RESUMEN
Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. To examine this question, we studied genome-wide microarray results from 5086 kidney transplant biopsies (4170 patients). An updated archetypal analysis designated 56% of biopsies as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower eGFR, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR respectively diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems.
RESUMEN
Donor-derived cell-free DNA (dd-cfDNA) is an emerging noninvasive biomarker that has the potential to detect allograft injury. The capacity of dd-cfDNA to detect kidney allograft rejection and its added clinical value beyond standard of care patient monitoring is unclear. We enrolled 2,882 kidney allograft recipients from 14 transplantation centers in Europe and the United States in an observational population-based study. The primary analysis included 1,134 patients. Donor-derived cell-free DNA levels strongly correlated with allograft rejection, including antibody-mediated rejection (P < 0.0001), T cell-mediated rejection (P < 0.0001) and mixed rejection (P < 0.0001). In multivariable analysis, circulating dd-cfDNA was significantly associated with allograft rejection (odds ratio 2.275; 95% confidence interval (CI) 1.902-2.739; P < 0.0001) independently of standard of care patient monitoring parameters. The inclusion of dd-cfDNA to a standard of care prediction model showed improved discrimination (area under the curve 0.777 (95% CI 0.741-0.811) to 0.821 (95% CI 0.784-0.852); P = 0.0011) and calibration. These results were confirmed in the external validation cohorts (n = 1,748) including a cohort of African American patients (n = 439). Finally, dd-cfDNA showed high predictive value to detect subclinical rejection in stable patients. Our study provides insights on the potential value of assessing dd-cfDNA, in addition to standard of care monitoring, to improve the detection of allograft rejection. ClinicalTrials.gov registration: NCT05995379 .
Asunto(s)
Ácidos Nucleicos Libres de Células , Rechazo de Injerto , Trasplante de Riñón , Humanos , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/inmunología , Rechazo de Injerto/genética , Trasplante de Riñón/efectos adversos , Ácidos Nucleicos Libres de Células/sangre , Ácidos Nucleicos Libres de Células/genética , Masculino , Femenino , Persona de Mediana Edad , Adulto , Aloinjertos/inmunología , Biomarcadores/sangre , Donantes de Tejidos , Trasplante Homólogo , AncianoRESUMEN
BACKGROUND: Standard-of-care biomarkers for renal allograft rejection are lagging indicators, signaling existing organ injury. This precludes early intervention, when immunological cascades leading to rejection are most susceptible. Donor-derived cell-free DNA (dd-cfDNA) shows promise as an early indicator of rejection, allowing earlier and possibly more effective treatment. This analysis was designed to assess this promise using real-world dd-cfDNA testing evidence. METHODS: This retrospective analysis of the prospective, observational ProActive registry study (NCT04091984) assessed dd-cfDNA and serum creatinine levels before biopsy in 424 patients with ≥1 dd-cfDNA test (nâ =â 1013) in the 6 mo before biopsy. RESULTS: Of 4667 enrolled patients, 1631 patients had ≥18 mo of follow-up data, of which 424 had a biopsy and were included in this analysis. Twenty-six biopsies showed antibody-mediated rejection (ABMR), 62 showed T cell-mediated rejection, and 336 showed nonrejection; each from a unique patient. dd-cfDNA fractions were significantly elevated 5 mo before ABMR biopsies, and 2 mo before T cell-mediated rejection biopsies, compared with nonrejection biopsies. In contrast, serum creatinine did not discriminate between rejection and nonrejection in advance, or concurrent with biopsy. Among patients with nonrejection biopsies, estimated glomerular filtration rate was significantly lower in cases with ≥2 increased dd-cfDNA results (≥1%), compared with those with 0 or 1 increased dd-cfDNA result. CONCLUSIONS: These data indicate that dd-cfDNA is an early indicator of biopsy-proven rejection, especially ABMR, suggesting a greater role for dd-cfDNA in surveillance to identify patients at high risk of ongoing or future rejection, thus requiring closer monitoring, biopsy, or other management changes.
