RESUMEN
BACKGROUND: Single-center trials and retrospective case series have reported promising outcomes using kidneys from donors with hepatitis C virus (HCV) infection. However, multicenter trials are needed to determine if those findings are generalizable. METHODS: We conducted a prospective trial at seven centers to transplant 30 kidneys from deceased donors with HCV viremia into HCV-uninfected recipients, followed by 8 weeks of once-daily coformulated glecaprevir and pibrentasvir, targeted to start 3 days posttransplant. Key outcomes included sustained virologic response (undetectable HCV RNA 12 weeks after completing treatment with glecaprevir and pibrentasvir), adverse events, and allograft function. RESULTS: We screened 76 patients and enrolled 63 patients, of whom 30 underwent kidney transplantation from an HCV-viremic deceased donor (median kidney donor profile index, 53%) in May 2019 through October 2019. The median time between consent and transplantation of a kidney from an HCV-viremic donor was 6.3 weeks. All 30 recipients achieved a sustained virologic response. One recipient died of complications of sepsis 4 months after achieving a sustained virologic response. No severe adverse events in any patient were deemed likely related to HCV infection or treatment with glecaprevir and pibrentasvir. Three recipients developed acute cellular rejection, which was borderline in one case. Three recipients developed polyomavirus (BK) viremia near or >10,000 copies/ml that resolved after reduction of immunosuppression. All recipients had good allograft function, with a median creatinine of 1.2 mg/dl and median eGFR of 57 ml/min per 1.73 m2 at 6 months. CONCLUSIONS: Our multicenter trial demonstrated safety and efficacy of transplantation of 30 HCV-viremic kidneys into HCV-negative recipients, followed by early initiation of an 8-week regimen of glecaprevir and pibrentasvir.
Asunto(s)
Ácidos Aminoisobutíricos/uso terapéutico , Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Ciclopropanos/uso terapéutico , Hepacivirus , Hepatitis C/prevención & control , Trasplante de Riñón , Lactamas Macrocíclicas/uso terapéutico , Leucina/análogos & derivados , Prolina/análogos & derivados , Quinoxalinas/uso terapéutico , ARN Viral/sangre , Sulfonamidas/uso terapéutico , Adulto , Aloinjertos/fisiología , Aloinjertos/virología , Ácidos Aminoisobutíricos/efectos adversos , Antivirales/efectos adversos , Bencimidazoles/efectos adversos , Ciclopropanos/efectos adversos , Combinación de Medicamentos , Femenino , Tasa de Filtración Glomerular , Hepatitis C/sangre , Humanos , Riñón/fisiología , Lactamas Macrocíclicas/efectos adversos , Leucina/efectos adversos , Leucina/uso terapéutico , Masculino , Prolina/efectos adversos , Prolina/uso terapéutico , Estudios Prospectivos , Pirrolidinas , Quinoxalinas/efectos adversos , Sulfonamidas/efectos adversos , Respuesta Virológica SostenidaRESUMEN
BACKGROUND: Thirty-seven patients have received a living-donor kidney transplant in a phase 2 study designed to induce tolerance with facilitated allogeneic hematopoietic stem cell transplant. The study protocol is based on tolerogenic CD8 + /T-cell receptor - facilitating cells (FCR001; also including hematopoietic stem cells and αß-T-cell receptor + T cells) and low-dose, nonmyeloablative conditioning. Persistent chimerism allowing full immunosuppression (IS) withdrawal was achieved in 26 patients (time off IS 36-123 mo). METHODS: We evaluated biomarkers of tolerance through urinary cell mRNA profiling and immunocompetence to respond to vaccination in these patients. We also assessed kidney function and metabolic parameters compared with standard-of-care patients on IS. RESULTS: Persistently chimeric patients retained chimerism after removal of IS and remained rejection free without donor HLA-specific antibody development. The presence of donor chimerism at >50% correlated with a signature of tolerance in urinary cell mRNA profiles, with a uniquely elevated increase in the ratio of cytotoxic T lymphocyte-associated protein 4 to granzyme B mRNA. Tolerance was associated with protection from recurrence of immune-mediated causes of kidney disease. Tolerant participants were safely vaccinated, developed protective immune responses, and did not lose chimerism after vaccination. When compared with kidney transplant recipients treated with standard IS, tolerant participants showed stable kidney function and reduced medication use for hypertension and hyperlipidemia. CONCLUSIONS: These results suggest that elimination of IS has distinct advantages in living-donor kidney allograft recipients.