSION: Endothelial dysfunction seems more frequent in KTx patients on EVR-based immunosuppressive regimen compared to standard immunosuppression.
Assuntos
Imunossupressores/farmacologia , Transplante de Rim/efeitos adversos , Microcirculação/efeitos dos fármacos , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos Transversais , Endotélio/fisiopatologia , Everolimo/farmacologia , Everolimo/uso terapêutico , Fator de Crescimento de Fibroblastos 23 , Humanos , Imunossupressores/uso terapêutico , Ácido Micofenólico/farmacologia , Ácido Micofenólico/uso terapêutico , Doenças Vasculares/diagnósticoRESUMO
The article "Rabbit anti-human thymocyte immunoglobulin for the rescue treatment of chronic antibody-mediated rejection after pediatric kidney transplantation", written by Yasemen Cihan, Nele Kanzelmeyer, Jens Drube, Martin Kreuzer, Christian Lerch, Imke Hennies, Kerstin Froede, Murielle Verboom.
RESUMO
BACKGROUND.: In 2011 Escherichia coli O104:H4 caused an outbreak with >800 cases of hemolytic uremic syndrome (HUS) in Germany, including 90 children. Data on the intermediate outcome in children after HUS due to E. coli O104:H4 have been lacking. METHODS.: Follow-up data were gathered retrospectively from the medical records of patients who had been included in the German Pediatric HUS Registry during the 2011 outbreak. RESULTS.: Seventy-two of the 89 (81%) patients were included after a median follow-up of 3.0 (0.9-4.7) years. Hypertension and proteinuria were present in 19% and 28% of these patients, respectively. Of 4 patients with chronic kidney disease (CKD) > stage 2 at short-term follow-up, 1 had a normalized estimated glomerular filtration rate, and 3 (4%) had persistent CKD > stage 2. In 1 of these patients, CKD improved from stage 4 to 3; 1 who had CKD stage 5 at presentation received kidney transplantation; and 1 patient required further hemodialysis during follow-up. One patient (1.4%) still had major neurological symptoms at the latest follow-up. Dialysis during the acute phase (P = .01), dialysis duration (P = .01), and the duration of oligo-/anuria (P = .005) were associated with the development of renal sequelae. Patients treated with eculizumab (n = 11) and/or plasmapheresis (n = 13) during the acute phase of HUS had comparable outcomes. CONCLUSIONS.: The overall outcome of pediatric patients after HUS due to E. coli O104:H4 was equivalent to previous reports on HUS due to other types of Shiga toxin-producing E. coli (STEC). Regular follow-up visits in patients are recommended after STEC-HUS.
Assuntos
Surtos de Doenças , Infecções por Escherichia coli/complicações , Infecções por Escherichia coli/microbiologia , Escherichia coli O104/isolamento & purificação , Síndrome Hemolítico-Urêmica/complicações , Síndrome Hemolítico-Urêmica/epidemiologia , Adolescente , Anticorpos Monoclonais Humanizados/uso terapêutico , Criança , Pré-Escolar , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/epidemiologia , Feminino , Seguimentos , Alemanha/epidemiologia , Taxa de Filtração Glomerular , Síndrome Hemolítico-Urêmica/microbiologia , Humanos , Hipertensão/epidemiologia , Hipertensão/etiologia , Transplante de Rim , Masculino , Prontuários Médicos , Prognóstico , Proteinúria/epidemiologia , Proteinúria/etiologia , Diálise Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , Estudos Retrospectivos , Adulto JovemRESUMO
Regardless of recipient age at kidney transplantation (KTx), patients are at greatest risk for graft loss in adolescence, partly due to nonadherence to an oral immunosuppressive regimen. Belatacept, a non-nephrotoxic, first-in-class immunosuppressant that inhibits costimulation of T cells requires intravenous application only every 4 weeks, potentially leading to better adherence. However, it is only approved for use in adults. We report here the findings of the first study of belatacept in adolescents, comprising all patients in our department switched to belatacept post-KTx. Six patients (median age 15.5 years) were switched after a median of 7.5 months (range 23 days to 12 years), treatment range 3-28 months (cumulative 83 months): Three patients switched early (<3 months after KTx) had increased estimated glomerular filtration rate (GFR); one patient switched 12 years post-KTx has stable GFR; two patients were switched following rapid decline of and with markedly impaired GFR, changing slope in one patient. One patient had one acute rejection. In addition of two patients who received belatacept for other conditions, the only relevant adverse event was neutropenia (after a cumulative 109 months). Belatacept as primary immunosuppression is an option in Epstein-Barr virus-seropositive nonadherent adolescents if administered sufficiently early before deterioration of graft function.
