Correction: CVVHD results in longer filter life than pre-filter CVVH: Results of a quasi-randomized clinical trial.

[This corrects the article DOI: 10.1371/journal.pone.0278550.].

A plasma protein-based risk score to predict hip fractures.

As there are effective treatments to reduce hip fractures, identification of patients at high risk of hip fracture is important to inform efficient intervention strategies. To obtain a new tool for hip fracture prediction, we developed a protein-based risk score in the Cardiovascular Health Study using an aptamer-based proteomic platform. The proteomic risk score predicted incident hip fractures and improved hip fracture discrimination in two Trøndelag Health Study validation cohorts using the same aptamer-based platform. When transferred to an antibody-based proteomic platform in a UK Biobank validation cohort, the proteomic risk score was strongly associated with hip fractures (hazard ratio per s.d. increase, 1.64; 95% confidence interval 1.53-1.77). The proteomic risk score, but not available polygenic risk scores for fractures or bone mineral density, improved the C-index beyond the fracture risk assessment tool (FRAX), which integrates information from clinical risk factors (C-index, FRAX 0.735 versus FRAX + proteomic risk score 0.776). The developed proteomic risk score constitutes a new tool for stratifying patients according to hip fracture risk; however, its improvement in hip fracture discrimination is modest and its clinical utility beyond FRAX with information on femoral neck bone mineral density remains to be determined.

Blood Pressure, Readmission, and Mortality Among Patients Hospitalized With Acute Kidney Injury.

Importance: Acute kidney injury (AKI) complicates 20% to 25% of hospital admissions and is associated with long-term mortality, especially from cardiovascular disease. Lower systolic blood pressure (SBP) following AKI may be associated with lower mortality, but potentially at the cost of higher short-term complications. Objective: To determine associations of SBP with mortality and hospital readmissions following AKI, and to determine whether time from discharge affects these associations. Design, Setting, and Participants: This retrospective cohort study of adults with AKI during a hospitalization in Veteran Healthcare Association (VHA) hospitals was conducted between January 2013 and December 2018. Patients with 1 year or less of data within the VA system prior to admission, severe or end-stage liver disease, stage 4 or 5 chronic kidney disease, end-stage kidney disease, metastatic cancer, and no blood pressure values within 30 days of discharge were excluded. Data analysis was conducted from May 2022 to February 2024. Exposure: SBP was treated as time-dependent (categorized as <120 mm Hg, 120-129 mm Hg, 130-139 mm Hg, 140-149 mm Hg, 150-159 mm Hg, and ≥160 mm Hg [comparator]). Time spent in each SBP category was accumulated over time and represented in 30-day increments. Main Outcomes and Measures: Primary outcomes were time to mortality and time to all-cause hospital readmission. Cox proportional hazards regression was adjusted for demographics, comorbidities, and laboratory values. To evaluate associations over time, hazard ratios (HRs) were calculated at 60 days, 90 days, 120 days, 180 days, 270 days, and 365 days from discharge. Results: Of 237 409 admissions with AKI, 80 960 (57 242 aged 65 years or older [70.7%]; 77 965 male [96.3%] and 2995 female [3.7%]) were included. The cohort had high rates of diabetes (16 060 patients [20.0%]), congestive heart failure (22 516 patients [28.1%]), and chronic lung disease (27 682 patients [34.2%]), and 1-year mortality was 15.9% (12 876 patients). Overall, patients with SBP between 130 and 139 mm Hg had the most favorable risk level for mortality and readmission. There were clear, time-dependent mediations on associations in all groups. Compared with patients with SBP of 160 mm Hg or greater, the risk of mortality for patients with SBP between 130 and 139 mm Hg decreased between 60 days (adjusted HR, 1.20; 99% CI, 1.00-1.44) and 365 days (adjusted HR, 0.58; 99% CI, 0.45-0.76). SBP less than 120 mm Hg was associated with increased risk of mortality at all time points. Conclusions and Relevance: In this retrospective cohort study of post-AKI patients, there were important time-dependent mediations of the association of blood pressure with mortality and readmission. These findings may inform timing of post-AKI blood pressure treatment.

Effect of glycocalyx-targeted therapy on vascular function in older adults: a randomized controlled trial.

