Renal Failure Trial Network Study Research Articles

Subgroups of Patients with Distinct Health Utility Profiles after AKI.

A large amount of inter-individual variability exists in health-related quality of life outcomes following acute kidney injury (AKI). This study aimed to determine if subgroups of early AKI survivors could be identified based on distinct health utility impairment profiles ascertained at 60 days after AKI and if these subgroups differed in clinical and biomarker characteristics at index hospitalization and outcomes at 1-year follow up. This retrospective analysis used data from the BioMaRK study, an observational subcohort of the Acute Renal Failure Trial Network study. Of 402 patients who survived to 60 days after AKI, 338 completed the Health Utility Index-3 survey which measures impairments in 8 health attributes. Latent class analysis was used to identify subgroups of patients with distinct health utility profiles. Three subgroups with distinct health utility impairment profiles were identified: Low (28% of participants), Moderate (58%) and High (14%) with a median of 1, 4, and 6 impairments across the 8 health attributes at 60 days after AKI, respectively. Patient subgroups differed in weight, history of cerebrovascular disease, intensity of dialysis, hospital length of stay, and dialysis dependence. Serum creatinine and blood urea nitrogen at index hospitalization did not differ among the 3 subgroups. The High impairment subgroup had higher levels of interleukin-6 and soluble tumor necrosis factor receptor-2 at study day 1. The 3 subgroups had different 1-year mortality rates: 5% in the Low, 21% in the Moderate, and 52% in the High impairment subgroup. Patient subgroups with distinct health utility impairment profiles can be identified 60 days after AKI. These subgroups have different characteristics at index hospitalization. A higher level of impairment at 60 days was associated with decreased survival.

Serum metabolite profiles predict outcomes in critically ill patients receiving renal replacement therapy

Acute kidney injury (AKI) requiring renal replacement therapy (RRT) is associated with increased incidence of dialysis dependence and portends high mortality in critically ill patients. At the early stage of RRT, serum metabolic biomarkers might differntiate patients with a high risk of mortality or permanent kidney injury from those who can recover. Serum samples from participants enrolled in the Veteran’s Affairs/National Institutes of Health Acute Renal Failure Trial Network study were collected on day 1 (n = 97) and day 8 (n = 105) of randomized RRT. The samples were further evaluated using LC/MS-based metabolic profiling. A model predicting mortality by day 8 was built from samples collected on day 1 and based on four metabolites with an area under the curve (AUC) of 0.641. A model most predictive of mortality by day 28 was built from the levels of 11 serum metabolites from day 8 with an AUC of 0.789. Both day 1 and day 8 samples had lower serum levels of 1-arachidonoyl-lysoPC and 1-eicosatetraenoyl-lysoPC (involved in anti-inflammatory processes) in the critically ill patients who died by day 8 or day 28. Higher levels of amino acids and amino acid metabolites in the day 8 model predicting < day 28 mortality may be indicative of muscle wasting. A kidney recovery biomarker panel based on the serum levels of three metabolites from day 8 samples with an AUC of 0.70 was devised. Serum metabolic profiling of AKI critically ill patients requiring RRT revealed predictive models of mortality based on observed differences in four serum metabolites at day 1 and 11 metabolites at day 8 which were predictive of mortality. Significant changes in the levels of these metabolites suggest links to inflammatory processes and/or muscle wasting.

Discovery of Novel Proteomic Biomarkers for the Prediction of Kidney Recovery from Dialysis-Dependent AKI Patients.