Assuntos
Abatacepte/administração & dosagem , Imunossupressores/administração & dosagem , Transplante de Rim , Adesão à Medicação , Adolescente , Feminino , Humanos , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Nephropathic cystinosis is a rare lysosomal storage disease which is characterized by the accumulation of free cystine in lysosomes and subsequent intracellular crystal formation of cystine throughout the body. If not treated with cysteamine, a cystine-depleting agent, end-stage renal disease will develop early, followed by multiple organ failure as the disease progresses. The established cysteamine formulation requires a strict dosing regimen at 6-h intervals. An extended release (ER) twice-daily formulation has recently been developed. The aim of our study was to evaluate the implementation and outcomes of this option in routine care. METHODS: All pediatric cystinosis patients' records in Hannover Medical School were screened, and data on cysteamine therapy, tolerability, dosing, estimated glomerular filtration rates (eGFR), white blood cell cystine levels, and proton pump inhibitor (PPI) use were extracted for the period January 2014 to January 2016. RESULTS: The median age of the 12 patients enrolled in the study was 12.5 (range 1-18) years. At the end of the study period ten of these patients received ER-cysteamine. There were no additional side effects. Halitosis/bad breath was often subjectively judged as improved or eliminated, and PPI use could be stopped in one of three patients. The main reasons for switching to the ER formulation were difficult night-time administration and uncontrolled disease. Mean eGFR values remained stable with a median of 67 ml/min/1.73 m2 before and after the transition. White blood cell (WBC) cystine values remained low after the switch (1 nmol/mg protein before and after transition; p = 0.64). CONCLUSIONS: In this single-center cohort, the switch from IR- to ER-cysteamine was safe and effective over the short term and provided advantages in terms of frequency of administration and less halitosis/bad breath. The long-term benefit of this option needs to be evaluated in future studies.
Assuntos
Cisteamina/administração & dosagem , Cisteamina/uso terapêutico , Cistinose/tratamento farmacológico , Fármacos Renais/administração & dosagem , Fármacos Renais/uso terapêutico , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Cisteamina/efeitos adversos , Cistina/sangue , Cistinose/etiologia , Preparações de Ação Retardada , Composição de Medicamentos , Feminino , Taxa de Filtração Glomerular , Humanos , Lactente , Leucócitos/metabolismo , Masculino , Fármacos Renais/efeitos adversos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Chronic antibody-mediated rejection (cAMR) is the leading cause of late kidney graft loss, but current therapies are often ineffective. Rabbit anti-human thymocyte immunoglobulin (rATG) may be helpful, but its use is virtually undocumented. METHODS: Data were analyzed retrospectively from nine pediatric kidney transplant patients with cAMR were treated with rATG (1.5 mg/kg × 5 days) at our center after non-response to pulsed prednisolone, intravenous immunoglobulin, rituximab, and increased immunosuppressive intensity (including switching to belatacept in some cases), with or without bortezomib. RESULTS: The median time from diagnosis to cAMR was 179 days. rATG was started 5-741 days after diagnosis. Median estimated glomerular filtration rate (eGFR) increased from 40 mL/min/1.73 m2 when rATG was started to 62 mL/min/1.73 m2 9 months later (p = 0.039). Four patients showed substantially higher eGFR after 9 months and 2 patients showed a small improvement; eGFR continued to decline in 3 patients after starting rATG. No grafts were lost during follow-up. At last follow-up, donor-specific antibodies (DSAs) were no longer detectable in 4 out of 8 patients for whom data were available, median fluorescence intensity had decreased substantially in 1 out of 8 patients; anti-HLA DQ DSAs persisted in 2 out of 8 patients. No adverse events with a suspected relation to rATG, including allergic reactions, leukocytopenia or infections, were observed in any of the patients. CONCLUSIONS: In this small series of patients, rATG appears a promising treatment for unresponsive cAMR. Further evaluation, including earlier introduction of rATG, is warranted.
