Is there an age cutoff to apply adult formulas for GFR estimation in children?

BACKGROUND Estimation of glomerular filtration rate (eGFR) using a common formula for both adult and pediatric populations is challenging. Using inulin clearances (iGFRs), this study aims to investigate the existence of a precise age cutoff beyond which the Modification of Diet in Renal Disease (MDRD), the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), or the Cockroft-Gault (CG) formulas, can be applied with acceptable precision. Performance of the new Schwartz formula according to age is also evaluated. METHOD We compared 503 iGFRs for 503 children aged between 33 months and 18 years to eGFRs. To define the most precise age cutoff value for each formula, a circular binary segmentation method analyzing the formulas' bias values according to the children's ages was performed. Bias was defined by the difference between iGFRs and eGFRs. To validate the identified cutoff, 30% accuracy was calculated. RESULTS For MDRD, CKD-EPI and CG, the best age cutoff was ≥14.3, ≥14.2 and ≤10.8 years, respectively. The lowest mean bias and highest accuracy were -17.11 and 64.7% for MDRD, 27.4 and 51% for CKD-EPI, and 8.31 and 77.2% for CG. The Schwartz formula showed the best performance below the age of 10.9 years. CONCLUSION For the MDRD and CKD-EPI formulas, the mean bias values decreased with increasing child age and these formulas were more accurate beyond an age cutoff of 14.3 and 14.2 years, respectively. For the CG and Schwartz formulas, the lowest mean bias values and the best accuracies were below an age cutoff of 10.8 and 10.9 years, respectively. Nevertheless, the accuracies of the formulas were still below the National Kidney Foundation Kidney Disease Outcomes Quality Initiative target to be validated in these age groups and, therefore, none of these formulas can be used to estimate GFR in children and adolescent populations.

New associations of classic acute macular neuroretinopathy

PURPOSE: To describe novel underlying associations of classic acute macular neuroretinopathy (AMN). METHODS: Multimodal imaging case series evaluating patients with classic AMN lesions and previously unreported underlying aetiologies. RESULTS: Six patients were included (five women, one man, mean age 30±7 years). Mean distance best corrected visual acuity at initial presentation was 0.21±0.3 logMAR (mean Snellen acuity: 20/30, range 20/15-20/100) and at last follow-up visit 0.09±0.17 logMAR (Snellen acuity: 20/20, range 20/15-20/60). All cases but one had bilateral lesions and showed typical parafoveal hyporeflective lesions on infrared imaging, which corresponded to the hyper-reflectivity in the Henle's layer with attenuation of the external limiting membrane, the ellipsoid zone and interdigitation zone. Underlying diseases included thrombocytopenia and anaemia associated with dengue fever, acute lymphoblastic leukaemia, chronic kidney disease and ulcerative colitis, while Valsalva-like manoeuvre was found to be a potential trigger. Other novel associations included the use of lisdexamphetamine. CONCLUSIONS: Classic AMN may be associated with leukaemia, dengue fever, ulcerative colitis and chronic kidney disease, probably as a result of chorioretinal hypoxia in the setting of thrombocytopenia and anaemia. Adrenergic agonists such as lisdexamphetamine may also contribute to the manifestation of AMN.

PCSK9 Plasma Concentrations Are Independent of GFR and Do Not Predict Cardiovascular Events in Patients with Decreased GFR.

