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Background and ObjectivesStudies of hypertensive disorders of pregnancy (HDP), including gestational or chronic hypertension (GH/CH) and preeclampsia/eclampsia (PE/E), suggest associations with early-life and mid-life cognition but have been limited by self-report or use of diagnostic codes, exclusion of nulliparous women, and lack of measurement of cognition in later life. We examined the effects of any HDP, GH/CH, PE/E, and nulliparity on cognition in later life.MethodsParticipants included 2,239 women (median age 73) enrolled in the Mayo Clinic Study of Aging with medical record–abstracted pregnancy information. A cognitive battery of 9 tests was conducted every 15 months. Global cognitive and domain-specific z scores (memory, executive/attention, visuospatial, and language) were outcomes. Linear mixed-effect models evaluated associations between pregnancy history (all normotensive, any HPD, HPD subtype [GH/CH, PE/E], or nulliparous) and cognitive decline, adjusting for age and education. Additional models adjusted for APOE, smoking, hypertension, dyslipidemia, body mass index (BMI), diabetes, stroke, and heart disease. Interactions between pregnancy history and age or education on cognitive performance were examined.ResultsOf the 2,239 women, 1,854 (82.8%) had at least 1 pregnancy (1,607 all normotensive, 100 GH/CH, and 147 PE/E); 385 (17.2%) were nulliparous. Cognitive performance did not cross-sectionally differ for women with a history of any HDP, GH/CH, or PE/E vs women with a history of all normotensive pregnancies; women who were nulliparous had lower global and domain-specific cognition (allp< 0.05) in age- and education-adjusted models. There was an interaction (p= 0.015) between nulliparity and education such that the lower cognitive performance was most pronounced among nulliparous women with ≤12 years of education (beta = −0.42,p< 0.001) vs 12 + years (b = −0.11,p= 0.049). Longitudinally, women with any HDP had greater declines in global cognition and attention/executive z scores compared with women with all normotensive pregnancies. When stratified by HDP type, only women with PE/E had greater declines in global cognition (beta = −0.04,p< 0.001), language (beta = −0.03,p= 0.001), and attention (beta = −0.04,p< 0.001) z scores. Adjustment for vascular risk factors, BMI, smoking, andAPOEdid not attenuate results.DiscussionWomen with a history of HDP, especially PE/E, are at greater risk of cognitive decline in later life.

Extracellular vesicles (EVs) are lipid bilayer nanovesicles secreted by cells. EVs contain biological information related to parental cells and provide biomarkers for disease diagnosis. We have previously shown that the levels of podocin and nephrin expression on urinary EVs may be used to diagnose renal injury associated with preeclampsia. This paper describes a nanoparticle-enabled immunoassay integrated with an electrochemical plate for quantifying podocin and nephrin expression in urinary EVs. The strategy entailed capturing EVs on an electrode surface and then labeling EVs with gold nanoparticles that are both functionalized with antibodies for target specificity and impregnated with redox-active metal ions for electrochemical detection. These immunoprobes produced an electrochemical redox signal proportional to the expression level of EV surface markers. Electrochemical immunoassays were carried out in a novel microtiter plate that contained 16 wells with working electrodes connected to onboard counter/reference electrodes via capillary valves. Upon validation with recombinant proteins, a microtiter plate was used for analysis of urinary EVs from healthy and preeclamptic pregnant women. This analysis revealed a higher podocin to nephrin ratio for preeclamptic women compared to healthy controls (4.31 vs 1.69) suggesting that this ratio may be used for disease diagnosis.

The aim of this study was to identify and quantify urinary Angiotensin-Converting-Enzyme (ACE) in hypertensive disorders of pregnancy.Urine samples were analyzed by Western blot. Patients were classified into: normotensive pregnancy (N); preeclampsia and superimposed preeclampsia (PE+SPE); and gestational hypertension (GH).Somatic ACE protein expression was higher in PE+SPE compared to N and GH. There was a positive correlation between ACE and urinary protein to creatinine ratio, systolic and diastolic blood pressures.These results indicate ACE overexpression in the urine of preeclamptic patients and suggest that it may be a new marker for the disease.

Beyond conventional risk factors for cardiovascular disease, women face an additional burden of sex-specific risk factors. Key stages of a woman’s reproductive history may influence or reveal short- and long-term cardiometabolic and cardiovascular trajectories. Early and late menarche, polycystic ovary syndrome, infertility, adverse pregnancy outcomes (eg, hypertensive disorders of pregnancy, gestational diabetes, preterm delivery, and intrauterine growth restriction), and absence of breastfeeding are all associated with increased future cardiovascular disease risk. The menopause transition additionally represents a period of accelerated cardiovascular disease risk, with timing (eg, premature menopause), mechanism, and symptoms of menopause, as well as treatment of menopause symptoms, each contributing to this risk. Differences in conventional cardiovascular disease risk factors appear to explain some, but not all, of the observed associations between reproductive history and later-life cardiovascular disease; further research is needed to elucidate hormonal effects and unique sex-specific disease mechanisms. A history of reproductive risk factors represents an opportunity for comprehensive risk factor screening, refinement of cardiovascular disease risk assessment, and implementation of primordial and primary prevention to optimize long-term cardiometabolic health in women.

