RESUMEN
BACKGROUND: Urinary CXCL10/creatinine (uCXCL10/Cr) is proposed as an effective biomarker of subclinical rejection in pediatric kidney transplant recipients. This study objective was to model implementation in the clinical setting. METHODS: Banked urine samples at a single center were tested for uCXCL10/Cr to validate published thresholds for rejection diagnosis (>80% specificity). The positive predictive value (PPV) for rejection diagnosis for uCXCL10/Cr-indicated biopsy was modeled with first-positive versus two-test-positive approaches, with accounting for changes associated with urinary tract infection (UTI), BK and CMV viremia, and subsequent recovery. RESULTS: Seventy patients aged 10.5 ± 5.6 years at transplant (60% male) had n = 726 urine samples with n = 236 associated biopsies (no rejection = 167, borderline = 51, and Banff 1A = 18). A threshold of 12 ng/mmol was validated for Banff 1A versus no-rejection diagnosis (AUC = 0.74, 95% CI = 0.57-0.92). The first-positive test approach (n = 69) did not resolve a clinical diagnosis in 38 cases (55%), whereas the two-test approach resolved a clinical diagnosis in the majority as BK (n = 17/60, 28%), CMV (n = 4/60, 7%), UTI (n = 8/60, 13%), clinical rejection (n = 5/60, 8%), and transient elevation (n = 18, 30%). In those without a resolved clinical diagnosis, PPV from biopsy for subclinical rejection is 24% and 71% (p = .017), for first-test versus two-test models, respectively. After rejection treatment, uCXCL10/Cr level changes were all concordant with change in it-score. Sustained uCXCL10/Cr after CMV and BK viremia resolution was associated with later acute rejection. CONCLUSIONS: Urinary CXCL10/Cr reliably identifies kidney allograft inflammation. These data support a two-test approach to reliably exclude other clinically identifiable sources of inflammation, for kidney biopsy indication to rule out subclinical rejection.
Asunto(s)
Infecciones por Citomegalovirus , Trasplante de Riñón , Niño , Femenino , Humanos , Masculino , Aloinjertos , Biomarcadores/orina , Quimiocina CXCL10 , Creatinina/orina , Infecciones por Citomegalovirus/diagnóstico , Rechazo de Injerto/patología , Inflamación/patología , Riñón/patología , Receptores de Trasplantes , Viremia , Preescolar , AdolescenteRESUMEN
BACKGROUND: Infants with a solitary functioning kidney (SFK) are at risk for chronic kidney injury (CKI). Lack of compensatory kidney growth (CKG) is associated with CKI, but measuring CKG is challenging since it is typically reported relative to normal kidneys. This study aims to (1) standardize SFK growth in infants, (2) investigate the relationship between standardized kidney length and clinical outcomes, and (3) use these results to develop a risk-based prediction model and local clinical pathway for SFK care. METHODS: This was a quality improvement study of 166 infants with an SFK. Linear regression was used to assess kidney growth from 0 to 180 days of life. Univariate binary regression analysis was used to identify kidney length to body length thresholds associated with the development of CKI, defined as the composite outcome of chronic kidney disease (eGFR < 60 mL/min/1.73 m2), hypertension, or proteinuria. RESULTS: Kidneys grew in length from 0 to 180 days, and growth was constant when standardized to body length. Over follow-up, infants with a baseline kidney length to body length ≤ 0.088 were more likely to experience CKI than the rest of the cohort (27 vs. 8%, p = 0.04). Kidney length to body length ≤ 0.088 was also significantly associated with CKI development (OR 4.17, 95% CI 1.14-15.28, p = 0.04). CONCLUSIONS: In this study, kidney length to body length ratio was a stable CKG metric over 0-180 days, and a baseline ratio ≤ 0.088 was a risk factor for CKI. Results will aid in developing a practical, point-of-care risk assessment tool, and overarching risk-stratified clinical pathway for infants with an SFK. A higher resolution version of the Graphical abstract is available as Supplementary information.