Advancing age increases cardiovascular disease risk, in part, because of impaired glycocalyx thickness and endothelial dysfunction. Glycocalyx-targeted therapies, such as Endocalyx Pro, could improve both glycocalyx thickness and endothelial function in older adults; however, this has yet to be tested. We hypothesized that Endocalyx Pro supplementation would increase glycocalyx thickness and endothelial function in older adults. Twenty-three older adults aged 66 ± 7 yr (52% female) were enrolled in a randomized, double-blind, placebo-controlled, parallel-arms study to investigate the effect of 12-wk Endocalyx Pro supplementation (3,712 mg/day) on glycocalyx thickness and endothelial function. Glycocalyx thickness was assessed using the GlycoCheck, and endothelial function was determined via brachial artery flow-mediated dilation (FMD). Between-group comparisons revealed Endocalyx Pro did not increase glycocalyx thickness in microvessels 4-25 µm (P = 0.33), 4-7 µm (P = 0.07), or 10-25 µm (P = 0.47) in diameter when compared with placebo. In addition, Endocalyx Pro did not significantly improve FMD [mean ratio (95%) confidence interval [CI]) for between-group comparisons, 1.16 (0.77-1.74); P = 0.48]. However, Endocalyx Pro improved FMD normalized to shear rate (SR) area under the curve [mean ratio (95% CI) for between-group comparisons, 2.41 (1.14,4.13); P = 0.001]. Moreover, Endocalyx Pro increased capillary glycocalyx thickness more than placebo in individuals not taking antihypertensive medication [mean difference (95% CI) for between-group comparison, -0.08 (-0.15, -0.01); P = 0.02]. Our pilot study suggests that Endocalyx Pro supplementation is feasible in older adults but has no measurable effect on overall glycocalyx thickness and FMD. However, Endocalyx Pro may have select effects on capillary glycocalyx thickness and FMD normalized to shear rate among older adults, but further investigation is warranted.NEW & NOTEWORTHY Endothelial glycocalyx thickness and vascular endothelial function decline with advancing age. Endocalyx Pro is a glycocalyx-targeted therapy that may improve endothelial glycocalyx thickness and vascular endothelial function in older adults. This study demonstrated that 12-wk Endocalyx Pro supplementation did not improve overall endothelial glycocalyx thickness or flow-mediated dilation in older adults; however, Endocalyx Pro did increase capillary glycocalyx thickness in individuals not taking antihypertensive medication and improve flow-mediated dilation normalized to the shear stimulus.

Does home blood pressure monitoring improve blood pressure-related outcomes in people living with chronic kidney disease? A systematic review.

High blood pressure is an important risk factor for cardiovascular disease and disease progression in chronic kidney disease (CKD). Evidence on the effects of home blood pressure monitoring (HBPM) is limited. This review aimed to determine the effect of HBPM on systolic (SBP) and diastolic blood pressure (DBP) in patients with CKD. We searched medical literature databases for eligible studies presenting pre- and post-data for interventions utilizing HBPM. Study quality was assessed using the NHLBI tools for quality assessment. Heterogeneity prohibited a meta-analysis so estimates of effects were calculated along a sign test to examine the probability of observing the given pattern of positive effect direction. Eighteen studies were included (n = 1187 participants, mean age 56.7 [± 7.7] years). In 15 studies, HBPM was conducted within the context of additional high-level tailored support. Overall, the quality of n = 7/18 studies was rated as "good"; n = 6/18 were "fair," and n = 5/18 were rated as "poor." Interventions utilizing HBPM had a significant effect on SBP, with 14/16 studies favoring the intervention (88% [95% CI: 62%-98%], P = .002). Favorable effects were also seen on DBP (73% [95% CI: 45%-92%], P = .059). HBPM had a favorable effect on blood pressure goal attainment (86% [95% CI: 42%-100%], P = .062). HBPM in patients with CKD as part of a multicomponent intervention may lead to clinically significant reductions in blood pressure; however, research is needed to support the validity of this claim due to the high heterogeneity across the studies included.

Large-scale circulating proteome association study (CPAS) meta-analysis identifies circulating proteins and pathways predicting incident hip fractures.

Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. In an exploratory search of the underlying biology as reflected through the circulating proteome, we performed a comprehensive Circulating Proteome Association Study (CPAS) meta-analysis for incident hip fractures. Analyses included 6430 subjects from two prospective cohort studies (Cardiovascular Health Study and Trøndelag Health Study) with circulating proteomics data (aptamer-based 5 K SomaScan version 4.0 assay; 4979 aptamers). Associations between circulating protein levels and incident hip fractures were estimated for each cohort using age and sex-adjusted Cox regression models. Participants experienced 643 incident hip fractures. Compared with the individual studies, inverse-variance weighted meta-analyses yielded more statistically significant associations, identifying 23 aptamers associated with incident hip fractures (conservative Bonferroni correction 0.05/4979, P < 1.0 × 10-5). The aptamers most strongly associated with hip fracture risk corresponded to two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR. High levels of several inflammation-related proteins (CD14, CXCL12, MMP12, ITIH3) were also associated with increased hip fracture risk. Ingenuity pathway analysis identified reduced LXR/RXR activation and increased acute phase response signaling to be overrepresented among those proteins associated with increased hip fracture risk. These analyses identified several circulating proteins and pathways consistently associated with incident hip fractures. These findings underscore the usefulness of the meta-analytic approach for comprehensive CPAS in a similar manner as has previously been observed for large-scale human genetic studies. Future studies should investigate the underlying biology of these potential novel drug targets.

Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. To increase the understanding of the underlying mechanisms, we performed a meta-analysis of the associations between 4860 circulating proteins and risk of fractures using two large cohorts, including 6430 participants with 643 incident hip fractures. We identified 23 proteins/aptamers associated with incident hip fractures. Two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR were most strongly associated with hip fracture risk. High levels of several inflammation-related proteins were also associated with increased hip fracture risk. Pathway analysis identified reduced LXR/RXR activation and increased acute phase response signaling to be overrepresented among those proteins associated with increased hip fracture risk. Future mechanistic studies should investigate the underlying biology of these novel protein biomarkers which may be potential drug targets.

Hydroxychloroquine use is associated with reduced mortality risk in older adults with rheumatoid arthritis.

BACKGROUND: There is little robust data about the cardiovascular safety of hydroxychloroquine in patients with rheumatoid arthritis (RA), who often have cardiovascular comorbidities. We examined the association between use of hydroxychloroquine (HCQ) in patients with RA and major adverse cardiovascular events (MACE). METHODS: In a retrospective cohort of Medicare beneficiaries aged ≥ 65 years with RA, we identified patients who initiated HCQ (users) and who did not initiate HCQ (non-users) between January 2015-June 2017. Each HCQ user was matched to 2 non-users of HCQ using propensity score derived from patient baseline characteristics. The primary outcome was the occurrence of MACE, defined as acute admissions for stroke, myocardial infarction, or heart failure. Secondary outcomes included all-cause mortality and the composite of MACE and all-cause mortality. Cox proportional hazards model was used to compare outcomes between HCQ users to non-users. RESULTS: The study included 2380 RA patients with incident HCQ use and matched 4633 HCQ non-users over the study period. The mean follow-up duration was 1.67 and 1.63 years in HCQ non-users and users, respectively. In multivariable models, use of HCQ was not associated with the risk of MACE (hazard ratio 1.1; 95% CI: 0.832-1.33). However, use of HCQ was associated with a lower risk of all-cause mortality (HR: 0.54; 95% CI: 0.45-0.64) and the composite of all-cause mortality and MACE (HR 0.67; 95% CI: 0.58-0.78). CONCLUSION: HCQ use was independently associated with a lower risk of mortality in older adults with RA but not with incidence of MACE events. Key Points • Using an incident user design (to avoid the biases of a prevalent user design) and a population-based approach, we examined the effect of hydroxychloroquine (HCQ) on the risk of major cardiovascular events (MACE) in older patients with RA. • We did not find an association between HCQ use and incident MACE. We did, however, find a significant association with the composite outcome (MACE and all-cause mortality) driven by a significant reduction in all-cause mortality with HCQ use.

Effect of acute heparin administration on glycocalyx thickness and endothelial function in healthy younger adults.

