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Do Extremely Low Gestational Age Neonates Regulate Iron Absorption via Hepcidin?
German, KR, Comstock, BA, Parikh, P, Whittington, D, Mayock, DE, Heagerty, PJ, Bahr, TM, Juul, SE
The Journal of pediatrics. 2022;:62-67.e1
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Abstract
OBJECTIVES To evaluate whether extremely preterm infants regulate iron status via hepcidin. STUDY DESIGN In this retrospective analysis of infants from the Preterm Epo Neuroprotection (PENUT) Trial, urine hepcidin (Uhep) normalized to creatinine (Uhep/UCr) was evaluated among infants randomized to erythropoietin (Epo) or placebo. RESULTS The correlation (r) between Uhep/UCr and serum markers of iron status (ferritin and zinc protoporphyrin-to-heme ratio [ZnPP/H]) and iron dose was assessed. A total of 243 urine samples from 76 infants born at 24-276/7 weeks gestation were analyzed. The median Uhep/UCr concentration was 0.3, 1.3, 0.4, and 0.1 ng/mg at baseline, 2 weeks, 4 weeks, and 12 weeks, respectively, in placebo-treated infants. The median Uhep/UCr value in Epo-treated infants were not significantly different, with the exception of the value at the 2-week time point (median Uhep/UCr, 0.1 ng/mg; P < .001). A significant association was seen between Uhep/UCr and ferritin at 2 weeks (r = 0.63; P < .001) and at 4 weeks (r = 0.41; P = .01) and between Uhep/UCr and ZnPP/H at 2 weeks (r = -0.49; P = .002). CONCLUSIONS Uhep/UCr values correlate with serum iron markers. Uhep/UCr values vary over time and are affected by treatment with Epo, suggesting that extremely preterm neonates can regulate hepcidin and therefore their iron status. Uhep is suppressed in extremely preterm neonates, particularly those treated with Epo.
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Effect of Dapagliflozin on Cardiovascular Outcomes According to Baseline Kidney Function and Albuminuria Status in Patients With Type 2 Diabetes: A Prespecified Secondary Analysis of a Randomized Clinical Trial.
Zelniker, TA, Raz, I, Mosenzon, O, Dwyer, JP, Heerspink, HHJL, Cahn, A, Goodrich, EL, Im, K, Bhatt, DL, Leiter, LA, et al
JAMA cardiology. 2021;(7):801-810
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Abstract
IMPORTANCE Sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, promote renal glucose excretion and reduce cardiovascular (CV) deaths and hospitalizations for heart failure (HHF) among patients with type 2 diabetes. The relative CV efficacy and safety of dapagliflozin according to baseline kidney function and albuminuria status are unknown. OBJECTIVE To assess the CV efficacy and safety of dapagliflozin according to baseline estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR). DESIGN, SETTING, AND PARTICIPANTS This secondary analysis of the randomized clinical trial Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 compared dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and a baseline creatinine clearance of 60 mL/min or higher. Patients were categorized according to prespecified subgroups of baseline eGFR (<60 vs ≥60 mL/min/1.73 m2), urinary albumin to creatinine ratio (UACR; <30 vs ≥30 mg/g), and of chronic kidney disease (CKD) markers using these subgroups (0, 1, or 2). The study was conducted from May 2013 to September 2018. INTERVENTIONS Dapagliflozin vs placebo. MAIN OUTCOMES AND MEASURES The dual primary end points were major adverse cardiovascular events (myocardial infarction, stroke, and CV death) and the composite of CV death or HHF. RESULTS At baseline, 1265 patients (7.4%) had an eGFR below 60 mL/min/1.73 m2, and 5199 patients (30.9%) had albuminuria. Among patients having data for both eGFR and UACR, 10 958 patients (65.1%) had an eGFR equal to or higher than 60 mL/min/1.73 m2 and an UACR below 30 mg/g (mean [SD] age, 63.7 [6.7] years; 40.1% women), 5336 patients (31.7%) had either an eGFR below 60 mL/min/1.73 m2 or albuminuria (mean [SD] age, 64.1 [7.1] years; 32.6% women), and 548 patients (3.3%) had both (mean [SD] age, 66.8 [6.9] years; 30.5% women). In the placebo group, patients with more CKD markers had higher event rates at 4 years as assessed using the Kaplan-Meier approach for the composite of CV death or HHF (3.9% for 0 markers, 8.3% for 1 marker, and 17.4% for 2 markers) and major adverse cardiovascular events (7.5% for 0 markers, 11.6% for 1 marker, and 18.9% for 2 markers). Estimates for relative risk reductions for the composite of CV death or HHF and for major adverse cardiovascular events were generally consistent across subgroups (both P > .24 for interaction), although greater absolute risk reductions were observed with more markers of CKD. The absolute risk difference for the composite of CV death or HHF was greater for patients with more markers of CKD (0 markers, -0.5%; 1 marker, -1.0%; and 2 markers, -8.3%; P = .02 for interaction). The numbers of amputations, cases of diabetic ketoacidosis, fractures, and major hypoglycemic events were balanced or numerically lower with dapagliflozin compared with placebo for patients with an eGFR below 60 mL/min/1.73 m2 and an UACR of 30 mg/g or higher. CONCLUSIONS AND RELEVANCE The effect of dapagliflozin on the relative risk for CV events was consistent across eGFR and UACR groups, with the greatest absolute benefit for the composite of CV death or HHF observed among patients with both reduced eGFR and albuminuria. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01730534.
