Ali Al-Khafaji

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.

Validation of Cell-Cycle Arrest Biomarkers for Acute Kidney Injury Using Clinical Adjudication

RATIONALE We recently reported two novel biomarkers for acute kidney injury (AKI), tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), both related to G1 cell cycle arrest. OBJECTIVES We now validate a clinical test for urinary [TIMP-2]·[IGFBP7] at a high-sensitivity cutoff greater than 0.3 for AKI risk stratification in a diverse population of critically ill patients. METHODS We conducted a prospective multicenter study of 420 critically ill patients. The primary analysis was the ability of urinary [TIMP-2]·[IGFBP7] to predict moderate to severe AKI within 12 hours. AKI was adjudicated by a committee of three independent expert nephrologists who were masked to the results of the test. MEASUREMENTS AND MAIN RESULTS Urinary TIMP-2 and IGFBP7 were measured using a clinical immunoassay platform. The primary endpoint was reached in 17% of patients. For a single urinary [TIMP-2]·[IGFBP7] test, sensitivity at the prespecified high-sensitivity cutoff of 0.3 (ng/ml)(2)/1,000 was 92% (95% confidence interval [CI], 85-98%) with a negative likelihood ratio of 0.18 (95% CI, 0.06-0.33). Critically ill patients with urinary [TIMP-2]·[IGFBP7] greater than 0.3 had seven times the risk for AKI (95% CI, 4-22) compared with critically ill patients with a test result below 0.3. In a multivariate model including clinical information, urinary [TIMP-2]·[IGFBP7] remained statistically significant and a strong predictor of AKI (area under the curve, 0.70, 95% CI, 0.63-0.76 for clinical variables alone, vs. area under the curve, 0.86, 95% CI, 0.80-0.90 for clinical variables plus [TIMP-2]·[IGFBP7]). CONCLUSIONS Urinary [TIMP-2]·[IGFBP7] greater than 0.3 (ng/ml)(2)/1,000 identifies patients at risk for imminent AKI. Clinical trial registered with www.clinicaltrials.gov (NCT 01573962).

Acute kidney injury following orthotopic liver transplantation: incidence, risk factors, and effects on patient and graft outcomes

BACKGROUND Liver transplant recipients frequently develop acute kidney injury (AKI), but the predisposing factors and long-term consequences of AKI are not well understood. The aims of this study were to identify predisposing factors for early post-transplant AKI and the impact of AKI on patient and graft survival and to construct a model to predict AKI using clinical variables. METHODS In this 5-year retrospective study, we analysed clinical and laboratory data from 424 liver transplant recipients from our centre. RESULTS By 72 h post-transplant, 221 patients (52%) had developed AKI [according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria]. Predisposing factors for development of AKI were female sex, weight (>100 kg), severity of liver disease (Child-Pugh score), pre-existing diabetes mellitus, number of units of blood or fresh frozen plasma transfused during surgery, and non-alcoholic steatohepatitis as the aetiology of end-stage liver disease (P≤0.05). Notably, preoperative serum creatinine (SCr) was not a significant predisposing factor. After fitting a forward stepwise regression model, female sex, weight >100 kg, high Child-Pugh score, and diabetes remained significantly associated with the development of AKI within 72 h (P≤0.05). The area under the receiver operator characteristic curve for the final model was 0.71. The incidence of new chronic kidney disease and requirement for dialysis at 3 months and 1 yr post-transplant were significantly higher among patients who developed AKI. CONCLUSIONS Development of AKI within the first 72 h after transplant impacted short-term and long-term graft survival.

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.

Medical management of hepatorenal syndrome

Hepatorenal syndrome (HRS) is defined as the occurrence of renal dysfunction in a patient with end-stage liver cirrhosis in the absence of another identifiable cause of renal failure. The prognosis of HRS remains poor, with a median survival without liver transplantation of <6 months. However, understanding the pathogenesis of HRS has led to the introduction of treatments designed to increase renal perfusion and mean arterial blood pressure using vasopressors and albumin, which has led to improvement in renal function in ∼50% of patients.

Propylene glycol toxicity associated with lorazepam infusion in a patient receiving continuous veno-venous hemofiltration with dialysis.

IMPLICATIONS We report a case of toxicity from the drug solvent propylene glycol resulting from prolonged, large-dose lorazepam infusion. The case is unusual in that toxicity developed during continuous veno-venous hemofiltration with dialysis, a renal replacement therapy that should been have been effective at eliminating the chemical and its metabolites.

Trial of shift scheduling with standardized sign-out to improve continuity of care in intensive care units.

