RESUMEN
Antibody-mediated rejection (AMR) is a major cause of graft failure limiting long-term graft survival after kidney transplantation. Current diagnostic strategy to detect AMR is suboptimal and requires further improvement. Previously suggested treatment regimens for AMR could not demonstrate efficacy, however novel therapeutic agents are currently under investigation. Donor-derived cell-free DNA (dd-cfDNA) is a novel non-invasive biomarker for allograft injury, that has been mainly studied in the context of rejection. Its short-half-life in circulation and injury-dependent release are its key advantages that contribute to its superior diagnostic accuracy, compared to traditional biomarkers. Moreover, previous studies showed that dd-cfDNA-release is well-linked to histological and molecular features of AMR, and thus able to reflect real-time injury. Further observations suggest that dd-cfDNA can be used as a suitable screening tool for early detection of AMR in patients with donor-specific-anti-HLA-antibodies (DSA), as well as for monitoring AMR activity after anti-rejection treatment. The weight of evidence suggests that the integration of dd-cfDNA in the graft surveillance of patients with AMR, or those suspicious of AMR (e.g., due to the presence of donor-specific anti-HLA-antibodies) has an added value and might have a positive impact on outcomes in this specific cohort.
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Biomarcadores , Ácidos Nucleicos Libres de Células , Rechazo de Injerto , Trasplante de Riñón , Donantes de Tejidos , Trasplante de Riñón/efectos adversos , Humanos , Rechazo de Injerto/inmunología , Rechazo de Injerto/diagnóstico , Ácidos Nucleicos Libres de Células/sangre , Biomarcadores/sangre , Antígenos HLA/inmunología , Isoanticuerpos/inmunología , Isoanticuerpos/sangre , Supervivencia de Injerto/inmunologíaRESUMEN
Antibody-mediated rejection (AMR) is among the most frequent causes for graft loss after kidney transplantation. While there are no approved therapies, several case reports with daratumumab and the very recent phase 2 trial of felzartamab in AMR have indicated the potential efficacy of therapeutic interventions targeting CD38. Donor-derived cell-free DNA (dd-cfDNA) is an emerging biomarker with injury-specific release and a short half-life, which could facilitate early diagnosis of AMR and monitoring of treatment response. We describe two cases of patients with chronic active AMR, who were treated with monthly daratumumab infusions, and in whom donor-derived cell-free DNA (dd-cfDNA) was measured longitudinally to monitor treatment response. In both patients, daratumumab treatment led to stabilization of kidney function parameters, a strong decline of dd-cfDNA below the previously established threshold for rejection, and partial or complete histologic resolution of AMR activity. Our case series suggests that dd-cfDNA may be a useful companion biomarker for longitudinal monitoring of anti-CD38 treatment in patients with AMR.
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Anticuerpos Monoclonales , Biomarcadores , Ácidos Nucleicos Libres de Células , Rechazo de Injerto , Trasplante de Riñón , Humanos , Ácidos Nucleicos Libres de Células/sangre , Anticuerpos Monoclonales/uso terapéutico , Rechazo de Injerto/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Biomarcadores/sangre , Femenino , Donantes de Tejidos , Adulto , ADP-Ribosil Ciclasa 1RESUMEN
BACKGROUND: The long-term outcomes of solid organ transplantation remain suboptimal. Therefore, appropriate biomarkers are needed in addition to immunosuppressive drugs and other traditional approaches for graft monitoring to achieve personalized immunosuppression and reduce premature graft loss. METHODS: Donor-derived cell-free DNA (dd-cfDNA) is a minimally invasive biomarker of cell death due to graft injury. It can be quantified using droplet digital polymerase chain reaction and next-generation sequencing. Fractional dd-cfDNA determination can be affected by changes in recipient cfDNA, such as those caused by leukopenia or infection, leading to false-positive or false-negative results, respectively. Absolute quantification of dd-cfDNA helps in overcoming this limitation. RESULTS: Overall, there is sufficient evidence of the clinical validity of dd-cfDNA. It detects rejection episodes early at an actionable stage and reflects the severity of graft injury without being rejection-specific. Owing to its high negative predictive value, dd-cfDNA is very useful for ruling out graft injury. Dd-cfDNA complements histological findings and can help in avoiding unnecessary biopsies. It indicates a response to rejection treatment and detects underimmunosuppression. CONCLUSIONS: Monitoring changes in dd-cfDNA over time may be helpful in adapting immunosuppression to prevent graft rejection. Moreover, serial dd-cfDNA determination may increase the effectiveness of transplant recipient surveillance and facilitate personalized immunosuppression when combined with other relevant clinical and diagnostic findings.
