RESUMEN
BACKGROUND: We studied longitudinal levels of angiotensin-II type 1 receptor antibody (AT1R-Ab) and their effects on adverse events (death, treated rejection and cardiac allograft vasculopathy) in patients who were bridged to heart transplant using a continuous flow left ventricular assist device (LVAD). METHODS AND RESULTS: Sera of 77 patients bridged to heart transplant (from 2009 to 2017) were tested for AT1R-Ab and CRP before and after LVAD. Elevated AT1R-Ab was defined as >10.0 U/mL. The median follow-up after transplant was 3.6 years (interquartile range, 2.2-5.6 years). After LVAD, AT1R-Ab levels increased from baseline and remained elevated until transplant. Freedom from adverse events at 5 years was lower in those with elevated AT1R-Ab levels at time of transplant. In an adjusted, multivariable Cox analysis, an AT1R-Ab level of >10 U/mL was associated with developing the primary end point (adjusted hazard ratio 3.4, 95% confidence interval 1.2-9.2, Pâ¯=â¯.017). Although C-reactive protein levels were high before and after LVAD placement, C-reactive protein did not correlate with AT1R-Ab. CONCLUSIONS: In LVAD patients bridged to heart transplant, an increased AT1R-Ab level at time of transplant was associated with poor outcomes after heart transplant. Post-LVAD AT1R-Ab elevations were not correlated with serum markers of systemic inflammation. Larger studies are needed to examine the pathologic role of AT1R-Ab in heart transplant.
Asunto(s)
Insuficiencia Cardíaca , Trasplante de Corazón , Corazón Auxiliar , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/terapia , Trasplante de Corazón/efectos adversos , Corazón Auxiliar/efectos adversos , Humanos , Morbilidad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
CONTEXT: Graft failure due to chronic rejection is greater among renal transplant patients with donor-specific antibody (DSA) than among DSA-free patients. For patients dependent on deceased donor transplantation, preoperative desensitization to eliminate DSAs may be impractical. We speculated that perioperative desensitization might eliminate preexisting DSAs and prevent de novo DSAs and improve graft outcomes. We report that brief perioperative desensitization using either intravenous immunoglobulin (IVIG) or plasmapheresis/IVIG (PP/IVIG) treatment improves clinical outcomes among patients with positive crossmatches. DESIGN: Immediately following deceased donor transplantation, 235 renal recipients were assigned points for PRA and flow crossmatches (FCXM): delayed graft function (DGF) ≤ 1 point received standard therapy; 2 points received high-dose IVIG; and ≥3 points received PP/IVIG. The DSAs were serially monitored by single antigen bead luminex for 1 year. Five-year clinical outcomes were determined from the chart review. RESULTS: All desensitized patients had preoperatively positive FCXM with DSA. Rejection was more common (P < .05) among desensitized than nonsensitized groups. However, overall graft survivals were similar between the groups (P = not significant) and superior to historic untreated patients (P < .05). Treatment with PP/IVIG more effectively eliminated preexisting DSAs (67% vs 33%, P < 0.05) than IVIG, but neither regimen prevented de novo formation of DSA (20%, P = not significant). Graft survival was >90% in all desensitizated patients with DSA elimination as well as PP/IVIG patients with residual DSA. In contrast, IVIG patients with persistent DSA had poorer graft survival (45%, P < .05). CONCLUSION: Preemptive perioperative desensitization improved overall graft survival of sensitized patients compared to historic untreated patients. Plasmapheresis/IVIG had greater impact on DSA eradication and graft survival than IVIG alone.
Asunto(s)
Desensibilización Inmunológica/métodos , Rechazo de Injerto/prevención & control , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Fallo Renal Crónico/cirugía , Trasplante de Riñón/métodos , Atención Perioperativa/métodos , Plasmaféresis/métodos , Adulto , Anticuerpos/inmunología , Suero Antilinfocítico/uso terapéutico , Cadáver , Estudios de Cohortes , Funcionamiento Retardado del Injerto , Femenino , Rechazo de Injerto/inmunología , Supervivencia de Injerto , Prueba de Histocompatibilidad , Humanos , Masculino , Hemisuccinato de Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapéutico , Tacrolimus/uso terapéuticoRESUMEN
BACKGROUND: Presence of antibody [Ab] against angiotensin receptor [AT1R] indicates heightened risk for antibody mediated rejection [AMR] after transplantation but is insufficient as a marker. We speculated AT1R might be released systemically because of AMR and might be a useful biomarker. METHODS: AT1R was measured in blood from 73 Normals and 72 renal patients pre- and post-transplantation. Patients were stratified as AMR-free [Gp1], AMR<1yr [Gp2] and AMR>1yr [Gp3]. RESULTS: AT1R was higher [13±26vs.367±537, p<0.01)] and more prevalent [20% vs. 92%, p<0.01] among renal patients than Normals. Pretransplant levels were similar [p=ns] between groups. One-year posttransplant levels approached [p<0.01] normalcy for Gps1+3 but spiked during AMR and remained elevated [155±58, p<0.01] for 50% Gp2 patients. One-year AT1R levels were higher among subsequent graft failures than surviving grafts [171±267vs. 38±50, p<0.01]. CONCLUSIONS: Pretransplant AT1R was abnormally elevated: possibly indicating ongoing tissue injury. Pretransplant AT1R didn't predict risk for AMR. However, AT1R spiked during early AMR and sustained elevations were associated with poorer outcomes.