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Serum creatine kinase and creatinine in adult spinal muscular atrophy under nusinersen treatment.
Freigang, M, Wurster, CD, Hagenacker, T, Stolte, B, Weiler, M, Kamm, C, Schreiber-Katz, O, Osmanovic, A, Petri, S, Kowski, A, et al
Annals of clinical and translational neurology. 2021;(5):1049-1063
Abstract
OBJECTIVE To determine whether serum creatine kinase activity (CK) and serum creatinine concentration (Crn) are prognostic and predictive biomarkers for disease severity, disease progression, and nusinersen treatment effects in adult patients with 5q-associated spinal muscular atrophy (SMA). METHODS Within this retrospective, multicenter observational study in 206 adult patients with SMA, we determined clinical subtypes (SMA types, ambulatory ability) and repeatedly measured CK and Crn and examined disease severity scores (Hammersmith Functional Motor Scale Expanded, Revised Upper Limb Module, and revised Amyotrophic Lateral Sclerosis Functional Rating Scale). Patients were followed under nusinersen treatment for 18 months. RESULTS CK and Crn differed between clinical subtypes and correlated strongly with disease severity scores (e.g., for Hammersmith Functional Motor Scale Expanded: (CK) ρ = 0.786/ (Crn) ρ = 0.558). During the 18 months of nusinersen treatment, CK decreased (∆CK = -17.56%, p < 0.0001), whereas Crn slightly increased (∆Crn = +4.75%, p < 0.05). INTERPRETATION Serum creatine kinase activity and serum creatinine concentration reflect disease severity of spinal muscular atrophy and are promising biomarkers to assess patients with spinal muscular atrophy during disease course and to predict treatment response. The decrease of creatine kinase activity, combined with the tendency of creatinine concentration to increase during nusinersen treatment, suggests reduced muscle mass wasting with improved muscle energy metabolism.
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The effects of 0.9% saline versus Plasma-Lyte 148 on renal function as assessed by creatinine concentration in patients undergoing major surgery: A single-centre double-blinded cluster crossover trial.
Weinberg, L, Li, MH, Churilov, L, Macgregor, C, Garrett, K, Eyles, J, Bellomo, R
PloS one. 2021;(5):e0251718
Abstract
OBJECTIVES Saline and Plasma-Lyte have different physiochemical contents; consequently, they may differently affect patients' renal function. We compared the effects of fluid therapy with 0.9% saline and with Plasma-Lyte 148 on renal function as assessed by creatinine concentration among patients undergoing major surgery. METHODS We conducted a prospective, double-blinded cluster crossover trial comparing the effects of the two fluids on major surgery patients. The primary aim was to establish the pilot feasibility, safety and preliminary efficacy evidence base for a large interventional trial to establish whether saline or Plasma-Lyte is the preferred crystalloid fluid for managing major surgery patients. The primary efficacy outcome was the proportion of patients with changes in renal function as assessed by creatinine concentration during their index hospital admission. We used changes in creatinine to define acute kidney injury (AKI) according to the RIFLE criteria. RESULTS The study was feasible with 100% patient and clinician acceptance. There were no deviations from the trial protocol. After screening, we allocated 602 patients to saline and 458 to Plasma-Lyte. The median (IQR) volume of intraoperative fluid received was 2000 mL (1000:2000) in both groups. Forty-nine saline patients (8.1%) and 49 Plasma-Lyte patients (10.7%) developed a postoperative AKI (adjusted incidence rate ratio [aIRR]: 1.34; 95% CI: 0.93-1.95; p = 0.120). No differences were observed in the development of postoperative complications (aIRR: 0.98; 95% CI: 0.89-1.08) or the severity of the worst complication (aIRR: 1.00; 95% CI: 0.78-1.30). The median (IQR) length of hospital stay was six days (3:11) for the saline group and five days (3:10) for the Plasma-Lyte group (aIRR: 0.85; 95% CI: 0.73-0.98). There were no serious adverse events relating to the trial fluids, nor were there fluid crossover or contamination events. CONCLUSIONS The study design was feasible to support a future follow-up larger clinical trial. Patients treated with saline did not demonstrate an increased incidence of postoperative AKI (defined as changes in creatinine) compared to those treated with Plasma-Lyte. Our findings imply that clinicians can reasonably use either solution intraoperatively for adult patients undergoing major surgery. TRIAL REGISTRATION Registry: Australian New Zealand Clinical Trials Registry; ACTRN12613001042730; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=364988.
