Single measurements of urinary biomarkers reflecting kidney tubule health are associated with chronic kidney disease (CKD) risk in HIV infection, but the prognostic value of repeat measurements over ...time is unknown.
Cohort study.
647 women living with HIV infection enrolled in the Women’s Interagency Health Study.
14 urinary biomarkers of kidney tubule health measured at 2 visits over a 3-year period.
Incident CKD, defined as estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2 at two 6-month visits and an average eGFR decline≥3% per year.
We used multivariable generalized estimating equations adjusting for CKD risk factors to evaluate baseline, time-updated, and change-over-time biomarker associations with incident CKD. We compared CKD discrimination between models with and without a parsimoniously selected set of biomarkers.
During a median 7 years of follow-up, 9.7% (63/647) developed CKD. In multivariable-adjusted analyses, 3 of 14 baseline biomarkers associated with incident CKD. In contrast, 10 of 14 time-updated biomarkers and 9 of 14 biomarkers modeled as change over time associated with incident CKD. Urinary epidermal growth factor (EGF), α1-microglobulin (A1M), and albumin were selected using penalized regression methods. In the time-updated model, lower urinary EGF (risk ratio RR per 2-fold higher time-updated biomarker levels, 0.69; 95% CI, 0.58-0.81), higher urinary A1M (RR, 1.47; 95% CI, 1.25-1.73), and higher urinary albumin excretion (RR, 1.21; 95% CI, 1.03-1.42) were jointly associated with increased risk for CKD. Compared with a base model (C statistic, 0.75), CKD discrimination improved after adding urinary EGF, A1M, and albumin values across baseline (C=0.81), time-updated (C=0.83), and change-over-time (C=0.83) models (P<0.01 for all).
Observational design, incident CKD definition limited to eGFR.
Repeat urinary biomarker measurements for kidney tubule health have stronger associations with incident CKD compared with baseline measurements and moderately improve CKD discrimination in women living with HIV infection.
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Objectives
Individual kidney tubule biomarkers are associated with chronic kidney disease (CKD) risk in people living with HIV (PLWH). Whether a combination of kidney biomarkers can be integrated ...into informative summary scores for PLWH is unknown.
Methods
We measured eight urine biomarkers of kidney tubule health at two visits over a 3‐year period in 647 women living with HIV in the Women's Interagency Health Study. We integrated biomarkers into factor scores using exploratory factor analysis. We evaluated associations between CKD risk factors and factor scores, and used generalized estimating equations to determine associations between factor scores and risk of incident CKD.
Results
Factor analysis identified two unique factor scores: a tubule reabsorption score comprising alpha‐1‐microglobulin, beta‐2‐microglobulin and trefoil factor‐3; and a tubule injury score comprising interleukin‐18 and kidney injury molecule‐1. We modelled the two factor scores in combination with urine epidermal growth factor (EGF) and urine albumin. Predominantly HIV‐related CKD risk factors were independently associated with worsening tubule reabsorption scores and tubule injury scores. During a median follow‐up of 7 years, 9.7% (63/647) developed CKD. In multivariable time‐updated models that adjusted for other factor scores and biomarkers simultaneously, higher tubule reabsorption scores risk ratio (RR) = 1.27, 95% confidence interval (CI): 1.01–1.59 per 1 SD higher time‐updated score, higher tubule injury scores (RR = 1.36, 95% CI: 1.05–1.76), lower urine EGF (RR = 0.75, 95% CI: 0.64–0.87), and higher urine albumin (RR = 1.20, 95% CI: 1.02–1.40) were jointly associated with risk of incident CKD.
Conclusions
We identified two novel and distinct dimensions of kidney tubule health that appear to quantify informative metrics of CKD risk in PLWH.
OBJECTIVE To investigate whether the severity of cystoid macular edema (CME) in neonates who were 31 to 36 weeks' postmenstrual age, as viewed by spectral-domain optical coherence tomography (SD-OCT) ...imaging, predicts the severity of retinopathy of prematurity (ROP) or is related to systemic health. DESIGN Of 62 prematurely born neonates in a prospective institutional review board–approved study, 42 met the following inclusion criteria: at least 1 SD-OCT imaging session prior to 37 weeks' postmenstrual age and prior to ROP laser treatment, if a laser treatment was performed, and an ophthalmic ROP examination at or after 41 weeks' postmenstrual age, evidence of complete retinal vascularization in zone III, or documentation through telephone report of such information after transfer of care. Measures of CME severity, including central foveal thickness, retinal layer thicknesses, and foveal-to-parafoveal thickness ratio in 1 eye per subject, were compared with ROP outcomes: laser treatment, maximum plus disease, and maximum ROP stage. Systemic health factors were also correlated. RESULTS Cystoid macular edema was present in 50% of neonates. Multiple elongated cystoid structures within the inner nuclear layer were most common. The presence of CME was not associated with ROP outcomes. The central foveal thickness, the thickness of the inner retinal layers, and the foveal-to-parafoveal thickness ratio were higher in eyes that required laser treatment or that developed plus disease or ROP stage 3. Cystoid macular edema was not clearly associated with systemic factors. CONCLUSIONS Cystoid macular edema is common in premature infants screened for ROP before 37 weeks' postmenstrual age, with the most common SD-OCT phenotype of a bulging fovea from multiple elongated cystoid spaces. Detection of CME is not associated with ROP severity; however, tomographic thickness measurements could potentially predict a higher risk of requiring laser treatment or developing plus disease or ROP stage 3. Systemic health factors are probably not related to the development of CME.