Asunto(s)
Biomarcadores/sangre , Rechazo de Injerto/diagnóstico , Isoanticuerpos/sangre , Trasplante de Riñón , Receptor de Angiotensina Tipo 2/sangre , Adulto , Anciano , Citotoxicidad Celular Dependiente de Anticuerpos , Femenino , Estudios de Seguimiento , Rechazo de Injerto/inmunología , Supervivencia de Injerto , Humanos , Isoanticuerpos/inmunología , Masculino , Persona de Mediana Edad , Pronóstico , Receptor de Angiotensina Tipo 2/inmunología , Riesgo , Trasplante HomólogoRESUMEN
The highly-sensitized kidney transplant candidate with no available living donors remains at a major disadvantage with decreased access and worse outcomes post-transplant. We have previously reported our initial data on both pre-transplant and post-transplant desensitization. We observed only a modest decline in unacceptable antigens with pretransplant intravenous immunoglobin (IVIG) and rituximab. Due to these observations, we have focused on a peri-operative post-transplant desensitization protocol in our program. Beginning in 2006, we implemented a simple point-based algorithm [variables included: panel reactive antibody (PRA) status; flow cytometric crossmatch (FCXM); and delayed graft function] to identify kidney transplant recipients who would undergo peri-operative plasmapheresis/IVIG to abrogate preformed antibody-mediated allograft rejection (AMR). Our previous results suggested acceptable 5-year outcomes. Here, in an expanded population (N=66), we report an overall death-censored graft survival of 73% at a mean follow-up of 8.5 years post-transplant. Our patients were largely African American (85%) and regrafts (39%), with a median PRA of 88%, and a mean T- and B-FCXM of 97 mean channel shifts (MCS) and 117 MCS, respectively. Although acute AMR rates were acceptable (12%), 22% of patients developed chronic AMR. A pre-transplant T-cell FCXM of > 200 MCS (p=0.02) or presence of donor specific antibodies (DSA) at most recent follow-up (p=0.02) were associated with graft loss. Current studies with revised protocols utilizing additional DSA information, surveillance biopsies, and proteasome inhibition are ongoing.
Asunto(s)
Desensibilización Inmunológica , Antígenos HLA , Trasplante de Riñón , Rechazo de Injerto , Supervivencia de Injerto , Prueba de Histocompatibilidad , HumanosRESUMEN
We used a simple point-based algorithm to identify patients who might benefit from desensitization because of their higher risk of antibody-mediated chronic rejection and graft failure. Points were assigned to known but easily determined risk factors (panel reactive antibody, flow crossmatch, delayed graft function) and calculated immediately after deceased donor kidney transplantation. Point totals were used to identify: 1) which patients would receive desensitization; and, 2) which regimen each patient would receive. This standardized approached resulted in improved overall graft survival in both modalities compared to historically untreated sensitized patients. While preemptive desensitization positively impacted clinical metrics, the improvements were unequal between regimens. PP/IVIG treatment clearly resulted in greater elimination of preexisting donor specific antibodies against HLA antigens (DSA), fewer late rejections, and superior 3-year graft survival among patients who resolved their DSA as well as those with persistent DSA. Since graft survival among PP/IVIG recipients was excellent even when preexisting DSA were still present one year post-transplant, it suggests that the benefit of this regimen is two-fold: first to increase DSA elimination among patients, and secondly, to minimize downstream immune activating events such as rejection. In contrast, IVIG patients with persistent DSA had more rejections and graft survival only slightly better than if they had no treatment at all. Since the IVIG group also had a preponderance of Class II directed DSA, we cannot discount the influence of that specificity upon graft outcomes. Additional studies are needed to confirm our findings and to allow more effective assessment of the impact of DSA specificity upon desensitization efficacy and graft success.