AKI requiring dialysis (AKI-D) is associated with prolonged hospitalization, mortality, and progressive CKD among survivors. Previous studies have examined only select urine or serum biomarkers for predicting kidney recovery from AKI. Serum samples collected on day 8 of randomized RRT from 72 patients enrolled in the Veteran's Affairs/National Institutes of Health Acute Renal Failure Trial Network study were analyzed by the SOMAscan proteomic platform to profile 1305 proteins in each sample. Of these patients, 38 recovered kidney function and dialysis was discontinued, whereas another 34 patients remained on dialysis by day 28. Differential serum levels of 119 proteins, with 53 higher and 66 lower, were detected in samples from patients who discontinued dialysis, compared with patients who remained on dialysis by day 28. Patients were classified into tertiles on the basis of SOMAscan protein measurements for the 25 proteins most differentially expressed. The association of serum levels of each protein with kidney recovery was further evaluated using logistic regression analysis. Higher serum levels of CXCL11, CXCL2/CXCL3, CD86, Wnt-7a, BTK, c-Myc, TIMP-3, CCL5, ghrelin, PDGF-C, survivin, CA2, IL-9, EGF, and neuregulin-1, and lower levels of soluble CXCL16, IL1RL1, stanniocalcin-1, IL-6, and FGF23 when classified in tertiles were significantly associated with better kidney recovery. This significant association persisted for each of these proteins after adjusting for potential confounding risk factors including age, sex, cardiovascular SOFA score, congestive heart failure, diabetes, modality of intensive dialysis treatment, cause of AKI, baseline serum creatinine, day 8 urine volume, and estimated 60-day mortality risk. These results suggest concerted changes between survival-related proteins and immune-regulatory chemokines in regulating angiogenesis, endothelial and epithelial remodeling, and kidney cell regeneration, illustrating potential mechanisms of kidney recovery. Thus, this study identifies potential novel predictive biomarkers of kidney recovery in patients with AKI-D.

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

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. 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? 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 35mL/kg per hour) vsless-intensive (hemodialysis or sustained low-efficiency dialysis three times per week or continuous venovenous hemodiafiltration at 20mL/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. 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 3.08days inthose who were assigned to less-intensive RRT (P< .001) over 14days from start of thestudy. 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.

Antibiotic Exposure Profiles in Trials Comparing Intensity of Continuous Renal Replacement Therapy.

To determine whether the probability of target attainment over 72 hours of initial therapy with beta-lactam (cefepime, ceftazidime, piperacillin/tazobactam) and carbapenem (imipenem, meropenem) antibiotics were substantially influenced between intensive and less-intensive continuous renal replacement therapy groups in the Acute Renal Failure Trial Network trial and The RENAL Replacement Therapy Study trial. The probability of target attainment was calculated using pharmacodynamic targets of percentage of time that free serum concentrations (fT): 1) were above the target organism's minimum inhibitory concentration (≥ fT > 1 × minimum inhibitory concentration); 2) were above four times the minimum inhibitory concentration (≥ % fT > 4 × minimum inhibitory concentration); and 3) were always above the minimum inhibitory concentration (≥ 100% fT > minimum inhibitory concentration) for the first 72 hours of antibiotic therapy. Demographic data and effluent rates from the Acute Renal Failure Trial Network and RENAL Replacement Therapy Study trials were used. Optimal doses were defined as the dose achieving greater than or equal to 90% probability of target attainment. Monte Carlo simulations using demographic data from Acute Renal Failure Trial Network and RENAL Replacement Therapy Study trials. Virtual critically ill patients requiring continuous renal replacement therapy. None. The pharmacodynamic target of fT greater than 1 × minimum inhibitory concentration led to similarly high rates of predicted response with antibiotic doses often used in continuous renal replacement therapy. Achieving 100% fT greater than minimum inhibitory concentration is a more stringent benchmark compared with T greater than 4 × minimum inhibitory concentration with standard antibiotic dosing. The intensity of effluent flow rates (less intensive vs intensive) did not substantially influence the probability of target attainment of antibiotic dosing regimens regardless of pharmacodynamic target. Antibiotic pharmacodynamic target attainment rates likely were not meaningfully different in the low- and high-intensity treatment arms of the Acute Renal Failure Trial Network and RENAL Replacement Therapy Study Investigators trials.