Introduction Women with advanced kidney disease are advised to wait until after transplant to pursue pregnancy, but the impact of pregnancy on estimated glomerular filtration rate (eGFR) decline and kidney histology is unclear. Methods We identified a cohort of women aged 18 to 44 years at transplant from 1996 to 2014 at our 3-site program (N = 816) and determined whether they had a pregnancy >20 weeks gestation post-transplant by chart review. Outcomes included rate of change in eGFR after pregnancy, changes in kidney histology before and after pregnancy, graft failure, and 50% reduction in eGFR. Results There were 37 women with one or more pregnancies lasting longer than 20 weeks gestation post-transplant. Comparing women with and without pregnancy post-transplant, there was a significant increase in the rate of eGFR decline after pregnancy (−2.4 ml/min per 1.73 m2 per year vs. −1.9 ml/min per 1.73 m2 per year in women with no pregnancy, P < 0.001). Pregnancy did not affect the risk of graft failure, death-censored graft failure, or 50% reduction in eGFR. Conclusion Pregnancy affects the rate of eGFR decline in the allograft. Postpregnancy biopsy findings revealed an increase in vascular injury, which could be a potential mechanism. We did not find a significant increase in risk of graft failure or reduction in eGFR by 50% owing to pregnancy., Graphical abstract

Objective To evaluate the relationship between hypertensive diseases in pregnancy and kidney function later in life. Methods We evaluated measured glomerular filtration rate (mGFR) using iothalamate urinary clearance in 725 women of the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Women were classified by self-report as nulliparous (n=62), a history of normotensive pregnancies (n=544), a history of hypertensive pregnancies (n=102), or a history of pre-eclampsia (n=17). We compared adjusted associations among these four groups with mGFR using generalized estimating equations to account for familial clustering. Chronic kidney disease (CKD) was defined as mGFR of less than 60 mL/min per 1.73 m2 or urinary albumin-creatinine ratio (UACR) greater than or equal to 30 mg/g. Results Among women with kidney function measurements (mean age, 59±9 years, 52.9% African American), those with a history of hypertensive pregnancy had lower mGFR (–4.66 ml/min per 1.73 m2; 95% CI, -9.12 to -0.20) compared with women with a history of normotensive pregnancies. Compared with women with a history of normotensive pregnancies, women with a history of hypertensive pregnancy also had higher odds of mGFR less than 60 ml/min per 1.73 m2 (odds ratio, 2.09; 95% CI, 1.21 to 3.60). Additionally, women with a history of hypertensive pregnancy had greater odds for chronic kidney disease (odds ratio, 4.89; 95% CI, 1.55 to 15.44), after adjusting for age, race, education, smoking history, hypertension, body mass index, and diabetes. Conclusion A history of hypertension in pregnancy is an important prognostic risk factor for kidney disease. To our knowledge, this is the first and largest investigation showing the association between hypertensive diseases in pregnancy and subsequent kidney disease using mGFR in a large biracial cohort.

Thyroid dysfunction in pregnancy has been associated with hypertensive disorders of pregnancy and poor maternal and fetal outcomes. In this article, we describe two cases of significant thyroid dysfunction leading to new diagnoses of chronic hypertension in pregnancy and review physiologic changes in the thyroid gland, placenta and maternal cardiovascular system during pregnancy.

Hypertensive disorders of pregnancy (HDP) remain one of the major causes of pregnancy-related maternal and fetal morbidity and mortality worldwide. Affected women are also at increased risk for cardiovascular disease later in life, independently of traditional cardiovascular disease risks. Despite the immediate and long-term cardiovascular disease risks, recommendations for diagnosis and treatment of HDP in the United States have changed little, if at all, over past decades, unlike hypertension guidelines for the general population. The reasons for this approach include the question of benefit from normalization of blood pressure treatment for pregnant women, coupled with theoretical concerns for fetal well-being from a reduction in utero-placental perfusion and in utero exposure to antihypertensive medication. This report is based on a review of current literature and includes normal physiological changes in pregnancy that may affect clinical presentation of HDP; HDP epidemiology and the immediate and long-term sequelae of HDP; the pathophysiology of preeclampsia, an HDP commonly associated with proteinuria and increasingly recognized as a heterogeneous disease with different clinical phenotypes and likely distinct pathological mechanisms; a critical overview of current national and international HDP guidelines; emerging evidence that reducing blood pressure treatment goals in pregnancy may reduce maternal severe hypertension without increasing the risk of pregnancy loss, high-level neonatal care, or overall maternal complications; and the increasingly recognized morbidity associated with postpartum hypertension/preeclampsia. Finally, we discuss the future of research in the field and the pressing need to study socioeconomic and biological factors that may contribute to racial and ethnic maternal health care disparities.

