Gene regulation contributes to explain the impact of early life socioeconomic disadvantage on adult inflammatory levels in two cohort studies

Individuals experiencing socioeconomic disadvantage in childhood have a higher rate of inflammation-related diseases decades later. Little is known about the mechanisms linking early life experiences to the functioning of the immune system in adulthood. To address this, we explore the relationship across social-to-biological layers of early life social exposures on levels of adulthood inflammation and the mediating role of gene regulatory mechanisms, epigenetic and transcriptomic profiling from blood, in 2,329 individuals from two European cohort studies. Consistently across both studies, we find transcriptional activity explains a substantive proportion (78% and 26%) of the estimated effect of early life disadvantaged social exposures on levels of adulthood inflammation. Furthermore, we show that mechanisms other than cis DNA methylation may regulate those transcriptional fingerprints. These results further our understanding of social-to-biological transitions by pinpointing the role of gene regulation that cannot fully be explained by differential cis DNA methylation

Routine Urinary Biochemistry Does Not Accurately Predict Stone Type Nor Recurrence in Kidney Stone Formers: A Multicentre, Multimodel, Externally Validated Machine-Learning Study

\ua9 Mary Ann Liebert, Inc.Objectives: Urinary biochemistry is used to detect and monitor conditions associated with recurrent kidney stones. There are no predictive machine learning (ML) tools for kidney stone type or recurrence. We therefore aimed to build and validate ML models for these outcomes using age, gender, 24-hour urine biochemistry, and stone composition. Materials and Methods: Data from three cohorts were used, Southampton, United Kingdom (n = 3013), Newcastle, United Kingdom (n = 5984), and Bern, Switzerland (n = 794). Of these 3130 had available 24-hour urine biochemistry measurements (calcium, oxalate, urate [Ur], pH, volume), and 1684 had clinical data on kidney stone recurrence. Predictive ML models were built for stone type (n = 5 models) and recurrence (n = 7 models) using the UK data, and externally validated with the Swiss data. Three sets of models were built using complete cases, multiple imputation, and oversampling techniques. Results: For kidney stone type one model (extreme gradient boosting [XGBoost] built using oversampled data) was able to effectively discriminate between calcium oxalate, calcium phosphate, and Ur on both internal and external validation. For stone recurrence, none of the models were able to discriminate between recurrent and nonrecurrent stone formers. Conclusions: Kidney stone recurrence cannot be accurately predicted using modeling tools built using specific 24-hour urinary biochemistry values alone. A single model was able to differentiate between stone types. Further studies to delineate accurate predictive tools should be undertaken using both known and novel risk factors, including radiomics and genomics

Complicated pregnancies in inherited distal renal tubular acidosis: importance of acid-base balance

Inherited distal renal tubular acidosis (dRTA) is caused by impaired urinary acid excretion resulting in hyperchloremic metabolic acidosis. Although the glomerular filtration rate (GFR) is usually preserved, and hypertension and overt proteinuria are absent, it has to be considered that patients with dRTA also suffer from chronic kidney disease (CKD) with an increased risk for adverse pregnancy-related outcomes. Typical complications of dRTA include severe hypokalemia leading to cardiac arrhythmias and paralysis, nephrolithiasis and nephrocalcinosis. Several physiologic changes occur in normal pregnancy including alterations in acid-base and electrolyte homeostasis as well as in GFR. However, data on pregnancy in women with inherited dRTA are scarce. We report the course of pregnancy in three women with hereditary dRTA. Complications observed were severe metabolic acidosis, profound hypokalemia aggravated by hyperemesis gravidarum, recurrent urinary tract infection (UTI) and ureteric obstruction leading to renal failure. However, the outcome of all five pregnancies (1 pregnancy each for mothers n. 1 and 2; 3 pregnancies for mother n. 3) was excellent due to timely interventions. Our findings highlight the importance of close nephrologic monitoring of women with inherited dRTA during pregnancy. In addition to routine assessment of creatinine and proteinuria, caregivers should especially focus on acid-base status, plasma potassium and urinary tract infections. Patients should be screened for renal obstruction in the case of typical symptoms, UTI or renal failure. Furthermore, genetic identification of the underlying mutation may (a) support early nephrologic referral during pregnancy and a better management of the affected woman, and (b) help to avoid delayed diagnosis and reduce complications in affected newborns

Treatment of Pediatric Chronic Kidney Disease-Mineral and Bone Disorder

Purpose of reviewIn this paper, we review the pathogenesis and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD), especially as it relates to pediatric CKD patients.Recent findingsDisordered regulation of bone and mineral metabolism in CKD may result in fractures, skeletal deformities, and poor growth, which is especially relevant for pediatric CKD patients. Moreover, CKD-MBD may result in extra-skeletal calcification and cardiovascular morbidity. Early increases in fibroblast growth factor 23 (FGF23) levels play a key, primary role in CKD-MBD pathogenesis. Therapeutic approaches in pediatric CKD-MBD aim to minimize complications to the growing skeleton and prevent extra-skeletal calcifications, mainly by addressing hyperphosphatemia and secondary hyperparathyroidism. Ongoing clinical trials are focused on assessing the benefit of FGF23 reduction in CKD. CKD-MBD is a systemic disorder that has significant clinical implications. Treatment of CKD-MBD in children requires special consideration in order to maximize growth, optimize skeletal health, and prevent cardiovascular disease