Role of Anemia in Dementia Risk Among Veterans With Incident CKD.

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]<60mL/min/1.73m2) 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,<11.0g/dL, respectively, for women, and≥13.0, 11.0-12.9,<11.0g/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 the time of incident CKD, the mean age of the participants was 72 years, 97% were male, and their mean eGFR was 51mL/min per 1.73m2. 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. PLAIN-LANGUAGE SUMMARY: Adults with chronic kidney disease (CKD) often have anemia. Prior studies among adults in the general population suggest anemia is a risk factor for dementia, though it is unclear whether this association persists among adults with CKD. In this large study of veterans in the United States, we studied the association between anemia and the risk of 2 important outcomes in this population: (1) dementia and (2) kidney failure or death. We found that anemia was associated with a greater risk of dementia as well as risk of kidney failure or death. The study findings therefore emphasize the role of anemia as a key predictor of dementia risk among adults with CKD.

Iron status, fibroblast growth factor 23 and cardiovascular and kidney outcomes in chronic kidney disease.

Disordered iron and mineral homeostasis are interrelated complications of chronic kidney disease that may influence cardiovascular and kidney outcomes. In a prospective analysis of 3747 participants in the Chronic Renal Insufficiency Cohort Study, we investigated risks of mortality, heart failure, end-stage kidney disease (ESKD), and atherosclerotic cardiovascular disease according to iron status, and tested for mediation by C-terminal fibroblast growth factor 23 (FGF23), hemoglobin and parathyroid hormone. Study participants were agnostically categorized based on quartiles of transferrin saturation and ferritin as "Iron Replete" (27.1% of participants; referent group for all outcomes analyses), "Iron Deficiency" (11.1%), "Functional Iron Deficiency" (7.6%), "Mixed Iron Deficiency" (iron indices between the Iron Deficiency and Functional Iron Deficiency groups; 6.3%), "High Iron" (9.2%), or "Non-Classified" (the remaining 38.8% of participants). In multivariable-adjusted Cox models, Iron Deficiency independently associated with mortality (hazard ratio 1.28, 95% confidence interval 1.04-1.58) and heart failure (1.34, 1.05- 1.72). Mixed Iron Deficiency associated with mortality (1.61, 1.27-2.04) and ESKD (1.33, 1.02-1.73). High Iron associated with mortality (1.54, 1.24-1.91), heart failure (1.58, 1.21-2.05), and ESKD (1.41, 1.13-1.77). Functional Iron Deficiency did not significantly associate with any outcome, and no iron group significantly associated with atherosclerotic cardiovascular disease. Among the candidate mediators, FGF23 most significantly mediated the risks of mortality and heart failure conferred by Iron Deficiency. Thus, alterations in iron homeostasis associated with adverse cardiovascular and kidney outcomes in patients with chronic kidney disease.

Longitudinal Changes in Prorenin and Renin in the Chronic Renal Insufficiency Cohort.

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.

Changes in brain functional connectivity and cognition related to white matter lesion burden in hypertensive patients from SPRINT.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: In hypertensive patients, greater WML volume is associated with lower FC of the DMN, which in turn is related to poorer cognitive test performance. TRIAL REGISTRATION: NCT01206062.

The Difference Between Cystatin C- and Creatinine-Based Estimated GFR and Associations With Frailty and Adverse Outcomes: A Cohort Analysis of the Systolic Blood Pressure Intervention Trial (SPRINT).