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Biomarcadores , Ácidos Nucleicos Libres de Células , Rechazo de Injerto , Trasplante de Riñón , Donantes de Tejidos , Humanos , Trasplante de Riñón/efectos adversos , Rechazo de Injerto/inmunología , Rechazo de Injerto/sangre , Rechazo de Injerto/diagnóstico , Ácidos Nucleicos Libres de Células/sangre , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Biopsia , Biomarcadores/sangre , Adulto , Riñón/patología , Riñón/inmunología , Sistema de Registros , Creatinina/sangre , Anciano , Factores de Tiempo , Valor Predictivo de las Pruebas , Estudios ProspectivosRESUMEN
INTRODUCTION: Living donor kidney evaluation has substantial time variations with significant intercenter variation. One-day donor evaluation has shown to be clinically efficient and improve transplant rates. However, patients' perception of 1-day evaluation is unknown. We hypothesized that 1 day LKD evaluation will improve patient satisfaction and improve living donation rates. METHODS: All interested LD candidates from April 2018 to May 2020 were enrolled in the study. Non-directed donors, donors greater than 60 years old, and recipients with more than three donors underwent multi-day evaluation (control group) while the rest underwent 1-day evaluation (intervention group). An anonymous survey was filled by both groups to assess their perceptions on different areas including time, communication, experience, information provided, and their preferences on living donor evaluation. RESULTS: Donor candidates in the 1-day evaluation group selected that the time from the questionnaire to clinic evaluation took "under 1 month" or "less than 3 months" (62.5% vs. 15.8%, p = .002), with "excellent" for both scheduling process (65% vs. 31.6%, p = .03) and communication (82.5% vs. 57.9%, p = .09) when compared to candidates in the multiple-days evaluation group. One-day candidates felt "very satisfied" with the overall experience (95% vs. 68.4%, p = .02) and felt "extremely well" with the information provided regarding the living donor process (87.5% vs. 47.4%, p = .003) when compared to multiple-day evaluation group. Regardless of the group, 53 (89.8%) patients preferred 1-day evaluation. CONCLUSION: We demonstrate 1-day living donor evaluation is efficient, patient preferred, and adds value through improved communication, and better overall patient satisfaction.
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Trasplante de Riñón , Humanos , Persona de Mediana Edad , Donadores Vivos , Riñón , Encuestas y Cuestionarios , Satisfacción del PacienteRESUMEN
The use of routine monitoring of donor-derived cell-free DNA (dd-cfDNA) after kidney transplant may allow clinicians to identify subclinical allograft injury and intervene prior to development of clinically evident graft injury. To evaluate this, data from 1092 kidney transplant recipients monitored for dd-cfDNA over a three-year period was analyzed to assess the association of dd-cfDNA with histologic evidence of allograft rejection. Elevation of dd-cfDNA (0.5% or more) was significantly correlated with clinical and subclinical allograft rejection. dd-cfDNA values of 0.5% or more were associated with a nearly three-fold increase in risk development of de novo donor-specific antibodies (hazard ratio 2.71) and were determined to be elevated a median of 91 days (interquartile range of 30-125 days) ahead of donor specific antibody identification. Persistently elevated dd-cfDNA (more than one result above the 0.5% threshold) predicted over a 25% decline in the estimated glomerular filtration rate over three years (hazard ratio 1.97). Therefore, routine monitoring of dd-cfDNA allowed early identification of clinically important graft injury. Biomarker monitoring complemented histology and traditional laboratory surveillance strategies as a prognostic marker and risk-stratification tool post-transplant. Thus, persistently low dd-cfDNA levels may accurately identify allograft quiescence or absence of injury, paving the way for personalization of immunosuppression trials.
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Ácidos Nucleicos Libres de Células , Aloinjertos , Anticuerpos , Ácidos Nucleicos Libres de Células/genética , Rechazo de Injerto/patología , Humanos , Riñón , Donantes de TejidosRESUMEN
BACKGROUND: The longitudinal time-course of dd-cfDNA after kidney transplant (KTx) is not well-described. The cut off values of dd-cfDNA in KTx derive from biopsy-coupled single measurements. Meaningful interpretation necessitates understanding of: (1) time variance of dd-cfDNA levels post-KTx, (2) factors determining biologic variability, and (3) relationship to donor and recipient characteristics. We hypothesized that an understanding of the aforementioned factors would better inform clinical decision-making using dd-cfDNA. METHODS: One hundred and twenty five KTx patients with dd-cfDNA obtained longitudinally were included. Univariate analyses were directed at inter-patient variability and intra-patient inter-occasion variability of dd-cfDNA. Multivariate linear regression was used in analyses accounting for repeat measures. RESULTS: At 1-month post KTx median dd-cfDNA: (1) were higher in repeat KTx (.57%, P < .001), and dual KTx (1.10%, P = ns) versus a first KTx (.31%); (2) showed a significant difference in donor after cardiac death (DCD [.45%]) versus living related (LRD [.27%]) donors (P = .036). Longitudinal (1-3 months) dd-cfDNA measurements showed a significant downtrend for all donor types. Panel-reactive antibodies (PRA) were positively correlated with dd-cfDNA. CONCLUSIONS: Repeat Tx, dual Tx, DCD, and PRA are associated with a higher dd-cfDNA. Incorporation of donor/recipient variables and time down post transplant is material for rational interpretation of dd-cfDNA.