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Sodium Intake and Proteinuria/Albuminuria in the Population-Observational, Cross-Sectional Study.
Cirillo, M, Cavallo, P, Zulli, E, Villa, R, Veneziano, R, Costanzo, S, Magnacca, S, Di Castelnuovo, A, Iacoviello, L, On Behalf Of Moli-Sani Study Investigators,
Nutrients. 2021;(4)
Abstract
Sodium effects on proteinuria are debated. This observational, cross-sectional, population-based study investigated relationships to proteinuria and albuminuria of sodium intake assessed as urinary sodium/creatinine ratio (NaCR). In 482 men and 454 women aged 35-94 years from the Moli-sani study, data were collected for the following: urinary NaCR (independent variable); urinary total proteins/creatinine ratio (PCR, mg/g), urinary albumin/creatinine ratio (ACR, mg/g), and urinary non-albumin-proteins/creatinine ratio (calculated as PCR minus ACR) (dependent variables). High values were defined as PCR ≥ 150 mg/g, ACR ≥ 30 mg/g, and urinary non-albumin-proteins/creatinine ratio ≥ 120 mg/g. Urinary variables were measured in first-void morning urine. Skewed variables were log-transformed in analyses. The covariates list included sex, age, energy intake, body mass index, waist/hip ratio, estimated urinary creatinine excretion, smoking, systolic pressure, diastolic pressure, diabetes, history of cardiovascular disease, reported treatment with antihypertensive drug, inhibitor or blocker of the renin-angiotensin system, diuretic, and log-transformed data of total physical activity, leisure physical activity, alcohol intake, and urinary ratios of urea nitrogen, potassium, and phosphorus to creatinine. In multivariable linear regression, standardized beta coefficients of urinary NaCR were positive with PCR (women and men = 0.280 and 0.242, 95% confidence interval = 0.17/0.39 and 0.13/0.35, p < 0.001), ACR (0.310 and 0.265, 0.20/0.42 and 0.16/0.38, p < 0.001), and urinary non-albumin-proteins/creatinine ratio (0.247 and 0.209, 0.14/0.36 and 0.09/0.33, p < 0.001). In multivariable logistic regression, higher quintile of urinary NaCR associated with odds ratio of 1.81 for high PCR (1.55/2.12, p < 0.001), 0.51 of 1.62 for high ACR (1.35/1.95, p < 0.001), and of 1.84 for high urinary non-albumin proteins/creatinine ratio (1.58/2.16, p < 0.001). Findings were consistent in subgroups. Data indicate independent positive associations of an index of sodium intake with proteinuria and albuminuria in the population.
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Endotrophin is associated with chronic multimorbidity and all-cause mortality in a cohort of elderly women.