RATIONALE & OBJECTIVE: In prior research and in practice, the difference between estimated glomerular filtration rate (eGFR) calculated from cystatin C level and eGFR calculated from creatinine level has not been assessed for clinical significance and relevance. We evaluated whether these differences contain important information about frailty. STUDY DESIGN: A cohort analysis of the Systolic Blood Pressure Intervention Trial (SPRINT). SETTING & PARTICIPANTS: 9,092 hypertensive SPRINT participants who had baseline measurements of serum creatinine, cystatin C, and frailty. EXPOSURE: eGFRs calculated using CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equations (eGFRcys and eGFRcr), and eGFRDiff, calculated as eGFRcys-eGFRcr. OUTCOMES: A validated 35-item frailty index that included questionnaire data for general and physical health, limitations of activities, pain, depression, sleep, energy level, self-care, and smoking status, as well as medical history, cognitive assessment, and laboratory data. We defined frailty as frailty index score>0.21 (range, 0-1). The incidence of injurious falls, hospitalizations, cardiovascular events, and mortality was also recorded. ANALYTICAL APPROACH: We used logistic regression to model the cross-sectional association of baseline eGFRDiff with frailty among all SPRINT participants. Adjusted proportional hazards regression was used to evaluate the association of eGFRDiff with adverse outcomes and mortality. RESULTS: Mean age was 68±9 (SD) years, mean eGFRcys and eGFRcr were 73±23 and 72±20mL/min/1.73m2, and mean eGFRDiff was 0.5±15mL/min/1.73m2. In adjusted models, each 1-SD higher eGFRDiff was associated with 24% lower odds of prevalent frailty (OR, 0.76; 95% CI, 0.71-0.81), as well as with lower incidence rate of injurious falls (HR, 0.84; 95% CI, 0.77-0.92), hospitalization (HR, 0.91; 95% CI, 0.88-0.95), cardiovascular events (HR, 0.89; 95% CI, 0.81-0.97), and all-cause mortality (HR, 0.71; 95% CI, 0.63-0.82); P<0.01. LIMITATIONS: Gold-standard measure of kidney function and assessment of muscle mass were not available. CONCLUSIONS: The difference between eGFRcys and eGFRcr is associated with frailty and health status. Positive eGFRDiff is strongly associated with lower risks for longitudinal adverse outcomes and mortality, even after adjusting for chronic kidney disease stage and baseline frailty.

Arterial stiffness and kidney disease progression in the systolic blood pressure intervention trial
.

AIMS: Arterial stiffness increases with both advancing age and chronic kidney disease (CKD) and may contribute to kidney function decline, but evidence is inconsistent. We hypothesized that greater baseline arterial stiffness (assessed as pulse pressure (PP) and carotid-femoral pulse-wave velocity CFPWV)) was independently associated with kidney disease progression over the follow-up period (3.8 years) in the Systolic Blood Pressure Intervention Trial (SPRINT). MATERIALS AND METHODS: 8,815 SPRINT participants were included in the analysis of PP. 592 adults who participated in a SPRINT ancillary study that measured CFPWV were included in subgroup analyses. Cox proportional hazards analysis was used to examine the association between PP and time to kidney disease progression endpoints: (A) incident estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 in non-CKD participants at baseline; (B) 50% decline in eGFR, initiation of dialysis, or transplant in those with baseline CKD. Mixed model analyses examined the association of baseline PP/CFPWV with follow-up eGFR. RESULTS AND CONCLUSION: Mean ± SD age was 68 ± 10 years, baseline PP was 62 ± 14 mmHg, and CFPWV was 10.8 ± 2.7 m/s. In the fully adjusted model, PP ≥ median was associated with an increased hazard of kidney disease progression endpoints (HR: 1.93 (1.43 - 2.61)). The association remained significant in individuals without (2.05 (1.47 - 2.87)) but not with baseline CKD (1.28 (0.55 - 2.65)). In fully adjusted models, higher baseline PP associated with eGFR decline (p < 0.0001 (all, CKD, non-CKD)), but baseline CFPWV did not. Among older adults at high risk for cardiovascular events, baseline PP was associated with kidney disease progression.

An increased mortality risk is associated with abnormal iron status in diabetic and non-diabetic Veterans with predialysis chronic kidney disease.