Assuntos
Soro Antilinfocitário/uso terapêutico , Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Adolescente , Animais , Bortezomib/uso terapêutico , Pré-Escolar , Doença Crônica , Feminino , Taxa de Filtração Glomerular , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Rim/imunologia , Rim/patologia , Rim/cirurgia , Masculino , Prednisolona/uso terapêutico , Coelhos , Estudos Retrospectivos , Rituximab/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: In contrast to atypical haemolytic uraemic syndrome (aHUS), only single case reports and limited data have been published on systemic activation of the complement system and mutations in complement genes in paediatric enterohaemorrhagic Escherichia coli-induced HUS (EHEC-HUS). METHODS: Complement activation (CH50, APH50, C3d, sC5b-9) was analysed at four timepoints (Week 1, Week 2, Month 3 and Month 6 after primary diagnosis of HUS) in 25 children with EHEC-HUS. Seven patients received the complement C5 inhibitor eculizumab. Targeted next generation sequencing for a total of 89 genes involved in complement regulation and coagulation and haemostasis was performed in all patients. RESULTS: Activity of classical (CH50) and alternative (APH50) complement pathways was normal or even elevated throughout the observation time, except for patients under eculizumab treatment. In contrast, the mean concentration of the soluble terminal complement complex (sC5b-9) was significantly elevated at the first timepoint (mean 498 ng/mL), dropping to normal values after 2 weeks. Initially elevated (42 mU/L) median C3d concentration reached normal levels from Week 2. Levels of sC5b-9 >320 ng/mL at the time of HUS diagnosis were associated with arterial hypertension, oedema and lower platelet counts, but not with the duration of dialysis. Genetic analysis revealed various changes that may have had a modifying impact on the clinical course. CONCLUSIONS: Complement activation at the acute phase of EHEC-HUS, indicated by increased levels of sC5b-9, predicts a poor outcome. Complement alterations appear to be more frequent in patients with EHEC-HUS than previously thought and are suspected to have a role in the severity of the disease.
Assuntos
Ativação do Complemento , Proteínas do Sistema Complemento/genética , Escherichia coli Êntero-Hemorrágica/imunologia , Síndrome Hemolítico-Urêmica/imunologia , Adolescente , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores/sangue , Criança , Pré-Escolar , Inativadores do Complemento/uso terapêutico , Proteínas do Sistema Complemento/metabolismo , Feminino , Síndrome Hemolítico-Urêmica/sangue , Síndrome Hemolítico-Urêmica/tratamento farmacológico , Humanos , Masculino , Transcriptoma/imunologiaRESUMO
Background: Tacrolimus, a calcineurin inhibitor (CNI), is currently the first-line immunosuppressive agent in kidney transplantation. The therapeutic index of tacrolimus is narrow due to due to the substantial impact of minor variations in drug concentration or exposure on clinical outcomes (i.e., nephrotoxicity), and it has a highly variable intra- and inter-individual bioavailability. Non-adherence to immunosuppressants is associated with rejection after kidney transplantation, which is the main cause of long-term graft loss. Once-daily formulations have been shown to significantly improve adherence compared to twice-daily dosing. Envarsus®, the once-daily prolonged-release formulation of tacrolimus, offers the same therapeutic efficacy as the conventional twice-daily immediate-release tacrolimus formulation (Prograf®) with improved bioavailability, a more consistent pharmacokinetic profile, and a reduced peak to trough, which may reduce CNI-related toxicity. Envarsus® has been approved as an immunosuppressive therapy in adults following kidney or liver