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Ácidos Nucleicos Libres de Células , Trasplante de Riñón , Trasplante de Órganos , Humanos , Biomarcadores , Terapia de Inmunosupresión , Donantes de Tejidos , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/prevención & controlRESUMEN
Personalized immunosuppression (IS) promises to improve the balance of necessary control of alloreactivity and dose-dependent adverse effects of long-term IS such as kidney insufficiency, infections, and malignancies. The majority of liver transplantation (LT) recipients exhibit graft injuries (graft inflammation and/or fibrosis) that are not eligible for an IS reduction according to current Banff criteria, even when liver enzymes are normal or only marginally elevated. This cross-sectional study evaluated the noninvasive prediction of such subclinical graft injuries in surveillance liver biopsies via donor-derived cell-free DNA (dd-cfDNA). Absolute and fractional dd-cfDNA increased stepwise from patients without histological signs of rejection (n = 26) over subclinical graft injury (n = 61), including subclinical T cell-mediated rejection to clinical overt T cell-mediated rejection (n = 21). Thus, fractional plasma dd-cfDNA was significantly elevated paired to surveillance biopsies with relevant subclinical graft injury according to 2016 Banff criteria compared with those with minimal or absent histological graft injury. In contrast, the presence of donor-specific anti-human leukocyte antigen antibodies was not associated with the amount of dd-cfDNA. The sensitivity and specificity of fractional dd-cfDNA to noninvasively predict relevant subclinical graft injury was rather limited with 73% and 52% at the cutoff value of 2.1% fractional dd-cfDNA. The positive predictive value of fractional dd-cfDNA above 2.1% was 76% to noninvasively predict subclinical graft injury, calculated on the prevalence of graft injury in our prospective surveillance biopsy program, whereas the negative predictive values was not predictive (47%). In conclusion, dd-cfDNA has a rather limited diagnostic fidelity in addition to other noninvasive markers for the assessment of subclinical graft injury in personalized IS approaches after LT in a cross-sectional setting.
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Ácidos Nucleicos Libres de Células , Trasplante de Hígado , Humanos , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/epidemiología , Rechazo de Injerto/genética , Trasplante de Hígado/efectos adversos , Estudios Transversales , Estudios Prospectivos , Donantes de TejidosRESUMEN
ABSTRACT: When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.
Asunto(s)
Monitoreo de Drogas , Inmunosupresores/administración & dosificación , Ácido Micofenólico/administración & dosificación , Trasplante de Órganos , Área Bajo la Curva , Consenso , Rechazo de Injerto/prevención & control , HumanosRESUMEN
BACKGROUND: Donor-derived cell-free DNA (dd-cfDNA) is reportedly a valuable tool for graft surveillance following kidney transplantation (KTx). Possible changes in dd-cfDNA(%) reference values over time have not been evaluated. For long-term monitoring after KTx, changes in host cfDNA might represent a biasing factor in dd-cfDNA(%) determinations. METHODS: Plasma samples were obtained (n = 929) 12-60 months after engraftment in a cross-sectional cohort of 303 clinically stable KTx recipients. Total cfDNA(copies/mL), dd-cfDNA(%), and dd-cfDNA(copies/mL) were determined using droplet-digital PCR. Stability of threshold values in these stable KTx recipients over time was assessed by 80th, 85th, and 90th quantile regression. RESULTS: Upper percentiles of total cfDNA showed a significant decline of -1902, -3589, and -4753 cp/mL/log(month) (P = 0.014, <0.001, and 0.017, respectively), resulting in increasing dd-cfDNA(%) percentiles by 0.25, 0.46, and 0.72%/log(month) (P = 0.04, 0.001, and 0.002, respectively), with doubling of the 85th percentile value by 5 years. In contrast, dd-cfDNA(cp/mL) was stable during the observation period (P = 0.52, 0.29, and 0.39). In parallel increasing white blood cell counts and decreasing tacrolimus concentrations over time were observed. After 5 years, the median total cfDNA was still 1.6-fold (P < 0.001) higher in KTx recipients than in healthy controls (n = 135) and 1.4-fold (P < 0.001) higher than patients with other medical conditions (n = 364). CONCLUSIONS: The time-dependent decrease of host cfDNA resulted in an apparent increase of dd-cfDNA fraction in stable KTx patients. For long-term surveillance, measurement of absolute dd-cfDNA concentrations appears to be superior to percentages to minimize false positive results.