Iron parameters have not been well characterized in pre-dialysis patients with chronic kidney disease (CKD), and it remains unclear if abnormal iron balance is associated with increased mortality. Therefore, we performed a historical cohort study using data from the Veterans Affairs Corporate Data Warehouse to evaluate the relationship between iron status and mortality. We identified a pre-dialysis CKD cohort with at least one set of iron indices between 2006-2015. The cohort was divided into four iron groups based on the joint quartiles of serum transferrin saturation (percent) and ferritin concentration (ng/ml): reference (16-28%, 55-205 ng/ml), low iron (0.4-16%, 0.4-55 ng/ml), high iron (28-99.6%, 205-4941 ng/ml), and function iron deficiency (0.8-16%, 109-2783 ng/ml). We compared mortality risk between the iron groups using matching weights based on multinomial propensity score models and Poisson rate-based regression. We also evaluated if the association between iron groups and mortality differs between the diabetic and non-diabetic subgroups. Of the 80,067 eligible veterans, 32,489 were successfully matched. During the mean follow-up period of 4.0 years, adjusted relative rate (95% confidence interval) for all-cause mortality in three abnormal iron groups were increased compared to the reference: functional iron deficiency [1.21 (1.17, 1.25)], low iron [1.10 (1.07, 1.14)], and high iron [1.09 (1.06, 1.13)]. The mortality risk was similar between diabetic and non-diabetic subgroups for each iron group. Thus, an abnormal iron balance, particularly functional iron deficiency, is associated with increased mortality in CKD.

Open-Label Clinical Trials of Oral Pulse Dexamethasone for Adults with Idiopathic Nephrotic Syndrome.

BACKGROUND: In adults with primary focal segmental glomerulosclerosis (FSGS), daily prednisone may induce complete remissions (CR) and partial remissions (PR), but relapses are frequent and adverse events are common. METHODS: We carried out 2 open-label, uncontrolled trials to explore the efficacy and tolerability of pulse oral dexamethasone as an alternative to daily prednisone. We enrolled adult patients with proteinuria > 3.5 g/day despite the use of renin-angiotensin-aldosterone blockade. In the first trial, we enrolled 14 subjects with FSGS and administered 4 dexamethasone doses (25 mg/m2) daily for 4 days, repeated every 28 days over 32 weeks. The second trial involved a more intensive regimen. Eight subjects received 4 dexamethasone doses of 50 mg/m2 every 4 weeks for 12 weeks, followed by 4 doses of 25 mg/m2 every 4 weeks for 36 weeks; subjects were randomized to 2 doses every 2 weeks or 4 doses every 4 weeks. RESULTS: In the first trial, we enrolled 13 subjects with FSGS and 1 with minimal change disease and found a combined CR and PR rate of 36%. In the second trial, we enrolled 8 subjects. The combined CR and PR rate was 29%. Analysis combining both trials showed a combined CR and PR rate of 33%. Adverse events were observed in 32% of subjects, with mood symptoms being most common. There were no serious adverse events related to the study. CONCLUSION: We conclude that high dose oral dexamethasone is well tolerated by adults with idiopathic nephrotic syndrome and may have some efficacy.

Effect of Intensive Blood Pressure Lowering on Left Ventricular Hypertrophy in Patients With Hypertension: SPRINT (Systolic Blood Pressure Intervention Trial).