Plasma Biomarkers in Predicting Renal Recovery from Acute Kidney Injury in Critically Ill Patients

Background: Numerous studies have suggested a possible role for acute kidney injury (AKI) biomarkers in predicting renal recovery both before and after renal replacement therapy (RRT). However, definitions for recovery and whether to include patients dying but free of RRT may influence results. Objectives: To validate plasma neutrophil gelatinase-associated lipocalin (pNGAL) as a useful biomarker for predicting or improving the ability of clinical predictors alone to predict recovery following AKI, including in our model plasma B-type natriuretic peptide (pBNP) to account for cardiovascular events. Methods: We analyzed 69 patients enrolled in the Acute Renal Failure Trial Network study. pNGAL and pBNP were measured on days 2, 7, and 14. We analyzed their predictive ability for subsequent recovery, defined as alive and independent from dialysis in 60 days. In sensitivity analyses, we explored changes in results with alternative definitions of recovery. Results: Twenty-nine patients (42%) recovered from AKI. Neither pNGAL nor pBNP, alone or in combination, was accurate predictors of renal recovery-the best area under the receiver-operating characteristics curve (AUC) was for pNGAL using the largest relative change (AUC 0.59, 95% CI 0.45–0.74). The best clinical model achieved superior performance to biomarkers (AUC 0.69, 95% CI 0.56–0.81). The AUC was greatest (0.75, 95% CI 0.60–0.91) when pNGAL + pBNP on day 14 were added to the clinical model but this increase did not achieve statistical significance. However, integrated discrimination improvement analysis showed that the addition of pNGAL and pBNP on day 14 to the clinical model significantly improved the prediction of renal recovery (p = 0.008). Conclusions: pNGAL and pBNP can improve the accuracy of clinical parameters in predicting AKI recovery and a full model using biomarkers together with age achieved adequate discrimination.

Effects of Baseline Thrombocytopenia and Platelet Decrease Following Renal Replacement Therapy Initiation in Patients With Severe Acute Kidney Injury*

Thrombocytopenia is common in critically ill patients with severe acute kidney injury and may be worsened by the use of renal replacement therapy. In this study, we evaluate the effects of renal replacement therapy on subsequent platelet values, the prognostic significance of a decrease in platelets, and potential risk factors for platelet decreases. Post hoc analysis of the Acute Renal Failure Trial Network Study. The Acute Renal Failure Trial Network study was a multicenter, prospective, randomized, parallel-group trial of two strategies for renal replacement therapy in critically ill patients with acute kidney injury conducted between November 2003 and July 2007 at 27 Veterans Affairs and university-affiliated medical centers. The Acute Renal Failure Trial Network study evaluated 1,124 patients with severe acute kidney injury requiring renal replacement therapy. Predictor variables were thrombocytopenia at initiation of renal replacement therapy and platelet decrease following renal replacement therapy initiation. Outcomes were mortality at 28 days, 60 days, and 1 year, renal recovery, renal replacement therapy free days, ICU-free days, and hospital-free days. Baseline thrombocytopenia in patients requiring renal replacement therapy was associated with increased mortality and was also associated with lower rates of renal recovery. A decrease in platelet values following renal replacement therapy initiation was associated with increased mortality. Continuous renal replacement therapy was not an independent predictor of worsening thrombocytopenia compared with those treated with intermittent hemodialysis. Baseline thrombocytopenia and platelet decrease following renal replacement therapy initiation were associated with increased mortality, and baseline thrombocytopenia was associated with decreased rates of renal recovery. Continuous renal replacement therapy did not decrease platelets compared with hemodialysis.

Urea reduction ratio may be a simpler approach for measurement of adequacy of intermittent hemodialysis in acute kidney injury