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Ácidos Nucleicos Libres de Células/metabolismo , Trasplante de Riñón/estadística & datos numéricos , Ácidos Nucleicos Libres de Células/sangre , Estudios de Cohortes , Estudios Transversales , Humanos , Estudios Prospectivos , Factores de TiempoRESUMEN
Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive biomarker for comprehensive monitoring of allograft injury and rejection in kidney transplantation (KTx). dd-cfDNA quantification of copies/mL plasma (dd-cfDNA[cp/mL]) was compared to dd-cfDNA fraction (dd-cfDNA[%]) at prespecified visits in 189 patients over 1 year post KTx. In patients (N = 15, n = 22 samples) with biopsy-proven rejection (BPR), median dd-cfDNA(cp/mL) was 3.3-fold and median dd-cfDNA(%) 2.0-fold higher (82 cp/mL; 0.57%, respectively) than medians in Stable Phase patients (N = 83, n = 408) without rejection (25 cp/mL; 0.29%). Results for acute tubular necrosis (ATN) were not significantly different from those with biopsy-proven rejection (BPR). dd-cfDNA identified unnecessary biopsies triggered by a rise in plasma creatinine. Receiver operating characteristic (ROC) analysis showed superior performance (P = .02) of measuring dd-cfDNA(cp/mL) (AUC = 0.83) compared to dd-cfDNA(%) (area under the curve [AUC] = 0.73). Diagnostic odds ratios were 7.31 for dd-cfDNA(cp/mL), and 6.02 for dd-cfDNA(%) at thresholds of 52 cp/mL and 0.43%, respectively. Plasma creatinine showed a low correlation (r = 0.37) with dd-cfDNA(cp/mL). In a patient subset (N = 24) there was a significantly higher rate of patients with elevated dd-cfDNA(cp/mL) with lower tacrolimus levels (<8 µg/L) compared to the group with higher tacrolimus concentrations (P = .0036) suggesting that dd-cfDNA may detect inadequate immunosuppression resulting in subclinical graft damage. Absolute dd-cfDNA(cp/mL) allowed for better discrimination than dd-cfDNA(%) of KTx patients with BPR and is useful to avoid unnecessary biopsies.
