Plasma metabolites and physical function in patients undergoing hemodialysis.

Impaired physical function contributes to falls, fractures, and mortality among patients undergoing dialysis. Using a metabolomic approach, we identified metabolite alterations and effect size-based composite scores for constructs of impaired gait speed and grip strength. 108 participants incident to dialysis had targeted plasma metabolomics via liquid chromatography-mass spectrometry and physical function assessed (i.e., 4 m walk, handgrip strength). Physical function measures were categorized as above/ below median, with grip utilizing sex-based medians. To develop composite scores, metabolites were identified via Wilcoxon uncorrected p < 0.05 and effect size > 0.40. Receiver operating characteristic analyses tested whether scores differentiated between above/below function groups. Participants were 54% male, 77% Black and 53 ± 14 y with dialysis vintage of 101 ± 50 days. Median (IQR) grip strength was 35.5 (11.1) kg (males) and 20 (8.4) kg (females); median gait speed was 0.82 (0.34) m/s. Of 246 measured metabolites, composite scores were composed of 22 and 12 metabolites for grip strength and gait speed, respectively. Area under the curve for metabolite composite was 0.88 (gait) and 0.911 (grip). Composite scores of physical function performed better than clinical parameters alone in patients on dialysis. These results provide potential pathways for interventions and needed validation in an independent cohort.

A Phase II randomized controlled trial evaluated antithrombotic treatment with fesomersen in patients with kidney failure on hemodialysis.

Patients with kidney failure on hemodialysis (KF-HD) are at high risk for both atherothrombotic events and bleeding. This Phase IIb study evaluated the dose-response of fesomersen, an inhibitor of hepatic Factor XI expression, versus placebo, for bleeding and atherothrombosis in patients with KF-HD. Patients were randomized to receive fesomersen 40, 80, or 120 mg once-monthly, or matching placebo, for up to 12 months. The primary safety endpoint was a composite of major bleeding and clinically relevant non-major bleeding (MB/CRNMB). Exploratory endpoints included post-dialysis arterio-venous (AV)-access bleeding, major atherothrombotic events (composite of fatal or non-fatal myocardial infarction, ischemic stroke, acute limb ischemia/major amputation, systemic embolism, symptomatic venous thromboembolism), AV-access thrombosis, and clotting of the hemodialysis circuit. Of 308 participants randomized, 307 received study treatment and were analyzed. Fesomersen led to a dose-dependent and sustained reduction of steady-state median FXI levels by 53.6% (40 mg group), 71.3% (80 mg group), 86.0% (120 mg group), and 1.9% in the placebo group. MB/CRNMB events occurred in 6.5% (40 mg group), 5.1% (80 mg group), 3.9% (120 mg group), and in 4.0% of those receiving placebo (pooled fesomersen versus placebo P = 0.78). Major atherothrombotic events occurred in 1 patient (1.3%) in each treatment arm. MB/CRNMB bleeding and post-dialysis AV-access bleeding were not related to predicted FXI levels. Lower predicted FXI levels were associated with reductions in hemodialysis circuit clotting (P = 0.002) and AV-access thrombosis (P = 0.014). In patients with KF-HD, fesomersen produced a dose-dependent reduction in FXI levels associated with similar rates of major bleeding compared with placebo. REGISTRATION: URL: https://www.clinicaltrials.gov; unique identifier: NCT04534114.

Translation of mechanistic advances in preeclampsia to the clinic: Long and winding road.

As one of the leading causes of premature birth and maternal and infant mortality worldwide, preeclampsia remains a major unmet public health challenge. Preeclampsia and related hypertensive disorders of pregnancy are estimated to cause >75 000 maternal and 500 000 infant deaths globally each year. Because of rising rates of risk factors such as obesity, in vitro fertilization and advanced maternal age, the incidence of preeclampsia is going up with rates ranging from 5% to 10% of all pregnancies worldwide. A major discovery in the field was the realization that the clinical phenotypes related to preeclampsia, such as hypertension, proteinuria, and other adverse maternal/fetal events, are due to excess circulating soluble fms-like tyrosine kinase-1 (sFlt-1, also referred to as sVEGFR-1). sFlt-1 is an endogenous anti-angiogenic protein that is made by the placenta and acts by neutralizing the pro-angiogenic proteins vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). During the last decade, this work has spawned a new era of molecular diagnostics for early detection of this condition. Antagonizing sFlt-1 either by reducing production or blocking its actions has shown salutary effects in animal models. Further, in early-stage human studies, the therapeutic removal of sFlt-1 from maternal circulation has shown promise in delaying disease progression and improving outcomes. Recently, the FDA approved the first molecular test for preterm preeclampsia (sFlt-1/PlGF ratio) for clinical use in the United States. Measuring serum sFlt-1/PlGF ratio in the acute hospital setting may aid short-term management, particularly regarding step-up or step-down of care, decision to transfer to settings better equipped to manage both the mother and the preterm neonate, appropriate timing of administration of steroids and magnesium sulfate, and in expectant management decisions. The test itself has the potential to save lives. Furthermore, the availability of a molecular test that correlates with adverse outcomes has set the stage for interventional clinical trials testing treatments for this disorder. In this review, we will discuss the role of circulating sFlt-1 and related factors in the pathogenesis of preeclampsia and specifically how this discovery is leading to concrete advances in the care of women with preeclampsia.

