F. Perry Wilson

Automated, electronic alerts for acute kidney injury: a single-blind, parallel-group, randomised controlled trial

BACKGROUND Acute kidney injury often goes unrecognised in its early stages when effective treatment options might be available. We aimed to determine whether an automated electronic alert for acute kidney injury would reduce the severity of such injury and improve clinical outcomes in patients in hospital. METHODS In this investigator-masked, parallel-group, randomised controlled trial, patients were recruited from the hospital of the University of Pennsylvania in Philadelphia, PA, USA. Eligible participants were adults aged 18 years or older who were in hospital with stage 1 or greater acute kidney injury as defined by Kidney Disease Improving Global Outcomes creatinine-based criteria. Exclusion criteria were initial hospital creatinine 4·0 mg/dL (to convert to μmol/L, multiply by 88·4) or greater, fewer than two creatinine values measured, inability to determine the covering provider, admission to hospice or the observation unit, previous randomisation, or end-stage renal disease. Patients were randomly assigned (1:1) via a computer-generated sequence to receive an acute kidney injury alert (a text-based alert sent to the covering provider and unit pharmacist indicating new acute kidney injury) or usual care, stratified by medical versus surgical admission and intensive care unit versus non-intensive care unit location in blocks of 4-8 participants. The primary outcome was a composite of relative maximum change in creatinine, dialysis, and death at 7 days after randomisation. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01862419. FINDINGS Between Sept 17, 2013, and April 14, 2014, 23,664 patients were screened. 1201 eligible participants were assigned to the acute kidney injury alert group and 1192 were assigned to the usual care group. Composite relative maximum change in creatinine, dialysis, and death at 7 days did not differ between the alert group and the usual care group (p=0·88), or within any of the four randomisation strata (all p>0·05). At 7 days after randomisation, median maximum relative change in creatinine concentrations was 0·0% (IQR 0·0-18·4) in the alert group and 0·6% (0·0-17·5) in the usual care group (p=0·81); 87 (7·2%) patients in the alert group and 70 (5·9%) patients in usual care group had received dialysis (odds ratio 1·25 [95% CI 0·90-1·74]; p=0·18); and 71 (5·9%) patients in the alert group and 61 (5·1%) patients in the usual care group had died (1·16 [0·81-1·68]; p=0·40). INTERPRETATION An electronic alert system for acute kidney injury did not improve clinical outcomes among patients in hospital. FUNDING Penn Center for Healthcare Improvement and Patient Safety.

False-Positive Rate of AKI Using Consensus Creatinine–Based Criteria

BACKGROUND AND OBJECTIVES Use of small changes in serum creatinine to diagnose AKI allows for earlier detection but may increase diagnostic false-positive rates because of inherent laboratory and biologic variabilities of creatinine. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We examined serum creatinine measurement characteristics in a prospective observational clinical reference cohort of 2267 adult patients with AKI by Kidney Disease Improving Global Outcomes creatinine criteria and used these data to create a simulation cohort to model AKI false-positive rates. We simulated up to seven successive blood draws on an equal population of hypothetical patients with unchanging true serum creatinine values. Error terms generated from laboratory and biologic variabilities were added to each simulated patients true serum creatinine value to obtain the simulated measured serum creatinine for each blood draw. We determined the proportion of patients who would be erroneously diagnosed with AKI by Kidney Disease Improving Global Outcomes creatinine criteria. RESULTS Within the clinical cohort, 75.0% of patients received four serum creatinine draws within at least one 48-hour period during hospitalization. After four simulated creatinine measurements that accounted for laboratory variability calculated from assay characteristics and 4.4% of biologic variability determined from the clinical cohort and publicly available data, the overall false-positive rate for AKI diagnosis was 8.0% (interquartile range =7.9%-8.1%), whereas patients with true serum creatinine ≥1.5 mg/dl (representing 21% of the clinical cohort) had a false-positive AKI diagnosis rate of 30.5% (interquartile range =30.1%-30.9%) versus 2.0% (interquartile range =1.9%-2.1%) in patients with true serum creatinine values <1.5 mg/dl (P<0.001). CONCLUSIONS Use of small serum creatinine changes to diagnose AKI is limited by high false-positive rates caused by inherent variability of serum creatinine at higher baseline values, potentially misclassifying patients with CKD in AKI studies.

Tumor Lysis Syndrome: New Challenges and Recent Advances

Tumor lysis syndrome (TLS) is an oncologic emergency triggered by the rapid release of intracellular material from lysing malignant cells. Most common in rapidly growing hematologic malignancies, TLS has been reported in virtually every cancer type. Central to its pathogenesis is the rapid accumulation of uric acid derived from the breakdown of nucleic acids, which leads to kidney failure by various mechanisms. Kidney failure then limits the clearance of potassium, phosphorus, and uric acid leading to hyperkalemia, hyperphosphatemia, and secondary hypocalcemia, which can be fatal. Prevention of TLS may be more effective than treatment, and identification of at-risk individuals in whom to target preventative efforts remains a key research area. Herein, we discuss the pathophysiology, epidemiology, and treatment of TLS with an emphasis on the kidney manifestations of the disease.

