The prevalence of anemia is high in people with chronic kidney disease (CKD) and increases as the disease advances. The Kidney Disease Outcomes Quality Initiative (KDOQI) convened a work group to review the Kidney Disease: Improving Global Outcomes (KDIGO) 2026 clinical practice guideline for the management of anemia in CKD. The previous KDIGO anemia guideline was published in 2012; in 2019 and 2021 KDIGO convened conferences addressing controversies in iron management and hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) use, respectively. The KDOQI work group provides perspective for implementation of the KDIGO 2026 anemia guideline within the context of clinical practice in the United States. The KDOQI work group agrees with most of the KDIGO recommendations, particularly the proactive use of intravenous (IV) iron in hemodialysis patients and the preference for erythropoiesis stimulating agents (ESAs) over HIF-PHIs for first-line anemia therapy, due to greater familiarity with safety of the former. Specific issues regarding recommendations and practice points for providers in the United States include higher serum ferritin targets and mean levels among people receiving hemodialysis than in the rest of the world; the availability of a single HIF-PHI product with approval only for patients receiving dialysis for ≥3 months; and payment barriers that may drive the choice of therapeutic agents. Additional commentary is provided on topics including IV iron therapy in people receiving hemodialysis and an iron-based phosphate binder, the incidence and significance of hypophosphatemia among people with CKD not on dialysis but receiving IV iron therapy, the physiologic importance of iron repletion in people with CKD and iron deficiency without anemia, possible therapeutic benefits of HIF-PHIs compared with ESAs, and assessing risk versus harm of red blood cell transfusions.

Chronic kidney disease (CKD) is a progressive, multisystemic disorder that augments the risks of cardiovascular (CV) morbidity and mortality as kidney function declines. The endothelium plays a key role in modulating vascular tone, integrity, and homeostasis by producing and releasing a variety of endothelium-derived relaxing factors, including nitric oxide (NO). Endothelial dysfunction is a salient pathogenic mechanism underlying the development and progression of CKD and is characterized by reduced production of vasodilators and increased production of vasoconstrictors (e.g., endothelin-1). Factors such as the uremic milieu, inflammation, and oxidative stress are putative contributors of endothelial dysfunction and reduced NO bioavailability that ultimately impact functional and structural integrity of the vasculature. Because endothelial dysfunction is an independent predictor of CV morbidity and mortality in patients with CKD, several clinical studies have examined disease-related changes in endothelium-dependent vasodilation across the arterial tree. This review will focus on the clinical evidence regarding CKD-associated endothelial dysfunction involving both the micro- and macrovasculature, briefly discussing underlying physiological mechanisms, and summarizing available and emerging pharmacotherapies along with a brief summary of exercise training as a lifestyle intervention.

Hemodialysis requires functional vascular access, which serves as the conduit for blood flow between the patient and the hemodialysis machine. The arteriovenous fistula (AVF), created by surgically connecting an artery to a nearby vein in the upper extremity, is the preferred form of vascular access for maintenance hemodialysis. Newly created AVFs must undergo a maturation process, during which the fistula vein enlarges and develops sufficient lumen size and blood flow to be used effectively for dialysis. However, since the invention of AVFs 60 years ago, rates of AVF maturation failure have remained high. Currently, no proven therapies exist to promote maturation or prevent maturation failure. This review examines the current understanding of the cellular and molecular mechanisms underlying AVF maturation failure, with particular focus on the impact of the chronic kidney disease (CKD) environment on the vascular system. In CKD, patients often have elevated levels of uremic toxins, increased oxidative stress, and chronic inflammation, all of which adversely affect the function of vascular wall cells (such as endothelial cells, vascular smooth muscle cells, and fibroblasts) and circulating cells (such as platelets and immune/inflammatory cells). The goal of this review is to explore the mechanisms influencing both native and AVF vasculature in the context of CKD. In addition, we will discuss current therapies aimed at improving native vasculature in patients with CKD, as well as investigational approaches to promote AVF maturation.

