Renal Failure Trial Network Study Research Articles

Model to Predict Mortality in Critically Ill Adults with Acute Kidney Injury

Acute kidney injury (AKI) requiring dialysis is associated with high mortality. Most prognostic tools used to describe case complexity and to project patient outcome lack predictive accuracy when applied in patients with AKI. In this study, we developed an AKI-specific predictive model for 60-day mortality and compared the model to the performance of two generic (Sequential Organ Failure Assessment [SOFA] and Acute Physiology and Chronic Health Evaluation II [APACHE II]) scores, and a disease specific (Cleveland Clinic [CCF]) score. Data from 1122 subjects enrolled in the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network study; a multicenter randomized trial of intensive versus less intensive renal support in critically ill patients with AKI conducted between November 2003 and July 2007 at 27 VA- and university-affiliated centers. The 60-day mortality was 53%. Twenty-one independent predictors of 60-day mortality were identified. The logistic regression model exhibited good discrimination, with an area under the receiver operating characteristic (ROC) curve of 0.85 (0.83 to 0.88), and a derived integer risk score yielded a value of 0.80 (0.77 to 0.83). Existing scoring systems, including APACHE II, SOFA, and CCF, when applied to our cohort, showed relatively poor discrimination, reflected by areas under the ROC curve of 0.68 (0.64 to 0.71), 0.69 (0.66 to 0.73), and 0.65 (0.62 to 0.69), respectively. Our new risk model outperformed existing generic and disease-specific scoring systems in predicting 60-day mortality in critically ill patients with AKI. The current model requires external validation before it can be applied to other patient populations.

Urinary Biomarkers and Renal Recovery in Critically Ill Patients with Renal Support

Despite significant advances in the epidemiology of acute kidney injury (AKI), prognostication remains a major clinical challenge. Unfortunately, no reliable method to predict renal recovery exists. The discovery of biomarkers to aid in clinical risk prediction for recovery after AKI would represent a significant advance over current practice. We conducted the Biological Markers of Recovery for the Kidney study as an ancillary to the Acute Renal Failure Trial Network study. Urine samples were collected on days 1, 7, and 14 from 76 patients who developed AKI and received renal replacement therapy (RRT) in the intensive care unit. We explored whether levels of urinary neutrophil gelatinase-associated lipocalin (uNGAL), urinary hepatocyte growth factor (uHGF), urinary cystatin C (uCystatin C), IL-18, neutrophil gelatinase-associated lipocalin/matrix metalloproteinase-9, and urine creatinine could predict subsequent renal recovery. We defined renal recovery as alive and free of dialysis at 60 days from the start of RRT. Patients who recovered had higher uCystatin C on day 1 (7.27 versus 6.60 ng/mg·creatinine) and lower uHGF on days 7 and 14 (2.97 versus 3.48 ng/mg·creatinine; 2.24 versus 3.40 ng/mg·creatinine). For predicting recovery, decreasing uNGAL and uHGF in the first 14 days was associated with greater odds of renal recovery. The most predictive model combined relative changes in biomarkers with clinical variables and resulted in an area under the receiver-operator characteristic curve of 0.94. We showed that a panel of urine biomarkers can augment clinical risk prediction for recovery after AKI.

Clinical review: Optimal dose of continuous renal replacement therapy in acute kidney injury

Continuous renal replacement therapy (CRRT) is the preferred treatment for acute kidney injury in intensive care units (ICUs) throughout much of the world. Despite the widespread use of CRRT, controversy and center-specific practice variation in the clinical application of CRRT continue. In particular, whereas two single-center studies have suggested survival benefit from delivery of higher-intensity CRRT to patients with acute kidney injury in the ICU, other studies have been inconsistent in their results. Now, however, two large multi-center randomized controlled trials - the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network (ATN) study and the Randomized Evaluation of Normal versus Augmented Level (RENAL) Replacement Therapy Study - have provided level 1 evidence that effluent flow rates above 25 mL/kg per hour do not improve outcomes in patients in the ICU. In this review, we discuss the concept of dose of CRRT, its relationship with clinical outcomes, and what target optimal dose of CRRT should be pursued in light of the high-quality evidence now available.