transplantation but has not yet been approved in children. The objective of this study is to evaluate the pharmacokinetic profile, efficacy, and tolerability of Envarsus® in children and adolescents aged ≥ 8 and ≤ 18 years to assess its potential role as an additional option for immunosuppressive therapy in children after kidney transplantation. Methods/design: The study is designed as a randomized, prospective crossover trial. Each patient undergoes two treatment sequences: sequence 1 includes 4 weeks of Envarsus® and sequence 2 includes 4 weeks of Prograf®. Patients are randomized to either group A (sequence 1, followed by sequence 2) or group B (sequence 2, followed by sequence 1). The primary objective is to assess equivalency between total exposure (of tacrolimus area under the curve concentration (AUC0-24)), immediate-release tacrolimus (Prograf®) therapy, and prolonged-release tacrolimus (Envarsus®) using a daily dose conversion factor of 0.7 for prolonged- versus immediate-release tacrolimus. Secondary objectives are the assessment of pharmacodynamics, pharmacogenetics, adherence, gut microbiome analyses, adverse events (including tacrolimus toxicity and biopsy-proven rejections), biopsy-proven rejections, difference in estimated glomerular filtration rate (eGFR), and occurrence of donor-specific antibodies (DSAs). Discussion: This study will test the hypothesis that once-daily prolonged-release tacrolimus (Envarsus®) is bioequivalent to twice-daily intermediate-release tacrolimus after pediatric kidney transplantation and may reduce toxicity and facilitate medication adherence. This novel concept may optimize immunosuppressive therapy for more stable graft function and increased graft survival by avoiding T-cell mediated and/or antibody-mediated rejection due to improved adherence. In addition, the study will provide data on the pharmacodynamics and pharmacogenetics of prolonged-release tacrolimus in children and adolescents. Clinical Trial Registration: EUDRA-CT 2019-003710-13 and ClinicalTrial.gov, identifier NCT06057545.
RESUMO
After pediatric kidney transplantation, immunosuppressive therapy is given to avoid acute and chronic rejections. However, the immunosuppression causes an increased risk of severe viral complications and bacterial infections and is associated with serious side effects. It is therefore crucial to achieve the optimal individual balance between over- and under-immunosuppression and thereby avoid unnecessary exposure to immunosuppressive drugs. In routine use, steering of immunosuppressants is performed primarily by monitoring of trough levels that mirror pharmacokinetics (although not, however, pharmacodynamics). Other diagnostic and prognostic markers to assess the individual intensity of immunosuppression are missing. Potential methods to determine immune function and grade of immunosuppression, such as analysis of the torque teno virus (TTV) load, QuantiFERON Monitor®, and ImmuKnow® as well as virus-specific T cells (Tvis), are currently being evaluated. In some studies TTV load, QuantiFERON Monitor® and ImmuKnow® were associated with the risk for post-transplant rejections and infections, but randomized controlled trials after pediatric kidney transplantation are not available. Post-transplant monitoring of Tvis levels seem to be promising because Tvis control virus replication and have been shown to correlate with virus-specific as well as general cellular immune defense, which represents the individual's susceptibility to infections. Additional Tvis-monitoring provides an innovative opportunity to personalize the antiviral management and the dosing of the immunosuppressive therapy after pediatric kidney transplantation to avoid unnecessary therapeutic interventions and identify over-immunosuppression.