The objective of this study was to characterize hypernatremia patients at hospital admission into clusters using an unsupervised machine learning approach and to evaluate the mortality risk among these distinct clusters. We performed consensus cluster analysis based on demographic information, principal diagnoses, comorbidities, and laboratory data among 922 hospitalized adult patients with admission serum sodium of > 145 mEq/L. We calculated the standardized difference of each variable to identify each cluster’s key features. We assessed the association of each hypernatremia cluster with hospital and 1-year mortality. There were three distinct clusters of patients with hypernatremia on admission: 318 (34%) patients in cluster 1, 339 (37%) patients in cluster 2, and 265 (29%) patients in cluster 3. Cluster 1 consisted of more critically ill patients with more severe hypernatremia and hypokalemic hyperchloremic metabolic acidosis. Cluster 2 consisted of older patients with more comorbidity burden, body mass index, and metabolic alkalosis. Cluster 3 consisted of younger patients with less comorbidity burden, higher baseline eGFR, hemoglobin, and serum albumin. Compared to cluster 3, odds ratios for hospital mortality were 15.74 (95% CI 3.75–66.18) for cluster 1, and 6.51 (95% CI 1.48–28.59) for cluster 2, whereas hazard ratios for 1-year mortality were 6.25 (95% CI 3.69–11.46) for cluster 1 and 4.66 (95% CI 2.73–8.59) for cluster 2. Our cluster analysis identified three clinically distinct phenotypes with differing mortality risk in patients hospitalized with hypernatremia.

Background: Reproductive health is an essential part of the care of women with kidney disease. However, the self-reported patient experience of reproductive issues has been underexplored. Materials and Methods: We identified a cohort of women ages 18 to 44 at the time of kidney transplant from 1996 to 2014 at our 3-site program (n = 816). We sent each woman a survey on her reproductive lifespan, characterizing features from menarche to menopause. Results: We received survey responses from 190 patients (27%). One third of respondents reported amenorrhea before transplant, and 61.5% of these women reported resumption of menses post-transplant. The average age of menopause was 45.5 years, earlier than the general population (51.3 years). There were 204 pregnancies pretransplant and 52 pregnancies post-transplant. Pregnancies post-transplant were more likely to be complicated by preeclampsia, preterm delivery, and small for gestational age babies than pregnancies that occurred >5 years before transplant. Pregnancies

BACKGROUND: Preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome share many clinical and biologic features with thrombotic microangiopathy syndromes caused by complement abnormalities. Our hypothesis was that similar functional and genetic alterations in the complement alternative pathway (CAP) are present in these disorders of pregnancy. METHODS: We conducted quantitative analysis of proteins involved in CAP using ELISA and nephelometry on prospectively collected blood samples from patients with severe phenotype preeclampsia (defined as delivery ≤34 weeks due to preeclampsia), HELLP syndrome, or eclampsia, and matched normotensive controls (n=25 in each arm) between 2011 and 2016. Sequencing was performed to interrogate 14 genes encoding CAP components. RESULTS: Both groups were similar in age, gravidity, parity, marital status, and race. The study group had a higher BMI (mean±SD, 32±8 versus 25±4 kg/m(2); P=0.002) and earlier gestational age at delivery (32.5±3.6 versus 40.3±1 weeks; P

RATIONALE & OBJECTIVE: While there are several well-known anatomical and physiological changes during pregnancy that could contribute to kidney stone formation, evidence that they increase the risk of kidney stones during pregnancy is lacking. This study aimed to determine whether there was an increased risk of a first-time symptomatic kidney stone during and after pregnancy. STUDY DESIGN: A population-based matched case-control study. SETTING & PARTICIPANTS: 945 female first-time symptomatic kidney stone formers aged 15–45 years and 1,890 age-matched female controls in Olmsted County, Minnesota from 1984–2012. Index date was the date of onset of a symptomatic kidney stone for both the case and their matched controls. EXPOSURE: The primary exposure was pregnancy with assessment for variation in risk across different time intervals before, during, and after pregnancy. Medical records were manually reviewed to determine the conception and delivery dates for pregnancies. OUTCOME: Medical record-validated first-time symptomatic kidney stone. ANALYTIC APPROACH: Conditional and unconditional multivariable logistic regression analysis. RESULTS: Compared to non-pregnant women, the odds of a symptomatic kidney stone in women was similar in the first trimester (OR, 0.92; p=0.8), began to increase during the second trimester (OR, 2.00; p=0.007), further increased during the third trimester (OR, 2.69; p=0.001), peaked at 0–3 months after delivery (OR, 3.53; p1 year ago) was also associated with a first-time symptomatic kidney stone (OR, 1.27; p=0.01). LIMITATIONS: Observational study design in predominantly white population. The exact timing of stone formation cannot be determined. CONCLUSIONS: Pregnancy increases the risk of a first-time symptomatic kidney stone. This risk peaks close to delivery and then improves by 1 year after delivery, though a modest risk of a kidney stone still exists beyond 1 year after delivery.

Background: Hypertension (HTN) affects almost half of the adults in the US, and most do not have their blood pressure (BP) under control. Minorities and individuals living in rural areas experience health disparities. The goal of this study was to assess the rate of BP control among adults in a large health system that included minorities and adults living in rural areas. Methods: Clinical cohort study of adults with HTN who live in Southeast Minnesota and had at least one outpatient clinic encounter within the Mayo Clinic Health System in the last 12 months (5/2021-5/2022). Data was extracted through the HTN registry of the electronic health record and included age, race, ethnicity, last office BP and any active anti-hypertensives drug use. Results: The overall rate of HTN control among 127,644 individuals with HTN, defined as an office BP < 130/80 mmHg, was 25.7%. The rates of BP control between HTN subjects living in rural (64527, 67.3%) versus urban areas (41285, 32.3 %), were significantly lower at 24.9% vs. 27% respectively, p< 0.001. A total of 8,722 (6.8%) were non-white, including 2640 Black, 1919 Asian, and 2867 Hispanics A total of 5,734 (45%) had a SBP ≥ 140 or DBP ≥ 90 mmHg and 7178 (12.5%) did not have any anti-hypertensives in their medication list. The percentage of White and Asian persons who were not on anti-hypertensives was 12.4% and 12.5%, respectively, while a larger percentage of Black (13.8%) and Hispanic (14%) persons were not (p Conclusion: Among hypertensive adults, BP was not at goal in most patients based on their most recent office BP measurement with a higher rate among those living in rural areas. About 12.5% were not on anti-hypertensives with a disproportionate larger percentage of Black and Hispanic compared to White and Asian persons.