The endothelial glycocalyx is a dynamic, gel-like layer that is critical to normal vascular endothelial function. Heparin impairs the endothelial glycocalyx and reduces vascular endothelial function in a murine model; however, this has yet to be tested in healthy humans. We hypothesized that a single bolus dose of heparin would increase circulating glycocalyx components and decrease endothelial glycocalyx thickness resulting in blunted brachial artery vasodilation in healthy younger adults. Healthy adults (n = 19, aged 18-39 yr, 53% female) underwent measurements of the endothelial glycocalyx and vascular endothelial function at baseline and after a single bolus 5,000 U dose of heparin. The glycocalyx components syndecan-1 and heparan sulfate were measured from plasma samples using enzyme-linked immunosorbent assays. Glycocalyx thickness was determined as perfused boundary region (PBR) in sublingual microvessels using the GlycoCheck. Endothelial function was measured via ultrasonography and quantified as brachial artery flow-mediated dilation (FMD). Following acute heparin administration, there was no increase in syndecan-1 or heparan sulfate (P = 0.90 and P = 0.49, respectively). In addition, there was no change in PBR 4-7 µm (P = 0.55), PBR 10-25 µm (P = 0.63), or 4-25 µm (P = 0.49) after heparin treatment. Furthermore, we did not observe a change in FMDmm (P = 0.23), FMD% (P = 0.35), or plasma nitrite concentrations (P = 0.10) in response to heparin. Finally, time to peak dilation and peak FMD normalized to shear stress were unchanged following heparin (P = 0.59 and P = 0.21, respectively). Our pilot study suggests that a single bolus intravenous dose of heparin does not result in endothelial glycocalyx degradation or vascular endothelial dysfunction in healthy younger adults.NEW & NOTEWORTHY The endothelial glycocalyx's role in modulating vascular endothelial dysfunction with aging and disease is becoming increasingly recognized. This study presents novel findings that acute heparin administration is not a feasible method to experimentally degrade the endothelial glycocalyx and measure concurrent changes in vascular endothelial function in healthy humans. Alternative approaches will be needed to translate findings from preclinical studies and test the effects of acute endothelial glycocalyx degradation on vascular endothelial function in humans.

Effect of Resveratrol on Endothelial Function in Patients with CKD and Diabetes: A Randomized Controlled Trial.

BACKGROUND: Patients with CKD and diabetes are at higher risk of developing cardiovascular disease, in part, because of impaired endothelial function. Cardioprotective compounds such as resveratrol could improve endothelial function and attenuate the cardiovascular burden in patients with CKD and diabetes. We hypothesized that resveratrol supplementation would improve endothelial function in patients with CKD and diabetes. METHODS: Twenty-eight adults aged 68±7 years (84% men) with stage 3 CKD and diabetes were enrolled in a randomized, double-blind, placebo-controlled, crossover study to investigate the effects of 6-week resveratrol supplementation (400 mg/d) on endothelial function. Endothelial function was determined through brachial artery flow-mediated dilation. RESULTS: The mean values for eGFR and hemoglobin A 1c were 40±9 ml/min per 1.73 m 2 and 7.36%±0.72%, respectively. Compared with placebo, resveratrol supplementation increased flow-mediated dilation (ratio of geometric mean changes and 95% confidence interval for between-group comparisons, 1.43 (1.15 to 1.77); P value = 0.001). eGFR, hemoglobin A 1c , BP, and nitroglycerin-mediated dilation were unchanged with resveratrol or placebo ( P = 0.15), suggesting the observed change in flow-mediated dilation was likely independent of changes in traditional cardiovascular risk factors. CONCLUSIONS: Resveratrol supplementation improved endothelial function in patients with CKD and diabetes. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Resveratrol and Vascular Function in CKD, NCT03597568 .

The prevalence and treatment of hypertension in Veterans Health Administration, assessing the impact of the updated clinical guidelines.

OBJECTIVE: Hypertension is the most common risk factor for cardiovascular disease (CVD). Several guidelines have lowered diagnostic blood pressure (BP) thresholds and treatment targets for hypertension. We evaluated the impact of the more stringent guidelines among Veterans, a population at high risk of CVD. METHODS: We conducted a retrospective analysis of Veterans with at least two office BP measurements between January 2016 and December 2017. Prevalent hypertension was defined as diagnostic codes related to hypertension, prescribed antihypertensive drugs, or office BP values according to the BP cutoffs at least 140/90 mmHg (Joint National Committee 7 [JNC 7]), at least 130/80 mmHg [American College of Cardiology/American Heart Association (ACC/AHA)], or the 2020 Veterans Health Administration (VHA) guideline (BP ≥130/90 mmHg). Uncontrolled BP was defined per the VHA guideline as mean SBP ≥130 mmHg or DBP ≥90 mmHg. RESULTS: The prevalence of hypertension increased from 71% for BP at least 140/90 to 81% for BP at least 130/90 mmHg and further to 87% for BP at least 130/80 mmHg. Among Veterans with known hypertension ( n  = 2 768 826), a majority [ n  = 1 818 951 (66%)] were considered to have uncontrolled BP per the VHA guideline. Lowering the treatment targets for SBP and DBP significantly increased the number of Veterans who would require initiation of or intensification of pharmacotherapy. The majority of Veterans with uncontrolled BP and at least one CVD risk factor remained uncontrolled after 5 years of follow-up. CONCLUSION: Lowering the BP diagnostic and treatment cutoffs increases the burden on healthcare systems significantly. Targeted interventions are needed to achieve the BP treatment goals.

