Determinants of Achieving Serum Urate Goal with Treat-to-Target Urate-Lowering Therapy in Gout.

OBJECTIVE: Using trial data comparing treat-to-target allopurinol and febuxostat in gout, we examined participant characteristics associated with serum urate (SU) goal achievement. METHODS: Participants with gout and SU ≥6.8 mg/dL were randomized to allopurinol or febuxostat, titrated during weeks 0 to 24, and maintained weeks 25 to 48. Participants were considered to achieve SU goal if the mean SU from weeks 36, 42, and 48 was <6.0 mg/dL or <5 mg/dL if tophi were present. Possible determinants of treatment response were preselected and included sociodemographics, comorbidities, diuretic use, health-related quality of life (HRQoL), body mass index, and gout measures. Determinants of SU response were assessed using multivariable logistic regression with additional analyses to account for treatment adherence. RESULTS: Of 764 study participants completing week 48, 618 (81%) achieved SU goal. After multivariable adjustment, factors associated with a greater likelihood of SU goal achievement included older age (adjusted odds ratio [aOR] 1.40 per 10 years), higher education (aOR 2.02), and better HRQoL (aOR 1.17 per 0.1 unit). Factors associated with a lower odds of SU goal achievement included non-White race (aORs 0.32-0.47), higher baseline SU (aOR 0.83 per 1 mg/dL), presence of tophi (aOR 0.29), and the use of diuretics (aOR 0.52). Comorbidities including chronic kidney disease, hypertension, diabetes, and cardiovascular disease were not associated with SU goal achievement. Results were not meaningfully changed in analyses accounting for adherence. CONCLUSIONS: Several patient-level factors were predictive of SU goal achievement among patients with gout who received treat-to-target urate-lowering therapy (ULT). Approaches that accurately predict individual responses to treat-to-target ULT hold promise in facilitating personalized management and improving outcomes in patients with gout.

Analysis of the human kidney transcriptome and plasma proteome identifies markers of proximal tubule maladaptation to injury.

Acute kidney injury (AKI) is a major risk factor for long-term adverse outcomes, including chronic kidney disease. In mouse models of AKI, maladaptive repair of the injured proximal tubule (PT) prevents complete tissue recovery. However, evidence for PT maladaptation and its etiological relationship with complications of AKI is lacking in humans. We performed single-nucleus RNA sequencing of 120,985 nuclei in kidneys from 17 participants with AKI and seven healthy controls from the Kidney Precision Medicine Project. Maladaptive PT cells, which exhibited transcriptomic features of dedifferentiation and enrichment in pro-inflammatory and profibrotic pathways, were present in participants with AKI of diverse etiologies. To develop plasma markers of PT maladaptation, we analyzed the plasma proteome in two independent cohorts of patients undergoing cardiac surgery and a cohort of marathon runners, linked it to the transcriptomic signatures associated with maladaptive PT, and identified nine proteins whose genes were specifically up- or down-regulated by maladaptive PT. After cardiac surgery, both cohorts of patients had increased transforming growth factor-ß2 (TGFB2), collagen type XXIII-α1 (COL23A1), and X-linked neuroligin 4 (NLGN4X) and had decreased plasminogen (PLG), ectonucleotide pyrophosphatase/phosphodiesterase 6 (ENPP6), and protein C (PROC). Similar changes were observed in marathon runners with exercise-associated kidney injury. Postoperative changes in these markers were associated with AKI progression in adults after cardiac surgery and post-AKI kidney atrophy in mouse models of ischemia-reperfusion injury and toxic injury. Our results demonstrate the feasibility of a multiomics approach to discovering noninvasive markers and associating PT maladaptation with adverse clinical outcomes.

Cystatin C as a GFR Estimation Marker in Acute and Chronic Illness: A Systematic Review.