ImportanceAdults experiencing homelessness in the US face numerous challenges, including the management of chronic kidney disease (CKD). The extent of a potentially greater risk of adverse health outcomes in the population with CKD experiencing homelessness has not been adequately explored.ObjectiveTo evaluate the association between a history of homelessness and the risk of end-stage kidney disease (ESKD) and death among veterans with incident CKD.Design, Setting, and ParticipantsThis retrospective cohort study was conducted between January 1, 2005, and December 31, 2017. Participants included veterans aged 18 years and older with incident stage 3 to 5 CKD utilizing the Veterans Health Administration health care network in the US. Patients were followed-up through December 31, 2018, for the occurrence of ESKD and death. Analyses were performed from September 2022 to October 2023.ExposureHistory of homelessness, based on utilization of homeless services in the Veterans Health Administration or International Classification of Diseases, Ninth Revision or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes. Homelessness was measured during the 2-year baseline period prior to the index date of incident CKD.Main Outcomes and MeasuresThe primary outcomes were ESKD, based on initiation of kidney replacement therapy, and all-cause death. Adjusted hazard ratios (HRs) were calculated to compare veterans with a history of homelessness with those without a history of homelessness.ResultsAmong 836 361 veterans, the largest proportion were aged 65 to 74 years (274 371 veterans [32.8%]) or 75 to 84 years (270 890 veterans [32.4%]), and 809 584 (96.8%) were male. A total of 26 037 veterans (3.1%) developed ESKD, and 359 991 (43.0%) died. Compared with veterans who had not experienced homelessness, those with a history of homelessness showed a significantly greater risk of ESKD (adjusted HR, 1.15; 95% CI, 1.10-1.20). A greater risk of all-cause death was also observed (HR, 1.48; 95% CI, 1.46-1.50). After further adjustment for body mass index, comorbidities, and medication use, results were attenuated for all-cause death (HR, 1.09; 95% CI, 1.07-1.11) and were no longer significant for ESKD (HR, 1.04; 95% CI, 0.99-1.09).Conclusions and RelevanceIn this cohort study of veterans with incident stage 3 to 5 CKD, a history of homelessness was significantly associated with a greater risk of ESKD and death, underscoring the role of housing as a social determinant of health.

Rationale & Objective: Although some evidence exists of increased dementia risk from anemia, it is unclear whether this association persists among adults with CKD. Anemia may be a key marker for dementia among adults with CKD, so we evaluated whether anemia is associated with an increased risk of dementia among adults with CKD. Study Design: Retrospective cohort study. Setting & Participants: The study included 620,095 veterans aged >= 45 years with incident stage 3 CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m(2)) between January 2005 and December 2016 in the US Veterans Health Administration system and followed through December 31, 2018, for incident dementia, kidney failure, or death. Exposure: Anemia was assessed based on the average of hemoglobin levels (g/L) during the 2 years before the date of incident CKD and categorized as normal, mild, or moderate/severe anemia (>= 12.0, 11.0-11.9, <11.0 g/dL, respectively, for women, and >= 13.0, 11.0-12.9, <11.0 g/dL for men). Outcome: Dementia and the composite outcome of kidney failure or death. Analytical Approach: Adjusted cause-specific hazard ratios were estimated for each outcome. Results: At t he time of incident CKD, the mean age of the participants was 72 years, 97% were male, and their mean eGFR was 51 mL/min per 1.73 m2. Over a median 4.1 years of follow-up, 92,306 veterans (15%) developed dementia before kidney failure or death. Compared with the veterans with CKD without anemia, the multivariable-adjusted models showed a 16% (95% CI, 14%-17%) significantly higher risk of dementia for those with mild anemia and a 27% (95% CI, 23%-31%) higher risk with moderate/ severe anemia. Combined risk of kidney failure or death was higher at 39% (95% CI, 37%-40%) and 115% (95% CI, 112%-119%) for mild and moderate/severe anemia, respectively, compared with no anemia. Limitations: Residual confounding from the observational study design. Findings may not be generalizable to the broader US population. Conclusions: Anemia was significantly associated with an increased risk of dementia among veterans with incident CKD, underscoring the role of anemia as a predictor of dementia risk.