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Biomarcadores/análisis , Ácidos Nucleicos Libres de Células/genética , Rechazo de Injerto/diagnóstico , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Donantes de Tejidos/provisión & distribución , Ácidos Nucleicos Libres de Células/análisis , Femenino , Estudios de Seguimiento , Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Supervivencia de Injerto , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Curva ROC , Factores de RiesgoRESUMEN
Genomic analyses in oncologic care allow for the development of more precise clinical laboratory tests that will be critical for personalized pharmacotherapy. Traditional biopsy-based approaches are limited by the availability of sequential tissue specimens to detect resistance. Blood-based genomic profiling ("liquid biopsy") is useful for longitudinal monitoring of tumor genomes and can complement biopsies. Tumor-associated mutations can be identified in cell-free tumor DNA (ctDNA) from patient blood samples and used for monitoring disease activity. The US Food and Drug Administration approved a liquid biopsy test for EGFR-activating mutations in patients with non-small-cell lung cancer as a companion diagnostic for therapy selection. ctDNA also allows for the identification of mutations selected by treatment such as EGFR T790M in non-small-cell lung cancer. ctDNA can also detect mutations such as KRAS G12V in colorectal cancer and BRAF V600E/V600K in melanoma. Chromosomal aberration pattern analysis by low-coverage whole genome sequencing is a new, broader approach. Genomic imbalances detected in cell-free DNA (cfDNA) can be used to compute a copy number instability (CNI) score. In clinical studies, it was demonstrated that the change in CNI score can serve as an early predictor of therapeutic response to chemotherapy/immunotherapy of many cancer types. In multivariable models, it could be shown that the CNI score was superior to clinical parameters for prediction of overall survival in patients with head and neck cancer. There is emerging evidence for the clinical validity of ctDNA testing regarding identification of candidates for targeted therapies, prediction of therapeutic response, early detection of recurrence, resistance mutation detection, measuring genetic heterogeneity, tumor burden monitoring, and risk stratification. Improvement of sensitivity to detect tumors at very early stages is difficult due to insufficient mutant DNA fraction of ≤0.01%. Further developments will include validation in prospective multicenter interventional outcome studies and the development of digital platforms to integrate diagnostic data.
Asunto(s)
Ácidos Nucleicos Libres de Células/sangre , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Medicina de Precisión/métodos , Pronóstico , HumanosRESUMEN
BACKGROUND: Clinicians face many challenges in disease stratification and outcome prediction in head and neck squamous cancer cell (HNSCC) patients. Given the limitations of currently used clinical scoring, repetitive biopsies, and imaging techniques, liquid biopsy approaches may provide valuable additional diagnostic and prognostic information. METHODS: A noninterventional, single-center observational study was performed with clinical data and plasma samples from HNSCC patients. Cell-free tumor DNA-derived copy number aberrations (CNAs) were determined in 116 patients by low-coverage next-generation sequencing (NGS). Significant CNAs were combined in a genome-wide copy number instability score (CNI), which was evaluated with respect to conventional clinical staging and patient outcome. RESULTS: Receiver-operating characteristic (ROC) curve analysis comparing the presurgery CNI in patients (n = 103) with that in tumor-free controls (n = 142) yielded an area under the ROC curve of 87.2% (95% CI, 79.4%-93.3%). At a specificity of 95%, the sensitivity to detect tumors varied between 46% (pT1) and 94% (pT4). A CNI above the median (i.e., >72) had a positive predictive value of 90% (95% CI, 79%-96%) for lymph node involvement (LNI), while the negative predictive value was 57% (95% CI, 43%-70%). For a CNI >72, overall survival (OS) was worse (hazard ratio, 4.89; 95% CI, 1.39-17.17; P = 0.01) with 62% and 90% survivors 3 years after surgery for a CNI >72 and ≤72, respectively. In multivariable models, the CNI was a superior predictor of OS compared to established disease features, including LNI. CONCLUSIONS: The CNI may assist in predicting LNI and prognosis in HNSCC with direct therapeutic implications concerning the need for neck dissection or more aggressive treatment.