Summary Background We sought to describe the incidence, pathogen distribution, and mortality associated with blood culture-proven sepsis in young infants with congenital heart disease (CHD) admitted ...to a neonatal intensive care unit (NICU). Methods Cohort study of all blood cultures obtained from infants with CHD between 4 and 120 days of age cared for in 250 NICUs managed by the Pediatrix Medical Group in the United States between 1996 and 2007. Results Of 11,638 infants with CHD, 656 (6%) had 821 episodes of sepsis: a cumulative incidence of 71/1000 admissions. Gram-positive organisms were the most common cause (64%), and coagulase-negative Staphylococcus and Staphylococcus aureus were the most frequently isolated species. On multivariable regression, infants with sepsis were more likely to die compared to infants with sterile blood cultures (odds ratio OR = 1.53 95% confidence interval: 1.09, 2.13). Infants with Gram-negative bacteraemia and candidaemia were more likely to die than infants with sterile blood cultures (OR = 2.01 1.20, 3.37, and OR = 3.18 1.60, 6.34, respectively). Conclusion Infants with CHD have a high incidence of culture-proven sepsis, especially with staphylococcal organisms. Gram-negative bacteraemia and candidaemia are strongly associated with increased mortality in this group of young infants.
Urine epidermal growth factor (uEGF) has been found to be inversely associated with kidney function loss, whereas its associations with cardiovascular disease (CVD) and mortality have not been ...studied.
We measured baseline uEGF levels among 2346 Systolic Blood Pressure Intervention Trial (SPRINT) participants with an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m2. A linear mixed-effects model was used to investigate the associations of uEGF with the annual eGFR change; Cox proportional hazards regression models were used to analyze its associations with the ≥30% eGFR decline, CVD, and all-cause mortality outcomes. To account for the competing risk of death, the Fine and Gray method was utilized for acute kidney injury (AKI) and end-stage kidney disease (ESKD) outcomes.
At baseline, the study participants had mean age of 73 ± 9 years, mean eGFR of 46 ± 11 ml/min per 1.73 m2, and median urine albumin-to-creatinine ratio (UACR) of 15 mg/g (interquartile range: 7–49). In the multivariable-adjusted analysis including baseline urine albumin and eGFR, each 50% lower uEGF concentration was associated with 0.74% (95% confidence interval CI: 0.29–1.19) per year faster decline in eGFR and 1.17 times higher risk of ≥30% eGFR decline (95% CI: 1.00–1.36). Lower uEGF concentrations were found to be associated with increased risks of ESKD, AKI, CVD, and all-cause mortality; however, these associations did not reach statistical significance when the models were controlled for baseline urine albumin and eGFR.
Among hypertensive adults with chronic kidney disease (CKD), lower baseline uEGF concentration was associated with faster eGFR decline independent of baseline albuminuria and eGFR; but not with ESKD, AKI, CVD, and all-cause mortality.
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Teratogenic drugs can lead to extreme fetal malformation and consequently critically influence the fetus’s health, yet the teratogenic risks associated with most approved drugs are unknown. Here, we ...propose a novel predictive tool, embryoTox, which utilizes a graph-based signature representation of the chemical structure of a small molecule to predict and classify molecules likely to be safe during pregnancy. embryoTox was trained and validated using in vitro bioactivity data of over 700 small molecules with characterized teratogenicity effects. Our final model achieved an area under the receiver operating characteristic curve (AUC) of up to 0.96 on 10-fold cross-validation and 0.82 on nonredundant blind tests, outperforming alternative approaches. We believe that our predictive tool will provide a practical resource for optimizing screening libraries to determine effective and safe molecules to use during pregnancy. To provide a simple and integrated platform to rapidly screen for potential safe molecules and their risk factors, we made embryoTox freely available online at https://biosig.lab.uq.edu.au/embryotox/.
Germline pathogenic variants in
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are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum ...management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype-phenotype correlations in a large cohort of
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mutation carriers.
A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in
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(n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses.
Tumour risks analysis provided novel penetrance estimates and genotype-phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the
p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising
missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in
and (paternally inherited)
mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband
mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for
mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%).
Overall risks of clinically apparent tumours for
mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype-tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for
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mutation carriers.
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