RESUMO
BACKGROUND: After kidney transplantation, uncontrolled BK polyomavirus (BKPyV) replication causes kidney graft failure through BKPyV-associated nephropathy (BKPyVAN), but markers predicting outcome are missing. BKPyV-specific T cells may serve as a predictive marker to identify patients at risk of persistent DNAemia and BKPyVAN. METHODS: Out of a total of 114 pediatric kidney recipients transplanted between 2008 and 2018, 36 children with posttransplant BKPyV-DNAemia were identified. In a prospective noninterventional study, BKPyV-specific CD4 and CD8 T cells were measured in 32 of 36 viremic pediatric kidney recipients using intracellular cytokine staining and flow cytometry. The course of the BKPyV replication was monitored with regard to duration of BKPyV-DNAemia and need of therapeutic intervention and diagnosis of proven BKPyVAN. RESULTS: Levels of BKPyV-specific T cells negatively correlated with subsequent duration of BKPyV-DNAemia. Patients with BKPyV-specific CD4 T cells ≥0.5 cells/µL and/or BKPyV-specific CD8 T cells ≥0.1 cells/µL had transient, self-limiting DNAemia (PPV 1.0, NPV 0.86). BKPyV-specific CD4 and CD8 T cells below these thresholds were found in children with persistent BKPyV-DNAemia and biopsy-proven BKPyVAN with need for therapeutic intervention. After reducing immunosuppressive therapy, levels of BKPyV-specific CD4 T cells increased while plasma BKPyV-DNAemia declined. CONCLUSIONS: This study found that BKPyV-specific T cell levels may help to distinguish patients with transient, self-limiting BKPyV-DNAemia from those with persisting BKPyV-DNAemia and biopsy-proven BKPyVAN, who would benefit from individualized therapeutic interventions such as reduced immunosuppression. Thereby the risk for rejection because of unnecessary reduction of immunosuppression in case of self-limiting BKPyV-DNAemia can be minimized.
Assuntos
Vírus BK/imunologia , Transplante de Rim/efeitos adversos , Infecções Oportunistas/imunologia , Infecções por Polyomavirus/imunologia , Linfócitos T/imunologia , Infecções Tumorais por Vírus/imunologia , Adolescente , Fatores Etários , Vírus BK/crescimento & desenvolvimento , Separação Celular , Criança , Pré-Escolar , Progressão da Doença , Feminino , Citometria de Fluxo , Interações Hospedeiro-Patógeno , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Lactente , Recém-Nascido , Contagem de Linfócitos , Masculino , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/virologia , Infecções por Polyomavirus/diagnóstico , Infecções por Polyomavirus/virologia , Valor Preditivo dos Testes , Estudos Prospectivos , Linfócitos T/virologia , Fatores de Tempo , Resultado do Tratamento , Infecções Tumorais por Vírus/diagnóstico , Infecções Tumorais por Vírus/virologia , Replicação ViralRESUMO
Data on protocol biopsies (PBs) after pediatric kidney transplantation are rare.We evaluated 6-month post-transplantation renal function in 86 children after PB as observational study. Patients were divided into 3 groups:Glomerular filtration rate (GFR) and delta GFR were determined.PBs 6 months post-kidney transplantation did not influence the clinical course in stable pediatric patients and are therefore of questionable value. Decreased kidney function may however be stabilized by therapeutic intervention according to results of PB.
Assuntos
Biópsia/métodos , Transplante de Rim/efeitos adversos , Adolescente , Biópsia/estatística & dados numéricos , Criança , Pré-Escolar , Protocolos Clínicos , Feminino , Taxa de Filtração Glomerular/fisiologia , Rejeição de Enxerto/patologia , Humanos , Rim/patologia , Transplante de Rim/métodos , Masculino , Pediatria/métodos , Pediatria/estatística & dados numéricosRESUMO
Different patterns of plasma cytokines can be expected in the case of chronic active-antibody-mediated (cAMR) and acute cellular rejection (AR) after kidney transplantation (KTx). METHODS: IL-2, 4, 6, 10, 17A, tumor necrosis factor alpha, and interferon gamma were measured in 51 pediatric KTx recipients at time of renal biopsy (17 AR, 14 cAMR, 20 normal). Patients were divided into a training (n = 30) and a validation (n = 21) set. RESULTS: IL-6 was significantly higher in AR patients and significantly lower in the case of cAMR. In children with s-creatinine increase, IL-6 values were significantly different between AR and cAMR. IL-10 levels showed similar tendencies. For IL-2, 4, 17A, tumor necrosis factor alpha, and interferon gamma, no differences were found. In the independent validation cohort, the receiver operating characteristic area under the curve for IL-6 was 0.79 and 0.70 for AR and cAMR. In children with AR, an IL-6 <1141 fg/ml, and in those with cAMR, an IL-6 >721 fg/ml was associated with a specificity of 86%/76%, a sensitivity of 71%/80%, a positive predictive value of 56%/45%, and a negative predictive value of 92%/94%. CONCLUSIONS: In this pilot study, the plasma IL-6 level is a promising biomarker to identify pediatric kidney transplant recipients free from AR and cAMR and might help to distinguish between both entities, whereas there is only a nonsignificant trend toward the usability of IL-10. Validation in larger cohorts in combination with other biomarkers are warranted.