The associations of markers of endothelial dysfunction with hip fracture risk.

Endothelial dysfunction underlies the development of atherosclerotic vascular disease, which in turn is associated with osteoporotic fractures. Here, we examined the association of two markers of endothelial dysfunction with incident hip fracture risk in older adults but found no statistically significant associations between them. PURPOSE/INTRODUCTION: Endothelial dysfunction underlies the development of atherosclerotic vascular disease. Vascular disease, in turn, is associated with the risk of osteoporotic fractures, such as hip fractures. Here, we examine whether two measures of endothelial dysfunction are related to hip fracture risk. METHODS: Participants for this study were 2792 individuals (mean age 78.6 years) who had flow-mediated dilation (FMD) measured after ischemia in the forearm and 2255 adults (mean age 73.3 years) with measured soluble intercellular adhesion molecule (siCAM) levels, a constitutive endothelial cell membrane protein associated with the initiation of atherosclerosis. Mean follow-up was 9.7 and 11.7 years, respectively. There were 375 and 265 incident hip fractures, respectively, in each group. RESULTS: In Cox proportional hazards models, there was no significant association between FMD response and incident hip fracture (HR per 1% higher FMD was 0.98 [0.93, 1.04]; p = 0.44). In exploratory analyses, when data were examined dichotomously, participants in the lowest 80% of FMD (≤ 4.5%) had an adjusted 1.29 (0.98, 1.68; p = 0.067) higher hazard of hip fracture compared to participants in the upper 20% of FMD change. There were no significant associations between siCAM and incident hip fracture whether examined as a continuous or dichotomized variable. CONCLUSIONS: Among older adults, two measures of endothelial dysfunction were not significantly associated with hip fracture risk. There was a trend for higher fracture risk with lower FMD.

Nephrotoxin Exposure and Acute Kidney Injury in Adults.

BACKGROUND: Rates of nephrotoxic AKI are not well described in adults due to lack of a clear definition, debate over which drugs should be considered nephrotoxins, and illness-related confounding. Nephrotoxic Injury Negated by Just-in Time Action (NINJA), a program that reduces rates of nephrotoxic AKI in pediatric populations, may be able to address these concerns, but whether NINJA can be effectively applied to adults remains unclear. METHODS: In this retrospective cohort study conducted at the University of Iowa Hospital, we included adult patients admitted to a general hospital floor for ≥48 hours during 2019. The NINJA algorithm screened charts for high nephrotoxin exposure and AKI. After propensity score matching, Cox proportional hazard modeling was used to evaluate the relationship between nephrotoxic exposure and all-stage AKI, stage 2-3 AKI, or death. Additional analyses evaluated the most frequent nephrotoxins used in this population. RESULTS: Of 11,311 patients, 1527 (16%) had ≥1 day of high nephrotoxin exposure. Patients with nephrotoxic exposures subsequently developed AKI in 29% of cases, and 22% of all inpatient AKI events met nephrotoxic AKI criteria. Common nephrotoxins were vancomycin, iodinated contrast dye, piperacillin-tazobactam, acyclovir, and lisinopril. After propensity score matching, Cox proportional hazard models for high nephrotoxin exposure were significantly associated with all AKI (hazard ratio [HR] 1.43, 1.19-1.72, P<0.001), stage 2-3 AKI (HR 1.78, 1.18-2.67, P=0.006), and mortality (HR 2.12, 1.09-4.11, P=0.03). CONCLUSIONS: Nephrotoxin exposure in adults is common and is significantly associated with AKI development, including stage 2-3 AKI.

CVVHD results in longer filter life than pre-filter CVVH: Results of a quasi-randomized clinical trial.