Background: Preeclampsia (PE) is a pregnancy-specific hypertensive disorder which affects up to 7% of all pregnancies. It is associated with increased risk for cardiovascular disease later in life. We have recently reported increased senescence and accelerated aging in women with PE. We hypothesize that senescence burden remains after PE. The aim of this study was to compare senescence profiles, and history of individual chronic conditions and multimorbidity, a marker of accelerated aging, in women with and without a history of PE. Methods: Forty women with histories of PE and 40 with histories of normotensive pregnancy confirmed by manual chart review were age- and parity-matched. None of the women had a history of CVD at the time of recruitment. Markers of senescence (p16, p21 and Klotho) and metabolic syndrome (leptin, adiponectin) were measured and compared between women with and without histories of preeclampsia using conditional logistic regression. The rates of chronic conditions and multimorbidity between the groups were also compared. Results: Urinary Klotho/creatinine levels were significantly lower (median [IQR]: 117 [87.4, 224] vs. 205 [101, 359], respectively, p=0.042), while leptin/adiponectin ratio was significantly higher (median [IQR]: 0.25 [0.13, 0.45] vs. 0.05 [0.02, 0.12], p=0.027) among women with histories of PE compared to controls. There were no significant differences observed in plasma p21 or p16 concentrations. Women with histories of PE experienced a higher prevalence of two or more co-morbidities compared to women with normotensive pregnancies [67.5% (27/40) vs. 22.5% (9/40), p Conclusion: Women with a history of PE had altered markers of senescence, metabolic syndrome and multimorbidity decades after PE.

ObjectivesEvaluate the associations between patients taking ACE inhibitors and angiotensin receptor blockers (ARBs) and their clinical outcomes after an acute viral respiratory illness (AVRI) due to COVID-19.DesignRetrospective cohort.SettingThe USA; 2017–2018 influenza season, 2018–2019 influenza season, and 2019–2020 influenza/COVID-19 season.ParticipantsPeople with hypertension (HTN) taking an ACEi, ARB or other HTN medications, and experiencing AVRI.Main outcome measuresChange in hospital admission, intensive care unit (ICU) or coronary care unit (CCU), acute respiratory distress (ARD), ARD syndrome (ARDS) and all-cause mortality, comparing COVID-19 to pre-COVID-19 influenza seasons.ResultsThe cohort included 1 059 474 episodes of AVRI (653 797 filled an ACEi or ARB, and 405 677 other HTN medications). 58.6% were women and 72.9% with age ≥65. The ACEi/ARB cohort saw a larger increase in risk in the COVID-19 influenza season than the other HTN medication cohort for four out of five outcomes, with an additional 1.5 percentage point (pp) increase in risk of an inpatient stay (95% CI 1.2 to 1.9 pp) and of ICU/CCU use (95% CI 0.3 to 2.7 pp) as well as a 0.7 pp (0.1 to 1.2 pp) additional increase in risk of ARD and 0.9 pp (0.4 to 1.3 pp) additional increase in risk of ARDS. There was no statistically significant difference in the absolute risk of death (−0.2 pp, 95% CI −0.4 to 0.1 pp). However, the relative risk of death in 2019/2020 versus 2017/2018 for the ACEi/ARB group was larger (1.40 (1.36 to 1.44)) than for the other HTN medication cohort (1.24 (1.21 to 1.28)).ConclusionsPeople with AVRI using ACEi/ARBs for HTN had a greater increase in poor outcomes during the COVID-19 pandemic than those using other medications to treat HTN. The small absolute magnitude of the differences likely does not support changes in clinical practice.

Preeclampsia is a pregnancy-specific hypertensive disorder characterized by proteinuria, and vascular injury in the second half of pregnancy. We hypothesized that endothelium-dependent vascular dysfunction is present in a murine model of preeclampsia based on administration of human preeclamptic sera to interleukin −10−/− mice and studied mechanisms that underlie vascular injury. Pregnant wild type and IL-10−/− mice were injected with either normotensive or severe preeclamptic patient sera (sPE) during gestation. A preeclampsia-like phenotype was confirmed by blood pressure measurements; assessment of albuminuria; measurement of angiogenic factors; demonstration of foot process effacement and endotheliosis in kidney sections; and by accumulation of glycogen in placentas from IL-10−/− mice injected with sPE sera (IL-10−/−sPE). Vasomotor function of isolated aortas was assessed. The IL-10−/−sPE murine model demonstrated significantly augmented aortic contractions to phenylephrine and both impaired endothelium-dependent and, to a lesser extent, endothelium-independent relaxation compared to wild type normotensive mice. Treatment of isolated aortas with indomethacin, a cyclooxygenase inhibitor, improved, but failed to normalize contraction to phenylephrine to that of wild type normotensive mice, suggesting the additional contribution from nitric oxide downregulation and effects of indomethacin-resistant vasoconstricting factors. In contrast, indomethacin normalized relaxation of aortas derived from IL-10−/−sPE mice. Thus, our results identify the role of IL-10 deficiency in dysregulation of the cyclooxygenase pathway and vascular dysfunction in the IL-10−/−sPE murine model of preeclampsia, and point towards a possible contribution of nitric oxide dysregulation. These compounds and related mechanisms may serve both as diagnostic markers and therapeutic targets for preventive and treatment strategies in preeclampsia.