Antihypertensive treatments benefit cerebrovascular health and cognitive function in patients with hypertension, but it is uncertain whether an intensive blood pressure target leads to potentially harmful cerebral hypoperfusion.To investigate the association of intensive systolic blood pressure (SBP) control vs standard control with whole-brain cerebral blood flow (CBF).This substudy of the Systolic Blood Pressure Intervention Trial (SPRINT) randomized clinical trial compared the efficacy of 2 different blood pressure-lowering strategies with longitudinal brain magnetic resonance imaging (MRI) including arterial spin labeled perfusion imaging to quantify CBF. A total of 1267 adults 50 years or older with hypertension and increased cardiovascular risk but free of diabetes or dementia were screened for the SPRINT substudy from 6 sites in the US. Randomization began in November 2010 with final follow-up MRI in July 2016. Analyses were performed from September 2020 through December 2021.Study participants with baseline CBF measures were randomized to an intensive SBP target less than 120 mm Hg or standard SBP target less than 140 mm Hg.The primary outcome was change in whole-brain CBF from baseline. Secondary outcomes were change in gray matter, white matter, and periventricular white matter CBF.Among 547 participants with CBF measured at baseline, the mean (SD) age was 67.5 (8.1) years and 219 (40.0%) were women; 315 completed follow-up MRI at a median (IQR) of 4.0 (3.7-4.1) years after randomization. Mean whole-brain CBF increased from 38.90 to 40.36 (difference, 1.46 [95% CI, 0.08-2.83]) mL/100 g/min in the intensive treatment group, with no mean increase in the standard treatment group (37.96 to 37.12; difference, -0.84 [95% CI, -2.30 to 0.61] mL/100 g/min; between-group difference, 2.30 [95% CI, 0.30-4.30; P = .02]). Gray, white, and periventricular white matter CBF showed similar changes. The association of intensive vs standard treatment with CBF was generally similar across subgroups defined by age, sex, race, chronic kidney disease, SBP, orthostatic hypotension, and frailty, with the exception of an indication of larger mean increases in CBF associated with intensive treatment among participants with a history of cardiovascular disease (interaction P = .05).Intensive vs standard antihypertensive treatment was associated with increased, rather than decreased, cerebral perfusion, most notably in participants with a history of cardiovascular disease.ClinicalTrials.gov Identifier: NCT01206062.

IMPORTANCE:Antihypertensive treatments benefit cerebrovascular health and cognitive function in patients with hypertension, but it is uncertain whether an intensive blood pressure target leads to potentially harmful cerebral hypoperfusion.OBJECTIVE:To investigate the association of intensive systolic blood pressure (SBP) control vs standard control with whole-brain cerebral blood flow (CBF).DESIGN, SETTING, AND PARTICIPANTS:This substudy of the Systolic Blood Pressure Intervention Trial (SPRINT) randomized clinical trial compared the efficacy of 2 different blood pressure-lowering strategies with longitudinal brain magnetic resonance imaging (MRI) including arterial spin labeled perfusion imaging to quantify CBF. A total of 1267 adults 50 years or older with hypertension and increased cardiovascular risk but free of diabetes or dementia were screened for the SPRINT substudy from 6 sites in the US. Randomization began in November 2010 with final follow-up MRI in July 2016. Analyses were performed from September 2020 through December 2021.INTERVENTIONS:Study participants with baseline CBF measures were randomized to an intensive SBP target less than 120 mm Hg or standard SBP target less than 140 mm Hg.MAIN OUTCOMES AND MEASURES:The primary outcome was change in whole-brain CBF from baseline. Secondary outcomes were change in gray matter, white matter, and periventricular white matter CBF.RESULTS:Among 547 participants with CBF measured at baseline, the mean (SD) age was 67.5 (8.1) years and 219 (40.0%) were women; 315 completed follow-up MRI at a median (IQR) of 4.0 (3.7-4.1) years after randomization. Mean whole-brain CBF increased from 38.90 to 40.36 (difference, 1.46 [95% CI, 0.08-2.83]) mL/100 g/min in the intensive treatment group, with no mean increase in the standard treatment group (37.96 to 37.12; difference, -0.84 [95% CI, -2.30 to 0.61] mL/100 g/min; between-group difference, 2.30 [95% CI, 0.30-4.30; P = .02]). Gray, white, and periventricular white matter CBF showed similar changes. The association of intensive vs standard treatment with CBF was generally similar across subgroups defined by age, sex, race, chronic kidney disease, SBP, orthostatic hypotension, and frailty, with the exception of an indication of larger mean increases in CBF associated with intensive treatment among participants with a history of cardiovascular disease (interaction P = .05).CONCLUSIONS AND RELEVANCE:Intensive vs standard antihypertensive treatment was associated with increased, rather than decreased, cerebral perfusion, most notably in participants with a history of cardiovascular disease.TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT01206062.