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Carcinoma de Células Escamosas/patología , Ácidos Nucleicos Libres de Células/aislamiento & purificación , Neoplasias de Cabeza y Cuello/patología , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/terapia , Estudios de Casos y Controles , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/terapia , Humanos , Biopsia Líquida , Estadificación de Neoplasias , Pronóstico , Curva ROC , Resultado del TratamientoRESUMEN
High-quality genomic analysis is critical for personalized pharmacotherapy in patients with cancer. Tumor-specific genomic alterations can be identified in cell-free DNA (cfDNA) from patient blood samples and can complement biopsies for real-time molecular monitoring of treatment, detection of recurrence, and tracking resistance. cfDNA can be especially useful when tumor tissue is unavailable or insufficient for testing. For blood-based genomic profiling, next-generation sequencing (NGS) and droplet digital PCR (ddPCR) have been successfully applied. The US Food and Drug Administration (FDA) recently approved the first such "liquid biopsy" test for EGFR mutations in patients with non-small cell lung cancer (NSCLC). Such non-invasive methods allow for the identification of specific resistance mutations selected by treatment, such as EGFR T790M, in patients with NSCLC treated with gefitinib. Chromosomal aberration pattern analysis by low coverage whole genome sequencing is a more universal approach based on genomic instability. Gains and losses of chromosomal regions have been detected in plasma tumor-specific cfDNA as copy number aberrations and can be used to compute a genomic copy number instability (CNI) score of cfDNA. A specific CNI index obtained by massive parallel sequencing discriminated those patients with prostate cancer from both healthy controls and men with benign prostatic disease. Furthermore, androgen receptor gene aberrations in cfDNA were associated with therapeutic resistance in metastatic castration resistant prostate cancer. Change in CNI score has been shown to serve as an early predictor of response to standard chemotherapy for various other cancer types (e.g. NSCLC, colorectal cancer, pancreatic ductal adenocarcinomas). CNI scores have also been shown to predict therapeutic responses to immunotherapy. Serial genomic profiling can detect resistance mutations up to 16 weeks before radiographic progression. There is a potential for cost savings when ineffective use of expensive new anticancer drugs is avoided or halted. Challenges for routine implementation of liquid biopsy tests include the necessity of specialized personnel, instrumentation, and software, as well as further development of quality management (e.g. external quality control). Validation of blood-based tumor genomic profiling in additional multicenter outcome studies is necessary; however, cfDNA monitoring can provide clinically important actionable information for precision oncology approaches.
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Biomarcadores de Tumor/sangre , ADN/sangre , Genómica/métodos , Medicina de Precisión/métodos , Neoplasias de la Próstata , Biomarcadores de Tumor/genética , ADN/química , Inestabilidad Genómica , Humanos , Masculino , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/terapiaRESUMEN
BACKGROUND: Graft-derived cell-free DNA (GcfDNA), which is released into the blood stream by necrotic and apoptotic cells, is a promising noninvasive organ integrity biomarker. In liver transplantation (LTx), neither conventional liver function tests (LTFs) nor immunosuppressive drug monitoring are very effective for rejection monitoring. We therefore hypothesized that the quantitative measurement of donor-derived cell-free DNA (cfDNA) would have independent value for the assessment of graft integrity, including damage from acute rejection. METHODS AND FINDINGS: Traditional LFTs were performed and plasma GcfDNA was monitored in 115 adults post-LTx at three German transplant centers as part of a prospective, observational, multicenter cohort trial. GcfDNA percentage (graft cfDNA/total cfDNA) was measured using droplet digital PCR (ddPCR), based on a limited number of predefined single nucleotide polymorphisms, enabling same-day turn-around. The same method was used to quantify blood microchimerism. GcfDNA was increased >50% on day 1 post-LTx, presumably from ischemia/reperfusion damage, but rapidly declined in patients without graft injury within 7 to 10 d to a median <10%, where it remained for the 1-y observation period. Of 115 patients, 107 provided samples that met preestablished criteria. In 31 samples taken from 17 patients during biopsy-proven acute rejection episodes, the percentage of GcfDNA was elevated substantially (median 29.6%, 95% CI 23.6%-41.0%) compared with that in 282 samples from 88 patients during stable periods (median 3.3%, 95% CI 2.9%-3.7%; p < 0.001). Only slightly higher values (median 5.9%, 95% CI 4.4%-10.3%) were found in 68 samples from 17 hepatitis C virus (HCV)-positive, rejection-free patients. LFTs had low overall correlations (r = 0.28-0.62) with GcfDNA and showed greater overlap between patient subgroups, especially between acute rejection and HCV+ patients. Multivariable logistic regression modeling demonstrated that GcfDNA provided additional LFT-independent information on graft integrity. Diagnostic sensitivity and specificity were 90.3% (95% CI 74.2%-98.0%) and 92.9% (95% CI 89.3%-95.6%), respectively, for GcfDNA at a threshold value of 10%. The area under the receiver operator characteristic curve was higher for GcfDNA (97.1%, 95% CI 93.4%-100%) than for same-day conventional LFTs (AST: 95.7%; ALT: 95.2%; γ-GT: 94.5%; bilirubin: 82.6%). An evaluation of microchimerism revealed that the maximum donor DNA in circulating white blood cells was only 0.068%. GcfDNA percentage can be influenced by major changes in host cfDNA (e.g., due to leukopenia or leukocytosis). One limitation of our study is that exact time-matched GcfDNA and LFT samples were not available for all patient visits. CONCLUSIONS: In this study, determination of GcfDNA in plasma by ddPCR allowed for earlier and more sensitive discrimination of acute rejection in LTx patients as compared with conventional LFTs. Potential blood microchimerism was quantitatively low and had no significant influence on GcfDNA value. Further research, which should ideally include protocol biopsies, will be needed to establish the practical value of GcfDNA measurements in the management of LTx patients.