Staunstrup, LM, Bager, CL, Frederiksen, P, Helge, JW, Brunak, S, Christiansen, C, Karsdal, M
EBioMedicine. 2021;:103391
Abstract
BACKGROUND The signalling peptide endotrophin is derived through proteolytic cleavage of the carboxyl-terminal during formation of type VI collagen. It is expressed by most descendants of the mesenchymal stem cells lineage, including adipocytes and fibroblasts, and have been proposed to be a central extracellular matrix hormone associated with several age-related diseases. We aimed to assess the association of endotrophin with chronic disease incidence and death in older women. METHODS 5,602 elderly Danish women from the observational, prospective cohort: The Prospective Epidemiological Risk Factor (PERF) study were included in the analysis which covered baseline (BL) and follow-up (FU) 14 years later. An elastic net was used to investigate the relative importance of 58 variables to serum endotrophin-levels. 20 chronic diseases were defined on the basis of clinical variables available along with diagnoses extracted from both the National Patient Register, the National Diabetes Register and the Danish Cancer Registry. The cross-sectional associations between endotrophin-levels and these 17 chronic age-related diseases were investigated using logistic regression and a set-analysis explored disease-combinations within multimorbidity. The association of endotrophin with mortality was assessed by Cox proportional hazard models. FINDINGS Formation of type III collagen (PRO-C3), age and creatine-levels were the most influential variables of endotrophin-levels. Several chronic diseases were significantly associated with endotrophin-levels independent of age and BMI including chronic kidney disease (BL OR=3.7, p < 0.001; FU OR = 7.9 p < 0.001), diabetes (BL OR = 1.5, p = 0.0015, FU OR=1.6, p = 0.004) and peripheral arterial disease (BL OR = 1.3, p = 0.029; FU OR=2.4, p < 0.001). Lastly, endotrophin-levels were significantly rising with number of morbidities (p < 0.001) and a predictor of death after adjusting for age and BMI (BL HR=1.95; FU HR = 2.00). INTERPRETATION Endotrophin was associated with death and increased with number of morbidities. Endotrophin may be a central hormone of fibroblast that warrant investigation and possible targeted intervention in several chronic diseases. FUNDING The funder of the PERF study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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Effects of vegetarian versus Mediterranean diet on kidney function: Findings from the CARDIVEG study.
Dinu, M, Colombini, B, Pagliai, G, Giangrandi, I, Cesari, F, Gori, A, Giusti, B, Marcucci, R, Sofi, F
European journal of clinical investigation. 2021;(9):e13576
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BACKGROUND The aim of the present study was to assess the effects of a lacto-ovo-vegetarian diet (VD), compared to a Mediterranean diet (MD), on kidney function in a group of subjects with medium-to-low cardiovascular risk profile. METHODS We analysed 107 subjects (82 women, 25 men; median age 52) who followed a VD (n = 54) and a MD (n = 53) for 3 months in the CARDIVEG study, a randomized, open, crossover trial that compared the effects of these 2 diets on cardiovascular disease risk. RESULTS The effect of the two diets on kidney function markers was evaluated by conducting a general linear model for repeated measurements adjusted for possible confounding factors such as age, sex, physical activity, alcohol, smoking, hypertension, LDL cholesterol, glucose and body weight change. A significant reduction in creatinine (-5.3%; P < .001), urea nitrogen levels (-9%; P = .001), blood urea nitrogen (BUN) (-8.7%; P = .001) and BUN/creatinine ratio (-5.8%; P < .001), and an increase in estimated glomerular filtration rate (eGFR) (+3.5%; P = .001) was observed during the VD period. On the contrary, no significant changes were noted in the MD group. Variations obtained in the two dietary interventions were significantly different (P < .0001) for creatinine levels, BUN/creatinine and eGFR, for which opposite trends were observed in the VD and MD groups. CONCLUSIONS In a selected group of subjects with medium-to-low cardiovascular risk profile, a 3 month VD period determined significant improvements in kidney function markers. Further trials are needed to confirm these results.
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Factors contributing to discrepant estimated glomerular filtration values measured by creatinine and cystatin C in patients with rheumatoid arthritis.
Nakashima, A, Horita, S, Matsunaga, T, Inoue, R, Zoshima, T, Mizushima, I, Hara, S, Ito, K, Fujii, H, Nomura, H, et al
Scientific reports. 2021;(1):9884
Abstract
This study aimed to clarify the factors underlying the discrepancy that has been noted between estimated glomerular filtration ratio (eGFR) measured using serum creatinine (Cr) and eGFR using serum cystatin C (CysC) in patients with rheumatoid arthritis (RA) and to identify those patients whose renal function should be evaluated using CysC. We retrospectively evaluated clinical features, disease activity, Steinbrocker radiological staging, and co-morbidities (diabetes mellitus, hypertension, dyslipidemia) in 238 RA patients. eGFR using serum creatinine (eGFR-Cr) and eGFR using serum cystatin C (eGFR-CysC) were calculated using the new Japanese coefficient-modified Modification of Diet in Renal Disease study equation. To clarify the cause(s) of differences of 20% or more between the two eGFRs, we divided our RA patients into Group A (eGFR-Cr/eGFR-CysC ≥ 1.2) and Group B (eGFR-Cr/eGFR-CysC < 1.2), and searched for factors independently related to Group A. Forty-five patients (18.9%) were assigned to Group A, and 193 (81.1%) to Group B. BMI (Odds Ratio [OR] 0.820, 95% confidence interval [CI] 0.675-0.996), Hb (OR 0.633, 95% CI 0.433-0.926), CK (OR 0.773 per 10 units, 95% CI 0.644-0.933), NSAID use (OR 0.099, 95% CI 0.020-0.494), diabetes mellitus (OR 6.024, 95% CI 1.508-24.390) and stage 4 Steinbrocker radiological stage (OR 10.309, 95% CI 2.994-35.714) were identified as independent relevant factors for Group A by a multifactorial analysis. Renal function in RA patients with low BMI, diabetes, anemia and low CK may be overestimated using eGFR-Cr alone, and such patients need to be evaluated using eGFR-CysC.
