Glomerular Filtration Rate in Former Extreme Low Birth Weight Infants over the Full Pediatric Age Range: A Pooled Analysis

Various cohort studies document a lower glomerular filtration rate (GFR) in former extremely low birth weight (ELBW, <1000 g) neonates throughout childhood when compared to term controls. The current aim is to pool these studies to describe the GFR pattern over the pediatric age range. To do so, we conducted a systematic review on studies reporting on GFR measurements in former ELBW cases while GFR data of healthy age-matched controls included in these studies were co-collected. Based on 248 hits, 6 case-control and 3 cohort studies were identified, with 444 GFR measurements in 380 former ELBW cases (median age 5.3-20.7 years). The majority were small (17-78 cases) single center studies, with heterogeneity in GFR measurement (inulin, cystatin C or creatinine estimated GFR formulae) tools. Despite this, the median GFR (mL/min/1.73 m2) within case-control studies was consistently lower (-13%, range -8% to -25%) in cases, so that a relevant minority (15-30%) has a eGFR<90 mL/min/1.73 m2). Consequently, this pooled analysis describes a consistent pattern of reduced eGFR in former ELBW cases throughout childhood. Research should focus on perinatal risk factors for impaired GFR and long-term outcome, but is hampered by single center cohorts, study size and heterogeneity of GFR assessment tools

Catch-up growth in the first two years of life in Extremely Low Birth Weight (ELBW) infants is associated with lower body fat in young adolescence

Aim To investigate growth patterns and anthropometrics in former extremely low birth weight (ELBW, <1000 g) children and link these outcomes to neurocognition and body

Extremely Low Birth Weight Predisposes to Impaired Renal Health: A Pooled Analysis

Background: A number of studies examined the association between preterm delivery and kidney size and function later in life. However, the number of cases in published cohort studies is low. This study was aimed at performing a multicenter collaboration to pool data to obtain more accurate results to quantify the extent of renal impairment in former extremely low birth weight (ELBW; <1,000 g) children. Methodology: We performed a subject-level metaanalysis to pool data from Cracow (64 cases/34 controls) and Leuven (93 cases/87 controls). We assessed and analyzed cystatin C, estimated glomerular filtration rate (eGFR), ultrasound kidney length, and blood pressure (BP) in 11-year-old ELBW children compared with controls born at term. The prevalence of hypertension (HT) and prehypertension (preHT) in both groups was also analyzed. Results: The study group comprised 157 former ELBW children (gestational age 23–33 weeks and birth weight 430–1,000 g) and 123 children born at term. Former ELBW children had lower mean eGFR (100.62 ± 16.53 vs. 111.89 ± 15.26 mL/min/1.73 m2; p < 0.001), smaller absolute kidney length (8.56 ± 0.78 vs. 9.008 ± 0.73 cm; <0.001), and higher systolic (111.8 ± 9.8 vs. 107.2 ± 9.07 mm Hg; p = 0.01) and diastolic (68.6 ± 6.8 vs. 66.3 ± 7.7 mm Hg; p = 0.03) BP. Smaller renal size in former ELBW children was positively associated with lower birth weight, shorter gestational age, and severity of perinatal complications (intraventricular hemorrhage, length of stay, mechanical ventilation, and oxygen therapy). Conclusion: ELBW is associated with lower eGFR and a high frequency of preHT and HT

Renal Precision Medicine in Neonates and Acute Kidney Injury: How to Convert a Cloud of Creatinine Observations to Support Clinical Decisions

Renal precision medicine in neonates is useful to support decision making on pharmacotherapy, signal detection of adverse (drug) events, and individual prediction of short- and long-term prognosis. To estimate kidney function or glomerular filtration rate (GFR), the most commonly measured and readily accessible biomarker is serum creatinine (Scr). However, there is extensive variability in Scr observations and GFR estimates within the neonatal population, because of developmental physiology and superimposed pathology. Furthermore, assay related differences still matter for Scr, but also exist for Cystatin C. Observations in extreme low birth weight (ELBW) and term asphyxiated neonates will illustrate how renal precision medicine contributes to neonatal precision medicine. When the Kidney Disease Improving Global Outcome (KDIGO) definition of acute kidney injury (AKI) is used, this results in an incidence up to 50% in ELBW neonates, associated with increased mortality and morbidity. However, urine output criteria needed adaptations to broader time intervals or weight trends, while Scr and its trends do not provide sufficient detail on kidney function between ELBW neonates. Instead, we suggest to use assay-specific centile Scr values to better describe postnatal trends and have illustrated its relevance by quantifying an adverse drug event (ibuprofen) and by explaining individual amikacin clearance. Term asphyxiated neonates also commonly display AKI. While oliguria is a specific AKI indicator, the majority of term asphyxiated cases are non-oliguric. Asphyxia results in a clinical significant—commonly transient—mean GFR decrease (−50%) with a lower renal drug elimination. But there is still major (unexplained) inter-individual variability in GFR and subsequent renal drug elimination between these asphyxiated neonates. Recently, the Baby-NINJA (nephrotoxic injury negated by just-in-time action) study provided evidence on the concept that a focus on nephrotoxic injury negation has a significant impact on AKI incidence and severity. It is hereby important to realize that follow-up should not be discontinued at discharge, as there are concerns about long-term renal outcome. These illustrations suggest that integration of renal (patho)physiology into neonatal precision medicine are an important tool to improve contemporary neonatal care, not only for the short-term but also with a positive health impact throughout life

Cysteamine–bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis

Nephropathic cystinosis is a severe monogenic kidney disorder caused by mutations in CTNS, encoding the lysosomal transporter cystinosin, resulting in lysosomal cystine accumulation. The sole treatment, cysteamine, slows down the disease progression, but does not correct the established renal proximal tubulopathy. Here, we developed a new therapeutic strategy by applying omics to expand our knowledge on the complexity of the disease and prioritize drug targets in cystinosis. We identified alpha-ketoglutarate as a potential metabolite to bridge cystinosin loss to autophagy, apoptosis and kidney proximal tubule impairment in cystinosis. This insight combined with a drug screen revealed a bicalutamide–cysteamine combination treatment as a novel dual-target pharmacological approach for the phenotypical correction of cystinotic kidney proximal tubule cells, patient-derived kidney tubuloids and cystinotic zebrafish

Cysteamine–bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis

Nephropathic cystinosis is a severe monogenic kidney disorder caused by mutations in CTNS, encoding the lysosomal transporter cystinosin, resulting in lysosomal cystine accumulation. The sole treatment, cysteamine, slows down the disease progression, but does not correct the established renal proximal tubulopathy. Here, we developed a new therapeutic strategy by applying omics to expand our knowledge on the complexity of the disease and prioritize drug targets in cystinosis. We identified alpha-ketoglutarate as a potential metabolite to bridge cystinosin loss to autophagy, apoptosis and kidney proximal tubule impairment in cystinosis. This insight combined with a drug screen revealed a bicalutamide–cysteamine combination treatment as a novel dual-target pharmacological approach for the phenotypical correction of cystinotic kidney proximal tubule cells, patient-derived kidney tubuloids and cystinotic zebrafish