A key immunomodulatory cytokine, IL-10 (interleukin-10), has been shown to be dysregulated in preeclampsia, a pregnancy-specific hypertensive disorder, further characterized by multi-system involvement. However, studies have reported inconsistent findings about circulating IL-10 levels in preeclamptic versus normotensive pregnancies. The aim of the present systematic review and meta-analysis was to assess circulating IL-10 levels in preeclamptic and normotensive pregnancies at 2 time points: before, and at the time of preeclampsia diagnosis. PubMED, EMBASE, and Web of Science databases were searched to include all published studies examining circulating IL-10 levels in preeclamptic and normotensive pregnancies. Differences in IL-10 levels were evaluated by standardized mean differences. Of 876 abstracts screened, 56 studies were included in the meta-analysis. Circulating IL-10 levels were not different before the time of active disease (standardized mean differences, −0.01 [95% CI, −0.11 to 0.08]; P =0.76). At the time of active disease, women with preeclampsia (n=1599) had significantly lower IL-10 levels compared with normotensive controls (n=1998; standardized mean differences, −0.79 [95% CI, −1.22 to −0.35]; P =0.0004). IL-10 levels were lower in both early/severe and late/mild forms of preeclampsia. Subgroup analysis revealed that IL-10 measurement methodology (ELISA or multiplex bead array) and the sample type (plasma or serum) significantly influenced the observed differences, with the use of sera paired with ELISA technology providing the best distinction in IL-10 levels between preeclamptic and normotensive pregnancies. These findings support the role of decreased IL-10 levels in the pathophysiology of preeclampsia. Future studies should address the therapeutic potential of IL-10 in preeclampsia.

The coronavirus disease 2019 (COVID-19) pandemic is associated with significant morbidity and mortality throughout the world, predominantly due to lung and cardiovascular injury. The virus responsible for COVID-19—severe acute respiratory syndrome coronavirus 2—gains entry into host cells via ACE2 (angiotensin-converting enzyme 2). ACE2 is a primary enzyme within the key counter-regulatory pathway of the renin-angiotensin system (RAS), which acts to oppose the actions of Ang (angiotensin) II by generating Ang-(1–7) to reduce inflammation and fibrosis and mitigate end organ damage. As COVID-19 spans multiple organ systems linked to the cardiovascular system, it is imperative to understand clearly how severe acute respiratory syndrome coronavirus 2 may affect the multifaceted RAS. In addition, recognition of the role of ACE2 and the RAS in COVID-19 has renewed interest in its role in the pathophysiology of cardiovascular disease in general. We provide researchers with a framework of best practices in basic and clinical research to interrogate the RAS using appropriate methodology, especially those who are relatively new to the field. This is crucial, as there are many limitations inherent in investigating the RAS in experimental models and in humans. We discuss sound methodological approaches to quantifying enzyme content and activity (ACE, ACE2), peptides (Ang II, Ang-[1–7]), and receptors (types 1 and 2 Ang II receptors, Mas receptor). Our goal is to ensure appropriate research methodology for investigations of the RAS in patients with severe acute respiratory syndrome coronavirus 2 and COVID-19 to ensure optimal rigor and reproducibility and appropriate interpretation of results from these investigations.

Men are consistently overrepresented in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and coronavirus disease 2019 (COVID-19) severe outcomes, including higher fatality rates. These differences are likely due to gender-specific behaviors, genetic and hormonal factors, and sex differences in biological pathways related to SARS-CoV-2 infection. Several social, behavioral, and comorbid factors are implicated in the generally worse outcomes in men compared with women. Underlying biological sex differences and their effects on COVID-19 outcomes, however, have received less attention. The present review summarizes the available literature regarding proposed molecular and cellular markers of COVID-19 infection, their associations with health outcomes, and any reported modification by sex. Biological sex differences characterized by such biomarkers exist within healthy populations and also differ with age- and sex-specific conditions, such as pregnancy and menopause. In the context of COVID-19, descriptive biomarker levels are often reported by sex, but data pertaining to the effect of patient sex on the relationship between biomarkers and COVID-19 disease severity/outcomes are scarce. Such biomarkers may offer plausible explanations for the worse COVID-19 outcomes seen in men. There is the need for larger studies with sex-specific reporting and robust analyses to elucidate how sex modifies cellular and molecular pathways associated with SARS-CoV-2. This will improve interpretation of biomarkers and clinical management of COVID-19 patients by facilitating a personalized medical approach to risk stratification, prevention, and treatment.