Rationale & Objective: Creatinine-based GFR estimating (eGFRcr) equations may be inaccurate in populations with acute or chronic illness. The accuracy of GFR equations that use cystatin C (eGFRcys) or creatinine-cystatin C (eGFRcr-cys) is not well studied in these populations. Study Design: A systematic review of original articles identified from PubMed and expert sources. Two reviewers screened articles independently and identified those meeting inclusion criteria. Setting & Study Populations: Adults and children with acute or chronic illness. Selection Criteria for Studies: Studies published since 2011 that compared performance of eGFRcr, eGFRcys, and eGFRcr-cys relative to measured GFR (mGFR), used standardized assays for creatinine or cystatin C, and used eGFR equations developed using such assays. Studies of ambulatory clinical populations or research studies in populations with only CKD, kidney transplant recipients, only diabetes, kidney donor candidates, and community-based cohorts were excluded. Data Extraction: Data extracted from full text. Analytical Approach: Bias and percentages of estimates within 30% of mGFR (P30) of eGFR compared with mGFR were evaluated. Results: Of the 179 citations, 26 studies met the inclusion criteria: 24 in adults and 2 in children in clinical populations with cancer (n=5), HIV (n=5), cirrhosis (n=3), liver transplant (n=3), heart failure (n=2), neuromuscular diseases (n=1) critical illness (n=5), and obesity (n=2). In general, eGFRcr-cys had greater accuracy than eGFRcr or eGFRcys equations among study populations with cancer, HIV, and obesity, but did not perform consistently better in cirrhosis, liver transplant, heart failure, neuromuscular disease, and critical illness. Limitations: Participants were selected because of concern for inaccurate eGFRcr, which may bias results. Most studies had small sample sizes, limiting generalizability. Conclusions: eGFRcr-cys improves GFR estimation in populations with a variety of acute and chronic illnesses, providing indications for cystatin C measurement. Performance was poor in many studies, suggesting the need for more frequent mGFR. Plain-Language Summary: Kidney function, specifically glomerular filtration rate (GFR), estimated using creatinine (eGFRcr) is often inaccurate in people with acute and chronic illness. The accuracy of estimates using cystatin C alone (eGFRcys) or together with creatinine (eGFRcr-cys) is not well studied in these populations. We conducted a systematic review to address the knowledge gap. Of the 179 papers reviewed, we identified 26 studies in clinical populations with cancer (n=5); HIV (n=5); cirrhosis (n=3); liver transplant (n=3); heart failure (n=2); neuromuscular disease (n=1); critical illness (n=5); and obesity (n=2). In general, eGFRcr-cys improved the GFR estimation in HIV, cancer, and obesity, providing indications for cystatin C measurement. Performance was poor in many studies, suggesting the need for more frequent measured GFR.

AACC/NKF Guidance Document on Improving Equity in Chronic Kidney Disease Care.

BACKGROUND: Kidney disease (KD) is an important health equity issue with Black, Hispanic, and socioeconomically disadvantaged individuals experiencing a disproportionate disease burden. Prior to 2021, the commonly used estimated glomerular filtration rate (eGFR) equations incorporated coefficients for Black race that conferred higher GFR estimates for Black individuals compared to non-Black individuals of the same sex, age, and blood creatinine concentration. With a recognition that race does not delineate distinct biological categories, a joint task force of the National Kidney Foundation and the American Society of Nephrology recommended the adoption of the CKD-EPI 2021 race-agnostic equations. CONTENT: This document provides guidance on implementation of the CKD-EPI 2021 equations. It describes recommendations for KD biomarker testing, and opportunities for collaboration between clinical laboratories and providers to improve KD detection in high-risk populations. Further, the document provides guidance on the use of cystatin C, and eGFR reporting and interpretation in gender-diverse populations. SUMMARY: Implementation of the CKD-EPI 2021 eGFR equations represents progress toward health equity in the management of KD. Ongoing efforts by multidisciplinary teams, including clinical laboratorians, should focus on improved disease detection in clinically and socially high-risk populations. Routine use of cystatin C is recommended to improve the accuracy of eGFR, particularly in patients whose blood creatinine concentrations are confounded by processes other than glomerular filtration. When managing gender-diverse individuals, eGFR should be calculated and reported with both male and female coefficients. Gender-diverse individuals can benefit from a more holistic management approach, particularly at important clinical decision points.

Utilization and Outcomes of Clinically Indicated Invasive Cardiac Care in Veterans with Acute Coronary Syndrome and Chronic Kidney Disease.