BACKGROUND: Filter clotting is a major issue in continuous kidney replacement therapy (CKRT) that interrupts treatment, reduces delivered effluent dose, and increases cost of care. While a number of variables are involved in filter life, treatment modality is an understudied factor. We hypothesized that filters in pre-filter continuous venovenous hemofiltration (CVVH) would have shorter lifespans than in continuous venovenous hemodialysis (CVVHD). METHODS: This was a single center, pragmatic, unblinded, quasi-randomized cluster trial conducted in critically ill adult patients with severe acute kidney injury (AKI) at the University of Iowa Hospitals and Clinics (UIHC) between March 2020 and December 2020. Patients were quasi-randomized by time block to receive pre-filter CVVH (convection) or CVVHD (diffusion). The primary outcome was filter life, and secondary outcomes were number of filters used, number of filters reaching 72 hours, and in-hospital mortality. RESULTS: In the intention-to-treat analysis, filter life in pre-filter CVVH was 79% of that observed in CVVHD (mean ratio 0.79, 95% CI 0.65-0.97, p = 0.02). Median filter life (with interquartile range) in pre-filter CVVH was 21.8 (11.4-45.3) and was 26.6 (13.0-63.5) for CVVHD. In addition, 11.8% of filters in pre-filter CVVH were active for >72 hours, versus 21.2% in the CVVHD group. Finally, filter clotting accounted for the loss of 26.7% of filters in the CVVH group compared to 17.5% in the CVVHD group. There were no differences in overall numbers of filters used or mortality between groups. CONCLUSIONS: Among critically patients with severe AKI requiring CKRT, use of pre-filter CVVH resulted in significantly shorter filter life compared to CVVHD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04762524. Registered 02/21/21-Retroactively registered, https://clinicaltrials.gov/ct2/show/NCT04762524?cond=The+Impact+of+CRRT+Modality+on+Filter+Life&draw=2&rank=1.

Risk Factors for Death Among Veterans Following Acute Kidney Injury.

BACKGROUND: Acute kidney injury is prevalent among hospitalized veterans, and associated with increased risk of death following discharge. However, risk factors for death following acute kidney injury have not been well defined. We developed a mortality prediction model using Veterans Health Administration data. METHODS: This retrospective cohort study included inpatients from 2013 through 2018 with a creatinine increase of ≥0.3 mg/dL. We evaluated 45 variables for inclusion in our final model, with a primary outcome of 1-year mortality. Bootstrap sampling with replacement was used to identify variables selected in >60% of models using stepwise selection. Best sub-sets regression using Akaike information criteria was used to identify the best-fitting parsimonious model. RESULTS: A total of 182,683 patients were included, and 38,940 (21.3%) died within 1 year of discharge. The 10-variable model to predict mortality included age, chronic lung disease, cancer within 5 years, unexplained weight loss, dementia, congestive heart failure, hematocrit, blood urea nitrogen, bilirubin, and albumin. Notably, acute kidney injury stage, chronic kidney disease, discharge creatinine, and proteinuria were not selected for inclusion. C-statistics in the primary validation cohorts were 0.77 for the final parsimonious model, compared with 0.52 for acute kidney injury stage alone. CONCLUSION: We identified risk factors for long-term mortality following acute kidney injury. Our 10-variable model did not include traditional renal variables, suggesting that non-kidney factors contribute to the risk of death more than measures of kidney disease in this population, a finding that may have implications for post-acute kidney injury care.

Oxidative stress contributes to reductions in microvascular endothelial- and nitric oxide-dependent dilation in women with a history of gestational diabetes.

Women with a history of gestational diabetes mellitus (GDM) are twice as likely to develop cardiovascular disease (CVD) and ∼7 times as likely to develop type 2 diabetes as their age-matched counterparts. However, the mechanism(s) mediating these associations remain unclear. We hypothesized that endothelium- and (nitric oxide) NO-dependent dilation would be attenuated through oxidant stress mechanisms in the microvasculature of women with a history of GDM compared with control women with a history of uncomplicated pregnancy (HC). Ten HC (35 ± 4 yr) and 10 GDM (34 ± 4 yr) underwent a standard local heating protocol (42°C; 0.1°C·s-1). Two intradermal microdialysis fibers were placed in the ventral forearm for local delivery of lactated Ringer's (control) or 5 mM l-ascorbate. After full expression of the local heating response, 15 mM NG-nitro-l-arginine methyl ester (NO synthase inhibition) was perfused. Red cell flux was measured continuously by laser-Doppler flowmetry, and cutaneous vascular conductance (CVC = flux/MAP) was standardized to maximum (% CVCmax; 28 mM SNP + 43°C). Urine albumin:creatinine ratio (ACR) was measured. GDM had attenuated endothelium-dependent (GDM: 67 ± 7 vs. HC: 90 ± 4% CVCmax; P < 0.001) and NO-dependent (GDM: 54 ± 7 vs. HC: 71 ± 3% CVCmax; P = 0.001) dilation at the control site and tended to have higher urine ACR (P = 0.06). Both endothelium-dependent (R2 = 0.53, P = 0.02) and NO-dependent (R2 = 0.56, P = 0.01) dilation were related to urine ACR in GDM. l-ascorbate perfusion improved endothelium-dependent (82 ± 5% CVCmax; P = 0.03 vs. control) and NO-dependent (68 ± 5% CVCmax; P = 0.02 vs. control) dilation in GDM but had no effect in HC (P > 0.05). Otherwise healthy women with a history of GDM have attenuated microvascular endothelial function and this dysfunction is mediated, in part, by oxidative stress.NEW & NOTEWORTHY Women who have gestational diabetes during pregnancy are at greater risk for cardiovascular disease and type 2 diabetes in the decade following pregnancy. However, the mechanisms mediating this increased risk are unclear. Herein, we demonstrate that microvascular dysfunction, mediated by increase in oxidative stress, persists after pregnancy in women who had gestational diabetes, despite the remission of glucose tolerance.

