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Rationale & Objective: Most living kidney donors are members of a hemodialysis patient's social network. Network members are divided into core members, those strongly connected to the patient and other members; and peripheral members, those weakly connected to the patient and other members. We identify how many hemodialysis patients' network members offered to become kidney donors, whether these offers were from core or peripheral network members, and whose offers the patients accepted., Study Design: A cross-sectional interviewer-administered hemodialysis patient social network survey., Setting & Participants: Prevalent hemodialysis patients in 2 facilities., Predictors: Network size and constraint, a donation from a peripheral network member., Outcomes: Number of living donor offers, accepting an offer., Analytical Approach: We performed egocentric network analyses for all participants. Poisson regression models evaluated associations between network measures and number of offers. Logistic regression models determined the associations between network factors and accepting a donation offer., Results: The mean age of the 106 participants was 60 years. Forty-five percent were female, and 75% self-identified as Black. Fifty-two percent of participants received at least one living donor offer (range 1-6); 42% of the offers were from peripheral members. Participants with larger networks received more offers (incident rate ratio [IRR], 1.26; 95% CI, 1.12-1.42; P  = 0.001), including networks with more peripheral members (constraint, IRR, 0.97; 95% CI, 0.96-0.98; P  < 0.001). Participants who received a peripheral member offer had 3.6 times greater odds of accepting an offer (OR, 3.56; 95% CI, 1.15-10.8; P  = 0.02) than those who did not receive a peripheral member offer., Limitations: A small sample of only hemodialysis patients., Conclusions: Most participants received at least one living donor offer, often from peripheral network members. Future living donor interventions should focus on both core and peripheral network members., (© 2023 The Authors.)

The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single-nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing., (Copyright © 2022 International Society of Nephrology. All rights reserved.)

End-stage kidney disease (ESKD) affects over 780,000 Americans and is associated with excess morbidity and premature death. Kidney disease health disparities are well-recognized, manifesting as ESKD overburden among racial and ethnic minority populations. Specifically, Black and Hispanic individuals have a 3.4-fold and 1.3-fold greater life risk of developing ESKD than their white counterparts. There is compelling evidence that communities of color have less opportunity to benefit from kidney-specific care throughout the course of their disease, from pre-ESKD, to ESKD home therapies and kidney transplantation. These healthcare inequities have the combined devastating impact of worse outcomes and quality of life for patients and families at a significant financial cost on the healthcare system. In the last three years, across two presidential administrations, bold, broad initiatives have been outlined that, together could lead to significant transformation in kidney health. The Advancing American Kidney Health (AAKH) initiative was established as a national framework to revolutionize kidney care but did not address health equity. More recently, the Advancing Racial Equity executive order was announced, outlining initiatives to promote equity for historically underserved communities. Building from these presidential directives, we outline strategies to address the complex issue of kidney health disparities, focusing on patient awareness, care delivery, scientific advancement, and workforce initiatives. An equity-focused framework will guide policy advancements to reduce the kidney disease burden in susceptible populations and positively impact the health and well-being of all Americans., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-22-566/coif). The series “Endovascular and Surgical Interventions in the End Stage Renal Disease Population” was commissioned by the editorial office without any funding or sponsorship. CAG is a council member of the American Society of Nephrology, speaker to COVID-19 for NIDDK and receives funding support from the National Institutes of Health and NIDDK. The authors have no other conflicts of interest to declare., (2023 Cardiovascular Diagnosis and Therapy. All rights reserved.)

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 CHA 2 DS 2 -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.