Asunto(s)
Desensibilización Inmunológica , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Antígenos HLA/inmunología , Histocompatibilidad , Isoanticuerpos/sangre , Trasplante de Riñón , Adulto , Biomarcadores/sangre , Desensibilización Inmunológica/métodos , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/mortalidad , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunosupresores/uso terapéutico , Estimación de Kaplan-Meier , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/mortalidad , Masculino , Persona de Mediana Edad , Selección de Paciente , Plasmaféresis , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
HIV/HCV coinfected patients tend to develop hepatitis C (HCV)-associated liver disorders. Because the chemokine receptor CXCR3 participates in lymphocyte trafficking during hepatic inflammation, it may participate in the escalated liver disorders of coinfected patients. However, to date, the relative frequency and density of receptor on lymphocytes has not been established. This study compared the CXCR3(+) phenotype under various in vitro conditions between lymphocytes from healthy and coinfected individuals. Peripheral lymphocytes were stimulated with phytohemagluttinin for 0-7 d and phenotypes were determined by flow cytometry. Secreted cytokines were measured in culture supernatants by ELISA. Phenotypic differences were observed between groups. CD4(+)CXCR3(+) frequency between groups was equivalent before and during early activation, but increased only among non-infected individuals during late activation (p<0.001). In contrast, CD8(+)CXCR3(+) frequency was consistently greater (p<0.05) among HIV/HCV patients throughout activation. Among those who were non-infected, CD8(+)CXCR3(+) frequency increased (p=0.002) during late activation. However, CD8(+)CXCR3(+) frequency among HIV/HCV patients increased within 24 h of activation (p=0.008), and was nearly universal by late activation (p<0.001). Both groups elaborated Th-1 cytokine profiles; however, coinfected patients released more inflammatory cytokines (p<0.01) than non-infected individuals. In summary, we demonstrated that CD8(+) lymphocytes from HIV/HCV-infected patients expressed more CXCR3 and showed greater upregulatory ability upon activation. The atypical CXCR3 expression and enhanced Th-1 cytokine elaboration among coinfected patients could potentially stimulate increased lymphocyte migration during hepatic inflammation.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Coinfección/virología , Infecciones por VIH/inmunología , Hepatitis C/inmunología , Receptores CXCR3/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/virología , Estudios de Casos y Controles , Proliferación Celular , Células Cultivadas , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/farmacología , Coinfección/complicaciones , Coinfección/inmunología , Medios de Cultivo/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , VIH/inmunología , VIH/patogenicidad , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , Hepacivirus/inmunología , Hepacivirus/patogenicidad , Hepatitis C/complicaciones , Hepatitis C/virología , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Fitohemaglutininas/farmacología , ARN Viral/genética , Factores de TiempoRESUMEN
BACKGROUND: Sustained maintenance on left ventricular assist device (LVAD) is associated with an increased frequency of severe infections. Although temporary changes in cellular immunity are seen immediately after implantation, the consequence of sustained LVAD treatment on immunity is unknown. METHODS: In vitro functional and phenotypic markers of T cell activation and 6 month clinical outcome were compared between patients with > or = 6-month LVAD therapy and heart failure control patients. RESULTS: Recipients of LVADs had more infections (45.5% versus 0%; p < 0.05) and mortality (54% versus 16%; p < 0.05) than control patients. T-cell proliferative responses were lower among LVAD recipients than control patients when challenged with phytohemagglutinin (3.4 +/- 4.7 versus 28.5 +/- 19.6; p < 0.01), anti-CD3 (4.3 +/- 4.5 versus 16.4 +/- 17; p < 0.01), and staphylococcal enterotoxin B (7.2 +/- 6.3 versus 26.1 +/- 15.6; p = 0.002). Proliferative hyporesponsiveness among LVAD recipients was not caused by apoptosis (2.6% +/- 2.7% versus 2.7% +/- 2.1%; p = 0.94) or insufficient CD4+ cells (42.1% +/- 11.3% versus 40.2% +/- 7.5%; p = 0.71) relative to control patients. Instead, CD3+ cells from LVAD patients expressed less interleukin 2 (2.5% +/- 1.5% versus 5.2% +/- 3.1%; p = 0.03) and tumor necrosis factor-alpha (6.0% +/- 3.5% versus 25.8% +/- 8.7%; p < 0.001) and more interleukin 10 (5.8% +/- 6.1% versus 2.6% +/- 2.1%; p < 0.05). In addition, suppressive T-regulatory cells were more prevalent in LVAD patients than control patients (12.9% +/- 3.2% versus 1.2% +/- 1.1%; p < 0.001). CONCLUSIONS: Cellular immunity is compromised among long-term LVAD recipients because of a downregulatory cytokine imbalance and emergence of suppressive T-regulatory cells.