BACKGROUND: It is currently unknown whether intensive blood pressure (BP) lowering beyond that recommended would lead to more lowering of the risk of left ventricular hypertrophy (LVH) in patients with hypertension and whether reducing the risk of LVH explains the reported cardiovascular disease (CVD) benefits of intensive BP lowering in this population. METHODS: This analysis included 8164 participants (mean age, 67.9 years; 35.3% women; 31.2% blacks) with hypertension but no diabetes mellitus from the SPRINT trial (Systolic Blood Pressure Intervention Trial): 4086 randomly assigned to intensive BP lowering (target SBP <120 mm Hg) and 4078 assigned to standard BP lowering (target SBP <140 mm Hg). Progression and regression of LVH as defined by Cornell voltage criteria derived from standard 12-lead ECGs recorded at baseline and biannually were compared between treatment arms during a median follow-up of 3.81 years. The effect of intensive (versus standard) BP lowering on the SPRINT primary CVD outcome (a composite of myocardial infarction, acute coronary syndrome, stroke, heart failure, and CVD death) was compared before and after adjustment for LVH as a time-varying covariate. RESULTS: Among SPRINT participants without baseline LVH (n=7559), intensive (versus standard) BP lowering was associated with a 46% lower risk of developing LVH (hazard ratio=0.54; 95% confidence interval, 0.43-0.68). Similarly, among SPRINT participants with baseline LVH (n=605, 7.4%), those assigned to the intensive (versus standard) BP lowering were 66% more likely to regress/improve their LVH (hazard ratio=1.66; 95% confidence interval, 1.31-2.11). Adjustment for LVH as a time-varying covariate did not substantially attenuate the effect of intensive BP therapy on CVD events (hazard ratio of intensive versus standard BP lowering on CVD, 0.76 [95% confidence interval, 0.64-0.90] and 0.77 [95% confidence interval, 0.65-0.91] before and after adjustment for LVH as a time-varying covariate, respectively). CONCLUSIONS: Among patients with hypertension but no diabetes mellitus, intensive BP lowering (target systolic BP <120 mm Hg) compared with standard BP lowering (target systolic BP <140 mm Hg) resulted in lower rates of developing new LVH in those without LVH and higher rates of regression of LVH in those with existing LVH. This favorable effect on LVH did not explain most of the reduction in CVD events associated with intensive BP lowering in the SPRINT trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062.

The Associations of Plant Protein Intake With All-Cause Mortality in CKD.

BACKGROUND: Plant protein intake is associated with lower production of uremic toxins and lower serum phosphorus levels. Therefore, at a given total protein intake, a higher proportion of dietary protein from plant sources might be associated with lower mortality in chronic kidney disease. STUDY DESIGN: Observational study. SETTINGS & PARTICIPANTS: 14,866 NHANES III participants 20 years or older without missing data for plant and animal protein intake and mortality. PREDICTORS: Plant protein to total protein ratio and total plant protein intake. Patients were stratified by estimated glomerular filtration rate (eGFR)<60 or ≥60mL/min/1.73m(2). OUTCOMES: All-cause mortality. MEASUREMENTS: Plant and total protein intakes were estimated from 24-hour dietary recalls. Mortality was ascertained by probabilistic linkage with National Death Index records through December 31, 2000. RESULTS: Mean values for plant protein intake and plant protein to total protein ratio were 24.6±13.2 (SD) g/d and 33.0% ± 14.0%, respectively. The prevalence of eGFRs<60mL/min/1.73m(2) was 4.9%. There were 2,163 deaths over an average follow-up of 8.4 years. Adjusted for demographics, smoking, alcohol use, comorbid conditions, body mass index, calorie and total protein intake, and physical inactivity, each 33% increase in plant protein to total protein ratio was not associated with mortality (HR, 0.88; 95% CI, 0.74-1.04) in the eGFR≥60mL/min/1.73m(2) subpopulation, but was associated with lower mortality risk (HR, 0.77; 95% CI, 0.61-0.96) in the eGFR<60mL/min/1.73m(2) subpopulation. In sensitivity analyses, results were similar in those with eGFR<60mL/min/1.73m(2) defined by serum cystatin C level. LIMITATIONS: Whether results are related to plant protein itself or to other factors associated with more plant-based diets is difficult to establish. CONCLUSIONS: A diet with a higher proportion of protein from plant sources is associated with lower mortality in those with eGFR<60mL/min/1.73m(2). Future studies are warranted to determine the causal role of plant protein intake in reducing mortality in those with eGFR<60mL/min/1.73m(2).

Association of Intensive vs Standard Blood Pressure Control With Cerebral Blood Flow: Secondary Analysis of the SPRINT MIND Randomized Clinical Trial.

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.

Heart Failure Hospitalization Risk associated with Iron Status in Veterans with CKD.

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.

Validation of Algorithms Used to Identify Red Blood Cell Transfusion Related Admissions in Veteran Patients with End Stage Renal Disease.