Obesity is a leading cause of hypertension (i.e., high blood pressure [BP]). While hypertension can be managed with antihypertensive medication, substantial weight loss can also lower BP, reducing the need for antihypertensive medication. Articles in this review (n = 60) presented data on antihypertensive medication use among adults pre- and postoperatively. Roux-en-Y gastric bypass was the most studied surgical approach followed by Laparoscopic Sleeve Gastrectomy. Antihypertensive medication was discontinued in a large proportion of patients after surgery, and the mean number of antihypertensive medications decreased by approximately one. In almost a third of the studies, over 75% of participants experienced hypertension remission. All articles aside from two reported a decrease in systolic BP, with about 40% reporting a decrease of ≥ 10 mm Hg., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In response to a national call for re-evaluation of the use of race in clinical algorithms, the National Kidney Foundation (NKF) and the American Society of Nephrology (ASN) established a Task Force to reassess inclusion of race in the estimation of glomerular filtration rate (GFR) in the United States and its implications for diagnosis and management of patients with, or at risk for, kidney diseases., Process & Deliberations: The Task Force organized its activities over 10 months in phases to (1) clarify the problem and evidence regarding GFR estimating equations in the United States (described previously in an interim report), and, in this final report, (2) evaluate approaches to address use of race in GFR estimation, and (3) provide recommendations. We identified 26 approaches for the estimation of GFR that did or did not consider race and narrowed our focus, by consensus, to 5 of those approaches. We holistically evaluated each approach considering 6 attributes: assay availability and standardization; implementation; population diversity in equation development; performance compared with measured GFR; consequences to clinical care, population tracking, and research; and patient centeredness. To arrive at a unifying approach to estimate GFR, we integrated information and evidence from many sources in assessing strengths and weaknesses in attributes for each approach, recognizing the number of Black and non-Black adults affected., Recommendations: (1) For US adults (>85% of whom have normal kidney function), we recommend immediate implementation of the CKD-EPI creatinine equation refit without the race variable in all laboratories in the United States because it does not include race in the calculation and reporting, included diversity in its development, is immediately available to all laboratories in the United States, and has acceptable performance characteristics and potential consequences that do not disproportionately affect any one group of individuals. (2) We recommend national efforts to facilitate increased, routine, and timely use of cystatin C, especially to confirm estimated GFR in adults who are at risk for or have chronic kidney disease, because combining filtration markers (creatinine and cystatin C) is more accurate and would support better clinical decisions than either marker alone. If ongoing evidence supports acceptable performance, the CKD-EPI eGFR-cystatin C (eGFR cys ) and eGFR creatinine-cystatin C (eGFR cr-cys&#95;R ) refit without the race variables should be adopted to provide another first-line test, in addition to confirmatory testing. (3) Research on GFR estimation with new endogenous filtration markers and on interventions to eliminate race and ethnic disparities should be encouraged and funded. An investment in science is needed for newer approaches that generate accurate, unbiased, and precise GFR measurement and estimation without the inclusion of race, and that promote health equity and do not generate disparate care., Implementation: This unified approach, without specification of race, should be adopted across the United States. High-priority and multistakeholder efforts should implement this solution., (Copyright © 2021 National Kidney Foundation, Inc and the American Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1's natural absence in laboratory animals makes studying its pathobiology challenging., Methods: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes., Results: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features., Conclusions: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes., (© 2021. IPNA.)

For almost 2 decades, equations that use serum creatinine, age, sex, and race to estimate glomerular filtration rate (GFR) have included "race" as Black or non-Black. Given considerable evidence of disparities in health and health care delivery in African American communities, some regard keeping a race term in GFR equations as a practice that differentially influences access to care and kidney transplantation. Others assert that race captures important non-GFR determinants of serum creatinine and its removal from the calculation may perpetuate other disparities. The National Kidney Foundation (NKF) and American Society of Nephrology (ASN) established a task force in 2020 to reassess the inclusion of race in the estimation of GFR in the United States and its implications for diagnosis and subsequent management of patients with, or at risk for, kidney diseases. This interim report details the process, initial assessment of evidence, and values defined regarding the use of race to estimate GFR. We organized activities in phases: (1) clarify the problem and examine evidence, (2) evaluate different approaches to address use of race in GFR estimation, and (3) make recommendations. In phase 1, we constructed statements about the evidence and defined values regarding equity and disparities; race and racism; GFR measurement, estimation, and equation performance; laboratory standardization; and patient perspectives. We also identified several approaches to estimate GFR and a set of attributes to evaluate these approaches. Building on evidence and values, the attributes of alternative approaches to estimate GFR will be evaluated in the next phases and recommendations will be made., (Copyright © 2021 National KidneyFoundation, Inc and the American Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