BackgroundAssessment of adequacy of intermittent hemodialysis (IHD) is conventionally based upon urea kinetic models for calculation of single pool Kt/Vurea (Kt/V), with 1.2 accepted as minimum adequate clearance for thrice weekly IHD. In the Acute Renal Failure Trial Network (ATN) Study, adequacy of IHD in patients with acute kidney injury (AKI) was assessed using Kt/V. However, equations for Kt/V require volume of distribution of urea, which is highly variable in AKI. Therefore, simpler methods are needed to assess adequacy of IHD in AKI. We assessed correlation of urea reduction ratio (URR) with Kt/V and determined URR thresholds corresponding to Kt/V values to determine if URR could be a simpler means to assess the delivered dose of IHD.MethodsUsing patients who received IHD for 2.5–6 h and with pre-dialysis BUN ≥20 mg/dL, we plotted URR against Kt/V. We determined URR thresholds (0.60 to 0.75) corresponding to Kt/V ≥ 1.2, 1.3, and 1.4. We generated receiver operating characteristic (ROC) curves for increasing URR values for each level of Kt/V to identify the corresponding thresholds of URR.ResultsThere was strong correlation between URR and Kt/V. ROC curves comparing URR with Kt/V ≥ 1.2, 1.3, and 1.4 had area under the curves (AUC) of 0.99. Sensitivity and specificity of URR ≥0.67 for corresponding values of Kt/V ≥ 1.2 were 0.769 (95% CI: 0.745 to 0.793) and 0.999 (95% CI: 0.997 to 1.000), respectively and the sensitivity and specificity of URR ≥0.67 for corresponding values of Kt/V ≥ 1.4 were 0.998 (95% CI: 0.995 to 1.000) and 0.791 (95% CI: 0.771 to 0.811), respectively.ConclusionsTargeting a URR ≥0.67 provides a simplified means of assessing adequacy of IHD in patients with AKI. Use of URR will enhance ability to assess delivery of small solute clearance and improve adherence with clinical practice guidelines in AKI.

Aptamer-Based Proteomics Identifies Mortality-Associated Serum Biomarkers in Dialysis-Dependent AKI Patients

IntroductionCurrently, no effective therapies exist to reduce the high mortality associated with dialysis-dependent acute kidney injury (AKI-D). Serum biomarkers may be useful in understanding the pathophysiological processes involved with AKI and the severity of injury, and point to novel therapeutic targets.MethodsStudy day 1 serum samples from 100 patients and day 8 samples from 107 patients enrolled in the Veteran’s Affairs/National Institutes of Health Acute Renal Failure Trial Network study were analyzed by the slow off-rate modified aptamers scan proteomic platform to profile 1305 proteins in each sample. Patients in each cohort were classified into tertiles based on baseline biomarker measurements. Cox regression analyses were performed to examine the relationships between serum levels of each biomarker and mortality.ResultsChanges in the serum levels of 54 proteins, 33 of which increased and 21 of which decreased, were detected when comparing samples of patients who died in the first 8 days versus patients who survived >8 days. Among the 33 proteins that increased, higher serum levels of fibroblast growth factor-23 (FGF23), tissue plasminogen activator (tPA), neutrophil collagenase (matrix metalloproteinase-8), and soluble urokinase plasminogen activator receptor, when stratified by tertiles, were associated with higher mortality. The association with mortality persisted for each of these proteins after adjusting for other potential risk factors, including age, sex, cardiovascular sequential organ failure assessment score, congestive heart failure, and presence of diabetes. Upper tertile levels of FGF23, tPA, and interleukin-6 on day 8 were associated with increased mortality; however, FGF23 barely lost significance after multivariable adjustment.ConclusionsOur results underscore an emerging proteomics tool capable of identifying low-abundance serum proteins important not only in the pathogenesis of AKI-D, but which is also helpful in discriminating AKI-D patients with high mortality.

Effect of Frequent Dialysis on Renal Recovery: Results From the Acute Renal Failure Trial Network Study

IntroductionThe optimal frequency of intermittent hemodialysis (IHD) in the treatment of acute kidney injury (AKI) remains unclear. Increasing the frequency of IHD, while offering the possible advantage of reduced ultrafiltration requirement and less hemodynamic instability per session, amplifies patient contact with an extracorporeal circuit with possible deleterious cardiovascular and immunological consequences. A recent study suggested that intensive renal replacement therapy (RRT) is associated with a decrease in urine output during AKI. We hypothesized that increased frequency of IHD may be associated with delayed renal recovery.MethodsThis is a post hoc analysis of the Acute Renal Failure Trial Network (ATN) study. The ATN study was a large randomized multicenter trial of intensive versus less-intensive RRT in critically ill patients with AKI. This study used either continuous RRT or IHD, depending on the hemodynamic status of the patient. Of 1124 patients, 246 were treated solely with IHD during the study period and were included in this analysis. The participants were randomized to receive IHD 3 days per week (L-IntRRT) or 6 days per week (IntRRT). The primary outcome of interest was renal recovery at day 28.ResultsL-IntRRT was associated with higher number of RRT-free days through day 28 than IntRRT (mean difference 2.5 days; 95% confidence interval [CI]: −4.79 to −0.27 days; P = 0.028). The likelihood for renal recovery at day 28 was lower in the IntRRT group (OR: 0.49; 95% CI: 0.28–0.87; P = 0.016).ConclusionIn hemodynamically stable patients with AKI, intensifying the frequency of IHD from 3 to 6 days per week may be associated with impaired renal recovery.