BACKGROUND: The goal of this study was to compare the performance of several database algorithms designed to identify red blood cell (RBC) Transfusion Related hospital Admissions (TRAs) in Veterans with end stage renal disease (ESRD). METHODS: Hospitalizations in Veterans with ESRD and evidence of dialysis between 01/01/2008 and 12/31/2013 were screened for TRAs using a clinical algorithm (CA) and four variations of claims-based algorithms (CBA 1-4). Criteria were implemented to exclude patients with non-ESRD-related anemia (e.g., injury, surgery, bleeding, medications known to produce anemia). Diagnostic performance of each algorithm was delineated based on two clinical representations of a TRA: RBC transfusion required to treat ESRD-related anemia on admission regardless of the reason for admission (labeled as TRA) and hospitalization for the primary purpose of treating ESRD-related anemia (labeled TRA-Primary). The performance of all algorithms was determined by comparing each to a reference standard established by medical records review. Population-level estimates of classification agreement statistics were calculated for each algorithm using inverse probability weights and bootstrapping procedures. Due to the low prevalence of TRAs, the geometric mean was considered the primary measure of algorithm performance. RESULTS: After application of exclusion criteria, the study consisted of 12,388 Veterans with 26,672 admissions. The CA had a geometric mean of 90.8% (95% Confidence Interval: 81.8, 95.6) and 94.7% (95% CI: 80.5, 98.7) for TRA and TRA-Primary, respectively. The geometric mean for the CBAs ranged from 60.3% (95% CI: 53.2, 66.9) to 91.8% (95% CI: 86.9, 95) for TRA, and from 80.7% (95% CI: 72.9, 86.7) to 96.7% (95% CI: 94.1, 98.2) for TRA-Primary. The adjusted proportions of admissions classified as TRAs was 3.2% (95% CI: 2.8, 3.8) and TRA-Primary was 1.3% (95% CI: 1.1, 1.7). CONCLUSIONS: The CA and select CBAs were able to identify TRAs and TRA-primary with high levels of accuracy and can be used to examine anemia management practices in ESRD patients.

Heart Failure Prevention in Older Patients Using Intensive Blood Pressure Reduction: Potential Role of Diuretics.

OBJECTIVES: This study assessed the potential role of differential diuretic drugs in preventing incident acute decompensated heart failure (ADHF) in the SPRINT (Systolic Blood Pressure Intervention Trial) study. BACKGROUND: SPRINT showed that intensive blood pressure reduction in older patients (50 to 97 years of age) resulted in 36% fewer incident cases of ADHF. However, some investigators have questioned whether this was due merely to intergroup differences in diuretic medications. METHODS: Detailed use of medication data prospectively collected throughout the trial were examined. RESULTS: ADHF events occurred in 173 of 9,361 participants. Diuretic medication increased in both arms from screening to baseline visit (from 45% to 50% in the standard arm; and from 43% to 63% in the intensive arm) and then remained steady. The lowest use of diuretic agents was among participants in the standard arm who never had an ADHF event. Withdrawal of diuretic agents at the baseline visit occurred in 6.1% (n = 284) of participants in the standard arm and 2.3% (n = 107) of participants in the intensive arm. Of these, only 11 developed ADHF during the trial (10 in the standard arm, 1 in the intensive arm), and only 1 occurred ≤1 month after diuretic withdrawal. The benefit of ADHF reduction remained significant even after excluding those 11 participants (hazard ratio [HR]: 0.69; 95% confidence interval [CI]: 0.5 to 0.94; p = 0.02). Most ADHF events occurred in participants who were taking prescribed diuretic therapy at the last visit, prior to the ADHF event. There was limited use of loop (<6%) and potassium-sparing diuretic agents (2%). Diuretic use was not a predictor of ADHF (HR: 0.96; 95% CI: 0.66 to 1.40; p = 0.83). CONCLUSIONS: No evidence was found to suggest that the reduction in new ADHF events in SPRINT was due to differential diuretic use. (Systolic Blood Pressure Intervention Trial [SPRINT]; NCT01206062).