New treatments, new understanding, and new approaches to translational research are transforming the outlook for patients with kidney diseases. A number of new initiatives dedicated to advancing the field of nephrology-from value-based care to prize competitions-will further improve outcomes of patients with kidney disease. Because of individual nephrologists and kidney organizations in the United States, such as the American Society of Nephrology, the National Kidney Foundation, and the Renal Physicians Association, and international nephrologists and organizations, such as the International Society of Nephrology and the European Renal Association-European Dialysis and Transplant Association, we are beginning to gain traction to invigorate nephrology to meet the pandemic of global kidney diseases. Recognizing the timeliness of this opportunity, the American Society of Nephrology convened a Division Chief Retreat in Dallas, Texas, in June 2019 to address five key issues: ( 1 ) asserting the value of nephrology to the health system; ( 2 ) productivity and compensation; ( 3 ) financial support of faculty's and divisions' educational efforts; ( 4 ) faculty recruitment, retention, diversity, and inclusion; and ( 5 ) ensuring that fellowship programs prepare trainees to provide high-value nephrology care and enhance attraction of trainees to nephrology. Herein, we highlight the outcomes of these discussions and recommendations to the American Society of Nephrology., (Copyright © 2021 by the American Society of Nephrology.)

Background: A kidney transplant candidate's social network serves as a pool of potential living donors. Sex and racial differences in network size, network strength, and living donor requests may contribute to disparities in living donor kidney transplantation., Methods: In this multicenter cross-sectional study, we performed an egocentric network analysis via a telephone survey of 132 waitlisted candidates (53% female and 69% Black) to identify demographic and network factors associated with requesting living kidney donations., Results: Female participants made requests to more network members than male participants: incidence rate ratio (IRR) 1.95, 95% confidence interval (CI) [1.24-3.06], P < 0.01. Black participants tended to make more requests than whites (IRR 1.65, 95% CI [0.99-2.73], P = 0.05). The number of requests increased with the size of the network (IRR 1.09, 95% CI [1.02-1.16], P = 0.01); however, network size did not differ by sex or race. Network members who provided greater instrumental support to the candidates were most likely to receive a request: odds ratio 1.39, 95% CI [1.08-1.78], P = 0.01., Conclusions: Transplant candidates' networks vary in size and in the number of requests made to the members. Previously observed racial and sex disparities in living donor kidney transplantation do not appear to be related to network size or to living donation requests, but rather to the network members themselves. Future living donor interventions should focus on the network members and be tailored to their relationship with the candidate.

Background: Non-traditional risk factors like inflammation and oxidative stress play an essential role in the increased cardiovascular disease (CVD) risk prevalent in chronic kidney disease (CKD). Tryptophan catabolism by the kynurenine pathway (KP) is linked to systemic inflammation and CVD in the general and dialysis population. However, the relationship of KP to incident CVD in the CKD population is unknown., Methods: We measured tryptophan metabolites using targeted mass spectrometry in 92 patients with a history of CVD (old CVD); 46 patients with no history of CVD and new CVD during follow-up (no CVD); and 46 patients with no CVD history who developed CVD in the median follow-up period of 2 years (incident CVD)., Results: The three groups are well-matched in age, gender, race, diabetes status and CKD stage, and only differed in total cholesterol and proteinuria. Tryptophan and kynurenine levels significantly decreased in patients with 'Incident CVD' compared with the no CVD or old CVD groups (P = 5.2E-7; P = 0.003 respectively). Kynurenic acid, 3-hydroxykynurenine and kynurenine are all increased with worsening CKD stage (P < 0.05). An increase in tryptophan levels at baseline was associated with 0.32-fold lower odds of incident CVD (P = 0.000014) compared with the no CVD group even after adjustment for classic CVD risk factors. Addition of tryptophan and kynurenine levels to the receiver operating curve constructed from discriminant analysis predicting incident CVD using baseline clinical variables increased the area under the curve from 0.76 to 0.82 (P = 0.04)., Conclusions: In summary, our study demonstrates that low tryptophan levels are associated with incident CVD in CKD., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Understanding the relationship between clinical and patient-reported outcomes (PROs) will help support clinical care and future clinical trial design of novel therapies for focal segmental glomerulosclerosis (FSGS)., Methods: FSGS patients ≥8 years of age enrolled in the Nephrotic Syndrome Study Network completed Patient-Reported Outcomes Measurement Information System PRO measures of health-related quality of life (HRQoL) (children: global health, mobility, fatigue, pain interference, depression, anxiety, stress and peer relationships; adults: physical functioning, fatigue, pain interference, sleep impairment, mental health, depression, anxiety and social satisfaction) at baseline and during longitudinal follow-up for a maximum of 5 years. Linear mixed-effects models were used to determine which demographic, clinical and laboratory features were associated with PROs for each of the eight children and eight adults studied., Results: There were 45 children and 114 adult FSGS patients enrolled that had at least one PRO assessment and 519 patient visits. Multivariable analyses among children found that edema was associated with global health (-7.6 points, P = 0.02) and mobility (-4.2, P = 0.02), the number of reported symptoms was associated with worse depression (-2.7 per symptom, P = 0.009) and anxiety (-2.3, P = 0.02) and the number of emergency room (ER) visits in the prior 6 months was associated with worse mobility (-2.8 per visit, P < 0.001) and fatigue (-2.4, P = 0.03). Multivariable analyses among adults found the number of reported symptoms was associated with worse function in all eight PROMIS measures and the number of ER visits was associated with worse fatigue, pain interference, sleep impairment, depression, anxiety and social satisfaction. Laboratory markers of disease severity (i.e. proteinuria, estimated glomerular filtration rate and serum albumin) did not predict PRO in multivariable analyses, with the single exception of complete remission and better pain interference scores among children (+9.3, P  =  0.03)., Conclusions: PROs provide important information about HRQoL for persons with FSGS that is not captured solely by the examination of laboratory-based markers of disease. However, it is critical that instruments capture the patient experience and FSGS clinical trials may benefit from a disease-specific instrument more sensitive to within-patient changes., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA.)