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Ácidos Nucleicos Libres de Células , Trasplante de Riñón , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/etiología , Humanos , Donantes de TejidosRESUMEN
BACKGROUND AND OBJECTIVES: Hypervolemia is a major cause of morbidity, in part because of the lack of well characterized diagnostic tests. The hypothesis was that relative plasma volume (RPV) slopes are influenced by ultrafiltration rate, directly associate with improvement in arterial oxygen saturation, and are reproducible. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: RPV slopes were measured on three consecutive hemodialysis sessions. Various relationships were tested using mixed models. Reproducibility was assessed by the intraclass correlation coefficient. RESULTS: RPV slopes averaged 1.37 ± 1.45% per hour. The mean RPV slopes were steeper on the first dialysis of the week, which correlated with a higher ultrafiltration rate; RPV slope and ultrafiltration rate were directly related. Increasing ultrafiltration rate quartiles were associated with similar change in RPV in the first 1 hour of dialysis but steeper changes in RPV subsequently. A direct relationship emerged between increasing RPV slopes and increasing arterial oxygen saturation slopes. The intraclass correlation coefficient for the relative plasma volume slope was 0.77. CONCLUSIONS: Although ultrafiltration rate is a major determinant of RPV slope, similar ultrafiltration rates are associated with varying RPV between individuals. Because RPV is associated with little change by ultrafiltration rate during the first 1 hour of dialysis, probing dry weight during the earlier part of dialysis may be safer. RPV slopes are physiologically meaningful, because they are associated with parallel changes in arterial oxygenation saturation slopes. RPV slopes are reproducible, and therefore, RPV may serve as a useful marker to judge changes in volume status within an individual.
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Hemodiafiltración , Fallo Renal Crónico/terapia , Oxígeno/sangre , Volumen Plasmático , Adulto , Femenino , Humanos , Hipovolemia/diagnóstico , Fallo Renal Crónico/fisiopatología , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Factores de TiempoRESUMEN
BACKGROUND: Current guidelines recommend the use of full therapeutic dosages of antihypertensive agents, or combination therapy, to improve BP control of hypertensive patients in primary healthcare. OBJECTIVE: The aim of this study was to assess the dose-dependent antihypertensive efficacy and safety of perindopril 4 and 8 mg/day in the clinical setting. STUDY DESIGN AND SETTING: The CONFIDENCE study was a prospective, observational, multicenter trial. This was a real-world, clinic-based, outpatient study involving 880 general practitioners/primary-care clinics and 113 specialists in Canada. PATIENTS: The study included untreated or inadequately managed patients with hypertension (i.e. seated BP ≥ 140/90 mmHg, or ≥ 130/80 mmHg in the presence of diabetes mellitus, renal disease, or proteinuria) without coronary artery disease (CAD). INTERVENTION: Treatment consisted of perindopril 4 mg/day, uptitrated to 8 mg/day as required for BP control at visit 2, for 12 weeks. Among the patients already being treated at baseline, perindopril either directly replaced all previous ACE inhibitors or angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), or was added to antihypertensive treatment with calcium channel blockers (CCBs), diuretics, or ß-adrenoceptor antagonists (ß-blockers). MAIN OUTCOMES MEASURES: The primary outcomes were the mean changes in BP from baseline following treatment with perindopril 4 and 8 mg/day as well as the proportion of patients achieving BP control (BP <140/90 mmHg, or <130/80 mmHg in diabetic patients) in the intent-to-treat (ITT) population. Secondary analyses included the incidence of adverse events and compliance. RESULTS: A total of 8298 hypertensive patients entered the study: 56% with newly diagnosed hypertension and 44% with uncontrolled hypertension. Mean SBP/DBP decreased significantly from baseline (152.5 ± 10.8/89.5 ± 9 mmHg) over 12 weeks (-18.5/-9.7 mmHg; p < 0.001). At visit 2, 23% of patients were uptitrated to perindopril 8 mg/day, which resulted in an additional mean 10.1/5.3 mmHg BP reduction; this reduction was even greater (15.1/5.7 mmHg) among a separate group of severely hypertensive patients (i.e. SBP >170 mmHg or DBP >109 mmHg at baseline). Target BP was achieved in 54% of the ITT population. Both perindopril 4 mg/day and perindopril 8 mg/day were well tolerated and compliance was high throughout the study. CONCLUSION: In the clinical outpatient setting, perindopril was found to be an effective dose-dependent and well tolerated antihypertensive treatment, with good compliance. Uptitration to the full therapeutic dosage of perindopril is an efficient approach for the management of a broad range of hypertensive patients without CAD.