Anticoagulation with osocimab in patients with kidney failure undergoing hemodialysis: a randomized phase 2 trial.

Individuals with kidney failure undergoing hemodialysis are at elevated risk for thromboembolic events. Factor (F) XI, which is in the intrinsic pathway of coagulation, is emerging as an attractive target for new anticoagulants that may be safer than existing agents. Osocimab-an inhibitory FXIa antibody-is a potential treatment option for such patients. We conducted a phase 2b, double-blind, placebo-controlled trial, in which 704 participants (448 male, 256 female) with kidney failure undergoing hemodialysis were randomized to receive lower- or higher-dose osocimab or placebo. In total, 686 participants (436 male, 250 female) received treatment for ≤18 months (planned minimal treatment period of 6 months). The co-primary outcomes were clinically relevant bleeding (a composite of major and clinically relevant nonmajor bleeding) and a composite of the incidence of moderate, severe or serious adverse events. Clinically relevant bleeding occurred in 16/232 (6.9%) and 11/224 (4.9%) participants who received lower- and higher-dose osocimab, respectively, and in 18/230 participants (7.8%) who received a placebo. For the composite adverse event endpoint, incidences were 51%, 47% and 43% in the lower-dose osocimab, higher-dose osocimab and placebo groups, respectively. These results suggest that osocimab is associated with a low risk of bleeding and is generally well tolerated in this population; findings that require confirmation in larger trials. ClinicalTrials.gov identifier, NCT04523220 .

Frailty and Clinical Outcomes in Patients Treated With Hemodialysis: A Prospective Cohort Study.

Rationale and Objective: Frailty is common among people with kidney failure treated with hemodialysis (HD). The objective was to describe how frailty evolves over time in people treated by HD, how improvements in frailty and frailty markers are associate with clinical outcomes, and the characteristics that are associated with improvement in frailty. Study Design: Prospective cohort study. Setting and Participants: Adults initiating thrice weekly in-center HD in Canada. Exposure: We classified frailty using a 5-point score (3 or more indicates frailty) based on physical inactivity, slowness or weakness, poor endurance or exhaustion, and malnutrition. We categorized the frailty trajectory as never present, improving, deteriorating, and always present. Outcomes: All-cause death, hospitalizations, and placement into long-term care. Analytical Approach: We examined the association between time-varying frailty measures and these outcomes using Cox and negative binomial models, after adjustment for potential confounders. Results: 985 participants were included and followed up for a median of 33 months; 507 (51%) died, 761 (77%) experienced ≥1 hospitalization and 115 (12%) entered long-term care. Overall, 760 (77%) reported frailty during follow-up. Three-quarters (78%) of those with frailty at baseline remained frail throughout the follow-up, 46% without baseline frailty became frail, and 23% with baseline frailty became nonfrail. Higher frailty scores were associated with an increased risk of mortality (fully adjusted HR, 1.58 per unit; 95% CI, 1.39-1.80) and an increased rate of hospitalization (RR, 1.16 per unit; 95% CI, 1.09-1.23). Compared with those who were frail throughout the follow-up, participants with frailty at baseline but improving during follow-up showed a lower mortality (HR, 0.59; 95% CI, 0.42-0.81), and a lower rate of hospitalization (RR, 0.70; 95% CI, 0.56-0.87). Limitations: There was missing data on frailty at baseline and during follow-up. Conclusions: Frailty was associated with a higher risk of poor outcomes compared with those without frailty, and participants whose status improved from frail to nonfrail showed better clinical outcomes than those who remained frail. These findings emphasize the importance of identifying and implementing effective treatments for frailty in patients receiving maintenance HD.

First Trimester Cardiac Biomarkers among Women with Peripartum Cardiomyopathy: Are There Early Clues to This Late-Pregnancy Phenomenon?