Vascular Access Site for Renal Replacement Therapy in Acute Kidney Injury: A Post hoc Analysis of the ATN Study.

Acute kidney injury requiring renal replacement therapy (RRT) in the intensive care unit portends a poor prognosis. The decisions regarding dialysis catheter placement is based mainly on physician discretion with little evidence to support the choice of dialysis catheter location. The Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study was a multicenter, prospective, randomized trial of intensive vs. less intensive RRT in critically ill patients with AKI. We assessed the association of dialysis catheter location with dialysis catheter-related outcomes including catheter-related complications, mortality, dialysis dependence, and dialysis dose delivered. Of the 1,124 patients enrolled in the ATN study, catheter data were available in 1,016 (90.39%) patients. A total of 91 (8.96%) subclavian, 387 (38.09%) internal jugular, and 538 (52.95%) femoral dialysis catheters were inserted. The femoral group was younger (58.39 ± 16.27), had greater bleeding tendency [lower platelet count (96.00 ± 109.35) with higher INR (2.01 ± 2.19)], and had a higher baseline sequential organ failure assessment score on admission (14.59 ± 3.61) compared to the other two groups. Dialysis catheter-related complications were low in this study with no significant difference in the rates of complications among all catheter locations. Mortality and dialysis dependence was lowest in the subclavian group, while the dose of dialysis delivered (Kt/V) remained lowest in the femoral group, after propensity score and center adjustments. Patient characteristics influence the choice of dialysis catheter location with a tendency to place femoral catheters in younger, sicker, and more coagulopathic patients. There were no statistically significant differences in complication rates among the three catheter locations, although femoral catheters may be associated with a lower delivered dose of dialysis during intermittent hemodialysis. www.ClinicalTrials.gov, identifier NCT00076219.

THE FACTORS INFLUENCING RENAL RECOVERY IN CARDIAC SURGERY ASSOCIATED ACUTE KIDNEY INJURY

Background. In-hospital mortality of cardiac surgery patients with AKI is 3-7 times higher than those without AKI. This prospective observational study was dedicated to evaluate a differential approach of applying continuous and intermittent modalities in CS-AKIpatients on the rate and grade of renalfunction recovery.&#x0D; Methods. One hundred and six adult cardiac surgery patients admitted hospital in 2008-2011 years, who had AKI and met inclusion criteria were allocated in CRRTorIRRTgroup.&#x0D; Results. Sixty eight cardiac surgery with AKI patients who needed RRT were discharged from hospital. Among them, recovery of renalfunction was observed in 54 patients (79,4%) and 14 patients (20,6%) remained RRT-depen- dant. Complete recovery of renalfunction was reached in 33 patients (48,5%), while partial was observed in 21 patients (30,9%). Univariate analysis showed that complete recovery of renalfunction in CS-AKI significantly associated with reducing of dopamine dose during thefirst day of RRT (p=0,01) and long-term use of dobutamine (p=0,009). Partial recovery was associated with early dobutamine withdrawal (p=0,005) and absence of MOT (p=0,016), while RRT- dependence at discharge was associated with absence of MOT (p=0,006) and escalation of dopamine dose on thefirst day of RRT (p=0,025). The rate of renal recovery was statistically significantly higher in patients with CS-AKI with MOFthan inpatients with CS-AKI without MOF. In univariate analysis RRT-dependance at discharge of patients with CS-AKI with MOF was statistically significantly associated with arising of dopamine dose during thefirst day of RRT (p=0,006) and no-use of dobutamine at RRT start (p=0,006). Partial recovery was associated with early withdrawal of dobutamine (p=0,038).&#x0D; Discussion. Frequency of renal recovery inpresented study was higher than in VA/NIHAcute Renal Failure Trial Network study because of differences inpatients'population and corresponds to otherstudies of CS-AKIpatients.&#x0D; Conclusions. Recovery of renalfunction in CS-AKI patients associated with decreasing dose of dopamine, prolonged use ofdobutamine, illness severity and does not associated with specific RRT modality.