SIGNIFICANCE STATEMENT: Of studies reporting an association of CKD with lower use of invasive cardiac care to treat acute coronary syndrome (ACS), just one accounted for the appropriateness of such care. However, its findings in patients hospitalized nearly 30 years ago may not apply to current practice. In a more recent cohort of 64,695 veterans hospitalized with ACS, CKD was associated with a 32% lower likelihood of receiving invasive care determined to be clinically indicated. Among patients with CKD, not receiving such care was associated with a 1.39-fold higher risk of 6-month mortality. Efforts to elucidate the reasons for this disparity in invasive care in patients with ACS and CKD and implement tailored interventions to enhance its use in this population may offer the potential to improve clinical outcomes. BACKGROUND: Previous studies have shown that patients with CKD are less likely than those without CKD to receive invasive care to treat acute coronary syndrome (ACS). However, few studies have accounted for whether such care was clinically indicated or assessed whether nonuse of such care was associated with adverse health outcomes. METHODS: We conducted a retrospective cohort study of US veterans who were hospitalized at Veterans Affairs Medical Centers from January 2013 through December 2017 and received a discharge diagnosis of ACS. We used multivariable logistic regression to investigate the association of CKD with use of invasive care (coronary angiography, with or without revascularization; coronary artery bypass graft surgery; or both) deemed clinically indicated based on Global Registry of Acute Coronary Events 2.0 risk scores that denoted a 6-month predicted all-cause mortality ≥5%. Using propensity scoring and inverse probability weighting, we examined the association of nonuse of clinically indicated invasive care with 6-month all-cause mortality. RESULTS: Among 34,430 patients with a clinical indication for invasive care, the 18,780 patients with CKD were less likely than the 15,650 without CKD to receive such care (adjusted odds ratio, 0.68; 95% confidence interval, 0.65 to 0.72). Among patients with CKD, nonuse of invasive care was associated with higher risk of 6-month all-cause mortality (absolute risk, 21.5% versus 15.5%; absolute risk difference 6.0%; adjusted risk ratio, 1.39; 95% confidence interval, 1.29 to 1.49). Findings were consistent across multiple sensitivity analyses. CONCLUSIONS: In contemporary practice, veterans with CKD who experience ACS are less likely than those without CKD to receive clinically indicated invasive cardiac care. Nonuse of such care is associated with increased mortality.

Rationale and design of the Kidney Precision Medicine Project.

Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision-medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living-donor kidney biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomic analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for 10 years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients.

Systematic Review and Meta-Analysis of Native Kidney Biopsy Complications.

BACKGROUND AND OBJECTIVES: Native kidney biopsies are commonly performed in the diagnosis of acute kidney diseases and CKD. Because of the invasive nature of the procedure, bleeding-related complications are not uncommon. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases-sponsored Kidney Precision Medicine Project requires that all participants undergo a kidney biopsy; therefore, the objective of this analysis was to study complication rates of native kidney biopsies performed using automated devices under kidney imaging. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a systematic review and meta-analysis of the literature published from January 1983 to March 2018. The initial PubMed search yielded 1139 manuscripts. Using predetermined selection criteria, 87 manuscripts were included in the final analysis. A random effects meta-analysis for proportions was used to obtain combined estimates of complication rates. Freeman-Tukey double-arcsine transformations were used to stabilize variance as complications were rare. RESULTS: A total of 118,064 biopsies were included in this study. Patient age ranged from 30 to 79 years, and 45% of patients were women. On the basis of our meta-analysis, pain at the site of biopsy is estimated to occur in 4.3% of biopsied patients, hematomas are estimated to occur in 11%, macroscopic hematuria is estimated to occur in 3.5%, bleeding requiring blood transfusions is estimated to occur in 1.6%, and interventions to stop bleeding are estimated to occur in only 0.3%. Death attributed to native kidney biopsy was a rare event, occurring only in an estimated 0.06% of all biopsies but only 0.03% of outpatient biopsies. Complication rates were higher in hospitalized patients and in those with acute kidney disease. The reported complications varied on the basis of study type and geographic location. CONCLUSIONS: Although the native kidney biopsy is an invasive diagnostic procedure, the rates of bleeding complications are low. Albeit rare, death can occur postbiopsy. Complications are more frequently seen after kidney biopsies of hospitalized patients with AKI.