OBJECTIVE: Whether biomarkers may enable early identification of women who develop peripartum cardiomyopathy (PPCM) prior to disease onset remains a question of interest. STUDY DESIGN: A retrospective nested case-control study was conducted to determine whether first trimester N-terminal pro-B type natriuretic peptide (NT-proBNP) or high sensitivity cardiac troponin I (hs-cTnI) differed among women who developed PPCM versus unaffected pregnancies. Cases were matched to unaffected women by age, race, parity, and gestational age of sample (control A) and then further by blood pressure and pregnancy weight gain (control B). RESULTS: First trimester NT-proBNP concentrations were numerically higher among women who subsequently developed PPCM (116 pg/mL [83-177]) as compared with women in control A (56.1 pg/mL [38.7-118.7], p = 0.3) or control B (37.6 [23.3 - 53.8], p <0.05). A higher proportion of women who subsequently developed PPCM (50%) had detectable levels of hs-cTnI as compared with control A (0%, p = 0.03) or control B (18.8%, p = 0.52). Among both cases and controls, hs-cTnI values were low and often below the limit of detection. CONCLUSION: There were differences in first trimester NT-proBNP and hs-cTnI concentrations between women who subsequently developed PPCM and those who did not, raising the possibility the early pregnancy subclinical myocardial dysfunction may be associated with this late-pregnancy disease. KEY POINTS: · First trimester NT-proBNP is numerically higher among women who subsequently develop PPCM.. · First trimester hs-cTnI was nominally higher among women who developed PPCM versus those who did not.. · A significant proportion of normal pregnant women have undetectable hs-cTnI..

Apixaban for Patients With Atrial Fibrillation on Hemodialysis: A Multicenter Randomized Controlled Trial.

BACKGROUND: There are no randomized data evaluating the safety or efficacy of apixaban for stroke prevention in patients with end-stage kidney disease on hemodialysis and with atrial fibrillation (AF). METHODS: The RENAL-AF trial (Renal Hemodialysis Patients Allocated Apixaban Versus Warfarin in Atrial Fibrillation) was a prospective, randomized, open-label, blinded-outcome evaluation (PROBE) of apixaban versus warfarin in patients receiving hemodialysis with AF and a CHA2DS2-VASc score ≥2. Patients were randomly assigned 1:1 to 5 mg of apixaban twice daily (2.5 mg twice daily for patients ≥80 years of age, weight ≤60 kg, or both) or dose-adjusted warfarin. The primary outcome was time to major or clinically relevant nonmajor bleeding. Secondary outcomes included stroke, mortality, and apixaban pharmacokinetics. Pharmacokinetic sampling was day 1, day 3, and month 1. RESULTS: From January 2017 through January 2019, 154 patients were randomly assigned to apixaban (n=82) or warfarin (n=72). The trial stopped prematurely because of enrollment challenges. Time in therapeutic range (international normalized ratio, 2.0-3.0) for warfarin-treated patients was 44% (interquartile range, 23%-59%). The 1-year rates for major or clinically relevant nonmajor bleeding were 32% and 26% in apixaban and warfarin groups, respectively (hazard ratio, 1.20 [95% CI, 0.63-2.30]), whereas 1-year rates for stroke or systemic embolism were 3.0% and 3.3% in apixaban and warfarin groups, respectively. Death was the most common major event in the apixaban (21 patients [26%]) and warfarin (13 patients [18%]) arms. The pharmacokinetic substudy enrolled the target 50 patients. Median steady-state 12-hour area under the curve was 2475 ng/mL×h (10th to 90th percentiles, 1342-3285) for 5 mg of apixaban twice daily and 1269 ng/mL×h (10th to 90th percentiles, 615-1946) for 2.5 mg of apixaban twice daily. There was substantial overlap between minimum apixaban blood concentration, 12-hour area under the curve, and maximum apixaban blood concentration for patients with and without a major or clinically relevant nonmajor bleeding event. CONCLUSIONS: There was inadequate power to draw any conclusion regarding rates of major or clinically relevant nonmajor bleeding comparing apixaban and warfarin in patients with AF and end-stage kidney disease on hemodialysis. Clinically relevant bleeding events were ≈10-fold more frequent than stroke or systemic embolism among this population on anticoagulation, highlighting the need for future randomized studies evaluating the risks versus benefits of anticoagulation among patients with AF and end-stage kidney disease on hemodialysis. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02942407.

Impact of Vitamin D3 Versus Placebo on Cardiac Structure and Function: A Randomized Clinical Trial.