Hypochloraemia is strongly and independently associated with mortality in patients with chronic heart failure.

Hyponatraemia is strongly associated with adverse outcomes in heart failure. However, accumulating evidence suggests that chloride may play an important role in renal salt sensing and regulation of neurohormonal and sodium‐conserving pathways. Our objective was to determine the prognostic importance of hypochloraemia in patients with heart failure.

Impact of Electronic-Alerting of Acute Kidney Injury: Workgroup Statements from the 15th ADQI Consensus Conference:

Purpose of the reviewAmong hospitalized patients, acute kidney injury is common and associated with significant morbidity and risk for mortality. The use of electronic health records (EHR) for prediction and detection of this important clinical syndrome has grown in the past decade. The steering committee of the 15th Acute Dialysis Quality Initiative (ADQI) conference dedicated a workgroup with the task of identifying elements that may impact the course of events following Acute Kidney Injury (AKI) e-alert.Sources of informationFollowing an extensive, non-systematic literature search, we used a modified Delphi process to reach consensus regarding several aspects of the utilization of AKI e-alerts.FindingsTopics discussed in this workgroup included progress in evidence base practices, the characteristics of an optimal e-alert, the measures of efficacy and effectiveness, and finally what responses would be considered best practices following AKI e-alerts. Authors concluded that the current evidence for e-alert system efficacy, although growing, remains insufficient. Technology and human-related factors were found to be crucial elements of any future investigation or implementation of such tools. The group also concluded that implementation of such systems should not be done without a vigorous plan to evaluate the efficacy and effectiveness of e-alerts. Efficacy and effectiveness of e-alerts should be measured by context-specific process and patient outcomes. Finally, the group made several suggestions regarding the clinical decision support that should be considered following successful e-alert implementation.LimitationsThis paper reflects the findings of a non-systematic review and expert opinion.ImplicationsWe recommend implementation of the findings of this workgroup report for use of AKI e-alerts.ABRÉGÉContexte et objectifs de la revueL’insuffisance rénale aigüe (IRA) est un problème de santé fréquent chez les patients hospitalisés, et elle présente un risque élevé de morbidité et de mortalité pour les personnes affectées. L’utilisation des dossiers médicaux électroniques (DMÉ) pour la prédiction et le dépistage de ce syndrome clinique est en croissance depuis une dizaine d’années. Le comité directeur de la 15e réunion annuelle de la Acute DIalysis Quality Initiative (ADQI) a désigné un groupe de travail à qui il a donné le mandat d’identifier les éléments susceptibles d’avoir une incidence sur le cours des événements à la suite d’une alerte électronique indiquant un changement dans le taux de créatinine sérique d’un patient (alerte électronique d’IRA).Sources et méthodologieÀ la suite d’une revue exhaustive, mais non systématique de la littérature, nous avons utilisé une version modifiée de la méthode Delphi afin de parvenir à un consensus sur plusieurs facteurs liés à l’utilisation des alertes électroniques IRA.Résultats/constatationsParmi les thèmes discutés par ce groupe de travail figuraient les progrès observés au niveau de la pratique factuelle, l’identification des caractéristiques d’une alerte électronique optimale, la façon de mesurer l’efficacité des alertes et enfin, les interventions qualifiées de pratiques exemplaires à appliquer à la suite d’une alerte électronique d’IRA. Les auteurs ont conclu que les connaissances actuelles sur l’efficacité des systèmes d’alertes électroniques, bien qu’en progression, demeurent insuffisantes. Ils ont de plus identifié les facteurs humains et technologiques comme étant des éléments clés à considérer lors d’investigations futures portant sur de tels systèmes ou lors de leur mise en œuvre dans le futur. Le groupe de travail a également conclu que la mise en place de tels systèmes d’alertes ne devrait toutefois pas se faire sans un programme rigoureux d’analyse de l’efficacité et de l’efficience des alertes émises, et que ces mesures devraient se faire dans un cadre précis et en tenant compte des résultats observés chez les patients. Enfin, les auteurs ont fait plusieurs suggestions de mécanismes d’aide à la prise de décisions cliniques à prendre en considération à la suite de la mise en œuvre réussie d’un système d’alertes électroniques.LimitesCet article fait état des conclusions obtenues dans le cadre d’une revue non systématique de la littérature et à partir des opinions d’un groupe d’experts.ConclusionNous recommandons la mise en application des conclusions émises dans le rapport présenté par le groupe de travail sur l’utilisation des alertes électroniques IRA.