Severe Hyponatremia and Continuous Renal Replacement Therapy: Safety and Effectiveness of Low-Sodium Dialysate.

RATIONALE & OBJECTIVE: In patients with severe hyponatremia in the setting of acute kidney injury or end-stage kidney disease, continuous renal replacement therapy (CRRT) using standard-sodium (140 mEq/L) fluids may lead to excessively rapid correction of plasma sodium concentration. Use of dialysate and replacement fluids with reduced sodium concentrations can provide a controlled rate of correction of plasma sodium concentration. STUDY DESIGN: We performed a single-center retrospective analysis of the safety and effectiveness of this approach in patients with plasma sodium concentrations ≤ 126 mEq/L who underwent CRRT for 24 or more hours using low-sodium (119 or 126 mEq/L) dialysate and replacement fluids. Change in plasma sodium level was assessed at 24 and 48 hours after initiation of low-sodium CRRT and at the end of treatment. SETTING & PARTICIPANTS: Between January 2016 and June 2018, a total of 23 hyponatremic patients underwent continuous venovenous hemodiafiltration using low-sodium dialysate and replacement fluids; 4 patients were excluded from analysis because of CRRT duration less than <24 hours. RESULTS: The 19 patients included in the study had a mean age of 56 years, 11 (58%) were men, and 15 (79%) were white. The initial mean plasma sodium level was 121 mEq/L and the initial CRRT effluent dose was 27 mL/kg/h. Only 2 (11%) patients had an increase in plasma sodium concentration > 6 mEq/L at 24 hours. Mean changes in plasma sodium levels at 24 and 48 hours and at the time of CRRT discontinuation were 3, 3, and 6 mEq/L, respectively. None of the patients developed osmotic demyelination syndrome. LIMITATIONS: Key limitations were small sample size and lack of a control group. CONCLUSIONS: Use of low-sodium dialysate and replacement fluids is a safe strategy for the prevention of overly rapid correction of plasma sodium levels in hyponatremic patients undergoing CRRT.

Intensity of Renal Replacement Therapy and Duration of Mechanical Ventilation: Secondary Analysis of the Acute Renal Failure Trial Network Study.

BACKGROUND: Randomized clinical trials have failed to show benefit from increasing intensity of renal replacement therapy (RRT) for acute kidney injury, but continue to be frequently used. In addition, intensive RRT is associated with an increase in adverse events potentially secondary to small solute losses, such as phosphate. We hypothesized that, compared with less-intensive RRT, intensive RRT would lead to longer duration of mechanical ventilation. RESEARCH QUESTION: Does more-intensive renal replacement therapy in critically ill patients with acute kidney injury increase time to extubation from mechanical ventilation when compared with less-intensive therapy? STUDY DESIGN AND METHODS: The Acute Renal Failure Trial Network study was a randomized multicenter trial of more-intensive (hemodialysis or sustained low-efficiency dialysis six times per week or continuous venovenous hemodiafiltration at 35 mL/kg per hour) vs less-intensive (hemodialysis or sustained low-efficiency dialysis three times per week or continuous venovenous hemodiafiltration at 20 mL/kg per hour) RRT in critically ill patients with acute kidney injury. Of 1124 patients, 907 who were supported by mechanical ventilation on study initiation were included in this Cox-proportional hazards analysis. The primary outcome was the time to first successful extubation off mechanical ventilation. RESULTS: Patients who were assigned randomly to more-intensive RRT had a 33.3% lower hazard rate of successful extubation (hazard ratio, 0.67; 95% CI, 0.52-0.88; P < .001) when compared with patients who were assigned to less-intensive RRT. Patients who were assigned to more-intensive RRT had, on average, 2.07 ventilator-free days, compared with 3.08 days in those who were assigned to less-intensive RRT (P < .001) over 14 days from start of the study. INTERPRETATION: Critically ill mechanically ventilated patients who were assigned randomly to more-intensive RRT had longer duration of mechanical ventilation compared with those who were assigned to less-intensive RRT. The reasons for this, such as excessive phosphate loss from more-intensive RRT, deserve further study to optimize the safety and effectiveness of CRRT delivery. This was a post hoc analysis of the Acute Renal Failure Trial Network study; clinical trial registration of the original trial is NCT00076219.