Background Vitamin D supplementation leads to regression of left ventricular (LV) hypertrophy and improves LV function in animal models. However, limited data exist from prospective human studies. We examined whether vitamin D supplementation improved cardiac structure and function in midlife/older individuals in a large randomized trial. Methods and Results The VITAL (Vitamin D and OmegA-3 Trial) was a nationwide double-blind, placebo-controlled randomized trial that tested the effects of vitamin D3 (2000 IU/d) and n-3 fatty acids (1 g/d) on cardiovascular and cancer risk in 25 871 individuals aged ≥50 years. We conducted a substudy of VITAL in which participants underwent echocardiography at baseline and 2 years. Images were interpreted by a blinded investigator at a central core laboratory. The primary end point was change in LV mass. Among 1054 Greater Boston-area participants attending in-clinic visits, we enrolled 1025 into this study. Seventy-nine percent returned for follow-up and had analyzable echocardiograms at both visits. At baseline, the median age was 64 years (interquartile range, 60-69 years), 52% were men, and 43% had hypertension. After 2 years, the change in LV mass did not significantly differ between the vitamin D and placebo arms (median +1.4 g versus +2.6 g, respectively; P=0.32). Changes in systolic and diastolic LV function also did not differ significantly between arms. There were no significant changes in cardiac structure and function between the n-3 fatty acids and placebo arms. Conclusions Among adults aged ≥50 years, neither vitamin D3 nor n-3 fatty acids supplementation had significant effects on cardiac structure and function after 2 years. Registration URL: https://clinicaltrials.gov/; Unique identifiers: NCT01169259 (VITAL) and NCT01630213 (VITAL-Echo).

FGF23 and Cardiovascular Structure and Function in Advanced Chronic Kidney Disease.

Background: Fibroblast growth factor 23 (FGF23) is a bone-derived phosphatonin that is elevated in chronic kidney disease (CKD) and has been implicated in the development of cardiovascular disease. It is unknown whether elevated FGF23 in CKD is associated with impaired cardiovascular functional capacity, as assessed by maximum exercise oxygen consumption (VO2Max). We sought to determine whether FGF23 is associated with cardiovascular functional capacity in patients with advanced CKD and after improvement of VO2Max by kidney transplantation. Methods: We performed secondary analysis of 235 patients from the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) cohort, which recruited patients with stage 5 CKD who underwent kidney transplantation or were waitlisted and hypertensive controls. All patients underwent cardiopulmonary exercise testing (CPET) and echocardiography and were followed longitudinally for 1 year after study enrollment. Results: Patients across FGF23 quartiles differed in BMI (P=0.004) and mean arterial pressure (P<0.001) but did not significantly differ in sex (P=0.5) or age (P=0.08) compared with patients with lower levels of FGF23. Patients with higher FGF23 levels had impaired VO2Max (Q1: 24.2±4.8 ml/min per kilogram; Q4: 18.6±5.2 ml/min per kilogram; P<0.001), greater left ventricular mass index (LVMI; P<0.001), reduced HR at peak exercise (P<0.001), and maximal workload (P<0.001). Kidney transplantation conferred a significant decline in FGF23 at 2 months (P<0.001) before improvement in VO2Max at 1 year (P=0.008). Multivariable regression modeling revealed that changes in FGF23 was significantly associated with VO2Max in advanced CKD (P<0.001) and after improvement after kidney transplantation (P=0.006). FGF23 was associated with LVMI before kidney transplantation (P=0.003), however this association was lost after adjustment for dialysis status (P=0.4). FGF23 was not associated with LVMI after kidney transplantation in all models. Conclusions: FGF23 levels are associated with alterations in cardiovascular functional capacity in advanced CKD and after kidney transplantation. FGF23 is only associated with structural cardiac adaptations in advanced CKD but this was modified by dialysis status, and was not associated after kidney transplantation.

Impaired renal reserve contributes to preeclampsia via the kynurenine and soluble fms-like tyrosine kinase 1 pathway.

To understand how kidney donation leads to an increased risk of preeclampsia, we studied pregnant outbred mice with prior uninephrectomy and compared them with sham-operated littermates carrying both kidneys. During pregnancy, uninephrectomized (UNx) mice failed to achieve a physiological increase in the glomerular filtration rate and during late gestation developed hypertension, albuminuria, glomerular endothelial damage, and excess placental production of soluble fms-like tyrosine kinase 1 (sFLT1), an antiangiogenic protein implicated in the pathogenesis of preeclampsia. Maternal hypertension in UNx mice was associated with low plasma volumes, an increased rate of fetal resorption, impaired spiral artery remodeling, and placental ischemia. To evaluate potential mechanisms, we studied plasma metabolite changes using mass spectrometry and noted that l-kynurenine, a metabolite of l-tryptophan, was upregulated approximately 3-fold during pregnancy when compared with prepregnant concentrations in the same animals, consistent with prior reports suggesting a protective role for l-kynurenine in placental health. However, UNx mice failed to show upregulation of l-kynurenine during pregnancy; furthermore, when UNx mice were fed l-kynurenine in drinking water throughout pregnancy, their preeclampsia-like state was rescued, including a reversal of placental ischemia and normalization of sFLT1 levels. In aggregate, we provide a mechanistic basis for how impaired renal reserve and the resulting failure to upregulate l-kynurenine during pregnancy can lead to impaired placentation, placental hypoperfusion, an antiangiogenic state, and subsequent preeclampsia.