Asunto(s)
Insuficiencia Renal Crónica , Riñón Único , Lactante , Humanos , Riñón Único/complicaciones , Tasa de Filtración Glomerular , Riñón/diagnóstico por imagen , Insuficiencia Renal Crónica/complicaciones , Proteinuria/etiología , Estudios RetrospectivosRESUMEN
BACKGROUND: Multicystic dysplastic kidney (MCDK) disease and unilateral renal agenesis (URA) are well-known causes of a solitary functioning kidney (SFK) and are associated with long-term kidney injury. The aims of this study were to characterize the natural history of SFK at our center, define the risk factors associated with chronic kidney injury, and identify distinguishing features between URA and MCDK that predict outcome. METHODS: This was a retrospective cohort study of 230 SFK patients. We compared MCDK (n=160) and URA (n=70) according to clinical features at diagnosis and kidney outcomes over follow-up. Univariate and multivariate binary regression analysis was used to determine independent risk factors for chronic kidney injury, defined as the composite outcome of hypertension, proteinuria, or chronic kidney disease (eGFR <60 mL/min/1.73m2). RESULTS: URA had a higher prevalence of comorbid genetic syndromes (15 vs. 6%, p=0.04), non-renal anomalies (39 vs. 11%, p<0.001), and congenital anomalies of the kidney and urinary tract (CAKUT) (51 vs. 26%, p<0.001) than MCDK. Over follow-up, URA experienced more hypertension (19 vs. 3%, p=0.002), proteinuria (12 vs. 3%, p=0.03), and the composite outcome (19 vs. 6%, p=0.003) than MCDK. Independent risk factors for chronic kidney injury included CAKUT (OR 5.01, p=0.002) and URA (OR 2.71, p=0.04). CONCLUSIONS: In our population, URA was more likely to have associated syndromes or anomalies, and to have worse outcomes over time than MCDK. URA diagnosis was an independent risk factor for chronic kidney injury. Our results will be used to develop a standardized clinical pathway for SFK management. A higher resolution version of the Graphical abstract is available as Supplementary information.
Asunto(s)
Anomalías Congénitas , Enfermedades Renales/congénito , Riñón/anomalías , Riñón Displástico Multiquístico , Riñón Único , Anomalías Congénitas/epidemiología , Estudios de Seguimiento , Humanos , Enfermedades Renales/epidemiología , Riñón Displástico Multiquístico/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Riñón Único/epidemiologíaRESUMEN
A plasmid DNA vaccine candidate (pCEIS) encoding two foot-and-mouth disease virus (FMDV) VP1 epitopes (amino acid residues 141-160 and 200-213) has been demonstrated to have the ability to elicit both FMDV-specific T cell proliferation and neutralizing antibody against FMD in swine. In this study, the efficiency of the pCEIS DNA vaccine when administrated by intramuscularly injection in swine was confirmed, and the immunogenicity of the pCEIS vaccine candidate was found to be enhanced through co-administration with a newly constructed plasmid (pIL2S) encoding the swine interleukin-2 (IL-2) cDNA. The expression of the pIL2S plasmid was driven by a CMV promotor provided by a pcDNA3.1 vector. Swine IL-2 cDNA was cloned by RT-PCR from swine spleen cells. The pIL2S plasmid was expressed in COS-7 cells after 24 and 96h of transfection in vitro. In an animal trial, results from T cell proliferation assay indicated that the stimulation index (SI) in response to stimulation of FMDV proteins in the swine groups injected with pCEIS plus pIL2S (SI ranging from 9.9 to 15.5) were significantly higher than that with pCEIS alone (SI ranging from 3.3 to 6.6). However, there was no significant difference in FMDV-neutralizing antibody level detected in these two swine groups. Mouse protection tests (MPTs) showed that the blood sera from immunized swine injected with either pCEIS alone or pCEIS plus pIL2S were able to protect suckling mice from FMDV challenge, with protection levels ranging from 10(1) to 10(2) lethal dose 50 (LD(50)) M. In a direct FMDV challenge, all swines immunized with either pCEIS plus pIL2S or with pCEIS alone were challenged with 50LD(50)S (50 x lethal dosage in swine) of FMDV. The animals were fully protected (100%) from the FMD viral challenge. These results suggest that co-administration of the plasmids, pCEIS and pIL2S, enhances of the immunogenicity of the pCEIS DNA vaccine candidate, and both intramuscular injection of pCEIS alone and co-administration of the vaccine candidate with pIL2S can protect the swine from direct FMD challenge.