Kianoush Kashani

Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

IntroductionAcute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.MethodsWe performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.ResultsModerate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.ConclusionsTwo novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI.Trial registrationClinicalTrials.gov number NCT01209169.

Derivation and validation of cutoffs for clinical use of cell cycle arrest biomarkers

Background Acute kidney injury (AKI) remains a deadly condition. Tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein (IGFBP)7 are two recently discovered urinary biomarkers for AKI. We now report on the development, and diagnostic accuracy of two clinical cutoffs for a test using these markers. Methods We derived cutoffs based on sensitivity and specificity for prediction of Kidney Disease: Improving Global Outcomes Stages 2–3 AKI within 12 h using data from a previously published multicenter cohort (Sapphire). Next, we verified these cutoffs in a new study (Opal) enrolling 154 critically ill adults from six sites in the USA. Results One hundred subjects (14%) in Sapphire and 27 (18%) in Opal met the primary end point. The results of the Opal study replicated those of Sapphire. Relative risk (95% CI) in both studies for subjects testing at ≤0.3 versus >0.3–2 were 4.7 (1.5–16) and 4.4 (2.5–8.7), or 12 (4.2–40) and 18 (10–37) for ≤0.3 versus >2. For the 0.3 cutoff, sensitivity was 89% in both studies, and specificity 50 and 53%. For 2.0, sensitivity was 42 and 44%, and specificity 95 and 90%. Conclusions Urinary [TIMP-2]•[IGFBP7] values of 0.3 or greater identify patients at high risk and those >2 at highest risk for AKI and provide new information to support clinical decision-making. Clinical Trials Registration Clintrials.gov # NCT01209169 (Sapphire) and NCT01846884 (Opal).

Predictors of Acute Kidney Injury in Septic Shock Patients: An Observational Cohort Study

BACKGROUND AND OBJECTIVES Acute kidney injury (AKI) is a frequent complication in critically ill patients and sepsis is the most common contributing factor. We aimed to determine the risk factors associated with AKI development in patients with septic shock. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Observational cohort study consisted of consecutive adults with septic shock admitted to a medical intensive care unit (ICU) of a tertiary care academic hospital from July 2005 to September 2007. AKI was defined according to RIFLE criteria (urine output and creatinine criteria). Demographic, clinical, and treatment variables were reviewed. Main outcomes measured were AKI occurrence, all-cause hospital mortality, and hospital and ICU length of stay. RESULTS Three hundred ninety patients met inclusion criteria, of which 237 (61%) developed AKI. AKI development was independently associated with delay to initiation of adequate antibiotics, intra-abdominal sepsis, blood product transfusion, use of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker, and body mass index (kg/m²). Higher baseline GFR and successful early goal directed resuscitation were associated with a decreased risk of AKI. Hospital mortality was significantly greater in patients who developed AKI (49 versus 34%). CONCLUSIONS In a contemporary cohort of patients with septic shock, both patient and health care delivery risk factors seemed to be important for AKI development.

Tissue Inhibitor Metalloproteinase-2 (TIMP-2)⋅IGF-Binding Protein-7 (IGFBP7) Levels Are Associated with Adverse Long-Term Outcomes in Patients with AKI

Tissue inhibitor metalloproteinase-2 (TIMP-2) and IGF-binding protein-7 (IGFBP7) have been validated for risk stratification in AKI. However, the association of urinary TIMP-2 and IGFBP7 with long-term outcomes is unknown. We evaluated the 9-month incidence of a composite end point of all-cause mortality or the need for RRT in a secondary analysis of a prospective observational international study of critically ill adults. Two predefined [TIMP-2]⋅[IGFBP7] cutoffs (0.3 for high sensitivity and 2.0 for high specificity) for the development of AKI were evaluated. Cox proportional hazards models were used to determine risk for the composite end point. Baseline [TIMP-2]⋅[IGFBP7] values were available for 692 subjects, of whom 382 (55.2%) subjects developed stage 1 AKI (defined by Kidney Disease Improving Global Outcomes guidelines) within 72 hours of enrollment and 217 (31.4%) subjects met the composite end point. Univariate analysis showed that [TIMP-2]⋅[IGFBP7]>2.0 was associated with increased risk of the composite end point (hazard ratio [HR], 2.11; 95% confidence interval [95% CI], 1.37 to 3.23; P<0.001). In a multivariate analysis adjusted for the clinical model, [TIMP-2]⋅[IGFBP7] levels>0.3 were associated with death or RRT only in subjects who developed AKI (compared with levels≤0.3: HR, 1.44; 95% CI, 1.00 to 2.06 for levels>0.3 to ≤2.0; P=0.05 and HR, 2.16; 95% CI, 1.32 to 3.53 for levels>2.0; P=0.002). In conclusion, [TIMP-2]⋅[IGFBP7] measured early in the setting of critical illness may identify patients with AKI at increased risk for mortality or receipt of RRT over the next 9 months.