Myocardial Cytoskeletal Adaptations in Advanced Kidney Disease.

Background The myocardial cytoskeleton functions as the fundamental framework critical for organelle function, bioenergetics and myocardial remodeling. To date, impairment of the myocardial cytoskeleton occurring in the failing heart in patients with advanced chronic kidney disease has been largely undescribed. Methods and Results We conducted a 3-arm cross-sectional cohort study of explanted human heart tissues from patients who are dependent on hemodialysis (n=19), hypertension (n=10) with preserved renal function, and healthy controls (n=21). Left ventricular tissues were subjected to pathologic examination and next-generation RNA sequencing. Mechanistic and interference RNA studies utilizing in vitro human cardiac fibroblast models were performed. Left ventricular tissues from patients undergoing hemodialysis exhibited increased myocardial wall thickness and significantly greater fibrosis compared with hypertension patients (P<0.05) and control (P<0.01). Transcriptomic analysis revealed that the focal adhesion pathway was significantly enriched in hearts from patients undergoing hemodialysis. Hearts from patients undergoing hemodialysis exhibited dysregulated components of the focal adhesion pathway including reduced ß-actin (P<0.01), ß-tubulin (P<0.01), vimentin (P<0.05), and increased expression of vinculin (P<0.05) compared with controls. Cytoskeletal adaptations in hearts from the hemodialysis group were associated with impaired mitochondrial bioenergetics, including dysregulated mitochondrial dynamics and fusion, and loss of cell survival pathways. Mechanistic studies revealed that cytoskeletal changes can be driven by uremic and metabolic abnormalities of chronic kidney disease, in vitro. Furthermore, focal adhesion kinase silencing via interference RNA suppressed major cytoskeletal proteins synergistically with mineral stressors found in chronic kidney disease in vitro. Conclusions Myocardial failure in advanced chronic kidney disease is characterized by impairment of the cytoskeleton involving disruption of the focal adhesion pathway, mitochondrial failure, and loss of cell survival pathways.

Effects of Vitamin D3 Supplementation on Cardiovascular and Cancer Outcomes by eGFR in VITAL.

Background: Reduced 25-hydroxyvitamin D (25[OH]D) metabolism and secondary hyperparathyroidism are common with lower estimated glomerular filtration rate (eGFR) and may contribute to cardiovascular disease and cancer risk. Methods: We assessed for heterogeneity by baseline eGFR of the effects of vitamin D3 on cardiovascular and cancer outcomes in the Vitamin D and Omega-3 Trial (VITAL). Participants were randomized to 2000 IU vitamin D3 and/or 1 g Ω-3 fatty acids daily using a placebo-controlled, two-by-two factorial design (5.3 years follow-up). Primary study end points were incident major cardiovascular events and invasive cancer. Changes in serum 25(OH)D and parathyroid hormone (PTH) were examined. Results: Baseline eGFR was available for 15,917 participants. Participants' mean age was 68 years, and 51% were women. Vitamin D3 resulted in higher serum 25(OH)D compared with placebo (difference in change 12.5 ng/ml; 95% CI, 12 to 13.1 ng/ml), without heterogeneity by eGFR (P interaction, continuous eGFR=0.2). Difference in change in PTH between vitamin D3 and placebo was larger with lower eGFR (P interaction=0.05): -6.9 (95% CI, -10.5 to -3.4), -5.8 (95% CI, -8.3 to -3.4), -4 (95% CI, -5.9 to -2.2), and -3.8 (95% CI, -5.6 to -2) pg/ml for eGFR <60, 60-74, 75-89, and ≥90 ml/min per 1.73 m2, respectively. Effects of vitamin D3 supplementation on cardiovascular events (P interaction=0.61) and cancer (P interaction=0.89) did not differ by eGFR: HR=1.14 (95% CI, 0.73 to 1.79), HR=1.06 (95% CI, 0.75 to 1.5), HR=0.92 (95% CI, 0.67 to 1.25), and HR=0.92 (95% CI, 0.66 to 1.27) across eGFR categories for cardiovascular events and HR=1.63 (95% CI, 1.03 to 2.58), HR=0.85 (95% CI, 0.64 to 1.11), HR=0.84 (95% CI, 0.68 to 1.03), and 1.11 (95% CI, 0.92 to 1.35) for cancer, respectively. Conclusions: We observed no significant heterogeneity by baseline eGFR in the effects of vitamin D3 supplementation versus placebo on cardiovascular or cancer outcomes, despite effects on 25(OH)D and PTH concentrations.