BACKGROUND/OBJECTIVES Chronic kidney disease (CKD) is associated with frailty. Fibroblast growth factor 23 (FGF23) is elevated in CKD and associated with frailty among non‐CKD older adults and individuals with human immunodeficiency virus. Whether FGF23 is associated with frailty and falls in CKD is unknown. DESIGN Cross‐sectional and longitudinal observational study. SETTING Systolic Blood Pressure Intervention Trial (SPRINT), a randomized trial evaluating standard (systolic blood pressure [SBP] <140 mm Hg) versus intensive (SBP <120 mm Hg) blood pressure lowering on cardiovascular and cognitive outcomes among older adults without diabetes mellitus. PARTICIPANTS A total of 2,376 participants with CKD (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m 2 ). MEASUREMENTS The exposure variable was intact FGF23. We used multinomial logistic regression to determine the cross‐sectional association of intact FGF23 with frailty and Cox proportional hazards analysis to determine the longitudinal association with incident falls. Models were adjusted for demographics, comorbidities, randomization group, antihypertensives, eGFR, mineral metabolism markers, and frailty. RESULTS After adjustment, the odds ratio for prevalent frailty versus non‐frailty per twofold higher FGF23 was 1.34 (95% confidence interval [CI] = 1.01–1.77). FGF23 levels in the highest quartile versus the lowest quartile demonstrated more than a twofold increased fall risk (hazard ratio [HR] = 2.32; 95% CI = 1.26–4.26), and the HR per twofold higher FGF23 was 1.99 (95% CI = 1.48–2.68). CONCLUSION Among SPRINT participants with CKD, FGF23 was associated with prevalent frailty and falls.

BACKGROUND AND OBJECTIVES CKD is an independent risk factor for heart failure. Iron dysmetabolism potentially contributes to heart failure, but this relationship has not been well characterized in CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We performed a historical cohort study using data from the Veterans Affairs Corporate Data Warehouse to evaluate the relationship between iron status and heart failure hospitalization. We identified a CKD cohort with at least one set of iron indices between 2006 and 2015. The first available date of serum iron indices was identified as the study index date. The cohort was divided into four iron groups on the basis of the joint quartiles of serum transferrin saturation (shown in percent) and ferritin (shown in nanograms per milliliter): reference (16%-28%, 55-205 ng/ml), low iron (0.4%-16%, 0.9-55 ng/ml), high iron (28%-99.5%, 205-4941 ng/ml), and function iron deficiency (0.8%-16%, 109-2783 ng/ml). We compared 1-year heart failure hospitalization risk between the iron groups using matching weights derived from multinomial propensity score models and Poisson rate-based regression. RESULTS A total of 78,551 veterans met the eligibility criteria. The covariates were well balanced among the iron groups after applying the propensity score weights (n=31,819). One-year adjusted relative rate for heart failure hospitalization in the iron deficiency groups were higher compared with the reference group (low iron: 1.29 [95% confidence interval, 1.19 to 1.41]; functional iron deficiency: 1.25 [95% confidence interval, 1.13 to 1.37]). The high-iron group was associated with lower 1-year relative rate of heart failure hospitalization (0.82; 95% confidence interval, 0.72 to 0.92). Furthermore, the association between iron deficiency and heart failure hospitalization risk remained consistent regardless of the diabetes status or heart failure history at baseline. CONCLUSIONS Iron deficiency, regardless of cause, was associated with higher heart failure hospitalization risk in CKD. Higher iron status was associated with lower heart failure hospitalization risks.