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ADN/sangre , Rechazo de Injerto/sangre , Trasplante de Hígado , Adulto , Anciano , Área Bajo la Curva , Biomarcadores/sangre , Quimerismo , Femenino , Alemania , Rechazo de Injerto/diagnóstico , Hepacivirus , Humanos , Leucocitos/metabolismo , Pruebas de Función Hepática , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Curva ROCRESUMEN
BACKGROUND: The pharmacokinetics of tacrolimus (TAC) and mycophenolic acid (MPA) are highly variable. An impact of single-nucleotide polymorphisms (SNPs) of the genes coding for enzymes and transporters involved in the pharmacokinetics of TAC and/or MPA is intuitively conceivable. Accordingly, we sought to analyze the influence of different SNPs on TAC and MPA exposure in pediatric renal transplant recipients. METHODS: A subpopulation of 37 patients (median age: 12.8 years, range 2.2-18.3 years) participating in the TWIST study was included in the analysis of SNPs of CYP3A5, ABCB1 (MDR1), ABCG2, SLCO1B3 (coding for OATP2), ABCC2 (coding for cMOAT), and UGT1/2. TAC trough concentrations and abbreviated area under the concentration-time curves (AUC) of MPA were measured on days 7, 28, 91, and 183 after transplant. Both of these were adjusted to the respective dose the patient received. RESULTS: The allele frequencies of analyzed SNP's were comparable to those reported previously for white populations. Dose-adjusted trough concentrations of TAC were approximately 60% lower in patients with the CYP3A5*1/*3 allele as compared with the CYP3A5*3/*3 allele (P = 0.004). Steroid-free patients in CYP3A5*3/*3 and CYP3A5*1/*3 carrier subgroups had comparable dose-adjusted TAC concentrations to the subgroup on steroids (P = 0.13). Patients younger than 10 years had a significantly lower median dose-adjusted TAC C0 concentration than patients older than 10 years; this age effect was comparable in heterozygous and homozygous CYP3A5 carriers as well as in patients on and off steroid medication. As for MPA, the genetic variability of transporters or enzymes had no impact on dose-adjusted MPA-AUC due to the low allele frequencies. Patients off steroids had a higher dose-adjusted MPA-AUC (0.18 mg·h/L per mg/m, 0.012-0.27) compared with patients on steroids (0.12 mg·h·L·mg, 0.09-0.19; P = 0.04). CONCLUSIONS: Genetic variability of CYP3A5 has an impact on TAC metabolism in pediatric renal transplant recipients, contributing partly to the variability of TAC exposure. Therefore, adjusting initial TAC dosing to the genotype of CYP3A5 might be of clinical benefit.