Introduction: Cardiac biomarkers soluble ST2 (sST2) and galectin-3 may reflect cardiac inflammation and fibrosis. It is plausible that these mechanisms may also contribute to the progression of kidney disease. We examined associations of sST2 and galectin-3 with kidney function decline in participants with chronic kidney disease (CKD)., Methods: This was a pooled analysis of 2 longitudinal cohorts of participants with CKD: the Clinical Phenotyping and Resource Biobank (C-PROBE) study and the Seattle Kidney Study (SKS). We measured circulating concentrations of sST2 and galectin-3 at baseline. Our primary outcome was progression to estimated glomerular filtration rate (eGFR) <15 ml/min per 1.73 m 2 or end-stage renal disease (ESRD). We used competing risk Cox regression models to study the association of sST2 and galectin-3 with CKD progression, adjusting for demographics, kidney function, and comorbidity., Results: Among the 841 participants in the pooled cohort, baseline eGFR was 51 ± 27 ml/min per 1.73 m 2 and median urine albumin-to-creatinine ratio (UACR) was 141 (interquartile range = 15-736) mg/g. Participants with higher sST2 and galectin-3 were more likely to be older, to have heart failure and diabetes, and to have lower eGFR. Adjusting for demographics, kidney function, and comorbidity, every doubling of sST2 was not associated with progression to eGFR <15 ml/min per 1.73 m 2 or ESRD (adjusted hazard ratio 1.02, 95% confidence interval = 0.76-1.38). Every doubling of galectin-3 was significantly associated with a 38% (adjusted hazard ratio = 1.35, 95% confidence interval = 1.01-1.80) increased risk of progression to eGFR <15 ml/min per 1.73 m 2 or ESRD., Conclusion: Higher concentrations of the cardiac biomarker galectin-3 may be associated with progression of CKD, highlighting potential novel mechanisms that may contribute to the progression of kidney disease.

Introduction: The goal of this study was to examine patterns in the likelihood of consent to genetic research among participants in a prospective kidney disease cohort and biobank, and to determine demographic, clinical, and socioeconomic factors linked to consent for ongoing and future genetic research., Methods: The Clinical Phenotyping Resource and Biobank Core (C-PROBE) enrolled 1628 adult and pediatric patients with chronic kidney disease from 2009 to 2017 across 7 sites in the United States. Participants were asked at annual study visits for consent to provide DNA samples for future genetic studies. We compared characteristics of participants by initial consent outcome and consent status at their most recent study visit., Results: Of the C-PROBE participants, 96% consented to genetic studies at their initial study visit. Although African Americans were slightly less likely to consent at baseline (93% vs. 97%, odds ratio = 0.3, P  < 0.02), there were no significant racial or ethnic differences with longitudinal participation. Also, pediatric and adult genetic consent rates were equivalent. The major persistent differences in the likelihood of consent were based on enrollment site, which ranged from 85% to 100% ( P  < 0.0001)., Conclusion: Overall, genetic consent rates for kidney research within the C-PROBE cohort were high. However, differences in consent rates over time and by recruitment site highlight the complexity of genetic consent for biobanking, and potential limitations for generalizability of observations.