Allopurinol Lowers Serum Urate but Does Not Reduce Oxidative Stress in CKD.

Xanthine oxidase (XO) contributes to oxidative stress and vascular disease. Hyperuricemia and gout are common in patients with chronic kidney disease (CKD), a population at increased risk of vascular disease. We evaluated effects of allopurinol on serum XO activity and metabolome of CKD patients who had participated in a randomized double-blind clinical trial of allopurinol vs. placebo. XO activity was measured in participants' serum. XO expression in venous endothelial cells was evaluated via immunofluorescence. Gas chromatography mass spectrometry (GC/MS) was utilized for metabolomics analysis. We found that in patients with stage 3 CKD and hyperuricemia, allopurinol lowered serum urate while increasing serum xanthine levels. Allopurinol, however, did not significantly suppress measured serum XO activity. Of note, baseline serum XO activity was low. Additionally, neither baseline serum XO activity nor XO protein expression were associated with measures of vascular dysfunction or with systemic or endothelial biomarkers of oxidative stress. Allopurinol affected several pathways, including pentose phosphate, pyrimidine, and tyrosine metabolism. Our findings suggest that circulating XO does not contribute to vascular disease in CKD patients. In addition to inhibition of XO activity, allopurinol was observed to impact other pathways; the implications of which require further study.

Association of rheumatoid arthritis with mortality in chronic kidney disease: a cohort study.

BACKGROUND: Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular disease (CVD) as well as with an increased risk of chronic kidney disease (CKD), also a known cardiovascular risk factor. However, it is not known if RA is a predictor of adverse outcomes in patients with CKD. We hypothesized that among a cohort of patients with CKD, RA would be associated with an increased risk of mortality. MATERIALS AND METHODS: We conducted a retrospective study of 3939 participants with CKD from the prospective Chronic Renal Insufficiency Cohort (CRIC) study. The primary outcome of interest was all-cause mortality. Secondary outcomes included CKD progression (defined as end-stage kidney disease or 50% decline in estimated glomerular filtration rate), cardiovascular endpoints, and composite of myocardial infarction, cerebrovascular accident, heart failure, or death. Multivariable Cox proportional hazards regression was utilized, adjusting for potential confounders including age, sex, race/ethnicity, body mass index, current smoker, and education. RESULTS: The study cohort included 83 participants with RA on a disease modifying anti-rheumatic drug (DMARD). In the adjusted analysis, CKD-RA status was significantly associated with an increased risk of death (adjusted HR, aHR, 1.73 (1.27, 2.35)) and composite outcome (aHR 1.65 (1.27-2.15)) even after adjusting for traditional risk factors. Similar statistically significant associations were observed between CKD-RA and other secondary outcomes except for CKD progression. CONCLUSION: RA was associated with higher mortality among individuals with CKD but not progressive renal decline. Further studies evaluating the mechanisms behind this association are needed. Key Points • Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular disease (CVD) as well as with an increased risk of chronic kidney disease (CKD), also a known cardiovascular risk factor. However, it is not known if RA is an independent predictor of adverse outcomes in patients with CKD • In this study, we observed that CKD patients with RA experience higher mortality as well as an increased risk of CVD compared to patients with CKD without comorbid RA • These data provide rationale for more aggressive monitoring for CVD in patients with CKD and RA. They also underscore the need for determining which interventions can help decrease the burden of mortality in these patients.

Platelet Decreases following Continuous Renal Replacement Therapy Initiation as a Novel Risk Factor for Renal Nonrecovery.