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Citocromo P-450 CYP3A/genética , Inmunosupresores/administración & dosificación , Trasplante de Riñón/métodos , Ácido Micofenólico/administración & dosificación , Tacrolimus/administración & dosificación , Adolescente , Alelos , Área Bajo la Curva , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Inmunosupresores/farmacocinética , Masculino , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Ácido Micofenólico/farmacocinética , Farmacogenética , Polimorfismo de Nucleótido Simple , Tacrolimus/farmacocinética , Factores de TiempoRESUMEN
Although short-term success after solid organ transplantation is good, long-term graft and recipient survival are both not satisfactory. Despite therapeutic drug monitoring (TDM) of immunosuppressive drugs (ISDs), both excessive and insufficient immunosuppression still do occur. There is a need for new biomarkers that, when combined with TDM, can be used to provide more effective and less toxic, personalized immunosuppression to improve long-term survival. Currently used methods are insufficient to rapidly, cost-effectively, and directly interrogate graft integrity after solid organ transplantation. However, because organ transplants are also genome transplants, measurement of graft-derived circulating cell-free DNA (GcfDNA) has shown promise as a way to improve both graft and recipient outcomes after solid organ transplantation through the early detection of severe graft injury, enabling an early intervention. A newly developed droplet digital polymerase chain reaction (ddPCR) method has advantages over expensive high-throughput sequencing methods to rapidly quantify GcfDNA percentages and absolute amounts. This procedure does not require donor DNA and therefore can be applied to any organ donor/recipient pair. The droplet digital polymerase chain reaction method allows for the early, sensitive, specific, and cost-effective direct assessment of graft integrity and can be used to define individual responses to ISDs including the minimal ISD exposures necessary to prevent rejection. This is especially important in patients undergoing ISD switches due to ISD toxicity, infections, or malignancies. Although prospective, multicenter clinical trials in liver, heart, and kidney transplantation have not been completed, early results suggest that GcfDNA can be combined with TDM to guide changes in immunosuppression to provide more effective, and less toxic treatment. Personalized immunosuppression will shift emphasis in transplantation from reaction to prevention and could improve outcome at lower health care costs.
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Biomarcadores/sangre , ADN/sangre , Rechazo de Injerto/sangre , Rechazo de Injerto/genética , Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto , Humanos , Inmunosupresores/uso terapéuticoRESUMEN
BACKGROUND: Considerable interest exists in identifying calcineurin inhibitor (CNI)-free and thus, less-toxic immunosuppressive regimens, with mycophenolic acid (MPA)-based treatments being a suitable approach. Because pharmacokinetic analyses of MPA treatments in stable CNI-free renal transplant recipients are lacking, the authors aimed at comparing the steady-state pharmacokinetic characteristics of MPA in patients on stable treatment with mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS) plus prednisone (≤5 mg/d). METHODS: In the prospective, nonrandomized, open-label study, patients with stable transplant function since ≥6 months received their routine single dose of either MMF (n = 12) or EC-MPS (n = 11). The MPA plasma concentration was recorded over 12 hours. Parameters assessed were predose MPA concentration (C0), postdose minimum and maximum concentration (Cmin and Cmax), time to maximum concentration (Tmax), and area under the concentration-time curve (AUC) for the 12-hours of exposure (AUC0-12). RESULTS: Baseline characteristics were comparable between both the groups. Consistent with enteric coating, the mean Tmax was significantly longer after the intake of EC-MPS compared with MMF (2.2 versus 0.8 hours; P = 0.0002). The exposure measures Cmin, Cmax, and AUC0-12 were not significantly different despite the higher mean MPA equivalent dose in patients receiving MMF compared with those receiving EC-MPS (85% versus 64% of the recommended single dose, respectively). Exposures as reflected by the median AUC0-12 values were 50.7 and 58.7 mg·h·L with MMF and EC-MPS, respectively (P = 0.340). All patients achieved a target AUC of >30 mg·h·L, and 61% had an AUC of >50 mg·h·L. CONCLUSIONS: The study provides first results on the steady-state pharmacokinetics of the 2 MPA drugs in CNI-free immunosuppressant regimens. Pharmacokinetic parameters measured in this study under real-life conditions were comparable in patients receiving MMF or EC-MPS.