BACKGROUND Impaired renal function causes dyslipidemia that contributes to elevated cardiovascular risk in patients with chronic kidney disease (CKD). The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulator of the LDL receptor and plasma cholesterol concentrations. Its relationship to kidney function and cardiovascular events in patients with reduced glomerular filtration rate (GFR) has not been explored. METHODS Lipid parameters including PCSK9 were measured in two independent cohorts. CARE FOR HOMe (Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Forth Homburg evaluation) enrolled 443 patients with reduced GFR (between 90 and 15 ml/min/1.73 m2) referred for nephrological care that were prospectively followed for the occurrence of a composite cardiovascular endpoint. As a replication cohort, PCSK9 was quantitated in 1450 patients with GFR between 90 and 15 ml/min/1.73 m2 enrolled in the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) that were prospectively followed for cardiovascular deaths. RESULTS PCSK9 concentrations did not correlate with baseline GFR (CARE FOR HOMe: r = -0.034; p = 0.479; LURIC: r = -0.017; p = 0.512). 91 patients in CARE FOR HOMe and 335 patients in LURIC reached an endpoint during a median follow-up of 3.0 [1.8-4.1] years and 10.0 [7.3-10.6] years, respectively. Kaplan-Meier analyses showed that PCSK9 concentrations did not predict cardiovascular events in either cohort [CARE FOR HOMe (p = 0.622); LURIC (p = 0.729)]. Sensitivity analyses according to statin intake yielded similar results. CONCLUSION In two well characterized independent cohort studies, PCSK9 plasma levels did not correlate with kidney function. Furthermore, PCSK9 plasma concentrations were not associated with cardiovascular events in patients with reduced renal function.

Gene expression profile in newborn rat lungs after two days of recovery of mechanical ventilation.

BACKGROUND Preterm infants having immature lungs often require respiratory support, potentially leading to bronchopulmonary dysplasia (BPD). Conventional BPD rodent models based on mechanical ventilation (MV) present outcome measured at the end of the ventilation period. A reversible intubation and ventilation model in newborn rats recently allowed discovering that different sets of genes modified their expression related to time after MV. In a newborn rat model, the expression profile 48 h after MV was analyzed with gene arrays to detect potentially interesting candidates with an impact on BPD development. METHODS Rat pups were injected P4-5 with 2 mg/kg lipopolysaccharide (LPS). One day later, MV with 21 or 60% oxygen was applied during 6 h. Animals were sacrified 48 h after end of ventilation. Affymetrix gene arrays assessed the total gene expression profile in lung tissue. RESULTS In fully treated animals (LPS + MV + 60% O(2)) vs. controls, 271 genes changed expression significantly. All modified genes could be classified in six pathways: tissue remodeling/wound repair, immune system and inflammatory response, hematopoiesis, vasodilatation, and oxidative stress. Major alterations were found in the MMP and complement system. CONCLUSION MMPs and complement factors play a central role in several of the pathways identified and may represent interesting targets for BPD treatment/prevention.Bronchopulmonary dysplasia (BPD) is a chronic lung disease occurring in ~30% of preterm infants born less than 30 wk of gestation (1). Its main risk factors include lung immaturity due to preterm delivery, mechanical ventilation (MV), oxygen toxicity, chorioamnionitis, and sepsis. The main feature is an arrest of alveolar and capillary formation (2). Models trying to decipher genes involved in the pathophysiology of BPD are mainly based on MV and oxygen application to young mammals with immature lungs of different species (3). In newborn rodent models, analyses of lung structure and gene and protein expression are performed for practical reasons directly at the end of MV (4,5,6). However, later appearing changes of gene expression might also have an impact on lung development and the evolution towards BPD and cannot be discovered by such models. Recently, we developed a newborn rat model of MV using an atraumatic (orotracheal) intubation technique that allows the weaning of the newborn animal off anesthesia and MV, the extubation to spontaneous breathing, and therefore allows the evaluation of effects of MV after a ventilation-free period of recovery (7). Indeed, applying this concept of atraumatic intubation by direct laryngoscopy, we recently were able to show significant differences between gene expression changes appearing directly after MV compared to those measured after a ventilation-free interval of 48 h. Immediately after MV, inflammation-related genes showed a transitory modified expression, while another set of more structurally related genes changed their expression only after a delay of 2 d (7). Lung structure, analyzed by conventional 2D histology and also by 3D reconstruction using synchrotron x-ray tomographic microscopy revealed, 48 h after end of MV, a reduced complexity of lung architecture compared to the nonventilated rat lungs, similar to the typical findings in BPD. To extend these observations about late gene expression modifications, we performed with a similar model a full gene expression profile of lung tissue 48 h after the end of MV with either room air or 60% oxygen. Essentially, we measured changes in the expression of genes related to the MMPs and complement system which played a role in many of the six identified mostly affected pathways.

