RESUMEN
OBJECTIVES: Belatacept may provide benefit in delayed graft function, but its association with infectious complications is understudied. We aim to assess the incidence of CMV and BK viremia in patients treated with sirolimus or belatacept as part of a three-drug immunosuppression regimen after kidney transplantation. MATERIALS AND METHODS: Kidney transplant recipients from 01/01/2015 to 10/01/2021 were retrospectively reviewed. Maintenance immunosuppression was either tacrolimus, mycophenolate and sirolimus (B0) or tacrolimus, mycophenolate, and belatacept (5.0 mg/kg monthly) (B1). Primary outcomes of interest were BK and CMV viremia which were followed until the end of the study period. Secondary outcomes included graft function (serum creatinine, eGFR) and acute rejection through 12 months. RESULTS: Belatacept was initiated in patients with a higher mean kidney donor profile index (B0:0.36 vs. B1:0.44, p = .02) with more delayed graft function (B0:6.1% vs. B1:26.1%, p < .001). Belatacept therapy was associated with more "severe" CMV viremia >25,000 copies/mL (B0:1.2% vs. B1:5.9%, p = .016) and CMV disease (B0:0.41% vs. B1:4.2%, p = .015). However, there was no difference in the overall incidence of CMV viremia >200 IU/mL (B0:9.4% vs. B1:13.5%, p = .28). There was no difference in the incidence of BK viremia >200 IU/mL (B0:29.7% vs. B1:31.1%, p = .78) or BK-associated nephropathy (B0:2.4% vs. B1:1.7%, p = .58), but belatacept was associated with "severe" BK viremia, defined as >10,000 IU/mL (B0:13.0% vs. B1:21.8%, p = .03). The mean serum Cr was significantly higher with belatacept therapy at 1-year follow up (B0:1.24 mg/dL vs. B1:1.43 mg/dL, p = .003). Biopsy-proven acute rejection (B0:1.2% vs. B1:2.6%, p = .35) and graft loss (B0:1.2% vs. B1:0.84%, p = .81) were comparable at 12 months. CONCLUSIONS: Belatacept therapy was associated with an increased risk of CMV disease and "severe" CMV and BK viremia. However, this regimen did not increase the overall incidence of infection and facilitated comparable acute rejection and graft loss at 12-month follow up.
Asunto(s)
Virus BK , Infecciones por Citomegalovirus , Infecciones por Polyomavirus , Humanos , Sirolimus/uso terapéutico , Abatacept/uso terapéutico , Tacrolimus/uso terapéutico , Viremia/tratamiento farmacológico , Viremia/epidemiología , Estudios Retrospectivos , Funcionamiento Retardado del Injerto/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Terapia de Inmunosupresión , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/epidemiología , Infecciones por Polyomavirus/tratamiento farmacológico , Infecciones por Polyomavirus/epidemiología , Rechazo de Injerto/epidemiologíaRESUMEN
Diagnosis of pyruvate kinase deficiency (PKD), the most common cause of hereditary non-spherocytic haemolytic anaemia, remains challenging in routine practice and no biomarkers for clinical severity have been characterised. This prospective study enrolled 41 patients with molecularly confirmed PKD from nine North American centres to evaluate the diagnostic sensitivity of pyruvate kinase (PK) enzyme activity and PK:hexokinase (HK) enzyme activity ratio, and evaluate the erythrocyte PK (PK-R) protein level and erythrocyte metabolites as biomarkers for clinical severity. In this population not transfused for ≥90 days before sampling, the diagnostic sensitivity of the PK enzyme assay was 90% [95% confidence interval (CI) 77-97%], whereas the PK:HK ratio sensitivity was 98% (95% CI 87-100%). There was no correlation between PK enzyme activity and clinical severity. Transfusion requirements correlated with normalised erythrocyte ATP levels (r = 0·527, P = 0·0016) and PK-R protein levels (r = -0·527, P = 0·0028). PK-R protein levels were significantly higher in the never transfused [median (range) 40·1 (9·8-73·9)%] versus ever transfused [median (range) 7·7 (0·4-15·1)%] patients (P = 0·0014). The PK:HK ratio had excellent sensitivity for PK diagnosis, superior to PKLR exon sequencing. Given that the number of PKLR variants and genotype combinations limits prognostication based on molecular findings, PK-R protein level may be a useful prognostic biomarker of disease severity and merits further study.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica/sangre , Eritrocitos/enzimología , Hexoquinasa/sangre , Piruvato Quinasa/sangre , Piruvato Quinasa/deficiencia , Errores Innatos del Metabolismo del Piruvato/sangre , Adolescente , Adulto , Anemia Hemolítica Congénita no Esferocítica/genética , Biomarcadores/sangre , Niño , Preescolar , Femenino , Hexoquinasa/genética , Humanos , Lactante , Masculino , Persona de Mediana Edad , Piruvato Quinasa/genética , Errores Innatos del Metabolismo del Piruvato/genética , Índice de Severidad de la EnfermedadRESUMEN
Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non-missense, including 20 stop-gain, 11 affecting splicing, five large deletions, four in-frame indels, and three promoter variants. Within the 177 unrelated patients, 35 were homozygous and 142 compound heterozygous (77 for two missense, 48 for one missense and one non-missense, and 17 for two non-missense variants); the two most frequent mutations were p.R510Q in 23% and p.R486W in 9% of mutated alleles. Fifty-five (21%) patients were found to have at least one previously unreported variant with 45 newly described mutations. Patients with two non-missense mutations had lower hemoglobin levels, higher numbers of lifetime transfusions, and higher rates of complications including iron overload, extramedullary hematopoiesis, and pulmonary hypertension. Rare severe complications, including lower extremity ulcerations and hepatic failure, were seen more frequently in patients with non-missense mutations or with missense mutations characterized by severe protein instability. The PKLR genotype did not correlate with the frequency of complications in utero or in the newborn period. With ICCs ranging from 0.4 to 0.61, about the same degree of clinical similarity exists within siblings as it does between siblings, in terms of hemoglobin, total bilirubin, splenectomy status, and cholecystectomy status. Pregnancy outcomes were similar across genotypes in PK deficient women. This report confirms the wide genetic heterogeneity of PK deficiency.