Simulation-Based Objective Assessment Discerns Clinical Proficiency in Central Line Placement : A Construct Validation

BACKGROUND Central venous catheterization (CVC) is associated with patient risks known to be inversely related to clinician experience. We developed and evaluated a performance assessment tool for use in a simulation-based central line workshop. We hypothesized that instrument scores would discriminate between less experienced and more experienced clinicians. METHODS Participants included trainees enrolled in an institutionally mandated CVC workshop and a convenience sample of faculty attending physicians. The workshop integrated several experiential learning techniques, including practice on cadavers and part-task trainers. A group of clinical and education experts developed a 15-point CVC Proficiency Scale using national and institutional guidelines. After the workshop, participants completed a certification exercise in which they independently performed a CVC in a part-task trainer. Two authors reviewed videotapes of the certification exercise to rate performance using the CVC Proficiency Scale. Participants were grouped by self-reported CVC experience. RESULTS One hundred and five participants (92 trainees and 13 attending physicians) participated. Interrater reliability on a subset of 40 videos was 0.71, and Cronbach a was 0.81. The CVC Proficiency Scale Composite score varied significantly by experience: mean of 85%, median of 87% (range 47%-100%) for low experience (0-1 CVCs in the last 2 years, n = 27); mean of 88%, median of 87% (range 60%-100%) for moderate experience (2-49 CVCs, n = 62); and mean of 94%, median of 93% (range 73%-100%) for high experience (> 49 CVCs, n = 16) (P = .02, comparing low and high experience). CONCLUSIONS Evidence from multiple sources, including appropriate content, high interrater and internal consistency reliability, and confirmation of hypothesized relations to other variables, supports the validity of using scores from this 15-item scale for assessing trainee proficiency following a central line workshop.

Urinalysis is more specific and urinary neutrophil gelatinase-associated lipocalin is more sensitive for early detection of acute kidney injury.

BACKGROUND Neutrophil gelatinase-associated lipocalin (NGAL) protein is a promising biomarker to detect acute kidney injury (AKI). Earlier detection of AKI could facilitate evaluation of novel therapeutic strategies. METHODS Random and 24-h urine samples were prospectively obtained from 125 normal volunteers for analytic validation of a urinary enzyme-linked immunosorbent assay for NGAL. For clinical validation of the test, urine from 363 emergency department patients admitted to the hospital was obtained for NGAL enzyme-linked immunosorbent assay and urinalysis and AKI was determined by the use of Acute Kidney Injury Network (AKIN) criteria. RESULTS NGAL was stable in urine for 7 days when ambient, 4 °C or frozen (-20 or -70 °C). The assay was linear between 0.24 and 10,000 ng/mL with a limit of quantitation of 0.24 ng/mL. Intra- and inter-assay precision were excellent (coefficient of variation <5%); however, urinary white blood cells were associated with increased NGAL levels. The 95th percentile reference value for NGAL in females is ≤ 65.0 and ≤ 23.4 ng/mL in males. Urinary NGAL levels increased with AKI stage but had only fair sensitivity (65%) and specificity (65%) to differentiate no AKI versus Stages 1, 2 or 3 (area under the curve 0.70). Urinalysis with microscopy was very specific (91%) but not very sensitive (22%) with an area under the curve of 0.57. CONCLUSIONS NGAL can be reliably measured in clinical urine samples, although pyuria is an important potential confounder. In our cohort, increased urinary NGAL was associated with AKI by the AKIN criteria; however, the sensitivity and specificity were only fair, in part because patients with pre-renal causes are not excluded by AKIN criteria. Conversely, findings on microscopic urinalysis are very specific for AKI.