Introduction: Prorenin, a precursor of renin, and renin play an important role in regulation of the renin-angiotensin system. More recently, receptor-bound prorenin has been shown to activate intracellular signaling pathways that mediate fibrosis, independent of angiotensin II. Prorenin and renin may thus be of physiologic significance in CKD, but their plasma concentrations have not been well characterized in CKD. Methods: We evaluated distribution and longitudinal changes of prorenin and renin concentrations in the plasma samples collected at follow-up years 1, 2, 3, and 5 of the Chronic Renal Insufficiency Cohort (CRIC) study, an ongoing longitudinal observational study of 3,939 adults with CKD. Descriptive statistics and multivariable regression of log-transformed values were used to describe cross-sectional and longitudinal variation and associations with participant characteristics. Results: A total of 3,361 CRIC participants had plasma available for analysis at year 1. The mean age (±standard deviation, SD) was 59 ± 11 years, and the mean estimated glomerular filtration rate (eGFR, ± SD) was 43 ± 17 mL/min per 1.73 m2. Median (interquartile range) values of plasma prorenin and renin at study entry were 4.4 (2.1, 8.8) ng/mL and 2.0 (0.8, 5.9) ng/dL, respectively. Prorenin and renin were positively correlated (Spearman correlation 0.51, p < 0.001) with each other. Women and non-Hispanic blacks had lower prorenin and renin values at year 1. Diabetes, lower eGFR, and use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, and diuretics were associated with higher levels. Prorenin and renin decreased by a mean of 2 and 5% per year, respectively. Non-Hispanic black race and eGFR <30 mL/min/1.73 m2 at year 1 predicted a steeper decrease in prorenin and renin over time. In addition, each increase in urinary sodium excretion by 2 SDs at year 1 increased prorenin and renin levels by 4 and 5% per year, respectively. Discussion/Conclusions: The cross-sectional clinical factors associated with prorenin and renin values were similar. Overall, both plasma prorenin and renin concentrations decreased over the years, particularly in those with severe CKD at study entry.

Hypertension is a risk factor for cognitive impairment; however, the mechanisms leading to cognitive changes remain unclear. In this cross-sectional study, we evaluate the impact of white matter lesion (WML) burden on brain functional connectivity (FC) and cognition in a large cohort of hypertensive patients from the Systolic Blood Pressure Intervention Trial (SPRINT) at baseline. Functional networks were identified from baseline resting state functional MRI scans of 660 SPRINT participants using independent component analysis. WML volumes were calculated from structural MRI. Correlation analyses were carried out between mean FC of each functional network and global WML as well as WML within atlas-defined white matter regions. For networks of interest, voxel-wise-adjusted correlation analyses between FC and regional WML volume were performed. Multiple variable linear regression models were built for cognitive test performance as a function of network FC, followed by mediation analysis. Mean FC of the default mode network (DMN) was negatively correlated with global WML volume, and regional WML volume within the precuneus. Voxel-wise correlation analyses revealed that regional WML was negatively correlated with FC of the DMN’s left lateral temporal region. FC in this region of the DMN was positively correlated to performance on the Montreal Cognitive Assessment and demonstrated significant mediation effects. Additional networks also demonstrated global and regional WML correlations; however, they did not demonstrate an association with cognition. In hypertensive patients, greater WML volume is associated with lower FC of the DMN, which in turn is related to poorer cognitive test performance. NCT01206062