Effect of Intensive Blood Pressure Reduction on Left Ventricular Mass, Structure, Function, and Fibrosis in the SPRINT-HEART.

In observational studies, left ventricular mass (LVM) and structure are strong predictors of mortality and cardiovascular events. However, the effect of hypertension treatment on LVM reduction and its relation to subsequent outcomes is unclear, particularly at lower blood pressure (BP) targets. In an ancillary study of SPRINT (Systolic Blood Pressure Intervention Trial), where participants were randomly assigned to intensive BP control (target systolic BP target <120 mm Hg) versus standard BP control (<140 mm Hg), cardiac magnetic resonance imaging was performed at baseline and 18-month follow-up to measure: LVM, volumes, ejection fraction, and native T1 mapping for myocardial fibrosis. At baseline, 337 participants were examined (age: 64±9 years, 45% women); 300 completed the 18-month exam (153 intensive control and 147 standard control). In the intensive versus standard BP control group at 18 months, there was no difference in change in LVM (mean±SE =-2.7±0.5 g versus -2.3±0.7 g; P=0.368), ejection fraction, or native T1 (P=0.79), but there was a larger decrease in LVM/end-diastolic volume ratio (-0.04±0.01 versus -0.01±0.01; P=0.002) a measure of concentric LV remodeling. There were fewer cardiovascular events in the intensive control group, but no significant association between the reduced events and change in LVM or any other cardiac magnetic resonance imaging measure. In SPRINT-HEART, contrary to our hypothesis, there were no significant between-group differences in LVM, function, or myocardial T1 at 18-month follow-up. These results suggests that mediators other than these LV measures contribute to the improved cardiovascular outcomes with intensive BP control.

Urinary exosomal transcription factors, a new class of biomarkers for renal disease.

Urinary exosomes are excreted from all nephron segments and constitute a rich source of intracellular kidney injury biomarkers. To study whether they contain transcription factors, we collected urine from two acute kidney injury models (cisplatin or ischemia-reperfusion), two podocyte injury models (puromycin-treated rats or podocin-Vpr transgenic mice) and from patients with focal segmental glomerulosclerosis, acute kidney injury and matched controls. Exosomes were isolated by differential centrifugation and found to contain activating transcription factor 3 (ATF3) and Wilms Tumor 1 (WT-1) proteins detected by Western blot. These factors were found in the concentrated exosomal fraction, but not in whole urine. ATF3 was continuously present in urine exosomes of the rat models following acute injury at times earlier than the increase in serum creatinine. ATF3 was found in exosomes isolated from patients with acute kidney injury but not from patients with chronic kidney disease or controls. Urinary WT-1 was present in animal models before significant glomerular sclerosis and in 9/10 patients with focal segmental glomerulosclerosis but not in 8 controls. Our findings suggest that transcription factor ATF3 may provide a novel renal tubular cell biomarker for acute kidney injury while WT-1 may detect early podocyte injury. Measurement of urinary exosomal transcription factors may offer insight into cellular regulatory pathways.

Sirolimus therapy of focal segmental glomerulosclerosis is associated with nephrotoxicity.