In the murine venous thrombosis model induced by ligation of the inferior vena cava (IVCL), genetic deficiency of heme oxygenase-1 (HO-1) increases clot size. This study examined whether induction of HO-1 or administration of its products reduces thrombosis. Venous HO-1 upregulation by gene delivery reduced clot size, as did products of HO activity, biliverdin, and carbon monoxide. Induction of HO-1 by hemin reduced clot formation, clot size, and upregulation of plasminogen activator inhibitor-1 (PAI-1) that occurs in the IVCL model, while leaving urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA) expression unaltered. The reductive effect of hemin on clot size required HO activity. The IVCL model exhibited relatively high concentrations of heme that peaked just before maximum clot size, then declined as clot size decreased. Administration of hemin decreased heme concentration in the IVCL model. HO-2 mRNA was induced twofold in the IVCL model (vs. 40-fold HO-1 induction), but clot size was not increased in HO-2−/− mice compared with HO-2+/+ mice. Hemopexin, the major heme-binding protein, was induced in the IVCL model, and clot size was increased in hemopexin−/− mice compared with hemopexin+/+ mice. We conclude that in the IVCL model, the heme-degrading protein HO-1 and HO products inhibit thrombus formation, as does the heme-binding protein, hemopexin. The reductive effects of hemin administration require HO activity and are mediated, in part, by reducing PAI-1 upregulation in the IVCL model. We speculate that HO-1, HO, and hemopexin reduce clot size by restraining the increase in clot concentration of heme (now recognized as a procoagulant) that otherwise occurs. NEW & NOTEWORTHY This study provides conclusive evidence that two proteins, one heme-degrading and the other heme-binding, inhibit clot formation. This may serve as a new therapeutic strategy in preventing and treating venous thromboembolic disease.

To profile juxtaglomerular cell tumors (JXG) and histologic mimics by analyzing renin expression; to identify non-JXG renin-producing tumors in The Cancer Genome Atlas (TCGA) data sets; and to define the prevalence of hypertension (HTN) and patient outcomes with angiotensin signaling inhibitor (ASI) use in tumors of interest.Thirteen JXGs and 10 glomus tumors (GTs), a histologic mimic, were evaluated for clinicopathologic features; TCGA data were analyzed to identify non-JXG renin-overexpressing tumors. An institutional registry was queried to determine the incidence of HTN, the use of ASIs in hypertensive patients, and the impact of ASIs on outcomes including progression-free survival (PFS) in a tumor type with high renin expression (clear cell renal cell carcinoma [CC-RCC] diagnosed between January 1, 2005, and December 31, 2012).We found an association between renin production and HTN in JXG compared with GT. Analysis of TCGA data found that a subset of CC-RCCs overexpress renin relative to 29 other tumor types. Furthermore, analysis of our institutional registry revealed a high prevalence (64%) of HTN among 1203 patients treated with radical or partial nephrectomy for nonmetastatic CC-RCC. On multivariable Cox regression, patients with HTN treated with ASIs (34%) had improved PFS (hazard ratio, 0.76; 95% CI, 0.57 to 1.00; P=.05) compared with patients with HTN not treated with ASIs (30%).The identification of renin expression in a subset of CC-RCC may provide a biologic rationale for the high prevalence of HTN and improved PFS with ASI use in hypertensive patients with nonmetastatic CC-RCC.

Background: The objectives of this study were to classify patients with serum magnesium derangement on hospital admission into clusters using unsupervised machine learning approach and to evaluate the mortality risks among these distinct clusters. Methods: Consensus cluster analysis was performed based on demographic information, principal diagnoses, comorbidities, and laboratory data in hypomagnesemia (serum magnesium ≤ 1.6 mg/dL) and hypermagnesemia cohorts (serum magnesium ≥ 2.4 mg/dL). Each cluster’s key features were determined using the standardized mean difference. The associations of the clusters with hospital mortality and one-year mortality were assessed. Results: In hypomagnesemia cohort (n = 13,320), consensus cluster analysis identified three clusters. Cluster 1 patients had the highest comorbidity burden and lowest serum magnesium. Cluster 2 patients had the youngest age, lowest comorbidity burden, and highest kidney function. Cluster 3 patients had the oldest age and lowest kidney function. Cluster 1 and cluster 3 were associated with higher hospital and one-year mortality compared to cluster 2. In hypermagnesemia cohort (n = 4671), the analysis identified two clusters. Compared to cluster 1, the key features of cluster 2 included older age, higher comorbidity burden, more hospital admissions primarily due to kidney disease, more acute kidney injury, and lower kidney function. Compared to cluster 1, cluster 2 was associated with higher hospital mortality and one-year mortality. Conclusion: Our cluster analysis identified clinically distinct phenotypes with differing mortality risks in hospitalized patients with dysmagnesemia. Future studies are required to assess the application of this ML consensus clustering approach to care for hospitalized patients with dysmagnesemia.