Longitudinal changes in glucose during pregnancy in women with gestational diabetes risk factors.

AIMS/HYPOTHESIS: Despite recommendations to screen women with diabetes risk factors for hyperglycaemia in the first trimester, criteria for normal glucose values in early pregnancy have not been firmly established. We aimed to compare glucose levels in early pregnancy with those later in gestation and outside of pregnancy in women with diabetes risk factors. METHODS: In pregnant women (N = 123) followed longitudinally through the postpartum period, and a separate cohort of non-pregnant women (N = 65), we performed 75 g oral glucose tolerance tests. All participants had one or more risk factors for diabetes. Using linear regression, we tested for differences in glucose levels between non-pregnant and pregnant women at early (7-15 weeks) and mid-late (24-32 weeks) gestation as well as postpartum, with adjustment for maternal age, parity, marital status and BMI. In a longitudinal analysis using mixed-effects models, we tested for differences in glucose levels across early and mid-late pregnancy compared with postpartum. Differences are expressed as ß (95% CI). RESULTS: Fasting glucose was lower in pregnant compared with non-pregnant women by 0.34 (0.18, 0.51) mmol/l (p < 0.0001) in early pregnancy and by 0.45 (0.29, 0.61) mmol/l (p < 0.0001) in mid-late pregnancy. In longitudinal models, fasting glucose was lower by 0.13 (0.04, 0.21) mmol/l (p = 0.003) in early pregnancy and by 0.16 (0.08, 0.25) mmol/l (p = 0.0003) in mid-late pregnancy compared with the same women postpartum. Early pregnancy post-load glucose levels did not differ from those in non-pregnant women or the same women postpartum. In mid-late pregnancy, compared with non-pregnant women, elevations in 1 h post-load glucose level (0.60 [-0.12, 1.33] mmol/l, p = 0.10) and 2 h post-load glucose (0.49 [-0.21, 1.19] mmol/l, p = 0.17) were not statistically significant. However, in longitudinal analyses, 1 h and 2 h post-load glucose levels were higher in mid-late pregnancy (by 0.78 [0.35, 1.21] mmol/l, p = 0.0004, and 0.67 [0.30, 1.04] mmol/l, p = 0.0005, respectively) when compared with postpartum. CONCLUSIONS/INTERPRETATION: In women with diabetes risk factors, fasting glucose declines in the first trimester. Post-load glucose increases later in pregnancy. These findings may inform criteria for diagnosing hyperglycaemia early in pregnancy.

Physiological subtypes of gestational glucose intolerance and risk of adverse pregnancy outcomes.

BACKGROUND: Women with gestational glucose intolerance, defined as an abnormal initial gestational diabetes mellitus screening test, are at risk of adverse pregnancy outcomes even if they do not have gestational diabetes mellitus. Previously, we defined the physiological subtypes of gestational diabetes mellitus based on the primary underlying physiology leading to hyperglycemia and found that women with different subtypes had differential risks of adverse outcomes. Physiological subclassification has not yet been applied to women with gestational glucose intolerance. OBJECTIVE: We defined the physiological subtypes of gestational glucose intolerance based on the presence of insulin resistance, insulin deficiency, or mixed pathophysiology and aimed to determine whether these subtypes are at differential risks of adverse outcomes. We hypothesized that women with the insulin-resistant subtype of gestational glucose intolerance would have the greatest risk of adverse pregnancy outcomes. STUDY DESIGN: In a hospital-based cohort study, we studied women with gestational glucose intolerance (glucose loading test 1-hour glucose, ≥140 mg/dL; n=236) and normal glucose tolerance (glucose loading test 1-hour glucose, <140 mg/dL; n=1472). We applied homeostasis model assessment to fasting glucose and insulin levels at 16 to 20 weeks' gestation to assess insulin resistance and deficiency and used these measures to classify women with gestational glucose intolerance into subtypes. We compared odds of adverse outcomes (large for gestational age birthweight, neonatal intensive care unit admission, pregnancy-related hypertension, and cesarean delivery) in each subtype to odds in women with normal glucose tolerance using logistic regression with adjustment for age, race and ethnicity, marital status, and body mass index. RESULTS: Of women with gestational glucose intolerance (12% with gestational diabetes mellitus), 115 (49%) had the insulin-resistant subtype, 70 (27%) had the insulin-deficient subtype, 40 (17%) had the mixed pathophysiology subtype, and 11 (5%) were uncategorized. We found increased odds of large for gestational age birthweight (primary outcome) in women with the insulin-resistant subtype compared with women with normal glucose tolerance (odds ratio, 2.35; 95% confidence interval, 1.43-3.88; P=.001; adjusted odds ratio, 1.74; 95% confidence interval, 1.02-3.48; P=.04). The odds of large for gestational age birthweight in women with the insulin-deficient subtype were increased only after adjustment for covariates (odds ratio, 1.69; 95% confidence interval, 0.84-3.38; P=.14; adjusted odds ratio, 2.05; 95% confidence interval, 1.01-4.19; P=.048). Among secondary outcomes, there was a trend toward increased odds of neonatal intensive care unit admission in the insulin-resistant subtype in an unadjusted model (odds ratio, 2.09; 95% confidence interval, 0.99-4.40; P=.05); this finding was driven by an increased risk of neonatal intensive care unit admission in women with the insulin-resistant subtype and a body mass index of <25 kg/m2. Infants of women with other subtypes did not have increased odds of neonatal intensive care unit admission. The odds of pregnancy-related hypertension in women with the insulin-resistant subtype were increased (odds ratio, 2.09; 95% confidence interval, 1.31-3.33; P=.002; adjusted odds ratio, 1.77; 95% confidence interval, 1.07-2.92; P=.03) compared with women with normal glucose tolerance; other subtypes did not have increased odds of pregnancy-related hypertension. There was no difference in cesarean delivery rates in nulliparous women across subtypes. CONCLUSION: Insulin-resistant gestational glucose intolerance is a high-risk subtype for adverse pregnancy outcomes. Delineating physiological subtypes may provide opportunities for a more personalized approach to gestational glucose intolerance.