Urinary Creatinine Excretion, Bioelectrical Impedance Analysis, and Clinical Outcomes in Patients with CKD: The CRIC Study

BACKGROUND AND OBJECTIVES Previous studies in chronic disease states have demonstrated an association between lower urinary creatinine excretion (UCr) and increased mortality, a finding presumed to reflect the effect of low muscle mass on clinical outcomes. Little is known about the relationship between UCr and other measures of body composition in terms of the ability to predict outcomes of interest. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Using data from the Chronic Renal Insufficiency Cohort (CRIC), the relationship between UCr, fat free mass (FFM) as estimated by bioelectrical impedance analysis, and (in a subpopulation) whole-body dual-energy x-ray absorptiometry assessment of appendicular lean mass were characterized. The associations of UCr and FFM with mortality and ESRD were compared using Cox proportional hazards models. RESULTS A total of 3604 CRIC participants (91% of the full CRIC cohort) with both a baseline UCr and FFM measurement were included; of these, 232 had contemporaneous dual-energy x-ray absorptiometry measurements. Participants were recruited between July 2003 and March 2007. UCr and FFM were modestly correlated (rho=0.50; P<0.001), while FFM and appendicular lean mass were highly correlated (rho=0.91; P<0.001). Higher urinary urea nitrogen, black race, younger age, and lower serum cystatin C level were all significantly associated with higher UCr. Over a median (interquartile range) of 4.2 (3.1-5.0) years of follow-up, 336 (9.3%) participants died and 510 (14.2%) reached ESRD. Lower UCr was associated with death and ESRD even after adjustment for FFM (adjusted hazard ratio for death per 1 SD higher level of UCr, 0.63 [95% confidence interval, 0.56 to 0.72]; adjusted hazard ratio for ESRD per 1 SD higher level of UCr, 0.70 [95% confidence interval, 0.63 to 0.75]). CONCLUSIONS Among a cohort of individuals with CKD, lower UCr is associated with death and ESRD independent of FFM as assessed by bioelectrical impedance analysis.

Kidney Transplant Outcomes for Prior Living Organ Donors

The Organ Procurement and Transplantation Network gives priority in kidney allocation to prior live organ donors who require a kidney transplant. In this study, we analyzed the effect of this policy on facilitating access to transplantation for prior donors who were wait-listed for kidney transplantation in the United States. Using 1:1 propensity score-matching methods, we assembled two matched cohorts. The first cohort consisted of prior organ donors and matched nondonors who were wait-listed during the years 1996-2010. The second cohort consisted of prior organ donors and matched nondonors who underwent deceased donor kidney transplantation. During the study period, there were 385,498 listings for kidney transplantation, 252 of which were prior donors. Most prior donors required dialysis by the time of listing (64% versus 69% among matched candidates; P=0.24). Compared with matched nondonors, prior donors had a higher rate of deceased donor transplant (85% versus 33%; P<0.001) and a lower median time to transplantation (145 versus 1607 days; P<0.001). Prior donors received higher-quality allografts (median kidney donor risk index 0.67 versus 0.90 for nondonors; P<0.001) and experienced lower post-transplant mortality (hazard ratio, 0.19; 95% confidence interval, 0.08 to 0.46; P<0.001) than matched nondonors. In conclusion, these data suggest that prior organ donors experience brief waiting time for kidney transplant and receive excellent-quality kidneys, but most need pretransplant dialysis. Individuals who are considering live organ donation should be provided with this information because this allocation priority will remain in place under the new US kidney allocation system.

Relevance of Changes in Serum Creatinine During a Heart Failure Trial of Decongestive Strategies: Insights From the DOSE Trial

BACKGROUND Worsening renal function (WRF) is a common endpoint in decompensated heart failure clinical trials because of associations between WRF and adverse outcomes. However, WRF has not universally been identified as a poor prognostic sign, challenging the validity of WRF as a surrogate endpoint. Our aim was to describe the associations between changes in creatinine and adverse outcomes in a clinical trial of decongestive therapies. METHODS AND RESULTS We investigated the association between changes in creatinine and the composite endpoint of death, rehospitalization or emergency room visit within 60 days in 301 patients in the Diuretic Optimization Strategies Evaluation (DOSE) trial. WRF was defined as an increase in creatinine >0.3 mg/dL and improvement in renal function (IRF) as a decrease >0.3 mg/dL. When examining linear changes in creatinine from baseline to 72 hours (the coprimary endpoint of DOSE), increasing creatinine was associated with lower risk for the composite outcome (HR = 0.81 per 0.3 mg/dL increase, 95% CI 0.67-0.98, P = .026). Compared with patients with stable renal function (n = 219), WRF (n = 54) was not associated with the composite endpoint (HR = 1.17, 95% CI = 0.77-1.78, P = .47). However, compared with stable renal function, there was a strong relationship between IRF (n = 28) and the composite endpoint (HR = 2.52, 95% CI = 1.57-4.03, P < .001). CONCLUSION The coprimary endpoint of the DOSE trial, a linear increase in creatinine, was paradoxically associated with improved outcomes. This was driven by absence of risk attributable to WRF and a strong risk associated with IRF. These results argue against using changes in serum creatinine as a surrogate endpoint in trials of decongestive strategies.