Background: Lactic acidosis is a heterogeneous condition with multiple underlying causes and associated outcomes. The use of multi-dimensional patient data to subtype lactic acidosis can personalize patient care. Machine learning consensus clustering may identify lactic acidosis subgroups with unique clinical profiles and outcomes. Methods: We used the Medical Information Mart for Intensive Care III database to abstract electronic medical record data from patients admitted to intensive care units (ICU) in a tertiary care hospital in the United States. We included patients who developed lactic acidosis (defined as serum lactate ≥ 4 mmol/L) within 48 h of ICU admission. We performed consensus clustering analysis based on patient characteristics, comorbidities, vital signs, organ supports, and laboratory data to identify clinically distinct lactic acidosis subgroups. We calculated standardized mean differences to show key subgroup features. We compared outcomes among subgroups. Results: We identified 1919 patients with lactic acidosis. The algorithm revealed three best unique lactic acidosis subgroups based on patient variables. Cluster 1 (n = 554) was characterized by old age, elective admission to cardiac surgery ICU, vasopressor use, mechanical ventilation use, and higher pH and serum bicarbonate. Cluster 2 (n = 815) was characterized by young age, admission to trauma/surgical ICU with higher blood pressure, lower comorbidity burden, lower severity index, and less vasopressor use. Cluster 3 (n = 550) was characterized by admission to medical ICU, history of liver disease and coagulopathy, acute kidney injury, lower blood pressure, higher comorbidity burden, higher severity index, higher serum lactate, and lower pH and serum bicarbonate. Cluster 3 had the worst outcomes, while cluster 1 had the most favorable outcomes in terms of persistent lactic acidosis and mortality. Conclusions: Consensus clustering analysis synthesized the pattern of clinical and laboratory data to reveal clinically distinct lactic acidosis subgroups with different outcomes.

Extracellular vesicles (EVs) are lipid bilayer particles secreted from various cells. EVs carry molecular information of parent cells and hold considerable promise for early disease diagnostics. This paper describes a general strategy for multiplexed immunosensing of EV surface proteins, focusing on surface markers CD63, CD81, nephrin, and podocin to prove the concept. This sensing strategy entailed functionalizing gold nanoparticles (AuNPs) with two types of antibodies and then tagging with metal ions, either Pb2+ or Cu2+. The metal ions served as redox reporters, generating unique redox peaks at -0.23 and 0.28 V (vs Ag/AgCl) during electrochemical oxidation of Pb2+ and Cu2+, respectively. Capture of EVs on the working electrode, followed by labeling with immunoprobes and square wave voltammetry, produced redox currents proportional to concentrations of EVs and levels of expression of EV surface markers. Importantly, metal-ion tagging of immunoprobes enabled detection of two EV surface markers simultaneously from the same electrode. We demonstrated dual detection of either CD63/CD81 or podocin/nephrin surface markers from urinary EVs. The NP-enabled immunoassay had a sensitivity of 2.46 × 105 particles/mL (or 40.3 pg/mL) for CD63- and 5.80 × 105 particles/mL (or 47.7 pg/mL) for CD81-expressing EVs and a linear range of four orders of magnitude. The limit of detection for podocin and nephrin was 3.1 and 3.8 pg/mL, respectively. In the future, the capacity for multiplexing may be increased by extending the repertoire of metal ions used for redox tagging of AuNPs.

Background: The goal of this study was to categorize patients with abnormal serum phosphate upon hospital admission into distinct clusters utilizing an unsupervised machine learning approach, and to assess the mortality risk associated with these clusters. Methods: We utilized the consensus clustering approach on demographic information, comorbidities, principal diagnoses, and laboratory data of hypophosphatemia (serum phosphate ≤ 2.4 mg/dL) and hyperphosphatemia cohorts (serum phosphate ≥ 4.6 mg/dL). The standardized mean difference was applied to determine each cluster’s key features. We assessed the association of the clusters with mortality. Results: In the hypophosphatemia cohort (n = 3113), the consensus cluster analysis identified two clusters. The key features of patients in Cluster 2, compared with Cluster 1, included: older age, a higher comorbidity burden, particularly hypertension, diabetes mellitus, coronary artery disease, lower eGFR, and more acute kidney injury (AKI) at admission. Cluster 2 had a comparable hospital mortality (3.7% vs. 2.9%, p = 0.17), but a higher one-year mortality (26.8% vs. 14.0%, p &lt, 0.001), and five-year mortality (20.2% vs. 44.3%, 0.001), compared to Cluster 1. In the hyperphosphatemia cohort (n = 7252), the analysis identified two clusters. The key features of patients in Cluster 2, compared with Cluster 1, included: older age, more primary admission for kidney disease, more history of hypertension, more end-stage kidney disease, more AKI at admission, and higher admission potassium, magnesium, and phosphate. Cluster 2 had a higher hospital (8.9% vs. 2.4%, 0.001) one-year mortality (32.9% vs. 14.8%, 0.001), and five-year mortality (24.5% vs. 51.1%, 0.001), compared with Cluster 1. Conclusion: Our cluster analysis classified clinically distinct phenotypes with different mortality risks among hospitalized patients with serum phosphate derangements. Age, comorbidities, and kidney function were the key features that differentiated the phenotypes.