Biomarkers of acute kidney injury: the pathway from discovery to clinical adoption

Abstract Acute kidney injury (AKI) is a common complication of critical illnesses and has a significant impact on outcomes, including mortality and morbidities. Unfortunately, apart from prophylactic measures, no effective treatment for this syndrome is known. Therefore, early recognition of AKI not only can provide better opportunities for preventive interventions, but also opens many gates for research and development of effective therapeutic options. Over the last few years, several new AKI biomarkers have been discovered and validated to improve early detection, differential diagnosis, and differentiation of patients into risk groups for progressive renal failure, need for renal replacement therapy (RRT), or death. These novel AKI biomarkers complement serum creatinine (SCr) and urine output, which are the standard diagnostic tools for AKI detection. In this article, we review the available literature on characteristics of promising AKI biomarkers that are currently the focus of preclinical and clinical investigations. These biomarkers include neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), liver-type fatty acid-binding protein, interleukin 18 (lL-18), insulin-like growth factor-binding protein 7, tissue inhibitor of metalloproteinase 2 (TIMP-2), calprotectin, urine angiotensinogen (AGT), and urine microRNA. We then describe the clinical performance of these biomarkers for diagnosis and prognostication. We also appraise each AKI biomarker’s advantages and limitations as a tool for early AKI recognition and prediction of clinical outcomes after AKI. Finally, we review the current and future states of implementation of biomarkers in the clinical practice.

TIMP2•IGFBP7 biomarker panel accurately predicts acute kidney injury in high-risk surgical patients

BACKGROUND Acute kidney injury (AKI) is an important complication in surgical patients. Existing biomarkers and clinical prediction models underestimate the risk for developing AKI. We recently reported data from two trials of 728 and 408 critically ill adult patients in whom urinary TIMP2•IGFBP7 (NephroCheck, Astute Medical) was used to identify patients at risk of developing AKI. Here we report a preplanned analysis of surgical patients from both trials to assess whether urinary tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor–binding protein 7 (IGFBP7) accurately identify surgical patients at risk of developing AKI. STUDY DESIGN We enrolled adult surgical patients at risk for AKI who were admitted to one of 39 intensive care units across Europe and North America. The primary end point was moderate-severe AKI (equivalent to KDIGO [Kidney Disease Improving Global Outcomes] stages 2–3) within 12 hours of enrollment. Biomarker performance was assessed using the area under the receiver operating characteristic curve, integrated discrimination improvement, and category-free net reclassification improvement. RESULTS A total of 375 patients were included in the final analysis of whom 35 (9%) developed moderate-severe AKI within 12 hours. The area under the receiver operating characteristic curve for [TIMP-2]•[IGFBP7] alone was 0.84 (95% confidence interval, 0.76–0.90; p < 0.0001). Biomarker performance was robust in sensitivity analysis across predefined subgroups (urgency and type of surgery). CONCLUSION For postoperative surgical intensive care unit patients, a single urinary TIMP2•IGFBP7 test accurately identified patients at risk for developing AKI within the ensuing 12 hours and its inclusion in clinical risk prediction models significantly enhances their performance. LEVEL OF EVIDENCE Prognostic study, level I.

AKI after Transcatheter or Surgical Aortic Valve Replacement

Transcatheter aortic valve replacement (TAVR) is an alternative to surgical aortic valve replacement (SAVR) for patients with symptomatic severe aortic stenosis who are at high risk of perioperative mortality. Previous studies showed increased risk of postoperative AKI with TAVR, but it is unclear whether differences in patient risk profiles confounded the results. To conduct a propensity-matched study, we identified all adult patients undergoing isolated aortic valve replacement for aortic stenosis at Mayo Clinic Hospital in Rochester, Minnesota from January 1, 2008 to June 30, 2014. Using propensity score matching on the basis of clinical characteristics and preoperative variables, we compared the postoperative incidence of AKI, defined by Kidney Disease Improving Global Outcomes guidelines, and major adverse kidney events in patients treated with TAVR with that in patients treated with SAVR. Major adverse kidney events were the composite of in-hospital mortality, use of RRT, and persistent elevated serum creatinine ≥200% from baseline at hospital discharge. Of 1563 eligible patients, 195 matched pairs (390 patients) were created. In the matched cohort, baseline characteristics, including Society of Thoracic Surgeons risk score and eGFR, were comparable between the two groups. Furthermore, no significant differences existed between the TAVR and SAVR groups in postoperative AKI (24.1% versus 29.7%; P=0.21), major adverse kidney events (2.1% versus 1.5%; P=0.70), or mortality >6 months after surgery (6.0% versus 8.3%; P=0.51). Thus, TAVR did not affect postoperative AKI risk. Because it is less invasive than SAVR, TAVR may be preferred in high-risk individuals.

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.