Serum Vitamin D: Correlates of Baseline Concentration and Response to Supplementation in VITAL-DKD.

CONTEXT: The effect of daily vitamin D supplementation on the serum concentration of vitamin D (the parent compound) may offer insight into vitamin D disposition. OBJECTIVE: To assess the total serum vitamin D response to vitamin D3 supplementation and whether it varies according to participant characteristics. To compare results with corresponding results for total serum 25-hydroxyvitamin D [25(OH)D], which is used clinically and measured in supplementation trials. DESIGN: Exploratory study within a randomized trial. INTERVENTION: 2000 International Units of vitamin D3 per day (or matching placebo). SETTING: Community-based. PARTICIPANTS: 161 adults (mean ± SD age 70 ± 6 years; 66% males) with type 2 diabetes. MAIN OUTCOME MEASURES: Changes in total serum vitamin D and total serum 25(OH)D concentrations from baseline to year 2. RESULTS: At baseline, there was a positive, nonlinear relation between total serum vitamin D and total serum 25(OH)D concentrations. Adjusted effects of supplementation were a 29.2 (95% CI: 24.3, 34.1) nmol/L increase in serum vitamin D and a 33.4 (95% CI: 27.7, 39.2) nmol/L increase in serum 25(OH)D. Among those with baseline 25(OH)D < 50 compared with ≥ 50 nmol/L, the serum vitamin D response to supplementation was attenuated (15.7 vs 31.2 nmol/L; interaction P-value = 0.02), whereas the serum 25(OH)D response was augmented (47.9 vs 30.7 nmol/L; interaction P-value = 0.05). CONCLUSIONS: Vitamin D3 supplementation increases total serum vitamin D and 25(OH)D concentrations with variation according to baseline 25(OH)D, which suggests that 25-hydroxylation of vitamin D3 is more efficient when serum 25(OH)D concentration is low.

Circulating Angiogenic Factor Levels in Hypertensive Disorders of Pregnancy.

Circulating Angiogenic Factor in Hypertension in PregnancyThis study measured serum soluble fms-like tyrosine kinase 1 to placental growth factor values in pregnant women hospitalized with hypertension. In women with a hypertensive disorder of pregnancy presenting between 23 and 35 weeks' gestation, a soluble fms-like tyrosine kinase 1:placental growth factor ratio ≥40 provided stratification of the risk of progressing to severe preeclampsia within 2 weeks.

Anticoagulation in patients with kidney failure on dialysis: factor XI as a therapeutic target.