Lifestyle modification and health behavior practice among the individuals with cardiometabolic diseases (CMD) are important for secondary prevention and disease control. This study was designed to investigate and compare health behavior practices among Chinese and Filipino Americans with CMD. Three hundred seventy-four Asian Americans (211 Chinese and 163 Filipino) who reside in the greater Philadelphia region and had either CMD or no identified disease were included in the study. Information on smoking, alcohol intake, physical activity, and salt and sweets consumption was collected, as well as demographic and acculturative characteristics. Of the 374 participants, 241 (64.4%) had CMD and 133 (35.6%) had no identified disease. The majority of Chinese and Filipino Americans with CMD failed to meet the dietary and physical activity guidelines, and only a small percentage of them restricted their amount of salt added to food and amount of sweets consumption. Compared to participants with no disease, Chinese participants with CMD were more likely to "never" add salt to food (AOR 4.42 compared to "frequently"). Filipino Americans with CMD were less likely to be those who "never" consume sweets than those who frequently consume sweets (AOR = 0.12). Among the participants with CMD, Chinese participants with CMD were less likely to restrict drinking (AOR 0.11) than Filipinos with CMD. The findings suggest that tailored interventions for Chinese and Filipino Americans with CMD should be developed to enhance their compliance to behavioral guidelines to prevent further disease progression and complications.

Despite that Filipino Americans represent an important target group for hypertension, health behaviors associated with hypertension in this population have not been well studied. Two hundred Filipino Americans from eight community-based organizations completed the study. Information was collected to determine whether modifiable behavioral factors, as well as acculturation and demographic characteristics, were associated with hypertension status in Filipino Americans. Approximately 67% of Filipino Americans were hypertensive. Logistic regression analysis showed that adding salt, physical inactivity, and old age were significantly associated with hypertension status after controlling for other covariates. The present study confirmed a high rate of hypertension among Filipino Americans and demonstrates the association of hypertension status with behavioral factors. These findings highlight the need for targeted interventions to prevent and manage hypertension in this high-risk community by facilitating health behaviors, particularly, salt reduction and physical activity.