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Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Perindopril/uso terapéutico , Adulto , Anciano , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Perindopril/efectos adversos , Estudios ProspectivosRESUMEN
Neurons in primary visual cortex (V1) are frequently classified based on their response linearity: the extent to which their visual responses to drifting gratings resemble a linear replica of the stimulus. This classification is supported by the finding that response linearity is bimodally distributed across neurons in area V1 of anesthetized animals. However, recent studies suggest that such bimodal distribution may not reflect two neuronal types but a nonlinear relationship between the membrane potential and the spike output. A main limitation of these previous studies is that they measured response linearity in anesthetized animals, where the distance between the neuronal membrane potential and the spike threshold is artificially increased by anesthesia. Here, we measured V1 response linearity in the awake brain and its correlation with the neuronal spontaneous firing rate, which is related to the distance between membrane potential and threshold. Our results demonstrate that response linearity is bimodally distributed in awake V1 but that it is poorly correlated with spontaneous firing rate. In contrast, the spontaneous firing rate is best correlated to the response selectivity and response latency to stimuli.
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Potenciales de Acción/fisiología , Modelos Neurológicos , Corteza Visual/fisiología , Percepción Visual/fisiología , Vigilia/fisiología , Animales , Sensibilidad de Contraste/fisiología , Electrofisiología , Macaca mulatta , Neuronas/fisiología , Distribución Normal , Orientación/fisiología , Estimulación Luminosa , Tiempo de Reacción/fisiología , Corteza Visual/citologíaRESUMEN
BACKGROUND AND OBJECTIVES: Hypertension, one of the major treatable cardiovascular (CV) risk factors, usually occurs in association with other major risk factors. As well as providing rapid blood pressure (BP) goal attainment, antihypertensive therapy should also provide reductions in CV events and mortality in a wide range of patients. For this, higher dosages and combinations of antihypertensive agents are often required. ACE inhibitors are recommended as first-line agents for control of hypertension in patients with additional CV risk factors. The PEACH (Perindopril's Effect At Controlling Hypertension) study was a community-based study performed to evaluate the effectiveness and safety of high-dose perindopril in patients with mild-to-moderate hypertension and additional risk factors for CV disease. METHODS: This was an open-label, multicentre observational study conducted in Canadian general practice clinics. The study assessed the efficacy and tolerability of perindopril given once daily for 10 weeks uptitrated to the maximal recommended dose of perindopril as required for BP control in newly diagnosed or previously treated patients with uncontrolled mild to moderate hypertension and >or=1 additional risk factor. Patients not achieving target BP after 2 weeks of therapy were uptitrated from perindopril 4 mg to perindopril 8 mg once daily. Efficacy endpoints included reduction in systolic (SBP) and diastolic (DBP) BP and BP control. Tolerability assessments included adverse effects and physicians' assessment of tolerability. The number of missed doses was also recorded. RESULTS: Overall, 2220 patients with hypertension and >or=1 other risk factor were prescribed perindopril at 291 centres; 51.9% were male, 78.3% Caucasian, 12.8% Asian, 36.2%>or=65 years of age and 34.5% had uncontrolled BP despite previous antihypertensive treatment. Compared with previously treated patients, treatment-naive patients had fewer risk factors, and a higher proportion were Asian (p<0.05 for all comparisons). Most patients (76%) had 1-2 risk factors. Perindopril produced significant SBP/DBP reductions at 2 and 10 weeks (-15.8/-8.0 and -21.1/-11.0 mmHg, respectively). Overall, at week 10, BP control rate was 53.6%, better than at week 2 in the overall cohort and in all subgroups. Uptitration to high-dose perindopril to achieve BP control was required in 46% of patients with one additional risk factor compared with 64% of patients with >or=4 additional risk factors. These results demonstrate that the more risk factors the patient has, the greater the need for high-dose perindopril to achieve BP control. Perindopril was well tolerated as indicated by the high proportion of physicians (95.9%) reporting 'good' to 'excellent' tolerability at week 10. CONCLUSION: In this community-based clinical practice trial, up to 10 weeks' perindopril therapy, uptitrated to the maximal recommended dose as required for BP control, significantly reduced SBP/DBP in patients with mild-to-moderate hypertension and additional CV risk factors. Patients with more risk factors were more likely to require high-dose perindopril.