Polypharmacy and specific comorbidities in university primary care settings.

AIMS Polypharmacy is associated with adverse events and multimorbidity, but data are limited on its association with specific comorbidities in primary care settings. We measured the prevalence of polypharmacy and inappropriate prescribing, and assessed the association of polypharmacy with specific comorbidities. METHODS We did a cross-sectional analysis of 1002 patients aged 50-80years followed in Swiss university primary care settings. We defined polypharmacy as ≥5 long-term prescribed drugs and multimorbidity as ≥2 comorbidities. We used logistic mixed-effects regression to assess the association of polypharmacy with the number of comorbidities, multimorbidity, specific sets of comorbidities, potentially inappropriate prescribing (PIP) and potential prescribing omission (PPO). We used multilevel mixed-effects Poisson regression to assess the association of the number of drugs with the same parameters. RESULTS Patients (mean age 63.5years, 67.5% ≥2 comorbidities, 37.0% ≥5 drugs) had a mean of 3.9 (range 0-17) drugs. Age, BMI, multimorbidity, hypertension, diabetes mellitus, chronic kidney disease, and cardiovascular diseases were independently associated with polypharmacy. The association was particularly strong for hypertension (OR 8.49, 95%CI 5.25-13.73), multimorbidity (OR 6.14, 95%CI 4.16-9.08), and oldest age (75-80years: OR 4.73, 95%CI 2.46-9.10 vs.50-54years). The prevalence of PPO was 32.2% and PIP was more frequent among participants with polypharmacy (9.3% vs. 3.2%, p<0.006). CONCLUSIONS Polypharmacy is common in university primary care settings, is strongly associated with hypertension, diabetes mellitus, chronic kidney disease and cardiovascular diseases, and increases potentially inappropriate prescribing. Multimorbid patients should be included in further trials for developing adapted guidelines and avoiding inappropriate prescribing.

Fibroblast growth factor 23 and markers of mineral metabolism in individuals with preserved renal function

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates phosphate homeostasis. Circulating FGF23 is elevated in chronic kidney disease (CKD) and independently associated with poor renal and cardiovascular outcomes and mortality. Because the study of FGF23 in individuals with normal renal function has received little attention, we examined in a large, population based study of 1128 participants the associations of FGF23 with markers of mineral metabolism and renal function. The median estimated glomerular filtration rate (eGFR) of the cohort was 105 ml/min per 1.73 m2, and the median plasma FGF23 was 78.5 RU/ml. FGF23 increased and plasma 1,25-dihydroxyvitamin D3 decreased significantly below an eGFR threshold of 102 and 99 ml/min per 1.73 m2, respectively. In contrast, plasma parathyroid hormone increased continuously with decreasing eGFR and was first significantly elevated at an eGFR of 126 ml/min per 1.73 m2. On multivariable analysis adjusting for sex, age, body mass index, and GFR, FGF23 was negatively associated with 1,25-dihydroxyvitamin D3, and urinary absolute and fractional calcium excretion but not with serum calcium or parathyroid hormone. We found a positive association of FGF23 with plasma phosphate, but no association with urinary absolute or fractional phosphate excretion and, unexpectedly, a positive association with tubular maximum phosphate reabsorption/GFR. Thus, in the absence of CKD, parathyroid hormone increases earlier than FGF23 when the eGFR decreases. The increase in FGF23 occurs at a higher eGFR threshold than previously reported and is closely associated with a decrease in 1,25-dihydroxyvitamin D3. We speculate that the main demonstrable effect of FGF23 in the setting of preserved renal function is suppression of 1,25-dihydroxyvitamin D3 rather than stimulation of renal phosphate excretion.