To assess apolipoprotein L1 gene (APOL1) renal-risk-variant effects on the brain, magnetic resonance imaging (MRI)-based cerebral volumes and cognitive function were assessed in 517 African American-Diabetes Heart Study (AA-DHS) Memory IN Diabetes (MIND) and 2568 hypertensive African American Systolic Blood Pressure Intervention Trial (SPRINT) participants without diabetes. Within these cohorts, 483 and 197 had cerebral MRI, respectively. AA-DHS participants were characterized as follows: 60.9% female, mean age of 58.6 years, diabetes duration 13.1 years, estimated glomerular filtration rate of 88.2 ml/min/1.73 m(2), and a median spot urine albumin to creatinine ratio of 10.0 mg/g. In additive genetic models adjusting for age, sex, ancestry, scanner, intracranial volume, body mass index, hemoglobin A1c, statins, nephropathy, smoking, hypertension, and cardiovascular disease, APOL1 renal-risk-variants were positively associated with gray matter volume (β = 3.4 × 10(-3)) and negatively associated with white matter lesion volume (β = -0.303) (an indicator of cerebral small vessel disease) and cerebrospinal fluid volume (β= -30707) (all significant), but not with white matter volume or cognitive function. Significant associations corresponding to adjusted effect sizes (β/SE) were observed with gray matter volume (0.16) and white matter lesion volume (-0.208), but not with cerebrospinal fluid volume (-0.251). Meta-analysis results with SPRINT Memory and Cognition in Decreased Hypertension (MIND) participants who had cerebral MRI were confirmatory. Thus, APOL1 renal-risk-variants are associated with larger gray matter volume and lower white matter lesion volume suggesting lower intracranial small vessel disease., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: This analysis from the Nephrotic Syndrome Study Network (NEPTUNE) assessed the phenotypic and pathology characteristics of proteinuric patients undergoing kidney biopsy and defined the frequency and factors associated with complete proteinuria remission (CRever)., Design, Setting, Participants, & Measurements: We enrolled adults and children with proteinuria ≥0.5 g/d at the time of first clinically indicated renal biopsy at 21 sites in North America from April 2010 to June 2014 into a prospective cohort study. NEPTUNE central pathologists assigned participants to minimal-change disease (MCD), FSGS, membranous nephropathy, or other glomerulopathy cohorts. Outcome measures for this analysis were (1) CRever with urine protein-to-creatinine ratio (UPC) <0.3 g/g with preserved native kidney function and (2) ESRD. Continuous variables are reported as median and interquartile range (IQR; 25th, 75th percentile). Cox proportional hazards modeling was used to assess factors associated with CRever., Results: We enrolled 441 patients: 116 (27%) had MCD, 142 (32%) had FSGS, 66 (15%) had membranous nephropathy, and 117 (27%) had other glomerulopathy. The baseline UPC was 4.1 g/g (IQR, 1.9, 7.7) and the eGFR was 81 ml/min per 1.73 m(2) (IQR, 50, 105). Median duration of observation was 19 months (IQR, 11, 30). CRever occurred in 46% of patients, and 4.6% progressed to ESRD. Multivariate analysis demonstrated that higher prebiopsy proteinuria (hazard ratio, 0.3; 95% confidence interval, 0.2 to 0.5) and pathology diagnosis (FSGS versus MCD; hazard ratio, 0.2; 95% confidence interval, 0.1 to 0.5) were inversely associated with CRever. The effect of immunosuppressive therapy on remission varied by pathology diagnosis., Conclusions: In NEPTUNE, the high frequency of other pathology in proteinuric patients affirms the value of the diagnostic kidney biopsy. Clinical factors, including level of proteinuria before biopsy, pathology diagnosis, and immunosuppression, are associated with complete remission., (Copyright © 2016 by the American Society of Nephrology.)

Chronic inflammation is increased in patients with chronic kidney disease (CKD) and contributes to cardiovascular morbidity and mortality. Specific immune mechanisms and pathways that drive and maintain chronic inflammation in CKD are not well described. The TAM ligands (Gas6 and protein S) and receptors (Axl and Mer) have been recently recognized as playing a prominent role in immune regulation. The receptors exist in both soluble and cell-bound forms; the soluble receptors (sAxl and sMer) are believed to compete with the bound receptors and thus inhibit their function. In this study, we determined the expression of cell-bound and soluble TAM proteins in patients with CKD. CKD patients had significantly lower expression of Mer in monocytes, yet increased expression of soluble TAM receptors sAxl and sMer in plasma compared to controls. The metalloproteinase ADAM 17, responsible for cleavage of Mer to its soluble form, was increased in patient monocytes. Elevated levels of soluble TAM receptors were more evident in patients with progressive renal failure. These observations suggest that functional deficiency of TAM receptor-mediated regulation of inflammation may contribute to chronic inflammation in patients with CKD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

It has been suggested that soluble urokinase receptor (suPAR) is a causative circulating factor for and a biomarker of focal and segmental glomerulosclerosis (FSGS). Here we undertook validation of these assumptions in both mouse and human models. Injection of recombinant suPAR in wild-type mice did not induce proteinuria within 24 h. Moreover, a disease phenotype was not seen in an inducible transgenic mouse model that maintained elevated suPAR concentrations for 6 weeks. Plasma and urine suPAR concentrations were evaluated as clinical biomarkers in 241 patients with glomerular disease from the prospective, longitudinal multicenter observational NEPTUNE cohort. The serum suPAR concentration at baseline inversely correlated with estimated glomerular filtration rate (eGFR) and the urine suPAR/creatinine ratio positively correlated with the urine protein/creatinine ratio. After adjusting for eGFR and urine protein, neither the serum nor urine suPAR level was an independent predictor of FSGS histopathology. A multivariable mixed-effects model of longitudinal data evaluated the association between the change in serum suPAR concentration from baseline with eGFR. After adjusting for baseline suPAR concentration, age, gender, proteinuria, and time, the change in suPAR from baseline was associated with eGFR, but this association was not different for patients with FSGS as compared with other diagnoses. Thus these results do not support a pathological role for suPAR in FSGS.