Chronic kidney disease is present in almost 10% of the world population and is associated with excess mortality and morbidity. Reduced glomerular filtration rate and the presence and extent of proteinuria, key domains of chronic kidney disease, have both been shown to be strong and independent risk factors for cardiovascular disease. Patients with kidney failure requiring dialysis are at highest risk for cardiovascular events (e.g., stroke or myocardial infarction), and of developing chronic cardiovascular conditions, such as heart failure. Despite the high burden of cardiovascular disease, there is a paucity of evidence supporting therapies to reduce this risk. Although long-term anticoagulant treatment has the potential to prevent thromboembolism in persons with kidney failure on dialysis, this possibility remains understudied. The limited data available on anticoagulation in patients with kidney failure has focused on vitamin K antagonists or direct oral anticoagulants that inhibit thrombin or factor (F) Xa. The risk of bleeding is a major concern with these agents. However, FXI is emerging as a potential safer target for new anticoagulants because FXI plays a greater part in thrombosis than in hemostasis. In this article, we (i) explain the rationale for considering anticoagulation therapy in patients with kidney failure to reduce atherothrombotic events, (ii) highlight the limitations of current anticoagulants in this patient population, (iii) explain the potential benefits of FXI inhibitors, and (iv) summarize ongoing studies investigating FXI inhibition in patients with kidney failure on dialysis.

Transmission of SARS-CoV-2 considering shared chairs in outpatient dialysis: a real-world case-control study.

BACKGROUND: SARS-CoV-2 can remain transiently viable on surfaces. We examined if use of shared chairs in outpatient hemodialysis associates with a risk for indirect patient-to-patient transmission of SARS-CoV-2. METHODS: We used data from adults treated at 2,600 hemodialysis facilities in United States between February 1st and June 8th, 2020. We performed a retrospective case-control study matching each SARS-CoV-2 positive patient (case) to a non-SARS-CoV-2 patient (control) treated in the same dialysis shift. Cases and controls were matched on age, sex, race, facility, shift date, and treatment count. For each case-control pair, we traced backward 14 days to assess possible prior exposure from a 'shedding' SARS-CoV-2 positive patient who sat in the same chair immediately before the case or control. Conditional logistic regression models tested whether chair exposure after a shedding SARS-CoV-2 positive patient conferred a higher risk of SARS-CoV-2 infection to the immediate subsequent patient. RESULTS: Among 170,234 hemodialysis patients, 4,782 (2.8 %) tested positive for SARS-CoV-2 (mean age 64 years, 44 % female). Most facilities (68.5 %) had 0 to 1 positive SARS-CoV-2 patient. We matched 2,379 SARS-CoV-2 positive cases to 2,379 non-SARS-CoV-2 controls; 1.30 % (95 %CI 0.90 %, 1.87 %) of cases and 1.39 % (95 %CI 0.97 %, 1.97 %) of controls were exposed to a chair previously sat in by a shedding SARS-CoV-2 patient. Transmission risk among cases was not significantly different from controls (OR = 0.94; 95 %CI 0.57 to 1.54; p = 0.80). Results remained consistent in adjusted and sensitivity analyses. CONCLUSIONS: The risk of indirect patient-to-patient transmission of SARS-CoV-2 infection from dialysis chairs appears to be low.

Development and analytical validation of a novel bioavailable 25-hydroxyvitamin D assay.

BACKGROUND: Bioavailable 25-hydroxyvitamin D (25OHD) may be a better indicator of vitamin D sufficiency than total 25OHD. This report describes a novel assay for measuring serum bioavailable 25OHD. METHODS: We developed an assay for 25OHD % bioavailability based on competitive binding of 25OHD tracer between vitamin D-binding protein (DBP)-coated affinity chromatography beads and serum DBP. Bioavailable 25OHD, total 25OHD, albumin, and DBP protein concentrations were measured in 89 samples from hospitalized patients and 42 healthy controls to determine how the DBP binding assay responds to differences in concentrations of DBP and compares to calculated bioavailable 25OHD values. RESULTS: DBP binding assay showed a linear relationship between DBP-bound 25OHD tracer recovered from bead supernatant and DBP calibrator concentrations (y = 0.0017x +0.731, R2 = 0.9961, p<0.001). Inversion of this relationship allowed interpolation of DBP binding equivalents based upon 25OHD tracer recovered. The relationship between DBP binding equivalents and % bioavailability fits a non-linear curve, allowing calculation of % bioavailable 25OHD from DBP binding equivalents (y = 10.625x-0.817, R2 = 0.9961, p<0.001). In hospitalized patient samples, there were linear relationships between DBP protein concentrations and DBP binding equivalents (y = 0.7905x + 59.82, R2 = 0.8597, p<0.001), between measured vs. calculated % bioavailability (y = 0.9528 + 0.0357, R2 = 0.7200, p<0.001), and between absolute concentrations of measured vs. calculated bioavailable 25OHD (y = 1.2403 + 0.1221, R2 = 0.8913, p<0.001). CONCLUSIONS: The DBP-binding assay for bioavailable 25OHD shows expected changes in 25OHD % bioavailability in response to changes in DBP concentrations and concordance with calculated bioavailable 25OHD concentrations.