Kidney Biomarkers of Injury and Repair as Predictors of Contrast-Associated AKI: A Substudy of the PRESERVE Trial.

RATIONALE & OBJECTIVE: The PRESERVE trial used a 2 × 2 factorial design to compare intravenous saline solution with intravenous sodium bicarbonate solution and oral N-acetylcysteine with placebo for the prevention of 90-day major adverse kidney events and death (MAKE-D) and contrast-associated acute kidney injury (CA-AKI) among patients with chronic kidney disease undergoing angiography. In this ancillary study, we evaluated the predictive capacities of preangiography injury and repair proteins in urine and plasma for MAKE-D, CA-AKI, and their impact on trial design. STUDY DESIGN: Longitudinal analysis. SETTING & PARTICIPANTS: A subset of participants from the PRESERVE trial. EXPOSURES: Injury (KIM-1, NGAL, and IL-18) and repair (MCP-1, UMOD, and YKL-40) proteins in urine and plasma 1 to 2 hours preangiography. OUTCOMES: MAKE-D and CA-AKI. ANALYTICAL APPROACH: We analyzed the associations of preangiography biomarkers with MAKE-D and with CA-AKI. We evaluated whether the biomarker levels could enrich the MAKE-D event rate and improve future clinical trial efficiency through an online biomarker prognostic enrichment tool available at prognosticenrichment.com. RESULTS: We measured plasma biomarkers in 916 participants and urine biomarkers in 797 participants. After adjusting for urinary albumin-creatinine ratio and baseline estimated glomerular filtration rate, preangiography levels of 4 plasma (KIM-1, NGAL, UMOD, and YKL-40) and 3 urine (NGAL, IL-18, and YKL-40) biomarkers were associated with MAKE-D. Only plasma KIM-1 level was significantly associated with CA-AKI after adjustment. Biomarker levels provided modest discriminatory capacity for MAKE-D. Screening patients using the 50th percentile of preangiography plasma KIM-1 or YKL-40 levels would have reduced the required sample size by 30% (∼2,000 participants). LIMITATIONS: Evaluation of prognostic enrichment does not account for changing trial costs, time needed to screen patients, or loss to follow-up. Most participants were male, limiting the generalizability of our findings. CONCLUSIONS: Preangiography levels of injury and repair biomarkers modestly predict the development of MAKE-D and can be used to improve the efficiency of future CA-AKI trials.

Iron, Hepcidin, and Death in Human AKI.

BACKGROUND: Iron is a key mediator of AKI in animal models, but data on circulating iron parameters in human AKI are limited. METHODS: We examined results from the ARF Trial Network study to assess the association of plasma catalytic iron, total iron, transferrin, ferritin, free hemoglobin, and hepcidin with 60-day mortality. Participants included critically ill patients with AKI requiring RRT who were enrolled in the study. RESULTS: Of the 807 study participants, 409 (51%) died by day 60. In both unadjusted and multivariable adjusted models, higher plasma concentrations of catalytic iron were associated with a significantly greater risk of death, as were lower concentrations of hepcidin. After adjusting for other factors, patients with catalytic iron levels in the highest quintile versus the lowest quintile had a 4.06-fold increased risk of death, and patients with hepcidin levels in the lowest quintile versus the highest quintile of hepcidin had a 3.87-fold increased risk of death. These findings were consistent across multiple subgroups. Other iron markers were also associated with death, but the magnitude of the association was greatest for catalytic iron and hepcidin. Higher plasma concentrations of catalytic iron and lower concentrations of hepcidin are each independently associated with mortality in critically ill patients with AKI requiring RRT. CONCLUSIONS: These findings suggest that plasma concentrations of catalytic iron and hepcidin may be useful prognostic markers in patients with AKI. Studies are needed to determine whether strategies to reduce catalytic iron or increase hepcidin might be beneficial in this patient population.

Strategies to Reduce Acute Kidney Injury and Improve Clinical Outcomes Following Percutaneous Coronary Intervention: A Subgroup Analysis of the PRESERVE Trial.