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Severe obesity and the impact of medical weight loss on estimated glomerular filtration rate.
Rothberg, AE, McEwen, LN, Herman, WH
PloS one. 2020;(2):e0228984
Abstract
OBJECTIVE To assess the impact of obesity, glucose tolerance, and weight loss on renal function, we measured serum creatinine and cystatin C and estimated glomerular filtration rate (GFR) indexed to 1.73m2 body surface area (BSA) and GFR indexed to actual BSA in subjects with normal and abnormal glucose tolerance before and up to 2 years after medical weight loss. METHODS We studied 146 subjects at baseline and 3-to-6 months after 18% reduction in weight; 43 were also studied at 2-years. GFR was estimated using the MDRD, CKD-EPICr, CKD-EPICysCr, and the CKD-EPICys equations. RESULTS eGFR was consistently lower when creatinine-based rather than cystatin C-based estimating equations were used. eGFR was lower when creatinine-based or cystatin C-based equations were indexed to 1.73m2 BSA than when they were indexed to actual BSA. eGFR indexed to actual BSA was more likely to demonstrate hyperfiltration (eGFR ≥135 ml/min) than eGFR indexed to 1.73m2 BSA and decreased into the normal range with weight loss. eGFR was highest in subjects with impaired fasting glucose but there was little difference in the patterns of change in eGFR across groups by glucose tolerance status. CONCLUSIONS With severe obesity, high fat-free mass and BSA result in low estimates of eGFR indexed to 1.73m2 BSA, especially when creatinine-based estimating equations are used. GFR indexed to actual BSA is approximately 50% higher. When eGFR is indexed to actual BSA, many subjects display evidence of renal hyperfiltration which improves with weight loss. In subjects with severe obesity undergoing medical weight loss, estimating equations that use cystatin C and are indexed to actual BSA may provide a more accurate assessment of renal function.
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Frequency of Clinical Monitoring of Serum Concentrations of Digoxin, Potassium, and Creatinine, and Recording of Electrocardiograms in Digoxin-Treated Patients: A Japanese Claims Database Analysis.
Ooba, N, Sente, A, Abe, M, Watanabe, F, Tsutsumi, D, Nakamura, K, Nakayama, T, Kimura, K, Fukuoka, N
Biological & pharmaceutical bulletin. 2020;(5):913-916
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Guidelines for cardiovascular drug therapy recommend monitoring serum digoxin concentration (SDC) in patients receiving digoxin treatment, especially those with renal dysfunction and hypokalemia. However, only a few studies have reported the prevalence of SDC monitoring and laboratory testing in clinical practice. Therefore, the aim of this study was to describe the frequency of SDC monitoring and laboratory testing in digoxin users and to assess the association between SDC monitoring and patient characteristics. We used the Japanese insurance claims data covering approximately 1.7 million patients aged 20-74 years between January 1, 2005 and March 31, 2014. All patients who had at least one prescription for digoxin were included. The frequency of SDC and laboratory tests was calculated and the association between patient characteristics and SDC monitoring was assessed using logistic regression analysis. A total of 98867 prescriptions of digoxin were issued to 3458 patients between 2005 and 2014. The annual mean frequencies of monitoring SDC, serum potassium level and serum creatinine level and of recording electrocardiograms was 16.8, 34.8, 38.7, and 24.1%, respectively. Atrial fibrillation, chronic heart failure, renal diseases, and use of oral anticoagulants were associated with SDC monitoring. We found the frequency of SDC monitoring to be relatively low in Japanese clinical practice.