A Markov Multi-State model of lupus nephritis urine biomarker panel dynamics in children: Predicting changes in disease activity.

BACKGROUND: A urine 'biomarker panel' comprising alpha-1-acid-glycoprotein, ceruloplasmin, transferrin and lipocalin-like-prostaglandin-D synthase performs to an 'excellent' level for lupus nephritis identification in children cross-sectionally. The aim of this study was to assess if this biomarker panel predicts lupus nephritis flare/remission longitudinally. METHODS: The novel urinary biomarker panel was quantified by enzyme linked immunoabsorbant assay in participants of the United Kingdom Juvenile Systemic Lupus Erythematosus (UK JSLE) Cohort Study, the Einstein Lupus Cohort, and the South African Paediatric Lupus Cohort. Monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1 were also quantified in view of evidence from other longitudinal studies. Serial urine samples were collected during routine care with detailed clinical and demographic data. A Markov Multi-State model of state transitions was fitted, with predictive clinical/biomarker factors assessed by a corrected Akaike Information Criterion (AICc) score (the better the model, the lower the AICc score). RESULTS: The study included 184 longitudinal observations from 80 patients. The homogeneous multi-state Markov model of lupus nephritis activity AICc score was 147.85. Alpha-1-acid-glycoprotein and ceruloplasmin were identified to be the best predictive factors, reducing the AICc score to 139.81 and 141.40 respectively. Ceruloplasmin was associated with the active-to-inactive transition (hazard ratio 0.60 (95% confidence interval [0.39, 0.93])), and alpha-1-acid-glycoprotein with the inactive-to-active transition (hazard ratio 1.49 (95% confidence interval [1.10, 2.02])). Inputting individual alpha-1-acid-glycoprotein/ceruloplasmin values provides 3, 6 and 12 months probabilities of state transition. CONCLUSIONS: Alpha-1-acid-glycoprotein was predictive of active lupus nephritis flare, whereas ceruloplasmin was predictive of remission. The Markov state-space model warrants testing in a prospective clinical trial of lupus nephritis biomarker led monitoring.

Fetal heart rate patterns and the timing of fetal injury.

We studied the nonstress test (NST) results and other perinatal features of 44 children with cerebral palsy, who had fetal heart rate (FHR) patterns during labor suggesting preexisting injury. This was a retrospective, descriptive study. All fetuses persistently showed absent variability and small, variable decelerations, with overshoot from the onset of monitoring during labor. During the initial NST, 84.1% of fetuses revealed normal reactive NST patterns (three with decelerations). Six fetuses (15.9%) had nonreactive NST results (three with decelerations). The conversion of the reactive NST to a pattern of persistently absent variability often occurred during advanced pregnancy (average estimated gestational age 40 weeks), in association with decreased amniotic fluid (AF) volume (70.5%) and maternal complaints of decreased fetal movement (52.4%). FHR decelerations consistent with acute fetal distress were uncommon during early labor but occurred in about half of cases in advanced labor. All but one neonate had low Apgar scores at birth, but acidosis occurred in about one third of infants. Seizures developed in about half the infants, usually in the first day. Follow-up studies revealed a high incidence of mental retardation, microcephaly, and seizure activity in addition to cerebral palsy, regardless of the presence of perinatal acidosis. The results of this retrospective study of a limited population base suggest that fetal neurologic injury preceding labor may develop late in pregnancy, and that decreased AF volume appears to be a significant risk factor. FHR patterns may provide clues to the presence and timing of fetal neurologic injury.