RESUMO
BACKGROUND: Data regarding the onset of puberty in children receiving mammalian target of rapamycin (mTOR) inhibitors are limited. METHODS: Kidney transplant patients aged <14 years were analyzed retrospectively to a maximum age of 18 years, with a minimal observation period of 1 year. Immunosuppression comprised (1) standard CNI-based regimen or (2) low-exposure mTOR inhibitor with reduced-exposure CNI, initiated either de novo or in the maintenance phase. RESULTS: Of 108 children analyzed, 67 received an mTOR inhibitor (56 everolimus, 11 sirolimus) and 41 did not. The age at which girls reached Tanner stage P2 was similar with mTOR inhibitor therapy (median 11.6 years) or without (median 11.1 years) (P = 0.262), as was age at stage B2 (median 11.6 vs. 11.2 years; P = 0.753). In boys, both the age of attaining Tanner stage P2 (median 12.9 vs. 13.0 years; P = 0.796) and Tanner stage G2 (median 13.1 vs. 12.9 years; P = 0.344) were also similar with or without an mTOR inhibitor. Age at menarche in girls, and age at spermarche in boys, did not differ between the 2 groups. CONCLUSIONS: In this retrospective analysis, sexual maturation ages and reproductive hormone levels were comparable in adolescent kidney transplant patients receiving low-exposure mTOR inhibitors and reduced CNI therapy or conventional CNI-based immunosuppression.
Assuntos
Terapia de Imunossupressão , Transplante de Rim , Puberdade/fisiologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adolescente , Androstenodiona/sangue , Criança , Pré-Escolar , Feminino , Taxa de Filtração Glomerular , Humanos , Lactente , Masculino , Estudos Retrospectivos , Testosterona/sangueRESUMO
In typical hemolytic uremic syndrome (HUS) approximately 25% of patients show central nervous system (CNS) involvement often leading to serious long-term disabilities. We used the C5-complement inhibitor Eculizumab as rescue therapy. From 2011 to 2014, 11 children (median age 22 months, range 11-175) with enterohemorrhagic Escherichia coli-positive HUS requiring dialysis who had seizures (11/11) and/or were in a stupor or coma (10/11) were treated with Eculizumab. Two patients enrolled on the Safety and Efficacy Study of Eculizumab in Shiga-Toxin Producing E coli Hemolytic-Uremic Syndrome (STEC-HUS) each received 6 doses of Eculizumab, 3 patients 2 doses, and 6 patients 1 dose. Laboratory diagnostics of blood samples and magnetic resonance imaging (MRI) were performed as per center practice. Data were analyzed retrospectively. Cranial MRI was abnormal in 8 of 10 patients with findings in the basal ganglia and/or white matter. A 2-year-old boy with severe cardiac involvement and status epilepticus needed repeated cardio-pulmonary resuscitation and extracorporeal membrane oxygenation. He died 8 days after start of Eculizumab treatment. Two patients with hemorrhagic colitis and repeated seizures required artificial ventilation for 6 and 16 days, respectively. At the time of discharge, 1 patient showed severe neurological impairment and 1 mild neurological impairment. The 8 surviving patients experienced no further seizures after the first dose of Eculizumab. Three patients showed mild neurological impairment at discharge, whilst the remaining 5 showed no impairment. The platelets normalized 4 days (median) after the first dose of Eculizumab (range 0-20 days). The mean duration of dialysis after the first dose of Eculizumab was 14.1 ± 6.1 days. In children with typical HUS and CNS involvement early use of Eculizumab appears to improve neurological outcome. In severe HUS cases which progress rapidly with multiple organ involvement, late treatment with Eculizumab seems to show less benefit. We speculate that prophylactic Eculizumab therapy before development of neurological symptoms could be advantageous.