Rapid and Highly Accurate Prediction of Poor Loop Diuretic Natriuretic Response in Patients With Heart Failure

Background—Removal of excess sodium and fluid is a primary therapeutic objective in acute decompensated heart failure and commonly monitored with fluid balance and weight loss. However, these parameters are frequently inaccurate or not collected and require a delay of several hours after diuretic administration before they are available. Accessible tools for rapid and accurate prediction of diuretic response are needed. Methods and Results—Based on well-established renal physiological principles, an equation was derived to predict net sodium output using a spot urine sample obtained 1 or 2 hours after loop diuretic administration. This equation was then prospectively validated in 50 acute decompensated heart failure patients using meticulously obtained timed 6-hour urine collections to quantify loop diuretic-induced cumulative sodium output. Poor natriuretic response was defined as a cumulative sodium output of <50 mmol, a threshold that would result in a positive sodium balance with twice-daily diuretic dosing. Following a median dose of 3 mg (2–4 mg) of intravenous bumetanide, 40% of the population had a poor natriuretic response. The correlation between measured and predicted sodium output was excellent (r=0.91; P<0.0001). Poor natriuretic response could be accurately predicted with the sodium prediction equation (area under the curve =0.95, 95% confidence interval 0.89–1.0; P<0.0001). Clinically recorded net fluid output had a weaker correlation (r=0.66; P<0.001) and lesser ability to predict poor natriuretic response (area under the curve =0.76, 95% confidence interval 0.63–0.89; P=0.002). Conclusions—In patients being treated for acute decompensated heart failure, poor natriuretic response can be predicted soon after diuretic administration with excellent accuracy using a spot urine sample.

Worsening Renal Function in Patients With Acute Heart Failure Undergoing Aggressive Diuresis Is Not Associated With Tubular Injury

Background: Worsening renal function (WRF) in the setting of aggressive diuresis for acute heart failure treatment may reflect renal tubular injury or simply indicate a hemodynamic or functional change in glomerular filtration. Well-validated tubular injury biomarkers, N-acetyl-&bgr;-D-glucosaminidase, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1, are now available that can quantify the degree of renal tubular injury. The ROSE-AHF trial (Renal Optimization Strategies Evaluation–Acute Heart Failure) provides an experimental platform for the study of mechanisms of WRF during aggressive diuresis for acute heart failure because the ROSE-AHF protocol dictated high-dose loop diuretic therapy in all patients. We sought to determine whether tubular injury biomarkers are associated with WRF in the setting of aggressive diuresis and its association with prognosis. Methods: Patients in the multicenter ROSE-AHF trial with baseline and 72-hour urine tubular injury biomarkers were analyzed (n=283). WRF was defined as a ≥20% decrease in glomerular filtration rate estimated with cystatin C. Results: Consistent with protocol-driven aggressive dosing of loop diuretics, participants received a median 560 mg IV furosemide equivalents (interquartile range, 300–815 mg), which induced a urine output of 8425 mL (interquartile range, 6341–10 528 mL) over the 72-hour intervention period. Levels of N-acetyl-&bgr;-D-glucosaminidase and kidney injury molecule 1 did not change with aggressive diuresis (both P>0.59), whereas levels of neutrophil gelatinase-associated lipocalin decreased slightly (−8.7 ng/mg; interquartile range, −169 to 35 ng/mg; P<0.001). WRF occurred in 21.2% of the population and was not associated with an increase in any marker of renal tubular injury: neutrophil gelatinase-associated lipocalin (P=0.21), N-acetyl-&bgr;-D-glucosaminidase (P=0.46), or kidney injury molecule 1 (P=0.22). Increases in neutrophil gelatinase-associated lipocalin, N-acetyl-&bgr;-D-glucosaminidase, and kidney injury molecule 1 were paradoxically associated with improved survival (adjusted hazard ratio, 0.80 per 10 percentile increase; 95% confidence interval, 0.69–0.91; P=0.001). Conclusions: Kidney tubular injury does not appear to have an association with WRF in the context of aggressive diuresis of patients with acute heart failure. These findings reinforce the notion that the small to moderate deteriorations in renal function commonly encountered with aggressive diuresis are dissimilar from traditional causes of acute kidney injury.