Continuous renal replacement therapy: recent advances and future research

Continuous renal replacement therapy (CRRT) is the preferred treatment for acute kidney injury (AKI) in intensive care units (ICUs) throughout much of the developed world. Despite its widespread use, however, no formal proof exists that patient outcomes are improved when CRRT is used in preference to intermittent hemodialysis (IHD). In addition, controversy and center-specific practice variation in the clinical application of CRRT continues, owing to a lack of randomized multicenter studies of both CRRT and IHD providing level 1 data to inform clinical practice. Now, however, the publication of results from the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network (ATN) study and the Randomized Evaluation of Normal versus Augmented Level Renal Replacement Therapy (RENAL) trial have provided an unparalleled quantity of information to guide clinicians. These pivotal trials investigated different intensities of CRRT in the ICU and provided level 1 evidence that effluent flow rates >25 ml/kg per hour do not improve outcomes in patients in the ICU. In this Review, we discuss the background and results of the ATN and RENAL trials and the emerging consensus that CRRT is the most appropriate treatment for AKI in vasopressor-dependent patients in the ICU. Finally, we describe the remaining controversies regarding the use of CRRT and the questions that remain to be answered.

Predictors of Health Utility among 60-Day Survivors of Acute Kidney Injury in the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study

Health-related quality of life (HRQOL) after acute kidney injury (AKI) is an area of great importance to patients. It was hypothesized that HRQOL after AKI would relate to intensity of dialysis during AKI and dialysis dependence at follow-up. The Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study was a multicenter, prospective, randomized trial of intensive versus less intensive renal replacement therapy in critically ill patients with AKI. Of 1124 participants, 415 survived at least 60 days and completed the Health Utilities Index (HUI), which measures 8 health attributes and calculates an overall HRQOL score, also called a utility score. How strongly pre-intensive care unit (ICU) health, severity of illness, hospital course, intensity of dialysis, and outcome were associated with 60-day HUI scores was assessed, after adjustment for demographics. The overall HUI score was 0.40 +/- 0.37, indicating severely compromised health utility and was associated with only admission from home and hospital and ICU length of stay (LOS). Ambulation was better among those with a shorter hospital and ICU LOS. Better cognition was associated with dialysis independence and with fewer comorbid chronic illnesses. Emotion was associated with only hospital LOS. Pain was associated with ICU LOS. Health utility was low in this cohort of patients after AKI, and intensity of dialysis did not affect subsequent health utility. The effects of a lengthy hospitalization generally outweighed the effects of delayed recovery of kidney function on HRQOL after AKI.

Middle-Molecule Clearance at 20 and 35 ml/kg/h in Continuous Venovenous Hemodiafiltration

Background: Of 5 clinical trials testing dose response of continuous renal replacement therapy (CRRT) in acute kidney injury, 2 showed a benefit, 2 showed none, and 1 appeared equivocal. However, blood-membrane interactions may dominate macromolecule transport in continuous venovenous hemodiafiltration, reducing the impact of dose adjustment. The dosing arms in the Acute Renal Failure Trial Network (ATN) study may have delivered similar clearances for middle molecules. Methods: We simulated the 2 CRRT doses in the ATN study using a synthetic polydisperse macromolecular probe in bovine blood. Clearance of tracers between 10 and 100 kDa molecular weight was measured during 6 h of therapy. Results: Middle-molecule clearance differed by less than 2 ml/min between the 2 dosing arms. Conclusion: The CRRT prescription used in the ATN study appears to have achieved dose separation for small molecules while holding middle-molecule clearance nearly constant. This may explain the outcome difference between the ATN study and earlier studies, and suggests subsequent trial designs.