BACKGROUND: Continuous renal replacement therapy (CRRT) is a form of dialysis used in critically ill patients, and has recently been associated with renal nonrecovery. Decreases in platelets following CRRT initiation are common and are associated with mortality, but associations with renal recovery are unclear. Our objective was to determine if platelet nadir or the degree of platelet decrease following CRRT initiation was associated with renal nonrecovery. METHODS: This is a secondary analysis of the Randomized Evaluation of Normal versus Augmented Level (RENAL) trial. Primary predictors were platelet nadir discretized by median value and percent platelet decrease following CRRT initiation, with cut points evaluated by decile from 30 to 60%. The 2 primary outcomes were time to RRT-independence and RRT-free days. Secondary outcomes were 28-day mortality, 90-day mortality, intensive care unit (ICU)-free, and hospital-free days. RESULTS: Time to RRT independence censored for death was achieved less frequently in patients with low platelet nadir (hazard ratio [HR] 0.77, confidence interval [CI] 0.66-0.91) and in those with >50% platelet decrease (HR 0.84, CI 0.72-0.97). RRT-free days were lower in both low platelet nadir (odds ratio [OR] 0.94, CI 0.90-0.97) and >50% platelet decrease (OR 0.91, CI 0.88-0.95). These groups also had higher rates of 28- and 90-day mortality and fewer ICU-free and hospital-free days. Thrombocytopenia at CRRT initiation was also associated with renal nonrecovery, although the clinical effect was small. CONCLUSIONS: Platelet nadir <100 × 103/µL and platelet decrease by >50% following CRRT initiation were both associated with lower rates of renal recovery. Further research is needed to evaluate mechanisms-linking platelet changes and renal nonrecovery in CRRT.

Natural antibody and complement activation characterize patients with idiopathic nephrotic syndrome.

Focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) are common forms of idiopathic nephrotic syndrome. The causes of these diseases are incompletely understood, but the response of patients to immunosuppressive therapies suggests that their pathogenesis is at least in part immune mediated. Preclinical and clinical research indicates that activation of the classical pathway of complement contributes to glomerular injury in FSGS. Glomerular IgM deposits are also prominent in some patients, raising the possibility that IgM is a trigger of classical pathway activation. In the present study, we examined the pattern of complement activation in the glomeruli and plasma of patients with nephrotic syndrome. We also tested whether patients with FSGS and MCD have elevated levels of natural IgM reactive with epitopes on glomerular endothelial cells and cardiolipin. We found evidence of classical pathway activation in patients with idiopathic nephrotic syndrome compared with healthy control subjects. We also detected higher levels of self-reactive IgM to both targets. Based on these results, IgM and classical pathway activation may contribute to disease pathogenesis in some patients with FSGS and MCD.NEW & NOTEWORTHY IgM is detected in biopsies from some patients with nephrotic syndrome, although this has been attributed to passive trapping of the protein. We found, however, that IgM colocalizes with complement activation fragments in some glomeruli. We also found that affected patients had higher levels of IgM reactive to glomerular endothelial cell epitopes. Thus, IgM activates the complement system in the glomeruli of some patients with nephrotic syndrome and may contribute to injury.

An Initiative to Improve 30-Day Readmission Rates Using a Transitions-of-Care Clinic Among a Mixed Urban and Rural Veteran Population.

BACKGROUND/OBJECTIVE: Hospital readmissions in the United States, especially in patients at high-risk, cost more than $17 billion annually. Although care transitions is an important area of research, data are limited regarding its efficacy, especially among rural patients. In this study, we describe a novel transitions-of-care clinic (TOCC) to reduce 30-day readmissions in a Veterans Health Administration setting that serves a high proportion of rural veterans. METHODS: In this quality improvement initiative we conducted a pre-post study evaluating clinical outcomes in adult patients at high risk for 30-day readmission (Care Assessment Needs score > 85) discharged from the Iowa City Veterans Affairs (ICVA) Health Care System from 2017 to 2020. The ICVA serves 184,000 veterans across 50 counties in eastern Iowa, western Illinois, and northern Missouri, with more than 60% of these patients residing in rural areas. We implemented a multidisciplinary TOCC to provide in-person or virtual follow-up to high-risk veterans after hospital discharge. The main purpose of this study was to assess how TOCC follow-up impacted the monthly 30-day patient readmission rate. RESULTS: The TOCC resulted in a 19.2% relative reduction in 30-day readmission rates in the 12-month postimplementation period compared to the preimplementation period (9.2% vs 11.4%, P = .04). Virtual visits were more popular than in-person visits among both urban and rural veterans. There was no difference in outcomes between these two follow-up options, and both groups had reduced readmission rates compared to non-TOCC follow-up. CONCLUSIONS: A multidisciplinary TOCC within the ICVA featuring both virtual and in-person visits reduced the 30-day readmission rate. This reduction was particularly notable among patients with congestive heart failure.