OBJECTIVES: The aim of this study was to compare intravenous (IV) sodium bicarbonate with IV sodium chloride and oral acetylcysteine with placebo for the prevention of contrast-associated acute kidney injury (CAAKI) and intermediate-term adverse outcomes. BACKGROUND: Data are conflicting on the optimal strategy to reduce CAAKI and related complications after percutaneous coronary intervention (PCI). METHODS: The PRESERVE (Prevention of Serious Adverse Events Following Angiography) trial used a 2 × 2 factorial design to randomize 5,177 patients with stage III or IV chronic kidney disease undergoing angiography to IV 1.26% sodium bicarbonate or IV 0.9% sodium chloride and 5 days of oral acetylcysteine or placebo. A subgroup analysis was conducted of the efficacy of these interventions in patients who underwent PCI during the study angiographic examination. The primary endpoint was a composite of death, need for dialysis, or persistent kidney impairment at 90 days; CAAKI was a secondary endpoint. RESULTS: A total of 1,161 PRESERVE patients (mean age 69 ± 8 years) underwent PCI. The median estimated glomerular filtration rate was 50.7 ml/min/1.73 m2 (interquartile range: 41.7 to 60.1 ml/min/1.73 m2), and 952 patients (82%) had diabetes mellitus. The primary endpoint occurred in 15 of 568 patients (2.6%) in the IV sodium bicarbonate group and 24 of 593 patients (4.0%) in the IV sodium chloride group (odds ratio: 0.64; 95% confidence interval: 0.33 to 1.24; p for interaction = 0.41) and in 23 of 598 patients (3.8%) in the acetylcysteine group and 16 of 563 patients (2.8%) in the placebo group (odds ratio: 1.37; 95% confidence interval: 0.71 to 2.62; p for interaction = 0.29). There were no significant between-group differences in the rates of CAAKI. CONCLUSIONS: Among patients with CKD undergoing PCI, there was no benefit of IV sodium bicarbonate over IV sodium chloride or of acetylcysteine over placebo for the prevention of CAAKI or intermediate-term adverse outcomes.

Net ultrafiltration intensity and mortality in critically ill patients with fluid overload.

BACKGROUND: Although net ultrafiltration (UFNET) is frequently used for treatment of fluid overload in critically ill patients with acute kidney injury, the optimal intensity of UFNET is unclear. Among critically ill patients with fluid overload receiving renal replacement therapy (RRT), we examined the association between UFNET intensity and risk-adjusted 1-year mortality. METHODS: We selected patients with fluid overload ≥ 5% of body weight prior to initiation of RRT from a large academic medical center ICU dataset. UFNET intensity was calculated as the net volume of fluid ultrafiltered per day from initiation of either continuous or intermittent RRT until the end of ICU stay adjusted for patient hospital admission body weight. We stratified UFNET as low (≤ 20 ml/kg/day), moderate (> 20 to ≤ 25 ml/kg/day) or high (> 25 ml/kg/day) intensity. We adjusted for age, sex, body mass index, race, surgery, baseline estimated glomerular filtration rate, oliguria, first RRT modality, pre-RRT fluid balance, duration of RRT, time to RRT initiation from ICU admission, APACHE III score, mechanical ventilation use, suspected sepsis, mean arterial pressure on day 1 of RRT, cumulative fluid balance during RRT and cumulative vasopressor dose during RRT. We fitted logistic regression for 1-year mortality, Gray's survival model and propensity matching to account for indication bias. RESULTS: Of 1075 patients, the distribution of high, moderate and low-intensity UFNET groups was 40.4%, 15.2% and 44.2% and 1-year mortality was 59.4% vs 60.2% vs 69.7%, respectively (p = 0.003). Using logistic regression, high-intensity compared with low-intensity UFNET was associated with lower mortality (adjusted odds ratio 0.61, 95% CI 0.41-0.93, p = 0.02). Using Gray's model, high UFNET was associated with decreased mortality up to 39 days after ICU admission (adjusted hazard ratio range 0.50-0.73). After combining low and moderate-intensity UFNET groups (n = 258) and propensity matching with the high-intensity group (n = 258), UFNET intensity > 25 ml/kg/day compared with ≤ 25 ml/kg/day was associated with lower mortality (57% vs 67.8%, p = 0.01). Findings were robust to several sensitivity analyses. CONCLUSIONS: Among critically ill patients with ≥ 5% fluid overload and receiving RRT, UFNET intensity > 25 ml/kg/day compared with ≤ 20 ml/kg/day was associated with lower 1-year risk-adjusted mortality. Whether tolerating intensive UFNET is just a marker for recovery or a mediator requires further research.

Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine.

BACKGROUND: Intravenous sodium bicarbonate and oral acetylcysteine are widely used to prevent acute kidney injury and associated adverse outcomes after angiography without definitive evidence of their efficacy. METHODS: Using a 2-by-2 factorial design, we randomly assigned 5177 patients at high risk for renal complications who were scheduled for angiography to receive intravenous 1.26% sodium bicarbonate or intravenous 0.9% sodium chloride and 5 days of oral acetylcysteine or oral placebo; of these patients, 4993 were included in the modified intention-to-treat analysis. The primary end point was a composite of death, the need for dialysis, or a persistent increase of at least 50% from baseline in the serum creatinine level at 90 days. Contrast-associated acute kidney injury was a secondary end point. RESULTS: The sponsor stopped the trial after a prespecified interim analysis. There was no interaction between sodium bicarbonate and acetylcysteine with respect to the primary end point (P=0.33). The primary end point occurred in 110 of 2511 patients (4.4%) in the sodium bicarbonate group as compared with 116 of 2482 (4.7%) in the sodium chloride group (odds ratio, 0.93; 95% confidence interval [CI], 0.72 to 1.22; P=0.62) and in 114 of 2495 patients (4.6%) in the acetylcysteine group as compared with 112 of 2498 (4.5%) in the placebo group (odds ratio, 1.02; 95% CI, 0.78 to 1.33; P=0.88). There were no significant between-group differences in the rates of contrast-associated acute kidney injury. CONCLUSIONS: Among patients at high risk for renal complications who were undergoing angiography, there was no benefit of intravenous sodium bicarbonate over intravenous sodium chloride or of oral acetylcysteine over placebo for the prevention of death, need for dialysis, or persistent decline in kidney function at 90 days or for the prevention of contrast-associated acute kidney injury. (Funded by the U.S. Department of Veterans Affairs Office of Research and Development and the National Health and Medical Research Council of Australia; PRESERVE ClinicalTrials.gov number, NCT01467466 .).

Predictors and outcomes of non-adherence in patients receiving maintenance hemodialysis.

PURPOSE: Predictors of and outcomes associated with non-adherent behavior among patients on chronic hemodialysis (HD) have been incompletely elucidated. We conducted a post hoc analysis of data from the SMILE trial to identify patient factors associated with non-adherence to dialysis-related treatments and the associations of non-adherence with clinical outcomes. METHODS: We defined non-adherence as missed HD and abbreviated HD. We used negative binomial regression to model the associations of demographic and clinical factors with measures of non-adherence, and negative binomial and Cox regression to analyze the associations of non-adherence with hospitalizations and mortality, respectively. RESULTS: We followed 286 patients for up to 24 months. Factors independently associated with missing HD included Tuesday/Thursday/Saturday HD schedule [incident rate ratio (IRR) 1.85, p < 0.01], current smoking (IRR 2.22, p < 0.01), higher pain score (IRR 1.04, p < 0.01), lower healthy literacy (IRR 3.01, p < 0.01), lower baseline quality of life (IRR 0.89, p = 0.01), and younger age (IRR 1.35, p < 0.01). Factors independently associated with abbreviating HD included dialysis vintage (IRR 1.07, p < 0.01), higher pain score (IRR 1.02, p < 0.01), current non-smoking (IRR 1.32, p = 0.03), and younger age (IRR 1.22, p < 0.01). Abbreviating HD was independently associated with an increased number of total (IRR 1.70, p < 0.01) and ESRD-related (IRR 1.66, p < 0.01) hospitalizations, while missing HD was independently associated with mortality (HR 2.36, p = 0.04). CONCLUSIONS: We identified several previously described and novel factors independently associated with non-adherence to HD-related treatments, and independent associations of non-adherence with hospitalization and mortality. These findings should inform the development and implementation of interventions to improve adherence and reduce health resource utilization.

Biomarker Enhanced Risk Prediction for Adverse Outcomes in Critically Ill Patients Receiving RRT.