Objective and Design: Plasma lipids enhance alpha1-adrenoceptor pressor sensitivity, impair baroreflex function, and correlate with increased blood pressure. This clinical study was designed to determine whether the enhanced alpha1-pressor sensitivity induced by acute hyperlipidemia is primarily mediated by increased vascular alpha1 responsiveness, reduced baroreflex sensitivity (BRS) or both., Method: Regional alpha1-adrenoceptor vasoreactivity was measured using a graded brachial artery infusion of the alpha1 agonist, phenylephrine, in seven subjects with stage 1 hypertension. Forearm blood flow was estimated from venous occlusion plethysmography. The phenylephrine dose-forearm blood flow response curve was used to determine alpha1-vascular reactivity (slope of the dose-response curve) and sensitivity, EC50 (phenylephrine dose inducing 50% maximal response). BRS (ms/mmHg) was measured as the slope of the progressive rise in systolic blood pressure and the resultant lengthening in the subsequent R-R interval after systemic intravenous boluses of phenylephrine. Subsequently, plasma lipids were raised with a 1-h systemic co-infusion of intralipid and heparin, after which measurements of regional vasoreactivity and BRS were repeated., Results: Mean arterial pressure was 109 +/- 4 versus 110 +/- 3 (P = NS), vasoreactivity was -0.71 +/- 0.10 versus -0.82 +/- 0.10 (P = NS) and log EC50 was 1.47 +/- 0.29 versus 1.52 +/- 0.34 nmol/l (P = NS) before and after raising non-esterified fatty acids, respectively. In contrast, mean BRS was acutely reduced from 8.2 +/- 2.1 to 6.2 +/- 1.8 ms/mmHg (P = 0.02) after the lipid infusion., Conclusions: These findings suggest that in hypertensive patients, the primary mechanism for short-term alpha1-pressor hypersensitivity in response to hyperlipidemia is via the acute impairment of BRS.

Background: Dyslipidemia in patients with chronic kidney disease (CKD) may contribute to hypertension (HT) by altering neurocirculatory control. To test this notion, we quantified the effects of acutely increasing levels of nonesterified fatty acids (NEFAs) and triglycerides on alpha1-adrenergic pressor sensitivity and baroreflex sensitivity (BRS) in subjects without diabetes with CKD., Methods: Alpha1 pressor sensitivity was determined before and after increasing NEFA and triglyceride levels with a fat emulsion and heparin infusion in 8 subjects with stage 2 to 3 CKD (glomerular filtration rate, 56 +/- 6 mL/min by 125 I-iothalamate clearance). Seven subjects with HT and 8 normotensive control (CO) subjects with normal renal function and matched to patients with CKD also were studied., Results: Fasting NEFA levels were greater in patients with CKD than in CO subjects (585 +/- 98 versus 321 +/- 32 micromol/L; P < 0.01), but not different from those in subjects with HT (501 +/- 68 micromol/L). Alpha1 pressor sensitivity, defined as the phenylephrine dose that increased mean blood pressure (BP) by 20 mm Hg, was greatest (lowest dose) in subjects with CKD (0.83 +/- 0.11 microg x kg(-1) x min(-1)), followed by those with HT (1.08 +/- 0.19 microg x kg(-1) x min(-1)) and CO subjects (1.34 +/- 0.19 microg x kg(-1) x min(-1); P < 0.05 versus CKD group). BRS, measured as the ratio of change in R-R interval to change in systolic BP during the phenylephrine infusion, was lowest, intermediate, and highest in the CKD, HT, and CO groups, respectively. Increasing NEFA and triglyceride levels significantly enhanced alpha1 pressor sensitivity in all 3 groups and reduced BRS in the CKD and CO groups., Conclusion: These observations suggest that the dyslipidemia prevalent in patients with stage 2 to 3 CKD may contribute to HT by enhancing alpha1 pressor sensitivity and impairing baroreflex function.