Intensity of renal replacement therapy in acute kidney injury: perspective from within the Acute Renal Failure Trial Network Study

Determination of the optimal dose of renal replacement therapy in critically ill patients with acute kidney injury has been controversial. Questions have recently been raised regarding the design and execution of the US Department of Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network (ATN) Study, which demonstrated no improvement in 60-day all-cause mortality with more intensive management of renal replacement therapy. In the present article we present our rationale for these aspects of the design and conduct of the study, including our use of both intermittent and continuous modalities of renal support, our approach to initiation of study therapy and the volume management during study therapy. In addition, the article presents data on hypotension during therapy and recovery of kidney function in the perspective of other studies of renal support in acute kidney injury. Finally, we address the implications of the ATN Study results for clinical practice from the perspective of the study investigators.

More-intensive renal replacement therapy has no benefit in critically ill patients with acute kidney injury

This Practice Point commentary discusses the strengths and limitations of the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network study. This multicenter, prospective, randomized parallel-group trial compared two treatment regimens—intensive and less-intensive—for each of three types of renal supportive therapy: intermittent hemodialysis (IHD; used in patients who were hemodynamically stable), sustained low-efficiency dialysis, and continuous venovenous hemodiafiltration (both used in patients who were less hemodynamically stable). Overall, there was no significant improvement in patient outcomes with the more-intensive regimens, particularly for IHD. A strategy of intensive renal support in critically ill patients with acute kidney injury does not decrease mortality, accelerate recovery of kidney function, or alter the rate of nonrenal organ failure as compared with a less-intensive regimen similar to usual-care practices, and, consequently, this study will change the clinical practice of IHD in acute kidney injury.

Lessons for Successful Study Enrollment from the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study

Design elements of clinical trials can introduce recruitment bias and reduce study efficiency. Trials involving the critically ill may be particularly prone to design-related inefficiencies. Enrollment into the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study was systematically monitored. Reasons for nonenrollment into this study comparing strategies of renal replacement therapy in critically ill patients with acute kidney injury were categorized as modifiable or nonmodifiable. 4339 patients were screened; 2744 fulfilled inclusion criteria. Of these, 1034 were ineligible by exclusion criteria. Of the remaining 1710 patients, 1124 (65.7%) enrolled. Impediments to informed consent excluded 21.4% of potentially eligible patients. Delayed identification of potential patients, physician refusal, and involvement in competing trials accounted for 4.4, 2.7, and 2.3% of exclusions. Comfort measures only status, chronic illness, chronic kidney disease, and obesity excluded 11.8, 7.8, 7.6, and 5.9% of potential patients. Modification of an enrollment window reduced the loss of patients from 6.6 to 2.3%. The Acute Renal Failure Trial Network Study's enrollment efficiency compared favorably with previous intensive care unit intervention trials and supports the representativeness of its enrolled population. Impediments to informed consent highlight the need for nontraditional acquisition methods. Restrictive enrollment windows may hamper recruitment but can be effectively modified. The low rate of physician refusal acknowledges clinical equipoise in the study design. Underlying comorbidities are important design considerations for future trials that involve the critically ill with acute kidney injury.

Toward the Promise of Renal Replacement Therapy

In this issue of JASN , Tumlin et al. [1][1] report results of a revolutionary phase 2 multicenter, randomized clinical trial comparing 72 h of continuous venovenous hemofiltration (CVVH) with and without a bioartificial kidney (referred to as a renal tubule assist device [RAD]) in the management of

Dialysis dose in acute kidney injury: no time for therapeutic nihilism – a critical appraisal of the Acute Renal Failure Trial Network study

The optimal dialysis dose for acute kidney injury is a matter of great controversy. Clinical trials, predominantly single-center studies, have shown conflicting results. The Acute Renal Failure Trial Network (ATN) Study was designed to compare clinical outcomes between patients allocated to an intensive dose versus a less-intensive dose of renal replacement therapy. Recently, the results of this large randomized controlled multicenter study were published. The present article will discuss certain aspects of this trial: the overall design, the baseline patient characteristics, and comparison of the results with earlier studies. Finally, the article will address the implications of the ATN Study results for clinical practice.