BACKGROUND AND OBJECTIVES: Higher plasma concentrations of inflammatory and apoptosis markers in critically ill patients receiving RRT are associated with RRT dependence and death. This study objective was to examine whether plasma inflammatory (IL-6, -8, -10, and -18; macrophage migration inhibitory factor) and apoptosis (death receptor-5, tumor necrosis factor receptor I and II) biomarkers augment risk prediction of renal recovery and mortality compared with clinical models. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Biologic Markers of Recovery for the Kidney study (n=817) was a prospective, nested, observational cohort study conducted as an ancillary to the Veterans Affairs/National Institutes of Health Acute renal failure Trial Network study, a randomized trial of intensive versus less intensive RRT in critically ill patients with AKI conducted between November 2003 and July 2007 at 27 Veterans Affairs- and university-affiliated centers. Primary outcomes of interest were renal recovery and mortality at day 60. RESULTS: A parsimonious clinical model consisting of only four variables (age, mean arterial pressure, mechanical ventilation, and bilirubin) predicted renal recovery (area under the receiver-operating characteristic curve [AUROC], 0.73; 95% confidence interval [95% CI], 0.68 to 0.78) and mortality (AUROC, 0.74; 95% CI, 0.69 to 0.78). By contrast, individual biomarkers were only modestly predictive of renal recovery (AUROC range, 0.55-0.63) and mortality (AUROC range, 0.54-0.68). Adding plasma IL-8 to a parsimonious model augmented prediction of recovery (AUROC, 0.76; 95% CI, 0.71 to 0.81; P=0.04) and mortality (AUROC, 0.78; 95% CI, 0.73 to 0.82; P<0.01) compared with the clinical model alone. CONCLUSIONS: This study suggests that a simple four-variable clinical model with plasma IL-8 had predictive value for renal recovery and mortality. These findings require external validation but could easily be used by clinicians.

Plasma inflammatory and apoptosis markers are associated with dialysis dependence and death among critically ill patients receiving renal replacement therapy.

BACKGROUND: Survivors of critical illness complicated by acute kidney injury requiring renal replacement therapy (RRT) are at an increased risk of dialysis dependence and death but the mechanisms are unknown. METHODS: In a multicenter, prospective, cohort study of 817 critically ill patients receiving RRT, we examined association between Day 1 plasma inflammatory [interleukin (IL)-1ß, IL-6, IL-8, IL-10 and IL-18; macrophage migration inhibitory factor (MIF) and tumor necrosis factor]; apoptosis [tumor necrosis factor receptor (TNFR)-I and TNFR-II and death receptor (DR)-5]; and growth factor (granulocyte macrophage colony stimulating factor) biomarkers and renal recovery and mortality at Day 60. Renal recovery was defined as alive and RRT independent. RESULTS: Of 817 participants, 36.5% were RRT independent and 50.8% died. After adjusting for differences in demographics, comorbid conditions; premorbid creatinine; nephrotoxins; sepsis; oliguria; mechanical ventilation; RRT dosing; and severity of illness, increased concentrations of plasma IL-8 and IL-18 and TNFR-I were independently associated with slower renal recovery [adjusted hazard ratio (AHR) range for all markers, 0.70-0.87]. Higher concentrations of IL-6, IL-8, IL-10 and IL-18; MIF; TNFR-I and DR-5 were associated with mortality (AHR range, 1.16-1.47). In an analysis of multiple markers simultaneously, increased IL-8 [AHR, 0.80, 95% confidence interval (95% CI) 0.70-0.91, P < 0.001] and TNFR-I (AHR, 0.63, 95% CI 0.50-0.79, P < 0.001) were associated with slower recovery, and increased IL-8 (AHR, 1.26, 95% CI 1.14-1.39, P < 0.001); MIF (AHR, 1.18, 95% CI 1.08-1.28, P < 0.001) and TNFR-I (AHR, 1.26, 95% CI 1.02-1.56, P < 0.03) were associated with mortality. CONCLUSIONS: Elevated plasma concentrations of inflammatory and apoptosis biomarkers are associated with RRT dependence and death. Our data suggest that future interventions should investigate broad-spectrum immune-modulation to improve outcomes.