To evaluate the safety and efficacy of sirolimus in treating patients with focal segmental glomerulosclerosis (FSGS), we performed a phase 2, open-label clinical trial. Inclusion criteria were adults and children 13 years and older with biopsy-proven idiopathic FSGS, proteinuria with protein of 3.5 g/d or greater while on angiotensin antagonist therapy, glomerular filtration rate (GFR) of 30 mL/min/1.73 m(2) or greater (>or=0.50 mL/s), and failure to achieve sustained remission with at least 1 immunosuppressive agent. Eligible patients received sirolimus doses adjusted to achieve trough levels of 5 to 15 ng/mL during the first 4 months and 10 to 20 ng/mL for the subsequent 8 months. The primary outcome was decrease in proteinuria, expressed as complete remission (protein < 0.3 g/d) or partial remission (protein >or= 50% decrease and <3.5 g/d). Six adult patients with FSGS were enrolled in the study; they had median disease duration of 4.0 years, mean age of 39 +/- 11 years, mean baseline Modification of Diet in Renal Disease-estimated GFR of 52 +/- 15 mL/min/1.73 m(2) (0.87 +/- 0.25 mL/s), and median baseline proteinuria with protein of 6.6 g/d (interquartile range, 4.2 to 9.4). Five patients had received cyclosporine. No patient experienced a complete or partial remission. Sirolimus therapy was stopped prematurely in 5 patients for the following reasons: (1) precipitous decrease in GFR in 4 patients after 7 to 9 months of therapy with a greater than 2-fold increase in proteinuria in 3 patients and (2) hypertriglyceridemia with triglyceride levels greater than 1,600 mg/dL (>18 mmol/L) at 5 months in 1 patient. Because of a rapid decrease in GFR with worsening proteinuria, the protocol was closed to further recruitment. We conclude that sirolimus may be associated with nephrotoxicity in some patients with FSGS, particularly those with prolonged disease duration and prior cyclosporine therapy.

The association between insulin resistance and atrial fibrillation: A cross-sectional analysis from SPRINT (Systolic Blood Pressure Intervention Trial).

It is unclear whether metabolic syndrome (MetS) is associated with atrial fibrillation (AF) in an older population with greater cardiovascular risk, including those with chronic kidney disease. The authors investigated the association between MetS and AF in participants in SPRINT (Systolic Blood Pressure Intervention Trial). MetS was defined based on the Modified Third National Cholesterol Education Program. The baseline prevalence rate for MetS was 55%, while 8.2% of the participants had AF. In multivariate regression analyses, AF was not associated with presence of MetS in either chronic kidney disease or non-chronic kidney disease subgroups. Age, race, history of cardiovascular diseases, decreased triglycerides, decreased pulse pressure, and albuminuria remained significantly associated with AF risk. In contrast to the general population, MetS was not associated with AF in the older population with increased cardiovascular risk studied in SPRINT.

Pirfenidone: an anti-fibrotic therapy for progressive kidney disease.

IMPORTANCE OF THE FIELD: Many chronic diseases of various etiologies lead to fibrosis and organ dysfunction. Despite many advances in medicine in recent years, options to slow the progression of fibrotic diseases have remained limited. The recent availability of pirfenidone, an antifibrotic and anti-inflammatory investigational agent, thus offers a new hope for treating progressive fibrotic diseases. AREAS COVERED IN THIS REVIEW: This review provides concise review of the available data regarding the mechanism and pharmacokinetics of pirfenidone and preclinical and clinical data regarding efficacy and safety in fibrotic diseases of the kidney. It also reviews results of clinical trials involving pirfenidone in other fibrotic diseases. WHAT THE READER WILL GAIN: The review will provide in-depth review of pirfenidone with a renal focus. TAKE HOME MESSAGE: Because many of the available clinical trials have been small and/or uncontrolled, conclusive evidence regarding efficacy and safety of pirfenidone is lacking, particularly in patients with renal or hepatic dysfunction. Larger studies are needed to better understand long-term efficacy and safety of this medication in various patient populations.

MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis.

The increased burden of chronic kidney and end-stage kidney diseases (ESKD) in populations of African ancestry has been largely unexplained. To identify genetic variants predisposing to idiopathic and HIV-1-associated focal segmental glomerulosclerosis (FSGS), we carried out an admixture-mapping linkage-disequilibrium genome scan on 190 African American individuals with FSGS and 222 controls. We identified a chromosome 22 region with a genome-wide logarithm of the odds (lod) score of 9.2 and a peak lod of 12.4 centered on MYH9, a functional candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and haplotypes were recessively associated with FSGS, most strongly a haplotype spanning exons 14 through 23 (OR = 5.0, 95% CI = 3.5-7.1; P = 4 x 10(-23), n = 852). This association extended to hypertensive ESKD (OR = 2.2, 95% CI = 1.5-3.4; n = 433), but not type 2 diabetic ESKD (n = 476). Genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive ESKD among African Americans.