Evolving Practices in Critical Care and Potential Implications for Management of Acute Kidney Injury

Acute kidney injury (AKI) is a common complication in hospitalized patients, with an incidence of 3 to 10% (1–4). In-hospital mortality rates that are associated with AKI remain high, in the range of 30 to 70% (5–8), despite significant improvements in dialytic technology as well as important advances in critical care, which have resulted in improved survival for other critical illnesses, including acute lung injury and sepsis (9). These improvements include continuous renal replacement therapies, which allow for continuous removal of solutes and fluid and may be tolerated better from a hemodynamic standpoint, and biocompatible dialysis membranes, which are associated with reduced complement and granulocyte activation. In general, indications for dialysis in the acute care setting have been extrapolated from those that are applied in chronic kidney disease, including volume overload that is refractory to diuretic therapy; electrolyte abnormalities (in particular hyperkalemia); uremic complications (pericarditis or pleuritis); severe acidosis (pH < 7.20); and selected toxic ingestions, such as methanol, ethylene glycol, and other water-soluble agents (10,11). However, the evidence base supporting specific dialysis practices in the acute care setting is limited. For example, several studies that were completed in the 1960s and 1970s compared “early” and “late” initiation of dialysis, using blood urea nitrogen (BUN) to define early and late (Table 1). These studies primarily were cohort studies that used historical controls, not randomized, clinical trials. The results of these investigations, along with extrapolation from the ESRD population, promoted recent practice patterns. Currently, many nephrologists often delay dialysis in the acute care setting until the patient has an impending complication of AKI, such as hyperkalemia leading to cardiac arrhythmias, acidosis resulting in hypotension, or oliguria leading to volume overload or hypoxemia, or until the BUN exceeds 100 mg/dl (18). Given differences in protein catabolism, …

Design of the VA/NIH Acute Renal Failure Trial Network (ATN) study: intensive versus conventional renal support in acute renal failure

The optimal management of renal replacement therapy (RRT) in acute renal failure (ARF) is uncertain. The VA/NIH Acute Renal Failure Trail Network Study (ATN Study) tests the hypothesis that a strategy of intensive RRT will decrease 60-day all-cause mortality in critically ill patients with ARF. Dose separation between the two treatment arms is achieved by increasing the frequency of intermittent hemodialysis (IHD) and sustained low efficiency dialysis (SLED) treatments from three times per week to six times per week, and by increasing continuous venovenous hemodiafiltration (CVVHDF) effluent volume from 20 mL/kg/hr to 35 mL/kg/hr. In both treatment arms, subjects convert between IHD and CVVHDF or SLED as hemodynamic status changes over time. This strategy attempts to replicate the conversion between modalities of RRT that occurs in clinical practice. However, in order to implement this strategy, flexible criteria needed to be developed to provide a balance between the need for uniformity of treatment between groups and practitioner discretion regarding modality of RRT to maintain patient safety. In order to address safety and ethical issues similar to those raised by the Office of Human Research Protections in its review of the ARDS Network studies, a survey of practitioner practices was performed and observational data on the management of RRT in comparable critically ill patients with ARF managed outside of the research context is being collected prospectively. These data will help inform the study's DSMB and site IRB's of the relationship between the study's treatment arms and concurrent clinical practice.

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<h3>Background and objectives</h3> 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. <h3>Design, setting, participants, &amp; measurements</h3> The Biologic Markers of Recovery for the Kidney study (<i>n</i>=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. <h3>Results</h3> 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; <i>P</i>=0.04) and mortality (AUROC, 0.78; 95% CI, 0.73 to 0.82; <i>P</i>&lt;0.01) compared with the clinical model alone. <h3>Conclusions</h3> 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.