Background and Objectives: Despite the association between hyperchloremia and adverse outcomes, mortality risks among patients with hyperchloremia have not consistently been observed among all studies with different patient populations with hyperchloremia. The objective of this study was to characterize hyperchloremic patients at hospital admission into clusters using an unsupervised machine learning approach and to evaluate the mortality risk among these distinct clusters. Materials and Methods: We performed consensus cluster analysis based on demographic information, principal diagnoses, comorbidities, and laboratory data among 11,394 hospitalized adult patients with admission serum chloride of &gt, 108 mEq/L. We calculated the standardized mean difference of each variable to identify each cluster’s key features. We assessed the association of each hyperchloremia cluster with hospital and one-year mortality. Results: There were three distinct clusters of patients with admission hyperchloremia: 3237 (28%), 4059 (36%), and 4098 (36%) patients in clusters 1 through 3, respectively. Cluster 1 was characterized by higher serum chloride but lower serum sodium, bicarbonate, hemoglobin, and albumin. Cluster 2 was characterized by younger age, lower comorbidity score, lower serum chloride, and higher estimated glomerular filtration (eGFR), hemoglobin, and albumin. Cluster 3 was characterized by older age, higher comorbidity score, higher serum sodium, potassium, and lower eGFR. Compared with cluster 2, odds ratios for hospital mortality were 3.60 (95% CI 2.33–5.56) for cluster 1, and 4.83 (95% CI 3.21–7.28) for cluster 3, whereas hazard ratios for one-year mortality were 4.49 (95% CI 3.53–5.70) for cluster 1 and 6.96 (95% CI 5.56–8.72) for cluster 3. Conclusions: Our cluster analysis identified three clinically distinct phenotypes with differing mortality risks in hospitalized patients with admission hyperchloremia.

Background: The objective of this study was to characterize patients with hyponatremia at hospital admission into clusters using an unsupervised machine learning approach, and to evaluate the short- and long-term mortality risk among these distinct clusters. Methods: We performed consensus cluster analysis based on demographic information, principal diagnoses, comorbidities, and laboratory data among 11,099 hospitalized adult hyponatremia patients with an admission serum sodium below 135 mEq/L. The standardized mean difference was utilized to identify each cluster’s key features. We assessed the association of each hyponatremia cluster with hospital and one-year mortality using logistic and Cox proportional hazard analysis, respectively. Results: There were three distinct clusters of hyponatremia patients: 2033 (18%) in cluster 1, 3064 (28%) in cluster 2, and 6002 (54%) in cluster 3. Among these three distinct clusters, clusters 3 patients were the youngest, had lowest comorbidity burden, and highest kidney function. Cluster 1 patients were more likely to be admitted for genitourinary disease, and have diabetes and end-stage kidney disease. Cluster 1 patients had the lowest kidney function, serum bicarbonate, and hemoglobin, but highest serum potassium and prevalence of acute kidney injury. In contrast, cluster 2 patients were the oldest and were more likely to be admitted for respiratory disease, have coronary artery disease, congestive heart failure, stroke, and chronic obstructive pulmonary disease. Cluster 2 patients had lowest serum sodium and serum chloride, but highest serum bicarbonate. Cluster 1 patients had the highest hospital mortality and one-year mortality, followed by cluster 2 and cluster 3, respectively. Conclusion: We identified three clinically distinct phenotypes with differing mortality risks in a heterogeneous cohort of hospitalized hyponatremic patients using an unsupervised machine learning approach.

Background Telenephrology has become an important health care delivery modality during the COVID-19 pandemic. However, little is known about patient perspectives on the quality of care provided via telenephrology compared to face-to-face visits. We aimed to use objective data to study patients’ perspectives on outpatient nephrology care received via telenephrology (phone and video) versus face-to-face visits. Methods We retrospectively studied adults who received care in the outpatient Nephrology & Hypertension division at Mayo Clinic, Rochester, from March to July 2020. We used a standardized survey methodology to evaluate patient satisfaction. The primary outcome was the percent of patients who responded with a score of good (4) or very good (5) on a 5-point Likert scale on survey questions that asked their perspectives on access to their nephrologist, relationship with care provider, their opinions on the telenephrology technology, and their overall assessment of the care received. Wilcoxon rank sum tests and chi-square tests were used as appropriate to compare telenephrology versus face-to-face visits. Results 3,486 of the patient encounters were face-to-face, 808 phone and 317 video visits. 443 patients responded to satisfaction surveys, and 21% of these had telenephrology encounters. Established patients made up 79.6% of telenephrology visits and 60.9% of face-to-face visits. There was no significant difference in patient perceived access to health care, satisfaction with their care provider, or overall quality of care between patients cared for via telenephrology versus face-to-face. Patient satisfaction was also equally high. Conclusions Patient satisfaction was equally high amongst those patients seen face-to-face or via telenephrology.

Progression of virtually all forms of chronic kidney disease (CKD) is associated with activation of pro-inflammatory and pro-fibrotic signaling pathways. Despite extensive research, progress in identifying therapeutic targets to arrest or slow progression of CKD has been limited by incomplete understanding of basic mechanisms underlying renal inflammation and fibrosis in CKD. Recent studies have identified Kruppel-like transcription factors that have been shown to play critical roles in renal development, homeostasis, and response to injury. Although KLF11 deficiency has been shown to increase collagen production in vitro and tissue fibrosis in other organs, no previous study has linked KLF11 to the development of CKD. We sought to test the hypothesis that KLF11 deficiency promotes CKD through upregulation of pro-inflammatory and pro-fibrogenic signaling pathways in murine unilateral ureteral obstruction (UUO), a well-established model of renal fibrosis. We found that KLF11-deficiency exacerbates renal injury in the UUO model through activation of the TGF-β/SMAD signaling pathway and through activation of several pro-inflammatory chemokine signaling pathways. Based on these considerations, we conclude that agents increase KLF11 expression may provide novel therapeutic targets to slow the progression of CKD.