Validity of low-efficacy continuous renal replacement therapy in critically ill patients.

The 1980s saw the use of continuous arteriovenous hemofiltration whose intensity hemofiltration rate was only 3 or 4 mL kg⁻¹ h⁻¹. With the installation of a blood pump, this dose went up to 8 or 10 mL kg⁻¹ h⁻1, and continued to increase, reaching about 20 mL kg⁻¹ h⁻¹ by the year 2000. Some studies found that a higher dose could be beneficial, and the world rapidly followed the trend, increasing the dose up to 35 mL kg⁻¹ h⁻¹. Then, two randomized control trials, namely the VA/NIH Acute Renal Failure Trial Network study and the RENAL study, came along in succession which changed the Kidney Disease: Improving Global Outcomes (KDIGO) recommendation to 20 to 25 mL kg⁻¹ h⁻¹. However, no good evidence exists to support this. Our recent multicenter retrospective studies from the JSEPTIC CRRT database show that the Japanese continuous renal replacement therapy dose of (14.3 mL kg⁻¹ h⁻¹) does not seem to have worse outcomes when compared with a higher dose.

Comparison of Urine Output among Patients Treated with More Intensive Versus Less Intensive RRT: Results from the Acute Renal Failure Trial Network Study

Comparison of Urine Output among Patients Treated with More Intensive Versus Less Intensive RRT: Results from the Acute Renal Failure Trial Network Study

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

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. 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. 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. 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.

Stigmata of death: for kidneys and patients.

Stigmata of death: for kidneys and patients.

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Introduction: Circulating concentrations of plasma inflammatory and apoptosis markers in critically ill patients with acute kidney injury requiring renal replacement therapy (RRT) are associated with RRT dependence and death. Whether these biomarkers predict clinical outcomes is unknown. Methods: The Biological Markers for Recovery of Kidney was a multicenter, prospective, nested, observational study conducted ancillary to the Veterans Affairs/Acute Renal Failure Trial Network study of 817 critically ill patients receiving RRT. Plasma markers were measured on day 1. Renal recovery was defined as alive and RRT independent by day 60. A parsimonious clinical model was determined using stepwise logistic regression and Least Absolute Shrinkage and Selection Operator (LASSO) based algorithms. We computed area under receiver operating characteristic curve (AUROC), integrated discrimination index (IDI), and category-free net reclassification index (CFNRI). Results: Of the 817 patients, 298 (36.5%) were alive and free of RRT and 415 (50.8%) died. The derivation (model building) and validation sets contained 394 and 423 subjects. In the validation dataset, a clinical model consisting of eight clinical variables (age, mechanical ventilation, arterial ph, bilirubin, platelets,mean arterial pressure, and Total ApacheII) predicted renal recovery and mortality (AUROC range: 0.74–0.77 and 0.75–0.80); with good calibration (P values range: 0.08–0.45); modest increment in IDI (ranges: 2%-5%, P values <0.05); and CFNRI (ranges: 27%-32%, p values <0.05). The AUROC of individual biomarkers were only modestly predictive of renal recovery, (range, 0.55–0.63) and mortality, (range 0.54–0.68). When added to the clinical model there was an increase in risk prediction for renal mortaltiy (AUROC, 0.78–0.82); but not for recovery (AUROC, 0.76–0.78); IDI (1%-2%: P value < 0.05) and CFNRI (27%-23%) for recovery and mortality. Conclusions: In a large cohort of severely ill patients with acute kidney injury requiring RRT, the addition of plasma inflammatory and apoptosis markers to a baseline clinical model resulted in a modest improvement in risk prediction of RRT independence and mortality.