Background:Since 2003, the Accreditation Council for Graduate Medical Education requires residency programs to restrict to 80 hrs/wk, averaged over 4 wks to improve patient safety. These restrictions force training programs with night call responsibilities to either maintain a traditional program with alternative night float schedules or adopt a “shift” model, both with increased handoffs. Objective:To assess whether a 65 hrs/wk shift-work schedule combined with structured sign-out curriculum is equivalent to a 65 hrs/wk traditional day coverage with night call schedule, as measured by multiple assessments. Design:Eight-month trial of shift-work schedule with structured sign-out curriculum (intervention) vs. traditional call schedule without curriculum (control) in alternating 1–2 month periods. Setting:A mixed medical–surgical intensive care unit at a tertiary care academic center. Subjects:Primary subjects: 19 fellows in a Multidisciplinary Critical Care Training Program; Secondary subjects: intensive care unit nurses and attending physicians, families of intensive care unit patients. Interventions:Implementation of shift-work schedule, combined with structured sign-out curriculum. Measurements:Workplace perception assessment through Continuity of Care Survey evaluation by faculty, fellows, and nurses through structured surveys; family assessment by the Critical Care Family Needs Index survey; clinical assessment through intensive care unit mortality, intensive care unit length of stay, and intensive care unit readmission within 48 hrs; and educational impact assessment by rate of fellow didactic lecture attendance. Main Results:There were no statistically significant differences in surveyed perceptions of continuity of care, intensive care unit mortality (8.5% vs. 6.0%, p = .20), lecture attendance (43% vs. 42%), or family satisfaction (Critical Care Family Needs Index score 24 vs. 22) between control and intervention periods. There was a significant decrease in intensive care unit length of stay (8.4 vs. 5.7 days, p = .04) with the shift model. Readmissions within 48 hrs were not different (3.6% vs. 4.9%, p = .39). Nurses preferred the intervention period (7% control vs. 73% intervention, n = 30, p = .00), and attending faculty preferred the intervention period and felt continuity of care was maintained (15% control vs. 54% intervention, n = 11, p = .15). Conclusions:A shift-work schedule with structured sign-out curriculum is a viable alternative to traditional work schedules for the intensive care unit in training programs.

Critical care management of patients with end-stage liver disease

Objectives:To review the management of complications related to end-stage liver disease in the intensive care unit. The goal of this review is to address topics important to the practicing physician. Data Sources:We performed an organ system-based PubMed literature review focusing on the diagnosis and treatment of critical complications of end-stage liver disease. Data Synthesis and Findings:When available, preferential consideration was given to randomized controlled trials. In the absence of trials, observational and retrospective studies and consensus opinions were included. We present our recommendations for the neurologic, cardiovascular, pulmonary, gastrointestinal, renal, and infectious complications of end-stage liver disease. Conclusions:Complications related to end-stage liver disease have significant morbidity and mortality. Management of these complications in the intensive care unit requires awareness and expertise among physicians from a wide variety of fields.

Succinylcholine-induced hyperkalemia in a patient with mucositis secondary to chemotherapy

Objective To report a case of fatal hyperkalemia owing to succinylcholine administration in a patient with mucositis secondary to chemotherapy. Design Case report. Setting Adult intensive care unit (ICU) at Dartmouth-Hitchcock Medical Center. Patients One patient with mucositis secondary to chemotherapy. Measurements and Main Results A 37-yr-old female with recently diagnosed acute myelogenous leukemia was admitted to the ICU with mental status changes and progressive dyspnea requiring intubation and mechanical ventilation. Before ICU admission, the patient had suffered from painful mucositis causing severe dysphagia and bleeding, which was thought to be the result of chemotherapy. By the 10th ICU day, the patient’s respiratory and mental status improved and the patient was successfully extubated. However, 8 hrs after extubation, she gradually developed severe respiratory distress, requiring reintubation and mechanical ventilation. The patient was given 14 mg of etomidate and 100 mg of succinylcholine intravenously. Immediately after the intubation, she suffered cardiac arrest. Her serum potassium level was 13.1 mEq/L and HCO−3 was 16 mEq/L. The resuscitation attempt was unsuccessful, and the patient was pronounced dead. Conclusion Oral mucositis is a frequent and potentially severe complication of cancer chemotherapy. We believe that mucositis was a contributing factor to this case of fatal hyperkalemia after administration of succinylcholine, with a mechanism similar to that reported with thermal injury. Only nondepolarizing muscle relaxants should be used in patients who are at risk for mucositis. Mucositis should be added to the list of conditions in which succinylcholine is contraindicated.

Acute kidney injury after orthotopic liver transplantation using living donor versus deceased donor grafts: A propensity score-matched analysis: Acute Kidney Injury after Liver Transplantation

Acute kidney injury (AKI) is a common complication after liver transplantation (LT). Few studies investigating the incidence and risk factors for AKI after living donor liver transplantation (LDLT) have been published. LDLT recipients have a lower risk for post‐LT AKI than deceased donor liver transplantation (DDLT) recipients because of higher quality liver grafts. We retrospectively reviewed LDLTs and DDLTs performed at the University of Pittsburgh Medical Center between January 2006 and December 2011. AKI was defined as a 50% increase in serum creatinine (SCr) from baseline (preoperative) values within 48 hours. One hundred LDLT and 424 DDLT recipients were included in the propensity score matching logistic model on the basis of age, sex, Model for End‐Stage Liver Disease score, Child‐Pugh score, pretransplant SCr, and preexisting diabetes mellitus. Eighty‐six pairs were created after 1‐to‐1 propensity matching. The binary outcome of AKI was analyzed using mixed effects logistic regression, incorporating the main exposure of interest (LDLT versus DDLT) with the aforementioned matching criteria and postreperfusion syndrome, number of units of packed red blood cells, and donor age as fixed effects. In the corresponding matched data set, the incidence of AKI at 72 hours was 23.3% in the LDLT group, significantly lower than the 44.2% in the DDLT group (P = 0.004). Multivariate mixed effects logistic regression showed that living donor liver allografts were significantly associated with reduced odds of AKI at 72 hours after LT (P = 0.047; odds ratio, 0.31; 95% confidence interval, 0.096‐0.984). The matched patients had lower body weights, better preserved liver functions, and more stable intraoperative hemodynamic parameters. The donors were also younger for the matched patients than for the unmatched patients. In conclusion, receiving a graft from a living donor has a protective effect against early post‐LT AKI. Liver Transpl 21:1179–1185, 2015.