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Inmunosupresores/administración & dosificación , Trasplante de Riñón/métodos , Ácido Micofenólico/administración & dosificación , Adulto , Anciano , Área Bajo la Curva , Femenino , Humanos , Inmunosupresores/farmacocinética , Masculino , Persona de Mediana Edad , Ácido Micofenólico/farmacocinética , Estudios Prospectivos , Comprimidos Recubiertos , Receptores de TrasplantesRESUMEN
Monitoring immunosuppressive drugs (ISDs) in blood or plasma is still a key therapeutic drug monitoring (TDM) application in clinical settings. Narrow target ranges and severe side effects at drug underexposure or overexposure make accurate and precise measurements a must. This overview prepared by the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology is intended to serve as a summary and guidance document describing the current state-of-the-art in the TDM of ISDs.
Asunto(s)
Monitoreo de Drogas , Inmunosupresores/sangre , Inmunosupresores/farmacocinética , HumanosRESUMEN
With current treatment regimens, a relatively high proportion of transplant recipients experience underimmunosuppression or overimmunosuppression. Recently, several promising biomarkers have been identified for determining patient alloreactivity, which help in assessing the risk of rejection and personal response to the drug; others correlate with graft dysfunction and clinical outcome, offering a realistic opportunity for personalized immunosuppression. This consensus document aims to help tailor immunosuppression to the needs of the individual patient. It examines current knowledge on biomarkers associated with patient risk stratification and immunosuppression requirements that have been generally accepted as promising. It is based on a comprehensive review of the literature and the expert opinion of the Biomarker Working Group of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. The quality of evidence was systematically weighted, and the strength of recommendations was rated according to the GRADE system. Three types of biomarkers are discussed: (1) those associated with the risk of rejection (alloreactivity/tolerance), (2) those reflecting individual response to immunosuppressants, and (3) those associated with graft dysfunction. Analytical aspects of biomarker measurement and novel pharmacokinetic-pharmacodynamic models accessible to the transplant community are also addressed. Conventional pharmacokinetic biomarkers may be used in combination with those discussed in this article to achieve better outcomes and improve long-term graft survival. Our group of experts has made recommendations for the most appropriate analysis of a proposed panel of preliminary biomarkers, most of which are currently under clinical evaluation in ongoing multicentre clinical trials. A section of Next Steps was also included, in which the Expert Committee is committed to sharing this knowledge with the Transplant Community in the form of triennial updates.
Asunto(s)
Biomarcadores/metabolismo , Monitoreo de Drogas , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/metabolismo , Inmunosupresores/uso terapéutico , Consenso , Humanos , Receptores de Trasplantes , TrasplanteRESUMEN
In 2014, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology called a meeting of international experts to provide recommendations to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice. EVR is a potent inhibitor of the mammalian target of rapamycin, approved for the prevention of organ transplant rejection and for the treatment of various types of cancer and tuberous sclerosis complex. EVR fulfills the prerequisites for TDM, having a narrow therapeutic range, high interindividual pharmacokinetic variability, and established drug exposure-response relationships. EVR trough concentrations (C0) demonstrate a good relationship with overall exposure, providing a simple and reliable index for TDM. Whole-blood samples should be used for measurement of EVR C0, and sampling times should be standardized to occur within 1 hour before the next dose, which should be taken at the same time everyday and preferably without food. In transplantation settings, EVR should be generally targeted to a C0 of 3-8 ng/mL when used in combination with other immunosuppressive drugs (calcineurin inhibitors and glucocorticoids); in calcineurin inhibitor-free regimens, the EVR target C0 range should be 6-10 ng/mL. Further studies are required to determine the clinical utility of TDM in nontransplantation settings. The choice of analytical method and differences between methods should be carefully considered when determining EVR concentrations, and when comparing and interpreting clinical trial outcomes. At present, a fully validated liquid chromatography tandem mass spectrometry assay is the preferred method for determination of EVR C0, with a lower limit of quantification close to 1 ng/mL. Use of certified commercially available whole-blood calibrators to avoid calibration bias and participation in external proficiency-testing programs to allow continuous cross-validation and proof of analytical quality are highly recommended. Development of alternative assays to facilitate on-site measurement of EVR C0 is encouraged.