Effect of ionized serum calcium on outcomes in acute kidney injury needing renal replacement therapy: secondary analysis of the acute renal failure trial network study

Background: Hypocalcemia is very common in critically ill patients. While the effect of ionized calcium (iCa) on outcome is not well understood, manipulation of iCa in critically ill patients is a common practice. We analyzed all-cause mortality and several secondary outcomes in patients with acute kidney injury (AKI) by categories of serum iCa among participants in the Acute Renal Failure Trial Network (ATN) Study. Methods: This is a post hoc secondary analysis of the ATN Study which was not preplanned in the original trial. Risk of mortality and renal recovery by categories of iCa were compared using multiple fixed and adjusted time-varying Cox regression models. Multiple linear regression models were used to explore the impact of baseline iCa on days free from ICU and hospital. Results: A total of 685 patients were included in the analysis. Mean age was 60 (SD = 15) years. There were 502 male patients (73.3%). Sixty-day all-cause mortality was 57.0%, 54.8%, and 54.4%, in patients with an iCa <1, 1–1.14, and ≥1.15 mmol/L, respectively (p = 0.87). Mean of days free from ICU or hospital in all patients and the 28-day renal recovery in survivors to Day 28 were not significantly different by categories of iCa. The hazard for death in a fully adjusted time-varying Cox regression survival model was 1.7 (95% CI: 1.3–2.4) comparing iCa <1 to iCa ≥ 1.15 mmol/L. No outcome was different for levels of iCa > 1 mmol/L. Conclusion: Severe hypocalcemia with iCa < 1 mmol/L independently predicted mortality in patients with AKI needing renal replacement therapy.

Piecewise Analysis of Patient Survival after Onset of AKI

AKI affects approximately 2%-7% of hospitalized patients and >35% of critically ill patients. Survival after AKI may be described as having an acute phase (including an initial hyperacute component) followed by a convalescent phase, which may itself have early and late components. Data from the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network (ATN) study was used to model mortality risk among patients with dialysis-requiring AKI. This study assumed that the mortality hazard can be described by a piecewise log-linear function with change points. Using an average likelihood method, the authors tested for the number of change points in a piecewise log-linear hazard model. The maximum likelihood approach to locate the change point(s) was then adopted, and associated parameters and standard errors were estimated. There were 1124 ATN participants with follow-up to 1 year. The mortality hazard of AKI decreased over time with inflections in the rate of decrease at days 4, 42, and 148, with the sharpest change at day 42. The daily rate of decline in the log of the hazard for death was 0.220 over the first 4 days, 0.046 between day 4 and day 42, 0.017 between day 42 and day 148, and 0.003 between day 148 and day 365. There appear to be two major phases of mortality risk after AKI: an early phase extending over the first 6 weeks and a late phase from 6 weeks to 1 year. Within the first 42 days, this can be further divided into hyperacute (days 1-4) and acute (days 4-42) phases. After 42 days, there appear to be early (days 42-148) and late (after day 148) convalescent phases. These findings may help to inform the design of AKI clinical trials and assist critical care physicians in prognostic stratification.

Timing, dose and mode of dialysis in acute kidney injury

In the past 3 years substantial progress has been made in the field of renal replacement therapy (RRT) for critically ill patients. Two important multicenter randomized clinical trials have been recently published and extensively discussed: the randomized evaluation of normal versus augmented level (RENAL) replacement therapy study and the VA/NIH Acute Renal Failure Trial Network (ATN) study. The RENAL and ATN studies were designed to compare 'normal' or 'less intensive' renal support to an 'augmented' or 'intensive' therapy: both studies showed no benefit in outcomes by increases in intensity of RRT dose. The definition of 'normal dose' is now recommended in a range of 20-30 ml/kg per h for continuous therapies and/or thrice weekly intermittent hemodialysis. On the contrary, the complex issue of RRT optimal timing still remains uncertain and controversial. Wide variations in clinical practice still require RRT for critically ill patients to be optimized. The ideal prescription does not exist; however, continuous hemofiltration at a dose of 30 ml/kg/h meets many requirements of optimal care. In order to shed some light in the issue of RRT timing, furthermore, in the near future a standardized and clinically relevant definition of 'early' RRT should be provided. Great expectations currently rely on the utilization of acute kidney injury severity classifications and on new biomarkers of renal function.